FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jang, JC Chen, G Wang, SH Barnes, MA Chung, JI Camberis, M Le Gros, G Cooper, PJ Steel, C Nutman, TB Lazar, MA Nair, MG AF Jang, Jessica C. Chen, Gang Wang, Spencer H. Barnes, Mark A. Chung, Josiah I. Camberis, Mali Le Gros, Graham Cooper, Philip J. Steel, Cathy Nutman, Thomas B. Lazar, Mitchell A. Nair, Meera G. TI Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden SO PLOS PATHOGENS LA English DT Article ID TOLL-LIKE RECEPTOR; INDUCED INTESTINAL INFLAMMATION; SMOOTH-MUSCLE-CELLS; NEMATODE INFECTION; T-CELL; INSULIN-RESISTANCE; TYPE-2 IMMUNITY; UP-REGULATION; IFN-GAMMA; ACTIVATION AB Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg(+)). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg(-) 2 mice, hRetnTg(+) mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology. C1 [Jang, Jessica C.; Chen, Gang; Wang, Spencer H.; Barnes, Mark A.; Chung, Josiah I.; Nair, Meera G.] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA. [Camberis, Mali; Le Gros, Graham] Malaghan Inst Med Res, Wellington, New Zealand. [Cooper, Philip J.] Lab Invest FEPIS, Quininde, Ecuador. [Cooper, Philip J.] Pontificia Univ Catolica Ecuador, Ctr Invest Enfermedades Infecciosas, Quito, Ecuador. [Cooper, Philip J.] St Georges Univ London, London, England. [Steel, Cathy; Nutman, Thomas B.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. RP Nair, MG (reprint author), Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA. EM meera.nair@ucr.edu RI Le Gros, Graham/C-6725-2011 FU NIH [1R01AI091759-01A1, P01DK49210, 1S10OD016290-01A1, MRI-1429826, 1S10RR028934-01]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases; UCR School of Medicine initial complement and Academic Senate grant; Health Research Council of New Zealand; Wellcome Trust [088862/Z/09/Z] FX These studies were supported by the NIH (1R01AI091759-01A1 to MGN; P01DK49210 to MAL), by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (to CS and TBN), UCR School of Medicine initial complement and Academic Senate grant to MGN, the Health Research Council of New Zealand (to GLG) and the Wellcome Trust (088862/Z/09/Z to PJC). The UCR NextGen sequencing and bioinformatics core (IIGB) are supported by NIH 1S10OD016290-01A1, MRI-1429826 and NIH 1S10RR028934-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 9 Z9 9 U1 1 U2 3 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 JAN PY 2015 VL 11 IS 1 AR e1004579 DI 10.1371/journal.ppat.1004579 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CA7OF UT WOS:000349106100016 PM 25568944 ER PT J AU Pitzer, VE Viboud, C Alonso, WJ Wilcox, T Metcalf, CJ Steiner, CA Haynes, AK Grenfell, BT AF Pitzer, Virginia E. Viboud, Cecile Alonso, Wladimir J. Wilcox, Tanya Metcalf, C. Jessica Steiner, Claudia A. Haynes, Amber K. Grenfell, Bryan T. TI Environmental Drivers of the Spatiotemporal Dynamics of Respiratory Syncytial Virus in the United States SO PLOS PATHOGENS LA English DT Article ID YOUNG-CHILDREN; NATIONAL-SURVEILLANCE; MEASLES EPIDEMICS; GROUP-B; GROUP-A; TRANSMISSION DYNAMICS; SPATIAL HIERARCHIES; INFECTIOUS-DISEASES; TRACT INFECTIONS; KILIFI DISTRICT AB Epidemics of respiratory syncytial virus (RSV) are known to occur in wintertime in temperate countries including the United States, but there is a limited understanding of the importance of climatic drivers in determining the seasonality of RSV. In the United States, RSV activity is highly spatially structured, with seasonal peaks beginning in Florida in November through December and ending in the upper Midwest in February-March, and prolonged disease activity in the southeastern US. Using data on both age-specific hospitalizations and laboratory reports of RSV in the US, and employing a combination of statistical and mechanistic epidemic modeling, we examined the association between environmental variables and state-specific measures of RSV seasonality. Temperature, vapor pressure, precipitation, and potential evapotranspiration (PET) were significantly associated with the timing of RSV activity across states in univariate exploratory analyses. The amplitude and timing of seasonality in the transmission rate was significantly correlated with seasonal fluctuations in PET, and negatively correlated with mean vapor pressure, minimum temperature, and precipitation. States with low mean vapor pressure and the largest seasonal variation in PET tended to experience biennial patterns of RSV activity, with alternating years of "early-big" and "ate-small" epidemics. Our model for the transmission dynamics of RSV was able to replicate these biennial transitions at higher amplitudes of seasonality in the transmission rate. This successfully connects environmental drivers to the epidemic dynamics of RSV; however, it does not fully explain why RSV activity begins in Florida, one of the warmest states, when RSV is a winter-seasonal pathogen. Understanding and predicting the seasonality of RSV is essential in determining the optimal timing of immunoprophylaxis. C1 [Pitzer, Virginia E.] Yale Univ, Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Pitzer, Virginia E.; Viboud, Cecile; Alonso, Wladimir J.; Wilcox, Tanya; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Metcalf, C. Jessica] Univ Oxford, Dept Zool, Oxford, England. [Metcalf, C. Jessica; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Steiner, Claudia A.] US Dept HHS, Healthcare Cost & Utilizat Project, Ctr Delivery Org & Markets, Agcy Healthcare Res & Qual, Rockville, MD USA. [Haynes, Amber K.] Ctr Dis Control & Prevent, Epidemiol Branch, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Pitzer, VE (reprint author), Yale Univ, Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. EM virginia.pitzer@yale.edu OI Pitzer, Virginia/0000-0003-1015-2289 FU Bill & Melinda Gates Foundation (Vaccine Modeling Initiative); Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the Bill & Melinda Gates Foundation (Vaccine Modeling Initiative; https://vaccinemodeling.org/) and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov/about/staff/pages/epidemiology-population.aspx) (VEP, CJM, and BTG). 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 14 U1 0 U2 9 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 JAN PY 2015 VL 11 IS 1 AR e1004591 DI 10.1371/journal.ppat.1004591 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CA7OF UT WOS:000349106100023 PM 25569275 ER PT J AU Zong, XF Hu, ML Li, ZC Cao, HB Chen, XG Tang, JS AF Zong, Xiaofen Hu, Maolin Li, Zongchang Cao, Hongbao Chen, Xiaogang Tang, Jinsong TI DNA methylation in schizophrenia: progress and challenges SO SCIENCE BULLETIN LA English DT Review DE Schizophrenia; Epigenetics; DNA methylation; Reelin; Catechol-O-methyltransferase ID PERIPHERAL-BLOOD CELLS; DE-NOVO METHYLATION; MB-COMT PROMOTER; BIPOLAR DISORDER; PSYCHIATRIC-DISORDERS; EPIGENETIC REGULATION; PLASMA HOMOCYSTEINE; PREFRONTAL CORTEX; LEUKOCYTE DNA; GENE PROMOTER AB Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epigenetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches. C1 [Zong, Xiaofen; Hu, Maolin; Li, Zongchang; Chen, Xiaogang; Tang, Jinsong] Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha 410011, Hunan, Peoples R China. [Cao, Hongbao] NIMH, Unit Stat Genom, NIH, Bethesda, MD 20852 USA. [Chen, Xiaogang] Cent S Univ, Key Lab Psychiat & Mental Hlth Hunan Prov, Changsha 410011, Hunan, Peoples R China. [Chen, Xiaogang] Cent S Univ, Natl Technol Inst Psychiat, Changsha 410011, Hunan, Peoples R China. RP Chen, XG (reprint author), Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha 410011, Hunan, Peoples R China. EM chenxghn@gmail.com; tangjinsonghn@gmail.com FU National Natural Science Foundation of China [81271484, 81471361, 30900486, 81371480]; National Key Basic Research and Development Program [2012CB517904] FX This work was supported by the National Natural Science Foundation of China (81271484 and 81471361 to X.C, 30900486 and 81371480 to J.T) and the National Key Basic Research and Development Program (2012CB517904 to X.C). NR 59 TC 0 Z9 0 U1 4 U2 15 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 2095-9273 EI 2095-9281 J9 SCI BULL JI Sci. Bull. PD JAN PY 2015 VL 60 IS 2 BP 149 EP 155 DI 10.1007/s11434-014-0690-y PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA5DA UT WOS:000348927000001 ER PT J AU Rybicki, FJ Mather, RT Kumamaru, KK Brinker, J Chen, MY Cox, C Matheson, MB Dewey, M DiCarli, MF Miller, JM Geleijns, J George, RT Paul, N Texter, J Vavere, A Yaw, TS Lima, JAC Clouse, ME AF Rybicki, Frank J. Mather, Richard T. Kumamaru, Kanako K. Brinker, Jeffrey Chen, Marcus Y. Cox, Christopher Matheson, Matthew B. Dewey, Marc DiCarli, Marcelo F. Miller, Julie M. Geleijns, Jacob George, Richard T. Paul, Narinder Texter, John Vavere, Andrea Yaw, Tan Swee Lima, Joao A. C. Clouse, Melvin E. TI Comprehensive Assessment of Radiation Dose Estimates for the CORE320 Study SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE coronary angiography; coronary vessels; CT; radiation dose; SPECT ID STRESS MYOCARDIAL-PERFUSION; CORONARY-ARTERY-DISEASE; CARDIAC MAGNETIC-RESONANCE; DUAL-SOURCE CT; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; FRACTIONAL FLOW RESERVE; DIAGNOSTIC PERFORMANCE; DIPYRIDAMOLE STRESS; 320-MDCT ANGIOGRAPHY; INCREMENTAL VALUE AB OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study (ClinicalTrials. gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA-perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA-perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion. C1 [Rybicki, Frank J.; Kumamaru, Kanako K.] Brigham & Womens Hosp, Dept Radiol, Appl Imaging Sci Lab, Boston, MA 02115 USA. [Rybicki, Frank J.; Kumamaru, Kanako K.; DiCarli, Marcelo F.; Clouse, Melvin E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mather, Richard T.] Toshiba Med Res Inst, Vernon Hills, IL USA. [Brinker, Jeffrey; Miller, Julie M.; Texter, John; Vavere, Andrea; Lima, Joao A. C.] John Hopkins Hosp & Sch Med, Baltimore, MD USA. [Cox, Christopher; Matheson, Matthew B.] NHLBI, NIH, Bethesda, MD 20892 USA. [Dewey, Marc] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [DiCarli, Marcelo F.] Charite, Berlin, Germany. [Geleijns, Jacob] Brigham & Womens Hosp, Boston, MA 02115 USA. [Geleijns, Jacob] Leiden Univ, Med Ctr, Leiden, Netherlands. [Paul, Narinder] Toronto Gen Hosp, Toronto, ON, Canada. [Yaw, Tan Swee] Natl Heart Ctr, Singapore, Singapore. [Clouse, Melvin E.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Rybicki, FJ (reprint author), Brigham & Womens Hosp, Dept Radiol, Appl Imaging Sci Lab, 75 Francis St, Boston, MA 02115 USA. EM frybicki@partners.org OI Dewey, Marc/0000-0002-4402-2733 FU Toshiba Medical Systems FX M. Dewey, J. Brinker, C. Cox, M. F. DiCarli, R. T. George, J. M. Miller, T. S. Yaw, A. Vavere, J. A. C. Lima, N. Paul, and F. J. Rybicki report that their institutions receive grant support from Toshiba Medical Systems. M. Dewey, T. S. Yaw, and N. Paul are on the speakers bureau for Toshiba Medical Systems Corporation. NR 68 TC 2 Z9 2 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JAN PY 2015 VL 204 IS 1 BP W27 EP W36 DI 10.2214/AJR.13.12375 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AZ9UO UT WOS:000348562300005 PM 25539270 ER PT S AU O'Shea, JJ Schwartz, DM Villarino, AV Gadina, M McInnes, IB Laurence, A AF O'Shea, John J. Schwartz, Daniella M. Villarino, Alejandro V. Gadina, Massimo McInnes, Iain B. Laurence, Arian BE Caskey, CT TI The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention SO ANNUAL REVIEW OF MEDICINE, VOL 66 SE Annual Review of Medicine LA English DT Review; Book Chapter DE cytokine; autoimmunity; immunodeficiency; cancer; kinase inhibitors ID JANUS KINASE INHIBITOR; ACTIVE RHEUMATOID-ARTHRITIS; SEVERE COMBINED IMMUNODEFICIENCY; GRANULAR LYMPHOCYTIC-LEUKEMIA; PLACEBO-CONTROLLED TRIAL; LONG-TERM EXTENSION; HYPER-IGE SYNDROME; TOFACITINIB CP-690,550; INADEQUATE RESPONSE; PLAQUE PSORIASIS AB The Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs. C1 [O'Shea, John J.; Schwartz, Daniella M.; Villarino, Alejandro V.; Gadina, Massimo; McInnes, Iain B.; Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; OI Laurence, Arian/0000-0003-0942-8292; McInnes, Iain/0000-0002-6462-4280; Villarino, Alejandro/0000-0001-8068-2176 NR 87 TC 81 Z9 81 U1 9 U2 44 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0066-4219 BN 978-0-8243-0566-6 J9 ANNU REV MED JI Annu. Rev. Med. PY 2015 VL 66 BP 311 EP 328 DI 10.1146/annurev-med-051113-024537 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BB9PT UT WOS:000348560300021 PM 25587654 ER PT S AU Safronetz, D Feldmann, H de Wit, E AF Safronetz, David Feldmann, Heinz de Wit, Emmie BE Abbas, AK Galli, SJ Howley, PM TI Birth and Pathogenesis of Rogue Respiratory Viruses SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 10 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE emerging viruses; hantavirus pulmonary syndrome; Nipah virus disease; Middle East respiratory syndrome ID HANTAVIRUS PULMONARY SYNDROME; SIN-NOMBRE-VIRUS; SYNDROME CORONAVIRUS INFECTION; DIPEPTIDYL PEPTIDASE 4; CENTRAL-NERVOUS-SYSTEM; NEW-WORLD HANTAVIRUSES; INNATE IMMUNE-SYSTEM; LETHAL DISEASE-MODEL; SYRIAN-HAMSTER MODEL; NIPAH-VIRUS AB Emerging infectious diseases of zoonotic origin are shaping today's infectious disease field more than ever. In this article, we introduce and review three emerging zoonotic viruses. Novel hantaviruses emerged in the Americas in the mid-1990s as the cause of severe respiratory infections, designated hantavirus pulmonary syndrome, with case fatality rates of around 40%. Nipah virus emerged a few years later, causing respiratory infections and encephalitis in Southeast Asia, with case fatality rates ranging from 40% to more than 90%. A new coronavirus emerged in 2012 on the Arabian Peninsula with a clinical syndrome of acute respiratory infections, later designated as Middle East respiratory syndrome (MERS), and an initial case fatality rate of more than 40%. Our current state of knowledge on the pathogenicity of these three severe, emerging viral infections is discussed. C1 [Safronetz, David; Feldmann, Heinz; de Wit, Emmie] NIAID, Lab Virol, Div Intramural Res, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Safronetz, D (reprint author), NIAID, Lab Virol, Div Intramural Res, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM safronetzd@niaid.nih.gov; feldmannh@niaid.nih.gov; emmie.deWit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural NIH HHS NR 143 TC 2 Z9 3 U1 1 U2 6 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 BN 978-0-8243-4310-1 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2015 VL 10 BP 449 EP 471 DI 10.1146/annurev-pathol-012414-040501 PG 23 WC Pathology SC Pathology GA BB9PX UT WOS:000348560600016 PM 25423349 ER PT S AU Insel, PA Amara, SG Blaschke, TF AF Insel, Paul A. Amara, Susan G. Blaschke, Terrence F. BE Insel, PA TI Introduction to the Theme "Precision Medicine and Prediction in Pharmacology" SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 SE Annual Review of Pharmacology and Toxicology LA English DT Editorial Material; Book Chapter C1 [Insel, Paul A.] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. [Amara, Susan G.] NIMH, Bethesda, MD 20892 USA. [Blaschke, Terrence F.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Blaschke, Terrence F.] Stanford Univ, Sch Med, Dept Clin Pharmacol, Stanford, CA 94305 USA. RP Insel, PA (reprint author), Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. EM pinsel@ucsd.edu; susan.amara@nih.gov; blaschke@stanford.edu NR 14 TC 2 Z9 2 U1 0 U2 9 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0455-3 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2015 VL 55 BP 11 EP 14 DI 10.1146/annurev-pharmtox-101714-123102 PG 4 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BB9PW UT WOS:000348560500002 PM 25562643 ER PT S AU Nussinov, R Tsai, CJ AF Nussinov, Ruth Tsai, Chung-Jung BE Insel, PA TI The Design of Covalent Allosteric Drugs SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE allosteric modulator; agonist; antagonist; pharmacology; toxicity; allosteric drug discovery ID PROTEIN-PROTEIN INTERACTIONS; HIV-1 REVERSE-TRANSCRIPTASE; INDUCED LIVER-INJURY; IRREVERSIBLE INHIBITORS; ACQUIRED-RESISTANCE; KINASE INHIBITORS; LUNG ADENOCARCINOMAS; FOLDING FUNNELS; RESIDENCE TIME; EGF RECEPTOR AB A key issue in drug discovery is how to reduce drug dosage and increase specificity while retaining or increasing efficacy, as high dosage is often linked to toxicity. There are two types of drugs on the market: orthosteric and allosteric. Orthosteric drugs can be noncovalent or covalent. The latter are advantageous because they may be prescribed in lower doses, but their potential off-target toxicity is a primary concern. The chief advantages of allosteric drugs are their higher specificity and their consequently lower chance of toxic side effects. Covalent allosteric drugs combine the pharmacological merits of covalent drugs with the additional benefit of the higher specificity of allosteric drugs. In a recent promising step in therapeutic drug development, allosteric, disulfide-tethered fragments successfully modulated the activity of a protein kinase and K-Ras. C1 [Nussinov, Ruth; Tsai, Chung-Jung] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 104 TC 21 Z9 22 U1 11 U2 54 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0455-3 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2015 VL 55 BP 249 EP 267 DI 10.1146/annurev-pharmtox-010814-124401 PG 19 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BB9PW UT WOS:000348560500015 PM 25149918 ER PT S AU Urban, DJ Roth, BL AF Urban, Daniel J. Roth, Bryan L. BE Insel, PA TI DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE synthetic biology; G protein-coupled receptors; GPCRs; systems biology; drug discovery ID PROTEIN-COUPLED RECEPTOR; TRANSLATIONAL PROFILING APPROACH; DIRECTED MOLECULAR EVOLUTION; BETA-CELL FUNCTION; CLOZAPINE-N-OXIDE; IN-VIVO; GENETIC IDENTIFICATION; G(Q)-COUPLED RECEPTOR; ALLOSTERIC MODULATION; FEEDING-BEHAVIOR AB In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics. C1 [Urban, Daniel J.; Roth, Bryan L.] UNC Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA. RP Urban, DJ (reprint author), UNC Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010 NR 100 TC 90 Z9 90 U1 20 U2 64 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0455-3 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2015 VL 55 BP 399 EP 417 DI 10.1146/annurev-pharmtox-010814-124803 PG 19 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BB9PW UT WOS:000348560500022 PM 25292433 ER PT S AU Radonjic-Hoesli, S Valent, P Klion, AD Wechsler, ME Simon, HU AF Radonjic-Hoesli, Susanne Valent, Peter Klion, Amy D. Wechsler, Michael E. Simon, Hans-Uwe BE Insel, PA TI Novel Targeted Therapies for Eosinophil-Associated Diseases and Allergy SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE tyrosine kinase inhibitors; biologicals; asthma; chronic eosinophilic leukemia; hypereosinophilic syndrome ID CHRONIC MYELOID-LEUKEMIA; 8P11 MYELOPROLIFERATIVE SYNDROME; THYMIC STROMAL LYMPHOPOIETIN; CRTH2 ANTAGONIST OC000459; CHURG-STRAUSS-SYNDROME; IDIOPATHIC HYPEREOSINOPHILIC SYNDROME; CHRONIC MYELOGENOUS LEUKEMIA; DUAL IL-4/IL-13 ANTAGONIST; TYROSINE KINASE INHIBITOR; GROWTH-FACTOR RECEPTOR AB Eosinophil-associated diseases often present with life-threatening manifestations and/or chronic organ damage. Currently available therapeutic options are limited to a few drugs that often have to be prescribed on a lifelong basis to keep eosinophil counts under control. In the past 10 years, treatment options and outcomes in patients with clonal eosinophilic and other eosinophilic disorders have improved substantially. Several new targeted therapies have emerged, addressing different aspects of eosinophil expansion and inflammation. In this review, we discuss available and currently tested agents as well as new strategies and drug targets relevant to both primary and secondary eosinophilic diseases, including allergic disorders. C1 [Radonjic-Hoesli, Susanne; Simon, Hans-Uwe] Univ Bern, Inst Pharmacol, CH-3010 Bern, Switzerland. [Valent, Peter] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria. [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Wechsler, Michael E.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. RP Radonjic-Hoesli, S (reprint author), Univ Bern, Inst Pharmacol, CH-3010 Bern, Switzerland. EM hus@pki.unibe.ch OI Klion, Amy/0000-0002-4986-5326 FU Austrian Science Fund FWF [F 4704]; Intramural NIH HHS; NIAID NIH HHS [U01 AI097073] NR 152 TC 9 Z9 9 U1 1 U2 10 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0455-3 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2015 VL 55 BP 633 EP 656 DI 10.1146/annurev-pharmtox-010814-124407 PG 24 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BB9PW UT WOS:000348560500033 PM 25340931 ER PT J AU Suner, A Karakulah, G Dicle, O Sokmen, S Celikoglu, CC AF Suner, A. Karakuelah, G. Dicle, O. Soekmen, S. Celikoglu, C. C. TI corRECTreatment: A web-based decision support tool for rectal cancer treatment that uses the analytic hierarchy process and decision tree SO APPLIED CLINICAL INFORMATICS LA English DT Article DE Clinical decision support; analytic hierarchy process; decision tree; rectal cancer ID COLORECTAL-CANCER; COST-EFFECTIVENESS; LIVER METASTASES; RISK-FACTORS; PROCESS AHP; CARE; MANAGEMENT; DIAGNOSIS; COMMUNITY; THERAPY AB Background: The selection of appropriate rectal cancer treatment is a complex multi-criteria decision making process, in which clinical decision support systems might be used to assist and enrich physicians' decision making. Objective: The objective of the study was to develop a web-based clinical decision support tool for physicians in the selection of potentially beneficial treatment options for patients with rectal cancer. Methods: The updated decision model contained 8 and 10 criteria in the first and second steps respectively. The decision support model, developed in our previous study by combining the Analytic Hierarchy Process (AHP) method which determines the priority of criteria and decision tree that formed using these priorities, was updated and applied to 388 patients data collected retrospectively. Later, a web-based decision support tool named corRECTreatment was developed. The compatibility of the treatment recommendations by the expert opinion and the decision support tool was examined for its consistency. Two surgeons were requested to recommend a treatment and an overall survival value for the treatment among 20 different cases that we selected and turned into a scenario among the most common and rare treatment options in the patient data set. Results: In the AHP analyses of the criteria, it was found that the matrices, generated for both decision steps, were consistent (consistency ratio<0.1). Depending on the decisions of experts, the consistency value for the most frequent cases was found to be 80% for the first decision step and 100% for the second decision step. Similarly, for rare cases consistency was 50% for the first decision step and 80% for the second decision step. Conclusions: The decision model and corRECTreatment, developed by applying these on real patient data, are expected to provide potential users with decision support in rectal cancer treatment processes and facilitate them in making projections about treatment options. C1 [Suner, A.] Ege Univ, Sch Med, Dept Biostat & Med Informat, TR-35040 Izmir, Turkey. [Karakuelah, G.] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Karakuelah, G.; Dicle, O.] Dokuz Eylul Univ, Hlth Sci Inst, Dept Med Informat, TR-35340 Izmir, Turkey. [Dicle, O.] Dokuz Eylul Univ, Sch Med, Dept Radiol, TR-35340 Izmir, Turkey. [Soekmen, S.] Dokuz Eylul Univ, Sch Med, Dept Gen Surg, Colorectal & Pelv Surg Unit, TR-35340 Izmir, Turkey. [Celikoglu, C. C.] Dokuz Eylul Univ, Fac Sci, Dept Stat, TR-35160 Izmir, Turkey. RP Suner, A (reprint author), Ege Univ, Sch Med, Dept Biostat & Med Informat, TR-35040 Izmir, Turkey. EM aslisuner@gmail.com RI SUNER, ASLI/C-1032-2012; OI SUNER, ASLI/0000-0002-6872-9901; Karakulah, Gokhan/0000-0001-6706-1375 NR 38 TC 1 Z9 2 U1 3 U2 10 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 1869-0327 J9 APPL CLIN INFORM JI Appl. Clin. Inform. PY 2015 VL 6 IS 1 BP 56 EP 74 DI 10.4338/ACI-2014-10-RA-0087 PG 19 WC Medical Informatics SC Medical Informatics GA CA2EF UT WOS:000348721000005 PM 25848413 ER PT J AU Veno, ST Witt, MB Kulikowicz, T Bohr, VA Stevnsner, T AF Veno, Susanne T. Witt, Marie B. Kulikowicz, Tomasz Bohr, Vilhelm A. Stevnsner, Tinna TI Regulation of the human Suv3 helicase on DNA by inorganic cofactors SO BIOCHIMIE LA English DT Article DE Helicase; Cofactor; Nucleotide; Divalent cations; DNA binding protein ID YEAST MITOCHONDRIAL DEGRADOSOME; WERNER-SYNDROME PROTEIN; RNA HELICASE; MAMMALIAN MITOCHONDRIA; TRYPANOSOMA-BRUCEI; RNA/DNA HELICASE; HSUV3P HELICASE; REPLICATION; TURNOVER; RIBONUCLEOTIDES AB Mitochondria are essential organelles and consequently proper expression and maintenance of the mitochondrial genome are indispensable for proper cell function. The mitochondrial Suv3 (SUPV3L1) helicase is known to have a central role in mitochondrial RNA metabolism and to be essential for maintenance of mitochondrial DNA stability. Here we have performed biochemical investigations to determine the potential regulation of the human Suv3 (hSuv3) helicase function by inorganic cofactors. We find that hSuv3 helicase and ATPase activity in vitro is strictly dependent on the presence of specific divalent cations. Interestingly, we show that divalent cations and nucleotide concentration have a direct effect on helicase substrate stability. Also, hSuy3 helicase is able to utilize several different nucleotide cofactors including both NTPs and dNTPs. Intriguingly, the potency of the individual nucleotide as energy source for hSuv3 unwinding differed depending on the included divalent cation and nucleotide concentration. At low concentrations, all four NTPs could support helicase activity with varying effectiveness depending on the included divalent cation. However, at higher nucleotide concentrations, only ATP was able to elicit the helicase activity of hSuv3. Consequently, we speculate that the capacity of hSuv3 DNA unwinding activity might be sensitive to the local availability of specific inorganic cofactors. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved. C1 [Veno, Susanne T.; Witt, Marie B.; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol & Genet, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Veno, Susanne T.; Witt, Marie B.; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol & Genet, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Kulikowicz, Tomasz; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Stevnsner, T (reprint author), Univ Aarhus, Dept Mol Biol & Genet, Danish Ctr Mol Gerontol, CF Moellers Alle,Bldg 1130, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk FU Intramural Program of the National Institute on Aging, National Institutes on Health; Velux Foundation FX This work was supported by the Intramural Program of the National Institute on Aging, National Institutes on Health and the Velux Foundation. NR 46 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 EI 1638-6183 J9 BIOCHIMIE JI Biochimie PD JAN PY 2015 VL 108 BP 160 EP 168 DI 10.1016/j.biochi.2014.11.003 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CA5PD UT WOS:000348959400020 PM 25446650 ER PT J AU Cohen, EJ Quarta, E Fulgenzi, G Minciacchi, D AF Cohen, Erez James Quarta, Eros Fulgenzi, Gianluca Minciacchi, Diego TI Acetylcholine, GABA and neuronal networks: A working hypothesis for compensations in the dystrophic brain SO BRAIN RESEARCH BULLETIN LA English DT Review DE Duchenne muscular dystrophy; Neuronal networks; mdx; Network oscillations; Acetylcholine ID DUCHENNE MUSCULAR-DYSTROPHY; LONG-TERM POTENTIATION; DEFICIENT MDX MICE; CEREBELLAR PURKINJE-CELLS; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE; SYNAPTIC PLASTICITY; RAT HIPPOCAMPUS; CHOLINERGIC MODULATION; GABAERGIC INTERNEURONS AB Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease's progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cohen, Erez James; Quarta, Eros; Minciacchi, Diego] Univ Florence, Dept Clin & Expt Med, Physiol Sci Sect, I-50134 Florence, Italy. [Fulgenzi, Gianluca] Univ Politecn Marche, Dept Clin & Mol Sci, Lab Expt Pathol, Ancona, Italy. [Fulgenzi, Gianluca] NCI, Neural Dev Sect, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Minciacchi, D (reprint author), Univ Florence, Dept Clin & Expt Med, Physiol Sci Sect, Viale Morgagni 63, I-50134 Florence, Italy. EM diego@unifi.it OI Fulgenzi, Gianluca/0000-0003-2646-7728 NR 175 TC 4 Z9 4 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 EI 1873-2747 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN PY 2015 VL 110 BP 1 EP 13 DI 10.1016/j.brainresbull.2014.10.004 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CA4OK UT WOS:000348884000001 PM 25445612 ER PT J AU Griffin, AJ Crane, DD Wehrly, TD Bosio, CM AF Griffin, Amanda J. Crane, Deborah D. Wehrly, Tara D. Bosio, Catharine M. TI Successful Protection against Tularemia in C57BL/6 Mice Is Correlated with Expansion of Francisella tularensis-Specific Effector T Cells SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID LIVE VACCINE STRAIN; SCHU S4; LISTERIA-MONOCYTOGENES; RESPIRATORY CHALLENGE; AEROSOL INFECTION; PURINE AUXOTROPH; GUINEA PIG; IMMUNITY; IMMUNIZATION; PULMONARY AB Francisella tularensis is an intracellular, Gram-negative bacterium that causes the fatal disease tularemia. Currently, there are no licensed vaccines for tularemia and the requirements for protection against infection are poorly defined. To identify correlates of vaccine-induced immunity against tularemia, we compared different strains of the live vaccine strain (LVS) for their relative levels of virulence and ability to protect C57BL/6 mice against challenge with virulent F. tularensis strain SchuS4. Successful vaccination, as defined by survival of C57BL/6 mice, was correlated with significantly greater numbers of effector T cells in the spleen and lung. Further, lung cells and splenocytes from fully protected animals were more effective than lung cells and splenocytes from vaccinated but nonimmune animals in limiting intracellular replication of SchuS4 in vitro. Together, our data provide a unique model to compare efficacious vaccines to nonefficacious vaccines, which will enable comprehensive identification of host and bacterial components required for immunization against tularemia. C1 [Griffin, Amanda J.; Crane, Deborah D.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 42 TC 9 Z9 9 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JAN PY 2015 VL 22 IS 1 BP 119 EP 128 DI 10.1128/CVI.00648-14 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CA2YK UT WOS:000348771800014 PM 25410207 ER PT J AU Hogan, MC Abebe, K Torres, VE Chapman, AB Bae, KT Tao, C Sun, HL Perrone, RD Steinman, TI Braun, W Winklhofer, FT Miskulin, DC Rahbari-Oskoui, F Brosnahan, G Masoumi, A Karpov, IO Spillane, S Flessner, M Moore, CG Schrier, RW AF Hogan, Marie C. Abebe, Kaleab Torres, Vicente E. Chapman, Arlene B. Bae, Kyongtae T. Tao, Cheng Sun, Hongliang Perrone, Ronald D. Steinman, Theodore I. Braun, William Winklhofer, Franz T. Miskulin, Dana C. Rahbari-Oskoui, Frederic Brosnahan, Godela Masoumi, Amirali Karpov, Irina O. Spillane, Susan Flessner, Michael Moore, Charity G. Schrier, Robert W. TI Liver Involvement in Early Autosomal-Dominant Polycystic Kidney Disease SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE HALT-PKD-A; Hepatic Cyst; CKD; MRI Analysis ID NORMAL SPLENIC VOLUME; STAGE RENAL-DISEASE; HEPATIC CYSTS; COMPUTED-TOMOGRAPHY; IMAGING EVALUATION; SOMATOSTATIN; ADULTS; CT; HYPERTROPHY; ACQUISITION AB BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (< 110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. C1 [Hogan, Marie C.; Torres, Vicente E.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Abebe, Kaleab; Bae, Kyongtae T.; Tao, Cheng; Sun, Hongliang; Karpov, Irina O.; Spillane, Susan; Moore, Charity G.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Chapman, Arlene B.; Rahbari-Oskoui, Frederic] Emory Univ, Sch Med, Atlanta, GA USA. [Perrone, Ronald D.; Miskulin, Dana C.] Tufts Med Ctr, Boston, MA USA. [Steinman, Theodore I.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Braun, William] Cleveland Clin, Cleveland, OH 44106 USA. [Winklhofer, Franz T.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Brosnahan, Godela; Masoumi, Amirali; Schrier, Robert W.] Univ Colorado, Aurora, CO USA. [Flessner, Michael] Natl Inst Diabet & Digest Dis, NIH, Bethesda, MD USA. RP Hogan, MC (reprint author), Mayo Clin, Div Nephrol, 200 First St SW, Rochester, MN 55905 USA. EM hogan.marie@mayo.edu OI Moore, Charity/0000-0002-0060-0124; Abebe, Kaleab/0000-0002-3644-8419 FU National Institutes of Health [U01 DK082230]; Boehringer Ingelheim Pharmaceuticals, Inc. FX Supported by funding from the National Institutes of Health (U01 DK082230) and supported in part by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc, had no role in the design, analysis, or interpretation of the results in this study and were given the opportunity to review the manuscript for medical and scientific accuracy as it relates to their respective substances as well as intellectual property considerations. NR 49 TC 18 Z9 18 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JAN PY 2015 VL 13 IS 1 BP 155 EP + DI 10.1016/j.cgh.2014.07.051 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AZ2BW UT WOS:000348040500027 PM 25111236 ER PT J AU Ghany, MG Perrillo, R Li, RS Belle, SH Janssen, HLA Terrault, NA Shuhart, MC Lau, DTY Kim, WR Fried, MW Sterling, RK Di Bisceglie, AM Han, SHB Ganova-Raeva, LM Chang, KM Lok, ASF AF Ghany, Marc G. Perrillo, Robert Li, Ruosha Belle, Steven H. Janssen, Harry L. A. Terrault, Norah A. Shuhart, Margaret C. Lau, Daryl T-Y. Kim, W. Ray Fried, Michael W. Sterling, Richard K. Di Bisceglie, Adrian M. Han, Steven-Huy B. Ganova-Raeva, Lilia Milkova Chang, Kyong-Mi Lok, Anna Suk-Fong CA Hepatitis B Res Network TI Characteristics of Adults in the Hepatitis B Research Network in North America Reflect Their Country of Origin and Hepatitis B Virus Genotype SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE HBeAg; Chronic Hepatitis B Virus Infection; USA; ALT ID UNITED-STATES; HBV INFECTION; EPIDEMIOLOGY; PREVALENCE; WORLDWIDE; DISEASE; BURDEN; HEALTH AB BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the United States and Canada might be affected disproportionately. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. METHODS: The HBRN collected data on the clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. RESULTS: Half of the subjects in the HBRN are men, and the median age is 42 years; 72% are Asian, 15% are black, and 11% are white; with 82% born outside of North America. The most common HBV genotype was B (39%); 74% of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log(10) IU/mL; 68% of male subjects and 67% of female subjects had alanine aminotransferase levels higher than the normal range. CONCLUSIONS: The HBRN cohort is used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America. C1 [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Perrillo, Robert] Baylor Univ, Med Ctr, Hepatol Div, Dallas, TX USA. [Li, Ruosha; Belle, Steven H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Janssen, Harry L. A.] Toronto Western Hosp, Div Gastroenterol, Univ Hlth Network, Toronto, ON M5T 2S8, Canada. [Janssen, Harry L. A.] Toronto Gen Hosp, Div Gastroenterol, Univ Hlth Network, Toronto, ON, Canada. [Terrault, Norah A.] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Shuhart, Margaret C.] Univ Washington, Harborview Med Ctr, Viral Hepatitis & Liver Clin, Seattle, WA 98104 USA. [Lau, Daryl T-Y.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gastroenterol, Boston, MA 02215 USA. [Kim, W. Ray] Stanford Univ, Sch Med, Div Gastroenterol, Palo Alto, CA 94304 USA. [Fried, Michael W.] Univ N Carolina, Ctr Liver, Sect Hepatol, Chapel Hill, NC USA. [Sterling, Richard K.] Virginia Commonwealth Univ Hlth Syst, Sect Hepatol, Richmond, VA USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Dept Internal Med, St Louis, MO USA. [Han, Steven-Huy B.] Univ Calif Los Angeles, David Geffen Sch Med, Pfleger Liver Inst Clin, Los Angeles, CA 90095 USA. [Ganova-Raeva, Lilia Milkova] Ctr Dis Control & Prevent, Div Viral Hepatitis, Mol Epidemiol & Bioinformat Sequencing Lab, Atlanta, GA USA. [Chang, Kyong-Mi] Univ Penn, Sch Med, Philadelphia Vet Affairs Med Ctr, Penn Ctr Viral Hepatitis, Philadelphia, PA 19104 USA. [Lok, Anna Suk-Fong] Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bdg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Barritt, Alfred/0000-0002-4200-3256; Cloonan, Yona/0000-0003-3893-3693; Wahed, Abdus/0000-0001-6911-7221 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK082872, DK082864, DK082874, U01 DK082944, DK082943, DK082919, DK 082843, DK082867, DK082923, DK082871, DK082927, DK082866, DK082863, A-DK-3002-001]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Immunology Center (National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Center of Molecular Studies in Digestive and Liver Diseases) [P30DK50306]; Immunology Center (National Institutes of Health Public Health Service Research) [M01RR00040]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000058]; Clinical and Translational Science Awards [UL1TR000004, UL1TR001111, UL1RR024986]; Gilead Sciences, Inc; Roche Molecular Systems through National Institute of Diabetes and Digestive and Kidney Diseases FX The Hepatitis B Research Network was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases to the following investigators: U01 DK082872 (W.L.), DK082864 (S.B.), DK082874 (H.J.), U01 DK082944 (N.T.), DK082943 (R.C.), DK082919 (D.T.-Y.L.), DK 082843 (L.R.R.), DK082867 (M.W.F.), DK082923 (R.K.S.), DK082871 (A.D.B.), DK082927 (S.-H.B.H.), DK082866 (K.-M.C.), and DK082863 (A.S.-F.L.); an interagency agreement with the National Institute of Diabetes and Digestive and Kidney Diseases: A-DK-3002-001 (L.M.G.-R.); and support from the intramural program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (M.G.G.). Additional funding for this study was provided by the Immunology Center (National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Center of Molecular Studies in Digestive and Liver Diseases: P30DK50306; and a National Institutes of Health Public Health Service Research grant: M01RR00040 to K.-M.C.), by the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR000058 to R.K.S.); and Clinical and Translational Science Awards grants: UL1TR000004 (N.A.T.), UL1TR001111 (M.W.F.), and UL1RR024986 (A.S.-F.L.). Additional support was provided by Gilead Sciences, Inc, and Roche Molecular Systems via a Cooperative Research And Development Agreement through the National Institute of Diabetes and Digestive and Kidney Diseases. NR 15 TC 11 Z9 11 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JAN PY 2015 VL 13 IS 1 BP 183 EP 192 DI 10.1016/j.cgh.2014.06.028 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AZ2BW UT WOS:000348040500032 PM 25010003 ER PT J AU Nunez, PL Srinivasan, R Fields, RD AF Nunez, Paul L. Srinivasan, Ramesh Fields, R. Douglas TI EEG functional connectivity, axon delays and white matter disease SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE White matter disease; Functional connectivity; Alpha rhythms; Multi-scale dynamics; Axon propagation speed; Local networks; Global dynamics; Cortico-cortical axons ID HIGH-RESOLUTION EEG; TOP-DOWN INFLUENCES; SHORT-TERM-MEMORY; NEOCORTICAL INTERACTIONS; STATISTICAL-MECHANICS; LOCAL NETWORKS; CONDUCTION TIME; CEREBRAL-CORTEX; HUMAN BRAIN; DYNAMICS AB Objective: Both structural and functional brain connectivities are closely linked to white matter disease. We discuss several such links of potential interest to neurologists, neurosurgeons, radiologists, and non-clinical neuroscientists. Methods: Treatment of brains as genuine complex systems suggests major emphasis on the multi-scale nature of brain connectivity and dynamic behavior. Cross-scale interactions of local, regional, and global networks are apparently responsible for much of EEG's oscillatory behaviors. Finite axon propagation speed, often assumed to be infinite in local network models, is central to our conceptual framework. Results: Myelin controls axon speed, and the synchrony of impulse traffic between distant cortical regions appears to be critical for optimal mental performance and learning. Results: Several experiments suggest that axon conduction speed is plastic, thereby altering the regional and global white matter connections that facilitate binding of remote local networks. Conclusions: Combined EEG and high resolution EEG can provide distinct multi-scale estimates of functional connectivity in both healthy and diseased brains with measures like frequency and phase spectra, covariance, and coherence. Significance: White matter disease may profoundly disrupt normal EEG coherence patterns, but currently these kinds of studies are rare in scientific labs and essentially missing from clinical environments. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Nunez, Paul L.] Cognit Dissonance LLC, Encinitas, CA 92024 USA. [Srinivasan, Ramesh] Univ Calif Irvine, Dept Cognit Sci, Irvine, CA 92617 USA. [Srinivasan, Ramesh] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92617 USA. [Fields, R. Douglas] NICHD, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Nunez, PL (reprint author), Cognit Dissonance LLC, 1726 Sienna Canyon Dr, Encinitas, CA 92024 USA. EM pnunez@tulane.edu FU National Institutes of Health of the United States [2R01MH68004] FX This research was supported by National Institutes of Health of the United States Grant 2R01MH68004. NR 112 TC 12 Z9 12 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JAN PY 2015 VL 126 IS 1 BP 110 EP 120 DI 10.1016/j.clinph.2014.04.003 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AZ9UJ UT WOS:000348561800016 PM 24815984 ER PT J AU Andres, SN Schellenberg, MJ Wallace, BD Tumbale, P Williams, RS AF Andres, Sara N. Schellenberg, Matthew J. Wallace, Bret D. Tumbale, Percy Williams, R. Scott TI Recognition and Repair of Chemically Heterogeneous Structures at DNA Ends SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE DNA damage response; X-ray crystallography; cancer; neurodegeneration ID STRAND-BREAK REPAIR; BASE EXCISION-REPAIR; APURINIC-APYRIMIDINIC SITES; DEOXYRIBOSE PHOSPHATE LYASE; HUMAN POLYNUCLEOTIDE KINASE; MAMMALIAN TOPOISOMERASE-I; DISEASE PROTEIN APRATAXIN; MAINTAIN GENOME INTEGRITY; YEAST APN2 PROTEIN; POLYMERASE-BETA AB Exposure to environmental toxicants and stressors, radiation, pharmaceutical drugs, inflammation, cellular respiration, and routine DNA metabolism all lead to the production of cytotoxic DNA strand breaks. Akin to splintered wood, DNA breaks are not clean. Rather, DNA breaks typically lack DNA 5-phosphate and 3-hydroxyl moieties required for DNA synthesis and DNA ligation. Failure to resolve damage at DNA ends can lead to abnormal DNA replication and repair, and is associated with genomic instability, mutagenesis, neurological disease, ageing and carcinogenesis. An array of chemically heterogeneous DNA termini arises from spontaneously generated DNA single-strand and double-strand breaks (SSBs and DSBs), and also from normal and/or inappropriate DNA metabolism by DNA polymerases, DNA ligases and topoisomerases. As a front line of defense to these genotoxic insults, eukaryotic cells have accrued an arsenal of enzymatic first responders that bind and protect damaged DNA termini, and enzymatically tailor DNA ends for DNA repair synthesis and ligation. These nucleic acid transactions employ direct damage reversal enzymes including Aprataxin (APTX), Polynucleotide kinase phosphatase (PNK), the tyrosyl DNA phosphodiesterases (TDP1 and TDP2), the Ku70/80 complex and DNA polymerase (POL). Nucleolytic processing enzymes such as the MRE11/RAD50/NBS1/CtIP complex, Flap endonuclease (FEN1) and the apurinic endonucleases (APE1 and APE2) also act in the chemical cleansing of DNA breaks to prevent genomic instability and disease, and promote progression of DNA- and RNA-DNA damage response (DDR and RDDR) pathways. Here, we provide an overview of cellular first responders dedicated to the detection and repair of abnormal DNA termini. Environ. Mol. Mutagen. 56:1-21, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Andres, Sara N.; Schellenberg, Matthew J.; Wallace, Bret D.; Tumbale, Percy; Williams, R. Scott] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, NIH, 111 TW Alexander Dr,F337,F3-03, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov RI Williams, Robert/A-6059-2015 FU US National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765] FX Grant sponsor: Intramural Research Program of the US National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS) Projects; Grant number: 1Z01ES102765 (to R. S. W.). NR 226 TC 18 Z9 18 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JAN PY 2015 VL 56 IS 1 BP 1 EP 21 DI 10.1002/em.21892 PG 21 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CA0ZC UT WOS:000348641000001 PM 25111769 ER PT J AU Mendola, P Mumford, SL Mannisto, TI Holston, A Reddy, UM Laughon, SK AF Mendola, Pauline Mumford, Sunni L. Mannisto, Tuija I. Holston, Alexander Reddy, Uma M. Laughon, S. Katherine TI Controlled Direct Effects of Preeclampsia on Neonatal Health After Accounting for Mediation by Preterm Birth SO EPIDEMIOLOGY LA English DT Article ID MARGINAL STRUCTURAL MODELS; CEREBRAL-PALSY; ANGIOGENIC FACTORS; GESTATIONAL-AGE; AMNIOTIC-FLUID; RISK; COHORT; PREGNANCY; COMPLICATIONS; EPIDEMIOLOGY AB Background: Preeclampsia is characterized by alterations in angiogenic factors that may increase neonatal morbidity independent of preterm birth. Methods: We estimated the controlled direct effect of preeclampsia on neonatal outcomes independent of preterm birth among 200,103 normotensive and 10,507 preeclamptic singleton pregnancies in the Consortium on Safe Labor (2002-2008). Marginal structural models with stabilized inverse probability weights accounted for potential confounders in the pathway from preeclampsia to preterm birth to neonatal outcomes, including mediator-outcome confounders related to preeclampsia status, such as cesarean delivery. Controlled direct effects of preeclampsia on perinatal mortality, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, respiratory distress syndrome, transient tachypnea of the newborn, anemia, apnea, asphyxia, peri-or intraventricular hemorrhage, and cardiomyopathy were estimated for the hypothesized intervention of term delivery for all infants. Results: When delivery was set at >= 37 weeks, preeclampsia increased the odds of perinatal mortality (odds ratio = 2.2 [95% confidence interval = 1.1-4.5], SGA = (1.9 [1.8-2.1]), NICU admission (1.9 [1.7-2.1]), respiratory distress syndrome (2.8 [2.0-3.7], transient tachypnea of the newborn (1.6 [1.3-1.9]), apnea (2.2 [1.6-3.1]), asphyxia (2.7 [1.5-4.9]), and peri-or intraventricular hemorrhage (3.2 [1.4-7.7]). No direct effect of preeclampsia at term was observed for anemia or cardiomyopathy. Our results appear robust in the presence of moderate confounding, and restriction to severe preeclampsia yielded similar findings. Conclusion: Preeclampsia was directly associated with adverse neonatal outcomes beyond morbidity mediated by preterm birth. Although severe neonatal outcomes were less common at later gestational ages, marginal structural models suggested elevated neonatal risk due to preeclampsia even if it was possible to deliver all infants at term. C1 [Mendola, Pauline; Mumford, Sunni L.; Mannisto, Tuija I.; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Mannisto, Tuija I.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Oulu, Finland. [Holston, Alexander] Naval Med Ctr Portsmouth, Dept Pediat, Portsmouth, VA USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Extramural Res, Rockville, MD 20852 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 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 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 Supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Consortium on Safe Labor 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 No. HHSN267200603425C. NR 35 TC 11 Z9 11 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2015 VL 26 IS 1 BP 17 EP 26 DI 10.1097/EDE.0000000000000213 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU8XZ UT WOS:000345878000016 PM 25437315 ER PT J AU Hofmann, JN Corley, DA Zhao, WK Colt, JS Shuch, B Chow, WH Purdue, MP AF Hofmann, Jonathan N. Corley, Douglas A. Zhao, Wei K. Colt, Joanne S. Shuch, Brian Chow, Wong-Ho Purdue, Mark P. TI Chronic Kidney Disease and Risk of Renal Cell Carcinoma: Differences by Race SO EPIDEMIOLOGY LA English DT Article ID CANCER-RISK; ALCOHOL INTAKE; UNITED-STATES; TRANSPLANTATION; HYPERTENSION; AMERICANS; DIALYSIS; ASSOCIATION; WHITE; APOL1 AB Background: The incidence of renal cell carcinoma in the United States differs by race/ethnicity. To better understand these disparities, we conducted a nested case-control study investigating renal cell carcinoma risk factors across racial/ethnic groups within the Kaiser Permanente Northern California health care network. Methods: Our study included 3136 renal cell carcinoma cases (2152 whites, 293 blacks, 425 Hispanics, and 255 Asians) diagnosed between 1998 and 2008 and 31031 individually matched controls (21478 whites, 2836 blacks, 4147 Hispanics, and 2484 Asians). Risk of renal cell carcinoma was assessed in relation to smoking status, body mass index (BMI), hypertension, and chronic kidney disease. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, and population attributable risk (PAR) to estimate by race the proportion of cases attributable to hypertension and chronic kidney disease. Results: The association between chronic kidney disease and renal cell carcinoma differed markedly by race (P-interaction < 0.001), with associations observed among blacks (OR = 10.4 [95% CI = 6.0-17.9]), Asians (5.1 [2.2-11.7]), and Hispanics (2.3 [1.1-4.6]) but not whites (1.1 [0.6-1.9]). Hypertension, high BMI, and smoking were associated with renal cell carcinoma, but findings generally did not differ by race. Relative to other racial/ethnic groups, blacks had the highest proportion of renal cell carcinoma incidence attributable to hypertension and chronic kidney disease (combined, PAR = 37%; hypertension only, PAR = 27%; chronic kidney disease, PAR = 10%). Conclusions: Our findings suggest that hypertension and chronic kidney disease likely have contributed to the observed excess in renal cell carcinoma incidence among blacks compared with whites. C1 [Hofmann, Jonathan N.; Colt, Joanne S.; Purdue, Mark P.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Corley, Douglas A.; Zhao, Wei K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT USA. [Chow, Wong-Ho] Univ Texas Houston, Dept Epidemiol, Houston, TX USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E132, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural Research Program of the National Institutes of Health FX Supported by Intramural Research Program of the National Institutes of Health. NR 20 TC 6 Z9 7 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2015 VL 26 IS 1 BP 59 EP 67 DI 10.1097/EDE.0000000000000205 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU8XZ UT WOS:000345878000021 PM 25393631 ER PT J AU Mumford, SL Schisterman, EF Cole, SR Westreich, D Platt, RW AF Mumford, Sunni L. Schisterman, Enrique F. Cole, Stephen R. Westreich, Daniel Platt, Robert W. TI Time at Risk and Intention-to-treat Analyses Parallels and Implications for Inference SO EPIDEMIOLOGY LA English DT Article ID IMMORTAL PERSON-TIME; SUN EXPOSURE; STATISTICAL-MODELS; SKIN-CANCER; BIAS; PREGNANCY; COHORT; FECUNDABILITY; NONCOMPLIANCE; CONCEPTION AB Although the standard recommendation is to exclude person-time not at risk (ie, time during which the outcome could not have occurred) from the denominators of disease rates, there are scenarios where person-time not at risk should be included. In particular, we draw an analogy between including person-time not at risk and intention-to-treat (IT) analyses of randomized trials, and excluding person-time not at risk and compliance-corrected analysis of these same trials. Excluding person-time not at risk is appropriate when addressing questions of the biologic or mechanistic effects of an exposure, whereas the IT-type approach typically addresses questions regarding the effect of an exposure under observed compliance patterns. The choice of approach directly affects the causal question being addressed and subsequent inference, with potential implications for public health. When interested in estimating treatment effects that allow and account for potential noncompliance, or where the exposure may be associated with the time at risk, we argue that person-time not at risk should be included. In the case of time to pregnancy, although the IT-type analysis may underestimate the biological fecundity of the population, it may also yield an answer to a question that is of more interest to couples trying to become pregnant. C1 [Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Cole, Stephen R.; Westreich, Daniel] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Platt, Robert W.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Mumford, SL (reprint author), NICHD, Epidemiol Branch, DIPHR, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Long-Range Research Initiative of the American Chemistry Council; National Scholar (Chercheur-national) award from the Fonds de Recherche du Quebec-Sante (FQR-S); FQR-S FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the Long-Range Research Initiative of the American Chemistry Council. Robert W. Platt is supported by a National Scholar (Chercheur-national) award from the Fonds de Recherche du Quebec-Sante (FQR-S) and is a member of the Research Institute of the McGill University Health Centre, which receives core funding from the FQR-S. NR 38 TC 1 Z9 1 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2015 VL 26 IS 1 BP 112 EP 118 DI 10.1097/EDE.0000000000000188 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU8XZ UT WOS:000345878000028 PM 25275571 ER PT J AU Tseng, WL Bones, BL Kayser, RR Olsavsky, AK Fromm, SJ Pine, DS Leibenluft, E Brotman, MA AF Tseng, W. -L. Bones, B. L. Kayser, R. R. Olsavsky, A. K. Fromm, S. J. Pine, D. S. Leibenluft, E. Brotman, M. A. TI An fMRI study of emotional face encoding in youth at risk for bipolar disorder SO EUROPEAN PSYCHIATRY LA English DT Article DE fMRI; Pediatric bipolar disorder; At risk; Face memory; Endophenotype ID RATING-SCALE; DYSREGULATION; RELIABILITY; ACTIVATION; VALIDITY; MEMORY; MANIA AB Face memory deficits may be a bipolar disorder (BD) endophenotype. BD (n = 27) and unaffected youth at risk (n = 13) exhibited middle frontal gyrus hypoactivation during successful vs. unsuccessful encoding. Parahippocampal gyrus dysfunction was found in BD and at-risk youth (vs. low-risk, n = 37). Middle occipital gyrus hypoactivation was only present in BD. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Tseng, W. -L.; Fromm, S. J.; Pine, D. S.; Leibenluft, E.; Brotman, M. A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bones, B. L.; Kayser, R. R.] Georgetown Univ, Sch Med, Washington, DC USA. [Olsavsky, A. K.] UCLA Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. RP Tseng, WL (reprint author), Bldg 15K,Room 208,MSC 2670,15K North Dr, Bethesda, MD 20892 USA. EM wan-ling.tseng@nih.gov RI Brotman, Melissa/H-7409-2013 FU Intramural Research Program of the NIMH; NIH; Pfizer Inc. FX This research was supported (in part) by the Intramural Research Program of the NIMH. Dr. Olsavsky's research was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 17 TC 8 Z9 8 U1 2 U2 9 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0924-9338 EI 1778-3585 J9 EUR PSYCHIAT JI Eur. Psychiat. PD JAN PY 2015 VL 30 IS 1 DI 10.1016/j.eurpsy.2014.05.004 PG 5 WC Psychiatry SC Psychiatry GA AZ1YX UT WOS:000348032300016 PM 25172156 ER PT J AU Crosslin, DR Carrell, DS Burt, A Kim, DS Underwood, JG Hanna, DS Comstock, BA Baldwin, E de Andrade, M Kullo, IJ Tromp, G Kuivaniemi, H Borthwick, KM McCarty, CA Peissig, PL Doheny, KF Pugh, E Kho, A Pacheco, J Hayes, MG Ritchie, MD Verma, SS Armstrong, G Stallings, S Denny, JC Carroll, RJ Crawford, DC Crane, PK Mukherjee, S Bottinger, E Li, R Keating, B Mirel, DB Carlson, CS Harley, JB Larson, EB Jarvik, GP AF Crosslin, D. R. Carrell, D. S. Burt, A. Kim, D. S. Underwood, J. G. Hanna, D. S. Comstock, B. A. Baldwin, E. de Andrade, M. Kullo, I. J. Tromp, G. Kuivaniemi, H. Borthwick, K. M. McCarty, C. A. Peissig, P. L. Doheny, K. F. Pugh, E. Kho, A. Pacheco, J. Hayes, M. G. Ritchie, M. D. Verma, S. S. Armstrong, G. Stallings, S. Denny, J. C. Carroll, R. J. Crawford, D. C. Crane, P. K. Mukherjee, S. Bottinger, E. Li, R. Keating, B. Mirel, D. B. Carlson, C. S. Harley, J. B. Larson, E. B. Jarvik, G. P. TI Genetic variation in the HLA region is associated with susceptibility to herpes zoster SO GENES AND IMMUNITY LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; EMERGE NETWORK; RISK-FACTOR; POPULATION; INFORMATION; HAPLOTYPE; TOOL AB Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22 981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 x 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine. C1 [Crosslin, D. R.; Burt, A.; Kim, D. S.; Jarvik, G. P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Crosslin, D. R.; Kim, D. S.; Underwood, J. G.; Hanna, D. S.; Jarvik, G. P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Carrell, D. S.; Baldwin, E.; Larson, E. B.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Comstock, B. A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [de Andrade, M.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Kullo, I. J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Tromp, G.; Kuivaniemi, H.; Borthwick, K. M.] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [McCarty, C. A.] Essentia Inst Rural Hlth, Duluth, MN USA. [McCarty, C. A.; Peissig, P. L.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI 54449 USA. [Doheny, K. F.; Pugh, E.] Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. [Kho, A.; Pacheco, J.] Northwestern Univ, Feinberg Sch Med, Div Gen Internal Med, Chicago, IL 60611 USA. [Kho, A.; Pacheco, J.] Northwestern Univ, Feinberg Sch Med, Div Prevent Med, Chicago, IL 60611 USA. [Hayes, M. G.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Ritchie, M. D.; Verma, S. S.; Armstrong, G.] Penn State Univ, Dept Biochem & Mol Biol, Ctr Syst Genom, University Pk, PA 16802 USA. [Stallings, S.; Denny, J. C.; Carroll, R. J.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Crawford, D. C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Crawford, D. C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Crane, P. K.; Mukherjee, S.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Bottinger, E.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Li, R.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Keating, B.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Mirel, D. B.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Carlson, C. S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Harley, J. B.] BCH, CCHMC, Boston, MA USA. RP Crosslin, DR (reprint author), Univ Washington, Dept Med, Div Med Genet, 1705 NE Pacific St,K253,Box 357720, Seattle, WA 98195 USA. EM davidcr@u.washington.edu OI Kuivaniemi, Helena/0000-0001-5753-8766 FU National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA [U01HG006375, U01HG006382, U01HG006379, U01HG006389, U01HG006388, HG004438, HG004424, U01HG006378, U01HG006385, U01HG006380, U01HG006828, U01HG006830]; State of Washington Life Sciences Discovery Fund award FX We are grateful to all the participants of the eMERGE study. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: (1) U01HG006375 (Group Health/University of Washington); (2) U01HG006382 (Geisinger Health System); (3) U01HG006379 (Mayo Clinic); (4) U01HG006389 (Essentia Health and Marshfield Clinic Research Foundation); (5) U01HG006388 (Northwestern University); (6) HG004438 (Center for Inherited Disease Research, Johns Hopkins University); (7) HG004424 (Broad Institute of Harvard and MIT); (8) U01HG006378, U01HG006385, U01HG006385 (Vanderbilt University); (9) U01HG006380 (The Mt Sinai Hospital); (10) U01HG006828 (Cincinnati Children's Hospital Medical Center/Harvard); and (11) U01HG006830 (Children's Hospital of Philadelphia). Additional support was provided by a State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (to GPJ). NR 26 TC 8 Z9 8 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD JAN-FEB PY 2015 VL 16 IS 1 BP 1 EP 7 DI 10.1038/gene.2014.51 PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA AZ6WG UT WOS:000348358100001 PM 25297839 ER PT J AU Moon, HY AF Moon, Hyo Youl TI N-methyl D-aspartate receptor synaptonuclear signaling and neuronal migration factor (Nsmf) plays a novel role in myoblast proliferation SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE Nsmf; Myocyte; Proliferation ID MUSCULAR-ATROPHY; HYPOGONADISM; TESTOSTERONE; THERAPIES; MICE AB Myogenesis, the formation and regeneration of muscular tissue, is a fundamental factor in embryonic development. N-methyl d-aspartate (NMDA) receptor synaptonuclear signaling and neuronal migration factor (Nsmf) mediates NMDA receptor endocytosis in GnRH neuronal cells. NMDA receptor is involved in myoblast differentiation by regulating Ca-2 (+) dependent fusion of myocytes. In this study, we investigated the role of Nsmf in myoblast proliferation and differentiation. Quantitative-PCR, immunoblotting, and immunohistochemistry results showed that the Nsmf expression levels increased during both the differentiation and proliferation of myocytes. Knockdown of Nsmf in myocytes by siRNA did not affect the myocyte differentiation marker myogenin. However, flow cytometry showed that the proliferation rate of the Nsmf-knockdown cells was reduced compared to the control cells. Therefore, our results indicate that Nsmf is a novel myogenic factor that can enhance myoblast proliferation. Furthermore, Nsmf may be an important therapeutic target in diseases associated with aging, muscular dystrophy, or cachexia. C1 [Moon, Hyo Youl] Pohang Univ Sci & Technol, Sch Interdisciplinary Biosci & Bioengn, Pohang 790784, South Korea. [Moon, Hyo Youl] NIA, Neuroplast & Behav Unit, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Moon, Hyo Youl] NIA, Res Resources Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Moon, HY (reprint author), Pohang Univ Sci & Technol, Sch Interdisciplinary Biosci & Bioengn, Pohang 790784, South Korea. EM hymoon@postech.ac.kr FU Korea Health Technology R&D Project through Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI13C1149] FX This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI13C1149). NR 19 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 EI 1543-706X J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD JAN PY 2015 VL 51 IS 1 BP 79 EP 84 DI 10.1007/s11626-014-9811-9 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CA6AF UT WOS:000348989700011 PM 25248434 ER PT J AU Orsega, S AF Orsega, Susan TI Adult HIV Infection Treatment Update 2014: An Approach to HIV Infection Management and Antiretroviral Treatment SO JNP-JOURNAL FOR NURSE PRACTITIONERS LA English DT Article DE adherence; antiretroviral therapy; HIV management; HIV/AIDS ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLINICAL-OUTCOMES; NEVIRAPINE USE; THERAPY; RISK; AIDS; SOCIETY; HAART AB It is critically important to keep up with the continuous advances in HIV treatment. With the key understanding of viral replication, combination therapy, treatment failure, and drug toxicities, the nurse practitioner has the knowledge to assist in monitoring the HIV patient. The purpose of this article is to provide an overview of the general principles of HIV disease and antiretroviral therapy, clarify the nurse practitioners role in how to manage patients receiving these medications, and present useful guidelines. C1 NIAID, United States Publ Hlth Serv, NIH, Bethesda, MD 20892 USA. RP Orsega, S (reprint author), NIAID, United States Publ Hlth Serv, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM susan.orsega@nih.gov NR 32 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1555-4155 EI 1878-058X J9 JNP-J NURSE PRACT JI JNP-J. Nurse Pract. PD JAN PY 2015 VL 11 IS 1 BP 95 EP 102 DI 10.1016/j.nurpra.2014.10.034 PG 8 WC Nursing SC Nursing GA CA1TS UT WOS:000348694900018 ER PT J AU Hartman, HN Niemela, J Hintermeyer, MK Garofalo, M Stoddard, J Verbsky, JW Rosenzweig, SD Routes, JM AF Hartman, Heather N. Niemela, Julie Hintermeyer, Mary K. Garofalo, Mary Stoddard, Jennifer Verbsky, James W. Rosenzweig, Sergio D. Routes, John M. TI Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE PIK3CD; immunodeficiency; primary sclerosing cholangitis; recurrent infections ID HYPER-IGM SYNDROME AB Gain of function (GOF) mutation in the p110 delta catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) is the cause of a primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections and lymphoproliferation. We describe a family of two adults and three children with GOF mutation in PIK3CD, all with recurrent sinopulmonary infections and varied infectious and non-infectious complications. The two adults have Primary Sclerosing Cholangitis (PSC) without evidence of Cryptosporidium parvum infection and have required liver transplantation. PSC is a novel phenotype of GOF mutation in PIK3CD. C1 [Hartman, Heather N.; Verbsky, James W.; Routes, John M.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Hartman, Heather N.; Routes, John M.] Med Coll Wisconsin, Div Allergy Clin Immunol, Milwaukee, WI 53226 USA. [Hintermeyer, Mary K.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Garofalo, Mary; Rosenzweig, Sergio D.] NIH, Primary Immunodeficiency Clin, Bethesda, MD 20892 USA. [Verbsky, James W.] Med Coll Wisconsin, Div Rheumatol, Milwaukee, WI 53226 USA. [Routes, John M.] Med Coll Wisconsin, MACC Fund Res Ctr, Milwaukee, WI 53226 USA. RP Rosenzweig, SD (reprint author), NIH, Primary Immunodeficiency Clin, 10 Ctr Dr,Clin Ctr,2C410F, Bethesda, MD 20892 USA. EM srosenzweig@cc.nih.gov; jroutes@mcw.edu OI Niemela, Julie/0000-0003-4197-3792 FU Intramural NIH HHS [Z99 CL999999] NR 11 TC 9 Z9 10 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JAN PY 2015 VL 35 IS 1 BP 11 EP 14 DI 10.1007/s10875-014-0109-1 PG 4 WC Immunology SC Immunology GA CA3KR UT WOS:000348805600002 PM 25352054 ER PT J AU Brohl, AS Stinson, JR Su, HC Badgett, T Jennings, CD Sukumar, G Sindiri, S Wang, W Kardava, L Moir, S Dalgard, CL Moscow, JA Khan, J Snow, AL AF Brohl, Andrew S. Stinson, Jeffrey R. Su, Helen C. Badgett, Thomas Jennings, Chester D. Sukumar, Gauthaman Sindiri, Sivasish Wang, Wei Kardava, Lela Moir, Susan Dalgard, Clifton L. Moscow, Jeffrey A. Khan, Javed Snow, Andrew L. TI Germline CARD11 Mutation in a Patient with Severe Congenital B Cell Lymphocytosis SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE CARD11; B-cell lymphocytosis; congenital; NF-kappa B; BENTA ID NF-KAPPA-B; COMBINED IMMUNODEFICIENCY; CYCLIN G2; LYMPHOMA; PROLIFERATION; DOMAIN; GENES; COOPERATION; EXPRESSION; PROTEIN AB Activating germline mutations in CARD11 have recently been linked to a rare genetic disorder associated with congenital B cell lymphocytosis. We describe a patient with a similar clinical phenotype who had a de novo germline G123D CARD11 mutation. Whole exome sequencing was performed on DNA from the patient and his biological parents. Laboratory studies examined characteristics of the patient's B and T lymphocytes. A CARD11 cDNA containing the mutation was transfected into a lymphocyte cell line to gain an understanding of its function. RNA sequencing was performed on samples from the patient and from patients with alternate germline CARD11 mutations and differential gene expression analysis was performed. The patient had a decade-long history of severe polyclonal B lymphocytosis in the 20,000-90,000 lymphocytes/mm(3) range, which was markedly exacerbated by EBV infection and splenectomy at different times. He had a heterozygous germline CARD11 mutation causing a G123D amino acid substitution, which was demonstrated to induce NF-kappa B activation in unstimulated lymphocytes. In contrast to previous patients with CARD11 mutations, this patient's B cells exhibited higher expression of several cell cycle progression genes, as well as enhanced proliferation and improved survival following B cell receptor stimulation. This is the third reported germline and first de novo CARD11 mutation shown to cause congenital B cell lymphocytosis. The mutation was associated with a dramatically greater lymphocytosis than in previously described cases, disproportionate to the level of constitutive NF-kappa B activation. However, comparative review of the patient's clinical history, combined with additional genomic and functional analyses, underscore other important variables that may affect pathophysiology or regulate mutant CARD11 function in B cell proliferation and disease. We now refer to these patients as having BENTA disease (B cell Expansion with NF-kappa B and T cell Anergy). C1 [Brohl, Andrew S.; Sindiri, Sivasish; Khan, Javed] NCI, Ctr Canc Res, NIH, Oncogen Sect Genet Branch, Bethesda, MD 20892 USA. [Stinson, Jeffrey R.; Snow, Andrew L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Su, Helen C.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Badgett, Thomas; Moscow, Jeffrey A.] Univ Kentucky, Dept Pediat, Lexington, KY USA. [Badgett, Thomas; Moscow, Jeffrey A.] Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY USA. [Jennings, Chester D.] Univ Kentucky, Coll Med, Dept Pathol, Lexington, KY USA. [Sukumar, Gauthaman; Dalgard, Clifton L.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Wang, Wei; Kardava, Lela; Moir, Susan] NIAID, Immunoregulat Lab, NIH, Immunopathogenesis Sect, Bethesda, MD 20892 USA. RP Khan, J (reprint author), NCI, Ctr Canc Res, NIH, Oncogen Sect Genet Branch, 37 Convent Dr,Bldg 37,Room 2016B, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov; andrew.snow@usuhs.edu RI Su, Helen/H-9541-2015; Khan, Javed/P-9157-2014; OI Su, Helen/0000-0002-5582-9110; Khan, Javed/0000-0002-5858-0488; sindiri, sivasish/0000-0003-2516-969X; Snow, Andrew/0000-0002-8728-6691 FU Intramural NIH HHS; NIAID NIH HHS [R21 AI109187] NR 30 TC 8 Z9 8 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JAN PY 2015 VL 35 IS 1 BP 32 EP 46 DI 10.1007/s10875-014-0106-4 PG 15 WC Immunology SC Immunology GA CA3KR UT WOS:000348805600006 PM 25352053 ER PT J AU Swenor, BK Simonsick, EM Ferrucci, L Newman, AB Rubin, S Wilson, V AF Swenor, Bonnielin K. Simonsick, Eleanor M. Ferrucci, Luigi Newman, Anne B. Rubin, Susan Wilson, Valerie CA Hlth Aging Body Composition Study TI Visual Impairment and Incident Mobility Limitations: The Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE visual impairment; mobility; physical functioning ID SALISBURY EYE EVALUATION; OLDER-ADULTS; CONTRAST SENSITIVITY; PHYSICAL FUNCTION; UNITED-STATES; SEE PROJECT; PERFORMANCE; PREVALENCE; RELIABILITY; ASSOCIATION AB ObjectivesTo examine the association between multiple measures of visual impairment (VI) and incident mobility limitations in older adults. DesignProspective observational cohort study. SettingMemphis, Tennessee, and Pittsburgh, Pennsylvania. ParticipantsHealth, Aging and Body Composition study participants aged 70 to 79 without mobility limitations at the Year 3 visit (N=1,862). MeasurementsVision was measured at the Year 3 visit, and VI was defined as distance visual acuity (VA) worse than 20/40, contrast sensitivity (CS) less than 1.55 log Contrast, and stereoacuity (SA) greater than 85 arcsec. Incident persistent walking and stair climbing limitation was defined as two consecutive 6-month reports of any difficulty walking one-quarter of a mile or walking up 10 steps after 1, 3, and 5years of follow-up. ResultsAt Year 3 (baseline for these analyses), 7.4% had impaired VA, 27.2% had impaired CS, and 29.2% had impaired SA. At all follow-up times, the incidence of walking and stair climbing limitations was higher in participants with VA, CS, or SA impairment. After 5years, impaired CS and SA were independently associated with greater risk of walking limitation (hazard ratio (HR)(CS)= 1.3, 95% confidence interval (CI)=1.1-1.7; HRSA=1.3, 95% CI=1.1-1.6) and stair climbing limitation (HRCS= 1.4, 95% CI=1.1-1.8; HRSA=1.3, 95% CI=1.1-1.7). Having impaired CS and SA was associated with greater risk of mobility limitations (HRwalking limitations=2.0, 95% CI=1.6-2.5; HRstair limitation= 2.1, 95% CI=1.6-2.8). ConclusionMultiple aspects of VI may contribute to mobility limitations in older adults. Addressing more than one component of vision may be needed to reduce the effect of vision impairment on functional decline. C1 [Swenor, Bonnielin K.; Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Longitudinal Study Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Rubin, Susan] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Wilson, Valerie] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Swenor, BK (reprint author), NIA, NIH, Harbor Hosp NM 538, 3001 S Hanover St, Baltimore, MD 21225 USA. EM bonnie.swenor@nih.gov RI Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; National Institute of Nursing Research Grant [R01-NR012459]; Intramural Research Program of the National Institutes of Health, NIA FX This research was 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 National Institute of Nursing Research Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 29 TC 7 Z9 7 U1 3 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 JAN PY 2015 VL 63 IS 1 BP 46 EP 54 DI 10.1111/jgs.13183 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AZ7BW UT WOS:000348374200006 PM 25536849 ER PT J AU Lo-Ciganic, WH Perera, S Gray, SL Boudreau, RM Zgibor, JC Strotmeyer, ES Donohue, JM Bunker, CH Newman, AB Simonsick, EM Bauer, DC Satterfield, S Caserotti, P Harris, T Shorr, RI Hanlon, JT AF Lo-Ciganic, Wei-Hsuan Perera, Subashan Gray, Shelly L. Boudreau, Robert M. Zgibor, Janice C. Strotmeyer, Elsa S. Donohue, Julie M. Bunker, Clareann H. Newman, Anne B. Simonsick, Eleanor M. Bauer, Douglas C. Satterfield, Suzanne Caserotti, Paolo Harris, Tamara Shorr, Ronald I. Hanlon, Joseph T. CA Hlth Aging Body Composition Study TI Statin Use and Decline in Gait Speed in Community-Dwelling Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE hydroxymethylglutaryl-CoA reductase inhibitors; statins; gait speed; physical function; aged ID PERIPHERAL ARTERIAL-DISEASE; COA REDUCTASE INHIBITORS; PHYSICAL PERFORMANCE; HEALTH; ATORVASTATIN; CHOLESTEROL; PREDICTOR; SYMPTOMS; THERAPY; PEOPLE AB ObjectivesTo examine the association between statin use and objectively assessed decline in gait speed in community-dwelling older adults. DesignLongitudinal cohort study. SettingHealth, Aging and Body Composition (Health ABC) Study. ParticipantsTwo thousand five participants aged 70-79 at baseline with medication and gait speed data at 1998-99, 1999-2000, 2001-02, and 2002-03. MeasurementsThe independent variables were any statin use and their standardized daily doses (low, moderate, high) and lipophilicity. The primary outcome measure was decline in gait speed of 0.1m/s or more in the following year of statin use. Multivariable generalized estimating equations were used, adjusting for demographic characteristics, health-related behaviors, health status, and access to health care. ResultsStatin use increased from 16.2% in 1998-99 to 25.6% in 2002-03. The overall proportions of those with decline in gait speed of 0.1m/s or more increased from 22.2% in 1998 to 23.9% in 2003. Statin use was not associated with decline in gait speed of 0.1m/s or more (adjusted odds ratio (AOR)=0.90, 95% confidence interval (CI)=0.77-1.06). Similar nonsignificant trends were also seen with the use of hydrophilic or lipophilic statins. Users of low-dose statins were found to have a 22% lower risk of decline in gait speed than nonusers (AOR=0.78, 95% CI=0.61-0.99), which was mainly driven by the results from 1999-2000 follow-up. ConclusionThese results suggest that statin use did not increase decline in gait speed in community-dwelling older adults. C1 [Lo-Ciganic, Wei-Hsuan; Hanlon, Joseph T.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Hlth Policy Inst, Pittsburgh, PA 15261 USA. [Perera, Subashan; Newman, Anne B.; Hanlon, Joseph T.] Univ Pittsburgh, Div Geriatr, Dept Med, Sch Med, Pittsburgh, PA 15261 USA. [Gray, Shelly L.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Boudreau, Robert M.; Zgibor, Janice C.; Strotmeyer, Elsa S.; Bunker, Clareann H.; Newman, Anne B.; Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Donohue, Julie M.] Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Simonsick, Eleanor M.; Harris, Tamara] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Sch Med, Div Gen Med, San Francisco, CA USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Caserotti, Paolo] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Shorr, Ronald I.] North Florida South Georgia Vet Hlth Syst, Geriatr Res Educ & Clin Ctr, Gainesville, FL USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Lo-Ciganic, WH (reprint author), Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, 130 DeSoto St,A636, Pittsburgh, PA 15261 USA. EM wel32@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036; Boudreau, Robert/0000-0003-0162-5187; Donohue, Julie/0000-0003-2418-6017 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 grants [R01-HS017695, R01-HS018721]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported 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, N01-AG-6-2106), National Institute of Nursing Research grants (R01-NR010135, R01-NR012459), Agency for Healthcare Research and Quality grants (R01-HS017695, R01-HS018721), and the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 30 TC 3 Z9 3 U1 0 U2 1 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 JAN PY 2015 VL 63 IS 1 BP 124 EP 129 DI 10.1111/jgs.13134 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AZ7BW UT WOS:000348374200017 PM 25537649 ER PT J AU Glynn, NW Santanasto, AJ Simonsick, EM Boudreau, RM Beach, SR Schulz, R Newman, AB AF Glynn, Nancy W. Santanasto, Adam J. Simonsick, Eleanor M. Boudreau, Robert M. Beach, Scott R. Schulz, Richard Newman, Anne B. TI The Pittsburgh Fatigability Scale for Older Adults: Development and Validation SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE fatigue; fatigability; performance measures; validation; mobility ID BODY-COMPOSITION; FATIGUE; POPULATION; HEALTH; INTERVENTIONS; ASSOCIATION; MORTALITY; OUTCOMES; FITNESS AB ObjectivesTo describe the development of the Pittsburgh Fatigability Scale (PFS) and establish its reliability and concurrent and convergent validity against performance measures. DesignCross-sectional. SettingUniversity of Pittsburgh, Pittsburgh, Pennsylvania. ParticipantsScale development sample: 1,013 individuals aged 60 and older from two registries; validation sample: 483 adults aged 60 and older from the Baltimore Longitudinal Study of Aging (BLSA). MeasurementsThe scale development sample and BLSA participants self-administered an initial 26-item perceived fatigability scale. BLSA participants also completed measures of performance fatigability (perceived exertion from a standard treadmill task and performance deterioration from a fast-paced long-distance corridor walk), a 6-m usual-paced corridor walk, and five timed chair stands. ResultsPrincipal components analysis with varimax rotation reduced the 26-item scale to the 10-item PFS. The PFS showed strong internal consistency (Cronbach's alpha 0.88) and excellent test-retest reliability (intraclass correlation 0.86). In the validation sample, PFS scores, adjusted for age, sex, and race, were greater for those with high performance fatigability, slow gait speed, worse physical function, and lower fitness, with differences between high and low fatigability ranging from 3.2 to 5.1 points (P<.001). ConclusionThe 10-item PFS physical fatigability score is a valid and reliable measure of perceived fatigability in older adults and can serve as an adjunct to performance-based fatigability measures for identifying older adults at risk of mobility limitation in clinical and research settings. C1 [Glynn, Nancy W.; Santanasto, Adam J.; Boudreau, Robert M.; Newman, Anne B.] Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Beach, Scott R.; Schulz, Richard] Univ Pittsburgh, Univ Ctr Social & Urban Res, Pittsburgh, PA 15261 USA. [Schulz, Richard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15261 USA. RP Glynn, NW (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, 130 DeSoto St,A531 Crabtree Hall, Pittsburgh, PA 15261 USA. EM glynnn@edc.pitt.edu RI Newman, Anne B./C-6408-2013; OI Newman, Anne B./0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187; Glynn, Nancy/0000-0003-2265-0162 FU Pittsburgh Claude D. Pepper Older Americans Independence Center Developmental Pilot Grant [NIH P30 AG024826]; Intramural Research Program, National Institute on Aging FX This research was funded by Pittsburgh Claude D. Pepper Older Americans Independence Center Developmental Pilot Grant NIH P30 AG024826 and the Intramural Research Program, National Institute on Aging. NR 25 TC 9 Z9 9 U1 1 U2 11 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 JAN PY 2015 VL 63 IS 1 BP 130 EP 135 DI 10.1111/jgs.13191 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AZ7BW UT WOS:000348374200018 PM 25556993 ER PT J AU Schonberg, MA Breslau, ES AF Schonberg, Mara A. Breslau, Erica S. TI Mammography Screening for Women Aged 70 and Older: At a Crossroads SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID BREAST-CANCER INCIDENCE; FOLLOW-UP; SURVIVAL; COMORBIDITY; DIAGNOSIS; OUTCOMES; TIME C1 [Schonberg, Mara A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gen Med & Primary Care,Dept Med, Boston, MA 02215 USA. [Breslau, Erica S.] NCI, Proc Care Res Branch, Behav Res Program, NIH, Bethesda, MD 20892 USA. RP Schonberg, MA (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gen Med & Primary Care,Dept Med, Boston, MA 02215 USA. FU NCI NIH HHS [R01 CA181357] NR 19 TC 0 Z9 0 U1 3 U2 3 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 JAN PY 2015 VL 63 IS 1 BP 170 EP 172 DI 10.1111/jgs.13189 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AZ7BW UT WOS:000348374200024 PM 25597565 ER PT J AU Gale, PJ Yergey, AL Duncan, MW Yu, K AF Gale, P. Jane Yergey, Alfred L. Duncan, Mark W. Yu, Kate TI Quantifying Small Molecules by Mass Spectrometry SO LC GC NORTH AMERICA LA English DT Article C1 [Gale, P. Jane] RCA Labs, New York, NY USA. [Gale, P. Jane] Bristol Myers Squibb Co, New York, NY 10154 USA. [Duncan, Mark W.] Biodesix Inc, Boulder, CO USA. [Yergey, Alfred L.] Rice Univ, Dept Chem, Houston, TX 77251 USA. [Yergey, Alfred L.] NICHD, NIH, Rockville, MD USA. [Yergey, Alfred L.] Sect Metab Anal & Mass Spectrometry, Bethesda, MD USA. [Yergey, Alfred L.] Inst Mass Spectrometry Facility, Bethesda, MD USA. RP Yu, K (reprint author), LC MS Technol, St Louis, MO 63122 USA. EM lcgcedit@lcgcmag.com NR 6 TC 0 Z9 0 U1 4 U2 8 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1527-5949 EI 1939-1889 J9 LC GC N AM JI LC GC N. AM. PD JAN PY 2015 VL 33 IS 1 BP 34 EP 41 PG 8 WC Chemistry, Analytical SC Chemistry GA CA0XL UT WOS:000348636700005 ER PT J AU Milenic, DE Baidoo, KE Kim, YS Brechbiel, MW AF Milenic, Diane E. Baidoo, Kwamena E. Kim, Young-Seung Brechbiel, Martin W. TI Evaluation of cetuximab as a candidate for targeted alpha-particle radiation therapy of HER1-positive disseminated intraperitoneal disease SO MABS LA English DT Article DE radioimmunotherapy; -particle; Pb-212; cetuximab; HER1; mAb; monoclonal antibody; RIT; radioimmunotherapy; EGFR; epidermal growth factor receptor; HulgG; human immunoglobulin; TCMC; 1; 4; 7; 10-tetraaza-1; 4; 7; 10-tetra-(2-carbamoyl methyl)-cyclododecane; BSA; bovine serum albumin; %ID; g; percent injected dose per gram; i; p; intraperitoneal; s; c; subcutaneous; PBS; phosphate-buffered saline; PET; positron emission tomography; MS; median survival ID GROWTH-FACTOR RECEPTOR; DISSEMINATED PERITONEAL DISEASE; SQUAMOUS-CELL CARCINOMA; ANTI-EGFR-ANTIBODY; MONOCLONAL-ANTIBODY; PROSTATE-CANCER; IN-VITRO; COLORECTAL-CANCER; SPECTROPHOTOMETRIC METHOD; PRECLINICAL EVALUATION AB Although the epidermal growth factor receptor (EGFR), also known as HER1, has been studied for over a decade, it continues to be a molecule of great interest and focus of investigators for development of targeted therapies. The marketed monoclonal antibody cetuximab binds to HER1, and thus might serve as the basis for creation of imaging or therapies that target this receptor. The potential of cetuximab as a vehicle for the delivery of -particle radiation was investigated in an intraperitoneal tumor mouse model. The effective working dose of 10Ci of Pb-212-cetuximab was determined from a dose (10-50Ci) escalation study. Toxicity, as indicated by the lack of animal weight loss, was not evident at the 10Ci dose of Pb-212-cetuximab. A subsequent study demonstrated Pb-212-cetuximab had a therapeutic efficacy similar to that of Pb-212-trastuzumab (p = 0.588). Gemcitabine given 24h prior to Pb-212-cetuximab increased the median survival from 174 d to 283 d, but carboplatin suppressed the effectiveness of Pb-212-cetuximab. Notably, concurrent treatment of tumor-bearing mice with Pb-212-labeled cetuximab and trastuzumab provided therapeutic benefit that was greater than either antibody alone. In conclusion, cetuximab proved to be an effective vehicle for targeting HER1-expressing tumors with -radiation for the treatment of disseminated intraperitoneal disease. These studies provide further evidence that the multimodality therapy regimens may have greater efficacy and benefit in the treatment of cancer patients. C1 [Milenic, Diane E.; Baidoo, Kwamena E.; Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Milenic, DE (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM milenicd@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 57 TC 5 Z9 5 U1 2 U2 11 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD JAN-FEB PY 2015 VL 7 IS 1 BP 255 EP 264 DI 10.4161/19420862.2014.985160 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AZ8KC UT WOS:000348463300024 PM 25587678 ER PT J AU Donninger, H Clark, J Rinaldo, F Nelson, N Barnoud, T Schmidt, ML Hobbing, KR Vos, MD Sils, B Clark, GJ AF Donninger, Howard Clark, Jennifer Rinaldo, Francesca Nelson, Nicholas Barnoud, Thibaut Schmidt, M. Lee Hobbing, Katharine R. Vos, Michele D. Sils, Brian Clark, Geoffrey J. TI The RASSF1A Tumor Suppressor Regulates XPA-Mediated DNA Repair SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; PIGMENTOSUM GROUP-A; REPLICATION PROTEIN-A; XERODERMA-PIGMENTOSUM; KNOCKOUT MICE; RAS; PATHWAY; CANCER; DAMAGE; ASSOCIATION AB RASSF1A may be the most frequently inactivated tumor suppressor identified in human cancer so far. It is a proapoptotic Ras effector and plays an important role in the apoptotic DNA damage response (DDR). We now show that in addition to DDR regulation, RASSF1A also plays a key role in the DNA repair process itself. We show that RASSF1A forms a DNA damage-regulated complex with the key DNA repair protein xeroderma pigmentosum A (XPA). XPA requires RASSF1A to exert full repair activity, and RASSF1A-deficient cells exhibit an impaired ability to repair DNA. Moreover, a cancer-associated RASSF1A single-nucleotide polymorphism (SNP) variant exhibits differential XPA binding and inhibits DNA repair. The interaction of XPA with other components of the repair complex, such as replication protein A (RPA), is controlled in part by a dynamic acetylation/deacetylation cycle. We found that RASSF1A and its SNP variant differentially regulate XPA protein acetylation, and the SNP variant hyperstabilizes the XPA-RPA70 complex. Thus, we identify two novel functions for RASSF1A in the control of DNA repair and protein acetylation. As RASSF1A modulates both apoptotic DDR and DNA repair, it may play an important and unanticipated role in coordinating the balance between repair and death after DNA damage. C1 [Donninger, Howard; Clark, Jennifer; Rinaldo, Francesca] Univ Louisville, JG Brown Canc Ctr, Dept Med, Mol Targets Program, Louisville, KY 40292 USA. [Nelson, Nicholas; Barnoud, Thibaut; Schmidt, M. Lee] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. [Hobbing, Katharine R.; Sils, Brian; Clark, Geoffrey J.] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Vos, Michele D.] NCI, NIH, Bethesda, MD 20892 USA. RP Clark, GJ (reprint author), Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. EM gjclar01@louisville.edu FU NCI intramural funds; [1P20 RR18733]; [NIH R01 CA133171] FX The work was supported by awards 1P20 RR18733, NIH R01 CA133171, and NCI intramural funds (G.J.C.). NR 53 TC 8 Z9 8 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2015 VL 35 IS 1 BP 277 EP 287 DI 10.1128/MCB.00202-14 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB0CL UT WOS:000349292400022 PM 25368379 ER PT J AU Paul, E Zhu, ZI Landsman, D Morse, RH AF Paul, Emily Zhu, Z. Iris Landsman, David Morse, Randall H. TI Genome-Wide Association of Mediator and RNA Polymerase II in Wild-Type and Mediator Mutant Yeast SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; CONTAINING GENES; COMPLEX; EXPRESSION; PROMOTER; BINDING; PROTEIN; MODULE AB Mediator is a large, multisubunit complex that is required for essentially all mRNA transcription in eukaryotes. In spite of the importance of Mediator, the range of its targets and how it is recruited to these is not well understood. Previous work showed that in Saccharomyces cerevisiae, Mediator contributes to transcriptional activation by two distinct mechanisms, one depending on the tail module triad and favoring SAGA-regulated genes, and the second occurring independently of the tail module and favoring TFIID-regulated genes. Here, we use chromatin immunoprecipitation sequencing (ChIP-seq) to show that dependence on tail module subunits for Mediator recruitment and polymerase II (Pol II) association occurs preferentially at SAGA-regulated over TFIID-regulated genes on a genome-wide scale. We also show that recruitment of tail module subunits to active gene promoters continues genome-wide when Mediator integrity is compromised in med17 temperature-sensitive (ts) yeast, demonstrating the modular nature of the Mediator complex in vivo. In addition, our data indicate that promoters exhibiting strong and stable occupancy by Mediator have a wide range of activity and are enriched for targets of the Tup1-Cyc8 repressor complex. We also identify a number of strong Mediator occupancy peaks that overlap dubious open reading frames (ORFs) and are likely to include previously unrecognized upstream activator sequences. C1 [Paul, Emily; Morse, Randall H.] New York State Dept Hlth, Wadsworth Ctr, Mol Genet Lab, Albany, NY USA. [Morse, Randall H.] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY USA. [Zhu, Z. Iris; Landsman, David] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Landsman, D (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM landsman@ncbi.nlm.nih.gov; randall.morse@health.ny.gov OI Morse, Randall/0000-0003-0000-8718; Landsman, David/0000-0002-9819-6675 FU NSF [MCB0949722]; Wadsworth Center; Intramural Research Program of the NIH, NLM, NCBI FX This work was supported by funding from the NSF (MCB0949722 to R. H. M.), the Wadsworth Center, and the Intramural Research Program of the NIH, NLM, NCBI. NR 48 TC 10 Z9 10 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2015 VL 35 IS 1 BP 331 EP 342 DI 10.1128/MCB.00991-14 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB0CL UT WOS:000349292400026 PM 25368384 ER PT J AU Agarwal, S Macfarlan, TS Sartor, MA Iwase, S AF Agarwal, Saurabh Macfarlan, Todd S. Sartor, Maureen A. Iwase, Shigeki TI Sequencing of first-strand cDNA library reveals full-length transcriptomes SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ANALYSIS; MULTIPLEX RNA-SEQ; ESCHERICHIA-COLI; ALTERNATIVE POLYADENYLATION; DIVERGENT TRANSCRIPTION; MAMMALIAN PROMOTERS; EXPRESSION ANALYSIS; ACTIVE PROMOTERS; SINGLE CELLS; POLYMERASE AB Massively parallel strand-specific sequencing of RNA (ssRNA-seq) has emerged as a powerful tool for profiling complex transcriptomes. However, many current methods for ssRNA-seq suffer from the underrepresentation of both the 5' and 3' ends of RNAs, which can be attributed to second-strand cDNA synthesis. The 5' and 3' ends of RNA harbour crucial information for gene regulation; namely, transcription start sites (TSSs) and polyadenylation sites. Here we report a novel ssRNA-seq method that does not involve second-strand cDNA synthesis, as we Directly Ligate sequencing Adaptors to the First-strand cDNA (DLAF). This novel method with fewer enzymatic reactions results in a higher quality of the libraries than the conventional method. Sequencing of DLAF libraries followed by a novel analysis pipeline enables the profiling of both 5' ends and polyadenylation sites at near-base resolution. Therefore, DLAF offers the first genomics tool to obtain the 'full-length' transcriptome with a single library. C1 [Agarwal, Saurabh; Iwase, Shigeki] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Macfarlan, Todd S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Sartor, Maureen A.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Iwase, S (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. EM siwase@umich.edu FU University of Michigan Medical School; Cooley's Anemia Foundation Fellowship; LICR; California Institute for Regenerative Medicine [RN2-00905]; Eunice Kennedy Shriver National Institute of Child Health and Human Development DIR [HD008933] FX We thank Dr Bing Ren at the Ludwig Institute for Cancer Research (LICR), San Diego, for helpful discussions and sequencing of the libraries. We also thank Dr Gary Hon at the LICR, San Diego, for helpful discussions and guidance with bioinformatics. We are grateful to Drs Jacob L. Mueller and John Kim in the Department of Human Genetics at the University of Michigan for their critical readings and suggestions for the manuscript. The work was supported by grants from the University of Michigan Medical School (to S.I.), Cooley's Anemia Foundation Fellowship (to S.I.), the LICR (to B.R.), the California Institute for Regenerative Medicine (RN2-00905 to B.R.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development DIR (HD008933 to T.S.M.). NR 57 TC 2 Z9 2 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 JAN PY 2015 VL 6 AR 6002 DI 10.1038/ncomms7002 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3NB UT WOS:000348812400003 PM 25607527 ER PT J AU Igartua, C Myers, RA Mathias, RA Pino-Yanes, M Eng, C Graves, PE Levin, AM Del-Rio-Navarro, BE Jackson, DJ Livne, OE Rafaels, N Edlund, CK Yang, JJ Huntsman, S Salam, MT Romieu, I Mourad, R Gern, JE Lemanske, RF Wyss, A Hoppin, JA Barnes, KC Burchard, EG Gauderman, WJ Martinez, FD Raby, BA Weiss, ST Williams, LK London, SJ Gilliland, FD Nicolae, DL Ober, C AF Igartua, Catherine Myers, Rachel A. Mathias, Rasika A. Pino-Yanes, Maria Eng, Celeste Graves, Penelope E. Levin, Albert M. Del-Rio-Navarro, Blanca E. Jackson, Daniel J. Livne, Oren E. Rafaels, Nicholas Edlund, Christopher K. Yang, James J. Huntsman, Scott Salam, Muhammad T. Romieu, Isabelle Mourad, Raphael Gern, James E. Lemanske, Robert F. Wyss, Annah Hoppin, Jane A. Barnes, Kathleen C. Burchard, Esteban G. Gauderman, W. James Martinez, Fernando D. Raby, Benjamin A. Weiss, Scott T. Williams, L. Keoki London, Stephanie J. Gilliland, Frank D. Nicolae, Dan L. Ober, Carole TI Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; MTHFR C677T POLYMORPHISM; MISSING HERITABILITY; LOCI; METAANALYSIS; POPULATION; EXPRESSION; GENES; RISK; DISEASE AB Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P = 4.31 x 10(-6); OR = 1.25; MAF = 1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P = 7.81 x 10(-8) and 4.09 x 10(-8), respectively) and MTHFR in the African ancestry sample (P = 1.72 x 10(-6)). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the 'missing heritability' of asthma. C1 [Igartua, Catherine; Myers, Rachel A.; Livne, Oren E.; Mourad, Raphael; Nicolae, Dan L.; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Mathias, Rasika A.; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. [Pino-Yanes, Maria; Eng, Celeste; Huntsman, Scott; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pino-Yanes, Maria] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid 28029, Spain. [Graves, Penelope E.; Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ 85721 USA. [Graves, Penelope E.; Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ 85721 USA. [Levin, Albert M.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Del-Rio-Navarro, Blanca E.] Hosp Infantil Mexico Dr Federico Gomez, Mexico City 06720, DF, Mexico. [Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53726 USA. [Rafaels, Nicholas] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21224 USA. [Edlund, Christopher K.; Salam, Muhammad T.; Gauderman, W. James; Gilliland, Frank D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Yang, James J.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48202 USA. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon, France. [Gern, James E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Internal Med, Madison, WI 53726 USA. [Lemanske, Robert F.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53726 USA. [Wyss, Annah; Hoppin, Jane A.; London, Stephanie J.] NIEHS, Div Intramural Res, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27607 USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Raby, Benjamin A.; Weiss, Scott T.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Raby, Benjamin A.] Harvard Univ, Sch Med, Div Pulm & Crit Care Med, Boston, MA USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI 48202 USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI 48202 USA. [Nicolae, Dan L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Nicolae, Dan L.] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. RP Ober, C (reprint author), Univ Chicago, Dept Human Genet, 920 East 58th St,CLSC 425, Chicago, IL 60637 USA. EM c-ober@bsd.uchicago.edu RI Pino-Yanes, Maria/C-8498-2017; OI Pino-Yanes, Maria/0000-0003-0332-437X; London, Stephanie/0000-0003-4911-5290 FU NIH [RC2 HL10165, P30 ES007048, P01 ES009581, P0 1ES01162, R01 HL118267, R01 AI079139]; Intramural Research Program of the NIH (NIEHS) [Z01 CP010119, Z01 ES049030, ES102385]; American Asthma Foundation; Hastings Foundation; Fund for Henry Ford Hospital; Computation Institute; Biological Sciences Division of the University of Chicago; Argonne National Laboratory [S10 RR029030-01]; Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government from the National Heart, Lung and Blood Institute [HHSN268201100037C]; Molecular Genomics Core at the University of Southern California [P30ES007048, P01ES009581]; Center for Inherited Disease Research at Johns Hopkins University; Fundacion Ramon Areces; National Institutes of Health [T32 GM007197]; Ruth L. Kirschstein National Research Service Award [PA-11-112]; Mary Beryl Patch Turnbull Scholar Program FX This work was supported by NIH grants RC2 HL10165, P30 ES007048, P01 ES009581, P0 1ES01162, R01 HL118267 and R01 AI079139, the Intramural Research Program of the NIH (NIEHS Z01 CP010119, Z01 ES049030 and ES102385), the American Asthma Foundation, the Hastings Foundation, the Fund for Henry Ford Hospital and through resources provided by the Computation Institute and the Biological Sciences Division of the University of Chicago and Argonne National Laboratory (S10 RR029030-01). Genotyping services were provided by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government contract number HHSN268201100037C from the National Heart, Lung and Blood Institute, and the Molecular Genomics Core at the University of Southern California (P30ES007048 and P01ES009581) and the Center for Inherited Disease Research at Johns Hopkins University. M.P.-Y. was funded by a Postdoctoral Fellowship from Fundacion Ramon Areces. C.I. was supported by National Institutes of Health Grant T32 GM007197 and by the Ruth L. Kirschstein National Research Service Award (PA-11-112). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. NR 46 TC 13 Z9 13 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2015 VL 6 AR 5965 DI 10.1038/ncomms6965 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3MO UT WOS:000348811100009 PM 25591454 ER PT J AU Kucuk, C Jiang, B Hu, XZ Zhang, WY Chan, JKC Xiao, WM Lack, N Alkan, C Williams, JC Avery, KN Kavak, P Scuto, A Sen, E Gaulard, P Staudt, L Iqbal, J Zhang, WW Cornish, A Gong, Q Yang, QP Sun, H d'Amore, F Leppa, S Liu, WP Fu, K de Leval, L McKeithan, T Chan, WC AF Kucuk, Can Jiang, Bei Hu, Xiaozhou Zhang, Wenyan Chan, John K. C. Xiao, Wenming Lack, Nathan Alkan, Can Williams, John C. Avery, Kendra N. Kavak, Pinar Scuto, Anna Sen, Emel Gaulard, Philippe Staudt, Lou Iqbal, Javeed Zhang, Weiwei Cornish, Adam Gong, Qiang Yang, Qunpei Sun, Hong d'Amore, Francesco Leppa, Sirpa Liu, Weiping Fu, Kai de Leval, Laurence McKeithan, Timothy Chan, Wing C. TI Activating mutations of STAT5B and STAT3 in lymphomas derived from gamma delta-T or NK cells SO NATURE COMMUNICATIONS LA English DT Article ID GRANULAR LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENE; SEQUENCING DATA; EXPRESSION; MALIGNANCIES; NEOPLASMS; FREQUENT; PATHOGENESIS; DISORDERS; LANDSCAPE AB Lymphomas arising from NK or gamma delta-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n - 51), gamma delta-T-cell lymphomas (n - 43) and their cell lines (n = 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gamma delta-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy. C1 [Kucuk, Can; Jiang, Bei; Hu, Xiaozhou; Scuto, Anna; McKeithan, Timothy; Chan, Wing C.] City Hope Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Zhang, Wenyan; Yang, Qunpei; Sun, Hong; Liu, Weiping; Fu, Kai] Sichuan Univ, West China Hosp, Dept Pathol, Chengdu 610041, Peoples R China. [Chan, John K. C.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Xiao, Wenming] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Rockville, MD 20857 USA. [Lack, Nathan; Sen, Emel] Koc Univ, Dept Pharmacol, TR-34450 Istanbul, Turkey. [Alkan, Can] Bilkent Univ, Dept Comp Engn, TR-06800 Ankara, Turkey. [Williams, John C.; Avery, Kendra N.] Beckman Res Inst City Hope, Dept Mol Med, Duarte, CA 91010 USA. [Kavak, Pinar] Bogazici Univ, Dept Comp Engn, TR-34342 Istanbul, Turkey. [Gaulard, Philippe] Univ Paris Est, INSERM, U955, Dept Pathol,Grp Henri Mondor Albert Chenevier, F-94000 Creteil, France. [Staudt, Lou] NCI, Ctr Canc Res, Mol Biol Lymphoid Malignancies Sect, Bethesda, MD 20892 USA. [Iqbal, Javeed; Zhang, Weiwei] Univ Nebraska, Ctr Med, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Cornish, Adam] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. [Gong, Qiang] Chinese Acad Sci, Beijing Inst Genom, Beijing 100029, Peoples R China. [d'Amore, Francesco] Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark. [Leppa, Sirpa] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki 00029, Finland. [de Leval, Laurence] Univ Pathol, Pathol Clin Inst, CH-1011 Lausanne, Switzerland. RP Chan, WC (reprint author), City Hope Med Ctr, Dept Pathol, Duarte, CA 91010 USA. EM jochan@coh.org RI Alkan, Can/D-2982-2009; Kucuk, Can/K-3913-2015; OI Alkan, Can/0000-0002-5443-0706; Kucuk, Can/0000-0001-5540-9012; McKeithan, Timothy/0000-0003-2242-3074; Leppa, Sirpa/0000-0002-8265-511X NR 44 TC 47 Z9 48 U1 8 U2 23 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 JAN PY 2015 VL 6 AR 6025 DI 10.1038/ncomms7025 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3TP UT WOS:000348829800003 PM 25586472 ER PT J AU Petkov, CI Kikuchi, Y Milne, AE Mishkin, M Rauschecker, JP Logothetis, NK AF Petkov, Christopher I. Kikuchi, Yukiko Milne, Alice E. Mishkin, Mortimer Rauschecker, Josef P. Logothetis, Nikos K. TI Different forms of effective connectivity in primate frontotemporal pathways SO NATURE COMMUNICATIONS LA English DT Article ID SUPERIOR TEMPORAL SULCUS; PARABELT AUDITORY-CORTEX; PREFRONTAL CORTEX; RHESUS-MONKEY; ELECTRICAL MICROSTIMULATION; MACAQUE MONKEYS; FRONTAL-CORTEX; FUNCTIONAL NETWORK; CEREBRAL-CORTEX; COMPLEX SOUNDS AB It is generally held that non-primary sensory regions of the brain have a strong impact on frontal cortex. However, the effective connectivity of pathways to frontal cortex is poorly understood. Here we microstimulate sites in the superior temporal and ventral frontal cortex of monkeys and use functional magnetic resonance imaging to evaluate the functional activity resulting from the stimulation of interconnected regions. Surprisingly, we find that, although certain earlier stages of auditory cortical processing can strongly activate frontal cortex, downstream auditory regions, such as voice-sensitive cortex, appear to functionally engage primarily an ipsilateral temporal lobe network. Stimulating other sites within this activated temporal lobe network shows strong activation of frontal cortex. The results indicate that the relative stage of sensory processing does not predict the level of functional access to the frontal lobes. Rather, certain brain regions engage local networks, only parts of which have a strong functional impact on frontal cortex. C1 [Petkov, Christopher I.; Kikuchi, Yukiko; Milne, Alice E.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Petkov, Christopher I.; Logothetis, Nikos K.] Max Planck Inst Biol Cybernet, Dept Physiol Cognit Proc, D-72076 Tubingen, Germany. [Kikuchi, Yukiko; Mishkin, Mortimer] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Kikuchi, Yukiko; Rauschecker, Josef P.] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. [Logothetis, Nikos K.] Univ Manchester, Div Imaging Sci & Biomed Engn, Manchester M13 9PT, Lancs, England. [Rauschecker, Josef P.] Tech Univ Munich, Inst Adv Study, D-85748 Garching, Germany. RP Petkov, CI (reprint author), Newcastle Univ, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM chris.petkov@ncl.ac.uk RI Petkov, Christopher/O-5318-2015 OI Petkov, Christopher/0000-0002-4932-7907 FU Max Planck Society; Alexander von Humboldt Foundation; Wellcome Trust Investigator Award [WT102961MA]; NSF [PIRE OISE-0730255]; NIMH, NIH; [NIH-R01DC003489]; [NIH-R56NS052494] FX We thank M. Augath for MRI experimental support and R. Saunders and D. Yu for invaluable assistance with histological processing. T. Griffiths, M. Kaiser, L. Orton, C. Perrodin, A. Rees, L. Romanski, K. Saleem, B. Scott and B. Wilson provided helpful comments on or discussion of the manuscript. Support provided by Max Planck Society (N.K.L.); Alexander von Humboldt Foundation (C.I.P.); Wellcome Trust Investigator Award WT102961MA (C.I.P.); NIH-R01DC003489 (J.P.R.), NIH-R56NS052494 (J.P.R.); NSF PIRE OISE-0730255 (J.P.R.); NIMH, NIH (M.M.). NR 61 TC 11 Z9 11 U1 0 U2 14 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 JAN PY 2015 VL 6 AR 6000 DI 10.1038/ncomms7000 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3NB UT WOS:000348812400001 PM 25613079 ER PT J AU Venditti, V Tugarinov, V Schwieters, CD Grishaev, A Clore, GM AF Venditti, Vincenzo Tugarinov, Vitali Schwieters, Charles D. Grishaev, Alexander Clore, G. Marius TI Large interdomain rearrangement triggered by suppression of micro- to millisecond dynamics in bacterial Enzyme I SO NATURE COMMUNICATIONS LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; MOLECULAR-WEIGHT PROTEINS; N-TERMINAL DOMAIN; X-RAY-SCATTERING; ESCHERICHIA-COLI; NMR-SPECTROSCOPY; SUBSTRATE-BINDING; BIOLOGICAL MACROMOLECULES; ALPHA-KETOGLUTARATE; CHEMICAL-EXCHANGE AB Enzyme I (EI), the first component of the bacterial phosphotransfer signal transduction system, undergoes one of the largest substrate-induced interdomain rearrangements documented to date. Here we characterize the perturbations generated by two small molecules, the natural substrate phosphoenolpyruvate and the inhibitor alpha-ketoglutarate, on the structure and dynamics of EI using NMR, small-angle X-ray scattering and biochemical techniques. The results indicate unambiguously that the open-to-closed conformational switch of EI is triggered by complete suppression of micro-to millisecond dynamics within the C-terminal domain of EI. Indeed, we show that a ligand-induced transition from a dynamic to a more rigid conformational state of the C-terminal domain stabilizes the interface between the N- and C-terminal domains observed in the structure of the closed state, thereby promoting the resulting conformational switch and autophosphorylation of EI. The mechanisms described here may be common to several other multidomain proteins and allosteric systems. C1 [Venditti, Vincenzo; Tugarinov, Vitali; Grishaev, Alexander; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov FU US Department of Energy [W-31-109-ENG-38]; NCI [PUP-77]; NIH [PUP-77]; Argonne National Laboratory; NIH Intramural Programs of NIDDK; CIT; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank S. Seifert and X. Zuo for assistance with SAXS data collection and gratefully acknowledge use of the Advanced Photon Source, supported by the US Department of Energy, contract no. W-31-109-ENG-38, and the shared scattering beamline resource allocated under the PUP-77 agreement between NCI, NIH and the Argonne National Laboratory. This work was supported by funds from the NIH Intramural Programs of NIDDK (to G.M.C.) and CIT (to C.D.S.) and from the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 43 TC 5 Z9 5 U1 0 U2 10 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 JAN PY 2015 VL 6 AR 5960 DI 10.1038/ncomms6960 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3MO UT WOS:000348811100004 PM 25581904 ER PT J AU Wessel, J Chu, AY Willems, SM Wang, S Yaghootkar, H Brody, JA Dauriz, M Hivert, MF Raghavan, S Lipovich, L Hidalgo, B Fox, K Huffman, JE An, P Lu, YC Rasmussen-Torvik, LJ Grarup, N Ehm, MG Li, L Baldridge, AS Stancakova, A Abrol, R Besse, CL Boland, A Bork-Jensen, J Fornage, M Freitag, DF Garcia, ME Guo, XQ Hara, K Isaacs, A Jakobsdottir, J Lange, LA Layton, JC Li, M Zhao, JH Meidtner, K Morrison, AC Nalls, MA Peters, MJ Sabater-Lleal, M Schurmann, C Silveira, A Smith, AV Southam, L Stoiber, MH Strawbridge, RJ Taylor, KD Varga, TV Allin, KH Amin, N Aponte, JL Aung, T Barbieri, C Bihlmeyer, NA Boehnke, M Bombieri, C Bowden, DW Burns, SM Chen, YN Chen, YD Cheng, CY Correa, A Czajkowski, J Dehghan, A Ehret, GB Eiriksdottir, G Escher, SA Farmaki, AE Franberg, M Gambaro, G Giulianini, F Goddard, WA Goel, A Gottesman, O Grove, ML Gustafsson, S Hai, Y Hallmans, G Heo, J Hoffmann, P Ikram, MK Jensen, RA Jorgensen, ME Jorgensen, T Karaleftheri, M Khor, CC Kirkpatrick, A Kraja, AT Kuusisto, J Lange, EM Lee, IT Lee, WJ Leong, A Liao, JM Liu, CY Liu, YM Lindgren, CM Linneberg, A Malerba, G Mamakou, V Marouli, E Maruthur, NM Matchan, A McKean-Cowdin, R McLeod, O Metcalf, GA Mohlke, KL Muzny, DM Ntalla, I Palmer, ND Pasko, D Peter, A Rayner, NW Renstrom, F Rice, K Sala, CF Sennblad, B Serafetinidis, I Smith, JA Soranzo, N Speliotes, EK Stahl, EA Stirrups, K Tentolouris, N Thanopoulou, A Torres, M Traglia, M Tsafantakis, E Javad, S Yanek, LR Zengini, E Becker, DM Bis, JC Brown, JB Cupples, LA Hansen, T Ingelsson, E Karter, AJ Lorenzo, C Mathias, RA Norris, JM Peloso, GM Sheu, WHH Toniolo, D Vaidya, D Varma, R Wagenknecht, LE Boeing, H Bottinger, EP Dedoussis, G Deloukas, P Ferrannini, E Franco, OH Franks, PW Gibbs, RA Gudnason, V Hamsten, A Harris, TB Hattersley, AT Hayward, C Hofman, A Jansson, JH Langenberg, C Launer, LJ Levy, D Oostra, BA O'Donnell, CJ O'Rahilly, S Padmanabhan, S Pankow, JS Polasek, O Province, MA Rich, SS Ridker, PM Rudan, I Schulze, MB Smith, BH Uitterlinden, AG Walker, M Watkins, H Wong, TY Zeggini, E Laakso, M Borecki, IB Chasman, DI Pedersen, O Psaty, BM Tai, ES van Duijn, CM Wareham, NJ Waterworth, DM Boerwinkle, E Kao, WHL Florez, JC Loos, RJF Wilson, JG Frayling, TM Siscovick, DS Dupuis, J Rotter, JI Meigs, JB Scott, RA Goodarzi, MO Sharp, SJ Forouhi, NG Kerrison, ND Lucarelli, DM Sims, M Barroso, I McCarthy, MI Arriola, L Balkau, B Barricarte, A Gonzalez, C Grioni, S Kaaks, R Key, TJ Navarro, C Nilsson, PM Overvad, K Palli, D Panico, S Quiros, JR Rolandsson, O Sacerdote, C Sanchez, MJ Slimani, N Tjonneland, A Tumino, R van der A, DL van der Schouw, YT Riboli, E AF Wessel, Jennifer Chu, Audrey Y. Willems, Sara M. Wang, Shuai Yaghootkar, Hanieh Brody, Jennifer A. Dauriz, Marco Hivert, Marie-France Raghavan, Sridharan Lipovich, Leonard Hidalgo, Bertha Fox, Keolu Huffman, Jennifer E. An, Ping Lu, Yingchang Rasmussen-Torvik, Laura J. Grarup, Niels Ehm, Margaret G. Li, Li Baldridge, Abigail S. Stancakova, Alena Abrol, Ravinder Besse, Celine Boland, Anne Bork-Jensen, Jette Fornage, Myriam Freitag, Daniel F. Garcia, Melissa E. Guo, Xiuqing Hara, Kazuo Isaacs, Aaron Jakobsdottir, Johanna Lange, Leslie A. Layton, Jill C. Li, Man Zhao, Jing Hua Meidtner, Karina Morrison, Alanna C. Nalls, Mike A. Peters, Marjolein J. Sabater-Lleal, Maria Schurmann, Claudia Silveira, Angela Smith, Albert V. Southam, Lorraine Stoiber, Marcus H. Strawbridge, Rona J. Taylor, Kent D. Varga, Tibor V. Allin, Kristine H. Amin, Najaf Aponte, Jennifer L. Aung, Tin Barbieri, Caterina Bihlmeyer, Nathan A. Boehnke, Michael Bombieri, Cristina Bowden, Donald W. Burns, Sean M. Chen, Yuning Chen, Yii-Deri Cheng, Ching-Yu Correa, Adolfo Czajkowski, Jacek Dehghan, Abbas Ehret, Georg B. Eiriksdottir, Gudny Escher, Stefan A. Farmaki, Aliki-Eleni Franberg, Mattias Gambaro, Giovanni Giulianini, Franco Goddard, William A., III Goel, Anuj Gottesman, Omri Grove, Megan L. Gustafsson, Stefan Hai, Yang Hallmans, Goeran Heo, Jiyoung Hoffmann, Per Ikram, Mohammad K. Jensen, Richard A. Jorgensen, Marit E. Jorgensen, Torben Karaleftheri, Maria Khor, Chiea C. Kirkpatrick, Andrea Kraja, Aldi T. Kuusisto, Johanna Lange, Ethan M. Lee, I. T. Lee, Wen-Jane Leong, Aaron Liao, Jiemin Liu, Chunyu Liu, Yongmei Lindgren, Cecilia M. Linneberg, Allan Malerba, Giovanni Mamakou, Vasiliki Marouli, Eirini Maruthur, Nisa M. Matchan, Angela McKean-Cowdin, Roberta McLeod, Olga Metcalf, Ginger A. Mohlke, Karen L. Muzny, Donna M. Ntalla, Ioanna Palmer, Nicholette D. Pasko, Dorota Peter, Andreas Rayner, Nigel W. Renstroem, Frida Rice, Ken Sala, Cinzia F. Sennblad, Bengt Serafetinidis, Ioannis Smith, Jennifer A. Soranzo, Nicole Speliotes, Elizabeth K. Stahl, Eli A. Stirrups, Kathleen Tentolouris, Nikos Thanopoulou, Anastasia Torres, Mina Traglia, Michela Tsafantakis, Emmanouil Javad, Sundas Yanek, Lisa R. Zengini, Eleni Becker, Diane M. Bis, Joshua C. Brown, James B. Cupples, L. Adrienne Hansen, Torben Ingelsson, Erik Karter, Andrew J. Lorenzo, Carlos Mathias, Rasika A. Norris, Jill M. Peloso, Gina M. Sheu, Wayne H. -H. Toniolo, Daniela Vaidya, Dhananjay Varma, Rohit Wagenknecht, Lynne E. Boeing, Heiner Bottinger, Erwin P. Dedoussis, George Deloukas, Panos Ferrannini, Ele Franco, Oscar H. Franks, Paul W. Gibbs, Richard A. Gudnason, Vilmundur Hamsten, Anders Harris, Tamara B. Hattersley, Andrew T. Hayward, Caroline Hofman, Albert Jansson, Jan-Hakan Langenberg, Claudia Launer, Lenore J. Levy, Daniel Oostra, Ben A. O'Donnell, Christopher J. O'Rahilly, Stephen Padmanabhan, Sandosh Pankow, James S. Polasek, Ozren Province, Michael A. Rich, Stephen S. Ridker, Paul M. Rudan, Igor Schulze, Matthias B. Smith, Blair H. Uitterlinden, Andre G. Walker, Mark Watkins, Hugh Wong, Tien Y. Zeggini, Eleftheria Laakso, Markku Borecki, Ingrid B. Chasman, Daniel I. Pedersen, Oluf Psaty, Bruce M. Tai, E. Shyong van Duijn, Cornelia M. Wareham, Nicholas J. Waterworth, Dawn M. Boerwinkle, Eric Kao, W. H. Linda Florez, Jose C. Loos, Ruth J. F. Wilson, James G. Frayling, Timothy M. Siscovick, David S. Dupuis, Josee Rotter, Jerome I. Meigs, James B. Scott, Robert A. Goodarzi, Mark O. Sharp, Stephen J. Forouhi, Nita G. Kerrison, Nicola D. Lucarelli, Debora M. E. Sims, Matt Barroso, Ines McCarthy, Mark I. Arriola, Larraitz Balkau, Beverley Barricarte, Aurelio Gonzalez, Carlos Grioni, Sara Kaaks, Rudolf Key, Timothy J. Navarro, Carmen Nilsson, Peter M. Overvad, Kim Palli, Domenico Panico, Salvatore Quiros, J. Ramon Rolandsson, Olov Sacerdote, Carlotta Sanchez, Maria-Jose Slimani, Nadia Tjonneland, Anne Tumino, Rosario van der A, Daphne L. van der Schouw, Yvonne T. Riboli, Elio CA The EPIC-InterAct Consortium TI Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility SO NATURE COMMUNICATIONS LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; GENOME-WIDE ASSOCIATION; RECEPTOR GENE; TRIGLYCERIDE LEVELS; GERMLINE MUTATIONS; INSULIN-RESISTANCE; CODING VARIATION; GLYCEMIC TRAITS; SEQUENCING DATA; PLASMA-GLUCOSE AB Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. C1 [Wessel, Jennifer] Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA. [Wessel, Jennifer] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Chu, Audrey Y.; Giulianini, Franco; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chu, Audrey Y.; Huffman, Jennifer E.; Liu, Chunyu; Cupples, L. Adrienne; O'Donnell, Christopher J.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Willems, Sara M.; Isaacs, Aaron; Amin, Najaf; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus Univ, Ctr Med, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CE Rotterdam, Netherlands. [Willems, Sara M.; Zhao, Jing Hua; Javad, Sundas; Langenberg, Claudia; Wareham, Nicholas J.; Scott, Robert A.; Sharp, Stephen J.; Forouhi, Nita G.; Kerrison, Nicola D.; Lucarelli, Debora M. E.; Sims, Matt] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0SL, England. [Wang, Shuai; Chen, Yuning; Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Yaghootkar, Hanieh; Pasko, Dorota; Hattersley, Andrew T.; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Brody, Jennifer A.; Jensen, Richard A.; Rice, Ken; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Brody, Jennifer A.; Fox, Keolu; Jensen, Richard A.; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Dauriz, Marco; Raghavan, Sridharan; Leong, Aaron; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dauriz, Marco; Raghavan, Sridharan; Leong, Aaron; O'Donnell, Christopher J.; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dauriz, Marco] Univ Verona, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, I-37126 Verona, Italy. [Dauriz, Marco] Hosp Trust Verona, I-37126 Verona, Italy. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Div Endocrinol & Metab, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France; Burns, Sean M.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA. [Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48202 USA. [Hidalgo, Bertha] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA. [Fox, Keolu] Univ Washington, Dept Gen Sci, Seattle, WA 98195 USA. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, MRC IGMM, MRC Human Genet, Edinburgh EH4 2XU, Midlothian, Scotland. [An, Ping; Czajkowski, Jacek; Kraja, Aldi T.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Lu, Yingchang; Hara, Kazuo; Isaacs, Aaron; Schurmann, Claudia; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Hara, Kazuo; Schurmann, Claudia; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Rasmussen-Torvik, Laura J.; Baldridge, Abigail S.] Northwestern Univ Feinberg, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Grarup, Niels; Bork-Jensen, Jette; Allin, Kristine H.; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Med & Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark. [Stancakova, Alena] Univ Eastern Finland, Inst Clin Med, FI-70211 Kuopio, Finland. [Abrol, Ravinder; Goodarzi, Mark O.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Abrol, Ravinder; Goodarzi, Mark O.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Abrol, Ravinder; Goddard, William A., III; Kirkpatrick, Andrea] CALTECH, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA. [Besse, Celine; Boland, Anne] CEA, Ctr Natl Genotypage, Inst Genom, F-91057 Evry, France. [Fornage, Myriam] Univ Texas Houston, Hlth Sci Ctr, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Freitag, Daniel F.; Southam, Lorraine; Matchan, Angela; Rayner, Nigel W.; Soranzo, Nicole; Stirrups, Kathleen; Zeggini, Eleftheria; Barroso, Ines] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Freitag, Daniel F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England. [Garcia, Melissa E.; Harris, Tamara B.; Launer, Lenore J.] Natl Inst Aging, Intramural Res Program, Bethesda, MD 21224 USA. [Guo, Xiuqing; Taylor, Kent D.; Chen, Yii-Deri; Hai, Yang; Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Jakobsdottir, Johanna; Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Lange, Leslie A.; Lange, Ethan M.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Layton, Jill C.] Indiana Univ, Fairbanks Sch Publ Hlth, Indianapolis, IN 46202 USA. [Li, Man; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Meidtner, Karina; Schulze, Matthias B.] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, DE-14558 Nuthetal, Germany. [Morrison, Alanna C.; Grove, Megan L.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77225 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Peters, Marjolein J.; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 Rotterdam, Netherlands. [Peters, Marjolein J.] NGI NCHA, NL-2300 RC Leiden, Netherlands. [Sabater-Lleal, Maria; Silveira, Angela; Strawbridge, Rona J.; Franberg, Mattias; McLeod, Olga; Sennblad, Bengt; Hamsten, Anders] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [Southam, Lorraine; Rayner, Nigel W.; McCarthy, Mark I.] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Stoiber, Marcus H.; Brown, James B.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA. [Varga, Tibor V.; Escher, Stefan A.; Renstroem, Frida; Franks, Paul W.; Nilsson, Peter M.] Lund Univ, Skane Univ Hosp, Dept Clin Sci Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden. [Aung, Tin; Cheng, Ching-Yu; Ikram, Mohammad K.; Liao, Jiemin; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Aung, Tin; Cheng, Ching-Yu; Khor, Chiea C.; Liao, Jiemin; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 119228, Singapore. [Aung, Tin; Cheng, Ching-Yu; Khor, Chiea C.; Liao, Jiemin; Wong, Tien Y.] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Barbieri, Caterina; Sala, Cinzia F.; Traglia, Michela; Toniolo, Daniela] San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy. [Bihlmeyer, Nathan A.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD 21205 USA. [Bihlmeyer, Nathan A.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. [Bombieri, Cristina; Malerba, Giovanni] Univ Verona, Dept Life & Reprod Sci, Sect Biol & Genet, I-37100 Verona, Italy. [Bowden, Donald W.; Palmer, Nicholette D.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Cheng, Ching-Yu; Khor, Chiea C.; Tai, E. Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119228, Singapore. [Cheng, Ching-Yu; Khor, Chiea C.; Tai, E. Shyong] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Cheng, Ching-Yu; Ikram, Mohammad K.; Wong, Tien Y.] Natl Univ Singapore, Duke NUS Grad Med Sch, Off Clin Sci, Singapore 169857, Singapore. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 Rotterdam, Netherlands. [Ehret, Georg B.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Ehret, Georg B.] Univ Hosp Geneva, Div Cardiol, CH-1211 Geneva, Switzerland. [Farmaki, Aliki-Eleni; Marouli, Eirini; Ntalla, Ioanna; Dedoussis, George] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens 17671, Greece. [Franberg, Mattias] Stockholm Univ, Dept Numer Anal & Comp Sci, Sci Life Lab, SE-10691 Stockholm, Sweden. [Gambaro, Giovanni] Catholic Univ, Columbus Gemelli Univ Hosp, Dept Internal Med & Med Specialties, Div Nephrol, I-00168 Rome, Italy. [Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX3 7BN, England. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, SE-75185 Uppsala, Sweden. [Hallmans, Goeran; Rolandsson, Olov] Umea Univ, Dept Biobank Res, SE-90187 Umea, Sweden. [Heo, Jiyoung] Sangmyung Univ, Dept Biomed Technol, Chungnam 330720, South Korea. [Hoffmann, Per] Univ Bonn, Life & Brain Ctr, Inst Human Genet, Dept Genom, DF-53127 Bonn, Germany. [Hoffmann, Per] Univ Basel Hosp, Dept Biomed, Div Med Genet, Human Genom Res Grp, CH-4031 Basel, Switzerland. [Hoffmann, Per] Genom Imaging Res Ctr Juelich, Inst Neurosci & Med INM 1, DE-52425 Julich, Germany. [Ikram, Mohammad K.] Natl Univ Hlth Syst, MACC, Singapore 117599, Singapore. [Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Jorgensen, Torben; Linneberg, Allan] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [Jorgensen, Torben] Aalborg Univ, Fac Med, DK-9220 Aalborg, Denmark. [Karaleftheri, Maria] Echinos Med Ctr, Fchinos 67300, Greece. [Khor, Chiea C.] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Inst Clin Med, FI-70211 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, FI-70211 Kuopio, Finland. [Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Lee, I. T.; Sheu, Wayne H. -H.] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung 407, Taiwan. [Lee, I. T.; Sheu, Wayne H. -H.] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Lee, Wen-Jane] Taichung Vet Gen Hosp, Dept Med Res, Taichung 407, Taiwan. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27106 USA. [Lindgren, Cecilia M.; Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Linneberg, Allan] Univ Copenhagen, Glostrup Hosp, Dept Clin Expt Res, DK-2600 Glostrup, Denmark. [Linneberg, Allan] Univ Copenhagen, Fac Med & Hlth Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Mamakou, Vasiliki] Univ Athens, Fac Med, Athens 11527, Greece. [Mamakou, Vasiliki; Zengini, Eleni] Dromokaiteio Psychiat Hosp, Athens 12461, Greece. [Maruthur, Nisa M.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Maruthur, Nisa M.; Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [McKean-Cowdin, Roberta; Torres, Mina; Varma, Rohit] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Metcalf, Ginger A.; Muzny, Donna M.; Gibbs, Richard A.; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ntalla, Ioanna] Univ Leicester, Leicester LE1 7RH, Leics, England. [Palmer, Nicholette D.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27106 USA. [Peter, Andreas] Univ Tubingen, Dept Internal Med, Div Endocrinol Metab Pathobiochem & Clin Chem, DE-72076 Tubingen, Germany. [Peter, Andreas] Univ Tubingen, Inst Diabet Res & Metab Dis, DE-72076 Tubingen, Germany. [Peter, Andreas; Schulze, Matthias B.] German Ctr Diabet Res DZD, DE-85764 Neuherberg, Germany. [Rayner, Nigel W.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Sennblad, Bengt] Karolinska Inst, Sci Life Lab, SE-17177 Stockholm, Sweden. [Serafetinidis, Ioannis] Gennimatas Gen Hosp, Dept Gastroenterol, Athens 11527, Greece. [Smith, Jennifer A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Soranzo, Nicole] Dept Hematol, Cambridge CB2 0XY, England. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Stahl, Eli A.] Icahn Sch Med Mt Sinai, Div Psychiat Gen, New York, NY 10029 USA. [Stirrups, Kathleen; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London E1 4NS, England. [Tentolouris, Nikos] Univ Athens, Laiko Gen Hosp, Sch Med, Dept Propaedeut & Internal Med 1, GR-11527 Athens, Greece. [Thanopoulou, Anastasia] Natl Tech Univ Athens, Hippokration Gen Hosp, Ctr Diabet, Dept Internal Med 2nd, Athens 11527, Greece. [Tsafantakis, Emmanouil] Anogia Med Ctr, Anogia 74051, Greece. [Isaacs, Aaron; Yanek, Lisa R.; Becker, Diane M.; Mathias, Rasika A.; Vaidya, Dhananjay] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med,GeneSTAR Res Program, Baltimore, MD 21205 USA. [Zengini, Eleni] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. [Brown, James B.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Hansen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen 1165, Denmark. [Karter, Andrew J.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Lorenzo, Carlos] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 77030 USA. [Norris, Jill M.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80204 USA. [Peloso, Gina M.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Peloso, Gina M.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sheu, Wayne H. -H.] Coll Med, Natl Def Med Ctr, Taipei 114, Taiwan. [Wagenknecht, Lynne E.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27106 USA. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, DE-14558 Nuthetal, Germany. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 22254, Saudi Arabia. [Ferrannini, Ele] CNR, Inst Clin Physiol, I-73100 Pisa, Italy. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, Paul W.; Jansson, Jan-Hakan] Umea Univ, Dept Publ Hlth & Clin Med, SE-90187 Umea, Sweden. [Jansson, Jan-Hakan] Res Unit, SE-93187 Skelleftea, Sweden. [Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [O'Rahilly, Stephen; Barroso, Ines] Univ Cambridge, Metab Res Labs, MRC Metab Dis Unit, Cambridge CB2 1TN, England. [O'Rahilly, Stephen; Barroso, Ines] Addenbrookes Hosp, Wellcome Trust MRC Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 1TN, England. [Padmanabhan, Sandosh] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split 21000, Croatia. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Smith, Blair H.] Univ Dundee, Med Res Inst, Dundee DD1 9SY, Scotland. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117597, Singapore. [van Duijn, Cornelia M.] Ctr Med Syst Biol, NL-2300 Leiden, Netherlands. [Waterworth, Dawn M.] GlaxoSmithKline, PCPS, Genet, Philadelphia, PA 19104 USA. [Kao, W. H. Linda] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Wilson, James G.] Univ Mississippi, Ctr Med, Dept Physiol & Biophys, University, MS 38677 USA. [Siscovick, David S.] New York Acad Med, New York, NY 10029 USA. [Siscovick, David S.] Univ Washington, Dept Med & Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. Oxford NIHR Biomed Res Ctr, Oxford, England. [Arriola, Larraitz] Publ Hlth Div Gipuzkoa, San Sebastian, Spain. [Arriola, Larraitz] Basque Govt, Inst BIO Donostia, San Sebastian, Spain. [Arriola, Larraitz; Barricarte, Aurelio; Navarro, Carmen; Sanchez, Maria-Jose] CIBERESP, Barcelona, Spain. [Balkau, Beverley] INSERM, CESP, U1018, Villejuif, France. [Balkau, Beverley] Univ Paris Sud, UMRS 1018, Villejuif, France. [Barricarte, Aurelio] Navarre Publ Hlth Inst ISPN, Pamplona, Spain. [Gonzalez, Carlos] Catalan Inst Oncol ICO, Barcelona, Spain. [Grioni, Sara] Epidemiol & Prevent Unit, Milan, Italy. [Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Navarro, Carmen] Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Navarro, Carmen] Univ Murcia, Sch Med, Unit Prevent Med & Publ Hlth, Murcia, Spain. [Overvad, Kim] Univ Aarhus, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark. [Overvad, Kim] Aalborg Univ Hosp, Aalborg, Denmark. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Florence, Italy. [Panico, Salvatore] Univ Naples Federico II, Dipt Med Clin & Chirurg, Naples, Italy. [Quiros, J. Ramon] Publ Hlth Directorate, Asturias, Spain. [Sacerdote, Carlotta] Univ Turin, Citta Salute & Sci Hosp, Canc Epidemiol Unit, Turin, Italy. [Sacerdote, Carlotta] Ctr Canc Prevent CPO, Turin, Italy. [Sacerdote, Carlotta] Human Genet Fdn HuGeF, Turin, Italy. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada, Spain. [Sanchez, Maria-Jose] Inst Invest Biosanitaria Granada Granada ibs, Granada, Spain. [Slimani, Nadia] Int Agcy Res Canc, F-69372 Lyon, France. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Tumino, Rosario] ASP Ragusa, Ragusa, Italy. [Tumino, Rosario] Aire Onlus, Ragusa, Italy. [van der A, Daphne L.] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Riboli, Elio] Imperial Coll London, Sch Publ Hlth, London, England. RP Wessel, J (reprint author), Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA. EM robert.scott@mrc-epid.cam.ac.uk; mark.goodarzi@cshs.org RI Grioni, Sara/K-5320-2016; SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Grarup, Niels/K-2807-2015; Gudnason, Vilmundur/K-6885-2015; Polasek, Ozren/B-6002-2011; Smith, Albert/K-5150-2015; Schurmann, Claudia/L-1204-2016; Deloukas, Panos/B-2922-2013; Padmanabhan, Sandosh/S-3963-2016; Dauriz, Marco/S-5843-2016; OI Hattersley, Andrew/0000-0001-5620-473X; Dehghan, Abbas/0000-0001-6403-016X; Linneberg, Allan/0000-0002-0994-0184; Sabater Lleal, Maria/0000-0002-0128-379X; Schulze, Matthias B./0000-0002-0830-5277; Sacerdote, Carlotta/0000-0002-8008-5096; Forouhi, Nita/0000-0002-5041-248X; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Khor, Chiea Chuen/0000-0002-1128-4729; Varga, Tibor/0000-0002-2383-699X; Smith, Blair/0000-0002-5362-9430; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Tai, E Shyong/0000-0003-2929-8966; Pankow, James/0000-0001-7076-483X; Strawbridge, Rona/0000-0001-8506-3585; Malerba, Giovanni/0000-0001-8705-8560; THANOPOULOU, ANASTASIA/0000-0002-2902-8053; Peters, Marjolein/0000-0003-3167-9063; Padmanabhan, Sandosh/0000-0003-3869-5808; Zeggini, Eleftheria/0000-0003-4238-659X; Wessel, Jennifer/0000-0002-7031-0085; Grioni, Sara/0000-0002-5891-8426; SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Grarup, Niels/0000-0001-5526-1070; Franks, Paul/0000-0002-0520-7604; Soranzo, Nicole/0000-0003-1095-3852; Gudnason, Vilmundur/0000-0001-5696-0084; Polasek, Ozren/0000-0002-5765-1862; Smith, Albert/0000-0003-1942-5845; Schurmann, Claudia/0000-0003-4158-9192; Deloukas, Panos/0000-0001-9251-070X; Dauriz, Marco/0000-0002-5542-5941; Meidtner, Karina/0000-0001-5810-4062 FU NIH through the American Recovery and Reinvestment Act [5RC2HL102419]; Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL103612, HL068986, N02-HL-6-4278]; CHARGE infrastructure grant [HL105756]; LDRD [14-200, 4R00HG006698-03]; NIA [N01-AG-12100, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; NEI; NIDCD; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-95159, N01-HC-95169, RR-024156]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, U01-HG004729, R01-HL093029, R01-HL084099]; NIH Roadmap for Medical Research; National Heart, Lung, and Blood Institute; University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging; Chinese-American Eye Study (CHES) [EY017337]; Research to Prevent Blindness; Genetics of Latinos Diabetic Retinopathy (GOLDR) [EY14684]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne, Switzerland; Swiss National Science Foundation [3200B0-105993, 33CSCO-122661]; GlaxoSmithKline (Drug Discovery-Verona, RD); Medical Research Council UK; Ministry of Science, Education and Sport in the Republic of Croatia [108-1080315-0302]; South West NHS Research and Development; Exeter NHS Research and Development; Darlington Trust; Peninsula NIHR Clinical Research Facility at the University of Exeter; European Research Council [SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC, ERC-2011-StG 280559-SEPI]; German Federal Ministry of Education and Research (BMBF); Federal Ministry of Science, Germany [01 EA 9401]; European Union [SOC 95201408 05 F02]; German Cancer Aid [70-2488-Ha I]; European Community [SOC 98200769 05 F02]; Netherlands Organization for Scientific Research (NWO); NWO; Russian Foundation for Basic research [047.016.009, 047.017.043]; Erasmus MC; Centre for Medical Systems Biology (CMSB; National Genomics Initiative); ZonMw [91111025]; NIH from NHLBI [R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-8925601, R01-DK-075681]; Medical Research Council [MC_U106179471, G0700931]; Wellcome Trust [098051, WT098051, WT091310, 084723/Z/08/Z]; National Heart, Lung and Blood Institute Division of Intramural Research; National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, R01DK079888, P30DK063491]; NIDDK [K24 DK080140]; American Diabetes Association Mentor-Based Postdoctoral Fellowship [7-09-MN-32]; Canadian Diabetes Association Research Fellowship Award; University of Verona, Italy; NIDDK Research Career Award [K23 DK65978]; Massachusetts General Hospital Physician Scientist Development Award; Doris Duke Charitable Foundation Clinical Scientist Development Award; Swedish Heart-Lung Foundation; Umea Medical Research Foundation; Vasterbotten County Council; NIH grants through the National Heart, Lung, and Blood Institute [HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, HL112064, HL087698]; National Institute of Nursing Research [NR0224103]; U.S. Federal Government from the National Heart, Lung, and Blood Institute [HHSN268201100037C]; Novo Nordisk; Swedish Research Council; Pahlssons Foundation; Heart Foundation of Northern Sweden; Swedish Heart Lung Foundation; Skane Regional Health Authority; Swedish Diabetes Association; Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]; Scottish Funding Council; Faculty of Biology and Medicine of Lausanne; Intramural Research Program of the NIH, National Institute on Aging [Z01 AG000949-02, Z01 AG007390-07]; Timber Merchant Vilhelm Bang's Foundation; Danish Heart Foundation [07-10-R61-A1754-B838-22392F]; Health Insurance Foundation (Helsefonden) [2012B233]; EU FP7 [257082, HEALTH-F5-2011-282510]; Danish Research Council; Danish Centre for Health Technology Assessment; Novo Nordisk Inc.; Research Foundation of Copenhagen County; Ministry of Internal Affairs and Health; Danish Heart Foundation; Danish Pharmaceutical Association; Augustinus Foundation; Ib Henriksen Foundation; Becket Foundation; Danish Diabetes Association; Lundbeck Foundation; Novo Nordisk Foundation; EU FP6 programme [LSHM_CT_2006_037197]; Andrea and Charles Bronfman Philanthropies; Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai; National Institute of Diabetes and Digestive and Kidney Diseases [HL060944, HL061019, HL060919, HL047887, HL047889, HL047890, HL47902]; National Heart, Lung and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; NHLBI of the National Institutes of Health [R01HL107816]; National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; British Heart Foundation [SP/04/002]; National Institute for Health Research [RP-PG-0407-10371]; United States Environmental Protection Agency (EPA) [RD83169701]; National Center for Advancing Translational Sciences [UL1-TR000124]; Cedars-Sinai Winnick Clinical Scholars Award; Academy of Finland [77299, 124243]; NIH [DK062370, DK093757, DK072193]; Diabetes UK; Magnus Bergvall Foundation; Foundation for Old Servants; Tore Nilsson foundation; Fredrik and Ingrid Thuring foundation; Ake-wiberg Foundation; Karolinska Institutet Foundation; Swedish e-science Research Center (SeRC); EU [QLG1-CT-2001-01252]; AstraZeneca (Sweden); European Union grant [QLG1-CT-2001-01252]; AstraZeneca; Boehringer-Ingelheim; LillyCo; Research Institute for Diseases in the Elderly [014-93-015; RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810]; CHANCES [242244]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; NWO grant veni (veni) [916.12.154]; EUR Fellowship; Foundation for Strategic Research; Swedish Research Council [8691, 12660, 20653]; European Commission [LSHM-CT-2007-037273]; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet; Stockholm County Council [560183]; National Medical Research Council (NMRC), Singapore [0796/2003, IRG07nov013, IRG09nov014, NMRC 1176/2008, STaR/0003/2008, CG/SERI/2010]; Biomedical Research Council (BMRC), Singapore [08/1/35/19/550, 09/1/35/19/616]; European Union (European Social Fund-ESF); National Strategic Reference Framework (NSRF); Uppsala University; Knut och Alice Wallenberg Foundation; European Research Council; Swedish Diabetes Foundation [2013-024]; Swedish Heart-Lung Foundation [20120197]; Wellcome Trust Research Career Development Fellowship [086596/Z/08/Z]; Fondazione Compagnia di San Paolo-Torino; Fondazione Cariplo-Milano; Italian Ministry of Health Progetto Finalizzato; Italian Ministry of Health Progetto [CCM 2010, PRIN 2009]; National Heart, Lung, and Blood Institute [HL043851, HL080467]; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Fondation Leducq; [HL120393]; [UL1RR025005]; [M01-RR000052]; [DK081350]; [HG007112]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL071258]; [R01HL071259] FX CHARGE: Funding support for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium' was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Sequence data for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium' was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). Further support came from HL120393, 'Rare variants and NHLBI traits in deeply phenotyped cohorts' (Bruce Psaty, principal investigator). Supporting funding was also provided by NHLBI with the CHARGE infrastructure grant HL105756. In addition, M.J.P. was supported through the 2014 CHARGE Visiting Fellow grant-HL105756, Dr Bruce Psaty, PI.; ENCODE: ENCODE collaborators Ben Brown and Marcus Stoiber were supported by the LDRD# 14-200 (B.B. and M.S.) and 4R00HG006698-03 (B.B.) grants.; AGES: This study has been funded by NIA contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).; ARIC: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; CARDIA: The CARDIA Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Exome chip genotyping and data analyses were funded in part by grants U01-HG004729, R01-HL093029 and R01-HL084099 from the National Institutes of Health to Dr Myriam Fornage. This manuscript has been reviewed by CARDIA for scientific content.; CHES: This work was supported in part by The Chinese-American Eye Study (CHES) grant EY017337, an unrestricted departmental grant from Research to Prevent Blindness, and the Genetics of Latinos Diabetic Retinopathy (GOLDR) Study grant EY14684.; CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL103612, HL068986 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; The CoLaus Study: We thank the co-primary investigators of the CoLaus study, Gerard Waeber and Peter Vollenweider, and the PI of the PsyColaus Study Martin Preisig. We gratefully acknowledge Yolande Barreau, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for their role in the CoLaus data collection. The CoLaus study was supported by research grants from GlaxoSmithKline and from the Faculty of Biology and Medicine of Lausanne, Switzerland. The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (#3200B0-105993) and from GlaxoSmithKline (Drug Discovery-Verona, R&D).; CROATIA-Korcula: The CROATIA-Korcula study would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. Exome array genotyping was performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. The CROATIA-Korcula study on the Croatian island of Korucla was supported through grants from the Medical Research Council UK and the Ministry of Science, Education and Sport in the Republic of Croatia (number 108-1080315-0302).; EFSOCH: We are extremely grateful to the EFSOCH study participants and the EFSOCH study team. The opinions given in this paper do not necessarily represent those of NIHR, the NHS or the Department of Health. The EFSOCH study was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust, and the Peninsula NIHR Clinical Research Facility at the University of Exeter. Timothy Frayling, PI, is supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC.; EPIC-Potsdam: We thank all EPIC-Potsdam participants for their invaluable contribution to the study. The study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). The recruitment phase of the EPIC-Potsdam study was supported by the Federal Ministry of Science, Germany (01 EA 9401) and the European Union (SOC 95201408 05 F02). The follow-up of the EPIC-Potsdam study was supported by German Cancer Aid (70-2488-Ha I) and the European Community (SOC 98200769 05 F02). Furthermore, we thank Ellen Kohlsdorf for data management as well as the follow-up team headed by Dr Manuala Bergmann for case ascertainment.; ERF: The ERF study was supported by grants from the Netherlands Organization for Scientific Research (NWO) and a joint grant from NWO and the Russian Foundation for Basic research (Pionier, 047.016.009, 047.017.043), Erasmus MC, and the Centre for Medical Systems Biology (CMSB; National Genomics Initiative). Exome sequencing analysis in ERF was supported by the ZonMw grant (91111025).; For the ERF Study, we are grateful to all participants and their relatives, to general practitioners and neurologists for their contributions, to P. Veraart for her help in genealogy and to P. Snijders for his help in data collection.; FamHS: The Family Heart Study (FamHS) was supported by NIH grants R01-HL-087700 and R01-HL-088215 (Michael A. Province, PI) from NHLBI; and R01-DK-8925601 and R01-DK-075681 (Ingrid B. Borecki, PI) from NIDDK.; FENLAND: The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust.; FHS: Genotyping, quality control and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O'Donnell, Principle Investigators). A portion of this research was conducted using the Linux Clusters for Genetic Analysis (LinGA) computing resources at Boston University Medical Campus. Also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616, NIDDK K24 DK080140 and American Diabetes Association Mentor-Based Postdoctoral Fellowship Award #7-09-MN-32, all to Dr Meigs, a Canadian Diabetes Association Research Fellowship Award to Dr Leong, a research grant from the University of Verona, Italy to Dr Dauriz, and NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist Development Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr Florez.; FIA3: We are indebted to the study participants who dedicated their time and samples to these studies. We thank Asa Agren (Umea Medical Biobank) for data organization and Kerstin Enquist and Thore Johansson (Vasterbottens County Council) for technical assistance with DNA extraction. This particular project was supported by project grants from the Swedish Heart-Lung Foundation, Umea Medical Research Foundation and Vasterbotten County Council.; The Genetics Epidemiology of Metabolic Syndrome (GEMS) Study: We thank Metabolic Syndrome GEMs investigators: Scott Grundy, Jonathan Cohen, Ruth McPherson, Antero Kesaniemi, Robert Mahley, Tom Bersot, Philip Barter and Gerard Waeber. We gratefully acknowledge the contributions of the study personnel at each of the collaborating sites: John Farrell, Nicholas Nikolopoulos and Maureen Sutton (Boston); Judy Walshe, Monica Prentice, Anne Whitehouse, Julie Butters and Tori Nicholls (Australia); Heather Doelle, Lynn Lewis and Anna Toma (Canada); Kari Kervinen, Seppo Poykko, Liisa Mannermaa and Sari Paavola (Finland); Claire Hurrel, Diane Morin, Alice Mermod, Myriam Genoud and Roger Darioli (Switzerland); Guy Pepin, Sibel Tanir, Erhan Palaoglu, Kerem Ozer, Linda Mahley and Aysen Agacdiken (Turkey); and Deborah A. Widmer, Rhonda Harris and Selena Dixon (United States). Funding for the GEMS study was provided by GlaxoSmithKline.; GeneSTAR: The Johns Hopkins Genetic Study of Atherosclerosis Risk (GeneSTAR) Study was supported by NIH grants through the National Heart, Lung, and Blood Institute (HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, HL112064, and HL087698) and the National Institute of Nursing Research (NR0224103) and by M01-RR000052 to the Johns Hopkins General Clinical Research Center. Genotyping services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute.; GLACIER: We are indebted to the study participants who dedicated their time, data and samples to the GLACIER Study as part of the Vasterbottens halsoundersokningar (Vasterbottens Health Survey). We thank John Hutiainen and Asa Agren (Northern Sweden Biobank) for data organization and Kerstin Enquist and Thore Johansson (Vasterbottens County Council) for extracting DNA. We also thank M. Sterner, M. Juhas and P. Storm (Lund University Diabetes Center) for their expert technical assistance with genotyping and genotype data preparation. The GLACIER Study was supported by grants from Novo Nordisk, the Swedish Research Council, Pahlssons Foundation, The Heart Foundation of Northern Sweden, the Swedish Heart Lung Foundation, the Skane Regional Health Authority, Umea Medical Research Foundation and the Wellcome Trust. This particular project was supported by project grants from the Swedish Heart-Lung Foundation, the Swedish Research Council, the Swedish Diabetes Association, Pahlssons Foundation and Novo nordisk (all grants to P. W. Franks).; GOMAP (Genetic Overlap between Metabolic and Psychiatric Disease): This work was funded by the Wellcome Trust (098051). We thank all participants for their important contribution. We are grateful to Georgia Markou, Laiko General Hospital Diabetes Centre, Maria Emetsidou and Panagiota Fotinopoulou, Hippokratio General Hospital Diabetes Centre, Athina Karabela, Dafni Psychiatric Hospital, Eirini Glezou and Marios Matzioros, Dromokaiteio Psychiatric Hospital, Angela Rentari, Harokopio University of Athens, and Danielle Walker, Wellcome Trust Sanger Institute.; Generation Scotland: Scottish Family Health Study (GS:SFHS): GS:SFHS is funded by the Chief Scientist Office of the Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK and performed at the Wellcome Trust Clinical Research Facility Genetics Core at Western General Hospital, Edinburgh, UK. We also acknowledge the invaluable contributions of the families who took part in the Generation Scotland: Scottish Family Health Study, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. The chief investigators of Generation Scotland are David J. Porteous (University of Edinburgh), Lynne Hocking (University of Aberdeen), Blair Smith (University of Dundee), and Sandosh Padmanabhan (University of Glasgow).; GSK (CoLaus, GEMS, Lolipop): We thank the GEMS Study Investigators: Philip Barter, PhD; Y. Antero Kesaniemi, PhD; Robert W. Mahley, PhD; Ruth McPherson, FRCP; and Scott M. Grundy, PhD. Dr Waeber MD, the CoLaus PI's Peter Vollenweider MD and Gerard Waeber MD, the LOLIPOP PI's, Jaspal Kooner MD and John Chambers MD, as well as the participants in all the studies. The GEMS study was sponsored in part by GlaxoSmithKline. The CoLaus study was supported by grants from GlaxoSmithKline, the Swiss National Science Foundation (Grant 33CSCO-122661) and the Faculty of Biology and Medicine of Lausanne.; Health ABC: The Health, Aging and Body Composition (HABC) Study is supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The exome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Z01 AG000949-02 and Z01 AG007390-07, Human subjects protocol UCSF IRB is H5254-12688-11). Portions of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http:/biowulf.nih.gov).; Health2008: The Health2008 cohort was supported by the Timber Merchant Vilhelm Bang's Foundation, the Danish Heart Foundation (Grant number 07-10-R61-A1754-B838-22392F), and the Health Insurance Foundation (Helsefonden) (Grant number 2012B233).; HELIC: This work was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). The MANOLIS cohort is named in honour of Manolis Giannakakis, 1978-2010. We thank the residents of Anogia and surrounding Mylopotamos villages, and of the Pomak villages, for taking part. The HELIC study has been supported by many individuals who have contributed to sample collection (including Antonis Athanasiadis, Olina Balafouti, Christina Batzaki, Georgios Daskalakis, Eleni Emmanouil, Chrisoula Giannakaki, Margarita Giannakopoulou,; Anastasia Kaparou, Vasiliki Kariakli, Stella Koinaki, Dimitra Kokori, Maria Konidari, Hara Koundouraki, Dimitris Koutoukidis, Vasiliki Mamakou, Eirini Mamalaki, Eirini Mpamiaki, Maria Tsoukana, Dimitra Tzakou, Katerina Vosdogianni, Niovi Xenaki, Eleni Zengini), data entry (Thanos Antonos, Dimitra Papagrigoriou, Betty Spiliopoulou), sample logistics (Sarah Edkins, Emma Gray), genotyping (Robert Andrews, Hannah Blackburn, Doug Simpkin, Siobhan Whitehead), research administration (Anja Kolb-Kokocinski, Carol Smee, Danielle Walker) and informatics (Martin Pollard, Josh Randall).; INCIPE: NIcole Soranzo's research is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510).; Inter99: The Inter99 was initiated by Torben Jorgensen (PI), Knut Borch-Johnsen (co-PI), Hans Ibsen and Troels F. Thomsen. The steering committee comprises the former two and Charlotta Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation and the Danish Diabetes Association. Genetic studies of both Inter99 and Health 2008 cohorts were funded by the Lundbeck Foundation and produced by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp, www.lucamp.org). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).; InterAct Consortium: Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). We thank all EPIC participants and staff for their contribution to the study. We thank the lab team at the MRC Epidemiology Unit for sample management and Nicola Kerrison for data management.; IPM BioMe Biobank: The Mount Sinai IPM BioMe Program is supported by The Andrea and Charles Bronfman Philanthropies. Analyses of BioMe data was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai.; The Insulin Resistance Atherosclerosis Family Study (IRASFS): The IRASFS was conducted and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (HL060944, HL061019, and HL060919). Exome chip genotyping and data analyses were funded in part by grants DK081350 and HG007112. A subset of the IRASFS exome chips were contributed with funds from the Department of Internal Medicine at the University of Michigan. Computing resources were provided, in part, by the Wake Forest School of Medicine Center for Public Health Genomics.; The Insulin Resistance Atherosclerosis Study (IRAS): The IRAS was conducted and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (HL047887, HL047889, HL047890 and HL47902). Exome chip genotyping and data analyses were funded in part by grants DK081350 and HG007112). Computing resources were provided, in part, by the Wake Forest School of Medicine Center for Public Health Genomics.; JHS: The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities. ExomeChip genotyping was supported by the NHLBI of the National Institutes of Health under award number R01HL107816 to S. Kathiresan. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; The London Life Sciences Prospective Population (LOLIPOP) Study: We thank the co-primary investigators of the LOLIPOP study: Jaspal Kooner, John Chambers and Paul Elliott. The LOLIPOP study is supported by the National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0700931), the Wellcome Trust (084723/Z/08/Z) and the National Institute for Health Research (RP-PG-0407-10371).; MESA: The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung, and Blood Institute (NHLBI). Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259. MESA Air is conducted and supported by the United States Environmental Protection Agency (EPA) in collaboration with MESA Air investigators; support is provided by grant RD83169701. We thank the participants of the MESA study, the Coordinating Center, MESA investigators, and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Additional support was provided by the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK079888 and P30DK063491 and the National Center for Advancing Translational Sciences grant UL1-TR000124. Further support came from the Cedars-Sinai Winnick Clinical Scholars Award (to M.O. Goodarzi).; METSIM: The METSIM study was funded by the Academy of Finland (grants no. 77299 and 124243). M.L. acknowledges funding from the Academy of Finland. M.B. and K.M. acknowledge grant funding from NIH grants DK062370, DK093757, DK072193.; MRC Ely: The Ely Study was funded by the Medical Research Council (MC_U106179471) and Diabetes UK. We are grateful to all the volunteers, and to the staff of St Mary's Street Surgery, Ely and the study team.; PROCARDIS: We thank all participants in this study. The European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Oxford British Heart Foundation Centre of Research Excellence, the Wellcome Trust (075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). Bengt Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. Rona J. Strawbridge is supported by the Swedish Heart-Lung Foundation, the Tore Nilsson foundation, the Fredrik and Ingrid Thuring foundation and the Foundation for Old Servants. Maria Sabater-Lleal acknowledges funding from Ake-wiberg, Tore Nilsson and Karolinska Institutet Foundations. Mattias Frnberg acknowledges funding from the Swedish e-science Research Center (SeRC).; RISC: We are extremely grateful to the RISC study participants and the RISC study team. The RISC Study is partly supported by EU grant QLG1-CT-2001-01252. Additional support for the RISC Study has been provided by AstraZeneca (Sweden). The RISC Study was supported by European Union grant QLG1-CT-2001-01252 and AstraZeneca. Ele Ferrannini acknowledges grant funding from Boehringer-Ingelheim and Lilly&Co and works as a consultant for Boehringer-Ingelheim, Lilly&Co., MSD, Sanofi, GSK, Janssen, Menarini, Novo Nordisk, AstraZeneca.; Rotterdam Study: The Rotterdam Study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project nr. 050-060-810, CHANCES (nr 242244), Erasmus Medical Center and Erasmus University Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. Abbas Dehghan is supported by NWO grant veni (veni, 916.12.154) and the EUR Fellowship. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists.; SCARF: We thank all participants in this study. The study was funded by the Foundation for Strategic Research, the Swedish Heart-Lung Foundation, the Swedish Research Council (8691, 12660, 20653), the European Commission (LSHM-CT-2007-037273), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and the Stockholm County Council, and the Stockholm County Council (560183). Bengt Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. Mattias Franberg acknowledges funding from the Swedish e-Science Research Center (SeRC).; SCES: The Singapore Chinese Eye Study (SCES) was supported by the National Medical Research Council (NMRC), Singapore (grants 0796/2003, IRG07nov013, IRG09nov014, NMRC 1176/2008, STaR/0003/2008, CG/SERI/2010) and Biomedical Research Council (BMRC), Singapore (08/1/35/19/550 and 09/1/35/19/616).; TEENAGE (TEENs of Attica: Genes and Environment): This research has been co-financed by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund. This work was funded by the Wellcome Trust (098051).; Uppsala Longitudinal Study of Adult Men (ULSAM): The exome chip genotyping and data analyses were supported by Uppsala University, Knut och Alice Wallenberg Foundation, European Research Council, Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). C.M.L. is supported by a Wellcome Trust Research Career Development Fellowship (086596/Z/08/Z).; INGI-VB: The Val Borbera study (INGI-VB) thanks the inhabitants of the Val Borbera for participating in the study, the local administrations and the ASL-Novi Ligure for support and Fiammetta Vigano for technical help. We also thank Professor Clara Camaschella, Professor Federico Caligaris-Cappio and the MDs of the Medicine Dept. of the San Raffaele Hospital for help with clinical data collection. The study was supported by funds from Fondazione Compagnia di San Paolo-Torino, Fondazione Cariplo-Milano, Italian Ministry of Health Progetto Finalizzato 2007 and 2012, Italian Ministry of Health Progetto CCM 2010, and PRIN 2009.; WGHS: The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. NR 70 TC 43 Z9 43 U1 5 U2 37 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 JAN PY 2015 VL 6 AR 5897 DI 10.1038/ncomms6897 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA2ME UT WOS:000348741700001 PM 25631608 ER PT J AU Ulrich, CM Grady, C AF Ulrich, Connie M. Grady, Christine TI Cardiopulmonary Resuscitation for Ebola patients: Ethical considerations SO NURSING OUTLOOK LA English DT Article ID VIRUS DISEASE; WEST-AFRICA C1 [Ulrich, Connie M.] Univ Penn, Philadelphia, PA 19104 USA. [Grady, Christine] NIH, Bethastha, MD USA. RP Ulrich, CM (reprint author), Univ Penn, 420 Curie Blvd, Philadelphia, PA 19104 USA. EM culrich@nursing.upenn.edu NR 11 TC 4 Z9 5 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 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD JAN-FEB PY 2015 VL 63 IS 1 BP 16 EP 18 DI 10.1016/j.outlook.2014.11.011 PG 3 WC Nursing SC Nursing GA CA9UF UT WOS:000349269600006 PM 25645475 ER PT J AU Matlock, AM Gutierrez, D Wallen, G Hastings, C AF Matlock, Ann Marie Gutierrez, Debbie Wallen, Gwenyth Hastings, Clare TI Providing nursing care to Ebola patients on the national stage: The National Institutes of Health experience SO NURSING OUTLOOK LA English DT Article C1 [Matlock, Ann Marie; Gutierrez, Debbie; Wallen, Gwenyth; Hastings, Clare] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Hastings, C (reprint author), NIH, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chastings@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 3 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD JAN-FEB PY 2015 VL 63 IS 1 BP 21 EP 24 DI 10.1016/j.outlook.2014.11.015 PG 4 WC Nursing SC Nursing GA CA9UF UT WOS:000349269600008 PM 25645477 ER PT J AU Williams, JK Cashion, AK Veenstra, DL AF Williams, Janet K. Cashion, Ann K. Veenstra, David L. TI Challenges in evaluating next-generation sequence data for clinical decisions SO NURSING OUTLOOK LA English DT Article DE Genetics; Genome sequencing; Clinical decisions; Nursing; Clinical genomics; Genomic medicine; Evidence ID CARE C1 [Williams, Janet K.] Univ Iowa, Iowa City, IA 52242 USA. [Cashion, Ann K.] NINR, NIH, Bethesda, MD 20892 USA. [Veenstra, David L.] Univ Washington, Seattle, WA 98195 USA. RP Williams, JK (reprint author), Univ Iowa, 50 Newton Rd, Iowa City, IA 52242 USA. EM janet-williams@uiowa.edu NR 12 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD JAN-FEB PY 2015 VL 63 IS 1 BP 48 EP 50 DI 10.1016/j.outlook.2014.08.007 PG 3 WC Nursing SC Nursing GA CA9UF UT WOS:000349269600013 PM 25261386 ER PT J AU Nussinov, R AF Nussinov, Ruth TI Advancements and Challenges in Computational Biology SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material ID ENERGY LANDSCAPES C1 [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. EM nussinor@helix.nih.gov NR 5 TC 2 Z9 2 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JAN PY 2015 VL 11 IS 1 AR e1004053 DI 10.1371/journal.pcbi.1004053 PG 2 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CB0IO UT WOS:000349309400028 PM 25569585 ER PT J AU Stepp, N Plenz, D Srinivasa, N AF Stepp, Nigel Plenz, Dietmar Srinivasa, Narayan TI Synaptic Plasticity Enables Adaptive Self-Tuning Critical Networks SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID NEURONAL AVALANCHES; NEURAL-NETWORKS; ORGANIZED CRITICALITY; CORTICAL NETWORKS; DEPENDENT PLASTICITY; IN-VIVO; RANGE; CIRCUITS; NOISE; FLUCTUATION AB During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short-and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. C1 [Stepp, Nigel; Srinivasa, Narayan] HRL Labs LLC, Informat & Syst Sci Lab, Ctr Neural & Emergent Syst, Malibu, CA 90265 USA. [Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Stepp, N (reprint author), HRL Labs LLC, Informat & Syst Sci Lab, Ctr Neural & Emergent Syst, Malibu, CA 90265 USA. EM nsrinivasa@hrl.com FU Defense Advanced Research Projects Agency (DARPA) [HR0011-10-C-0052]; Division of Intramural Research Program of the National Institute of Mental Health, NIH, USA FX This material is based upon work supported by the Defense Advanced Research Projects Agency (DARPA) under contract HR0011-10-C-0052. Any opinions, findings and conclusions or recommendations expressed in this material are those of author(s) and do not necessarily reflect the views of the Defense Advanced Research Projects Agency. This research was supported by the Division of Intramural Research Program of the National Institute of Mental Health, NIH, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 5 Z9 5 U1 1 U2 25 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JAN PY 2015 VL 11 IS 1 AR e1004043 DI 10.1371/journal.pcbi.1004043 PG 28 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CB0IO UT WOS:000349309400025 PM 25590427 ER PT J AU Mahajan, A Sim, X Ng, HJ Manning, A Rivas, MA Highland, HM Locke, AE Grarup, N Im, HK Cingolani, P Flannick, J Fontanillas, P Fuchsberger, C Gaulton, KJ Teslovich, TM Rayner, NW Robertson, NR Beer, NL Rundle, JK Bork-Jensen, J Ladenvall, C Blancher, C Buck, D Buck, G Burtt, NP Gabriel, S Gjesing, AP Groves, CJ Hollensted, M Huyghe, JR Jackson, AU Jun, G Justesen, JM Mangino, M Murphy, J Neville, M Onofrio, R Small, KS Stringham, HM Syvanen, AC Trakalo, J Abecasis, G Bell, GI Blangero, J Cox, NJ Duggirala, R Hanis, CL Seielstad, M Wilson, JG Christensen, C Brandslund, I Rauramaa, R Surdulescu, GL Doney, ASF Lannfelt, L Linneberg, A Isomaa, B Tuomi, T Jorgensen, ME Jorgensen, T Kuusisto, J Uusitupa, M Salomaa, V Spector, TD Morris, AD Palmer, CNA Collins, FS Mohlke, KL Bergman, RN Ingelsson, E Lind, L Tuomilehto, J Hansen, T Watanabe, RM Prokopenko, I Dupuis, J Karpe, F Groop, L Laakso, M Pedersen, O Florez, JC Morris, AP Altshuler, D Meigs, JB Boehnke, M McCarthy, MI Lindgren, CM Gloyn, AL AF Mahajan, Anubha Sim, Xueling Ng, Hui Jin Manning, Alisa Rivas, Manuel A. Highland, Heather M. Locke, Adam E. Grarup, Niels Im, Hae Kyung Cingolani, Pablo Flannick, Jason Fontanillas, Pierre Fuchsberger, Christian Gaulton, Kyle J. Teslovich, Tanya M. Rayner, N. William Robertson, Neil R. Beer, Nicola L. Rundle, Jana K. Bork-Jensen, Jette Ladenvall, Claes Blancher, Christine Buck, David Buck, Gemma Burtt, Noel P. Gabriel, Stacey Gjesing, Anette P. Groves, Christopher J. Hollensted, Mette Huyghe, Jeroen R. Jackson, Anne U. Jun, Goo Justesen, Johanne Marie Mangino, Massimo Murphy, Jacquelyn Neville, Matt Onofrio, Robert Small, Kerrin S. Stringham, Heather M. Syvanen, Ann-Christine Trakalo, Joseph Abecasis, Goncalo Bell, Graeme I. Blangero, John Cox, Nancy J. Duggirala, Ravindranath Hanis, Craig L. Seielstad, Mark Wilson, James G. Christensen, Cramer Brandslund, Ivan Rauramaa, Rainer Surdulescu, Gabriela L. Doney, Alex S. F. Lannfelt, Lars Linneberg, Allan Isomaa, Bo Tuomi, Tiinamaija Jorgensen, Marit E. Jorgensen, Torben Kuusisto, Johanna Uusitupa, Matti Salomaa, Veikko Spector, Timothy D. Morris, Andrew D. Palmer, Colin N. A. Collins, Francis S. Mohlke, Karen L. Bergman, Richard N. Ingelsson, Erik Lind, Lars Tuomilehto, Jaakko Hansen, Torben Watanabe, Richard M. Prokopenko, Inga Dupuis, Josee Karpe, Fredrik Groop, Leif Laakso, Markku Pedersen, Oluf Florez, Jose C. Morris, Andrew P. Altshuler, David Meigs, James B. Boehnke, Michael McCarthy, Mark I. Lindgren, Cecilia M. Gloyn, Anna L. CA T2D-GENES Consortium Go T2D Consortium TI Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus SO PLOS GENETICS LA English DT Article ID TYPE-2 DIABETES RISK; FASTING PLASMA-GLUCOSE; GENETIC ARCHITECTURE; TRIGLYCERIDE LEVELS; QUANTITATIVE TRAIT; P446L VARIANT; ASSOCIATION; GENOME; PROTEIN; POLYMORPHISMS AB Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5x10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights. C1 [Mahajan, Anubha; Rivas, Manuel A.; Gaulton, Kyle J.; Rayner, N. William; Robertson, Neil R.; Morris, Andrew D.; Ingelsson, Erik; Prokopenko, Inga; Morris, Andrew P.; McCarthy, Mark I.; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England. [Sim, Xueling; Locke, Adam E.; Fuchsberger, Christian; Teslovich, Tanya M.; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Stringham, Heather M.; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Sim, Xueling; Locke, Adam E.; Fuchsberger, Christian; Teslovich, Tanya M.; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Stringham, Heather M.; Abecasis, Goncalo; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Ng, Hui Jin; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Groves, Christopher J.; Neville, Matt; Prokopenko, Inga; Karpe, Fredrik; McCarthy, Mark I.; Gloyn, Anna L.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Manning, Alisa; Flannick, Jason; Fontanillas, Pierre; Burtt, Noel P.; Gabriel, Stacey; Murphy, Jacquelyn; Onofrio, Robert; Florez, Jose C.; Altshuler, David; Lindgren, Cecilia M.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Highland, Heather M.] Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Ctr Human Genet, Houston, TX 77030 USA. [Grarup, Niels; Bork-Jensen, Jette; Gjesing, Anette P.; Hollensted, Mette; Justesen, Johanne Marie; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Im, Hae Kyung] Univ Chicago, Dept Hlth Studies, Biostat Lab, Chicago, IL 60637 USA. [Cingolani, Pablo] McGill Univ, Sch Comp Sci, Montreal, PQ, Canada. [Cingolani, Pablo] McGill Univ, Montreal, PQ, Canada. [Cingolani, Pablo] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Flannick, Jason; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Rayner, N. William] Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England. [Ladenvall, Claes; Groop, Leif] Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Blancher, Christine; Buck, David; Buck, Gemma; Trakalo, Joseph] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom Oxford Genom Ctr, Oxford, England. [Mangino, Massimo; Small, Kerrin S.; Surdulescu, Gabriela L.; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden. [Bell, Graeme I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Bell, Graeme I.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Blangero, John; Duggirala, Ravindranath] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Cox, Nancy J.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Seielstad, Mark] Blood Syst Res Inst, San Francisco, CA USA. [Seielstad, Mark] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Christensen, Cramer] Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark. [Brandslund, Ivan] Vejle Hosp, Dept Clin Biochem, Vejle, Denmark. [Brandslund, Ivan] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark. [Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio, Finland. [Doney, Alex S. F.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee DD1 9SY, Scotland. [Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Linneberg, Allan] Glostrup Univ Hosp, Dept Clin Expt Res, Glostrup, Denmark. [Linneberg, Allan] Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark. [Linneberg, Allan; Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Endocrinol, Helsinki, Finland. [Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Jorgensen, Torben] Aalborg Univ, Fac Med, Aalborg, Denmark. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Inst Clin Med Internal Med, Fac Hlth Sci, Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Clin Res Ctr, Ctr Mol Med, Dundee DD1 9SY, Scotland. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee DD1 9SY, Scotland. [Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA. [Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia. [Tuomilehto, Jaakko] Autonomous Univ Madrid, Univ Hosp LaPaz, Inst Invest Sanitaria Hosp Univ LaPaz IdiPAZ, E-28049 Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Diabet & Obes Res Inst, Los Angeles, CA 90033 USA. [Prokopenko, Inga] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Dupuis, Josee] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Karpe, Fredrik; McCarthy, Mark I.; Gloyn, Anna L.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Florez, Jose C.; Altshuler, David] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Morris, Andrew P.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Altshuler, David] MIT, Dept Biol, Cambridge, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Mahajan, A (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England. EM celi@well.ox.ac.uk; anna.gloyn@drl.ox.ac.uk RI Palmer, Colin/C-7053-2008; Grarup, Niels/K-2807-2015; Prokopenko, Inga/H-3241-2014; Justesen, Johanne Marie/L-6023-2015; kinnunen, leena/B-7059-2012; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Hrabe de Angelis, Martin/F-5531-2012; Jun, Goo/F-1941-2017; OI Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Tuomi, Tiinamaija/0000-0002-8306-6202; Jorgensen, Torben/0000-0001-9453-2830; Small, Kerrin/0000-0003-4566-0005; Khor, Chiea Chuen/0000-0002-1128-4729; Tai, E Shyong/0000-0003-2929-8966; Linneberg, Allan/0000-0002-0994-0184; Palmer, Colin/0000-0002-6415-6560; Grarup, Niels/0000-0001-5526-1070; Prokopenko, Inga/0000-0003-1624-7457; Justesen, Johanne Marie/0000-0002-0484-8522; kinnunen, leena/0000-0001-8739-4812; mangino, massimo/0000-0002-2167-7470; Hrabe de Angelis, Martin/0000-0002-7898-2353; Jun, Goo/0000-0003-0891-0204; Fuchsberger, Christian/0000-0002-5918-8947; Kim, Yongkang/0000-0002-8837-2620; Locke, Adam/0000-0001-6227-198X FU Agency for Science, Technology and Research in Singapore; Austrian Science Fund (FWF) [J-3401]; MGH Research Scholars Award; NIDDK [R01 DK078616, K24 DK080140, DK098032]; NIH [U01 DK085526, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, U01 DK088389]; Wellcome Trust [090367, 098381, 090532, 083948, 085475, WT098017, WT064890, WT090532]; MRC [G0601261]; EU (Framework 7) [HEALTH-F4-2007-201413]; Oxford Biomedical Research Centre; National NIHR Bioresource; Uppsala University; Uppsala University Hospital; Swedish Research Council; Swedish Heart-Lung Foundation; Wellcome Trust Study Cohort Wellcome Trust Functional Genomics Grant [072960/2/03/2]; Wellcome Trust Scottish Health Informatics Programme (SHIP) [086113/Z/08/Z]; Wellcome Trust; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; ERC Advanced Principal Investigator award; Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp)); Danish Council for Independent Research; Novo Nordisk Foundation; Academy of Finland [124243, 139635, 129293, 117844, 40758, 211497, 118590, 102318, 123885]; Finnish Heart Foundation; Finnish Diabetes Foundation; Tekes [1510/31/06, 70103/06, 40058/07]; Commission of the European Community [HEALTH-F2-2007-201681]; US National Institutes of Health [DK093757, DK072193, DK062370, 1Z01 HG000024]; Finnish Foundation for Cardiovascular Research; hospital district of Pirkanmaa; hospital district of South Ostrobothnia; hospital district of Central Finland; National Institute for Health and Welfare; Finnish Diabetes Association; Ministry of Social Affairs and Health in Finland; Commission of the European Communities; Directorate C-Public Health [2004310]; Finland's Slottery Machine Association; Ministry of Health and Social Affairs [5254]; Finnish Funding Agency for Technology and Innovation [40058/07]; Nordic Centre of Excellence on 'Systems biology in controlled dietary interventions and cohort studies, SYSDIET [070014]; Finnish Diabetes Research Foundation; Yrjo Jahnsson Foundation [56358]; Sigrid Juselius Foundation; Ministry of Education and Culture of Finland [627]; Kuopio University Hospital; Finnish Heart Association; Paivikki and Sakari Sohlberg Foundation; European Commission FP6 Integrated Project (EXGENESIS); City of Kuopio and Social Insurance Institution of Finland [LSHM-CT-2004-005272] FX HJN was supported by the Agency for Science, Technology and Research in Singapore. CF was supported by the Austrian Science Fund (FWF) grant J-3401. JCF was supported by MGH Research Scholars Award. APM is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science. JBM was supported by NIDDK R01 DK078616 and K24 DK080140. MIM is a Wellcome Trust Senior Investigator (WT098381); and a National Institute of Health Research Senior Investigator. CML is a Wellcome Trust Research Career Development Fellow (086596/Z/08/Z). ALG is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science (095010/Z/10/Z). Funding for the GoT2D and T2D-GENES studies was provided by grants NIH U01s DK085526, DK085501, DK085524, DK085545, and DK085584 (Multiethnic Study of Type 2 Diabetes Genes) and DK088389 (Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes). Analysis and genotyping of the British UK cohorts was supported by Wellcome Trust funding 090367, 098381, 090532, 083948, 085475, MRC (G0601261), EU (Framework 7) HEALTH-F4-2007-201413, and NIDDK DK098032. The Oxford Biobank is supported by the Oxford Biomedical Research Centre and part of the National NIHR Bioresource. The PIVUS/ULSAM cohort was supported by Wellcome Trust Grants WT098017, WT064890, WT090532, Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. GoDARTS study was funded by The Wellcome Trust Study Cohort Wellcome Trust Functional Genomics Grant (2004-2008) (Grant No: 072960/2/03/2) and The Wellcome Trust Scottish Health Informatics Programme (SHIP) (2009-2012) (Grant No: 086113/Z/08/Z). TwinsUK study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. TDS is holder of an ERC Advanced Principal Investigator award. The Danish studies were supported by the Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp); http://www.lucamp.org/) and the Danish Council for Independent Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/). The METSIM study was supported by the Academy of Finland (contract 124243), the Finnish Heart Foundation, the Finnish Diabetes Foundation, Tekes (contract 1510/31/06), and the Commission of the European Community (HEALTH-F2-2007-201681), and the US National Institutes of Health grants DK093757, DK072193, DK062370, and 1Z01 HG000024. The FUSION study was supported by DK093757, DK072193, DK062370, and 1Z01 HG000024. Genotyping of the METSIM and DPS studies was conducted at the Genetic Resources Core Facility (GRCF) at the Johns Hopkins Institute of Genetic Medicine. VS is funded by the Finnish Foundation for Cardiovascular Research and the Academy of Finland (grant # 139635).; The FIN-D2D 2007 study has been financially supported by the hospital districts of Pirkanmaa, South Ostrobothnia, and Central Finland, the Finnish National Public Health Institute (current National Institute for Health and Welfare), the Finnish Diabetes Association, the Ministry of Social Affairs and Health in Finland, the Academy of Finland (grant number 129293), Commission of the European Communities, Directorate C-Public Health (grant agreement no. 2004310) and Finland's Slottery Machine Association. The DPS has been financially supported by grants from the Academy of Finland (117844 and 40758, 211497, and 118590 (MU); The EVO funding of the Kuopio University Hospital from Ministry of Health and Social Affairs (5254), Finnish Funding Agency for Technology and Innovation (40058/07), Nordic Centre of Excellence on 'Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014), The Finnish Diabetes Research Foundation, Yrjo Jahnsson Foundation (56358), Sigrid Juselius Foundation and TEKES grants 70103/06 and 40058/07. The DR's EXTRA Study was supported by grants to RR by the Ministry of Education and Culture of Finland (627; 2004-2011), Academy of Finland (102318; 123885), Kuopio University Hospital, Finnish Diabetes Association, Finnish Heart Association, Paivikki and Sakari Sohlberg Foundation and by grants from European Commission FP6 Integrated Project (EXGENESIS); LSHM-CT-2004-005272, City of Kuopio and Social Insurance Institution of Finland (4/26/2010). The Broad Genomics Platform for genotyping of the FIN-D2D 2007, FINRISK 2007, DR'sEXTRA, FUSION, and PPP studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 21 Z9 21 U1 2 U2 15 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 JAN PY 2015 VL 11 IS 1 AR e1004876 DI 10.1371/journal.pgen.1004876 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA CB0KL UT WOS:000349314600012 PM 25625282 ER PT J AU Rattray, A Santoyo, G Shafer, B Strathern, JN AF Rattray, Alison Santoyo, Gustavo Shafer, Brenda Strathern, Jeffrey N. TI Elevated Mutation Rate during Meiosis in Saccharomyces cerevisiae SO PLOS GENETICS LA English DT Article ID DOUBLE-STRAND-BREAK; MEIOTIC RECOMBINATION; GENE CONVERSION; CROSSOVER INTERFERENCE; ADAPTIVE MUTATION; DNA-POLYMERASE; CHROMOSOME-III; YEAST; REPAIR; MUTAGENESIS AB Mutations accumulate during all stages of growth, but only germ line mutations contribute to evolution. While meiosis contributes to evolution by reassortment of parental alleles, we show here that the process itself is inherently mutagenic. We have previously shown that the DNA synthesis associated with repair of a double-strand break is about 1000-fold less accurate than S-phase synthesis. Since the process of meiosis involves many programmed DSBs, we reasoned that this repair might also be mutagenic. Indeed, in the early 1960's Magni and Von Borstel observed elevated reversion of recessive alleles during meiosis, and found that the revertants were more likely to be associated with a crossover than non-revertants, a process that they called "the meiotic effect." Here we use a forward mutation reporter (CAN1 HIS3) placed at either a meiotic recombination coldspot or hotspot near the MAT locus on Chromosome III. We find that the increased mutation rate at CAN1 (6 to 21 -fold) correlates with the underlying recombination rate at the locus. Importantly, we show that the elevated mutation rate is fully dependent upon Spo11, the protein that introduces the meiosis specific DSBs. To examine associated recombination we selected for random spores with or without a mutation in CAN1. We find that the mutations isolated this way show an increased association with recombination (crossovers, loss of crossover interference and/or increased gene conversion tracts). Polf appears to contribute about half of the mutations induced during meiosis, but is not the only source of mutations for the meiotic effect. We see no difference in either the spectrum or distribution of mutations between mitosis and meiosis. The correlation of hotspots with elevated mutagenesis provides a mechanism for organisms to control evolution rates in a gene specific manner. C1 [Rattray, Alison; Santoyo, Gustavo; Shafer, Brenda; Strathern, Jeffrey N.] NCI Frederick, Gene Regulat & Chromosome Biol Lab, FNLCR, Frederick, MD 21702 USA. RP Rattray, A (reprint author), NCI Frederick, Gene Regulat & Chromosome Biol Lab, FNLCR, Frederick, MD 21702 USA. EM stratherj@mail.nih.gov OI Santoyo, Gustavo/0000-0002-0374-9661 FU Intramural program of the National Cancer Institute FX Funding was provided by the Intramural program of the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 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 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2015 VL 11 IS 1 AR e1004910 DI 10.1371/journal.pgen.1004910 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CB0KL UT WOS:000349314600030 PM 25569256 ER PT J AU Shakhova, O Cheng, P Mishra, PJ Zingg, D Schaefer, SM Debbache, J Hausel, J Matter, C Guo, T Davis, S Meltzer, P Mihic-Probst, D Moch, H Wegner, M Merlino, G Levesque, MP Dummer, R Santoro, R Cinelli, P Sommer, L AF Shakhova, Olga Cheng, Phil Mishra, Pravin J. Zingg, Daniel Schaefer, Simon M. Debbache, Julien Haeusel, Jessica Matter, Claudia Guo, Theresa Davis, Sean Meltzer, Paul Mihic-Probst, Daniela Moch, Holger Wegner, Michael Merlino, Glenn Levesque, Mitchell P. Dummer, Reinhard Santoro, Raffaella Cinelli, Paolo Sommer, Lukas TI Antagonistic Cross-Regulation between Sox9 and Sox10 Controls an Anti-tumorigenic Program in Melanoma SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION FACTOR SOX10; CREST-DERIVED MELANOCYTES; CELL LUNG-CANCER; NEURAL CREST; HIRSCHSPRUNG-DISEASE; MOUSE MODEL; CAMPOMELIC DYSPLASIA; SPINAL-CORD; STEM-CELLS; EXPRESSION AB Melanoma is the most fatal skin cancer, but the etiology of this devastating disease is still poorly understood. Recently, the transcription factor Sox10 has been shown to promote both melanoma initiation and progression. Reducing SOX10 expression levels in human melanoma cells and in a genetic melanoma mouse model, efficiently abolishes tumorigenesis by inducing cell cycle exit and apoptosis. Here, we show that this anti-tumorigenic effect functionally involves SOX9, a factor related to SOX10 and upregulated in melanoma cells upon loss of SOX10. Unlike SOX10, SOX9 is not required for normal melanocyte stem cell function, the formation of hyperplastic lesions, and melanoma initiation. To the contrary, SOX9 overexpression results in cell cycle arrest, apoptosis, and a gene expression profile shared by melanoma cells with reduced SOX10 expression. Moreover, SOX9 binds to the SOX10 promoter and induces downregulation of SOX10 expression, revealing a feedback loop reinforcing the SOX10 low/SOX9 high ant, m/ii-tumorigenic program. Finally, SOX9 is required in vitro and in vivo for the anti-tumorigenic effect achieved by reducing SOX10 expression. Thus, SOX10 and SOX9 are functionally antagonistic regulators of melanoma development. C1 [Shakhova, Olga; Zingg, Daniel; Schaefer, Simon M.; Debbache, Julien; Haeusel, Jessica; Sommer, Lukas] Univ Zurich, Inst Anat, Zurich, Switzerland. [Cheng, Phil; Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Mishra, Pravin J.; Guo, Theresa; Davis, Sean; Meltzer, Paul; Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Mihic-Probst, Daniela; Moch, Holger] Univ Zurich Hosp, Inst Surg Pathol, Dept Pathol, CH-8091 Zurich, Switzerland. [Wegner, Michael] FAU Univ Erlangen Nuernberg, Inst Biochem, Emil Fischer Ctr, Erlangen, Germany. [Santoro, Raffaella] Univ Zurich, Inst Vet Biochem & Mol Biol, Zurich, Switzerland. [Cinelli, Paolo] Univ Zurich Hosp, Clin Res Ctr, Div Trauma Surg, CH-8091 Zurich, Switzerland. [Shakhova, Olga; Matter, Claudia] Univ Zurich Hosp, Dept Oncol, Schlieren, Switzerland. RP Shakhova, O (reprint author), Univ Zurich Hosp, Dept Oncol, Schlieren, Switzerland. EM lukas.sommer@anatom.uzh.ch RI Santoro, Raffaella/L-2637-2013; OI Davis, Sean/0000-0002-8991-6458; Zingg, Daniel/0000-0001-6450-2534; Wegner, Michael/0000-0002-4586-3294 FU Swiss National Science Foundation; National Research Program [NRP-63]; Swiss Cancer League; UBS-Promedica Stiftung; University Research Priority Program (URPP) of the University of Zurich FX This work was supported by the Swiss National Science Foundation, the National Research Program (NRP-63) "Stem Cells and Regenerative Medicine", the Swiss Cancer League, the UBS-Promedica Stiftung, and the University Research Priority Program (URPP) "Translational Cancer Research" of the University of Zurich. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 12 Z9 13 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2015 VL 11 IS 1 AR e1004877 DI 10.1371/journal.pgen.1004877 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA CB0KL UT WOS:000349314600013 PM 25629959 ER PT J AU Su, D Wang, XT Campbell, MR Song, LY Safi, A Crawford, GE Bell, DA AF Su, Dan Wang, Xuting Campbell, Michelle R. Song, Lingyun Safi, Alexias Crawford, Gregory E. Bell, Douglas A. TI Interactions of Chromatin Context, Binding Site Sequence Content, and Sequence Evolution in Stress-Induced p53 Occupancy and Transactivation SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION-FACTOR-BINDING; EMBRYONIC STEM-CELLS; HUMAN GENOME; REGULATORY ELEMENTS; RESPONSE ELEMENT; GENE-EXPRESSION; TARGET GENES; DNA-DAMAGE; IDENTIFICATION; PATTERNS AB Cellular stresses activate the tumor suppressor p53 protein leading to selective binding to DNA response elements (REs) and gene transactivation from a large pool of potential p53 REs (p53REs). To elucidate how p53RE sequences and local chromatin context interact to affect p53 binding and gene transactivation, we mapped genome-wide binding localizations of p53 and H3K4me3 in untreated and doxorubicin (DXR)-treated human lymphoblastoid cells. We examined the relationships among p53 occupancy, gene expression, H3K4me3, chromatin accessibility (DNase 1 hypersensitivity, DHS), ENCODE chromatin states, p53RE sequence, and evolutionary conservation. We observed that the inducible expression of p53-regulated genes was associated with the steady-state chromatin status of the cell. Most highly inducible p53-regulated genes were suppressed at baseline and marked by repressive histone modifications or displayed CTCF binding. Comparison of p53RE sequences residing in different chromatin contexts demonstrated that weaker p53REs resided in open promoters, while stronger p53REs were located within enhancers and repressed chromatin. p53 occupancy was strongly correlated with similarity of the target DNA sequences to the p53RE consensus, but surprisingly, inversely correlated with pre-existing nucleosome accessibility (DHS) and evolutionary conservation at the p53RE. Occupancy by p53 of REs that overlapped transposable element (TE) repeats was significantly higher (p<10(-7)) and correlated with stronger p53RE sequences (p<10(-110)) relative to nonTE-associated p53REs, particularly for MLT1H, LTR10B, and Mer61 TEs. However, binding at these elements was generally not associated with transactivation of adjacent genes. Occupied p53REs located in L2-like TEs were unique in displaying highly negative PhyloP scores (predicted fast-evolving) and being associated with altered H3K4me3 and DHS levels. These results underscore the systematic interaction between chromatin status and p53RE context in the induced transactivation response. This p53 regulated response appears to have been tuned via evolutionary processes that may have led to repression and/or utilization of p53REs originating from primate-specific transposon elements. C1 [Su, Dan; Wang, Xuting; Campbell, Michelle R.; Bell, Douglas A.] NIEHS, Environm Genom Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC USA. [Song, Lingyun; Safi, Alexias; Crawford, Gregory E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. RP Su, D (reprint author), NIEHS, Environm Genom Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC USA. EM BELL1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU Intramural Research Program of National Institute of Environmental Health Sciences-National Institutes of Health [ZO1ES100475] FX This work was funded by the Intramural Research Program of National Institute of Environmental Health Sciences-National Institutes of Health, ZO1ES100475 to DAB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 12 Z9 12 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JAN PY 2015 VL 11 IS 1 AR e1004885 DI 10.1371/journal.pgen.1004885 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA CB0KL UT WOS:000349314600014 PM 25569532 ER PT J AU Elmore, SA Cora, MC Gruebbel, MM Hayes, SA Hoane, JS Koizumi, H Peters, R Rosol, TJ Singh, BP Szabo, KA AF Elmore, Susan A. Cora, Michelle C. Gruebbel, Margarita M. Hayes, Schantel A. Hoane, Jessica S. Koizumi, Haruko Peters, Rachel Rosol, Thomas J. Singh, Bhanu P. Szabo, Kathleen A. TI Proceedings of the 2014 National Toxicology Program Satellite Symposium SO TOXICOLOGIC PATHOLOGY LA English DT Review DE NTP Satellite Symposium; mucinous adenoma; plexiform vasculopathy; vaginal cytology; chronic-active pancreatitis; retinal dysplasia; thymoma; mesenteric lymph node angiomatous lesion; fovea cyst; endocrine nomenclature; acute tumor lysis syndrome ID INDUCED VASCULAR INJURY; SPRAGUE-DAWLEY RATS; HANNOVER GALAS RATS; SPONTANEOUS THYMOMA RATS; GOBLET CELL METAPLASIA; INHIBITOR SCH 351591; TUMOR LYSIS SYNDROME; CONTROL WISTAR RATS; ESTROUS-CYCLE; 2-YEAR CARCINOGENICITY AB The 2014 annual National Toxicology Program (NTP) Satellite Symposium, entitled Pathology Potpourri was held in Washington, D.C., in advance of the Society of Toxicologic Pathology's 33rd annual meeting. The goal of this annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included a pulmonary mucinous adenocarcinoma in a male B6C3F1 mouse; plexiform vasculopathy in Wistar Han (Crl:WI[Han]) rats; staging of the estrous cycle in rats and mice; peri-islet fibrosis, hemorrhage, lobular atrophy and inflammation in male Sprague-Dawley (SD) rats; retinal dysplasia in Crl:WI[Han] rats and B6C3F1 mice; multicentric lymphoma with intravascular microemboli and tumor lysis syndrome, and 2 cases of myopathy and vascular anomaly in Tg.rasH2 mice; benign thymomas in Crl:WI[Han] rats; angiomatous lesions in the mesenteric lymph nodes of Crl:WI[Han] rats; an unusual foveal lesion in a cynomolgous monkey; and finally a series of nomenclatures challenges from the endocrine International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) Organ Working Group (OWG). C1 [Elmore, Susan A.; Cora, Michelle C.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Gruebbel, Margarita M.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Hayes, Schantel A.; Hoane, Jessica S.; Szabo, Kathleen A.] Pathol Associates Inc, Charles River Labs, Durham, NC USA. [Koizumi, Haruko] Ina Res Inc, Nagano, Japan. [Peters, Rachel] Takeda Pharmaceut Int Co, Cambridge, MA USA. [Rosol, Thomas J.] Ohio State Univ, Columbus, OH 43210 USA. [Singh, Bhanu P.] Janssen Res & Dev, Spring House, PA USA. RP Elmore, SA (reprint author), NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 124 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2015 VL 43 IS 1 BP 10 EP 40 DI 10.1177/0192623314555526 PG 31 WC Pathology; Toxicology SC Pathology; Toxicology GA CA4ZT UT WOS:000348917300001 PM 25385331 ER PT J AU Morrison, JP Sharma, AK Rao, D Pardo, ID Garman, RH Kaufmann, W Bolon, B AF Morrison, James P. Sharma, Alok K. Rao, Deepa Pardo, Ingrid D. Garman, Robert H. Kaufmann, Wolfgang Bolon, Brad TI Fundamentals of Translational Neuroscience in Toxicologic Pathology: Optimizing the Value of Animal Data for Human Risk Assessment SO TOXICOLOGIC PATHOLOGY LA English DT Article DE nervous system; neuroanatomy; neuropathology; neurotoxicity; neuroscience; translational medicine; PEGylation ID NONCLINICAL GENERAL TOXICITY; MAGNETIC-RESONANCE HISTOLOGY; HUMAN CEREBRAL-CORTEX; NERVOUS-SYSTEM; DEVELOPMENTAL NEUROTOXICITY; NEUROPATHOLOGY ASSESSMENT; SPECIES-DIFFERENCES; CORPUS-CALLOSUM; TECHNICAL GUIDE; MOUSE STRAINS AB A half-day Society of Toxicologic Pathology continuing education course on Fundamentals of Translational Neuroscience in Toxicologic Pathology presented some current major issues faced when extrapolating animal data regarding potential neurological consequences to assess potential human outcomes. Two talks reviewed functional-structural correlates in rodent and nonrodent mammalian brains needed to predict behavioral consequences of morphologic changes in discrete neural cell populations. The third lecture described practical steps for ensuring that specimens from rodent developmental neurotoxicity tests will be processed correctly to produce highly homologous sections. The fourth talk detailed demographic factors (e.g., species, strain, sex, and age); physiological traits (body composition, brain circulation, pharmacokinetic/pharmacodynamic patterns, etc.); and husbandry influences (e.g., group housing) known to alter the effects of neuroactive agents. The last presentation discussed the appearance, unknown functional effects, and potential relevance to humans of polyethylene glycol (PEG)-associated vacuoles within the choroid plexus epithelium of animals. Speakers provided real-world examples of challenges with data extrapolation among species or with study design considerations that may impact the interpretability of results. Translational neuroscience will be bolstered in the future as less invasive and/or more quantitative techniques are devised for linking overt functional deficits to subtle anatomic and chemical lesions. C1 [Morrison, James P.] Charles River Pathol Associates, Durham, NC USA. [Sharma, Alok K.] Covance Inc, Madison, WI USA. [Rao, Deepa] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Rao, Deepa] Integrated Syst Lab, Res Triangle Pk, NC USA. [Pardo, Ingrid D.] Pfizer Inc, Groton, CT 06340 USA. [Garman, Robert H.] Consultants Vet Pathol Inc, Murrysville, PA USA. [Kaufmann, Wolfgang] Merck KGaA, Darmstadt, Germany. [Bolon, Brad] Ohio State Univ, Coll Vet Med, Columbus, OH 43210 USA. RP Bolon, B (reprint author), Ohio State Univ, 1900 Coffey Rd,450 VMAB, Columbus, OH 43210 USA. EM bolon.15@osu.edu FU Society of Toxicologic Pathology's (STP) Annual Symposium Committee; Continuing Education Sub-Committee; Scientific Program Planning Committee FX The authors thank the Society of Toxicologic Pathology's (STP) Annual Symposium Committee, the Continuing Education Sub-Committee, and the Scientific Program Planning Committee for their support of this program. We would also like to thank the staff of the STP for organizational support in producing the materials and arranging the meeting space and Steve Van Adestine of Covance Laboratories Inc. for assisting with the figures. NR 85 TC 1 Z9 1 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2015 VL 43 IS 1 BP 132 EP 139 DI 10.1177/0192623314558306 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA CA4ZT UT WOS:000348917300014 PM 25398755 ER PT J AU Gowdy, KM Martinu, T Nugent, JL Manzo, ND Zhang, HL Kelly, FL Holtzman, MJ Palmer, SM AF Gowdy, Kymberly M. Martinu, Tereza Nugent, Julia L. Manzo, Nicholas D. Zhang, Helen L. Kelly, Francine L. Holtzman, Michael J. Palmer, Scott M. TI Impaired CD8(+) T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection SO TRANSPLANT IMMUNOLOGY LA English DT Article DE Bone marrow transplant; Respiratory virus; Lung; CD8(+) T cells ID HEMATOPOIETIC STEM-CELL; INFLUENZA-VIRUS INFECTION; VERSUS-HOST-DISEASE; SENDAI-VIRUS; PSEUDOMONAS-AERUGINOSA; PROTECTIVE IMMUNITY; MEMORY; RECIPIENTS; CLEARANCE; MICE AB Rationale: Bone marrow transplant (BMT) recipients experience frequent and severe respiratory viral infections (RVIs). However, the immunological mechanisms predisposing to RVIs are uncertain. Therefore, we hypothesized that antiviral T cell immunity is impaired as a consequence of allogeneic BMT, independent of pharmacologic immunosuppression, and is responsible for increased susceptibility to RVI. Methods: Bone marrow and splenocytes from C57BL/6(H2(b)) mice were transplanted into B10.BR(H2(k)) (Allo) or C57BL/6(H2(b)) (Syn) recipients. Five weeks after transplantation, recipient mice were inoculated intranasally with mouse parainfluenza virus type 1 (mPIV-1), commonly known as Sendai virus (SeV), and monitored for relevant immunological and disease endpoints. Main results: Severe and persistent airway inflammation, epithelial injury, and enhanced mortality are found after viral infection in Allo mice but not in control Syn and non-transplanted mice. In addition, viral clearance is delayed in Allo mice as evidenced by prolonged detection of viral transcripts at Day 15 post-inoculation (p.i.) but not in control mice. In concert with these events, we also detected decreased levels of total and virus-specific CD8(+) T cells, as well as increased T cellexpression of inhibitory receptor programmed death-1 (PD-1), in the lungs of Allo mice at Day 8 p.i. Adoptive transfer of CD8(+) T cells from non-transplanted mice recovered from SeV infection into Alio mice at Day 8 p.i. restored normal levels of viral clearance, epithelial repair, and lung inflammation. Conclusions: Taken together these results indicate that allogeneic BMT results in more severe RVI based on the failure to develop an appropriate pulmonary CD8(+) T cell response, providing an important potential mechanism to target in improving outcomes of RVI after BMT. Published by Elsevier B.V. C1 [Gowdy, Kymberly M.; Martinu, Tereza; Nugent, Julia L.; Manzo, Nicholas D.; Zhang, Helen L.; Kelly, Francine L.; Palmer, Scott M.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Holtzman, Michael J.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Palmer, Scott M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. RP Gowdy, KM (reprint author), NIEHS, LRB, 111 TW Alexander Dr,Bldg 101,Mail Drop, Res Triangle Pk, NC 27709 USA. EM kymberly.gowdy@nih.gov FU NIH/NHLBI [1P50-HL084917-01 (SCCOR)]; Project 3; NIH [1 K24 HL91140-01] FX NIH/NHLBI 1P50-HL084917-01 (SCCOR), Project 3 (SMP), Training core (to KG and TM), NIH 1 K24 HL91140-01 (SMP). NR 52 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 EI 2210-3384 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD JAN PY 2015 VL 32 IS 1 BP 51 EP 60 DI 10.1016/j.trim.2014.10.005 PG 10 WC Immunology; Transplantation SC Immunology; Transplantation GA CA4RT UT WOS:000348892900009 PM 25446809 ER PT J AU Montgomery, DC Sorum, AW Meier, JL AF Montgomery, David C. Sorum, Alexander W. Meier, Jordan L. TI Defining the Orphan Functions of Lysine Acetyltransferases SO ACS CHEMICAL BIOLOGY LA English DT Review ID PYRUVATE-DEHYDROGENASE COMPLEX; SMALL-MOLECULE INHIBITOR; HISTONE ACETYLTRANSFERASE; TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; PROTEIN ACETYLATION; ELONGATOR COMPLEX; ALPHA-TUBULIN; TRANSCRIPTIONAL COACTIVATOR; MITOCHONDRIAL PROTEIN AB Long known for their role in histone acetylation, recent studies have demonstrated that lysine acetyltransferases also carry out distinct orphan functions. These activities impact a wide range of biological phenomena including metabolism, RNA modification, nuclear morphology, and mitochondrial function. Here, we review the discovery and characterization of orphan lysine acetyltransferase functions. In addition to highlighting the evidence and biological role for these functions in human disease, we discuss the part emerging chemical tools may play in investigating this versatile enzyme superfamily. C1 [Montgomery, David C.; Sorum, Alexander W.; Meier, Jordan L.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014 NR 94 TC 8 Z9 8 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JAN PY 2015 VL 10 IS 1 BP 85 EP 94 DI 10.1021/cb500853p PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AZ6LU UT WOS:000348332100008 PM 25591746 ER PT J AU Kiyatkin, EA Wakabayashi, KT AF Kiyatkin, Eugene A. Wakabayashi, Ken T. TI Parsing Glucose Entry into the Brain: Novel Findings Obtained with Enzyme-Based Glucose Biosensors SO ACS CHEMICAL NEUROSCIENCE LA English DT Review DE Brain metabolism; amperometry; enzyme-based glucose sensors; neuronal activity; metabolic brain activation; cerebral blood flow ID FREELY-MOVING RATS; NATURAL AROUSING STIMULI; NUCLEUS-ACCUMBENS SHELL; EXTRACELLULAR GLUCOSE; INTRAVENOUS COCAINE; NEURONAL-ACTIVITY; SUBSTANTIA-NIGRA; RAPID CHANGES; PHYSIOLOGICAL FLUCTUATIONS; RETICULATA NEURONS AB Extracellular levels of glucose in brain tissue reflect dynamic balance between its gradient-dependent entry from arterial blood and its use for cellular metabolism. In this work, we present several sets of previously published and unpublished data obtained by using enzyme-based glucose biosensors coupled with constant-potential high-speed amperometry in freely moving rats. First, we consider basic methodological issues related to the reliability of electrochemical measurements of extracellular glucose levels in rats under physiologically relevant conditions. Second, we present data on glucose responses induced in the nucleus accumbens (NAc) by salient environmental stimuli and discuss the relationships between local neuronal activation and rapid glucose entry into brain tissue. Third, by presenting data on changes in NAc glucose induced by intravenous and intragastric glucose delivery, we discuss other mechanisms of glucose entry into the extracellular domain following changes in glucose blood concentrations. Lastly, by showing the pattern of NAc glucose fluctuations during glucose-drinking behavior, we discuss the relationships between "active" and "passive" glucose entry to the brain, its connection to behavior-related metabolic activation, and the possible functional significance of these changes in behavioral regulation. These data provide solid experimental support for the "neuronal" hypothesis of neurovascular coupling, which postulates the critical role of neuronal activity in rapid regulation of vascular tone, local blood flow, and entry of glucose and oxygen to brain tissue to maintain active cellular metabolism. C1 [Kiyatkin, Eugene A.; Wakabayashi, Ken T.] NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU National Institute on Drug Abuse Intramural Research Program, NIH FX Supported by the National Institute on Drug Abuse Intramural Research Program, NIH. NR 60 TC 6 Z9 6 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD JAN PY 2015 VL 6 IS 1 BP 108 EP 116 DI 10.1021/cn5002304 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA AZ6ON UT WOS:000348338900013 PM 25490002 ER PT J AU Zhao, HY Schuck, P AF Zhao, Huaying Schuck, Peter TI Combining biophysical methods for the analysis of protein complex stoichiometry and affinity in SEDPHAT SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article DE GMMA; SEDPHAT ID ISOTHERMAL TITRATION CALORIMETRY; FLUORESCENCE-DETECTED SEDIMENTATION; SURFACE-PLASMON RESONANCE; VELOCITY ANALYTICAL ULTRACENTRIFUGATION; MASS-TRANSPORT LIMITATION; LAMM EQUATION; COOPERATIVE INTERACTIONS; BINDING CONSTANTS; GLOBAL ANALYSIS; LIGAND-BINDING AB Reversible macromolecular interactions are ubiquitous in signal transduction pathways, often forming dynamic multi-protein complexes with three or more components. Multivalent binding and cooperativity in these complexes are often key motifs of their biological mechanisms. Traditional solution biophysical techniques for characterizing the binding and cooperativity are very limited in the number of states that can be resolved. A global multi-method analysis (GMMA) approach has recently been introduced that can leverage the strengths and the different observables of different techniques to improve the accuracy of the resulting binding parameters and to facilitate the study of multi-component systems and multi-site interactions. Here, GMMA is described in the software SEDPHAT for the analysis of data from isothermal titration calorimetry, surface plasmon resonance or other biosensing, analytical ultracentrifugation, fluorescence anisotropy and various other spectroscopic and thermodynamic techniques. The basic principles of these techniques are reviewed and recent advances in view of their particular strengths in the context of GMMA are described. Furthermore, a new feature in SEDPHAT is introduced for the simulation of multi-method data. In combination with specific statistical tools for GMMA in SEDPHAT, simulations can be a valuable step in the experimental design. C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Zhao, HY (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM zhaoh3@mail.nih.gov; schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 71 TC 8 Z9 8 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2015 VL 71 SI SI BP 3 EP 14 DI 10.1107/S1399004714010372 PN 1 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AZ9WE UT WOS:000348563900002 PM 25615855 ER PT J AU Kris-Etherton, PM Akabas, SR Douglas, P Kohlmeier, M Laur, C Lenders, CM Levy, MD Nowson, C Ray, S Pratt, CA Seidner, DL Saltzman, E AF Kris-Etherton, Penny M. Akabas, Sharon R. Douglas, Pauline Kohlmeier, Martin Laur, Celia Lenders, Carine M. Levy, Matthew D. Nowson, Caryl Ray, Sumantra Pratt, Charlotte A. Seidner, Douglas L. Saltzman, Edward TI Nutrition Competencies in Health Professionals' Education and Training: A New Paradigm SO ADVANCES IN NUTRITION LA English DT Editorial Material DE health professional; inter-professional; nutrition; nutrition education; competency-based education; health policy ID CLINICAL-OUTCOMES; CARE; CALL AB Most health care professionals are not adequately trained to address diet and nutrition-related issues with their patients, thus missing important opportunities to ameliorate chronic diseases and improve outcomes in acute illness. In this symposium, the speakers reviewed the status of nutrition education for health care professionals in the United States, United Kingdom, and Australia. Nutrition education is not required for educating and training physicians in many countries. Nutrition education for the spectrum of health care professionals is uncoordinated, which runs contrary to the current theme of interprofessional education. The central role of competencies in guiding medical education was emphasized and the urgent need to establish competencies in nutrition-related patient care was presented. The importance of additional strategies to improve nutrition education of health care professionals was highlighted. Public health legislation such as the Patient Protection and Affordable Care Act recognizes the role of nutrition, however, to capitalize on this increasing momentum, health care professionals must be trained to deliver needed services. Thus, there is a pressing need to garner support from stakeholders to achieve this goal. Promoting a research agenda that provides outcome-based evidence on individual and public health levels is needed to improve and sustain effective interprofessional nutrition education. C1 [Kris-Etherton, Penny M.] Penn State Univ, University Pk, PA 16802 USA. [Akabas, Sharon R.] Columbia Univ, New York, NY USA. [Douglas, Pauline] Univ Ulster, Coleraine BT52 1SA, Londonderry, North Ireland. [Kohlmeier, Martin] UNC Sch Med & Publ Hlth, Chapel Hill, NC USA. [Kohlmeier, Martin] UNC Nutr Res Inst, Chapel Hill, NC USA. [Laur, Celia; Ray, Sumantra] UK Med Res Council, Human Nutr Res Unit, Cambridge, England. [Lenders, Carine M.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Levy, Matthew D.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Levy, Matthew D.] Bipartisan Policy Ctr, University Pk, PA USA. [Nowson, Caryl] Deakin Univ, Sch Exercise & Nutr Sci, Geelong, Vic 3217, Australia. [Pratt, Charlotte A.] NIH, Bethesda, MD 20892 USA. [Seidner, Douglas L.] Vanderbilt Univ, Med Ctr, Nashville, TN 37235 USA. [Saltzman, Edward] Tufts Univ, Boston, MA 02111 USA. RP Kris-Etherton, PM (reprint author), Penn State Univ, University Pk, PA 16802 USA. EM pmk3@psu.edu FU American Society for Nutrition (ASN); ASN Medical Nutrition Council; ASH Global Nutrition Council; New Balance Foundation; Boston Nutrition Obesity Research Center [P30DK46200]; National Institute of Diabetes and Digestive and Kidney Diseases [5-K23DK082732]; Abbott Fund FX This article is a summary of the symposium "Nutrition Competencies in Health Professionals' Education and Training. A New Paradigm" held 27 April 2014 at the ASH Scientific Sessions and Annual Meeting at Experimental Biology 2014 in San Diego, CA. The symposium was sponsored by the American Society for Nutrition (ASN), the ASN Medical Nutrition Council, and the ASH Global Nutrition Council; ASN provided partial travel support for speakers to attend Experimental Biology 2014. CML received educational support for this activity from the New Balance Foundation (www.newbalancefoundation.org), Boston Nutrition Obesity Research Center (P30DK46200), National Institute of Diabetes and Digestive and Kidney Diseases (5-K23DK082732). Other support also includes the Abbott Fund (www.abbottfund.org). NR 20 TC 7 Z9 7 U1 1 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2015 VL 6 IS 1 BP 83 EP 87 DI 10.3945/an.114.006734 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AZ8SG UT WOS:000348484300008 PM 25593146 ER PT J AU Dwyer, JT Wiemer, KL Dary, O Keen, CL King, JC Miller, KB Philbert, MA Tarasuk, V Taylor, CL Gaine, PC Jarvis, AB Bailey, RL AF Dwyer, Johanna T. Wiemer, Kathryn L. Dary, Omar Keen, Carl L. King, Janet C. Miller, Kevin B. Philbert, Martin A. Tarasuk, Valerie Taylor, Christine L. Gaine, P. Courtney Jarvis, Ashley B. Bailey, Regan L. TI Fortification and Health: Challenges and Opportunities SO Advances in Nutrition LA English DT Article DE dietary intake; dietary supplements; folate; folic acid; vitamin B-9 ID CORONARY-ARTERY-DISEASE; USE DIETARY-SUPPLEMENTS; NEURAL-TUBE DEFECTS; FOOD FORTIFICATION; FOLIC-ACID; PROSPECTIVE COHORT; FLAVONOID INTAKE; US CHILDREN; NANOPARTICLES; VITAMIN AB Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness. C1 [Dwyer, Johanna T.] Tufts Med Ctr, Boston, MA 02111 USA. [Wiemer, Kathryn L.; Miller, Kevin B.] Gen Mills Inc, Minneapolis, MN USA. [Dary, Omar] Bur Global Hlth, Washington, DC USA. [Keen, Carl L.] Univ Calif Davis, Davis, CA 95616 USA. [King, Janet C.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Philbert, Martin A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Tarasuk, Valerie] Univ Toronto, Toronto, ON, Canada. [Taylor, Christine L.; Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Jarvis, Ashley B.] ILSI North Amer, Washington, DC USA. RP Dwyer, JT (reprint author), Tufts Med Ctr, Boston, MA 02111 USA. EM jciwyer1@tuftsmedicalcenter.org OI Dwyer, Johanna/0000-0002-0783-1769 FU American Society for Nutrition (ASN); International Life Sciences Institute (LSI), North America; ILSI North America Committee on Fortification FX This article is the result of presentations at the symposium "Fortification and Health: Opportunities and Challenges" held 26 April 2014 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 in San Diego, CA The symposium was sponsored by the American Society for Nutrition (ASN) and the International Life Sciences Institute (LSI), North America; Supported by the ILSI North America Committee on Fortification. Detailed information about the group can be found at http://www.ilsi.org/NorthAmerica/Pages/Fortification.aspx. ILSI North America is a public, nonprofit foundation that provides a forum to advance understanding of scientific issues related to the nutntional quality and safety of the food supply by sponsoring research programs, educational seminars and workshops, and publications. !LSI North America receives support primarily from its industry membership, which works collaboratively with academic scientific advisors on the development of its programs Science writer Densie Webb, PhD, RD, contributed to development of drafts of this article and received funds from the ILSI North America Committee on Fortification. This is a free access article, distributed under terms (http://www.nutritionorg/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 69 TC 6 Z9 6 U1 4 U2 36 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD JAN PY 2015 VL 6 IS 1 BP 124 EP 131 DI 10.3945/an.114.007443 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AZ8SG UT WOS:000348484300013 PM 25593151 ER PT J AU Newport, MT VanItallie, TB Kashiwaya, Y King, MT Veech, RL AF Newport, Mary T. VanItallie, Theodore B. Kashiwaya, Yoshihiro King, Michael Todd Veech, Richard L. TI A new way to produce hyperketonemia: Use of ketone ester in a case of Alzheimer's disease SO Alzheimers & Dementia LA English DT Article DE Ketone bodies; beta-Hydroxybutyrate; Pyruvate dehydrogenase; Brain insulin resistance; Fasting; Ketogenic diet; Medium-chain triglyceride; Ketone monoester ID BRAIN INSULIN-RESISTANCE; (R)-3-HYDROXYBUTYL (R)-3-HYDROXYBUTYRATE; KETOGENIC DIET; METABOLISM; BODIES; MILD AB Background: Providing ketone bodies to the brain can bypass metabolic blocks to glucose utilization and improve function in energy-starved neurons. For this, plasma ketones must be elevated well above the <= 0.2 mM default concentrations normally prevalent. Limitations of dietary methods currently used to produce therapeutic hyperketonemia have stimulated the search for better approaches. Method: Described herein is a new way to produce therapeutic hyperketonemia, entailing prolonged oral administration of a potent ketogenic agent-ketone monoester (KME)-to a patient with Alzheimer's disease dementia and a pretreatment Mini-Mental State Examination score of 12. Results: The patient improved markedly in mood, affect, self-care, and cognitive and daily activity performance. The KME was well tolerated throughout the 20-month treatment period. Cognitive performance tracked plasma beta-hydroxybutyrate concentrations, with noticeable improvements in conversation and interaction at the higher levels, compared with predose levels. Conclusion: KME-induced hyperketonemia is robust, convenient, and safe, and the ester can be taken as an oral supplement without changing the habitual diet. Published by Elsevier Inc. on behalf of The Alzheimer's Association. C1 [Newport, Mary T.] Spring Hill Neonatol Inc, Spring Hill, FL USA. [VanItallie, Theodore B.] St Lukes Hosp, Dept Med, New York, NY USA. [Kashiwaya, Yoshihiro] Tominaga Hosp, Div Neurol, Osaka, Japan. [King, Michael Todd; Veech, Richard L.] NIAAA, Lab Metab Control, NIH, Bethesda, MD 20892 USA. RP Veech, RL (reprint author), NIAAA, Lab Metab Control, NIH, Bethesda, MD 20892 USA. EM rlveech@comcast.net FU Intramural NIH HHS [Z01 AA000110-10] NR 23 TC 16 Z9 16 U1 6 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD JAN PY 2015 VL 11 IS 1 BP 99 EP 103 DI 10.1016/j.jalz.2014.01.006 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CA0UX UT WOS:000348632800009 PM 25301680 ER PT J AU Scheidweiler, KB Jarvis, MJY Huestis, MA AF Scheidweiler, Karl B. Jarvis, Michael J. Y. Huestis, Marilyn A. TI Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Synthetic cannabinoids; Urine; Metabolites; High-resolution mass spectrometry; Nontargeted; SWATH; LCMSMS ID HUMAN HEPATOCYTES; PYROLYSIS PRODUCT; SMOKING MIXTURES; LC-MS/MS; JWH-018; MS; IDENTIFICATION; IMMUNOASSAY; TOXICOLOGY; UR-144 AB Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative scheduling efforts, challenging and complicating toxicological analysis. Sundstrom et al. (Anal Bioanal Chem 405(26):8463-8474, [9]) and Kronstrand et al. (Anal Bioanal Chem 406(15):3599-3609, [10]) published nontargeted liquid chromatography, high-resolution, quadrupole/time-of-flight mass spectrometric (LC-QTOF) assays with validated detection of 18 and 38 urinary synthetic cannabinoid metabolites, respectively. We developed and validated a LC-QTOF urine method for simultaneously identifying the most current 47 synthetic cannabinoid metabolites from 21 synthetic cannabinoid families (5-fluoro AB-PINACA, 5-fluoro-AKB48, 5-fluoro PB-22, AB-PINACA, ADB-PINACA, AKB48, AM2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, JWH-398, MAM2201, PB-22, RCS-4, UR-144, and XLR11). beta-Glucuronidase-hydrolyzed urine was extracted with 1-mL Biotage SLE+ columns. Specimens were reconstituted in 150-mu L mobile phase consisting of 80 % A (0.1 % formic acid in water) and 20 % B (0.1 % formic acid in acetonitrile). Fifty microliters was injected, and SWATH (TM) MS data were acquired in positive electrospray mode. The LC-QTOF instrument consisted of a Shimadzu UFLCxr system and an ABSciex 5600+ TripleTOFA (R) mass spectrometer. Gradient chromatographic separation was achieved with a Restek Ultra Biphenyl column with a 0.5-mL/min flow rate and an overall run time of 15 min. Identification criteria included molecular ion mass error, isotopic profiles, retention time, and library fit criteria. Limits of detection were 0.25-5 mu g/L (N = 10 unique fortified urine samples), except for two PB-22 metabolites with limits of 10 and 20 mu g/L. Extraction efficiencies and matrix effects (N = 10) were 55-104 and -65-107 %, respectively. We present a highly useful novel LC-QTOF method for simultaneously confirming 47 synthetic cannabinoid metabolites in human urine. C1 [Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Jarvis, Michael J. Y.] AB Sciex, Concord, ON L4K 4V8, Canada. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, 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, National Institutes of Health FX The authors would like to recognize Xiang He and David Cox's advice during method development along with Kevin L. Klette and Thomas M. Martin for providing the anonymized authentic urine specimens from the Department of Defense drug testing program. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 41 TC 26 Z9 26 U1 12 U2 67 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2015 VL 407 IS 3 BP 883 EP 897 DI 10.1007/s00216-014-8118-8 PG 15 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AZ7ZY UT WOS:000348435600025 PM 25224637 ER PT J AU Liu, C Miao, LY Sun, WB Wu, XN Yan, FH Sun, HC Zheng, CY AF Liu, Chao Miao, Leiying Sun, Weibin Wu, Xiaonan Yan, Fuhua Sun, Hongchen Zheng, Changyu TI Assessment of Transfection of AdCMV-EGFP to Rat Submandibular Gland Cells SO CELL BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Gene transfection; Cell culture; Adenoviral vector ID GREEN FLUORESCENT PROTEIN; GENE-THERAPY; SALIVARY-GLANDS; DELIVERY; VECTORS; STRATEGIES; EXPRESSION; SYSTEMS; TISSUE AB We evaluated the efficiency of transfecting adenoviral vectors encoding enhanced green fluorescent protein (AdCMV-EGFP) into rat submandibular gland cells and the effects of gene transfer on cell proliferation and secretory function. Isolated submandibular gland cells were transfected with different titers (or multiplicity of infection, MOI) of AdCMV-EGFP. The transfection efficiency was evaluated by quantifying EGFP-positive cells by inverted fluorescence microscopy, cell proliferation by MTT assay, and cell secretory activity by measuring alpha-amylase in culture medium. A transfection efficiency of up to 70.8 % was achieved in submandibular gland cells. MTT assay showed that increased viral titers resulted in significant inhibition of cell proliferation, which occurs on day 5 post-transfection. Simultaneously, the amylase levels started to reduce with a significant decrease on day 7 after transfection. The results show that AdCMV-EGFP transfection of submandibular gland cells at higher MOI results in cytotoxicity, decreased cell proliferation, and secretory function. However, the lower adenoviral titers (e.g., 200 particles/cell) could be an efficient and safe labeling tool for gene transfer to submandibular gland cells. C1 [Liu, Chao; Miao, Leiying; Sun, Weibin; Wu, Xiaonan; Yan, Fuhua] Nanjing Univ, Inst & Hosp Stomatol, Dept Cariol & Endodont, Sch Med, Nanjing 210008, Peoples R China. [Sun, Hongchen] Jilin Univ, Sch Stomatol, Changchun 130021, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, DHHS, Bethesda, MD USA. RP Miao, LY (reprint author), Nanjing Univ, Inst & Hosp Stomatol, Dept Cariol & Endodont, Sch Med, Nanjing 210008, Peoples R China. EM mly0720@163.com; drhcsun@163.com FU National Natural Science Foundation [81271155, 30830108, 81300852]; Jiangsu Province Natural Science Foundation of China [BK20130079]; Science and Technology Bureau of Jiangsu Province [BL2013002]; Youth Start Fund of Nanjing City [2011-19-198*]; Third Level Fund for the Young Talents in the Health Field of Nanjing City FX This work was supported by Grants from the National Natural Science Foundation (No: 81271155, 30830108, 81300852), Jiangsu Province Natural Science Foundation of China (BK20130079), Key Project of Science and Technology Bureau of Jiangsu Province(No. BL2013002), the Youth Start Fund of Nanjing City, (No. 2011-19-198*), and The Third Level Fund for the Young Talents in the Health Field of Nanjing City. NR 26 TC 0 Z9 0 U1 2 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1085-9195 EI 1559-0283 J9 CELL BIOCHEM BIOPHYS JI Cell Biochem. Biophys. PD JAN PY 2015 VL 71 IS 1 BP 147 EP 153 DI 10.1007/s12013-014-0177-0 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AZ4XG UT WOS:000348223500021 PM 25108736 ER PT J AU Demner-Fushman, D Antani, S Kalpathy-Cramer, J Muller, H AF Demner-Fushman, Dina Antani, Sameer Kalpathy-Cramer, Jayashree Mueller, Henning TI A decade of community-wide efforts in advancing medical image understanding and retrieval SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Editorial Material C1 [Demner-Fushman, Dina; Antani, Sameer] Natl Lib Med, NIH, Bethesda, MD USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, Boston, MA USA. [Mueller, Henning] Univ Appl Sci Western Switzerland HES SO, Sierre, Switzerland. RP Muller, H (reprint author), Univ Appl Sci Western Switzerland HES SO, Sierre, Switzerland. EM henning.mueller@hevs.ch OI Muller, Henning/0000-0001-6800-9878; Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 NR 11 TC 0 Z9 0 U1 4 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD JAN PY 2015 VL 39 SI SI BP 1 EP 2 DI 10.1016/j.compmedimag.2014.12.002 PG 2 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AZ6NZ UT WOS:000348337500001 PM 25572585 ER PT J AU Simpson, MS You, D Rahman, MM Xue, ZY Demner-Fushman, D Antani, S Thoma, G AF Simpson, Matthew S. You, Daekeun Rahman, Md Mahmudur Xue, Zhiyun Demner-Fushman, Dina Antani, Sameer Thoma, George TI Literature-based biomedical image classification and retrieval SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article DE Image-based retrieval; Case-based retrieval; Modality classification; Compound figure separation ID TEXT; OPTIMIZATION AB Literature-based image informatics techniques are essential for managing the rapidly increasing volume of information in the biomedical domain. Compound figure separation, modality classification, and image retrieval are three related tasks useful for enabling efficient access to the most relevant images contained in the literature. In this article, we describe approaches to these tasks and the evaluation of our methods as part of the 2013 medical track of ImageCLEF. In performing each of these tasks, the textual and visual features used to represent images are an important consideration often left unaddressed. Therefore, we also describe a gradient-based optimization strategy for determining meaningful combinations of features and apply the method to the image retrieval task. An evaluation of our optimization strategy indicates the method is capable of producing statistically significant improvements in retrieval performance. Furthermore, the results of the 2013 ImageCLEF evaluation demonstrate the effectiveness of our techniques. In particular, our text-based and mixed image retrieval methods ranked first among all the participating groups. Published by Elsevier Ltd. C1 [Simpson, Matthew S.; You, Daekeun; Rahman, Md Mahmudur; Xue, Zhiyun; Demner-Fushman, Dina; Antani, Sameer; Thoma, George] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. RP Demner-Fushman, D (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. EM ddemner@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU intramural research program of the U.S. National Library of Medicine; National Institutes of Health FX This work is supported by the intramural research program of the U.S. National Library of Medicine, National Institutes of Health, and by appointments to the U.S. National Library of Medicine Research Participation Program administered by the Oak Ridge Institute for Science and Education. NR 32 TC 4 Z9 4 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD JAN PY 2015 VL 39 SI SI BP 3 EP 13 DI 10.1016/j.compmedimag.2014.06.006 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AZ6NZ UT WOS:000348337500002 PM 25016956 ER PT J AU Kalpathy-Cramer, J de Herrera, AGS Demner-Fushman, D Antani, S Bedrick, S Muller, H AF Kalpathy-Cramer, Jayashree de Herrera, Alba Garcia Seco Demner-Fushman, Dina Antani, Sameer Bedrick, Steven Mueller, Henning TI Evaluating performance of biomedical image retrieval systems An overview of the medical image retrieval task at ImageCLEF 2004-2013 SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article DE Multimodal medical retrieval; Image retrieval; Biomedical literature; Content-based retrieval; Text-based image retrieval ID INFORMATION; FUSION; TRACK; TEXT AB Medical image retrieval and classification have been extremely active research topics over the past 15 years. Within the ImageCLEF benchmark in medical image retrieval and classification, a standard test bed was created that allows researchers to compare their approaches and ideas on increasingly large and varied data sets including generated ground truth. This article describes the lessons learned in ten evaluation campaigns. A detailed analysis of the data also highlights the value of the resources created. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, Boston, MA USA. [de Herrera, Alba Garcia Seco; Mueller, Henning] Univ Appl Sci Western Switzerland HES SO, Sierre, Switzerland. [Demner-Fushman, Dina; Antani, Sameer] Natl Lib Med, NIH, Bethesda, MD USA. [Bedrick, Steven] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Kalpathy-Cramer, J (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM kalpathy@nmr.mgh.harvard.edu OI Bedrick, Steven/0000-0002-0163-9397; Muller, Henning/0000-0001-6800-9878; Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Antani, Sameer/0000-0002-0040-1387 FU NIH [U01CA154602, R00LM009889] FX JKC is funded in part by the NIH grants U01CA154602 and R00LM009889. NR 46 TC 11 Z9 11 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD JAN PY 2015 VL 39 SI SI BP 55 EP 61 DI 10.1016/j.compmedimag.2014.03.004 PG 7 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AZ6NZ UT WOS:000348337500007 PM 24746250 ER PT J AU King, HE Wetzell, B Rice, KC Riley, AL AF King, Heather E. Wetzell, Bradley Rice, Kenner C. Riley, Anthony L. TI An assessment of MDPV-induced place preference in adult Sprague-Dawley rats SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE MDPV; Place preference; Reward ID CONDITIONED TASTE-AVERSION; BATH SALTS; SYNTHETIC CATHINONES; MEASURING REWARD; ADDICTIVE DRUGS; APPARATUS BIAS; MOUSE STRAINS; COCAINE; AMPHETAMINE; PARADIGM AB Objective: Most drugs of abuse have both aversive and rewarding effects, and the use and abuse potential of such drugs is thought to be a function of a balance of these affective properties. Characterizing these effects and their relative balance may provide insight into abuse vulnerability. One drug that has received recent attention is methylenedioxypyrovalerone (MDPV), a monoamme transport inhibitor similar to, but significantly more potent than, cocaine. MDPV is self-administered and has been shown to produce aversive and rewarding effects in adult rats. The present study extended this characterization of the affective properties of MDPV by examining its ability to support place conditioning at a range of doses known to produce taste avoidance. Methods: Male Sprague-Dawley rats were injected with MDPV (1, 1.8 or 3.2 mg/kg) or saline and placed on the non-preferred side of a place conditioning apparatus for 30 min. On the next day, they were given an injection of saline and placed on the preferred side. This was repeated three times for a total of four conditioning cycles, and side preference was assessed on a final test. Results: All doses of MDPV produced significant increases in time spent in the drug-paired chamber, an effect not seen in vehicle-treated animals. Conclusions: That the same doses of MDPV induced both taste avoidance and place preference allows assessments of how other factors might impact these effects and how they may, in turn, contribute to its abuse liability. (C) 2014 Published by Elsevier Ireland Ltd. C1 [King, Heather E.; Wetzell, Bradley; Riley, Anthony L.] Amer Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD 20892 USA. RP King, HE (reprint author), Amer Univ, Dept Psychol, 4400 Massachusetts Ave,NW, Washington, DC 20016 USA. EM hk9905a@american.edu RI Wetzell, B Bradley/J-6802-2013 OI Wetzell, B Bradley/0000-0002-2723-5542 FU Mellon Foundation FX This research was supported by a grant from the Mellon Foundation to ALR. The Mellon Foundation had no further role in the study design, data collection, analysis and interpretation, the writing of the report, or the decision to submit the manuscript for publication. NR 49 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 1 PY 2015 VL 146 BP 116 EP 119 DI 10.1016/j.drugalcdep.2014.11.002 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AZ5LD UT WOS:000348261600018 PM 25468817 ER PT J AU Dzutsev, A Goldszmid, RS Viaud, S Zitvogel, L Trinchieri, G AF Dzutsev, Amiran Goldszmid, Romina S. Viaud, Sophie Zitvogel, Laurence Trinchieri, Giorgio TI The role of the microbiota in inflammation, carcinogenesis, and cancer therapy SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Review DE Cancer; Cancer Therapy; Cancerogenesis; Inflammation; Microbiota ID SEGMENTED FILAMENTOUS BACTERIA; HEPATITIS-B-VIRUS; MERKEL CELL POLYOMAVIRUS; GUT MICROBIOTA; INTESTINAL MICROBIOTA; IMMUNE-SYSTEM; HUMAN-PAPILLOMAVIRUS; HELICOBACTER-PYLORI; DENDRITIC CELLS; MYELOID CELLS AB Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments. C1 [Dzutsev, Amiran; Goldszmid, Romina S.; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Dzutsev, Amiran] Leidos Biomed Res Inc, Frederick, MD USA. [Viaud, Sophie; Zitvogel, Laurence] Inst Gustave Roussy, INSERM, U1015, F-94805 Villejuif, France. [Viaud, Sophie; Zitvogel, Laurence] Univ Paris 11, Le Kremlin Bicetre, France. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 560 Room 31-93, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov FU National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN26120080001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract HHSN26120080001E. 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 185 TC 16 Z9 20 U1 6 U2 37 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 JAN PY 2015 VL 45 IS 1 BP 17 EP 31 DI 10.1002/eji.201444972 PG 15 WC Immunology SC Immunology GA AZ0SO UT WOS:000347955100004 PM 25328099 ER PT J AU Tripathi, BK Lowy, DR Zelenka, PS AF Tripathi, Brajendra K. Lowy, Douglas R. Zelenka, Peggy S. TI The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Cdk5; p39; Muskelin; Myosin; Stress fibers; Cytoskeleton; Cell migration; Lens ID ESSENTIAL LIGHT-CHAIN; CELL-MIGRATION; DEPENDENT KINASE; PHOSPHORYLATION; FILAMENT; DIFFERENTIATION; MECHANISMS; EXPRESSION; ADHESION; MEDIATOR AB Cyclin dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, requires p39 for its enzymatic activity, and is implicated in cytoskeletal organization and contraction in numerous cell types. The C-terminus of p39 binds muskelin, a multi-domain scaffolding protein known to affect cytoskeletal organization, but the mechanisms by which muskelin affects cytoskeletal organization remain unclear. The present study sought to determine whether p39 might serve as an adaptor protein that links muskelin to stress fibers and to investigate the possible biological relevance of such an interaction. Double immunoprecipitation showed that muskelin, p39, and myosin II are components of a single intracellular complex, and suppressing p39 abrogated the interaction between muskelin and the myosin subunits, demonstrating that p39 is required to link muskelin to myosin II. Muskelin is colocalized with myosin regulatory light chain (MRLC) and on stress fibers. The suppression of muskelin reduced Rho-GTP, MRLC phosphorylation, disrupted stress fiber organization, and promoted cell migration, all of which closely mimic the effect of Cdk5 inhibition. Moreover, suppressing muskelin and inhibiting Cdk5 together have no additional effect, indicating that muskelin plays an important role in Cdk5-dependent signaling. p39 is necessary and sufficient for Cdk5-dependent regulation of MRLC phosphorylation, as suppression of p39, but not p35, reduces MRLC phosphorylation. Together, these results demonstrate that p39 specifically links muskelin to myosin II and consequently, to stress fibers and reveal a novel role for muskelin in regulating myosin phosphorylation and cytoskeletal organization. Published by Elsevier Inc. C1 [Tripathi, Brajendra K.; Lowy, Douglas R.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Tripathi, Brajendra K.; Zelenka, Peggy S.] NEI, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Tripathi, BK (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Room 4112, Bethesda, MD 20892 USA. EM tripathib@mail.nih.gov FU National Institutes of Health, USA, Intramural Research Program [Z01-EY000238-20] FX We thank Dr. John Reddan, Oakland University, for providing the human lens epithelial cells (FHL124), the NIH Imaging Core Facility for confocal microscopy, and the FACS Core facility for isolating the GFP-positive transfected cells. This work is supported by the National Institutes of Health, USA, Intramural Research Program Z01-EY000238-20. NR 39 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD JAN 1 PY 2015 VL 330 IS 1 BP 186 EP 198 DI 10.1016/j.yexcr.2014.08.003 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ7PX UT WOS:000348411500016 PM 25128817 ER PT J AU Nemeth, K Mezey, E AF Nemeth, Krisztian Mezey, Eva TI Bone marrow stromal cells as immunomodulators. A primer for dermatologists SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Review DE Bone marrow stromal cells; Mesenchymal stem cells; Immunomodulation; Inflammatory; Skin conditions ID MESENCHYMAL STEM-CELLS; VERSUS-HOST-DISEASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PROGRESSIVE MULTIPLE-SCLEROSIS; HEMATOPOIETIC STEM; PEDIATRIC-PATIENTS; IN-VITRO; INDOLEAMINE 2,3-DIOXYGENASE; HEMATOLOGIC MALIGNANCY AB Bone marrow stromal cells (BMSCs, also known as mesenchymal stem cells or MSCs) represent a unique cell population in the bone marrow with a long-known function to support hematopoiesis and replace skeletal tissues. The recent discovery that BMSCs also possess potent immunoregulatory features attracted a great deal of attention from stem cell biologists, immunologists and clinicians of different specialties worldwide. Initial clinical experience along with several animal models suggested that intravenously delivered BMSCs are able to regulate a wide variety of host immune cells and act in a way that is beneficial for the recipient in a variety of diseases. The role of the present review is to give a short introduction to the biology of BMSCs and to summarize our current understanding of how BMSCs modulate the immune system with special emphasis on available clinical data. Considering the audience of this journal we will also attempt to guide dermatologists in choosing the right skin conditions where BMSCs might be considered as a therapeutic alternative. Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology. C1 [Nemeth, Krisztian; Mezey, Eva] NIDCR, Adult Stem Cell Sect, CSDB, NIH, Bethesda, MD USA. RP Nemeth, K (reprint author), NIDCR, Adult Stem Cell Sect, CSDB, NIH, Bethesda, MD USA. EM nemethk@mail.nih.gov FU NIH, NIDCR Intramural Research Program FX This work was supported by the NIH, NIDCR Intramural Research Program. We would like to thank Dr. Sarolta Karpati for her expert opinion regarding possible uses of MSCs in dermatology. NR 112 TC 4 Z9 4 U1 2 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 EI 1873-569X J9 J DERMATOL SCI JI J. Dermatol. Sci. PD JAN PY 2015 VL 77 IS 1 BP 11 EP 20 DI 10.1016/j.jdermsci.2014.10.004 PG 10 WC Dermatology SC Dermatology GA CA0PO UT WOS:000348619500002 PM 25476233 ER PT J AU Kondo, T Namiki, T Coelho, SG Valencia, JC Hearing, VJ AF Kondo, Taisuke Namiki, Takeshi Coelho, Sergio G. Valencia, Julio C. Hearing, Vincent J. TI Oculocutaneous albinism: Developing novel antibodies targeting the proteins associated with OCA2 and OCA4 SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Article DE OCA2; OCA4; P protein; MATP protein; BLOC-1; Albinism ID LYSOSOME-RELATED ORGANELLES; MELANOSOMAL PROTEINS; SKIN PIGMENTATION; EYE COLOR; GENE; MELANOCYTES; TRAFFICKING; MUTATION; BLOC-2; AP-3 AB Background: Patients with oculocutaneous albinism (OCA) have severely decreased pigmentation of their skin, hair and eyes. OCA2 and OCA4 result from mutations of the OCA2 and SLC45A2 genes, respectively, both of which disrupt the trafficking of the critical melanogenic enzyme tyrosinase to melanosomes. Both proteins encoded by those loci (termed P and MATP, respectively) have 12 putative transmembrane regions and are thought to function as transporters, although their functions and subcellular localizations remain to be characterized. Objective: To generate specific antibodies against unique synthetic peptides encoded by P and MATP that could be used to characterize their functions and subcellular localizations. Methods: Western blotting and immunohistochemistry were used to assess the specificity of antibodies and to colocalize P and MATP proteins with various subcellular markers. Results: Specific antibodies to the P and MATP proteins were generated that work well for Western blotting and immunohistochemistry. The localizations of P and MATP with various subcellular organelles were characterized using confocal microscopy, which revealed that they colocalize to some extent with LAMP2, but do not significantly colocalize with markers of the ER, Golgi or melanosomes. Interestingly, both P and MATP colocalize significantly with BLOC-1, a sorting component involved in the intracellular trafficking of melanosomal/lysosomal constituents. Conclusion: These results provide a basis to understand how disrupted functions of P or MATP result in the misrouting of tyrosinase and cause the hypopigmentation seen in OCA2 and OCA4. (C) 2014 Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology. C1 [Kondo, Taisuke; Namiki, Takeshi; Coelho, Sergio G.; Valencia, Julio C.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132,MSC 4256, Bethesda, MD 20892 USA. EM hearingv@nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. The authors wish to thank Joe Mindell and Pascal Courville of NINDS and David Adams of NHGRI for advice and useful discussions about this study. NR 42 TC 1 Z9 2 U1 1 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 EI 1873-569X J9 J DERMATOL SCI JI J. Dermatol. Sci. PD JAN PY 2015 VL 77 IS 1 BP 21 EP 27 DI 10.1016/j.jdermsci.2014.11.006 PG 7 WC Dermatology SC Dermatology GA CA0PO UT WOS:000348619500003 PM 25530116 ER PT J AU Murphy, E AF Murphy, Elizabeth TI Solving mitochondrial mysteries SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID PERMEABILITY TRANSITION PORE; ATP SYNTHASE; PROTEIN-DEGRADATION; CALCIUM UNIPORTER; INNER MEMBRANE; C-SUBUNIT C1 NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [ZIA HL002066] NR 30 TC 1 Z9 1 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JAN PY 2015 VL 78 BP 1 EP 2 DI 10.1016/j.yjmcc.2014.11.016 PG 2 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AZ8SH UT WOS:000348484400001 PM 25463271 ER PT J AU Harrington, JL Murphy, E AF Harrington, Josephine L. Murphy, Elizabeth TI The mitochondrial calcium uniporter: Mice can live and die without it SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Mitochondria; Calcium; Necrosis; Ischemia-reperfusion; Mitochondrial permeability pore ID RAT-HEART MITOCHONDRIA; CA2+ UNIPORTER; RUTHENIUM RED; OXIDATIVE-PHOSPHORYLATION; PERMEABILITY TRANSITION; ENDOPLASMIC-RETICULUM; ESSENTIAL COMPONENT; CYCLOSPORINE-A; CELL-DEATH; MCU AB Calcium is of critical importance to mitochondrial and cell function, and calcium signaling is highly localized in the cell. When stimulated, mitochondria are capable of rapidly taking up calcium, affecting both matrix energetics within mitochondria and shaping the amplitude and frequency of cytosolic calcium "waves". During pathological conditions a large increase in mitochondrial calcium levels is thought to activate the mitochondrial permeability transition pore, resulting in cell death. The protein responsible for mitochondrial calcium uptake, the mitochondrial calcium uniporter (MCU), was identified in 2011 and its molecular elucidation has stimulated and invigorated research in this area. MCU knockout mice have been created, a variety of other regulators have been identified, and a disease phenotype in humans has been attributed to the loss of a uniporter regulator. In the three years since its molecular elucidation, further research into the MCU has revealed a complex uniporter, and raised many questions about its physiologic and pathologic cell roles. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". Published by Elsevier Ltd. C1 [Harrington, Josephine L.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD USA. RP Murphy, E (reprint author), NHLBI, NIH, Mail Stop 1770, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU NHLBI [ZIA HL002066]; National Institutes of Health (NIH) Medical Research Scholars Program [ZIA HL002065]; NIH FX EM was supported by the NHLBI Intramural Research Program (ZIA HL002066). Support for JH was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program (ZIA HL002065), a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-researchscholars-progr am. NR 72 TC 10 Z9 10 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JAN PY 2015 VL 78 BP 46 EP 53 DI 10.1016/j.yjmcc.2014.10.013 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AZ8SH UT WOS:000348484400006 PM 25451167 ER PT J AU Chan, XCY Black, CM Lin, AJ Ping, PP Lau, E AF Chan, X'avia C. Y. Black, Caitlin M. Lin, Amanda J. Ping, Peipei Lau, Edward TI Mitochondrial protein turnover: Methods to measure turnover rates on a large scale SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Mitochondria; Protein turnover; Proteome dynamics; Proteomics; Heavy water ID ISOTOPOMER DISTRIBUTION ANALYSIS; HEART-FAILURE; IN-VIVO; CARDIAC MITOCHONDRIA; CALORIC RESTRICTION; MASS-SPECTROMETRY; MAMMALIAN-CELLS; ANIMAL-CELLS; AMINO-ACIDS; DYNAMICS AB Mitochondrial proteins carry out diverse cellular functions including ATP synthesis, ion homeostasis, cell death signaling, and fatty acid metabolism and biogenesis. Compromised mitochondrial quality control is implicated in various human disorders including cardiac diseases. Recently it has emerged that mitochondrial protein turnover can serve as an informative cellular parameter to characterize mitochondrial quality and uncover disease mechanisms. The turnover rate of a mitochondrial protein reflects its homeostasis and dynamics under the quality control systems acting on mitochondria at a particular cell state. This review article summarizes some recent advances and outstanding challenges for measuring the turnover rates of mitochondrial proteins in health and disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". (C) 2014 Elsevier Ltd. All rights reserved. C1 [Chan, X'avia C. Y.; Black, Caitlin M.; Lin, Amanda J.; Ping, Peipei; Lau, Edward] Univ Calif Los Angeles, NHLBI, Prote Ctr, Los Angeles, CA 90095 USA. [Chan, X'avia C. Y.; Black, Caitlin M.; Lin, Amanda J.; Ping, Peipei; Lau, Edward] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Bioinformat, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, 675 Charles E Young Dr S1-619, Los Angeles, CA 90095 USA. EM pping@mednet.ucla.edu; edwardlau@ucla.edu OI Ping, Peipei/0000-0003-3583-3881; Lau, Edward/0000-0001-9083-5922 FU National Institutes of Health [HL-R37-63901, HHSN268201000035C]; T.C. Laubisch endowment at UCLA; American Heart Association [12PRE11610024] FX This work was supported by the National Institutes of Health awards HL-R37-63901 and HHSN268201000035C, the T.C. Laubisch endowment at UCLA to Peipei Ping; and the American Heart Association fellowships 12PRE11610024 to Edward Lau. NR 72 TC 5 Z9 5 U1 2 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JAN PY 2015 VL 78 BP 54 EP 61 DI 10.1016/j.yjmcc.2014.10.012 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AZ8SH UT WOS:000348484400007 PM 25451168 ER PT J AU Perry, MR Benson, EM Kohne, JW Plahovinsak, JL Babin, MC Platoff, GE Yeung, DT AF Perry, Mark R. Benson, Eric M. Kohne, Jonathon W. Plahovinsak, Jennifer L. Babin, Michael C. Platoff, Gennady E., Jr. Yeung, David T. TI A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Dosimetry; Inhalation exposure; Inhaled dose; Methods; Sulfur mustard vapor AB Introduction: A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. Methods: Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by an in-line pneumotach, pressure transducer, and Buxco pulmonary analysis computer/software. For each exposure, the challenge atmosphere was allowed to stabilize at the desired concentration while the anesthetized animal was provided humidity controlled clean air. Once the target concentration was achieved and stable, a portion of the challenge atmosphere was drawn past the endotracheal tube, where the animal inhaled the exposure ad libitum. During the exposure, HD vapor concentration and animal weight were used to calculate the needed inhaled volume to achieve the target inhaled dose (mu g/kg). The exposures were halted when the inhaled volume was achieved. Results: The exposure system successfully controlled HD concentrations from 22.2 to 278 mg/m(3) and accurately delivered inhaled doses between 49.3 and 1120 mu g/kg with actual administered doses being within 4% of the target level. Discussion: This exposure system administers specific HD inhaled doses to evaluate physiological effects and for evaluation of potential medical countermeasure treatments. (C) 2014 Elsevier Inc. All rights reserved. C1 [Perry, Mark R.; Benson, Eric M.; Kohne, Jonathon W.; Plahovinsak, Jennifer L.; Babin, Michael C.] Battelle Biomed Res Ctr, Columbus, OH 43201 USA. [Platoff, Gennady E., Jr.] NIAID, NIH, Bethesda, MD 20892 USA. [Yeung, David T.] NINDS, NIH, Bethesda, MD 20892 USA. RP Perry, MR (reprint author), Battelle Biomed Res Ctr, 505 King Ave, Columbus, OH 43201 USA. EM perrym@battelle.org OI /0000-0001-5692-0170 FU National Institutes of Health (NIH) [Y1-OD-0387-01]; National Institute of Allergy and Infectious Diseases (NIAID); Department of Defense (DoD); NIH; NIAID; National Institute of Neurological Disorders and Stroke (NINDS); DoD Defense Technical Information Center (DTIC) under the Chemical, Biological, Radiological & Nuclear Defense Information Analysis Center (CBRNIAC) program [SP0700-00-D-3180, 0687, 832/CB-IO-OOI2] FX This work was supported by the National Institutes of Health (NIH) Office of the Director through an interagency agreement (OD#: Y1-OD-0387-01) between the National Institute of Allergy and Infectious Diseases (NIAID) and Department of Defense (DoD) and prepared under the auspices of the NIH, NIAID, National Institute of Neurological Disorders and Stroke (NINDS), and DoD Defense Technical Information Center (DTIC) under the Chemical, Biological, Radiological & Nuclear Defense Information Analysis Center (CBRNIAC) program, contract no. SP0700-00-D-3180, delivery order number 0687, CBRNIAC Task 832/CB-IO-OOI2. NR 21 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD JAN-FEB PY 2015 VL 71 BP 120 EP 128 DI 10.1016/j.vascn.2014.09.009 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AZ8FX UT WOS:000348451500017 PM 25291290 ER PT J AU Noursi, S Begg, L Lee, N Clayton, JA AF Noursi, Samia Begg, Lisa Lee, Nancy Clayton, Janine Austin TI Intimate Partner Violence, Consequences on Women's Health, and Promising Interventions Introduction SO JOURNAL OF WOMENS HEALTH LA English DT Editorial Material C1 [Noursi, Samia] NIDA, Women & Sex Gender Differences Res Program, NIH, Bethesda, MD 20892 USA. [Begg, Lisa] NIH, Off Res Womens Hlth, Off NIH Director DPCPSI, Bethesda, MD 20892 USA. [Lee, Nancy] US Dept HHS, Off Secretary, Washington, DC 20201 USA. [Clayton, Janine Austin] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Clayton, Janine Austin] NIH, Bethesda, MD 20892 USA. RP Noursi, S (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM snoursi@mail.nih.gov NR 4 TC 0 Z9 0 U1 3 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JAN 1 PY 2015 VL 24 IS 1 BP 49 EP 50 DI 10.1089/jwh.2014.1516 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AZ6JC UT WOS:000348325100009 PM 25549341 ER PT J AU Weaver, TL Gilbert, L El-Bassel, N Resnick, HS Noursi, S AF Weaver, Terri L. Gilbert, Louisa El-Bassel, Nabila Resnick, Heidi S. Noursi, Samia TI Identifying and Intervening with Substance-Using Women Exposed to Intimate Partner Violence: Phenomenology, Comorbidities, and Integrated Approaches Within Primary Care and Other Agency Settings SO JOURNAL OF WOMENS HEALTH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PERPETRATOR ALCOHOL-USE; POSTTRAUMATIC-STRESS; DRUG-USE; EMERGENCY CARE; HIV PREVENTION; PTSD SYMPTOMS; UNITED-STATES; USE DISORDERS; METAANALYSIS AB Substance use and/or disorders (SUDs) have been identified as a significant correlate of intimate partner violence (IPV) exposure and present complex issues that intersect with the topography of IPV, attendant mental health, and physical co-morbidities and may pose barriers to primary care- and other agency-based screening and intervention efforts. Despite substantial research indicating significantly higher rates of all types and severity of IPV victimization among women with SUDs and bidirectional associations between partner or self-use of drugs or alcohol and IPV victimization, effective screening, brief interventions, coordinated systems of care, and treatment approaches to address these co-occurring problems remain very limited. We integrated select research examining the intersection of IPV victimization and SUDs and several comorbidities that have significant public health impact and provided recommendations for scaling up targeted interventions to redress these co-occurring problems among women in primary, emergency, and other care settings. C1 [Weaver, Terri L.] St Louis Univ, Dept Psychol, St Louis, MO 63108 USA. [Gilbert, Louisa; El-Bassel, Nabila] Columbia Univ, Sch Social Work, New York, NY USA. [Resnick, Heidi S.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Noursi, Samia] NIDA, NIH, Bethesda, MD 20892 USA. RP Weaver, TL (reprint author), St Louis Univ, Dept Psychol, 3700 Lindell Blvd,Morrissey Hall,Suite 2729, St Louis, MO 63108 USA. EM weavert@slu.edu FU NIDA [R01DA023099] FX Dr. Resnick's effort was partially supported by NIDA grant R01DA023099 (PI: Resnick). Views expressed herein are those of the authors and do not necessarily reflect those of NIDA or other institutions. NR 46 TC 3 Z9 3 U1 4 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JAN 1 PY 2015 VL 24 IS 1 BP 51 EP 56 DI 10.1089/jwh.2014.4866 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AZ6JC UT WOS:000348325100010 PM 25554915 ER PT J AU Ghandour, RM Campbell, JC Lloyd, J AF Ghandour, Reem M. Campbell, Jacquelyn C. Lloyd, Jacqueline TI Screening and Counseling for Intimate Partner Violence: A Vision for the Future SO JOURNAL OF WOMENS HEALTH LA English DT Article ID PREVENTIVE SERVICES; CARE SETTINGS; SURVIVORS; WOMEN; INTERVENTION; HEALTH; ABUSE AB We describe a vision of screening and intervention for Intimate Partner Violence informed by deliberations during the December 2013 Intimate Partner Violence Screening and Counseling Research Symposium and the resultant manuscripts featured in this special issue of the Journal of Women's Health. Our vision includes universal screening and intervention, when indicated, which occurs routinely as part of comprehensive physical and behavioral health services that are both patient centered and trauma informed. Areas for future research needed to realize this vision are discussed. C1 [Ghandour, Reem M.] Maternal & Child Hlth Bur, US Dept HHS, Hlth Resources & Serv Adm, Off Epidemiol & Res, Rockville, MD 20857 USA. [Campbell, Jacquelyn C.] Johns Hopkins Univ, Sch Nursing, Dept Community Publ Hlth, Baltimore, MD USA. [Lloyd, Jacqueline] NIDA, US Dept HHS, NIH, Div Epidemiol Serv & Prevent Res,Prevent Res Bran, Bethesda, MD 20892 USA. RP Ghandour, RM (reprint author), Maternal & Child Hlth Bur, Div Epidemiol, Off Epidemiol & Res, Hlth Resources & Serv Adm, 5600 Fishers Lane,Room 10-77, Rockville, MD 20857 USA. EM rghandour@hrsa.gov NR 34 TC 8 Z9 8 U1 5 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JAN 1 PY 2015 VL 24 IS 1 BP 57 EP 61 DI 10.1089/jwh.2014.4885 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AZ6JC UT WOS:000348325100011 PM 25405270 ER PT J AU Hamberger, LK Rhodes, K Brown, J AF Hamberger, L. Kevin Rhodes, Karin Brown, Jeremy TI Screening and Intervention for Intimate Partner Violence in Healthcare Settings: Creating Sustainable System-Level Programs SO JOURNAL OF WOMENS HEALTH LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; DOMESTIC VIOLENCE; WOMEN; EMERGENCY; BARRIERS; VICTIMS; MODEL; IDENTIFICATION; OUTCOMES; ALCOHOL AB Among the barriers to routine screening for intimate partner violence (IPV) are time constraints, a lack of protocols and policies, and departmental philosophies of care that may conflict with IPV screening recommendations. To address these barriers, systems-level interventions are needed; in this article, we describe one model that may overcome these obstacles. We discuss how this systemic approach may best be implemented in both out-patient clinics and emergency departments (EDs) and note that evidence for its success will be required. C1 [Hamberger, L. Kevin] Med Coll Wisconsin, Dept Family & Community Med, Milwaukee, WI 53226 USA. [Rhodes, Karin] Univ Penn, Dept Emergency Med, Perlman Sch Med, Philadelphia, PA 19104 USA. [Brown, Jeremy] NIH, Off Emergency Care Res, Bethesda, MD 20892 USA. RP Hamberger, LK (reprint author), Wheaton Franciscan All St Family Care Ctr, 2400 W Villard Ave, Milwaukee, WI 53209 USA. EM kevinh@mcw.edu FU HHS FX This article is based on presentations by the authors at the HHS-sponsored Intimate Partner Violence Screening and Counseling Research Symposium, December 9, 2013, Rockville, MD. NR 57 TC 1 Z9 1 U1 4 U2 15 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JAN 1 PY 2015 VL 24 IS 1 BP 86 EP 91 DI 10.1089/jwh.2014.4861 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AZ6JC UT WOS:000348325100014 PM 25412012 ER PT J AU Miller, E McCaw, B Humphreys, BL Mitchell, C AF Miller, Elizabeth McCaw, Brigid Humphreys, Betsy L. Mitchell, Connie TI Integrating Intimate Partner Violence Assessment and Intervention into Healthcare in the United States: A Systems Approach SO JOURNAL OF WOMENS HEALTH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DOMESTIC VIOLENCE; PREVENTIVE SERVICES; WOMENS EXPERIENCES; MEDICAL-CARE; PANDORA BOX; BARRIERS; ABUSE; SETTINGS; PROGRAM AB The Institute of Medicine, United States Preventive Services Task Force (USPSTF), and national healthcare organizations recommend screening and counseling for intimate partner violence (IPV) within the US healthcare setting. The Affordable Care Act includes screening and brief counseling for IPV as part of required free preventive services for women. Thus, IPV screening and counseling must be implemented safely and effectively throughout the healthcare delivery system. Health professional education is one strategy for increasing screening and counseling in healthcare settings, but studies on improving screening and counseling for other health conditions highlight the critical role of making changes within the healthcare delivery system to drive desired improvements in clinician screening practices and health outcomes. This article outlines a systems approach to the implementation of IPV screening and counseling, with a focus on integrated health and advocacy service delivery to support identification and interventions, use of electronic health record (EHR) tools, and cross-sector partnerships. Practice and policy recommendations include (1) ensuring staff and clinician training in effective, client-centered IPV assessment that connects patients to support and services regardless of disclosure; (2) supporting enhancement of EHRs to prompt appropriate clinical care for IPV and facilitate capturing more detailed and standardized IPV data; and (3) integrating IPV care into quality and meaningful use measures. Research directions include studies across various health settings and populations, development of quality measures and patient-centered outcomes, and tests of multilevel approaches to improve the uptake and consistent implementation of evidence-informed IPV screening and counseling guidelines. C1 [Miller, Elizabeth] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Div Adolescent & Young Adult Med, Pittsburgh, PA 15213 USA. [McCaw, Brigid] Kaiser Permanente, Family Violence Prevent Program, Oakland, CA USA. [Humphreys, Betsy L.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Mitchell, Connie] Calif Dept Publ Hlth, Ctr Family Hlth, Sacramento, CA USA. RP Miller, E (reprint author), Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Div Adolescent & Young Adult Med, 3420 Fifth Ave, Pittsburgh, PA 15213 USA. EM elizabeth.miller@chp.edu FU National Institute of Child Health and Human Development [R01HD064407]; Intramural Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) FX This article was supported in part by funding from the National Institute of Child Health and Human Development (R01HD064407, Miller). This work was supported in part by the Intramural Program of the National Institutes of Health (NIH), National Library of Medicine (NLM). NR 65 TC 15 Z9 15 U1 5 U2 28 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JAN 1 PY 2015 VL 24 IS 1 BP 92 EP 99 DI 10.1089/jwh.2014.4870 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AZ6JC UT WOS:000348325100015 PM 25606823 ER PT J AU Vrancken, B Lemey, P Rambaut, A Bedford, T Longdon, B Guenthard, HF Suchard, MA AF Vrancken, Bram Lemey, Philippe Rambaut, Andrew Bedford, Trevor Longdon, Ben Guenthard, Huldrych F. Suchard, Marc A. TI Simultaneously estimating evolutionary history and repeated traits phylogenetic signal: applications to viral and host phenotypic evolution SO METHODS IN ECOLOGY AND EVOLUTION LA English DT Article DE adaptation; Bayesian phylogenetics; comparative approach; virulence; virus evolution ID NEUTRALIZING ANTIBODIES; DRUG-RESISTANCE; HIV-1 INFECTION; INFLUENZA-VIRUS; MODELS; DYNAMICS; ADAPTATION; TIME; EPIDEMIOLOGY; TRANSMISSION AB Phylogenetic signal quantifies the degree to which resemblance in continuously valued traits reflects phylogenetic relatedness. Measures of phylogenetic signal are widely used in ecological and evolutionary research and are recently gaining traction in viral evolutionary studies. Standard estimators of phylogenetic signal frequently condition on data summary statistics of the repeated trait observations and fixed phylogenetics trees, resulting in information loss and potential bias. To incorporate the observation process and phylogenetic uncertainty in a model-based approach, we develop a novel Bayesian inference method to simultaneously estimate the evolutionary history and phylogenetic signal from molecular sequence data and repeated multivariate traits. Our approach builds upon a phylogenetic diffusion framework that models continuous trait evolution as a Brownian motion process and incorporates Pagel's transformation parameter to estimate dependence among traits. We provide a computationally efficient inference implementation in the BEAST software package. We evaluate the synthetic performance of the Bayesian estimator of phylogenetic signal against standard estimators and demonstrate the use of our coherent framework to address several virus-host evolutionary questions, including virulence heritability for HIV, antigenic evolution in influenza and HIV, and Drosophila sensitivity to sigma virus infection. Finally, we discuss model extensions that will make useful contributions to our flexible framework for simultaneously studying sequence and trait evolution. C1 [Vrancken, Bram; Lemey, Philippe] KU Leuven Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Longdon, Ben] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Guenthard, Huldrych F.] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath & Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. RP Vrancken, B (reprint author), KU Leuven Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. EM bram.vrancken@rega.kuleuven.be RI SHCS, int. coll. B/G-4090-2011; SHCS, all/G-4072-2011; Longdon, Ben/F-4132-2010; Infektiologie, USZ/A-6921-2011; gunthard, huldrych/F-1724-2011; OI Longdon, Ben/0000-0001-6936-1697; gunthard, huldrych/0000-0002-1142-6723; Bedford, Trevor/0000-0002-4039-5794; Rambaut, Andrew/0000-0003-4337-3707 FU European Union [278433-PREDEMICS, 223131]; ERC [260864]; National Institutes of Health [R01 AI107034, R01 HG006139]; National Science Foundation [DMS 1264153, IIS 1251151]; Fonds door Wetenschappelijk Onderzoek Vlaanderen (FWO) [1.5.252.12N]; Swiss HIV Cohort Study - Swiss National Science Foundation (SNF) [33CS30-134277, 33CS30-148522]; SHCS [470, 528, 569]; SHCS Research Foundation; Swiss National Science Foundation [324730-130865]; Yvonne-Jacob Foundation; Union Bank of Switzerland; Gilead, Switzerland; University of Zurichs Clinical Research Priority Program (CRPP) Viral Infectious Diseases: Zurich Primary HIV Infection Study FX The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement No. 278433-PREDEMICS and ERC Grant Agreement No. 260864. This work was also supported by National Institutes of Health Grants R01 AI107034 and R01 HG006139 and National Science Foundation Grants DMS 1264153 and IIS 1251151. This research was supported by the Fonds door Wetenschappelijk Onderzoek Vlaanderen (FWO) (krediet no. 1.5.252.12N). The SHCS is financed in the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (SNF grant #33CS30-134277 and #33CS30-148522). Furthermore, the SHCS drug resistance data base was financed by the following funding sources: the SHCS projects #470, 528, 569, the SHCS Research Foundation, the Swiss National Science Foundation (grant #324730-130865 (to HFG), the European Union Seventh Framework Program (Grant FP7/2007-2013), under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; Grant 223131, to HFG), the Yvonne-Jacob Foundation (to HFG), and by a further research grant of the Union Bank of Switzerland, in the name of an anonymous donor to HFG, an unrestricted research grant from Gilead, Switzerland, to the SHCS Research Foundation, and by the University of Zurichs Clinical Research Priority Program (CRPP) Viral Infectious Diseases: Zurich Primary HIV Infection Study (to HFG). We thank Samuel Alizon for sharing data and R scripts, Tanja Stadler for sharing python scripts, Hanneke Schuitemaker & Zelda Euler for sharing sequence data and Christophe Fraser & George Shirreff for sharing insights into their preliminary work. We thank the patients participating in the SHCS and the members of the SHCS: Aubert V, Battegay M, Bernasconi E, Boni J, Bucher HC, Burton-Jeangros C, Calmy A, Cavassini M, Egger M, Elzi L, Fehr J, Fellay J, Francioli P, Furrer H (Chairman of the Clinical and Laboratory Committee), Fux CA, Gorgievski M, Gunthard H (President of the SHCS), Haerry D (Deputy of 'Positive Council'), Hasse B, Hirsch HH, Hirschel B, Hosli I, Kahlert C, Kaiser L, Keiser O, Kind C, Klimkait T, Kovari H, Ledergerber B, Martinetti G, Martinez de Tejada B, Metzner K, Muller N, Nadal D, Pantaleo G, Rauch A (Chairman of the Scientific Board), Regenass S, Rickenbach M (Head of Data Center), Rudin C (Chairman of the Mother & Child Substudy), Schmid P, Schultze D, Schoni-Affolter F, Schupbach J, Speck R, Taffe P, Tarr P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S. NR 71 TC 3 Z9 3 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-210X EI 2041-2096 J9 METHODS ECOL EVOL JI Methods Ecol. Evol. PD JAN PY 2015 VL 6 IS 1 BP 67 EP 82 DI 10.1111/2041-210X.12293 PG 16 WC Ecology SC Environmental Sciences & Ecology GA AZ9MC UT WOS:000348537800007 PM 25780554 ER PT J AU Vega, MG Zarek, SM Bhagwat, M Segars, JH AF Vega, Mario G. Zarek, Shvetha M. Bhagwat, Medha Segars, James H. TI Gonadotropin Surge-inhibiting/attenuating Factors: A Review of Current Evidence, Potential Applications, and Future Directions for Research SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Review ID FOLLICLE-STIMULATING-HORMONE; ATTENUATING FACTOR GNSAF; RFAMIDE-RELATED PEPTIDE-3; HUMAN MENOPAUSAL GONADOTROPIN; POLYCYSTIC-OVARY-SYNDROME; HUMAN GRANULOSA-CELLS; HUMAN SERUM-ALBUMIN; LUTEINIZING-HORMONE; SUPEROVULATED WOMEN; INHIBITING FACTOR AB Animal studies in the 1980s suggested the existence of an ovarian hormone, termed gonadotropin surge-inhibiting/attenuating factor (GnSIF/AF), that modulates pituitary secretion of luteinizing hormone (LH). Given the importance of identifying regulatory factors of the hypothalamic-pituitary-ovarian axis and the accumulating data suggesting its existence, we conducted a comprehensive literature search using PubMed, Web of Science, Scopus, and Embase to identify articles related to GnSIF/AF. The search generated 161 publications, of which 97 were included in this study. Several attempts have been made to identify and characterize this hormone and several candidates have been identified, but the protein sequences of these putative GnSIF/AF factors differ widely from one study to another. In addition, while the RF-amide RFRP-3 is known foremost as a neuropeptide, some research supports an ovarian origin for this non-steroidal hormone, thereby suggesting a role for RFRP-3 either as a co-modulator of GnSIF/AF or as a gonadotropin-inhibiting factor in the hypothalamus (GnIH). Discovery of the KNDy neurons that modulate GnRH secretion, on the other hand, further encourages the search for substance(s) that modulate their activity and that indirectly affect LH secretion and the hypothalamic-pituitary-ovarian axis. While it has remained an elusive hormone, GnSIF/AF holds many potential applications for contraception, in vitro fertilization, and/or cancer as well as for understanding polycystic ovary syndrome, metabolic diseases, and/or pubertal development. In this review, we rigorously examine the available evidence regarding the existence of GnSIF/AF, previous attempts at its identification, limitations to its discovery, future directions of research, and potential clinical applications. Mol. Reprod. Dev. 82: 2-16, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Vega, Mario G.] St Lukes Roosevelt Hosp, Dept Obstet & Gynecol, New York, NY 10025 USA. [Zarek, Shvetha M.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Bhagwat, Medha] NIH, Bioinformat Support Program, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institutes of Health [ZIA-HD 008737-13] FX Grant sponsor: National Institutes of Health; Grant number: ZIA-HD 008737-13 NR 120 TC 1 Z9 1 U1 0 U2 9 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 JAN PY 2015 VL 82 IS 1 BP 2 EP 16 DI 10.1002/mrd.22439 PG 15 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA CA1EX UT WOS:000348656700002 PM 25581424 ER PT J AU Frank, GA Narayan, K Bess, JW Del Prete, GQ Wu, XW Moran, A Hartnell, LM Earl, LA Lifson, JD Subramaniam, S AF Frank, Gabriel A. Narayan, Kedar Bess, Julian W., Jr. Del Prete, Gregory Q. Wu, Xiongwu Moran, Amy Hartnell, Lisa M. Earl, Lesley A. Lifson, Jeffrey D. Subramaniam, Sriram TI Maturation of the HIV-1 core by a non-diffusional phase transition SO Nature Communications LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CRYOELECTRON MICROSCOPY; MATRIX PROTEIN; ELECTRON CRYOTOMOGRAPHY; ENVELOPE INCORPORATION; GAG PROTEIN; VIRIONS; MEMBRANE; DOMAIN; PHOSPHATIDYLINOSITOL-(4,5)-BISPHOSPHATE AB The formation of the HIV-1 core is the final step in the viral maturation pathway, resulting in the formation of infectious virus. Most current models for HIV-1 core formation suggest that, upon proteolytic cleavage from the immature Gag, capsid (CA) dissociates into the viral interior before reforming into the core. Here we present evidence for an alternate view of core formation by taking advantage of our serendipitous observation of large membrane-enclosed structures in HIV-1 supernatants from infected cells. Cryo-electron tomographic studies show that these structures, which contain ordered arrays of what is likely the membrane-associated matrix protein, contain multiple cores that can be captured at different stages of maturation. Our studies suggest that HIV maturation involves a non-diffusional phase transition in which the detaching layer of the cleaved CA lattice is gradually converted into a roll that ultimately forms the surface of the mature conical core. C1 [Frank, Gabriel A.; Narayan, Kedar; Hartnell, Lisa M.; Earl, Lesley A.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bess, Julian W., Jr.; Del Prete, Gregory Q.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Moran, Amy] NIH, Natl Lab Med, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU NIH IATAP program; Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD; National Cancer Institute, the National Institutes of Health [HHSN261200800001E] FX This work was supported by funds from the NIH IATAP program and Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD (to S.S.) and from the National Cancer Institute, the National Institutes of Health contract #HHSN261200800001E (to J.D.L.). We thank S. Fellini, S. Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH. We thank Kunio Nagashima for assistance with preparation of EM blocks for imaging. NR 53 TC 22 Z9 22 U1 1 U2 6 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 JAN PY 2015 VL 6 AR 5854 DI 10.1038/ncomms6854 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA1XF UT WOS:000348701500002 PM 25569620 ER PT J AU Furusawa, T Rochman, M Taher, L Dimitriadis, EK Nagashima, K Anderson, S Bustin, M AF Furusawa, Takashi Rochman, Mark Taher, Leila Dimitriadis, Emilios K. Nagashima, Kunio Anderson, Stasia Bustin, Michael TI Chromatin decompaction by the nucleosomal binding protein HMGN5 impairs nuclear sturdiness SO NATURE COMMUNICATIONS LA English DT Article ID DILATED CARDIOMYOPATHY; GENE-EXPRESSION; LINKER HISTONE; LAMIN; HETEROCHROMATIN; ENVELOPE; DIFFERENTIATION; MOUSE; DNA; INTEGRITY AB In most metazoan nuclei, heterochromatin is located at the nuclear periphery in contact with the nuclear lamina, which provides mechanical stability to the nucleus. We show that in cultured cells, chromatin decompaction by the nucleosome binding protein HMGN5 decreases the sturdiness, elasticity and rigidity of the nucleus. Mice overexpressing HMGN5, either globally or only in the heart, are normal at birth but develop hypertrophic heart with large cardiomyoctyes, deformed nuclei and disrupted lamina and die of cardiac malfunction. Chromatin decompaction is seen in cardiomyocytes of newborn mice but misshaped nuclei with disrupted lamina are seen only in adult cardiomyocytes, suggesting that loss of heterochromatin diminishes the ability of the nucleus to withstand the mechanical forces of the contracting heart. Thus, heterochromatin enhances the ability of the nuclear lamina to maintain the sturdiness and shape of the eukaryotic nucleus; a structural role for chromatin that is distinct from its genetic functions. C1 [Furusawa, Takashi; Rochman, Mark; Bustin, Michael] NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Taher, Leila] Univ Rostock, Inst Biostat & Informat Med & Ageing Res, D-18057 Rostock, Germany. [Dimitriadis, Emilios K.] Natl Inst Biomed Imaging & Bioengn, Biomed Engn & Phys Sci Shared Resource Program, NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] SAIC Frederick Inc, Leidos Biomed Res Inc, Elect Microscopy Lab, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Anderson, Stasia] NHLBI, Anim Core Facil, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM bustinm@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research; National Cancer Institute [HHSN26120080001E]; National Library of Medicine, NIH FX The research was supported by the Center for Cancer Research, the National Cancer Institute, in part under contract HHSN26120080001E and by the National Library of Medicine, NIH. We thank Drs Tom Misteli and Nard Kubben for a gift of Lmna-/- and Lmna+/+ cells, to Dr Nina Bubunenko, LMT, Frederick for help with the Affymetrix arrays, to Susan Garfield (CCR Confocal Microscopy Core Facility, Laboratory of Experimental Carcinogenesis, NCI, NIH) for Confocal Microscopy, to Dr Corrinne Lobe (University of Toronto) for CAG-LacZ vector, to Lauren Brinster (Division of Veterinary Resources, Office of Research Services, NIH) for pathology, to Dr Chinmay Trivedi (the University of Pennsylvania School of Medicine) for primer sequences for alpha-MHC and beta-MHC, and to Dr Michael Schneider (Imperial College London) for alpha-MHC-Cre mouse. We thank Dr Robert Adelstein (NHLBI, NIH) for numerous helpful discussions and advice on cardiac function, to Dr Gabi Gerlitz (the Ariel University, Israel) for discussions on the non-genomic functions of chromatin and to Dr Tamar Kleinberger (Technion, Israel) for comments on the manuscript. NR 60 TC 7 Z9 7 U1 0 U2 3 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 JAN PY 2015 VL 6 AR 6138 DI 10.1038/ncomms7138 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3UM UT WOS:000348832300009 PM 25609380 ER PT J AU Khaled, WT Lee, SC Stingl, J Chen, XF Ali, HR Rueda, OM Hadi, F Wang, JX Yu, Y Chin, SF Stratton, M Futreal, A Jenkins, NA Aparicio, S Copeland, NG Watson, CJ Caldas, C Liu, P AF Khaled, Walid T. Lee, Song Choon Stingl, John Chen, Xiongfeng Ali, H. Raza Rueda, Oscar M. Hadi, Fazal Wang, Juexuan Yu, Yong Chin, Suet-Feung Stratton, Mike Futreal, Andy Jenkins, Nancy A. Aparicio, Sam Copeland, Neal G. Watson, Christine J. Caldas, Carlos Liu, Pentao TI BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells SO Nature Communications LA English DT Article ID MAMMARY-GLAND; LYMPHOID DEVELOPMENT; MOLECULAR PORTRAITS; SUPPRESSOR GENE; EXPRESSION; TUMORS; MOUSE; IDENTIFICATION; DIFFERENTIATION; OVEREXPRESSION AB Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies. C1 [Khaled, Walid T.; Lee, Song Choon; Wang, Juexuan; Yu, Yong; Stratton, Mike; Futreal, Andy; Liu, Pentao] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Khaled, Walid T.; Hadi, Fazal] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England. [Stingl, John; Ali, H. Raza; Rueda, Oscar M.; Chin, Suet-Feung; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England. [Stingl, John; Ali, H. Raza; Rueda, Oscar M.; Chin, Suet-Feung; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge CB2 0RE, England. [Chen, Xiongfeng] NCI, SAIC Frederic, Frederick, MD 21701 USA. [Ali, H. Raza; Caldas, Carlos] Cambridge Expt Canc Med Ctr, Cambridge CB2 0RE, England. [Jenkins, Nancy A.; Copeland, Neal G.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Aparicio, Sam] BC Canc Agcy, Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada. [Watson, Christine J.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Caldas, Carlos] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Caldas, Carlos] NIHR Cambridge Biomed Res Ctr, Cambridge CB2 2QQ, England. RP Khaled, WT (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. EM wtk22@cam.ac.uk; pl2@sanger.ac.uk OI chin, suet-feung/0000-0001-5697-1082 FU Sanger Institute; BBSRC project grant; Junior Research Fellowship, King's College, Cambridge; Cancer Research UK Career establishment award; Cancer Research UK; University of Cambridge; Hutchison Whampoa Limited; BBSRC; MRC; BCC; Wellcome Trust [098051] FX W.T.K., S.C.L. and J.W. were funded by the Sanger Institute. W.T.K. was also funded by a BBSRC project grant and a Junior Research Fellowship, King's College, Cambridge and a Cancer Research UK Career establishment award. J.S. is funded by Cancer Research UK, The University of Cambridge and Hutchison Whampoa Limited. C.J.W. is funded by BBSRC, MRC and BCC. We would like to thank Dr Floris Foijer and Professor Allan Bradley for providing the p53 cko mice. We thank Dr Shannon Burke, Dr Sara Pensa and Lauma Skruzmane for comments on the manuscript. We thank Miss Malgorzata Gawedzka from the W.T.K. lab for the technical assistance. We thank the Sanger Institute RSF, the flow cytometry core and microarray facilities for the technical assistance. This work is supported by Wellcome Trust (Grant number-098051) (P.L.). NR 60 TC 19 Z9 19 U1 2 U2 14 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 JAN PY 2015 VL 6 AR 1038 DI 10.1038/ncomms6987 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3MY UT WOS:000348812100005 PM 25574598 ER PT J AU Wang, YC Sui, YJ Kato, S Hogg, AE Steel, JC Morris, JC Berzofsky, JA AF Wang, Yichuan Sui, Yongjun Kato, Shingo Hogg, Alison E. Steel, Jason C. Morris, John C. Berzofsky, Jay A. TI Vaginal type-II mucosa is an inductive site for primary CD8(+) T-cell mucosal immunity SO Nature Communications LA English DT Article ID PERIPHERAL LYMPHOID ORGANS; INTRAVAGINAL IMMUNIZATION; ABNORMAL-DEVELOPMENT; PRIMARY ACTIVATION; LANGERHANS CELLS; DENDRITIC CELLS; GENITAL HERPES; DEFICIENT MICE; CUTTING EDGE; NAIVE CD4(+) AB The structured lymphoid tissues are considered the only inductive sites where primary T-cell immune responses occur. The naive T cells in structured lymphoid tissues, once being primed by antigen-bearing dendritic cells, differentiate into memory T cells and traffic back to the mucosal sites through the bloodstream. Contrary to this belief, here we show that the vaginal type-II mucosa itself, despite the lack of structured lymphoid tissues, can act as an inductive site during primary CD8(+) T-cell immune responses. We provide evidence that the vaginal mucosa supports both the local immune priming of naive CD8(+) T cells and the local expansion of antigen-specific CD8(+) T cells, thereby demonstrating a different paradigm for primary mucosal T-cell immune induction. C1 [Wang, Yichuan; Sui, Yongjun; Kato, Shingo; Hogg, Alison E.; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hogg, Alison E.] Aeras, Rockville, MD 20850 USA. [Steel, Jason C.] Univ Queensland, Brisbane, Qld 4120, Australia. [Steel, Jason C.] Gallipoli Med Res Fdn, Greenslopes, Qld 4120, Australia. [Morris, John C.] Univ Cincinnati, Inst Canc, Cincinnati, OH 45267 USA. RP Sui, YJ (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Suiy@mail.nih.gov; berzofsj@mail.nih.gov RI Steel, Jason/D-1805-2013 OI Steel, Jason/0000-0003-3608-7542 FU NCI [ZO1 SC 004020] FX This work is supported by NCI intramural funding ZO1 SC 004020. We thank Drs Warren Strober and Brian Kelsall for the critical reading of this manuscript, Dr Leonid Margolis' lab for valuable suggestions on vaginal tissue culture, Dr Shunsuke Sakai and Dr Daniel L. Barber for the advice on intravascular T-cell staining, the NIH tetramer facility for providing tetramer reagents, Dr Laurel Lagenaur and NIAID Biological Imaging Facility for photomicrography of the IHC stained vaginal tissue sections. NR 62 TC 1 Z9 1 U1 1 U2 2 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 JAN PY 2015 VL 6 AR 6100 DI 10.1038/ncomms7100 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3TJ UT WOS:000348828900003 PM 25600442 ER PT J AU Imperiale, A Moussallieh, FM Roche, P Battini, S Cicek, AE Sebag, F Brunaud, L Barlier, A Elbayed, K Loundou, A Bachellier, P Goichot, B Stratakis, CA Pacak, K Namer, IJ Taieb, D AF Imperiale, Alessio Moussallieh, Franois-Marie Roche, Philippe Battini, Stephanie Cicek, A. Ercument Sebag, Frederic Brunaud, Laurent Barlier, Anne Elbayed, Karim Loundou, Anderson Bachellier, Philippe Goichot, Bernard Stratakis, Constantine A. Pacak, Karel Namer, Izzie-Jacques Taieb, david TI Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications SO NEOPLASIA LA English DT Article ID CARNEY TRIAD; CROSS-VALIDATION; GENE-MUTATIONS; METABONOMICS; INFORMATION; REGRESSION; DATABASE; CANCER; CELLS; HMDB AB Succinate dehydrogenase gene (SDHx) mutations increase susceptibility to develop pheochromocytomas/paragangliomas (PHEOs/PGLs). In the present study, we evaluate the performance and clinical applications of H-1 high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy-based global metabolomic profiling in a large series of PHEOs/PGLs of different genetic backgrounds. Eighty-seven PHEOs/PGLs (48 sporadic/23 SDHx/7 von Hippel-Lindau/5 REarranged during Transfection/3 neurofibromatosis type 1/1 hypoxia-inducible factor 2 alpha), one SDHD variant of unknown significance, and two Carney triad (CTr)-related tumors were analyzed by HRMAS-NMR spectroscopy. Compared to sporadic, SDHx-related PHEOs/PGLs exhibit a specific metabolic signature characterized by increased levels of succinate (P < .0001), methionine (P =.002), glutamine (P =.002), and myoinositol (P < .0007) and decreased levels of glutamate (P < .0007), regardless of their location and catecholamine levels. Uniquely, ATP/ascorbate/glutathione was found to be associated with the secretory phenotype of PHEOs/PGLs, regardless of their genotype (P < .0007). The use of succinate as a single screening test retained excellent accuracy in distinguishing SDHx versus non-SDHx-related tumors (sensitivity/specificity: 100/100%). Moreover, the quantification of succinate could be considered a diagnostic alternative for assessing SDHx-related mutations of unknown pathogenicity. We were also able, for the first time, to uncover an SDH-like pattern in the two CTr-related PGLs. The present study demonstrates that HRMAS-NMR provides important information for SDHx-related PHEO/PGL characterization. Besides the high succinate-low glutamate hallmark, SDHx tumors also exhibit high values of methionine, a finding consistent with the hypermethylation pattern of these tumors. We also found important levels of glutamine, suggesting that glutamine metabolism might be involved in the pathogenesis of SDHx-related PHEOs/PGLs. C1 [Imperiale, Alessio; Battini, Stephanie; Namer, Izzie-Jacques] Haukeland Hosp, Hautepierre Hosp, Dept Biophys & Nucl Med, F-67098 Strasbourg, France. [Imperiale, Alessio; Moussallieh, Franois-Marie; Battini, Stephanie; Elbayed, Karim; Namer, Izzie-Jacques] Univ Strasbourg, ICube, UMR 7357, Strasbourg, France. [Imperiale, Alessio; Moussallieh, Franois-Marie; Battini, Stephanie; Elbayed, Karim; Namer, Izzie-Jacques] FMTS, Fac Med, Strasbourg, France. [Roche, Philippe] ISCB, Marseille, France. [Roche, Philippe] Aix Marseille Univ UM105, INT 3D Mol Modeling Platform, CNRS, INSERM U1068,UMR7258,Canc Res Ctr,Inst Paoli Clam, Marseille, France. [Cicek, A. Ercument] Carnegie Mellon Univ, Lane Ctr Computat Biol, Sch Comp Sci, Pittsburgh, PA USA. [Sebag, Frederic] Aix Marseille Univ, La Timone Univ Hosp, Dept Endocrine Surg, Marseille, France. [Brunaud, Laurent] Brabois Univ Hosp, Dept Digest Hepatobiliary & Endocrine Surg, Nancy, France. [Barlier, Anne] Aix Marseille Univ, Concept Hosp, Lab Biochem & Mol Biol, Marseille, France. [Loundou, Anderson] Aix Marseille Univ, Dept Publ Hlth, Marseille, France. [Bachellier, Philippe] Univ Hosp, Hautepierre Hosp, Dept Visceral Surg & Transplantat, Strasbourg, France. [Goichot, Bernard] Univ Hosp, Hautepierre Hosp, Dept Internal Med Diabet & Metab, Strasbourg, France. [Stratakis, Constantine A.] NICHHD, Sect Genet & Endocrinol SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [Pacak, Karel] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Taieb, david] Aix Marseille Univ, La Timone Univ Hosp, European Ctr Res Med Imaging, Marseille, France. RP Imperiale, A (reprint author), Haukeland Hosp, Dept Biophys & Nucl Med, 1 Ave Moliere, F-67098 Strasbourg, France. EM alessio.imperiale@chru-strasbourg.fr RI Battini, Stephanie/M-2575-2013; OI Battini, Stephanie/0000-0003-0839-4553; Barlier, Anne/0000-0002-3740-6173 FU Region Alsace; Oseo; Communaute Urbaine de Strasbourg; Conseil Departemental du Bas-Rhin; Bruker BioSpin; University of Strasbourg; Strasbourg University Hospital FX This work is part of the CARMeN project and was supported by grants from Region Alsace, Oseo, Communaute Urbaine de Strasbourg, Conseil Departemental du Bas-Rhin, Bruker BioSpin, University of Strasbourg, and Strasbourg University Hospital. NR 37 TC 9 Z9 9 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1522-8002 EI 1476-5586 J9 NEOPLASIA JI Neoplasia PD JAN PY 2015 VL 17 IS 1 BP 55 EP 65 DI 10.1016/j.neo.2014.10.010 PG 11 WC Oncology SC Oncology GA AZ8IG UT WOS:000348458300005 PM 25622899 ER PT J AU El Haj, M Antoine, P Kapogiannis, D AF El Haj, Mohamad Antoine, Pascal Kapogiannis, Dimitrios TI Similarity between remembering the past and imagining the future in Alzheimer's disease: Implication of episodic memory SO NEUROPSYCHOLOGIA LA English DT Article DE Alzheimer's disease; Episodic memory; Future thinking; Imagination ID SELF-DEFINING MEMORIES; MILD COGNITIVE IMPAIRMENT; MENTAL TIME-TRAVEL; AUTOBIOGRAPHICAL MEMORY; AUTONOETIC CONSCIOUSNESS; NEURODEGENERATIVE DISEASES; DEPRESSION SCALE; HOSPITAL ANXIETY; DEFAULT-MODE; DEMENTIA AB Recent studies suggest that common cognitive processes and neuroanatomical substrates underlie the ability to remember the past and imagine the future. We studied these cognitive processes in patients with Alzheimer's Disease (AD). We asked 27 participants with AD and 30 older controls, matched by age, sex, and educational level, to generate past and future autobiographical events. Autobiographical generation was analyzed with respect to theme, general autobiographical performance, contextual performance, self-defining memories, and autonoetic reliving/re-experiencing. Unlike older controls, most AD participants evoked similar themes when generating past and future events (n=23/30 participants). These participants also showed similar autobiographical and contextual performance, similar amount of self-defining memories, and similar autonoetic states when generating past and future events. Further, significant correlations were detected between hippocampal-dependent memory decline in AD participants and their ability to relive past and future events. These outcomes suggest striking similarities between remembering the past and imagining the future in AD. Due to their memory decline, imagining the future in AD patients is likely to draw heavily from the little amount of available information from past episodes, resulting in striking similarities between remembering the past and imagining the future. Finally, and unlike AD participants, older controls mentally "try out" alternative approaches to upcoming situations without replicating the same schemes of past events. (C) 2014 Elsevier Ltd. All rights reserved. C1 [El Haj, Mohamad; Antoine, Pascal] Univ North France, Res Unit Cognit & Affect Sci URECA EA1059, Lille, France. [El Haj, Mohamad; Antoine, Pascal] Univ North France, Dept Psychol, UMR SCALAB, Lille, France. [Kapogiannis, Dimitrios] NIA, Neurosci Lab, Baltimore, MD USA. RP El Haj, M (reprint author), Univ Lille 3, Dept Psychol, BP 59653, Villeneuve Dascq, France. EM mohamad.elhaj@univ-lille3.fr OI el haj, mohamad/0000-0001-7635-7557 FU LABEX (Excellence Laboratory, Program Investment for the Future) DIS-TALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer Disease); National Institute on Aging/National Institutes of Health FX Dr. El Haj and Dr. Antoine were supported by the LABEX (Excellence Laboratory, Program Investment for the Future) DIS-TALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer Disease). This research was supported in part by the Intramural Research Program of the National Institute on Aging/National Institutes of Health (Dimitrios Kapogiannis). NR 63 TC 16 Z9 16 U1 6 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JAN PY 2015 VL 66 BP 119 EP 125 DI 10.1016/j.neuropsychologia.2014.11.015 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA CA0SG UT WOS:000348626200013 PM 25448861 ER PT J AU Kandi, SK Manohar, S Gerena, CEV Zayas, B Malhotra, SV Rawat, DS AF Kandi, Shamseer Kulangara Manohar, Sunny Gerena, Christian E. Velez Zayas, Beatriz Malhotra, Sanjay V. Rawat, Diwan S. TI C-5-curcuminoid-4-aminoquinoline based molecular hybrids: design, synthesis and mechanistic investigation of anticancer activity SO NEW JOURNAL OF CHEMISTRY LA English DT Article ID CELL-CYCLE ARREST; IMPROVED IN-VITRO; CANCER-CHEMOTHERAPY; ANTIMALARIAL ACTIVITY; ALKYLATING-AGENTS; CURCUMIN ANALOGS; APOPTOSIS; BIOAVAILABILITY; ANTIMETABOLITES; INDUCTION AB The privileged scaffolds of curcumin and 4-aminoquinolines are extensively used in the design and synthesis of biodynamic agents having remarkable efficacy against diseases like cancer and malaria. Therefore, we anticipated that covalent hybridization of these two pharmacophores via the triazole linker may lead to molecules with better anticancer activity. The synthesized hybrid compounds were tested for their anti-cancer activity on 60 human cancer cell lines, which represent diverse histologies. Our study has identified a set of these hybrids that showed excellent growth inhibition at nano-molar concentrations. The mechanistic investigations through a series of assays showed apoptotic induction as a cause for their displayed anticancer activity. C1 [Kandi, Shamseer Kulangara; Manohar, Sunny; Rawat, Diwan S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Gerena, Christian E. Velez; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. [Malhotra, Sanjay V.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov; dsrawat@chemistry.du.ac.in FU University Grant Commission, New Delhi, India [41-202/2012 (SR)]; DU-DST PURSE, University of Delhi, Delhi, India; CSIR; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX DSR acknowledges University Grant Commission [41-202/2012 (SR)], New Delhi, India and DU-DST PURSE, University of Delhi, Delhi, India for financial support. S. K. K. and S. M. are thankful to CSIR for the award of junior and senior research fellowship. S. V. M. would like to acknowledge the support from National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. Authors are also thankful to CIF-USIC, University of Delhi, Delhi for NMR spectral data and RSIC, CDRI, Lucknow for mass data. We thank Alfredo Blakeley, Julie Early, Stephanie Florio, and Juliane Ollinger for technical assistance. NR 55 TC 7 Z9 7 U1 0 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1144-0546 EI 1369-9261 J9 NEW J CHEM JI New J. Chem. PD JAN PY 2015 VL 39 IS 1 BP 224 EP 234 DI 10.1039/c4nj00936c PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA AZ6LS UT WOS:000348331900030 ER PT J AU Bates, SE AF Bates, Susan E. TI Central Nervous System Metastasis From Breast Cancer SO ONCOLOGIST LA English DT Editorial Material ID BRAIN METASTASES; EFFICACY; BARRIER; PLUS C1 [Bates, Susan E.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM batess@helix.nih.gov NR 11 TC 2 Z9 2 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JAN PY 2015 VL 20 IS 1 BP 3 EP 4 DI 10.1634/theoncologist.2014-0469 PG 2 WC Oncology SC Oncology GA AZ8IO UT WOS:000348459100002 PM 25542449 ER PT J AU Leclezio, L Jansen, A Whittemore, VH de Vries, PJ AF Leclezio, Loren Jansen, Anna Whittemore, Vicky H. de Vries, Petrus J. TI Pilot Validation of the Tuberous Sclerosis-Associated Neuropsychiatric Disorders (TAND) Checklist SO PEDIATRIC NEUROLOGY LA English DT Article DE tuberous sclerosis complex; TAND; autism; mental health; neuropsychology; cognition; academic; psychosocial ID COMPLEX CONSENSUS CONFERENCE; DIAGNOSTIC-CRITERIA; ATTENTION DEFICITS; POPULATION; BEHAVIOR; RECOMMENDATIONS; IDENTIFICATION; CHILDREN; SAMPLE; GENE AB BACKGROUND: Tuberous sclerosis complex is a multisystem disorder that includes a range of tuberous sclerosis associated neuropsychiatric disorders (TAND). The lifetime prevalence rates of TAND are very high; yet surveys suggest that the majority of individuals with tuberous sclerosis never receive appropriate assessment or treatment for TAND. To aid systematic enquiry, a TAND Checklist was developed. Here, we performed pilot validation of the TAND Checklist. METHOD: Mixed methods were used across two stages. In stage 1, we gathered feedback on the Checklist from tuberous sclerosis "expert professionals" and "expert parents and caregivers." The aim was to examine face and content validity. Stage 2 involved the administration of the refined TAND Checklist to 20 parents of individuals with tuberous sclerosis concurrently with four widely used validated rating scales, to examine external validity and obtain qualitative feedback on face-to-face administration of the TAND Checklist. RESULTS: Twenty professionals and 62 parents and caregivers from 28 countries participated in the pilot. The TAND Checklist demonstrated good face and content validity with high overall mean and median scores. Qualitative analysis highlighted concerns about the likely use of the TAND Checklist, suggesting that family members and individuals with tuberous sclerosis should drive usage. Stage 2 results showed moderate-to-very good external validity across TAND domain and key subdomains. Internal consistency of domains and subdomains was acceptable to very good. Ninety-three percent of all participants (93%) reported four or more lifetime TAND behavioral difficulties. CONCLUSION: The pilot validation suggested that the TAND Checklist could provide a useful screening tool in clinical settings. C1 [Leclezio, Loren; de Vries, Petrus J.] Univ Cape Town, Div Child & Adolescent Psychiat, Dept Psychiat & Mental Hlth, ZA-7700 Cape Town, South Africa. [Jansen, Anna] Vrije Univ Brussel, UZ Brussel, Dept Pediat, Pediat Neurol Unit, Brussels, Belgium. [Whittemore, Vicky H.] NINDS, NIH, Bethesda, MD 20892 USA. RP de Vries, PJ (reprint author), Univ Cape Town, Div Child & Adolescent Psychiat, 46 Sawkins Rd, ZA-7700 Cape Town, South Africa. EM petrus.devries@uct.ac.za RI Jansen, Anna/P-3121-2014 OI Jansen, Anna/0000-0002-3835-2824 FU Australasian Tuberous Sclerosis Society; Tuberous Sclerosis International; National Research Foundation; Struengmann Fund; University of Cape Town; Tuberous Sclerosis Alliance FX We are grateful to all expert professionals, expert parents, caregivers, and individuals with TSC who participated in this study. A particular thanks to the Australasian Tuberous Sclerosis Society and Tuberous Sclerosis International for support. The study was supported by funding from the National Research Foundation, Struengmann Fund, University of Cape Town, and the Tuberous Sclerosis Alliance. NR 42 TC 9 Z9 9 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JAN PY 2015 VL 52 IS 1 BP 16 EP 24 DI 10.1016/j.pediatrneurol.2014.10.006 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AZ7QA UT WOS:000348411800003 PM 25499093 ER PT J AU de Vries, PJ Whittemore, VH Leclezio, L Byars, AW Dunn, D Ess, KC Hook, D King, BH Sahin, M Jansen, A AF de Vries, Petrus J. Whittemore, Vicky H. Leclezio, Loren Byars, Anna W. Dunn, David Ess, Kevin C. Hook, Dena King, Bryan H. Sahin, Mustafa Jansen, Anna TI Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist SO PEDIATRIC NEUROLOGY LA English DT Article DE behavior; psychiatric disorders; autism; mental health; neurocognition; learning disorders; neuropsychological; psycho-social ID COMPLEX CONSENSUS CONFERENCE; SPORADIC LYMPHANGIOLEIOMYOMATOSIS; SIROLIMUS THERAPY; SAMPLE; TRIAL; RECOMMENDATIONS; ANGIOMYOLIPOMA; QUESTIONNAIRE; MULTICENTER; ADOLESCENTS AB BACKGROUND: Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant "treatment gap" and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex. METHODS: The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND tuberous sclerosis complex-associated neuropsychiatric disorders to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening. RESULTS: Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist. CONCLUSION: We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders. C1 [de Vries, Petrus J.; Leclezio, Loren] Univ Cape Town, Div Child & Adolescent Psychiat, Dept Psychiat & Mental Hlth, ZA-7700 Cape Town, South Africa. [Whittemore, Vicky H.] NINDS, NIH, Bethesda, MD 20892 USA. [Byars, Anna W.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Dunn, David] Indiana Univ Sch Med, Riley Child & Adolescent Psychiat Clin, Indianapolis, IN 46202 USA. [Ess, Kevin C.] Vanderbilt Univ, Ctr Med, Dept Pediat, Div Pediat Neurol, Nashville, TN 37232 USA. [Hook, Dena] TB Sclerosis Alliance, Silver Spring, MD USA. [King, Bryan H.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [King, Bryan H.] Seattle Childrens Hosp, Seattle, WA USA. [Sahin, Mustafa] Boston Childrens Hosp, FM Kirby Ctr Neurosci, Dept Neurol, Boston, MA USA. [Jansen, Anna] VUB, Dept Publ Hlth, UZ Brussel, Pediat Neurol Unit, Brussels, Belgium. RP Whittemore, VH (reprint author), Univ Cape Town, Div Child & Adolescent Psychiat, 46 Sawkins Rd, ZA-7700 Cape Town, South Africa. EM petrus.devries@uct.ac.za RI Jansen, Anna/P-3121-2014; OI Jansen, Anna/0000-0002-3835-2824; SAHIN, MUSTAFA/0000-0001-7044-2953 FU Tuberous Sclerosis Alliance; NRF; PERC; Struengmann Fund; NIH [1U01NS082320-01]; Rothberg Institute for Childhood Diseases; Novartis Pharmaceuticals; Sandra and Brian O'Brien; Questcor Pharmaceuticals FX The 2012 International TSC Clinical Consensus Conference was organized by the Tuberous Sclerosis Alliance. The conference was supported by sponsors of the Tuberous Sclerosis Alliance without playing a role in the planning or having a presence at the conference and the resulting recommendations: the Rothberg Institute for Childhood Diseases, Novartis Pharmaceuticals, Sandra and Brian O'Brien, and Questcor Pharmaceuticals. P.J.d.V. receives support from NRF, PERC and the Struengmann Fund. MS. receives support from the NIH 1U01NS082320-01. NR 39 TC 28 Z9 28 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JAN PY 2015 VL 52 IS 1 BP 25 EP 35 DI 10.1016/j.pediatrneurol.2014.10.004 PG 11 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AZ7QA UT WOS:000348411800004 PM 25532776 ER PT J AU Beydoun, MA Fanelli-Kuczmarski, MT Kitner-Triolo, MH Beydoun, HA Kaufman, JS Mason, MA Evans, MK Zonderman, AB AF Beydoun, May A. Fanelli-Kuczmarski, Marie T. Kitner-Triolo, Melissa H. Beydoun, Hind A. Kaufman, Jay S. Mason, Marc A. Evans, Michele K. Zonderman, Alan B. TI Dietary Antioxidant Intake and Its Association With Cognitive Function in an Ethnically Diverse Sample of US Adults SO PSYCHOSOMATIC MEDICINE LA English DT Article DE antioxidants; cognitive function; depressive symptoms; midlife ID INCIDENT ALZHEIMER-DISEASE; MULTIPLE-PASS METHOD; POLYUNSATURATED FATTY-ACIDS; C SUPPLEMENT USE; VITAMIN-E LEVELS; DEPRESSIVE SYMPTOMS; OLDER-ADULTS; SOCIOECONOMIC-STATUS; OXIDATIVE STRESS; CACHE COUNTY AB Background Dietary antioxidants can inhibit reactions accompanying neurodegeneration and thus prevent cognitive impairment. We describe associations of dietary antioxidants with cognitive function in a large biracial population, while testing moderation by sex, race, and age and mediation by depressive symptoms. Methods This was a cross-sectional analysis of 1274 adults (541 men and 733 women) aged 30 to 64 years at baseline (mean [standard deviation] = 47.5 [9.3]) in the Healthy Aging in Neighborhoods of Diversity Across the Lifespan Study, Baltimore city, MD. Cognitive performance in the domains of memory, language/verbal, attention, spatial, psychomotor speed, executive function, and global mental status were assessed. The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms. Dietary intake was assessed with two 24-hour recalls, estimating daily consumption of total carotenoids and vitamins A, C, and E per 1000 kcal. Results Among key findings, 1 standard deviation (approximate to 2.02 mg/1000 kcal) higher vitamin E was associated with a higher score on verbal memory, immediate recall ( = +0.64 [0.19], p = .001), and better language/verbal fluency performance ( = +0.53 [0.16], p = .001), particularly among the younger age group. Women with higher vitamin E intake ( = +0.68 [0.21], p = .001) had better performance on a psychomotor speed test. The vitamin E-verbal memory association was partially mediated by depressive symptoms (proportion mediated = 13%-16%). Conclusions In sum, future cohort studies and dietary interventions should focus on associations of dietary vitamin E with cognitive decline, specifically for domains of verbal memory, verbal fluency, and psychomotor speed. C1 [Beydoun, May A.; Kitner-Triolo, Melissa H.; Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, IRP, Baltimore, MD 21224 USA. [Fanelli-Kuczmarski, Marie T.] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Kaufman, Jay S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Mason, Marc A.] MedStar Res Inst, Stat Informat Syst, Baltimore, MD USA. RP Beydoun, MA (reprint author), NIA, NIH Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Kaufman, Jay/0000-0003-1606-401X; Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, Intramural Research Program (NIA/NIH/IRP) FX This study was entirely supported by the National Institute on Aging, Intramural Research Program (NIA/NIH/IRP). The authors declare no conflict of interest. NR 100 TC 2 Z9 2 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD JAN PY 2015 VL 77 IS 1 BP 68 EP 82 DI 10.1097/PSY.0000000000000129 PG 15 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA AZ8WT UT WOS:000348493100009 PM 25478706 ER PT J AU Desmond, R Townsley, DM Dunbar, C Young, NS AF Desmond, Ronan Townsley, Danielle M. Dunbar, Cynthia Young, Neal S. TI Eltrombopag in Aplastic Anemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; BONE-MARROW FAILURE; ANTITHYMOCYTE GLOBULIN; LONG-TERM; IMMUNOSUPPRESSIVE THERAPY; CYTOGENETIC ABNORMALITIES; MYELODYSPLASTIC SYNDROMES; GROWTH-FACTORS; THROMBOPOIETIN AB The treatment of aplastic anemia is currently with immunosuppressive therapy (IT) with anti-thymocyte globulin (ATG) and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST-refractory SAA and in moderate disease. (C) Published by Elsevier Inc. C1 [Desmond, Ronan] Tallaght Hosp, Dept Haematol, Dublin, Ireland. [Desmond, Ronan; Townsley, Danielle M.; Dunbar, Cynthia; Young, Neal S.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Desmond, R (reprint author), Tallaght Hosp, Dept Haematol, Dublin, Ireland. EM ronan.desmond@amnch.ie FU Intramural NIH HHS [Z99 HL999999] NR 45 TC 1 Z9 1 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 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2015 VL 52 IS 1 BP 31 EP 37 DI 10.1053/j.seminhematol.2014.10.002 PG 7 WC Hematology SC Hematology GA AZ2YO UT WOS:000348095400006 PM 25578417 ER PT J AU Kozak, CA AF Kozak, Christine A. TI Origins of the Endogenous and Infectious Laboratory Mouse Gammaretroviruses SO VIRUSES-BASEL LA English DT Review DE mouse endogenous retroviruses; mouse leukemia viruses; house mouse subspecies; ecotropic/xenotropic/polytropic gammaretroviruses; retrovirus restriction factors; recombinant mouse gammaretroviruses ID MURINE-LEUKEMIA-VIRUS; CELL-SURFACE RECEPTOR; LONG TERMINAL REPEATS; FOCUS-FORMING VIRUS; ECOTROPIC RETROVIRUS RECEPTOR; MUS-MUSCULUS-MOLOSSINUS; GROWTH IN-VIVO; C-TYPE VIRUSES; CAS-BR-E; AKR/J MICE AB The mouse gammaretroviruses associated with leukemogenesis are found in the classical inbred mouse strains and in house mouse subspecies as infectious exogenous viruses (XRVs) and as endogenous retroviruses (ERVs) inserted into their host genomes. There are three major mouse leukemia virus (MuLV) subgroups in laboratory mice: ecotropic, xenotropic, and polytropic. These MuLV subgroups differ in host range, pathogenicity, receptor usage and subspecies of origin. The MuLV ERVs are recent acquisitions in the mouse genome as demonstrated by the presence of many full-length nondefective MuLV ERVs that produce XRVs, the segregation of these MuLV subgroups into different house mouse subspecies, and by the positional polymorphism of these loci among inbred strains and individual wild mice. While some ecotropic and xenotropic ERVs can produce XRVs directly, others, especially the pathogenic polytropic ERVs, do so only after recombinations that can involve all three ERV subgroups. Here, I describe individual MuLV ERVs found in the laboratory mice, their origins and geographic distribution in wild mouse subspecies, their varying ability to produce infectious virus and the biological consequences of this expression. C1 NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX The work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 199 TC 5 Z9 5 U1 4 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JAN PY 2015 VL 7 IS 1 BP 1 EP 26 DI 10.3390/v7010001 PG 26 WC Virology SC Virology GA AZ7LY UT WOS:000348401600001 ER PT J AU Baker, EH Sloan, JL Hauser, NS Gropman, AL Adams, DR Toro, C Manoli, I Venditti, CP AF Baker, E. H. Sloan, J. L. Hauser, N. S. Gropman, A. L. Adams, D. R. Toro, C. Manoli, I. Venditti, C. P. TI MRI Characteristics of Globus Pallidus Infarcts in Isolated Methylmalonic Acidemia SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID NIGRA PARS RETICULATA; SUBSTANTIA-NIGRA; BASAL GANGLIA; DYSFUNCTION; MANAGEMENT; ACIDURIA; PRIMATES AB BACKGROUND: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated methylmalonic acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with methylmalonic acidemia, we have devised a staging system for methylmalonic acidemia related globus pallidus infarcts. MATERIALS AND METHODS: Forty patients with isolated methylmalonic acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured. RESULTS: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by methylmalonic acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut(o) (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in methylmalonic acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct. CONCLUSIONS: The staged pattern of globus pallidus infarcts in isolated methylmalonic acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallid us interna, supports the concept of cell-specific pathology. C1 [Baker, E. H.] NHGRI, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. [Sloan, J. L.; Manoli, I.; Venditti, C. P.] NHGRI, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Sloan, J. L.; Manoli, I.; Venditti, C. P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Adams, D. R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Toro, C.] NHGRI, Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA. [Hauser, N. S.] Childrens Hosp Cent Calif, Med Genet & Metab Dept, Madera, CA USA. [Gropman, A. L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. RP Baker, EH (reprint author), 10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM bakere@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU Intramural Research Program of the National Human Genome Research Institute (National Institutes of Health) [04-HG-0127] FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute (National Institutes of Health protocol 04-HG-0127 "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders," clinicaltrials.gov identifier NCT00078078). NR 32 TC 5 Z9 6 U1 1 U2 4 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 JAN PY 2015 VL 36 IS 1 BP 194 EP 201 DI 10.3174/ajnr.A4087 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AZ1ON UT WOS:000348008200033 PM 25190203 ER PT J AU Jairath, S Sukumaran, N Madhavan, P Natarajan, B Chandrashekharan, U Jayaschandran, V Leung, S Ali, N Basu, A Bhaskaran, M Molmenti, E AF Jairath, Sapna Sukumaran, Neenu Madhavan, Parvathy Natarajan, Balaji Chandrashekharan, Umashankar Jayaschandran, Vivek Leung, Sam Ali, Nicole Basu, Amit Bhaskaran, Madhu Molmenti, Ernesto TI Pre-Transplant Plasmapheresis Allows Long-Term Allograft Survival in Renal Transplant Recipients With Donor Specific Antibodies SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 15th Annual State of the Art Winter Symposium of the American-Society-of-Transplant-Surgeons (ASTS) CY JAN 15-18, 2015 CL Miami, FL SP Amer Soc Transplant Surg C1 [Jairath, Sapna; Sukumaran, Neenu; Madhavan, Parvathy; Chandrashekharan, Umashankar; Jayaschandran, Vivek; Leung, Sam; Ali, Nicole; Basu, Amit; Bhaskaran, Madhu; Molmenti, Ernesto] North Shore LIJ Hlth Syst, Manhasset, NY USA. [Natarajan, Balaji] 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2015 VL 15 SU 1 SI SI MA P-71 BP 81 EP 81 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA AZ1YF UT WOS:000348030600099 ER PT J AU Bailey, JA Pablo, J Niangaly, A Travassos, MA Ouattara, A Coulibaly, D Laurens, MB Takala-Harrison, SL Lyke, KE Skinner, J Berry, AA Jasinskas, A Nakajima-Sasaki, R Kouriba, B Thera, MA Felgner, PL Doumbo, OK Plowe, CV AF Bailey, Jason A. Pablo, Jozelyn Niangaly, Amadou Travassos, Mark A. Ouattara, Amed Coulibaly, Drissa Laurens, Matthew B. Takala-Harrison, Shannon L. Lyke, Kirsten E. Skinner, Jeff Berry, Andrea A. Jasinskas, Algis Nakajima-Sasaki, Rie Kouriba, Bourema Thera, Mahamadou A. Felgner, Philip L. Doumbo, Ogobara K. Plowe, Christopher V. TI Short Report: Seroreactivity to a Large Panel of Field-Derived Plasmodium falciparum Apical Membrane Antigen 1 and Merozoite Surface Protein 1 Variants Reflects Seasonal and Lifetime Acquired Responses to Malaria SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ALLELE-SPECIFIC EFFICACY; MALIAN ADULTS; VACCINE; IMMUNOGENICITY; INFECTION; CHILDREN; SAFETY; MICROARRAYS AB Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP1(19), n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy. C1 [Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. NIH, Immunogenet Lab, Bethesda, MD 20892 USA. Univ Sci Tech & Technol, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali. [Bailey, Jason A.; Travassos, Mark A.; Ouattara, Amed; Laurens, Matthew B.; Takala-Harrison, Shannon L.; Lyke, Kirsten E.; Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Pablo, Jozelyn; Jasinskas, Algis; Nakajima-Sasaki, Rie; Felgner, Philip L.] Univ Calif Irvine, Div Infect Dis, Irvine, CA USA. [Niangaly, Amadou; Coulibaly, Drissa; Thera, Mahamadou A.] Univ Bamako, Fac Med, Malaria Res & Training Ctr Bamako, Bamako, Mali. [Niangaly, Amadou; Coulibaly, Drissa; Thera, Mahamadou A.] Mali Univ Sci Tech & Technol Bamako, Malaria Res & Training Ctr, Bamako, Mali. [Skinner, Jeff] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Kouriba, Bourema; Doumbo, Ogobara K.] Univ Sci Tech & Technol Bamako, Malaria Res & Training Ctr, Bamako, Mali. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, 685 West Baltimore St,HSF1 480, Baltimore, MD 21201 USA. EM jbail006@umaryland.edu; jozelynp@gmail.com; niangaly@icermali.org; aouattara@medicine.umaryland.edu; coulibalyd@icermali.org; mlaurens@medicine.umaryland.edu; stakala@medicine.umaryland.edu; klyke@medicine.umaryland.edu; skinnerj@niaid.nih.gov; ajasinsk@uci.edu; rie3@uci.edu; kouriba@icermali.org; mthera@icermali.org; okd@icermali.org; cplowe@medicine.umaryland.edu RI Laurens, Matthew/E-7293-2013; OI Laurens, Matthew/0000-0003-3874-581X; Skinner, Jeff/0000-0001-5697-0442 FU FIC NIH HHS [D43 TW001589]; NIAID NIH HHS [R01 AI095916]; NIGMS NIH HHS [R25 GM055036] NR 20 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2015 VL 92 IS 1 BP 9 EP 12 DI 10.4269/ajtmh.14-0140 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AZ4GU UT WOS:000348180600005 PM 25294612 ER PT J AU Gromowski, GD Firestone, CY Bustos-Arriaga, J Whitehead, SS AF Gromowski, Gregory D. Firestone, Cai-Yen Bustos-Arriaga, Jose Whitehead, Stephen S. TI Genetic and Phenotypic Properties of Vero Cell-Adapted Japanese Encephalitis Virus SA14-14-2 Vaccine Strain Variants and a Recombinant Clone, which Demonstrates Attenuation and Immunogenicity in Mice SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; SA 14-14-2 VACCINE; WILD-TYPE; ALPHA/BETA-INTERFERON; NUCLEOTIDE-SEQUENCE; NEPALESE CHILDREN; MOLECULAR-BASIS; INFECTION; IMMUNIZATION AB The live-attenuated Japanese encephalitis virus (JEV) SA14-14-2 vaccine, produced in primary hamster kidney cells, is safe and effective. Past attempts to adapt this virus to replicate in cells that are more favorable for vaccine production resulted in mutations that significantly reduced immunogenicity. In this study, 10 genetically distinct Vero cell-adapted JEV SA14-14-2 variants were isolated and a recombinant wild-type JEV clone, modified to contain the JEV SA14-14-2 polyprotein amino acid sequence, was recovered in Vero cells. A single capsid protein mutation (S66L) was important for Vero cell-adaptation. Mutations were also identified that modulated virus sensitivity to type I interferon-stimulation in Vero cells. A subset of JEV SA14-14-2 variants and the recombinant clone were evaluated in vivo and exhibited levels of attenuation that varied significantly in suckling mice, but were avirulent and highly immunogenic in weanling mice and are promising candidates for the development of a second-generation, recombinant vaccine. C1 [Gromowski, Gregory D.; Firestone, Cai-Yen; Bustos-Arriaga, Jose; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Gromowski, GD (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM gromowskig@niaid.nih.gov; cfirestone@niaid.nih.gov; bustosarriagaj2@mail.nih.gov; swhitehead@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health FX This work was supported by the National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health. NR 66 TC 3 Z9 3 U1 1 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2015 VL 92 IS 1 BP 98 EP 107 DI 10.4269/ajtmh.14-0427 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AZ4GU UT WOS:000348180600021 PM 25311701 ER PT J AU Rao, HY Wang, DJ Yang, YH He, Y AF Rao, Hengyi Wang, Danny Jiongjiong Yang, Yihong He, Yong TI Neuroimaging of Brain Networks and Function SO BIOMED RESEARCH INTERNATIONAL LA English DT Editorial Material C1 [Rao, Hengyi] Univ Penn, Perelman Sch Med, Ctr Funct Neuroimaging, Dept Neurol, Philadelphia, PA 19104 USA. [Wang, Danny Jiongjiong] Univ Calif Los Angeles, Ahmanson Lovelace Brain Mapping Ctr, Dept Neurol, Los Angeles, CA 90095 USA. [Yang, Yihong] NIDA, Magnet Resonance Imaging & Spect Sect, Baltimore, MD 21224 USA. [He, Yong] Beijing Normal Univ, Natl Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [He, Yong] Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China. RP Rao, HY (reprint author), Univ Penn, Perelman Sch Med, Ctr Funct Neuroimaging, Dept Neurol, Philadelphia, PA 19104 USA. EM hengyi@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2015 AR 509141 DI 10.1155/2015/509141 PG 2 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AZ5YR UT WOS:000348295000001 ER PT J AU Little, JW Ford, A Symons-Liguori, AM Chen, ZM Janes, K Doyle, T Xie, J Luongo, L Tosh, DK Maione, S Bannister, K Dickenson, AH Vanderah, TW Porreca, F Jacobson, KA Salvemini, D AF Little, Joshua W. Ford, Amanda Symons-Liguori, Ashley M. Chen, Zhoumou Janes, Kali Doyle, Timothy Xie, Jennifer Luongo, Livio Tosh, Dillip K. Maione, Sabatino Bannister, Kirsty Dickenson, Anthony H. Vanderah, Todd W. Porreca, Frank Jacobson, Kenneth A. Salvemini, Daniela TI Endogenous adenosine A(3) receptor activation selectively alleviates persistent pain states SO BRAIN LA English DT Article DE adenosine; A(3)AR; chronic pain; spontaneous pain; rostral ventromedial medulla ID ANTIINFLAMMATORY PROPERTIES; CANNABINOID RECEPTOR; INTERNATIONAL UNION; KINASE INHIBITOR; NEUROPATHIC PAIN; 1ST POTENT; RAT; AGONISTS; CELLS; CLASSIFICATION AB Adenosine's analgesic effects have previously been attributed to A(1) and A(2A) adenosine receptors. However, Little et al. now show that A(3) adenosine receptor activation by endogenous adenosine and potent agonists selectively suppresses persistent pain states by activating brain-to-spinal cord circuits that inhibit pain processing. Targeting A(3) receptors could help relieve chronic pain.Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A(3) adenosine receptor (A(3)AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A(3)AR agonist. These effects were prevented by blockade of spinal and supraspinal A(3)AR, lost in A(3)AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A(3)AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A(3)AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A(3)AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A(3)AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A(3)AR agonists as novel therapeutics to treat chronic pain. C1 [Little, Joshua W.; Ford, Amanda; Chen, Zhoumou; Janes, Kali; Doyle, Timothy; Salvemini, Daniela] St Louis Univ, Sch Med, St Louis, MO USA. [Symons-Liguori, Ashley M.; Xie, Jennifer; Vanderah, Todd W.; Porreca, Frank] Univ Arizona, Dept Pharmacol & Anesthesiol, Tucson, AZ USA. [Luongo, Livio; Maione, Sabatino] Univ Naples 2, Dept Expt Med, Div Pharmacol, Naples, Italy. [Tosh, Dillip K.; Jacobson, Kenneth A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Bannister, Kirsty; Dickenson, Anthony H.] UCL, Dept Neurosci Physiol & Pharmacol, London, England. RP Salvemini, D (reprint author), 1402 S Grand Ave, St Louis, MO 63104 USA. EM salvemd@slu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Cancer Institute [RO1CA169519]; NIH [5T32GM008306]; NIDDK Intramural Research Program; FIRB "Futuro in Ricerca" MIUR, Italy [RBFR126IGO_001]; Saint Louis Cancer Centre FX This work was supported by grants from the National Cancer Institute (RO1CA169519), NIH predoctoral fellowship (5T32GM008306), NIDDK Intramural Research Program, FIRB "Futuro in Ricerca" MIUR, Italy (RBFR126IGO_001) and with additional support from the Saint Louis Cancer Centre. NR 33 TC 29 Z9 31 U1 3 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD JAN 1 PY 2015 VL 138 BP 28 EP 35 DI 10.1093/brain/awu330 PN 1 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AZ4KM UT WOS:000348189800013 PM 25414036 ER PT J AU Senatorov, VV Damadzic, R Mann, CL Schwandt, ML George, DT Hommer, DW Heilig, M Momenan, R AF Senatorov, Vladimir V. Damadzic, Ruslan Mann, Claire L. Schwandt, Melanie L. George, David T. Hommer, Daniel W. Heilig, Markus Momenan, Reza TI Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons SO BRAIN LA English DT Article DE insula; amygdala; von Economo neurons; alcoholism; MRI ID CIGARETTE-SMOKING; SOCIAL EXCLUSION; DECISION-MAKING; BRAIN VOLUMES; DEPENDENCE; CORTEX; SCHIZOPHRENIA; ADDICTION; CONNECTIVITY; REDUCTION AB The insula, a structure involved in higher order representation of interoceptive states, has recently been implicated in drug craving and social stress. Here, we performed brain magnetic resonance imaging to measure volumes of the insula and amygdala, a structure with reciprocal insular connections, in 26 alcohol-dependent patients and 24 healthy volunteers (aged 22-56 years, nine females in each group). We used an established morphometry method to quantify total and regional insular volumes. Volumetric measurements of the amygdala were obtained using a model-based segmentation/ registration tool. In alcohol-dependent patients, anterior insula volumes were bilaterally reduced compared to healthy volunteers (left by 10%, right by 11%, normalized to total brain volumes). Furthermore, alcohol-dependent patients, compared with healthy volunteers, had bilaterally increased amygdala volumes. The left amygdala was increased by 28% and the right by 29%, normalized to total brain volumes. Postmortem studies of the anterior insula showed that the reduced anterior insular volume may be associated with a population of von Economo neurons, which were 60% diminished in subjects with a history of alcoholism (n = 6) as compared to subjects without a history of alcoholism (n = 6) (aged 32-56 years, all males). The pattern of neuroanatomical change observed in our alcoholdependent patients might result in a loss of top-down control of amygdala function, potentially contributing to impaired social cognition as well as an inability to control negatively reinforced alcohol seeking and use. C1 [Senatorov, Vladimir V.; Mann, Claire L.; Hommer, Daniel W.; Momenan, Reza] NIAAA, Sect Brain Elect & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Damadzic, Ruslan; Schwandt, Melanie L.; George, David T.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Momenan, R (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,MSC 1108, Bethesda, MD 20892 USA. EM rezam@nih.gov RI Schwandt, Melanie/L-9866-2016 FU NIH, NIAAA FX This research was supported by the Intramural Research Program of the NIH, NIAAA. NR 48 TC 5 Z9 6 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD JAN 1 PY 2015 VL 138 BP 69 EP 79 DI 10.1093/brain/awu305 PN 1 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AZ4KM UT WOS:000348189800017 PM 25367022 ER PT J AU Horne, HN Devi, CRB Sung, H Tang, TS Rosenberg, PS Hewitt, SM Sherman, ME Anderson, WF Yang, XHR AF Horne, Hisani N. Devi, C. R. Beena Sung, Hyuna Tang, Tieng Swee Rosenberg, Philip S. Hewitt, Stephen M. Sherman, Mark E. Anderson, William F. Yang, Xiaohong R. TI Greater absolute risk for all subtypes of breast cancer in the US than Malaysia SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Intrinsic subtypes; SEER; Incidence rates ID PREVALENCE; DISPARITIES; CHINESE; WOMEN AB Hormone receptor (HR) negative breast cancers are relatively more common in low-risk than high-risk countries and/or populations. However, the absolute variations between these different populations are not well established given the limited number of cancer registries with incidence rate data by breast cancer subtype. We, therefore, used two unique population-based resources with molecular data to compare incidence rates for the 'intrinsic' breast cancer subtypes between a low-risk Asian population in Malaysia and high-risk non-Hispanic white population in the National Cancer Institute's surveillance, epidemiology, and end results 18 registries database (SEER 18). The intrinsic breast cancer subtypes were recapitulated with the joint expression of the HRs (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor-2 (HER2). Invasive breast cancer incidence rates overall were fivefold greater in SEER 18 than in Malaysia. The majority of breast cancers were HR-positive in SEER 18 and HR-negative in Malaysia. Notwithstanding the greater relative distribution for HR-negative cancers in Malaysia, there was a greater absolute risk for all subtypes in SEER 18; incidence rates were nearly 7-fold higher for HR-positive and 2-fold higher for HR-negative cancers in SEER 18. Despite the well-established relative breast cancer differences between low-risk and high-risk countries and/or populations, there was a greater absolute risk for HR-positive and HR-negative subtypes in the US than Malaysia. Additional analytical studies are sorely needed to determine the factors responsible for the elevated risk of all subtypes of breast cancer in high-risk countries like the United States. C1 [Horne, Hisani N.; Sung, Hyuna; Rosenberg, Philip S.; Anderson, William F.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Devi, C. R. Beena; Tang, Tieng Swee] Sarawak Gen Hosp, Dept Radiotherapy Oncol & Palliat Care, Kuching, Sarawak, Malaysia. [Hewitt, Stephen M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, NIH, Rockville, MD USA. [Yang, Xiaohong R.] NCI, DCEG, GEB, NIH, Bethesda, MD 20892 USA. RP Yang, XHR (reprint author), NCI, DCEG, GEB, NIH, 9609 Med Ctr Dr Rm 6E426,MSC 9769, Bethesda, MD 20892 USA. EM royang@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU NIH, NCI, DCEG FX We would like to thank the Pathology Department of Sarawak General Hospital and Ms. Rokia Iren for their assistance in tissue block retrieval. Research support Intramural Research Program of the NIH, NCI, DCEG. NR 24 TC 2 Z9 2 U1 3 U2 6 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 JAN PY 2015 VL 149 IS 1 BP 285 EP 291 DI 10.1007/s10549-014-3243-9 PG 7 WC Oncology SC Oncology GA AZ4IB UT WOS:000348183700031 PM 25537643 ER PT J AU Shaitelman, SF Cromwell, KD Rasmussen, JC Stout, NL Armer, JM Lasinski, BB Cormier, JN AF Shaitelman, Simona F. Cromwell, Kate D. Rasmussen, John C. Stout, Nicole L. Armer, Jane M. Lasinski, Bonnie B. Cormier, Janice N. TI Recent Progress in the Treatment and Prevention of Cancer-Related Lymphedema SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review DE lymphedema; morbidities; treatment; diagnosis ID QUALITY-OF-LIFE; LOWER-LIMB LYMPHEDEMA; SENTINEL-NODE BIOPSY; NEAR-INFRARED FLUORESCENCE; LOWER-EXTREMITY LYMPHEDEMA; PROSPECTIVE SURVEILLANCE MODEL; REVERSE MAPPING ARM; PREOPERATIVE ASSESSMENT ENABLES; INTRAVASCULAR STENTING METHOD; LYMPHATIC VENOUS ANASTOMOSIS AB This article provides an overview of the recent developments in the diagnosis, treatment, and prevention of cancer-related lymphedema. Lymphedema incidence by tumor site is evaluated. Measurement techniques and trends in patient education and treatment are also summarized to include current trends in therapeutic and surgical treatment options as well as longer-term management. Finally, an overview of the policies related to insurance coverage and reimbursement will give the clinician an overview of important trends in the diagnosis, treatment, and management of cancer-related lymphedema. CA Cancer J Clin 2015;65:55-81. (c) 2014 American Cancer Society. C1 [Shaitelman, Simona F.] Univ Texas MD Anderson Canc Ctr, Dept Breast Radiat Oncol, Div Radiat Oncol, Houston, TX 77030 USA. [Cromwell, Kate D.; Cormier, Janice N.] Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Surg Oncol, Houston, TX 77030 USA. [Rasmussen, John C.] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Stout, Nicole L.; Lasinski, Bonnie B.] NIH, Off Strateg Res, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Armer, Jane M.] Univ Missouri, Sinclair Sch Nursing, Ellis Fischel Canc Ctr, Columbia, MO USA. [Lasinski, Bonnie B.] Lymphedema Therapy & Boris Lasinski Sch, Woodbury, NY USA. RP Cormier, JN (reprint author), Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Surg Oncol, Unit 1484, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jcormier@mdanderson.org FU National Institutes of Health through The University of Texas MD Anderson Cancer Center [CA016672]; Elekta; MD Anderson Physicians Network; National Institutes of Health; NIRF Imaging FX Supported in part by the National Institutes of Health through The University of Texas MD Anderson Cancer Center Support Grant CA016672. Dr. Shaitelman has received a grant from Elekta and has acted as a paid consultant for the MD Anderson Physicians Network for work performed outside of the current study. Dr. Rasmussen has received a grant from the National Institutes of Health for the development of near-infrared fluorescence imaging for work performed as part of the current study and has acted as a paid consultant for NIRF Imaging for work performed outside of the current study. In addition, Dr. Rasmussen has patents for Method of Measuring Propulsion in Lymphatic Structures and Functional Near-Infrared Fluorescence Lymphatic Mapping for Diagnosing, Accessing, Monitoring and Directing Therapy of Lymphatic Disorders, both of which are licensed to NIRF Imaging and controlled by UTHealth. The remaining authors report no conflicts of interest. NR 245 TC 16 Z9 16 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD JAN-FEB PY 2015 VL 65 IS 1 BP 55 EP 81 DI 10.3322/caac.21253 PG 27 WC Oncology SC Oncology GA AZ0YD UT WOS:000347966900005 PM 25410402 ER PT J AU Hamilton, JG Breen, N Klabunde, CN Moser, RP Leyva, B Breslau, ES Kobrin, SC AF Hamilton, Jada G. Breen, Nancy Klabunde, Carrie N. Moser, Richard P. Leyva, Bryan Breslau, Erica S. Kobrin, Sarah C. TI Opportunities and Challenges for the Use of Large-Scale Surveys in Public Health Research: A Comparison of the Assessment of Cancer Screening Behaviors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID FORCE RECOMMENDATION STATEMENT; TRENDS SURVEY HINTS; COLORECTAL-CANCER; CERVICAL-CANCER; INTERVIEW SURVEY; UNITED-STATES; BREAST-CANCER; FAMILY-HISTORY; HUMAN-PAPILLOMAVIRUS; SEXUAL ORIENTATION AB Large-scale surveys that assess cancer prevention and control behaviors are a readily available, rich resource for public health researchers. Although these data are used by a subset of researchers who are familiar with them, their potential is not fully realized by the research community for reasons including lack of awareness of the data and limited understanding of their content, methodology, and utility. Until now, no comprehensive resource existed to describe and facilitate use of these data. To address this gap and maximize use of these data, we catalogued the characteristics and content of four surveys that assessed cancer screening behaviors in 2005, the most recent year with concurrent periods of data collection: the National Health Interview Survey, Health Information National Trends Survey, Behavioral Risk Factor Surveillance System, and California Health Interview Survey. We documented each survey's characteristics, measures of cancer screening, and relevant correlates; examined how published studies (n = 78) have used the surveys' cancer screening data; and reviewed new cancer screening constructs measured in recent years. This information can guide researchers in deciding how to capitalize on the opportunities presented by these data resources. (C) 2014 AACR. C1 [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10022 USA. [Breen, Nancy; Klabunde, Carrie N.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD USA. [Moser, Richard P.] NCI, Sci Res & Technol Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD USA. [Leyva, Bryan; Breslau, Erica S.; Kobrin, Sarah C.] NCI, Proc Care Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD USA. RP Hamilton, JG (reprint author), Mem Sloan Kettering Canc Ctr, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM hamiltoj@mskcc.org FU National Cancer Institute Cancer Prevention Fellowship Program FX G. Hamilton was supported, in part, by the National Cancer Institute Cancer Prevention Fellowship Program. NR 104 TC 3 Z9 3 U1 3 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 3 EP 14 DI 10.1158/1055-9965.EPI-14-0568 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700001 PM 25300474 ER PT J AU Kim, C Bassig, BA Seow, WJ Hu, W Purdue, MP Huang, WY Liu, CS Cheng, WL Mannisto, S Vermeulen, R Weinstein, SJ Lim, U Hosgood, HD Bonner, MR Caporaso, NE Albanes, D Lan, Q Rothman, N AF Kim, Christopher Bassig, Bryan A. Seow, Wei Jie Hu, Wei Purdue, Mark P. Huang, Wen-Yi Liu, Chin-San Cheng, Wen-Ling Mannisto, Satu Vermeulen, Roel Weinstein, Stephanie J. Lim, Unhee Hosgood, H. Dean Bonner, Matthew R. Caporaso, Neil E. Albanes, Demetrius Lan, Qing Rothman, Nathaniel TI Mitochondrial DNA Copy Number and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Risk in Two Prospective Studies SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKIN-LYMPHOMA; OXIDATIVE STRESS; CANCER RISK; COHORT; PROGRESSION; LEUKOCYTES; MARKERS; CELLS; TRIAL AB Background: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data. Methods: In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI). Results: Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03-4.72; P-trend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72-5.68; P-trend: 0.0002). Association was stronger among male smokers (P-trend: < 0.0001) and essentially identical for cases diagnosed < 6, > 6-8, and > 8 years from blood draw (pooled: P-interaction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association. Conclusions and Impact: Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development. (C)2014 AACR. C1 [Kim, Christopher; Bassig, Bryan A.; Seow, Wei Jie; Hu, Wei; Purdue, Mark P.; Huang, Wen-Yi; Weinstein, Stephanie J.; Caporaso, Neil E.; Albanes, Demetrius; Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Liu, Chin-San; Cheng, Wen-Ling] Changhua Christian Hosp, Changhua, Taiwan. [Liu, Chin-San; Cheng, Wen-Ling] Changhua Christian Hosp, Vasc & Genom Ctr, Changhua, Taiwan. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Lim, Unhee] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Hosgood, H. Dean] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY USA. [Bonner, Matthew R.] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. RP Kim, C (reprint author), 9609 Med Ctr Dr,MSSC 9771, Bethesda, MD 20892 USA. EM christopher.kim@nih.gov RI Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016; Vermeulen, Roel/F-8037-2011; OI Purdue, Mark/0000-0003-1177-3108; Vermeulen, Roel/0000-0003-4082-8163; Mannisto, Satu/0000-0002-8668-3046 FU NIH intramural research program FX This study was supported by the NIH intramural research program. NR 31 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 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 148 EP 153 DI 10.1158/1055-9965.EPI-14-0753 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700017 PM 25293880 ER PT J AU Ananthakrishnan, AN Du, MM Berndt, SI Brenner, H Caan, BJ Casey, G Chang-Claude, J Duggan, D Fuchs, CS Gallinger, S Giovannucci, EL Harrison, TA Hayes, RB Hoffmeister, M Hopper, JL Hou, LF Hsu, L Jenkins, MA Kraft, P Ma, J Nan, HM Newcomb, PA Ogino, S Potter, JD Seminara, D Slattery, ML Thornquist, M White, E Wu, KN Peters, U Chan, AT AF Ananthakrishnan, Ashwin N. Du, Mengmeng Berndt, Sonja I. Brenner, Hermann Caan, Bette J. Casey, Graham Chang-Claude, Jenny Duggan, David Fuchs, Charles S. Gallinger, Steven Giovannucci, Edward L. Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hopper, John L. Hou, Lifang Hsu, Li Jenkins, Mark A. Kraft, Peter Ma, Jing Nan, Hongmei Newcomb, Polly A. Ogino, Shuji Potter, John D. Seminara, Daniela Slattery, Martha L. Thornquist, Mark White, Emily Wu, Kana Peters, Ulrike Chan, Andrew T. TI Red Meat Intake, NAT2, and Risk of Colorectal Cancer: A Pooled Analysis of 11 Studies SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; GENETIC SUSCEPTIBILITY; COLON-CANCER; HETEROCYCLIC AMINES; EXCISION-REPAIR; POULTRY INTAKE; POLYMORPHISMS; CONSUMPTION; SMOKING; COHORT AB Background: Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported. Methods: We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. Results: From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [ OR, 1.41; 95% confidence interval (CI), 1.29-1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20-1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28-1.61; P interaction = 0.9). Conclusion: We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case-control studies and not modified by NAT2 enzyme activity. Impact: Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer. (C)2014 AACR. C1 [Ananthakrishnan, Ashwin N.; Chan, Andrew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Ogino, Shuji; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Du, Mengmeng; Harrison, Tabitha A.; Hsu, Li; Newcomb, Polly A.; Potter, John D.; Seminara, Daniela; Slattery, Martha L.; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Berndt, Sonja I.] NCI, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Caan, Bette J.] German Canc Consortium, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care, Oakland, CA USA. [Casey, Graham] Univ So Calif, Los Angeles, CA USA. [Chang-Claude, Jenny] German Canc Res Ctr DFKZ, Div Canc Epidemiol, Heidelberg, Germany. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Fuchs, Charles S.; Ma, Jing] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Ma, Jing; Ogino, Shuji; Wu, Kana] Channing Div Network Med, Boston, MA USA. [Gallinger, Steven] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia. [Hou, Lifang] Northwestern Univ, Dept Prevent Med, Evanston, IL USA. [Hou, Lifang] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Evanston, IL USA. [Nan, Hongmei] Indiana Univ, Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Potter, John D.; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Slattery, Martha L.] Univ Utah Hlth Sci, Salt Lake City, UT USA. RP Chan, AT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM upeters@fhcrc.org; achan@mgh.harvard.edu RI Hoffmeister, Michael/B-5745-2012; Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Hayes, Richard/0000-0002-0918-661X FU NIH [K23 DK097142, UM1 CA167551, U01 CA122839, R01 CA143237, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993, P01 CA 087969, P50 CA 127003, R01 CA042182, U01 HG004446, K05 CA154337]; GECCO; NCI; U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, R25 CA094880]; Australasian Colorectal Cancer Family Registry [U01/U24 CA097735]; Ontario Registry for Studies of Familial Colorectal Cancer [U01/U24 CA074783]; Seattle Colorectal Cancer Family Registry [U01/U24 CA074794]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NIH through Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; Ontario Research Fund [GL2]; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Intramural Research Program of the Division of Cancer Epidemiology and Genetics and; Division of Cancer Prevention, NCI, NIH, DHHS; NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH GEI [U01 HG 004438]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX A. Ananthakrishnan is supported by a grant from the NIH (K23 DK097142). M. Du, T. A Harrison, L. Hsu, M. Thornquist, and U. Peters are affiliated with GECCO, which is supported by the following grants from the NCI, NIH and U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, R25 CA094880; to M. Du).; G. Casey, J.L. Hopper, M.A. Jenkins, and P.A. Newcomb are affiliated with CCFR, which is supported by the NIH (UM1 CA167551) and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators. This genome-wide scan was supported by the NCI, NIH by U01 CA122839 and R01 CA143237 (to G. Casey). The following Colon CFR centers contributed data to this article and were supported by the NIH:; Australasian Colorectal Cancer Family Registry (U01/U24 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01/U24 CA074783). Seattle Colorectal Cancer Family Registry (U01/U24 CA074794).; H. Brenner, J. Chang-Claude, and M. Hoffmeister are affiliated with DACHS, which was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814).; J.D. Potter and M.L. Slattery are affiliated with DALS, which was supported by the NIH (R01 CA48998; to M.L. Slattery).; A.T. Chan, C.S. Fuchs, K. Wu, E.L. Giovannucci, J. Ma, and S. Ogino are affiliated with HPFS, NHS, and PHS, which are supported by the NIH. HPFS is supported by the NIH (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993, and P50 CA 127003), NHS by the NIH (R01 CA137178, R01 CA151993, P01 CA 087969, and P50 CA 127003) and PHS by the NIH (R01 CA042182).; S. Gallinger is affiliated with theOFCCR, which is supported by funding from the NIH through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute.; S.I. Berndt and R.B. Hayes are affiliated with the PLCO, which is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, NCI, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager and colleagues Nat Genet 2007; 39: 645-9), Colon CGEMS pancreatic cancer scan (PanScan; Amundadottir and colleagues Nat Genet 2009; 41: 986-90 and Petersen and colleagues Nat Genet 2010; 42: 224-8), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206. v3. p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www. ncbi. nlm. nih. gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping.; P. A. Newcomb is affiliated with PMH, which is supported by the NIH (R01 CA076366; to P. A. Newcomb).; E. White is affiliated with VITAL, which is supported by the NIH (K05 CA154337).; D. Duggan is affiliated with TGEN and funded through a subaward with GECCO (R01 CA059045).; The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 51 TC 6 Z9 6 U1 2 U2 20 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 198 EP 205 DI 10.1158/1055-9965.EPI-14-0897 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700023 PM 25342387 ER PT J AU Loeb, S Peskoe, SB Joshu, CE Huang, WY Hayes, RB Carter, HB Isaacs, WB Platz, EA AF Loeb, Stacy Peskoe, Sarah B. Joshu, Corinne E. Huang, Wen-Yi Hayes, Richard B. Carter, H. Ballentine Isaacs, William B. Platz, Elizabeth A. TI Do Environmental Factors Modify the Genetic Risk of Prostate Cancer? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GENOME-WIDE ASSOCIATION; SELENIUM SUPPLEMENTATION; SEQUENCE VARIANTS; TRIAL; PREVENTION; LOCI; SUSCEPTIBILITY; ANTIGEN; VEGETABLES AB Background: Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown. Methods: We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (>= 12 SNPs) and prostate cancer within environmental factor strata and tested for interaction. Results: Men with >= 12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for >= 12 alleles was 2.06 [95% confidence interval (CI), 1.67-2.55] in nonusers and 0.99 (0.38-2.58) in users (P-interaction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with < 12 alleles and nonusers, the OR for >= 12 alleles was 2.25 (1.69-3.00) in nonusers and 1.70 (1.25-2.32) in users (P-interaction = 0.009). This pattern was similar for ibuprofen (P-interaction = 0.023) and vegetables (P-interaction = 0.010). Conclusions: This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer. Impact: The effect of genetic factors on prostate cancer risk may vary by lifestyle interventions. (C)2014 AACR. C1 [Loeb, Stacy] NYU, Dept Urol, New York, NY 10016 USA. [Loeb, Stacy; Hayes, Richard B.] NYU, New York, NY 10016 USA. [Peskoe, Sarah B.; Joshu, Corinne E.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Huang, Wen-Yi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Carter, H. Ballentine; Isaacs, William B.; Platz, Elizabeth A.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Carter, H. Ballentine; Isaacs, William B.; Platz, Elizabeth A.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. RP Loeb, S (reprint author), NYU, 550 1st Ave,VZ30 6th Floor 612, New York, NY 10016 USA. EM stacyloeb@gmail.com FU National Cancer Institute, NIH, Department of Health and Human Services [P50 CA58236, K07 CA178258]; Louis Feil Charitable Lead Trust FX This work was supported by P50 CA58236 (to W.G. Nelson) from the National Cancer Institute, NIH, Department of Health and Human Services, and by K07 CA178258 from the National Cancer Institute, NIH, Department of Health and Human Services (to S. Loeb). This work was also supported by the Louis Feil Charitable Lead Trust to S. Loeb. NR 34 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 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 213 EP 220 DI 10.1158/1055-9965.EPI-14-0786-T PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700025 PM 25342390 ER PT J AU Trabert, B Wentzensen, N Felix, AS Yang, HP Sherman, ME Brinton, LA AF Trabert, Britton Wentzensen, Nicolas Felix, Ashley S. Yang, Hannah P. Sherman, Mark E. Brinton, Louise A. TI Metabolic Syndrome and Risk of Endometrial Cancer in the United States: A Study in the SEER-Medicare Linked Database SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BODY-SIZE; CARCINOMA; ABNORMALITIES; HYPERTENSION; OVERWEIGHT; HEALTH; ADULTS; WOMEN; LIFE; MASS AB Background: Metabolic syndrome and its component feature, central obesity, are associated with endometrial cancer risk. It remains unclear whether associations with the other metabolic factors that comprise metabolic syndrome are independent of the obesity-endometrial cancer association. Furthermore, the link with specific endometrial cancer subtypes remains ill-defined, despite evidence of etiologic heterogeneity among these tumors. Methods: In a case-control study within the SEER-Medicare linked database, we examined whether metabolic factors, individually or combined, were associated with endometrial cancer. Cases (n = 16,323) were women diagnosed with endometrial cancer from 1993 through 2007. Controls (n = 100,751) were a 5% sample of female Medicare enrollees residing in the same SEER registry area as cases. Metabolic syndrome was defined using ICD-9-CM codes from inpatient/outpatient diagnoses 1 to 3 years before case diagnosis and a comparable time period in controls. ORs and 95% confidence intervals (CI) were estimated using logistic regression. Results: Endometrial cancer risk was associated with metabolic syndrome [OR (95% CI): 1.39 (1.32-1.47)] and its component factors: overweight/obesity [1.95 (1.80-2.11)], impaired fasting glucose [1.36 (1.30-1.43)], high blood pressure [1.31 (1.25-1.36)], and high triglycerides [1.13 (1.08-1.18)]. After adjusting for overweight/obesity, the increased risks associated with the metabolic syndrome factors remained. Heterogeneity of associations by subtype were not identified (P-heterogeneity - 0.82). Conclusions: Among women age 65 and older in the United States, metabolic syndrome, and its component factors, increased endometrial cancer risk similarly across endometrial cancer subtypes. Impact: Strategies to reduce the prevalence of metabolic syndrome factors might have a favorable effect on endometrial cancer incidence.(C) 2015 AACR. C1 [Trabert, Britton; Wentzensen, Nicolas; Felix, Ashley S.; Yang, Hannah P.; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Trabert, B (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; Felix, Ashley/A-3240-2016 OI Brinton, Louise/0000-0003-3853-8562; FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This research was supported by Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 30 TC 18 Z9 18 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 261 EP 267 DI 10.1158/1055-9965.EPI-14-0923 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700031 PM 25587111 ER PT J AU Peterlongo, P Chang-Claude, J Moysich, KB Rudolph, A Schmutzler, RK Simard, J Soucy, P Eeles, RA Easton, DF Hamann, U Wilkening, S Chen, BW Rookus, MA Schmidt, M van der Baan, FH Spurdle, AB Walker, LC Lose, F Maia, AT Montagna, M Matricardi, L Lubinski, J Jakubowska, A Garcia, EBG Olopade, OI Nussbaum, RL Nathanson, KL Domchek, SM Rebbeck, TR Arun, BK Karlan, BY Orsulic, S Lester, J Chung, WK Miron, A Southey, MC Goldgar, DE Buys, SS Janavicius, R Dorfling, CM van Rensburg, EJ Ding, YC Neuhausen, SL Hansen, TVO Gerdes, AM Ejlertsen, B Jonson, L Osorio, A Martinez-Bouzas, C Benitez, J Conway, EE Blazer, KR Weitzel, JN Manoukian, S Peissel, B Zaffaroni, D Scuvera, G Barile, M Ficarazzi, F Mariette, F Fortuzzi, S Viel, A Giannini, G Papi, L Martayan, A Tibiletti, MG Radice, P Vratimos, A Fostira, F Garber, JE Donaldson, A Brewer, C Foo, C Evans, DGR Frost, D Eccles, D Brady, A Cook, J Tischkowitz, M Adlard, J Barwell, J Walker, L Izatt, L Side, LE Kennedy, MJ Rogers, MT Porteous, ME Morrison, PJ Platte, R Davidson, R Hodgson, SV Ellis, S Cole, T Godwin, AK Claes, K Van Maerken, T Meindl, A Gehrig, A Sutter, C Engel, C Niederacher, D Steinemann, D Plendl, H Kast, K Rhiem, K Ditsch, N Arnold, N Varon-Mateeva, R Wappenschmidt, B Wang-Gohrke, S Bressac-de Paillerets, B Buecher, B Delnatte, C Houdayer, C Stoppa-Lyonnet, D Damiola, F Coupier, I Barjhoux, L Venat-Bouvet, L Golmard, L Boutry-Kryza, N Sinilnikova, OM Caron, O Pujol, P Mazoyer, S Belotti, M Piedmonte, M Friedlander, ML Rodriguez, GC Copeland, LJ de la Hoya, M Segura, PP Nevanlinna, H Aittomaki, K van Os, TAM Meijers-Heijboer, HEJ van der Hout, AH Vreeswijk, MPG Hoogerbrugge, N Ausems, MGEM van Doorn, HC Collee, JM Olah, E Diez, O Blanco, I Lazaro, C Brunet, J Feliubadalo, L Cybulski, C Gronwald, J Durda, K Jaworska-Bieniek, K Sukiennicki, G Arason, A Chiquette, J Teixeira, MR Olswold, C Couch, FJ Lindor, NM Wang, XS Szabo, CI Offit, K Corines, M Jacobs, L Robson, ME Zhang, LY Joseph, V Berger, A Singer, CF Rappaport, C Kaulich, DG Pfeiler, G Tea, MKM Phelan, CM Greene, MH Mai, PL Rennert, G Mulligan, AM Glendon, G Tchatchou, S Andrulis, IL Toland, AE Bojesen, A Pedersen, IS Thomassen, M Jensen, UB Laitman, Y Rantala, J von Wachenfeldt, A Ehrencrona, H Askmalm, MS Borg, A Kuchenbaecker, KB McGuffog, L Barrowdale, D Healey, S Lee, A Pharoah, PDP Chenevix-Trench, G Antoniou, AC Friedman, E AF Peterlongo, Paolo Chang-Claude, Jenny Moysich, Kirsten B. Rudolph, Anja Schmutzler, Rita K. Simard, Jacques Soucy, Penny Eeles, Rosalind A. Easton, Douglas F. Hamann, Ute Wilkening, Stefan Chen, Bowang Rookus, Matti A. Schmidt, MarjankaK. van der Baan, Frederieke H. Spurdle, Amanda B. Walker, Logan C. Lose, Felicity Maia, Ana-Teresa Montagna, Marco Matricardi, Laura Lubinski, Jan Jakubowska, Anna Garcia, Encarna B. Gomez Olopade, Olufunmilayo I. Nussbaum, Robert L. Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy R. Arun, Banu K. Karlan, Beth Y. Orsulic, Sandra Lester, Jenny Chung, Wendy K. Miron, Alex Southey, Melissa C. Goldgar, David E. Buys, Saundra S. Janavicius, Ramunas Dorfling, Cecilia M. van Rensburg, Elizabeth J. Ding, Yuan Chun Neuhausen, Susan L. Hansen, Thomas V. O. Gerdes, Anne-Marie Ejlertsen, Bent Jonson, Lars Osorio, Ana Martinez-Bouzas, Cristina Benitez, Javier Conway, Edye E. Blazer, Kathleen R. Weitzel, Jeffrey N. Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Scuvera, Giulietta Barile, Monica Ficarazzi, Filomena Mariette, Frederique Fortuzzi, Stefano Viel, Alessandra Giannini, Giuseppe Papi, Laura Martayan, Aline Tibiletti, Maria Grazia Radice, Paolo Vratimos, Athanassios Fostira, Florentia Garber, Judy E. Donaldson, Alan Brewer, Carole Foo, Claire Evans, D. Gareth R. Frost, Debra Eccles, Diana Brady, Angela Cook, Jackie Tischkowitz, Marc Adlard, Julian Barwell, Julian Walker, Lisa Izatt, Louise Side, Lucy E. Kennedy, M. John Rogers, Mark T. Porteous, Mary E. Morrison, Patrick J. Platte, Radka Davidson, Rosemarie Hodgson, Shirley V. Ellis, Steve Cole, Trevor Godwin, Andrew K. Claes, Kathleen Van Maerken, Tom Meindl, Alfons Gehrig, Andrea Sutter, Christian Engel, Christoph Niederacher, Dieter Steinemann, Doris Plendl, Hansjoerg Kast, Karin Rhiem, Kerstin Ditsch, Nina Arnold, Norbert Varon-Mateeva, Raymonda Wappenschmidt, Barbara Wang-Gohrke, Shan Bressac-de Paillerets, Brigitte Buecher, Bruno Delnatte, Capucine Houdayer, Claude Stoppa-Lyonnet, Dominique Damiola, Francesca Coupier, Isabelle Barjhoux, Laure Venat-Bouvet, Laurence Golmard, Lisa Boutry-Kryza, Nadia Sinilnikova, Olga M. Caron, Olivier Pujol, Pascal Mazoyer, Sylvie Belotti, Muriel Piedmonte, Marion Friedlander, Michael L. Rodriguez, Gustavo C. Copeland, Larry J. de la Hoya, Miguel Perez Segura, Pedro Nevanlinna, Heli Aittomaeki, Kristiina van Os, Theo A. M. Meijers-Heijboer, Hanne E. J. van der Hout, Annemarie H. Vreeswijk, Maaike P. G. Hoogerbrugge, Nicoline Ausems, Margreet G. E. M. van Doorn, Helena C. Collee, J. Margriet Olah, Edith Diez, Orland Blanco, Ignacio Lazaro, Conxi Brunet, Joan Feliubadalo, Lidia Cybulski, Cezary Gronwald, Jacek Durda, Katarzyna Jaworska-Bieniek, Katarzyna Sukiennicki, Grzegorz Arason, Adalgeir Chiquette, Jocelyne Teixeira, Manuel R. Olswold, Curtis Couch, Fergus J. Lindor, Noralane M. Wang, Xianshu Szabo, Csilla I. Offit, Kenneth Corines, Marina Jacobs, Lauren Robson, Mark E. Zhang, Liying Joseph, Vijai Berger, Andreas Singer, Christian F. Rappaport, Christine Kaulich, Daphne Geschwantler Pfeiler, Georg Tea, Muy-Kheng M. Phelan, Catherine M. Greene, Mark H. Mai, Phuong L. Rennert, Gad Mulligan, Anna Marie Glendon, Gord Tchatchou, Sandrine Andrulis, Irene L. Toland, Amanda Ewart Bojesen, Anders Pedersen, Inge Sokilde Thomassen, Mads Jensen, Uffe Birk Laitman, Yael Rantala, Johanna von Wachenfeldt, Anna Ehrencrona, Hans Askmalm, Marie Stenmark Borg, Ake Kuchenbaecker, Karoline B. McGuffog, Lesley Barrowdale, Daniel Healey, Sue Lee, Andrew Pharoah, Paul D. P. Chenevix-Trench, Georgia Antoniou, Antonis C. Friedman, Eitan CA EMBRACE GEMO Study Collaborators HEBON KConFab Investigators TI Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASSOCIATION AB Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR. C1 [Peterlongo, Paolo; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano] Fdn Ist FIRC Oncol Molecolare, IFOM, I-20139 Milan, Italy. [Peterlongo, Paolo; Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Cancer Epidemiol, Heidelberg, Germany. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Fac Med, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany. [Simard, Jacques; Soucy, Penny] Ctr Hosp Univ Quebec Res Ctr, Quebec City, PQ, Canada. [Simard, Jacques; Soucy, Penny] Univ Laval, Quebec City, PQ, Canada. [Eeles, Rosalind A.] Inst Canc Res, Oncogenet Team, Surrey, England. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, Surrey, England. [Easton, Douglas F.; Frost, Debra; Platte, Radka; Ellis, Steve; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Antoniou, Antonis C.; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Hamann, Ute; Wilkening, Stefan; Chen, Bowang] German Canc Res Ctr, Heidelberg, Germany. [Rookus, Matti A.; van der Baan, Frederieke H.; HEBON] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Schmidt, MarjankaK.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Spurdle, Amanda B.; Lose, Felicity; Healey, Sue; Chenevix-Trench, Georgia] QIMR Berghofer, Dept Genet & Computat Biol, Brisbane, Qld, Australia. [Walker, Logan C.] Univ Otago, Dept Pathol, Christchurch, New Zealand. [Maia, Ana-Teresa] Univ Algarve, Dept Biomed Sci & Med, Algarve, Portugal. [Montagna, Marco; Matricardi, Laura] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [Lubinski, Jan; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Garcia, Encarna B. Gomez] MUMC, Dept Clin Genet, Maastricht, Netherlands. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Dept Med & Human Genet, Ctr Clin Canc Genet, Chicago, IL 60637 USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Dept Epidemiol & Biostat, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Chung, Wendy K.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Chung, Wendy K.] Columbia Univ, Dept Med, New York, NY USA. [Miron, Alex] Case Western Reserve Med Sch, Dept Genet & Genom, Cleveland, OH USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [Buys, Saundra S.] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Vilnius, Lithuania. [Janavicius, Ramunas] State Res Inst Ctr Innovat Med, Vilnius, Lithuania. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa. [Ding, Yuan Chun; Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Hansen, Thomas V. O.; Jonson, Lars] Univ Copenhagen Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [Gerdes, Anne-Marie] Univ Copenhagen Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Ejlertsen, Bent] Univ Copenhagen Hosp, Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark. [Osorio, Ana; Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Martinez-Bouzas, Cristina] Cruces Hosp Barakaldo, Dept Biochem, Mol Genet Lab, Barakaldo Bizkaia 48903, Spain. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Genotyping Unit, Madrid, Spain. [Conway, Edye E.] City Hope Clin Canc Genet Community Res Network, St Alphonsus Reg Med Ctr, Duarte, CA USA. [Blazer, Kathleen R.] City Hope Natl Med Ctr, Duarte, CA USA. [Weitzel, Jeffrey N.] City Hope Clin Canc Genet Community Res Network, City Hope, Duarte, CA USA. [Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predictive Med, Unit Med Genet, Milan, Italy. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano] Cogentech Canc Genet Test Lab, Milan, Italy. [Viel, Alessandra] CRO Aviano Natl Canc Inst, Div Expt Oncol 1, Aviano, PN, Italy. [Giannini, Giuseppe] Univ Roma La Sapienza, Dept Mol Med, I-00185 Rome, Italy. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy. [Martayan, Aline] Ist Nazl Tumori Regina Elena, Dept Med Oncol, Unit Genet Counseling, Rome, Italy. [Tibiletti, Maria Grazia] Polo Univ Varese, UO Anat Patolog Osped Circolo & Fdn Macchi, Varese, Italy. [Vratimos, Athanassios; Fostira, Florentia] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Donaldson, Alan] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Foo, Claire] Liverpool Womens NHS Fdn Trust, Cheshire & Merseyside Clin Genet Serv, Liverpool, Merseyside, England. [Evans, D. Gareth R.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp NHS Trust, Southampton SO9 5NH, Hants, England. [Brady, Angela] Kennedy Galton Ctr, North West Thames Reg Genet Serv, Harrow, Middx, England. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Tischkowitz, Marc] Addenbrookes Hosp, East Anglian Reg Genet Serv, Dept Clin Genet, Cambridge, England. [Adlard, Julian] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Barwell, Julian] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Side, Lucy E.] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London WC1N 3JH, England. [Kennedy, M. John] Univ Dublin Trinity Coll, Acad Unit Clin & Mol Oncol, Dublin 2, Ireland. [Kennedy, M. John] St James Hosp, Dublin 8, Ireland. [Rogers, Mark T.] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales. [Porteous, Mary E.] Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Morrison, Patrick J.] Queens Univ Belfast, Dept Med Genet, Belfast HSC Trust, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland. [Davidson, Rosemarie] So Gen Hosp, West Scotland Reg Genet Serv, Glasgow G51 4TF, Lanark, Scotland. [Hodgson, Shirley V.] St Georges Univ London, Med Genet Unit, London, England. [Cole, Trevor] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, MO USA. [Claes, Kathleen; Van Maerken, Tom] Univ Ghent, Ctr Genet Med, B-9000 Ghent, Belgium. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Gynecol & Obstet, D-80290 Munich, Germany. [Gehrig, Andrea] Univ Wurzburg, Inst Human Genet, Wurzburg, Germany. [Sutter, Christian] Heidelberg Univ, Heidelberg, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dusseldorf, Germany. [Steinemann, Doris] Hannover Med Sch, Hannover, NH, Germany. [Plendl, Hansjoerg] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein, Kiel, Germany. [Kast, Karin] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Gynecol & Obstet, Dresden, Germany. [Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany. [Ditsch, Nina] Univ Munich, Dept Gynecol & Obstet, Munich, Germany. [Arnold, Norbert] Univ Kiel, Dept Gynecol & Obstet, Univ Hosp Schleswig Holstein, Kiel, Germany. [Varon-Mateeva, Raymonda] Charite, Inst Human Genet, Berlin, Germany. [Wang-Gohrke, Shan] Univ Hosp Ulm, Dept Gynecol & Obstet, Ulm, Germany. [Bressac-de Paillerets, Brigitte] Fdn Jean Dausset, INSERM U946, Paris, France. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Villejuif, France. [Buecher, Bruno; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Golmard, Lisa; Belotti, Muriel] Inst Curie, Dept Tumour Biol, Paris, France. [Delnatte, Capucine] Ctr Rene Gauducheau, F-44035 Nantes, France. [Houdayer, Claude; Stoppa-Lyonnet, Dominique] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Stoppa-Lyonnet, Dominique] INSERM U830, Inst Curie, Paris, France. [Damiola, Francesca; Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon 1, Ctr Rech Cancerol Lyon, INSERM U1052, CNRS UMR5286, F-69365 Lyon, France. [Coupier, Isabelle; Pujol, Pascal] CHU Arnaud Villeneuve, Unit Oncogenet, Montpellier, France. [Coupier, Isabelle; Barjhoux, Laure] CRLCC Val Aurelle, Unit Oncogenet, Montpellier, France. [Venat-Bouvet, Laurence] Ctr Hosp Univ Dupuytren, Dept Med Oncol, Limoges, France. [Boutry-Kryza, Nadia; Sinilnikova, Olga M.] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France. [Caron, Olivier] Inst Cancerol Gustave Roussy, Dept Med, Villejuif, France. [Pujol, Pascal] INSERM 896, CRCM Val Aurelle, Montpellier, France. [GEMO Study Collaborators] GEMO Study Natl Canc Genet Network, UNICANCER Genet Grp, Paris, France. [Piedmonte, Marion] Roswell Pk Canc Inst, Stat & Data Ctr, Gynecol Oncol Grp, Buffalo, NY 14263 USA. [Friedlander, Michael L.] Australia New Zealand Gynaecol Oncol Grp, Coordinating Ctr, Camperdown, NSW, Australia. [Rodriguez, Gustavo C.] NorthShore Univ HealthSyst, Div Gynecol Oncol, Evanston, IL USA. [Copeland, Larry J.] Ohio State Univ, Dept Obstet & Gynecol, Hilliard, OH USA. [de la Hoya, Miguel] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain. [Perez Segura, Pedro] Hosp Clin San Carlos, IdISSC, Dept Oncol, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Nevanlinna, Heli] Univ Helsinki, Helsinki, Finland. [Aittomaeki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [van Os, Theo A. M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Meijers-Heijboer, Hanne E. J.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [van der Hout, Annemarie H.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Vreeswijk, Maaike P. G.] Leiden Univ, Med Ctr LUMC, Dept Human Genet, Leiden, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Ausems, Margreet G. E. M.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Doorn, Helena C.] Erasmus Univ, Dept Obstet & Ginecol, Div Gynecol Oncol, MC Canc Inst, Rotterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Diez, Orland] Univ Hosp Vall Hebron, Oncol Grp, Barcelona, Spain. [Diez, Orland] Univ Autonoma Barcelona, E-08193 Barcelona, Spain. [Diez, Orland] Vall Hebron Inst Oncol, Barcelona, Spain. [Diez, Orland] Vall Hebron Res Inst, Barcelona, Spain. [Blanco, Ignacio] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain. [Lazaro, Conxi] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain. [Brunet, Joan] IDIBGI Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain. [Feliubadalo, Lidia; Arason, Adalgeir] Univ Iceland, Fac Med, BMC, Reykjavik, Iceland. [Arason, Adalgeir] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Chiquette, Jocelyne] Univ Quebec, Ctr Rech FRSQ Ctr Hosp Affilie, Ctr Malad Sein Deschenes Fabia, Unite Rech Sante Populat, Quebec City, PQ, Canada. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Olswold, Curtis] Mayo Clin, Dept Hlth Sci Res, Rochester, NY USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol & Hlth Sci Res, Rochester, NY USA. [Lindor, Noralane M.] Mayo Clin, Scottsdale, AZ USA. [Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, NY USA. [Szabo, Csilla I.] NIH, NHGRI, Bethesda, MD 20892 USA. [Offit, Kenneth; Robson, Mark E.; Joseph, Vijai] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, New York, NY 10021 USA. [Corines, Marina; Jacobs, Lauren] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Zhang, Liying] Mem Sloan Kettering Canc Ctr, Dept Pathol, Diagnost Mol Genet Lab, New York, NY 10021 USA. [Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.] Med Univ Vienna, Dept OB GYN, Vienna, Austria. [Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Greene, Mark H.; Mai, Phuong L.] NIH, Natl Canc Inst, Div Canc Epidemiol & Genet, Clin Genet Branch, Rockville, MD USA. [Rennert, Gad] Clalit Natl Canc Control Ctr, Haifa, Israel. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Tchatchou, Sandrine; Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Ohio State Univ, Ctr Comprehens Canc, Dept Med Genet, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med & Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Dept Biochem, Sect Mol Diagnost, Aalborg, Denmark. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Laitman, Yael] Sheba Med Ctr, Tel Aviv, Israel. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [von Wachenfeldt, Anna] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Ehrencrona, Hans] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden. [Ehrencrona, Hans] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Askmalm, Marie Stenmark] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, Linkoping, Sweden. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [KConFab Investigators] kConFab Kathleen Cuningham Consortium Res Familia, Peter Mac Callum Canc Ctr, Melbourne, Vic, Australia. RP Peterlongo, P (reprint author), Fdn Ist FIRC Oncol Molecolare, IFOM, Via Adamello 16, I-20139 Milan, Italy. EM paolo.peterlongo@ifom.eu; eitan.friedman@sheba.health.gov.il RI Spurdle, Amanda/A-4978-2011; Feliubadalo, Lidia/G-4577-2016; Andrulis, Irene/E-7267-2013; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Giannini, Giuseppe/B-5672-2013; montagna, marco/E-2225-2012; Hoogerbrugge, Nicoline/O-1016-2013; Osorio, Ana/I-4324-2014; Maia, Ana-Teresa/F-4404-2012; Teixeira, Manuel/E-4885-2011; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; OI Brunet, Joan/0000-0003-1945-3512; Joseph, Vijai/0000-0002-7933-151X; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Papi, Laura/0000-0003-4552-9517; Robson, Mark/0000-0002-3109-1692; Barrowdale, Daniel/0000-0003-1661-3939; Lose, Felicity/0000-0001-8337-3547; Nevanlinna, Heli/0000-0002-0916-2976; Eeles, Rosalind/0000-0002-3698-6241; Blanco, Ignacio/0000-0002-7414-7481; Spurdle, Amanda/0000-0003-1337-7897; Feliubadalo, Lidia/0000-0002-1736-0112; Ehrencrona, Hans/0000-0002-5589-3622; Rappaport-Fuerhauser, Christine/0000-0002-6820-0020; Giannini, Giuseppe/0000-0003-0299-4056; montagna, marco/0000-0002-4929-2150; Osorio, Ana/0000-0001-8124-3984; Maia, Ana-Teresa/0000-0002-0454-9207; Teixeira, Manuel/0000-0002-4896-5982; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Fortuzzi, Stefano/0000-0002-5662-3800 FU European Community (COGS) [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692, C1287/A16563, C1287/A17523, C5047/A8385]; NIH [CA128978, R01-CA102776, R01CA083855]; Post-Cancer GWAS initiative [1U19CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920, RC4CA153828]; Research Council of Lithuania [LIG-07/2012]; Cancer Association of South Africa (CANSA); Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI12/00070]; Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry (COH-CCGCRN); Fondazione IRCCS Istituto Nazionale dei Tumori; DKFZ; NIHR grant to the Biomedical Research Centre, Manchester; NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; German Cancer Aid [109078]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society and the Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005]; BBMRI [NWO 184.021.007/CP46]; Hungarian Research Grants [KTIA OTKA CK-80745, OTKA K-112228]; Asociacion Espanola Contra el Cancer; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, 2009SGR290]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Ministero della Salute; Istituto Oncologico Veneto; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; David and Margaret T. Grohne Family Foundation; Ting Tsung and Wei Fong Chao Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Ohio State University Comprehensive Cancer Center; Swedish Cancer Society; Women's Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute - American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; NEYE Foundation; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology:; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; NCI's Community Clinical Oncology Program (CCOP) grant [CA 101165]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Israel Cancer Association; Israeli Inherited Breast Cancer Consortium; Susan G. Komen Foundation; Basser Research Center; ISCIII [RD12/00369/0006]; European Regional Development funds, Spain; Morris and Horowitz Families Endowed Professorship; Chancellors Distinguished Chair in Biomedical Sciences Professorship; Intramural Research Program of the US National Cancer Institute; NIH; Westat, Inc; [PBZ_KBN_122/P05/2004]; [1R01 CA149429-01]; [5U01CA113916]; [R01CA140323]; [NO2-CP-11019- 50]; [N02-CP-65504]; Associazione Italiana per la Ricerca sul Cancro FX Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692), the NIH (CA128978) and Post-Cancer GWAS initiative (1U19CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAMEON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. BFBOCC was partly supported by: Research Council of Lithuania grant LIG-07/2012; BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; the CNIO study was supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060 and FISPI12/00070 and Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry (COH-CCGCRN) was supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. CONSIT TEAM was partially supported by funds from Italian citizens who allocated the 5 x 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale dei Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'); the DKFZ study was supported by the DKFZ; EMBRACE was supported by Cancer Research UK Grants C1287/A10118, C1287/A16563 and C1287/A17523. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385; the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is kindly supported by the German Cancer Aid to Rita K. Schmutzler (grant no. 109078) and by the Center for Molecular Medicine Cologne (CMMC); the GEMO study was supported by the Ligue National Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; and the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; the HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation; The HEBON study was supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.; 007/CP46; Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA OTKA CK-80745 and OTKA K-112228; ICO was sponsored by Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia, contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, and 2009SGR290; The IHCC was supported by Grant PBZ_KBN_122/P05/2004; The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund; IOVHBOCS was supported by Ministero della Salute and "5 x 1000" Istituto Oncologico Veneto grant; kConFab was supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; MAYO was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and a grant from the Breast Cancer Research Foundation, the David and Margaret T. Grohne Family Foundation, and the Ting Tsung and Wei Fong Chao Foundation; MSKCC was supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative; OSUCCG was supported by the Ohio State University Comprehensive Cancer Center; SWE-BRCA collaborators are supported by the Swedish Cancer Society; the Women's Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).; This work was supported by the NEYE Foundation; by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research& Technology: ARISTEIA, Investing in knowledge society through the European Social Fund; by the University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program; by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517), and by NCI's Community Clinical Oncology Program (CCOP) grant (CA 101165); by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade - grant #PSR-SIIRI-701; through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium; by NIH (R01-CA102776 and R01CA083855; by Breast Cancer Research Foundation; by Susan G. Komen Foundation; by Basser Research Center; by RD12/00369/0006 from ISCIII and the European Regional Development funds, Spain and by 1R01 CA149429-01 grant.; Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship; Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship; the research of Mark H Greene and Phuong L Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019- 50 and N02-CP-65504 with Westat, Inc, Rockville, MD. NR 8 TC 3 Z9 3 U1 3 U2 29 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2015 VL 24 IS 1 BP 308 EP 316 DI 10.1158/1055-9965.EPI-14-0532 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AZ1YG UT WOS:000348030700038 PM 25336561 ER PT J AU Fleg, JL Cooper, LS Borlaug, BA Haykowsky, MJ Kraus, WE Levine, BD Pfeffer, MA Pina, IL Poole, DC Reeves, GR Whellan, DJ Kitzman, DW AF Fleg, Jerome L. Cooper, Lawton S. Borlaug, Barry A. Haykowsky, Mark J. Kraus, William E. Levine, Benjamin D. Pfeffer, Marc A. Pina, Ileana L. Poole, David C. Reeves, Gordon R. Whellan, David J. Kitzman, Dalane W. CA Natl Heart Lung Blood Inst Working TI Exercise Training as Therapy for Heart Failure Current Status and Future Directions SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; therapy ID PRESERVED EJECTION FRACTION; RANDOMIZED CONTROLLED-TRIAL; CARDIAC RESYNCHRONIZATION THERAPY; VENTRICULAR SYSTOLIC FUNCTION; MUSCLE BLOOD-FLOW; QUALITY-OF-LIFE; PHYSICAL-ACTIVITY; ELDERLY-PATIENTS; REHABILITATION PROGRAM; OXYGEN-CONSUMPTION C1 [Fleg, Jerome L.; Cooper, Lawton S.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Borlaug, Barry A.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Haykowsky, Mark J.] Univ Alberta, Fac Rehabil Med, Edmonton, AB, Canada. [Kraus, William E.] Duke Univ, Sch Med, Div Cardiol, Durham, NC USA. [Levine, Benjamin D.] Univ Texas SW Med Ctr Dallas, Inst Exercise & Environm Med, Dallas, TX 75390 USA. [Pfeffer, Marc A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Div Cardiol, Bronx, NY 10467 USA. [Poole, David C.] Kansas State Univ, Dept Kinesiol, Manhattan, KS 66506 USA. [Poole, David C.] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Reeves, Gordon R.; Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Div Cardiol, Philadelphia, PA 19107 USA. [Kitzman, Dalane W.] Wake Forest Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC USA. [Kitzman, Dalane W.] Wake Forest Sch Med, Dept Internal Med, Sect Geriatr, Winston Salem, NC USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8147, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov FU AtCor Medical; Amgen; Celladon; Hamilton Health Sciences; Novartis; Sanofi Aventis FX Dr Borlaug reports research grant support from AtCor Medical and consultancy for Amgen, Merck, GlaxoSmithKline, and Cardiokinetix. Dr Pfeffer reports research grant support from Amgen, Celladon, Hamilton Health Sciences, Novartis, and Sanofi Aventis and consultancy for Aastrom, Abbott Vascular, Amgen, Bristol-Myers Squibb, Cerenis, Concert, Keryx, Medtronic, Merck, Novartis, Roche, Servier, Teva, and University of Oxford. The other authors report no conflicts NR 92 TC 17 Z9 18 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JAN PY 2015 VL 8 IS 1 BP 209 EP 220 DI 10.1161/CIRCHEARTFAILURE.113.001420 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AZ3RX UT WOS:000348145400025 PM 25605639 ER PT J AU Bal-Price, A Crofton, KM Sachana, M Shafer, TJ Behl, M Forsby, A Hargreaves, A Landesmann, B Lein, PJ Louisse, J Monnet-Tschudi, F Paini, A Rolaki, A Schrattenholz, A Sunol, C van Thriel, C Whelan, M Fritsche, E AF Bal-Price, Anna Crofton, Kevin M. Sachana, Magdalini Shafer, Timothy J. Behl, Mamta Forsby, Anna Hargreaves, Alan Landesmann, Brigitte Lein, Pamela J. Louisse, Jochem Monnet-Tschudi, Florianne Paini, Alicia Rolaki, Alexandra Schrattenholz, Andre Sunol, Cristina van Thriel, Christoph Whelan, Maurice Fritsche, Ellen TI Putative adverse outcome pathways relevant to neurotoxicity SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE adverse outcome pathway; in vitro testing; key events; molecular initiating event; pathways of neurotoxicity; predictive toxicology ID POSTOPERATIVE COGNITIVE DYSFUNCTION; ESTROGEN-RECEPTOR BINDING; DEVELOPMENTAL NEUROTOXICITY; RISK-ASSESSMENT; NERVOUS-SYSTEM; ALTERNATIVE METHODS; MAGNETIC-RESONANCE; MATURE HIPPOCAMPUS; PROGENITOR CELLS; ANIMAL-MODELS AB The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. C1 [Bal-Price, Anna; Sachana, Magdalini; Landesmann, Brigitte; Louisse, Jochem; Paini, Alicia; Rolaki, Alexandra; Whelan, Maurice] European Commiss Joint Res Ctr, Inst Hlth & Consumer Protect, Ispra, Italy. [Crofton, Kevin M.; Shafer, Timothy J.] US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC USA. [Behl, Mamta] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Res Triangle Pk, NC USA. [Forsby, Anna] Stockholm Univ, Arrhenius Labs NaturalSci, Dept Neurochem, S-10691 Stockholm, Sweden. [Forsby, Anna] Swedish Toxicol Sci Res Ctr, Swetox, Sodertalje, Sweden. [Hargreaves, Alan] Nottingham Trent Univ, Nottingham, England. [Lein, Pamela J.] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Monnet-Tschudi, Florianne] Univ Lausanne, Dept Physiol, Lausanne, Switzerland. [Monnet-Tschudi, Florianne] Univ Lausanne, SCAHT, Lausanne, Switzerland. [Schrattenholz, Andre] ProteoSys AG, Mainz, Germany. [Sunol, Cristina] CIBERESP, IDIBAPS, IIBB CSIC, Inst Invest Biomed Barcelona, Barcelona, Spain. [van Thriel, Christoph] IfADo Leibniz Res Ctr Working Environm & Human Fa, Dortmund, Germany. [Fritsche, Ellen] IUF Leibniz Res Inst Environm Med, Dusseldorf, Germany. RP Bal-Price, A (reprint author), Commiss European Communities, Joint Res Ctr, Inst Hlth & Consumer Protect, Syst Toxicol Unit,EURL ECVAM, TP 580,Via Fermi 1, I-21026 Ispra, VA, Italy. EM anna.price@jrc.ec.europa RI Crofton, Kevin/J-4798-2015; OI Crofton, Kevin/0000-0003-1749-9971; Forsby, Anna/0000-0001-6298-201X; Cristina, Sunol/0000-0001-9367-8483; Hargreaves, Alan/0000-0001-9754-5477 FU European Commission FX The employment affiliation of the authors is shown on the cover page. The authors have sole responsibility for the writing and content of this paper. The contributing authors were participants of the workshop organized by the EURL ECVAM. The external workshop participants were invited on the basis of a survey performed by EURL ECVAM neurotoxicity experts of the latest literature to identify those with specific expertise in the relevant research fields. The workshop organization was financially supported by the European Commission, including the cost of travelling and per diem of all invited external experts. The strategy for preparing the report, the literature selected for review, the conclusions drawn and the recommendations made are exclusively the collective scientific output of the workshop participants and do not necessarily represent the views of the participants' employers. NR 66 TC 13 Z9 13 U1 4 U2 34 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD JAN PY 2015 VL 45 IS 1 BP 83 EP 91 DI 10.3109/10408444.2014.981331 PG 9 WC Toxicology SC Toxicology GA AZ4NN UT WOS:000348199100005 PM 25605028 ER PT J AU Tayeira-DaSilya, AM Jones, AM Julien-Williams, P Yao, JH Stylianou, M Moss, J AF Tayeira-DaSilya, Angelo M. Jones, Amanda M. Julien-Williams, Patricia Yao, Jianhua Stylianou, Mario Moss, Joel TI Severity and outcome of cystic lung disease in women with tuberous sclerosis complex SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID PULMONARY LYMPHANGIOLEIOMYOMATOSIS; TSC2 MUTATIONS; SIROLIMUS; HETEROZYGOSITY; PREVALENCE; LYMPHANGIOMYOMATOSIS; STANDARDIZATION; TRANSPLANTATION; PATHOGENESIS; DIAGNOSIS AB What are the clinical features, severity, and rate of progression of lung disease in women with tuberous sclerosis and lymphangioleiomyomatosis (LAM) and how do they differ from patients with sporadic LAM? Data from 94 tuberous sclerosis/LAM and 460 sporadic LAM women were compared. 40 tuberous sclerosis/LAM and 40 sporadic LAM patients were age- and lung function-matched, and changes in volume occupied by cysts (cyst score) and pulmonary function occurring over 6.5 years were evaluated. Tuberous sclerosis/LAM patients had better lung function than sporadic LAM patients, but no difference was observed from sporadic LAM patients in yearly rates of change in forced expiratory volume in 1 s (-1.9 +/- 2.7 versus 1.9 +/- 1.9% predicted; p=0.302), diffusing capacity of the lung for CO (-2.1 +/- 2.8 versus -1.9 +/- 2.7% predicted; p=0.282) or cyst scores (+1.0 +/- 1.3 versus +1.4 +/- 1.7%, p=0.213). However, the proportion of patients with abnormal lung function and higher rates of FEVI decline was greater in sporadic LAM. Some young tuberous sclerosis/LAM patients (mean age 25.7 +/- 3 years) progressed rapidly from minimal to severe lung disease. Tuberous sclerosis/LAM patients may experience abrupt declines in lung function. Consequently, women with tuberous sclerosis found to have lung cysts should undergo periodic functional and radiological testing to follow disease progression and determine need for therapy. C1 [Tayeira-DaSilya, Angelo M.; Jones, Amanda M.; Julien-Williams, Patricia; Moss, Joel] NIH, Cardiovasc & Pulm Branch, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. [Yao, Jianhua] NIH, Radiol & Imaging Sci Dept, Bethesda, MD 20892 USA. [Stylianou, Mario] NIH, Off Biostat Res, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. RP Tayeira-DaSilya, AM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU National Institutes of Health, National Heart, Lung, and Blood Institute FX This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 39 TC 0 Z9 0 U1 0 U2 2 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JAN PY 2015 VL 45 IS 1 BP 171 EP 180 DI 10.1183/09031936.00088314 PG 10 WC Respiratory System SC Respiratory System GA AZ4GM UT WOS:000348179800022 ER PT J AU Schully, SD Lam, TK Dotson, WD Chang, CQ Aronson, N Birkeland, ML Brewster, SJ Boccia, S Buchanan, AH Calonge, N Calzone, K Djulbegovic, B Goddard, KAB Klein, RD Klein, TE Lau, J Long, R Lyman, GH Morgan, RL Palmer, CGS Ling, MVR Rubinstein, WS Swen, JJ Terry, SF Williams, MS Khoury, MJ AF Schully, Sheri D. Lam, Tram Kim Dotson, W. David Chang, Christine Q. Aronson, Naomi Birkeland, Marian L. Brewster, Stephanie Jo Boccia, Stefania Buchanan, Adam H. Calonge, Ned Calzone, Kathleen Djulbegovic, Benjamin Goddard, Katrina A. B. Klein, Roger D. Klein, Teri E. Lau, Joseph Long, Rochelle Lyman, Gary H. Morgan, Rebecca L. Palmer, Christina G. S. Ling, Mary V. Re Rubinstein, Wendy S. Swen, Jesse J. Terry, Sharon F. Williams, Marc S. Khoury, Muin J. TI Evidence synthesis and guideline development in genomic medicine: current status and future prospects SO GENETICS IN MEDICINE LA English DT Article DE evidence synthesis; genomic medicine; guideline development ID INCIDENTAL FINDINGS; RECOMMENDATIONS; PHARMACOGENOMICS; CONSORTIUM; QUALITY; CANCER; ERA AB Purpose: With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field. Methods: To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report "Clinical Practice Guidelines We Can Trust." Results: The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence. Conclusion: Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine. C1 [Schully, Sheri D.; Lam, Tram Kim; Chang, Christine Q.; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dotson, W. David; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Gen, Atlanta, GA USA. [Aronson, Naomi] Blue Cross Blue Shield Assoc, Technol Evaluat Ctr, Chicago, IL USA. [Birkeland, Marian L.] Natl Comprehens Canc Network, Ft Washington, PA USA. [Brewster, Stephanie Jo] Boston Childrens Hosp, Boston, MA USA. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Publ Hlth, Sect Hyg, Rome, Italy. [Buchanan, Adam H.] Duke Canc Inst, Durham, NC USA. [Calonge, Ned] Colorado Trust, Denver, CO USA. [Calzone, Kathleen] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Djulbegovic, Benjamin] Univ S Florida, Tampa, FL USA. [Djulbegovic, Benjamin] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Djulbegovic, Benjamin] Res Inst, Tampa, FL USA. [Goddard, Katrina A. B.] Kaiser Permanente NW, Portland, OR USA. [Klein, Roger D.] Cleveland Clin, Dept Mol Pathol, Cleveland, OH 44106 USA. [Klein, Teri E.] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Lau, Joseph] Brown Univ, Providence, RI 02912 USA. [Long, Rochelle] Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. [Lyman, Gary H.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Morgan, Rebecca L.] Ctr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA USA. [Palmer, Christina G. S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Ling, Mary V. Re] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Rubinstein, Wendy S.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Swen, Jesse J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Terry, Sharon F.] Genet Alliance, Washington, DC USA. [Williams, Marc S.] Genom Med Inst, Danville, PA USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. RP Schully, SD (reprint author), NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM schullys@mail.nih.gov RI Djulbegovic, Benjamin/I-3661-2012; OI Djulbegovic, Benjamin/0000-0003-0671-1447; Dotson, William David/0000-0002-9606-6594 FU National Institutes of Health [R24GM61374, U01GM 92666, U01HL 105198] FX The authors are grateful to all of the workshop participants, who fully engaged in the meeting discussions. In addition, the work presented here was partially supported by National Institutes of Health grants R24GM61374, U01GM 92666, and U01HL 105198. The findings and conclusions in this article are those of the authors and do not necessarily reflect the views of the Department of Health and Human Services. NR 18 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JAN PY 2015 VL 17 IS 1 BP 63 EP 67 DI 10.1038/gim.2014.69 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AY7MT UT WOS:000347744900010 PM 24946156 ER PT J AU Ma, T Yu, MY Chen, ZY Fei, CL Shung, KK Zhou, QF AF Ma, Teng Yu, Mingyue Chen, Zeyu Fei, Chunlong Shung, K. Kirk Zhou, Qifa TI Multi-Frequency Intravascular Ultrasound (IVUS) Imaging SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article; Proceedings Paper CT 23rd International Symposium on the Applications of Ferroelectrics (ISAF) CY MAY 12-16, 2014 CL Pennsylvania State Univ, Univ Pk, PA HO Pennsylvania State Univ ID OPTICAL COHERENCE TOMOGRAPHY; RADIOFREQUENCY DATA-ANALYSIS; HIGH-FREQUENCY ULTRASOUND; COMPOSITE TRANSDUCER; PLAQUE MORPHOLOGY; IN-VITRO; DESIGN; MHZ; CLASSIFICATION; CRYSTAL AB Acute coronary syndrome (ACS) is frequently associated with the sudden rupture of a vulnerable atherosclerotic plaque within the coronary artery. Several unique physiological features, including a thin fibrous cap accompanied by a necrotic lipid core, are the targeted indicators for identifying the vulnerable plaques. Intravascular ultrasound (IVUS), a catheter-based imaging technology, has been routinely performed in clinics for more than 20 years to describe the morphology of the coronary artery and guide percutaneous coronary interventions. However, conventional IVUS cannot facilitate the risk assessment of ACS because of its intrinsic limitations, such as insufficient resolution. Renovation of the IVUS technology is essentially needed to overcome the limitations and enhance the coronary artery characterization. In this paper, a multi-frequency intravascular ultrasound (IVUS) imaging system was developed by incorporating a higher frequency IVUS transducer (80 to 150 MHz) with the conventional IVUS (30-50 MHz) system. The newly developed system maintains the advantage of deeply penetrating imaging with the conventional IVUS, while offering an improved higher resolution image with IVUS at a higher frequency. The prototyped multi-frequency catheter has a clinically compatible size of 0.95 mm and a favorable capability of automated image co-registration. In vitro human coronary artery imaging has demonstrated the feasibility and superiority of the multi-frequency IVUS imaging system to deliver a more comprehensive visualization of the coronary artery. This ultrasonic-only intravascular imaging technique, based on a moderate refinement of the conventional IVUS system, is not only cost-effective from the perspective of manufacturing and clinical practice, but also holds the promise of future translation into clinical benefits. C1 [Ma, Teng; Yu, Mingyue; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Ma, Teng; Yu, Mingyue; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, Resource Ctr Med Ultrason Transducer Technol, NIH, Los Angeles, CA USA. [Fei, Chunlong] Wuhan Univ, Sch Phys & Technol, Wuhan 430072, Hubei, Peoples R China. RP Ma, T (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu FU National Institute of Health [P41-EB002182, R01-EB10090] FX This work is supported by the National Institute of Health under grants P41-EB002182 and R01-EB10090. NR 32 TC 19 Z9 21 U1 3 U2 22 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 EI 1525-8955 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD JAN PY 2015 VL 62 IS 1 BP 97 EP 107 DI 10.1109/TUFFC.2014.006679 PG 11 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA AZ0PU UT WOS:000347948000010 PM 25585394 ER PT J AU Bei, AK Diouf, A Miura, K Larremore, DB Ribacke, U Tullo, G Moss, EL Neafsey, DE Daniels, RF Zeituni, AE Nosamiefan, I Volkman, SK Ahouidi, AD Ndiaye, D Dieye, T Mboup, S Buckee, CO Long, CA Wirth, DF AF Bei, Amy K. Diouf, Ababacar Miura, Kazutoyo Larremore, Daniel B. Ribacke, Ulf Tullo, Gregory Moss, Eli L. Neafsey, Daniel E. Daniels, Rachel F. Zeituni, Amir E. Nosamiefan, Iguosadolo Volkman, Sarah K. Ahouidi, Ambroise D. Ndiaye, Daouda Dieye, Tandakha Mboup, Souleymane Buckee, Caroline O. Long, Carole A. Wirth, Dyann F. TI Immune Characterization of Plasmodium falciparum Parasites with a Shared Genetic Signature in a Region of Decreasing Transmission SO INFECTION AND IMMUNITY LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; RED-CELL SURFACE; INFECTED ERYTHROCYTES; ACQUIRED-IMMUNITY; FLOW-CYTOMETRY; SEVERE DISEASE; BLOOD-STAGES; IN-VITRO; MALARIA; ANTIBODIES AB As the intensity of malaria transmission has declined, Plasmodium falciparum parasite populations have displayed decreased clonal diversity resulting from the emergence of many parasites with common genetic signatures (CGS). We have monitored such CGS parasite clusters from 2006 to 2013 in Thies, Senegal, using the molecular barcode. The first, and one of the largest observed clusters of CGS parasites, was present in 24% of clinical isolates in 2008, declined to 3.4% of clinical isolates in 2009, and then disappeared. To begin to explore the relationship between the immune responses of the population and the emergence and decline of specific parasite genotypes, we have determined whether antibodies to CGS parasites correlate with their prevalence. We measured (i) antibodies capable of inhibiting parasite growth in culture and (ii) antibodies recognizing the surfaces of infected erythrocytes (RBCs). IgG obtained from volunteers in 2009 showed increased reactivity to the surfaces of CGS-parasitized erythrocytes over IgG from 2008. Since P. falciparum EMP-1 (PfEMP-1) is a major variant surface antigen, we used var Ups quantitative reverse transcription-PCR (qRT-PCR) and sequencing with degenerate DBL1 alpha domain primers to characterize the var genes expressed by CGS parasites after short-term in vitro culture. CGS parasites show upregulation of UpsA var genes and 2-cysteine-containing PfEMP-1 molecules and express the same dominant var transcript. Our work indicates that the CGS parasites in this cluster express similar var genes, more than would be expected by chance in the population, and that there is year-to-year variation in immune recognition of surface antigens on CGS parasite-infected erythrocytes. This study lays the groundwork for detailed investigations of the mechanisms driving the expansion or contraction of specific parasite clones in the population. C1 [Bei, Amy K.; Ribacke, Ulf; Daniels, Rachel F.; Nosamiefan, Iguosadolo; Volkman, Sarah K.; Wirth, Dyann F.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Bei, Amy K.; Ahouidi, Ambroise D.; Dieye, Tandakha; Mboup, Souleymane] Cheikh Anta Diop Univ, Le Dantec Hosp, Fac Med & Pharm, Lab Bacteriol & Virol, Dakar, Senegal. [Diouf, Ababacar; Miura, Kazutoyo; Tullo, Gregory; Zeituni, Amir E.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Larremore, Daniel B.; Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Larremore, Daniel B.; Buckee, Caroline O.] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Moss, Eli L.; Neafsey, Daniel E.; Daniels, Rachel F.; Volkman, Sarah K.; Wirth, Dyann F.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Volkman, Sarah K.] Simmons Coll, Boston, MA 02115 USA. [Ndiaye, Daouda] Cheikh Anta Diop Univ, Fac Med & Pharm, Lab Parasitol & Mycol, Dakar, Senegal. RP Wirth, DF (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM dfwirth@hsph.harvard.edu FU ASTMH Centennial Travel Award; Bill and Melinda Gates Foundation; Intramural Research Program of NIAID; NIH; PATH/Malaria Vaccine Initiative; National Institute of General Medical Sciences [R21GM100207] FX A.K.B. is funded by an ASTMH Centennial Travel Award. This work was funded by the Bill and Melinda Gates Foundation. Partial support also came from the Intramural Research Program of NIAID, NIH, and from the PATH/Malaria Vaccine Initiative (to C.A.L.). D.B.L. and C.O.B. are supported by award R21GM100207 from the National Institute of General Medical Sciences. NR 54 TC 2 Z9 2 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JAN PY 2015 VL 83 IS 1 BP 276 EP 285 DI 10.1128/IAI.01979-14 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AZ0SR UT WOS:000347955500028 PM 25368109 ER PT J AU Sun, J Zhao, XQ Balu, N Hippe, DS Hatsukami, TS Isquith, DA Yamada, K Neradilek, MB Canton, G Xue, YJ Fleg, JL Desvigne-Nickens, P Klimas, MT Padley, RJ Vassileva, MT Wyman, BT Yuan, C AF Sun, Jie Zhao, Xue-Qiao Balu, Niranjan Hippe, Daniel S. Hatsukami, Thomas S. Isquith, Daniel A. Yamada, Kiyofumi Neradilek, Moni B. Canton, Gador Xue, Yunjing Fleg, Jerome L. Desvigne-Nickens, Patrice Klimas, Michael T. Padley, Robert J. Vassileva, Maria T. Wyman, Bradley T. Yuan, Chun TI Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Magnetic resonance imaging; Carotid artery; Atherosclerosis; Reproducibility; Multicenter study ID RICH NECROTIC CORE; SAMPLE-SIZE CALCULATION; LIPID-LOWERING THERAPY; IN-VIVO; HIGH-RESOLUTION; QUANTITATIVE ASSESSMENT; AORTIC PLAQUES; FIBROUS-CAP; SCAN-RESCAN; MRI AB This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 +/- A 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression. C1 [Sun, Jie; Balu, Niranjan; Hippe, Daniel S.; Yamada, Kiyofumi; Xue, Yunjing; Yuan, Chun] Univ Washington, Dept Radiol, Seattle, WA 98109 USA. [Zhao, Xue-Qiao; Isquith, Daniel A.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. [Hatsukami, Thomas S.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Neradilek, Moni B.] Mt Whisper Light Stat, Seattle, WA USA. [Canton, Gador] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Fleg, Jerome L.; Desvigne-Nickens, Patrice] NHLBI, NIH, Bethesda, MD 20892 USA. [Klimas, Michael T.] Merck, Whitehouse Stn, NJ USA. [Padley, Robert J.] Abbvie, N Chicago, IL USA. [Vassileva, Maria T.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Wyman, Bradley T.] Pfizer, New London, CT USA. RP Sun, J (reprint author), Univ Washington, Dept Radiol, 850 Republican St Brotman 127, Seattle, WA 98109 USA. EM sunjie@u.washington.edu; cyuan@u.washington.edu RI Canton, Gador/H-4227-2016; Sun, J./M-8778-2016 OI Canton, Gador/0000-0002-0594-2764; FU Foundation for the National Institutes of Health Biomarkers Consortium; Merck; Pfizer; Abbott; [R01HL088214] FX This study was supported by a Grant from the Foundation for the National Institutes of Health Biomarkers Consortium made possible by funds from Merck, Pfizer, and Abbott, and by R01HL088214. Carotid coils were provided by GE Healthcare and Philips Healthcare. This manuscript represents the views of the authors and not necessarily those of the National Institutes of Health or the United States government. NR 33 TC 10 Z9 10 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JAN PY 2015 VL 31 IS 1 BP 95 EP 103 DI 10.1007/s10554-014-0532-7 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AZ3JI UT WOS:000348123000013 PM 25216871 ER PT J AU Sengupta, I Gao, M Arachchige, RJ Nadaud, PS Cunningham, TF Saxena, S Schwieters, CD Jaroniec, CP AF Sengupta, Ishita Gao, Min Arachchige, Rajith J. Nadaud, Philippe S. Cunningham, Timothy F. Saxena, Sunil Schwieters, Charles D. Jaroniec, Christopher P. TI Protein structural studies by paramagnetic solid-state NMR spectroscopy aided by a compact cyclen-type Cu(II) binding tag SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Solid-state NMR; Magic-angle spinning; Paramagnetic relaxation; Metal binding tag; Protein structure ID TRANSITION-METAL-IONS; ANGLE-SPINNING NMR; PSEUDOCONTACT SHIFTS; MEMBRANE-PROTEINS; DYNAMICS; SITE; RESTRAINTS; DISTANCE; ACID; GENERATION AB Paramagnetic relaxation enhancements (PREs) are a rich source of structural information in protein solid-state NMR spectroscopy. Here we demonstrate that PRE measurements in natively diamagnetic proteins are facilitated by a thiol-reactive compact, cyclen-based, high-affinity Cu2+ binding tag, 1-[2-(pyridin-2-yldisulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (TETAC), that overcomes the key shortcomings associated with the use of larger, more flexible metal-binding tags. Using the TETAC-Cu2+ K28C mutant of B1 immunoglobulin-binding domain of protein G as a model, we find that amino acid residues located within similar to 10 angstrom of the Cu2+ center experience considerable transverse PREs leading to severely attenuated resonances in 2D N-15-C-13 correlation spectra. For more distant residues, electron-nucleus distances are accessible via quantitative measurements of longitudinal PREs, and we demonstrate such measurements for N-15-Cu2+ distances up to similar to 20 angstrom. C1 [Sengupta, Ishita; Gao, Min; Arachchige, Rajith J.; Nadaud, Philippe S.; Jaroniec, Christopher P.] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [Cunningham, Timothy F.; Saxena, Sunil] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [Schwieters, Charles D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Jaroniec, CP (reprint author), Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. EM jaroniec@chemistry.ohio-state.edu RI Jaroniec, Christopher/A-4948-2008; Gao, Min/H-9266-2015; OI Jaroniec, Christopher/0000-0003-0364-2888; Saxena, Sunil/0000-0001-9098-6114 FU National Science Foundation [MCB-1243461, MCB-1157712]; National Institutes of Health [R01GM094357]; Camille & Henry Dreyfus Foundation (Camille Dreyfus Teacher-Scholar Award); National Institutes of Health Intramural Research Program of the Center for Information Technology FX This work was supported by grants from the National Science Foundation (MCB-1243461 to C.P.J. and MCB-1157712 to S.S.), the National Institutes of Health (R01GM094357 to C.P.J.) and the Camille & Henry Dreyfus Foundation (Camille Dreyfus Teacher-Scholar Award to C.P.J.). C.D.S. was supported by the National Institutes of Health Intramural Research Program of the Center for Information Technology. NR 52 TC 3 Z9 3 U1 3 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD JAN PY 2015 VL 61 IS 1 BP 1 EP 6 DI 10.1007/s10858-014-9880-9 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA AZ7UY UT WOS:000348424400001 PM 25432438 ER PT J AU Longobardi, E Rossi-Arnaud, C Spataro, P Putnick, DL Bornstein, MH AF Longobardi, Emiddia Rossi-Arnaud, Clelia Spataro, Pietro Putnick, Diane L. Bornstein, Marc H. TI Children's acquisition of nouns and verbs in Italian: contrasting the roles of frequency and positional salience in maternal language SO JOURNAL OF CHILD LANGUAGE LA English DT Article ID EARLY LEXICAL DEVELOPMENT; GRAMMATICAL CATEGORIES; VOCABULARY DEVELOPMENT; JAPANESE CHILDREN; UNIVERSAL GRAMMAR; YOUNG-CHILDREN; UNITED-STATES; SPEECH; INFANTS; INPUT AB Because of its structural characteristics, specifically the prevalence of verb types in infant-directed speech and frequent pronoun-dropping, the Italian language offers an attractive opportunity to investigate the predictive effects of input frequency and positional salience on children's acquisition of nouns and verbs. We examined this issue in a sample of twenty-six mother-child dyads whose spontaneous conversations were recorded, transcribed, and coded at 1;4 and 1;8 The percentages of nouns occurring in the final position of maternal utterances at 1;4 predicted children's production of noun types at 1;8. For verbs, children's growth rates were positively predicted by the percentages of input verbs occurring in utterance-initial position, but negatively predicted by the percentages of verbs located in the final position of maternal utterances at 1;4. These findings clearly illustrate that the effects of positional salience vary across lexical categories. C1 [Longobardi, Emiddia] Univ Roma La Sapienza, Dept Dynam & Clin Psychol, I-00185 Rome, Italy. [Rossi-Arnaud, Clelia; Spataro, Pietro] Univ Roma La Sapienza, Dept Psychol, I-00185 Rome, Italy. [Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Longobardi, E (reprint author), Univ Roma La Sapienza, Dept Dynam & Clin Psychol, Via Marsi 78, I-00185 Rome, Italy. EM emiddia.longobardi@uniroma1.it OI ROSSI-ARNAUD, Clelia /0000-0001-5006-6583; Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS NR 84 TC 5 Z9 5 U1 3 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0305-0009 EI 1469-7602 J9 J CHILD LANG JI J. Child Lang. PD JAN PY 2015 VL 42 IS 1 BP 95 EP 121 DI 10.1017/S0305000913000597 PG 27 WC Psychology, Developmental; Linguistics; Psychology, Experimental SC Psychology; Linguistics GA CA2BK UT WOS:000348713800004 PM 24524564 ER PT J AU Kruszka, P Hart, RA Hadley, DW Muenke, M Habal, MB AF Kruszka, Paul Hart, Rachel A. Hadley, Donald W. Muenke, Maximilian Habal, Mutaz B. TI Expanding the Phenotypic Expression of Sonic Hedgehog Mutations Beyond Holoprosencephaly SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Editorial Material ID MANAGEMENT; RECOMMENDATIONS; PERSPECTIVES; CHILDREN C1 [Kruszka, Paul; Hart, Rachel A.; Hadley, Donald W.; Muenke, Maximilian; Habal, Mutaz B.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov NR 21 TC 1 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD JAN PY 2015 VL 26 IS 1 BP 7 EP 9 DI 10.1097/SCS.0000000000001377 PG 3 WC Surgery SC Surgery GA AZ0SH UT WOS:000347954400039 PM 25569381 ER PT J AU Zhu, N Jacobs, DR Meyer, KA He, K Launer, L Reis, JP Yaffe, K Sidney, S Whitmer, RA Steffen, LM AF Zhu, N. Jacobs, D. R. Meyer, K. A. He, K. Launer, L. Reis, J. P. Yaffe, K. Sidney, S. Whitmer, R. A. Steffen, L. M. TI COGNITIVE FUNCTION IN A MIDDLE AGED COHORT IS RELATED TO HIGHER QUALITY DIETARY PATTERN 5 AND 25 YEARS EARLIER: THE CARDIA STUDY SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Cohort study; epidemiology; middle age; diet pattern; cognitive tests ID ARTERY RISK DEVELOPMENT; YOUNG-ADULTS CARDIA; MEDITERRANEAN DIET; ALZHEIMER-DISEASE; PHYSICAL-ACTIVITY; ASSOCIATION; IMPAIRMENT; HEALTH; RECRUITMENT; POPULATION AB Background: Preserving cognitive function is an important public health issue. We investigated whether dietary pattern associates with cognitive function in middle-age. Methods: We studied 2435 participants in the community-based Coronary Artery Risk Development in Young Adults ( CARDIA) study of black and white men and women aged 18-30 in 1985-86 ( year 0, Y0). We hypothesized that a higher A Priori Diet Quality Score, measured at Y0 and Y20, is associated with better cognitive function measured at Y25. The diet score incorporated 46 food groups ( each in servings/day) as the sum of quintile ranks of food groups rated beneficial, 0 for food groups rated neutral, and reversed quintile ranks for food groups rated adverse; higher score indicated better diet quality. Y25 cognitive testing included verbal memory (Rey Auditory-Verbal Learning Test ( RAVLT)), psychomotor speed ( Digit Symbol Substitution Test ( DSST)) and executive function ( Stroop). Results: Per 10-unit higher diet score at Y20, the RAVLT was 0.32 words recalled higher, the DSST was 1.76 digits higher, and the Stroop was 1.00 seconds+errors lower ( better performance) after adjusting for race, sex, age, clinic, and energy intake. Further adjustment for physical activity, smoking, education, and body mass index attenuated the association slightly. Diet score at Y0 and increase in diet score over 20 years were also positively associated with each cognitive test. Conclusions: A higher quality dietary pattern was associated with better cognitive function 5 years and even 25 years later in apparently healthy middle-aged adults. C1 [Zhu, N.; Jacobs, D. R.; Steffen, L. M.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Meyer, K. A.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [He, K.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Launer, L.] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA. [Reis, J. P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sidney, S.; Whitmer, R. A.] Kaiser Permanente Div Res, Oakland, CA 94612 USA. RP Jacobs, DR (reprint author), 1300 South 2nd St,Ste 300, Minneapolis, MN 55454 USA. EM jacob004@umn.edu FU National Heart, Lung, and Blood Institute [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging; [R01-HL-053560] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Institute on Aging, as well as by a grant (R01-HL-053560). NR 41 TC 5 Z9 5 U1 0 U2 5 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD JAN PY 2015 VL 19 IS 1 BP 33 EP 38 PG 6 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA AZ1WD UT WOS:000348024800005 PM 25560814 ER PT J AU Xu, Z Wu, CC Xie, F Slysz, GW Tolic, N Monroe, ME Petyuk, VA Payne, SH Fujimoto, GM Moore, RJ Fillmore, TL Schepmoes, AA Levine, DA Townsend, RR Davies, SR Li, SQ Ellis, M Boja, E Rivers, R Rodriguez, H Rodland, KD Liu, T Smith, RD AF Xu, Zhe Wu, Chaochao Xie, Fang Slysz, Gordon W. Tolic, Nikola Monroe, Matthew E. Petyuk, Vladislav A. Payne, Samuel H. Fujimoto, Grant M. Moore, Ronald J. Fillmore, Thomas L. Schepmoes, Athena A. Levine, Douglas A. Townsend, R. Reid Davies, Sherri R. Li, Shunqiang Ellis, Matthew Boja, Emily Rivers, Robert Rodriguez, Henry Rodland, Karin D. Liu, Tao Smith, Richard D. TI Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE protein degradation; peptidomics; proteases; tumor; ovarian cancer; breast cancer; ischemia ID MOLECULAR-WEIGHT PROTEOME; MASS-SPECTROMETRY; INTRACELLULAR PEPTIDES; CONTROLLED PROTEOLYSIS; SOFTWARE PACKAGE; ACCURATE MASS; PROTEASOME; SERUM; METHIONINE; IDENTIFICATION AB Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, which is suitable for high-throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with postexcision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics and provides insights not readily obtainable from such approaches. C1 [Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Schepmoes, Athena A.; Rodland, Karin D.; Liu, Tao; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99354 USA. [Tolic, Nikola; Fillmore, Thomas L.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99354 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA. [Townsend, R. Reid; Davies, Sherri R.; Li, Shunqiang; Ellis, Matthew] Washington Univ, Dept Med, St Louis, MO 63130 USA. [Boja, Emily; Rivers, Robert; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. RP Liu, T (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99354 USA. EM tao.liu@pnnl.gov; dick.smith@pnnl.gov RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Petyuk, Vladislav/0000-0003-4076-151X; Payne, Samuel/0000-0002-8351-1994 FU National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), National Institutes of Health [U24CA160019, P41GM103493]; Department of Defense Interagency [MIPR2DO89M2058]; Department of Energy (DOE) Early Career Award; DOE [DE-AC05-76RL0 1830] FX Portions of this work were supported by Grant U24CA160019, from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), National Institutes of Health Grant P41GM103493, Department of Defense Interagency Agreement MIPR2DO89M2058, and Department of Energy (DOE) Early Career Award (to S.H.P.). 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 52 TC 9 Z9 10 U1 1 U2 15 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 JAN PY 2015 VL 14 IS 1 BP 422 EP 433 DI 10.1021/pr500840w PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AY3UA UT WOS:000347506600036 PM 25350482 ER PT J AU Buerger, C Senegas, J Kabus, S Carolus, H Schulz, H Agarwal, H Turkbey, B Choyke, PL Renisch, S AF Buerger, C. Senegas, J. Kabus, S. Carolus, H. Schulz, H. Agarwal, H. Turkbey, B. Choyke, P. L. Renisch, S. TI Comparing nonrigid registration techniques for motion corrected MR prostate diffusion imaging SO MEDICAL PHYSICS LA English DT Article DE non-rigid image registration; diffusion imaging; prostate ID IMAGES; DISTORTION AB Purpose: T-2-weighted magnetic resonance imaging (MRI) is commonly used for anatomical visualization in the pelvis area, such as the prostate, with high soft-tissue contrast. MRI can also provide functional information such as diffusion-weighted imaging (DWI) which depicts the molecular diffusion processes in biological tissues. The combination of anatomical and functional imaging techniques is widely used in oncology, e.g., for prostate cancer diagnosis and staging. However, acquisition-specific distortions as well as physiological motion lead to misalignments between T-2 and DWI and consequently to a reduced diagnostic value. Image registration algorithms are commonly employed to correct for such misalignment. Methods: The authors compare the performance of five state-of-the-art nonrigid image registration techniques for accurate image fusion of DWI with T-2. Results: Image data of 20 prostate patients with cancerous lesions or cysts were acquired. All registration algorithms were validated using intensity-based as well as landmark-based techniques. Conclusions: The authors' results show that the "fast elastic image registration" provides most accurate results with a target registration error of 1.07 +/- 0.41 mm at minimum execution times of 11 +/- 1 s. (c) 2015 American Association of Physicists in Medicine. C1 [Buerger, C.; Senegas, J.; Kabus, S.; Carolus, H.; Schulz, H.; Renisch, S.] Philips Res Hamburg, D-22335 Hamburg, Germany. [Agarwal, H.] Philips Res North Amer, Briarcliff Manor, NY 10510 USA. [Agarwal, H.; Turkbey, B.; Choyke, P. L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Buerger, C (reprint author), Philips Res Hamburg, D-22335 Hamburg, Germany. EM christian.buerger@philips.com NR 20 TC 0 Z9 0 U1 0 U2 6 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 JAN PY 2015 VL 42 IS 1 BP 69 EP 80 DI 10.1118/1.4903262 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AZ0TJ UT WOS:000347957200007 PM 25563248 ER PT J AU Liu, JF Wang, SJ Turkbey, EB Linguraru, MG Yao, JH Summers, RM AF Liu, Jianfei Wang, Shijun Turkbey, Evrim B. Linguraru, Marius George Yao, Jianhua Summers, Ronald M. TI Computer-aided detection of renal calculi from noncontrast CT images using TV-flow and MSER features SO MEDICAL PHYSICS LA English DT Article DE renal calculi; kidney stone; total variation flow; maximally stable extremal regions; computer-aided detection ID EXTRACOLONIC FINDINGS; VIRTUAL COLONOSCOPY; ANISOTROPIC DIFFUSION; ASYMPTOMATIC ADULTS; KIDNEY-STONES; COLONOGRAPHY; SEGMENTATION; MANAGEMENT; EFFICIENT; OUTCOMES AB Purpose: Renal calculi are common extracolonic incidental findings on computed tomographic colonography (CTC). This work aims to develop a fully automated computer-aided diagnosis system to accurately detect renal calculi on CTC images. Methods: The authors developed a total variation (TV) flow method to reduce image noise within the kidneys while maintaining the characteristic appearance of renal calculi. Maximally stable extremal region (MSER) features were then calculated to robustly identify calculi candidates. Finally, the authors computed texture and shape features that were imported to support vector machines for calculus classification. The method was validated on a dataset of 192 patients and compared to a baseline approach that detects calculi by thresholding. The authors also compared their method with the detection approaches using anisotropic diffusion and nonsmoothing. Results: At a false positive rate of 8 per patient, the sensitivities of the new method and the baseline thresholding approach were 69% and 35% (p < 1e-3) on all calculi from 1 to 433 mm(3) in the testing dataset. The sensitivities of the detection methods using anisotropic diffusion and nonsmoothing were 36% and 0%, respectively. The sensitivity of the new method increased to 90% if only larger and more clinically relevant calculi were considered. Conclusions: Experimental results demonstrated that TV-flow and MSER features are efficient means to robustly and accurately detect renal calculi on low-dose, high noise CTC images. Thus, the proposed method can potentially improve diagnosis. (c) 2015 American Association of Physicists in Medicine. C1 [Liu, Jianfei; Wang, Shijun; Turkbey, Evrim B.; Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Linguraru, Marius George] Childrens Natl Hlth Syst Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Linguraru, Marius George] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20010 USA. RP Summers, RM (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center. The authors thank Dr. Perry Pickhardt, Dr. J. Richard Choi, and Dr. William Schindler for providing CT colonography data. NR 49 TC 3 Z9 3 U1 1 U2 6 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 JAN PY 2015 VL 42 IS 1 BP 144 EP 153 DI 10.1118/1.4903056 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AZ0TJ UT WOS:000347957200014 PM 25563255 ER PT J AU Gudino, N Sonmez, M Yao, Z Baig, T Nielles-Vallespin, S Faranesh, AZ Lederman, RJ Martens, M Balaban, RS Hansen, MS Griswold, MA AF Gudino, N. Sonmez, M. Yao, Z. Baig, T. Nielles-Vallespin, S. Faranesh, A. Z. Lederman, R. J. Martens, M. Balaban, R. S. Hansen, M. S. Griswold, M. A. TI Parallel transmit excitation at 1.5 T based on the minimization of a driving function for device heating SO MEDICAL PHYSICS LA English DT Article DE RF heating; parallel transmission ID MRI-GUIDED INTERVENTIONS; CURRENT AMPLITUDE; RF SAFETY; WIRES; FIELD; COIL; AMPLIFICATION; REDUCTION; CATHETER; MONITOR AB Purpose: To provide a rapid method to reduce the radiofrequency (RF) E-field coupling and consequent heating in long conductors in an interventional MRI (iMRI) setup. Methods: A driving function for device heating (W) was defined as the integration of the E-field along the direction of the wire and calculated through a quasistatic approximation. Based on this function, the phases of four independently controlled transmit channels were dynamically changed in a 1.5 T MRI scanner. During the different excitation configurations, the RF induced heating in a nitinol wire immersed in a saline phantom was measured by fiber-optic temperature sensing. Additionally, a minimization of W as a function of phase and amplitude values of the different channels and constrained by the homogeneity of the RF excitation field (B-1) over a region of interest was proposed and its results tested on the benchtop. To analyze the validity of the proposed method, using a model of the array and phantom setup tested in the scanner, RF fields and SAR maps were calculated through finite-difference time-domain (FDTD) simulations. In addition to phantom experiments, RF induced heating of an active guidewire inserted in a swine was also evaluated. Results: In the phantom experiment, heating at the tip of the device was reduced by 92% when replacing the body coil by an optimized parallel transmit excitation with same nominal flip angle. In the benchtop, up to 90% heating reduction was measured when implementing the constrained minimization algorithm with the additional degree of freedom given by independent amplitude control. The computation of the optimum phase and amplitude values was executed in just 12 s using a standard CPU. The results of the FDTD simulations showed similar trend of the local SAR at the tip of the wire and measured temperature as well as to a quadratic function of W, confirming the validity of the quasistatic approach for the presented problem at 64 MHz. Imaging and heating reduction of the guidewire were successfully performed in vivo with the proposed hardware and phase control. Conclusions: Phantom and in vivo data demonstrated that additional degrees of freedom in a parallel transmission system can be used to control RF induced heating in long conductors. A novel constrained optimization approach to reduce device heating was also presented that can be run in just few seconds and therefore could be added to an iMRI protocol to improve RF safety. (c) 2015 American Association of Physicists in Medicine. C1 [Gudino, N.; Griswold, M. A.] Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. [Gudino, N.; Sonmez, M.; Nielles-Vallespin, S.; Faranesh, A. Z.; Lederman, R. J.; Balaban, R. S.; Hansen, M. S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Yao, Z.; Baig, T.; Martens, M.] Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. [Griswold, M. A.] Univ Hosp Cleveland, Dept Radiol, Cleveland, OH 44106 USA. RP Gudino, N (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. EM natalia.gudino@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU Siemens Healthcare; LFMI, NIH FX The authors would like to acknowledge Siemens Healthcare for its financial support. The author would also like to thank Jeffrey Duerk, Kenneth Loparo, Robert Brown, Xin Yu, Peter Kellman, and Peter Van Gelderen for their important feedback. To Katherine Lucas, Victor Wright, Majdi Halabi, Bill Schenke, and Toby Rogers for their assistance during animal experiments Finally, to the LFMI, NIH research group for their help and constant support. NR 29 TC 0 Z9 0 U1 0 U2 3 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 JAN PY 2015 VL 42 IS 1 BP 359 EP 371 DI 10.1118/1.4903894 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AZ0TJ UT WOS:000347957200035 PM 25563276 ER PT J AU Chang, KE Wei, BR Madigan, JP Hall, MD Simpson, RM Zhuang, ZP Gottesman, MM AF Chang, Ki-Eun Wei, Bih-Rong Madigan, James P. Hall, Matthew D. Simpson, R. Mark Zhuang, Zhengping Gottesman, Michael M. TI The Protein Phosphatase 2A Inhibitor LB100 Sensitizes Ovarian Carcinoma Cells to Cisplatin-Mediated Cytotoxicity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DNA-DAMAGE RESPONSE; PLATINUM COMPLEXES; INDUCED APOPTOSIS; CANCER; RESISTANCE; LINES; PHOSPHORYLATION; REPAIR; CYCLE; MICE AB Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and gH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation. (C) 2014 AACR. C1 [Chang, Ki-Eun; Madigan, James P.; Hall, Matthew D.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20982 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20982 USA. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20982 USA. EM mgottesman@nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; National Institute of Neurological Disorders and Stroke FX This research was funded by the Intramural Research Program of the NIH, the National Cancer Institute, and the National Institute of Neurological Disorders and Stroke. NR 53 TC 6 Z9 8 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2015 VL 14 IS 1 BP 90 EP 100 DI 10.1158/1535-7163.MCT-14-0496 PG 11 WC Oncology SC Oncology GA AZ0MF UT WOS:000347938700010 PM 25376608 ER PT J AU Sato, K Hanaoka, H Watanabe, R Nakajima, T Choyke, PL Kobayashi, H AF Sato, Kazuhide Hanaoka, Hirofumi Watanabe, Rira Nakajima, Takahito Choyke, Peter L. Kobayashi, Hisataka TI Near Infrared Photoimmunotherapy in the Treatment of Disseminated Peritoneal Ovarian Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VIVO; PHOTODYNAMIC THERAPY; MONOCLONAL-ANTIBODY; TARGETED THERAPY; BIOLUMINESCENCE; IMMUNOTHERAPY; SPHEROIDS; RETENTION; EFFICACY; MODELS AB Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of disseminated peritoneal ovarian cancer. In vitro and in vivo experiments were conducted with a HER2-expressing, luciferase-expressing, ovarian cancer cell line (SKOV-luc). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized (tra-IR700) and cells or tumors were exposed to NIR light. In vitro PIT cytotoxicity was assessed with dead staining and luciferase activity in freely growing cells and in a three-dimensional (3D) spheroid model. In vivo NIR-PIT was performed in mice with tumors implanted in the peritoneum and in the flank and these were assessed by tumor volume and/or bioluminescence. In vitro NIRPIT-induced cytotoxicity was light dose dependent. Repeated light exposures induced complete tumor cell killing in the 3D spheroid model. In vivo the antitumor effects of NIR-PIT were confirmed by significant reductions in both tumor volume and luciferase activity in the flank model (NIR-PIT vs. control in tumor volume changes at day 10, P = 0.0001; NIR-PIT vs. control in luciferase activity at day 4, P = 0.0237), and the peritoneal model (NIR-PIT vs. control in luciferase activity at day 7, P = 0.0037). NIR-PIT provided effective cell killing in this HER2-positive model of disseminated peritoneal ovarian cancer. Thus, NIR-PIT is a promising new therapy for the treatment of disseminated peritoneal tumors. (C) 2014 AACR. C1 [Sato, Kazuhide; Hanaoka, Hirofumi; Watanabe, Rira; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,RoomB3B69,MSC1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU NIH, NCI, Center for Cancer Research; JSPS FX This work was supported by grants from the Intramural Research Program of the NIH, NCI, Center for Cancer Research. Kazuhide Sato is supported by a JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. NR 36 TC 16 Z9 16 U1 1 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2015 VL 14 IS 1 BP 141 EP 150 DI 10.1158/1535-7163.MCT-14-0658 PG 10 WC Oncology SC Oncology GA AZ0MF UT WOS:000347938700015 PM 25416790 ER PT J AU Lahusen, TJ Deng, CX AF Lahusen, Tyler J. Deng, Chu-Xia TI SRT1720 Induces Lysosomal-Dependent Cell Death of Breast Cancer Cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MITOCHONDRIAL-FUNCTION; MAMMALIAN SIRTUINS; DISEASE RELEVANCE; SIRT1; TUMORIGENESIS; MICE; RESVERATROL; AUTOPHAGY; BRCA1; DEFICIENCY AB SRT1720 is an activator of SIRT1, a NAD(+)-dependent protein and histone deacetylase that plays an important role in numerous biologic processes. Several studies have illustrated that SRT1720 treatment could improve metabolic conditions in mouse models and in a study in cancer SRT1720 caused increased apoptosis of myeloma cells. However, the effect of SRT1720 on cancer may be complex, as some recent studies have demonstrated that SRT1720 may not directly activate SIRT1 and another study showed that SRT1720 treatment could promote lung metastasis. To further investigate the role of SRT1720 in breast cancer, we treated SIRT1 knockdown and control breast cancer cell lines with SRT1720 both in vitro and in vivo. We showed that SRT1720 more effectively decreased the viability of basal-type MDA-MB-231 and BT20 cells as compared with luminal-type MCF-7 breast cancer cells or nontumorigenic MCF-10A cells. We demonstrated that SRT1720 induced lysosomal membrane permeabilization and necrosis, which could be blocked by lysosomal inhibitors. In contrast, SRT1720-induced cell death occurred in vitro irrespective of SIRT1 status, whereas in nude mice, SRT1720 exhibited a more profound effect in inhibiting the growth of allograft tumors of SIRT1 proficient cells as compared with tumors of SIRT1-deficient cells. Thus, SRT1720 causes lysosomal-dependent necrosis and may be used as a therapeutic agent for breast cancer treatment. (C) 2014 AACR. C1 [Lahusen, Tyler J.; Deng, Chu-Xia] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), Natl Inst Diabet Digest & Kidney Dis, NIH, Bldg 10,Room 9N-105, Bethesda, MD 20892 USA. EM tylerlah@gmail.com; cxdeng@umac.mo RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), Bethesda, MD FX This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), Bethesda, MD. NR 44 TC 4 Z9 4 U1 3 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2015 VL 14 IS 1 BP 183 EP 192 DI 10.1158/1535-7163.MCT-14-0584 PG 10 WC Oncology SC Oncology GA AZ0MF UT WOS:000347938700019 PM 25411356 ER PT J AU Lin, SR Pan, CJ Mansfield, BC Chou, JY AF Lin, Su Ru Pan, Chi-Jiunn Mansfield, Brian C. Chou, Janice Yang TI Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-beta deficiency SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE G6PC3; Mutation analysis; Recombinant adenoviral vector ID STORAGE-DISEASE TYPE-1A; G6PC3 MUTATIONS; GENE; DYSFUNCTION; IB; IA AB Glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) deficiency is characterized by neutropenia and dysfunction in both neutrophils and macrophages. G6Pase-beta is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. To date, 33 separate G6PC3 mutations have been identified in G6Pase-beta-deficient patients but only the p.R253H and p.G260R missense mutations have been characterized functionally for pathogenicity. Here we functionally characterize 16 of the 19 known missense mutations using a sensitive assay, based on a recombinant adenoviral vector-mediated expression system, to demonstrate pathogenicity. Fourteen missense mutations completely abolish G6Pase-beta enzymatic activity while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of wild type G6Pase-beta activity. A database of residual enzymatic activity retained by the G6Pase-beta mutations will serve as a reference for evaluating genotype phenotype relationships. Published by Elsevier Inc. C1 [Lin, Su Ru; Pan, Chi-Jiunn; Mansfield, Brian C.; Chou, Janice Yang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Mansfield, Brian C.] Fdn Fighting Blindness, Columbia, MD 21046 USA. RP Chou, JY (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health FX The research was supported by the Intramural Research Program of the Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health. NR 30 TC 1 Z9 1 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2015 VL 114 IS 1 BP 41 EP 45 DI 10.1016/j.ymgme.2014.11.012 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AZ4GD UT WOS:000348178900007 PM 25492228 ER PT J AU Ikawa, Y Hess, R Dorward, H Cullinane, AR Huizing, M Gochuico, BR Gahl, WA Candotti, F AF Ikawa, Yasuhiro Hess, Richard Dorward, Heidi Cullinane, Andrew R. Huizing, Marjan Gochuico, Bernadette R. Gahl, William A. Candotti, Fabio TI In vitro functional correction of Hermansky-Pudlak Syndrome type-1 by lentiviral-mediated gene transfer SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Hermansky-Pudlak syndrome; Pulmonary fibrosis; Gene therapy; Lentivirus; Melanocytes ID MOUSE MODEL; CELLS; FIBROSIS; DISEASE; RAB38 AB Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, bleeding tendency and susceptibility to pulmonary fibrosis. No curative therapy is available. Genetic correction directed to the lungs, bone marrow and/or gastro-intestinal tract might provide alternative forms of treatment for the diseases multi-systemic complications. We demonstrate that lentiviral-mediated gene transfer corrects the expression and function of the HPS1 gene in patient dermal melanocytes, which opens the way to development of gene therapy for HPS. Published by Elsevier Inc. C1 [Ikawa, Yasuhiro; Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Hess, Richard; Dorward, Heidi; Cullinane, Andrew R.; Huizing, Marjan; Gochuico, Bernadette R.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), Univ Lausanne Hosp, Div Immunol & Allergy, Rue Bugnon 46,BH10-513, CH-1011 Lausanne, Switzerland. EM fabio.candotti@chuv.ch FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA [ZIA HG000122]; UNIL-CHUV [CGRB 29583] FX The authors thank Dr. Adrian J. Thrasher for providing the pHR'SINcPPT construct and the 2.6-kb fragment of UCOE sequence from the human HNRPA2B1-CBX locus (A2UCOE), and Dr. Inder Verma for the pMD.G, pCMVDR8.91 plasmids. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA (ZIA HG000122) and the UNIL-CHUV grant no. CGRB 29583. NR 15 TC 1 Z9 1 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2015 VL 114 IS 1 BP 62 EP 65 DI 10.1016/j.ymgme.2014.11.006 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AZ4GD UT WOS:000348178900011 PM 25468649 ER PT J AU Lee, S Lee, TA Lee, E Kang, S Park, A Kim, SW Park, HJ Yoon, JH Ha, SJ Park, T Lee, JS Cheon, JH Park, B AF Lee, Sungwook Lee, Taeyun A. Lee, Eunhye Kang, Sujin Park, Areum Kim, Seung Won Park, Hyo Jin Yoon, Je-Hyun Ha, Sang-Jun Park, Taesun Lee, Ju-Seog Cheon, Jae Hee Park, Boyoun TI Identification of a subnuclear body involved in sequence-specific cytokine RNA processing SO NATURE COMMUNICATIONS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CAJAL BODIES; TDP-43; EXPRESSION; OBESITY; SNRNPS; INTERLEUKIN-10; LOCALIZATION; AGGREGATION; METABOLISM AB Processing of interleukin RNAs must be tightly controlled during the immune response. Here we report that a subnuclear body called the interleukin-6 and -10 splicing activating compartment (InSAC) is a nuclear site of cytokine RNA production and stability. Tat-activating regulatory DNA-binding protein-43 (TDP-43) acts as an InSAC scaffold that selectively associates with IL-6 and IL-10 RNAs in a sequence-specific manner. TDP-43 also recruits key spliceosomal components from Cajal bodies. LPS induces posttranslational modifications of TDP-43; in particular, TDP-43 ubiquitination provides a driving force for InSAC formation. As a consequence, in vivo depletion of TDP-43 leads to a dramatic reduction in the RNA processing and the protein levels of IL-6 in serum. Collectively, our findings highlight the importance of TDP-43-mediated InSAC biogenesis in immune regulation. C1 [Lee, Sungwook; Lee, Taeyun A.; Lee, Eunhye; Kang, Sujin; Park, Areum; Park, Boyoun] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Syst Biol, Seoul 120749, South Korea. [Kim, Seung Won; Cheon, Jae Hee] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 120752, South Korea. [Kim, Seung Won; Cheon, Jae Hee] Yonsei Univ, Coll Med, Inst Gastroenterol, Seoul 120752, South Korea. [Kim, Seung Won; Cheon, Jae Hee] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Seoul 120752, South Korea. [Park, Hyo Jin] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biochem, Seoul 120749, South Korea. [Yoon, Je-Hyun] Natl Inst Aging Intramural Res Program, Genet Lab, NIH, Baltimore, MD 21224 USA. [Park, Hyo Jin] Yonsei Univ, Coll Human Ecol, Dept Food & Nutr, Seoul 120749, South Korea. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA. RP Park, B (reprint author), Yonsei Univ, Coll Life Sci & Biotechnol, Dept Syst Biol, 50 Yonsei Ro, Seoul 120749, South Korea. EM bypark@yonsei.ac.kr RI Lee, Sungwook/K-3697-2013 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2010-0009203, 2011-0015372]; National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [1220060]; Korean Health Technology R& D Project, Ministry of Health & Welfare, Republic of Korea [HI14C2542]; Yonsei University Research Fund [2014-12-0135]; NIA-IRP, NIH; Brain Korea (BK21) PLUS Program FX We thank Dr Philip C. Wong (Departments of Pathology, Neuroscience and Neurology, The Johns Hopkins University School of Medicine, Baltimore) for critical reading of the manuscript, and Dr Alxander Hoffmann (University of San Diego, USA) for NF-kappa B-deficient MEF cells. This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0009203 and 2011-0015372), from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1220060), and from the Korean Health Technology R& D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2542). S.L. and J.-H. Y. were supported by the Yonsei University Research Fund of 2014 (2014-12-0135) and by the NIA-IRP, NIH, respectively. S.L., S.K., T.A.L., E.L. and A.P. were supported by Brain Korea (BK21) PLUS Program. NR 40 TC 5 Z9 5 U1 1 U2 7 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 JAN PY 2015 VL 6 AR 5791 DI 10.1038/ncomms6791 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA1WQ UT WOS:000348700100001 PM 25557830 ER PT J AU Pers, TH Karjalainen, JM Chan, Y Westra, HJ Wood, AR Yang, J Lui, JC Vedantam, S Gustafsson, S Esko, T Frayling, T Speliotes, EK Boehnke, M Raychaudhuri, S Fehrmann, RSN Hirschhorn, JN Franke, L AF Pers, Tune H. Karjalainen, Juha M. Chan, Yingleong Westra, Harm-Jan Wood, Andrew R. Yang, Jian Lui, Julian C. Vedantam, Sailaja Gustafsson, Stefan Esko, Tonu Frayling, Tim Speliotes, Elizabeth K. Boehnke, Michael Raychaudhuri, Soumya Fehrmann, Rudolf S. N. Hirschhorn, Joel N. Franke, Lude CA Genetic Invest ANthropometric Trai TI Biological interpretation of genome-wide association studies using predicted gene functions SO NATURE COMMUNICATIONS LA English DT Article ID CANDIDATE GENES; DATA SETS; DISEASE; NETWORK; LOCI; IDENTIFICATION; ARCHITECTURE; INTEGRATION; HEIGHT; COMMON AB The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes. C1 [Pers, Tune H.; Chan, Yingleong; Vedantam, Sailaja; Esko, Tonu; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Pers, Tune H.; Chan, Yingleong; Vedantam, Sailaja; Esko, Tonu; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Pers, Tune H.; Chan, Yingleong; Vedantam, Sailaja; Esko, Tonu; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA. [Karjalainen, Juha M.; Fehrmann, Rudolf S. N.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9711 Groningen, Netherlands. [Chan, Yingleong; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Westra, Harm-Jan; Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Wood, Andrew R.] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia. [Lui, Julian C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, Program Dev Endocrinol, NIH, Bethesda, MD 20892 USA. [Gustafsson, Stefan] Uppsala Univ, Dept Med Sci Mol Epidemiol & Sci Life Lab, S-75185 Uppsala, Sweden. [Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Raychaudhuri, Soumya] Partners HealthCare Ctr Personalized Genet Med, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England. RP Pers, TH (reprint author), Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. EM tunepers@broadinstitute.org; joelh@broadinstitute.org; lude@ludesign.nl RI Lui, Chun Kin Julian/E-2253-2012; Yang, Jian/A-5852-2010; Deloukas, Panos/B-2922-2013; kinnunen, leena/B-7059-2012; Vermeulen, H.H.M./L-4716-2015; de Bakker, Paul/B-8730-2009; Boehm, Bernhard/F-8750-2015; Fehrmann, Rudolf/E-2551-2011; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Sarzynski, Mark/A-9798-2014; Bovet, Pascal/F-4477-2011; Bouchard, Claude/A-7637-2009; Smith, Albert Vernon/K-5150-2015; Sundstrom, Johan/A-6286-2009; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Slagboom, P. Eline/R-4790-2016; OI Yang, Jian/0000-0003-2001-2474; Deloukas, Panos/0000-0001-9251-070X; kinnunen, leena/0000-0001-8739-4812; de Bakker, Paul/0000-0001-7735-7858; Fehrmann, Rudolf/0000-0002-7516-315X; Gudnason, Vilmundur/0000-0001-5696-0084; Bovet, Pascal/0000-0002-0242-4259; Forouhi, Nita/0000-0002-5041-248X; Nothen, Markus/0000-0002-8770-2464; Medina-Gomez, Carolina/0000-0001-7999-5538; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Hattersley, Andrew/0000-0001-5620-473X; Peters, Annette/0000-0001-6645-0985; Beekman, Marian/0000-0003-0585-6206; Esko, Tonu/0000-0003-1982-6569; Smith, Albert Vernon/0000-0003-1942-5845; Deelen, Joris/0000-0003-4483-3701; Locke, Adam/0000-0001-6227-198X; Mannisto, Satu/0000-0002-8668-3046; Lakka, Timo/0000-0002-9199-2871; Folkersen, Lasse/0000-0003-0708-9530; Humphries, Stephen E/0000-0002-8221-6547; Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685; Sundstrom, Johan/0000-0003-2247-8454; Franke, Lude/0000-0002-5159-8802; Slagboom, P. Eline/0000-0002-2875-4723; Shungin, Dmitry/0000-0001-7900-5856; Stanton, Alice/0000-0002-4961-165X; Kristiansson, Kati/0000-0003-4688-107X; Moayyeri, Alireza/0000-0002-9143-2161; Magi, Reedik/0000-0002-2964-6011; van der Velde, Nathalie/0000-0002-6477-6209; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153 FU Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Netherlands Organization for Scientific Research [916-10135, 917-14374]; Horizon Breakthrough grant from the Netherlands Genomics Initiative [92519031]; European Community's Health Seventh Framework Programme (FP7) [259867]; National Institute of Diabetes and Digestive and Kidney Diseases [2R01DK075787] FX T.H.P. was supported by The Danish Council for Independent Research Medical Sciences (FSS) The Alfred Benzon Foundation. J.C.L. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. L.F. was financially supported by grants from the Netherlands Organization for Scientific Research (NWO-VENI grant 916-10135 and NWO VIDI grant 917-14374) and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259867. We thank the DGI Consortium for making raw genotype and phenotype data available, and the Global Lipids Genetics Consortium and the International Inflammatory Bowel Disease Genetics Consortium for making summary statistics available. We thank Drs. Ayellet V. Segre, Elizabeth J. Rossin, Jeffrey Baron, Kasper Lage and Pascal Timshel for helpful comments and discussions. This work was supported by The National Institute of Diabetes and Digestive and Kidney Diseases [2R01DK075787 to J.N.H.]. NR 39 TC 71 Z9 71 U1 8 U2 37 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 JAN PY 2015 VL 6 AR 5890 DI 10.1038/ncomms6890 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA2MA UT WOS:000348741300001 PM 25597830 ER PT J AU Vijai, J Wang, ZM Berndt, SI Skibola, CF Slager, SL de Sanjose, S Melbye, M Glimelius, B Bracci, PM Conde, L Birmann, BM Wang, SS Brooks-Wilson, AR Lan, Q de Bakker, PIW Vermeulen, RCH Portlock, C Ansell, SM Link, BK Riby, J North, KE Gu, J Hjalgrim, H Cozen, W Becker, N Teras, LR Spinelli, JJ Turner, J Zhang, YW Purdue, MP Giles, GG Kelly, RS Zeleniuch-Jacquotte, A Ennas, MG Monnereau, A Bertrand, KA Albanes, D Lightfoot, T Yeager, M Chung, CC Burdett, L Hutchinson, A Lawrence, C Montalvan, R Liang, LM Huang, JY Ma, B Villano, DJ Maria, A Corines, M Thomas, T Novak, AJ Dogan, A Liebow, M Thompson, CA Witzig, TE Habermann, TM Weiner, GJ Smith, MT Holly, EA Jackson, RD Tinker, LF Ye, Y Adami, HO Smedby, KE De Roos, AJ Hartge, P Morton, LM Severson, RK Benavente, Y Boffetta, P Brennan, P Foretova, L Maynadie, M Mckay, J Staines, A Diver, WR Vajdic, CM Armstrong, BK Kricker, A Zheng, TZ Holford, TR Severi, G Vineis, P Ferri, GM Ricco, R Miligi, L Clavel, J Giovannucci, E Kraft, P Virtamo, J Smith, A Kane, E Roman, E Chiu, BCH Fraumeni, JF Wu, XF Cerhan, JR Offit, K Chanock, SJ Rothman, N Nieters, A AF Vijai, Joseph Wang, Zhaoming Berndt, Sonja I. Skibola, Christine F. Slager, Susan L. de Sanjose, Silvia Melbye, Mads Glimelius, Bengt Bracci, Paige M. Conde, Lucia Birmann, Brenda M. Wang, Sophia S. Brooks-Wilson, Angela R. Lan, Qing de Bakker, Paul I. W. Vermeulen, Roel C. H. Portlock, Carol Ansell, Stephen M. Link, Brian K. Riby, Jacques North, Kari E. Gu, Jian Hjalgrim, Henrik Cozen, Wendy Becker, Nikolaus Teras, Lauren R. Spinelli, John J. Turner, Jenny Zhang, Yawei Purdue, Mark P. Giles, Graham G. Kelly, Rachel S. Zeleniuch-Jacquotte, Anne Ennas, Maria Grazia Monnereau, Alain Bertrand, Kimberly A. Albanes, Demetrius Lightfoot, Tracy Yeager, Meredith Chung, Charles C. Burdett, Laurie Hutchinson, Amy Lawrence, Charles Montalvan, Rebecca Liang, Liming Huang, Jinyan Ma, Baoshan Villano, Danylo J. Maria, Ann Corines, Marina Thomas, Tinu Novak, Anne J. Dogan, Ahmet Liebow, Mark Thompson, Carrie A. Witzig, Thomas E. Habermann, Thomas M. Weiner, George J. Smith, Martyn T. Holly, Elizabeth A. Jackson, Rebecca D. Tinker, Lesley F. Ye, Yuanqing Adami, Hans-Olov Smedby, Karin E. De Roos, Anneclaire J. Hartge, Patricia Morton, Lindsay M. Severson, Richard K. Benavente, Yolanda Boffetta, Paolo Brennan, Paul Foretova, Lenka Maynadie, Marc Mckay, James Staines, Anthony Diver, W. Ryan Vajdic, Claire M. Armstrong, Bruce K. Kricker, Anne Zheng, Tongzhang Holford, Theodore R. Severi, Gianluca Vineis, Paolo Ferri, Giovanni M. Ricco, Rosalia Miligi, Lucia Clavel, Jacqueline Giovannucci, Edward Kraft, Peter Virtamo, Jarmo Smith, Alex Kane, Eleanor Roman, Eve Chiu, Brian C. H. Fraumeni, Joseph F. Wu, Xifeng Cerhan, James R. Offit, Kenneth Chanock, Stephen J. Rothman, Nathaniel Nieters, Alexandra TI A genome-wide association study of marginal zone lymphoma shows association to the HLA region SO NATURE COMMUNICATIONS LA English DT Article ID NON-HODGKIN-LYMPHOMA; EPIDEMIOLOGIC RESEARCH; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; FOLLICULAR LYMPHOMA; GASTRIC LYMPHOMA; CELL DEVELOPMENT; GENE-EXPRESSION; RISK LOCI; CLASSIFICATION AB Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P - 3.95 x 10(-15)) and HLA-B (rs2922994, P - 2.43 x 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility. C1 [Vijai, Joseph; Portlock, Carol; Villano, Danylo J.; Maria, Ann; Corines, Marina; Thomas, Tinu; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Wang, Zhaoming; Yeager, Meredith; Burdett, Laurie; Hutchinson, Amy] NCI, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Gaithersburg, MD 20877 USA. [Berndt, Sonja I.; Lan, Qing; Purdue, Mark P.; Albanes, Demetrius; Chung, Charles C.; Hartge, Patricia; Morton, Lindsay M.; Fraumeni, Joseph F.; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques] Sch Publ Hlth & Comprehens Canc Ctr, Dept Epidemiol, Birmingham, AL 35233 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Slager, Susan L.; Cerhan, James R.] Mayo Clin, Dept Hlth Sci, Rochester, MN 55905 USA. [de Sanjose, Silvia; Benavente, Yolanda] IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc UNIC, Barcelona 8907, Spain. [de Sanjose, Silvia; Benavente, Yolanda] CIBERESP, Barcelona 8036, Spain. [Melbye, Mads; Hjalgrim, Henrik] State Serum Inst, Dept Epidemiol Res, Div Hlth Surveillance & Res, Copenhagen 2300, Denmark. [Melbye, Mads] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Glimelius, Bengt] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden. [Glimelius, Bengt] Uppsala Univ, Dept Radiol Oncol & Radiat Sci, S-75105 Uppsala, Sweden. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Birmann, Brenda M.; Bertrand, Kimberly A.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Birmann, Brenda M.; Bertrand, Kimberly A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Sophia S.] City Hope Beckman Res Inst, Dept Canc Etiol, Duarte, CA 91030 USA. [Brooks-Wilson, Angela R.] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Brooks-Wilson, Angela R.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 156, Canada. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, NL-3584 CG Utrecht, Netherlands. [de Bakker, Paul I. W.; Vermeulen, Roel C. H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands. [Vermeulen, Roel C. H.] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. [Ansell, Stephen M.; Novak, Anne J.; Liebow, Mark; Thompson, Carrie A.; Witzig, Thomas E.; Habermann, Thomas M.] Mayo Clin, Dept Med, Rochester, MN 55905 USA. [Link, Brian K.; Weiner, George J.] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Gu, Jian; Ye, Yuanqing; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Becker, Nikolaus] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Teras, Lauren R.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Spinelli, John J.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 1L3, Canada. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, Canada. [Turner, Jenny] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Turner, Jenny] Douglass Hanly Moir Pathol, Dept Histopathol, Macquarie Park, NSW 2113, Australia. [Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3053, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Kelly, Rachel S.; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Inst Canc, New York, NY 10016 USA. [Ennas, Maria Grazia] Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy. [Monnereau, Alain; Clavel, Jacqueline] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc Grp, U1018, F-94807 Villejuif, France. [Monnereau, Alain; Clavel, Jacqueline] Univ Paris Sud, UMRS 1018, F-94807 Villejuif, France. [Monnereau, Alain] Inst Bergonie, Registre Hemopath Malignes Gironde, F-33076 Bordeaux, France. [Bertrand, Kimberly A.; Liang, Liming; Huang, Jinyan; Ma, Baoshan; Adami, Hans-Olov; Giovannucci, Edward; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lightfoot, Tracy] Univ York, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Lawrence, Charles; Montalvan, Rebecca; Smith, Alex; Kane, Eleanor; Roman, Eve] Hlth Studies Sect, Rockville, MD 20850 USA. [Liang, Liming; Kraft, Peter] Harvard Univ, Sch Med, Dept Biostat, Boston, MA 02115 USA. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Peoples R China. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Lab Med & Pathol, New York, NY 10065 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Tinker, Lesley F.; De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Smedby, Karin E.] Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brennan, Paul] Int Agcy Res Canc, Genet Sect, Grp Genet Epidemiol, F-69372 Lyon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic. [Foretova, Lenka] MF MU, Brno 65653, Czech Republic. [Maynadie, Marc] Univ Burgundy, Registre Hemopathies Malignes de Cote DOr, EA 4184, F-21070 Dijon, France. [Maynadie, Marc] Dijon Univ Hosp, F-21070 Dijon, France. [Mckay, James] Int Agcy Res Canc, Genet Sect, Genet Canc Susceptibil, F-69372 Lyon, France. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Vajdic, Claire M.] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW 2052, Australia. [Armstrong, Bruce K.; Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06520 USA. [Dogan, Ahmet; Severi, Gianluca; Vineis, Paolo] Human Genet Fdn, I-10126 Turin, Italy. [Ferri, Giovanni M.] Univ Bari, Interdisciplinary Dept Med, I-70124 Bari, Italy. [Ricco, Rosalia] Univ Bari, Dept Pathol Anat, I-70124 Bari, Italy. [Miligi, Lucia] Canc Prevent & Res Inst ISPO, Environm & Occupat Epidemiol Unit, I-50139 Florence, Italy. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Chiu, Brian C. H.] Univ Chicago, Dept Hlth Sci, Chicago, IL 60637 USA. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Germany. RP Vijai, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. EM josephv@mskcc.org RI Albanes, Demetrius/B-9749-2015; de Bakker, Paul/B-8730-2009; Armstrong, Bruce/K-9464-2015; Conde, Lucia/D-9295-2011; Brooks-Wilson, Angela/E-9399-2012; Purdue, Mark/C-9228-2016; de Sanjose Llongueras, Silvia/H-6339-2014; Clavel, Jacqueline/Q-2750-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; de Bakker, Paul/0000-0001-7735-7858; Armstrong, Bruce/0000-0001-8940-7525; Brooks-Wilson, Angela/0000-0003-1009-6408; Purdue, Mark/0000-0003-1177-3108; Clavel, Jacqueline/0000-0002-3616-7676; Staines, Anthony/0000-0001-9161-1357; Joseph, Vijai/0000-0002-7933-151X; Giles, Graham/0000-0003-4946-9099 FU Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; U.S. Public Health Service contracts [N01-CN-45165, N01-RC-45035, N01-RC-37004]; Canadian Institutes for Health Research (CIHR); Canadian Cancer Society, Michael Smith Foundation for Health Research; The American Cancer Society funds the creation, maintenance and updating of the CPS-II cohort; National Cancer Institute Surveillance Epidemiology and End Results program; Leukaemia & Lymphoma Research; Fondation ARC pour la Recherche sur le Cancer; Fondation de France; French Agency for Food, Environmental and Occupational Health Safety (ANSES); French National Cancer Institute (INCa); Coordinated Action [006438, SP23-CT-2005-006438]; HuGeF (Human Genetics Foundation), Torino, Italy; EpiLymph-European Commission [QLK4-CT-2000-00422, FOOD-CT-2006-023103]; Spanish Ministry of Health [PI11/01810, C03/09, C03/10, RD06/0020/0095]; Marato de TV3 Foundation [051210]; Agencia de Gestiod'AjutsUniversitarisi de Recerca-Generalitat de Catalunya [2009SGR1465]; NIH [NO1-CO-12400]; Compagnia di San Paolo-Programma Oncologia; Federal Office for Radiation Protection grants [StSch4261, StSch4420]; Jose Carreras Leukemia Foundation [DJCLS-R12/23]; German Federal Ministry for Education and Research [BMBF-01-EO-1303]; Health Research Board, Ireland; Cancer Research Ireland; MH CZ-DRO (MMCI) [00209805]; RECAMO [CZ.1.05/2.1.00/03.0101]; Association de Recherche Contre le Cancer; National Institutes of Health [CA167552, CA97274, R01 CA92153, CA87969, CA49449, CA098122, CA098566, K07 CA115687, 5R01 CA69669-02, RO1CA1046282, RO1CA154643]; Specialized Programs of Research Excellence (SPORE) in Human Cancer [P50 CA97274]; Molecular Epidemiology of Non-Hodgkin Lymphoma Survival [R01 CA129539]; Henry J. Predolin Foundation; Italian Ministry for Education, University and Research [2007WEJLZB, 20092ZELR2]; Italian Association for Cancer Research (AIRC) [11855]; Regional Administration of Sardinia [CRP-59812/2012]; Fondazione Banco di Sardegna [20102012]; National Center for Advancing Translational Science [UL1 TR000135]; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Geoffrey Beene Cancer Research Grant, Lymphoma Foundation [LF5541]; Barbara K. Lipman Lymphoma Research Fund [74419]; Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative [57470, U01 HG007033]; NCI-SEER-Intramural Research Program of the National Cancer Institute, National Institutes of Health; Public Health Service [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105]; Australian National Health and Medical Research Council [ID990920]; Cancer Council NSW; University of Sydney Faculty of Medicine; NYU-WHS-National Cancer Institute [R01 CA098661, P30 CA016087]; National Institute of Environmental Health Sciences [ES000260]; Intramural Research Program of the National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; Swedish Cancer Society [2009/659]; Stockholm County Council [20110209]; Strategic Research Program in Epidemiology at Karolinska Institute; Swedish Cancer Society grant [02 6661]; Danish Cancer Research Foundation Grant; Lundbeck Foundation Grant [R19-A2364]; Danish Cancer Society Grant [DP 08-155]; Plan Denmark; California Department of Health Services; National Cancer Institute's Surveillance, Epidemiology and End Results Program [HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [1U58 DP000807-01]; National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; National Cancer Institute [CA62006] FX Support for individual studies: ATBC-Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004); BCCA (J.J.S., A.R.B.-W.)-Canadian Institutes for Health Research (CIHR). Canadian Cancer Society, Michael Smith Foundation for Health Research; CPS-II (L.F.T.)-The American Cancer Society funds the creation, maintenance and updating of the CPS-II cohort. We thank the CPS-II participants and the Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from the central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program; ELCCS (E.R.)-Leukaemia & Lymphoma Research; ENGELA (J.C.)-Fondation ARC pour la Recherche sur le Cancer. Fondation de France. French Agency for Food, Environmental and Occupational Health & Safety (ANSES), the French National Cancer Institute (INCa); EPIC (E.R.)-Coordinated Action (Contract #006438, SP23-CT-2005-006438). HuGeF (Human Genetics Foundation), Torino, Italy; EpiLymph-European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006-023103); the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marato de TV3 Foundation (grant reference 051210), the Agencia de Gestiod'AjutsUniversitarisi de Recerca-Generalitat de Catalunya (grant reference 2009SGR1465) who had no role in the data collection, analysis or interpretation of the results; the NIH (contract NO1-CO-12400); the Compagnia di San Paolo-Programma Oncologia; the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the Jose Carreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303); the Health Research Board, Ireland and Cancer Research Ireland; Czech Republic supported by MH CZ-DRO (MMCI, 00209805) and RECAMO, CZ.1.05/2.1.00/03.0101; Fondation de France and Association de Recherche Contre le Cancer; HPFS (Walter C. Willet)-The HPFS was supported in part by National Institutes of Health grants CA167552, CA149445, CA098122, CA098566 (K.A.B.) and K07 CA115687 (B.M.B.). We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data; Iowa-Mayo SPORE (G.J.W., J.R.C., T.E.W.)-National Institutes of Health (CA97274). Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274). Molecular Epidemiology of Non-Hodgkin Lymphoma Survival (R01 CA129539). Henry J. Predolin Foundation; Italian GxE (P.C.)-Italian Ministry for Education, University and Research (PRIN 2007 prot.2007WEJLZB, PRIN 2009 prot. 20092ZELR2); the Italian Association for Cancer Research (AIRC, Investigator Grant 11855). (M.G.E.)-Regional Law N.; 7, 2007: 'Basic research' (Progetti di ricerca fondamentale o di base) by the Regional Administration of Sardinia (CRP-59812/2012), Fondazione Banco di Sardegna 20102012; Mayo Clinic Case-Control (J.R.C.)-National Institutes of Health (R01 CA92153). National Center for Advancing Translational Science (UL1 TR000135); MCCS (G.G.G., G.S.)-The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria; MD Anderson (X.W.)-Institutional support to the Center for Translational and Public Health Genomics; MSKCC (K.O.)-Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541). Barbara K. Lipman Lymphoma Research Fund (74419). Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470), U01 HG007033; NCI-SEER-Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105); NHS (Meir J. Stampfer)-The NHS was supported in part by National Institutes of Health grants CA87969, CA49449, CA149445, CA098122, CA098566 (K.A.B.), and K07 CA115687 (B.M.B.). We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data; NSW (C.M. Vajdic)-was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW, and the University of Sydney Faculty of Medicine; NYU-WHS-National Cancer Institute (R01 CA098661, P30 CA016087). National Institute of Environmental Health Sciences (ES000260); PLCO-This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; SCALE (K.E.S., H.O.A., H.H.)-Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institute. Swedish Cancer Society grant (02 6661). Danish Cancer Research Foundation Grant. Lundbeck Foundation Grant (R19-A2364). Danish Cancer Society Grant (DP 08-155). National Institutes of Health (5R01 CA69669-02). Plan Denmark; UCSF2 (C.F.S.)-National Institutes of Health RO1CA1046282 and RO1CA154643; (E.A.H., P.M.B.; )-The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute, or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred; WHI-WHI investigators are: Program Office-(National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center-(Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers-(Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; Women's Health Initiative Memory Study-(Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C; YALE (T.Z.)-National Cancer Institute (CA62006). NR 39 TC 12 Z9 12 U1 1 U2 15 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 JAN PY 2015 VL 6 AR UNSP 5751 DI 10.1038/ncomms6751 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA1BA UT WOS:000348646500001 PM 25569183 ER PT J AU Rouault, TA AF Rouault, Tracey A. TI Mammalian iron-sulphur proteins: novel insights into biogenesis and function SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID CYSTEINE DESULFURASE ACTIVITY; LINKED SIDEROBLASTIC ANEMIA; MULTIPLE RESPIRATORY-CHAIN; FE-S PROTEINS; CLUSTER BIOGENESIS; SCAFFOLD PROTEIN; FRIEDREICHS-ATAXIA; COMPLEX-II; PARAMAGNETIC-RESONANCE; MITOCHONDRIAL DISEASE AB Iron-sulphur (Fe-S) clusters are inorganic cofactors that are found in nearly all species and are composed of various combinations of iron and sulphur atoms. Fe-S clusters can accept or donate single electrons to carry out oxidation and reduction reactions and to facilitate electron transport. Many details of how these complex modular structures are assembled and ligated to cellular proteins in the mitochondrial, nuclear and cytosolic compartments of mammalian cells remain unclear. Recent evidence indicates that a Leu-Tyr-Arg (LYR) tripeptide motif found in some Fe-S recipient proteins may facilitate the direct and shielded transfer of Fe-S clusters from a scaffold to client proteins. Fe-S clusters are probably an unrecognized and elusive cofactor of many known proteins. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM Rouault@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA FX This work was supported by the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. The author thanks members of the Rouault group, particularly N. Maio, G. Holmes-Hampton and W. Hang-Tong for their help with the figures and narrative. NR 111 TC 30 Z9 31 U1 4 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 EI 1471-0080 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JAN PY 2015 VL 16 IS 1 BP 45 EP 55 DI 10.1038/nrm3909 PG 11 WC Cell Biology SC Cell Biology GA CA0ZU UT WOS:000348642900008 PM 25425402 ER PT J AU Ligibel, JA Alfano, CM Courneya, KS Demark-Wahnefried, W Burger, RA Chlebowski, RT Fabian, CJ Gucalp, A Hershman, DL Hudson, MM Jones, LW Kakarala, M Ness, KK Merrill, JK Wollins, DS Hudis, CA AF Ligibel, Jennifer A. Alfano, Catherine M. Courneya, Kerry S. Demark-Wahnefried, Wendy Burger, Robert A. Chlebowski, Rowan T. Fabian, Carol J. Gucalp, Ayca Hershman, Dawn L. Hudson, Melissa M. Jones, Lee W. Kakarala, Madhuri Ness, Kirsten K. Merrill, Janette K. Wollins, Dana S. Hudis, Clifford A. TI American Society of Clinical Oncology Position Statement on Obesity and Cancer EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. [Courneya, Kerry S.] Univ Alberta, Edmonton, AB, Canada. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham, AL USA. [Burger, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Chlebowski, Rowan T.] Harbor Univ Calif Los Angeles Med Ctr, Torrance, CA USA. [Fabian, Carol J.] Univ Kansas, Med Ctr, Westwood, KS USA. [Gucalp, Ayca; Jones, Lee W.; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hershman, Dawn L.] Columbia Univ, Med Ctr, New York, NY USA. [Hudson, Melissa M.; Ness, Kirsten K.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kakarala, Madhuri] Van Andel Inst, Grand Rapids, MI USA. [Merrill, Janette K.; Wollins, Dana S.] Amer Soc Clin Oncol, Alexandria, VA USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JAN PY 2015 VL 70 IS 1 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AZ3QI UT WOS:000348141400015 ER PT J AU Kuban, KCK O'Shea, M Allred, EN Fichorova, RN Heeren, T Paneth, N Hirtz, D Dammann, O Leviton, A AF Kuban, Karl C. K. O'Shea, Michael Allred, Elizabeth N. Fichorova, Raina N. Heeren, Tim Paneth, Nigel Hirtz, Deborah Dammann, Olaf Leviton, Alan CA ELGAN Study Investigators TI The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns SO PEDIATRIC NEUROLOGY LA English DT Article DE extremely preterm infants; inflammation-related proteins; adverse neurological outcomes; early life predictors of outcome ID EXTREMELY PRETERM INFANTS; PERINATAL BRAIN-DAMAGE; CEREBRAL-PALSY; IMMUNE CELLS; PROTEINS; INJURY; BLOOD; CHILDREN; AGE; HUMANS AB BACKGROUND: We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration. METHODS: In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing six functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14. We evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers screen, and in a subset of these children from 12 of 14 sites (n = 826), an attention problem identified with the Child Behavior Checklist. RESULTS: The risk of abnormal brain structure and function overall was increased among children who had recurrent and/or persistent elevations of the 25 proteins. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index on the Bayley Scales of Infant Development-II, microcephaly, and a Child Behavior Checklist-defined attention problem increased with higher numbers of these recurrently and/or persistently elevated proteins. INTERPRETATION: Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely preterm. C1 [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA 02118 USA. [O'Shea, Michael] Wake Forest Sch Med, Dept Pediat, Winston Salem, NC USA. [Allred, Elizabeth N.; Fichorova, Raina N.; Leviton, Alan] Harvard Univ, Sch Med, Boston, MA USA. [Allred, Elizabeth N.; Leviton, Alan] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Allred, Elizabeth N.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Heeren, Tim] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. [Dammann, Olaf] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. RP Kuban, KCK (reprint author), Boston Med Ctr, Dept Pediat, 1 Boston Med Ctr Pl,Dowling 3 South, Boston, MA 02118 USA. EM karl.kuban@bmc.org FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05, 2R01NS040069-08] FX This study was supported by a cooperative agreement with the National Institute of Neurological Disorders and Stroke (grants 5U01NS040069-05 and 2R01NS040069-08). NR 49 TC 10 Z9 11 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JAN PY 2015 VL 52 IS 1 BP 42 EP 48 DI 10.1016/j.pediatrneurol.2014.10.005 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AZ7QA UT WOS:000348411800006 PM 25459361 ER PT J AU Moaddel, R Luckenbaugh, DA Xie, Y Villasenor, A Brutsche, NE Machado-Vieira, R Ramamoorthy, A Lorenzo, MP Garcia, A Bernier, M Torjman, MC Barbas, C Zarate, CA Wainer, IW AF Moaddel, Ruin Luckenbaugh, David A. Xie, Ying Villasenor, Alma Brutsche, Nancy E. Machado-Vieira, Rodrigo Ramamoorthy, Anuradha Paz Lorenzo, Maria Garcia, Antonia Bernier, Michel Torjman, Marc C. Barbas, Coral Zarate, Carlos A., Jr. Wainer, Irving W. TI D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression SO PSYCHOPHARMACOLOGY LA English DT Article DE (R,S)-ketamine; Antidepressant; Treatment-resistant depression; Bipolar depression; D-serine; N-methyl-D-aspartate receptor; Serine racemase; Plasma response marker ID EXCITATORY AMINO-ACIDS; MAJOR DEPRESSION; FATTY-ACID; RECEPTOR ANTAGONISTS; SERUM-LEVELS; KETAMINE; METABOLISM; DISORDER; RACEMASE; GLYCINE AB (R,S)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression (TRD). The underlying biochemical differences between a (R,S)-ketamine responder (KET-R) and non-responder (KET-NR) have not been definitively identified but may involve serine metabolism. The aim of the study was to examine the relationship between baseline plasma concentrations of D-serine and its precursor L-serine and antidepressant response to (R,S)-ketamine in TRD patients. Plasma samples were obtained from 21 TRD patients at baseline, 60 min before initiation of the (R,S)-ketamine infusion. Patients were classified as KET-Rs (n = 8) or KET-NRs (n = 13) based upon the difference in Montgomery-sberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a a parts per thousand yen50 % decrease in MADRS score. The plasma concentrations of D-serine and L-serine were determined using liquid chromatography-mass spectrometry. Baseline D-serine plasma concentrations were significantly lower in KET-Rs (3.02 +/- 0.21 mu M) than in KET-NRs (4.68 +/- 0.81 mu M), p < 0.001. A significant relationship between baseline D-serine plasma concentrations and percent change in MADRS at 230 min was determined using a Pearson correlation, r = 0.77, p < 0.001, with baseline D-serine explaining 60 % of the variance in (R,S)-ketamine response. The baseline concentrations of L-serine (L-Ser) in KET-Rs were also significantly lower than those measured in KET-NRs (66.2 +/- 9.6 mu M vs 242.9 +/- 5.6 mu M, respectively; p < 0.0001). The results demonstrate that the baseline D-serine plasma concentrations were significantly lower in KET-Rs than in KET-NRs and suggest that this variable can be used to predict an antidepressant response following (R,S)-ketamine administration. C1 [Moaddel, Ruin; Xie, Ying; Ramamoorthy, Anuradha; Bernier, Michel; Wainer, Irving W.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Luckenbaugh, David A.; Brutsche, Nancy E.; Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Villasenor, Alma; Paz Lorenzo, Maria; Garcia, Antonia; Barbas, Coral] Univ CEU San Pablo, Fac Farm, Ctr Metabol & Bioanal CEMBIO, Madrid, Spain. [Torjman, Marc C.; Wainer, Irving W.] Rowan Univ, Dept Anesthesiol, Cooper Med Sch, Camden, NJ USA. [Wainer, Irving W.] NIA, Bioanalyt & Drug Discovery Unit, Lab Clin Invest, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, Lab Clin Invest, NIH,Biomed Res Ctr, Suite 100,251 Bayview Boul, Baltimore, MD 21224 USA. EM Wainerir@grc.nia.nih.gov RI Garcia Fernandez, Antonia/C-4296-2008; MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Bernier, Michel/0000-0002-5948-368X FU Intramural Research Program of the National Institute on Aging of the National Institutes of Health (NIH); Intramural Research Program of the National Institute of Mental Health of the National Institutes of Health (NIH); Spanish Ministry of Science and Technology (MCIT) [CTQ2011-23562]; EADS CASA FX This work was supported in part by the Intramural Research Programs of the National Institute on Aging (IWW) and National Institute of Mental Health (CAZ) of the National Institutes of Health (NIH) and the Spanish Ministry of Science and Technology (MCIT) grant CTQ2011-23562 (CB). A. V. acknowledges her fellowship provided by EADS CASA. NR 36 TC 11 Z9 11 U1 4 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2015 VL 232 IS 2 BP 399 EP 409 DI 10.1007/s00213-014-3669-0 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AZ3IL UT WOS:000348120700009 PM 25056852 ER PT J AU Simon, SL Hoffman, FO Hofer, E AF Simon, Steven L. Hoffman, F. Owen Hofer, Eduard TI The Two-Dimensional Monte Carlo: A New Methodologic Paradigm for Dose Reconstruction for Epidemiological Studies SO RADIATION RESEARCH LA English DT Article ID EXPOSURE-MEASUREMENT ERROR; UTAH THYROID COHORT; RISK-ASSESSMENT; INTERINDIVIDUAL VARIABILITY; CHERNOBYL ACCIDENT; JOINT PROPAGATION; RESPONSE ANALYSES; UNCERTAINTY; DOSIMETRY; CANCER AB Retrospective dose estimation, particularly dose reconstruction that supports epidemiological investigations of health risk, relies on various strategies that include models of physical processes and exposure conditions with detail ranging from simple to complex. Quantification of dose uncertainty is an essential component of assessments for health risk studies since, as is well understood, it is impossible to retrospectively determine the true dose for each person. To address uncertainty in dose estimation, numerical simulation tools have become commonplace and there is now an increased understanding about the needs and what is required for models used to estimate cohort doses (in the absence of direct measurement) to evaluate dose response. It now appears that for dose-response algorithms to derive the best, unbiased estimate of health risk, we need to understand the type, magnitude and interrelationships of the uncertainties of model assumptions, parameters and input data used in the associated dose estimation models. Heretofore, uncertainty analysis of dose estimates did not always properly distinguish between categories of errors, e. g., uncertainty that is specific to each subject (i.e., unshared error), and uncertainty of doses from a lack of understanding and knowledge about parameter values that are shared to varying degrees by numbers of subsets of the cohort. While mathematical propagation of errors by Monte Carlo simulation methods has been used for years to estimate the uncertainty of an individual subject's dose, it was almost always conducted without consideration of dependencies between subjects. In retrospect, these types of simple analyses are not suitable for studies with complex dose models, particularly when important input data are missing or otherwise not available. The dose estimation strategy presented here is a simulation method that corrects the previous deficiencies of analytical or simple Monte Carlo error propagation methods and is termed, due to its capability to maintain separation between shared and unshared errors, the two-dimensional Monte Carlo (2DMC) procedure. Simply put, the 2DMC method simulates alter-native, possibly true, sets (or vectors) of doses for an entire cohort rather than a single set that emerges when each individual's dose is estimated independently from other subjects. Moreover, estimated doses within each simulated vector maintain proper inter-relationships such that the estimated doses for members of a cohort subgroup that share common lifestyle attributes and sources of uncertainty are properly correlated. The 2DMC procedure simulates inter-individual variability of possibly true doses within each dose vector and captures the influence of uncertainty in the values of dosimetric parameters across multiple realizations of possibly true vectors of cohort doses. The primary characteristic of the 2DMC approach, as well as its strength, are defined by the proper separation between uncertainties shared by members of the entire cohort or members of defined cohort subsets, and uncertainties that are individual-specific and therefore unshared. (C) 2015 by Radiation Research Society C1 [Simon, Steven L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hoffman, F. Owen] Oak Ridge Ctr Risk Anal, Oak Ridge, TN USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU National Cancer Institute Intramural Research Program; National Institute of Allergy and Infectious Diseases [Y2-Al-5077]; National Cancer Institute [Y3-CO-5117] FX This work was supported by the National Cancer Institute Intramural Research Program and by the Intra-Agency Agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement Y2-Al-5077 and NCI agreement Y3-CO-5117. We would like to acknowledge the contributions to this work by our colleague Robert M. Weinstock (deceased). We also wish to thank our numerous colleagues worldwide, especially those at the National Cancer Institute and the Oak Ridge Center for Risk Analysis for assisting in a variety of ways toward the development of our concepts and understanding, as well as the implementation and presentation of the example material presented here. NR 54 TC 6 Z9 6 U1 1 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD JAN PY 2015 VL 183 IS 1 BP 27 EP 41 DI 10.1667/RR13729.1 PG 15 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AZ0WI UT WOS:000347962400002 PM 25496314 ER PT J AU Duncan, MW Yergey, AL Gale, PJ AF Duncan, Mark W. Yergey, Alfred L. Gale, P. Jane TI Quantifying Proteins by Mass Spectrometry SO SPECTROSCOPY LA English DT Article ID DIFFERENCE GEL-ELECTROPHORESIS; LINKED-IMMUNOSORBENT-ASSAY; MICROARRAY TECHNOLOGY; QUANTITATIVE PROTEOMICS; INTERNAL STANDARD; IMMUNOGLOBULIN-G; HIGH-RESOLUTION; HUMAN SERUM; QUANTIFICATION; IMMUNOASSAY AB The quantification of proteins in a complex biological sample is an important and challenging task. Mass spectrometry (MS) is increasingly used for this purpose, not only to give a global survey of the components and their amounts, but also to precisely and accurately quantify specific target proteins. Here, we review the essential elements of MS approaches to protein quantification and critically compare the available options. C1 [Duncan, Mark W.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Duncan, Mark W.] Biodesix Inc, Boulder, CO USA. [Duncan, Mark W.] King Saud Univ, Riyadh, Saudi Arabia. [Yergey, Alfred L.] NICHD, Mass Spectrometry Facil, Bethesda, MD USA. RP Duncan, MW (reprint author), Univ Colorado, Sch Med, Boulder, CO 80309 USA. NR 44 TC 0 Z9 0 U1 2 U2 7 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 0887-6703 J9 SPECTROSCOPY-US JI Spectroscopy PD JAN PY 2015 VL 30 IS 1 BP 42 EP 58 PG 17 WC Spectroscopy SC Spectroscopy GA AZ4HF UT WOS:000348181600006 ER PT J AU Chen, RT Carbery, B Mac, L Berns, KI Chapman, L Condit, RC Excler, JL Gurwith, M Hendry, M Khan, AS Khuri-Bulos, N Klug, B Robertson, JS Seligman, SJ Sheets, R Williamson, AL AF Chen, Robert T. Carbery, Baevin Mac, Lisa Berns, Kenneth I. Chapman, Louisa Condit, Richard C. Excler, Jean-Louis Gurwith, Marc Hendry, Michael Khan, Arifa S. Khuri-Bulos, Najwa Klug, Bettina Robertson, James S. Seligman, Stephen J. Sheets, Rebecca Williamson, Anna-Lise CA V3SWG TI The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) SO VACCINE LA English DT Article DE Vaccines; Viral Vector; Safety; Immunization ID ROTAVIRUS VACCINE; HIV-1 VACCINE; DOUBLE-BLIND; RISK; EFFICACY; IMMUNIZATION; INFECTION; TRIAL; STEP; H1N1 AB Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed. Published by Elsevier Ltd. C1 [Chen, Robert T.; Carbery, Baevin; Mac, Lisa; Chapman, Louisa; Hendry, Michael] Ctr Dis Control & Prevent, DHAP, NCHHSTP, Atlanta, GA 30333 USA. [Carbery, Baevin] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Berns, Kenneth I.; Condit, Richard C.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Excler, Jean-Louis] Int AIDS Vaccine Initiat, New York, NY USA. US Mil HIV Res Program MHRP, Bethesda, MD 20817 USA. [Gurwith, Marc] PaxVax, San Diego, CA 92121 USA. [Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Khuri-Bulos, Najwa] Jordan Univ Hosp, Div Infect Dis, Amman, Jordan. [Klug, Bettina] Paul Ehrlich Inst, D-63225 Langen, Germany. [Robertson, James S.] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. [Seligman, Stephen J.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Sheets, Rebecca] NIAID, Div Aids, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Williamson, Anna-Lise] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Williamson, Anna-Lise] Natl Hlth Lab Serv, Cape Town, South Africa. RP Chen, RT (reprint author), Ctr Dis Control & Prevent, DHAP, NCHHSTP, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM brightoncollaborationv3swg@gmail.com FU Intramural CDC HHS [CC999999] NR 35 TC 5 Z9 5 U1 2 U2 13 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 JAN 1 PY 2015 VL 33 IS 1 BP 73 EP 75 DI 10.1016/j.vaccine.2014.09.035 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AY6FX UT WOS:000347663700013 PM 25305565 ER PT J AU Broadbent, AJ Santos, CP Paskel, M Matsuoka, Y Lu, JN Chen, ZY Jin, H Subbarao, K AF Broadbent, Andrew J. Santos, Celia P. Paskel, Myeisha Matsuoka, Yumiko Lu, Janine Chen, Zhongying Jin, Hong Subbarao, Kanta TI Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates SO VACCINE LA English DT Article DE H2N2; Influenza; Vaccine; LAIV; Non-human primate; Monkey ID ANN-ARBOR STRAIN; PROTECTIVE EFFICACY; AVIAN RESERVOIR; A VIRUSES; IMMUNOGENICITY; INFECTION; FERRETS; AGE; IDENTIFICATION; SPECIFICITY AB The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAN candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 CO virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to alpha 2-3 linked sialic acids, and one had leucine and serine that binds to alpha 2-3 and alpha-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 CO virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from alpha 2-3 to both alpha 2-3 and alpha 2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation. Published by Elsevier Ltd. C1 [Broadbent, Andrew J.; Santos, Celia P.; Paskel, Myeisha; Matsuoka, Yumiko; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lu, Janine; Chen, Zhongying; Jin, Hong] MedImmune LLC, Mountain View, CA USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Room 3E13C-1,Bldg 33,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov OI Broadbent, Andrew/0000-0002-4716-1835 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). The pandemic influenza vaccine program is part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID and MedImmune. We would like to thank Dr. Arnold Monto for providing the sample from which the Tec67 HA and NA were amplified and Dr. Richard Herbert, Joanne Swerczek, Mark Szarowicz and the staff of the NIH Animal Center at Poolesville for technical support in the animal studies. NR 34 TC 1 Z9 2 U1 0 U2 1 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 JAN 1 PY 2015 VL 33 IS 1 BP 193 EP 200 DI 10.1016/j.vaccine.2014.10.065 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AY6FX UT WOS:000347663700030 PM 25444799 ER PT J AU Shapiro, SZ AF Shapiro, Stuart Z. TI A Proposal to Use Iterative, Small Clinical Trials to Optimize Therapeutic HIV Vaccine Immunogens to Launch Therapeutic HIV Vaccine Development SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID T-CELL RESPONSE; INFECTION; DIVERSITY; ESCAPE AB The HIV cure agenda has rekindled interest in the development of a therapeutic HIV vaccine. An iterative clinical trial strategy that proved successful for the development of effective cancer chemotherapies in the 1960s may be applicable to the development of a CD8 T lymphocyte-based therapeutic HIV vaccine. However, while cancer chemotherapy development could begin with iterative clinical trials to improve the use of active drugs, the first step in therapeutic HIV vaccine design should be discovery of immunogen constructs with potential for activity and their optimization to meet the challenges of HIV-1 sequence diversity and human polymorphism in T cell antigen presentation. A strategy for doing this is discussed in this article. The proposed strategy relies on a major commitment by funding organizations to fund organized and coordinated manufacture and clinical testing of a series of first- and second-generation constructs to test basic concepts in product design. This is presented as an alternative to funding a more traditional competition among private manufacturers and product champions of individual, already designed products. C1 NIAID, Vaccine Res Program, Div Aids, Bethesda, MD 20892 USA. RP Shapiro, SZ (reprint author), NIAID, Vaccine Res Program, Div Aids, 5601 Fishers Lane,Room 9C20B, Bethesda, MD 20892 USA. EM sshapiro@niaid.nih.gov NR 22 TC 0 Z9 0 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 1 PY 2015 VL 31 IS 1 SI SI BP 49 EP 55 DI 10.1089/aid.2014.0172 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AY8DO UT WOS:000347784900009 PM 25286142 ER PT J AU Moniuszko, M Liyanage, NPM Doster, MN Parks, RW Grubczak, K Lipinska, D McKinnon, K Brown, C Hirsch, V Vaccari, M Gordon, S Pegu, P Fenizia, C Flisiak, R Grzeszczuk, A Dabrowska, M Robert-Guroff, M Silvestri, G Stevenson, M McCune, J Franchini, G AF Moniuszko, Marcin Liyanage, Namal P. M. Doster, Melvin N. Parks, Robyn Washington Grubczak, Kamil Lipinska, Danuta McKinnon, Katherine Brown, Charles Hirsch, Vanessa Vaccari, Monica Gordon, Shari Pegu, Poonam Fenizia, Claudio Flisiak, Robert Grzeszczuk, Anna Dabrowska, Milena Robert-Guroff, Marjorie Silvestri, Guido Stevenson, Mario McCune, Joseph Franchini, Genoveffa TI Glucocorticoid Treatment at Moderate Doses of SIVmac251-Infected Rhesus Macaques Decreases the Frequency of Circulating CD14(+)CD16(++) Monocytes But Does Not Alter the Tissue Virus Reservoir SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; PREFERENTIALLY HARBORS HIV-1; INNATE IMMUNE ACTIVATION; CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS; SIMIAN-IMMUNODEFICIENCY; INFECTED PATIENTS; BLOOD MONOCYTES; IN-VIVO; SUBSET AB Subsets of CD16-positive monocytes produce proinflammatory cytokines and expand during chronic infection with the human immunodeficiency virus type 1 (HIV). HIV-infected macrophage in tissues may be long lived and contribute to the establishment and maintenance of the HIV reservoir. We found that the (intermediate) CD14(++)CD16(+) and (nonclassical) CD14(+)CD16(++) monocyte subsets are significantly expanded during infection of Rhesus macaques with pathogenic SIVmac251 but not during infection of sooty mangabeys with the nonpathogenic isolate SIVSM. In vitro glucocorticoid (GC) treatment of peripheral blood mononuclear cells (PBMCs) from uninfected or SIVmac251-infected Rhesus macaques and HIV-infected patients treated or not with antiretroviral therapy (ART) resulted in a significant decrease in the frequency of both CD16-positive monocyte subsets. Short-term in vivo treatment with high doses of GC of chronically SIVmac251-infected macaques resulted in a significant decrease in the CD14(+)CD16(++) population and, to a lesser extent, in the CD14(++)CD16(+) monocytes, as well as a significant decrease in the number of macrophages in tissues. Surprisingly, treatment of SIVmac251-infected macaques with ART significantly increased the CD14(++)CD16(+) population and the addition of GC resulted in a significant decrease in only the CD14(+)CD16(++) subset. No difference in SIV DNA levels in blood, lymph nodes, gut, and spleen was found between the groups treated with ART or ART plus GC. Thus, it appears that high doses of GC treatment in the absence of ART could affect both CD16-positive populations in vivo. Whether the efficacy of this treatment at higher doses to decrease virus levels outweighs its risks remains to be determined. C1 [Moniuszko, Marcin; Grubczak, Kamil] Med Univ Bialystok, Dept Allergol & Internal Med, Bialystok, Poland. [Moniuszko, Marcin] Med Univ Bialystok, Dept Regenerat Med & Immune Regulat, Bialystok, Poland. [Liyanage, Namal P. M.; Doster, Melvin N.; Parks, Robyn Washington; Vaccari, Monica; Gordon, Shari; Pegu, Poonam; Fenizia, Claudio; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Lipinska, Danuta] Med Univ Bialystok, Dept Endocrinol Diabetol & Internal Med, Bialystok, Poland. [McKinnon, Katherine] NCI, FACS Core Facil, NIH, Bethesda, MD 20892 USA. [Brown, Charles; Hirsch, Vanessa] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Flisiak, Robert; Grzeszczuk, Anna] Med Univ Bialystok, Dept Infect Dis & Hepatol, Bialystok, Poland. [Dabrowska, Milena] Med Univ Bialystok, Dept Hematol Diagnost, Bialystok, Poland. [Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Silvestri, Guido] Emory Univ, Atlanta, GA 30322 USA. [Stevenson, Mario] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [McCune, Joseph] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. RP Franchini, G (reprint author), NCI, NIH, Bldg 41,Room D-804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research, DARE collaboratory Grant from NIAID [P30AI073961]; Polish National Science Center [NN401530240]; [R37A1-6698]; [PS10D1107] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, DARE collaboratory Grant P30AI073961 from NIAID, grant R37A1-6698 to Guido Silvestri and Grant PS10D1107 to Yerkes National Primate Research center. We thank Teresa Habina for editorial assistance, Hue Chung and Ranajit Pal for the viral SIV DNA measurement, and Dr. Alan Landay for useful discussions. Marcin Moniuszko was supported by a grant from the Polish National Science Center (NN401530240). FTC and PMPA was a generous gift from Gilead Science, Inc. and Raltegrevir was a generous gift from Merck and Co. NR 44 TC 5 Z9 5 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 1 PY 2015 VL 31 IS 1 SI SI BP 115 EP 126 DI 10.1089/aid.2013.0220 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AY8DO UT WOS:000347784900017 PM 24432835 ER PT J AU Zanussi, S Bortolin, MT Pratesi, C Tedeschi, R Basaglia, G Abbruzzese, L Mazzucato, M Spina, M Vaccher, E Tirelli, U Rupolo, M Michieli, M Di Mascio, M De Paoli, P AF Zanussi, Stefania Bortolin, Maria Teresa Pratesi, Chiara Tedeschi, Rosamaria Basaglia, Giancarlo Abbruzzese, Luciano Mazzucato, Mario Spina, Michele Vaccher, Emanuela Tirelli, Umberto Rupolo, Maurizio Michieli, Mariagrazia Di Mascio, Michele De Paoli, Paolo TI Autograft HIV-DNA Load Predicts HIV-1 Peripheral Reservoir After Stem Cell Transplantation for AIDS-Related Lymphoma Patients SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; CD4 T-CELLS; ANTIRETROVIRAL THERAPY; BONE-MARROW; IMMUNE RECONSTITUTION; UNDIFFERENTIATED CARCINOMA; NASOPHARYNGEAL TYPE; INFECTION; PERSISTENCE; LYMPHOCYTES AB Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p=0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R-2=0.84, p=0.01) to month 12 follow-up (R-2=0.99, p=0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure. C1 [Zanussi, Stefania; Bortolin, Maria Teresa; Pratesi, Chiara; Tedeschi, Rosamaria; Basaglia, Giancarlo] CRO Natl Canc Inst, Microbiol Immunol & Virol Unit, I-33081 Aviano, PN, Italy. [Abbruzzese, Luciano; Mazzucato, Mario] CRO Natl Canc Inst, Stem Cell Collect & Proc Unit, I-33081 Aviano, PN, Italy. [Spina, Michele; Vaccher, Emanuela; Tirelli, Umberto] CRO Natl Canc Inst, Div Med Oncol A, I-33081 Aviano, PN, Italy. [Rupolo, Maurizio; Michieli, Mariagrazia] CRO Natl Canc Inst, Cellular Therapy & High Dose Chemotherapy Unit, I-33081 Aviano, PN, Italy. [Di Mascio, Michele] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [De Paoli, Paolo] CRO Natl Canc Inst, Sci Directorate, I-33081 Aviano, PN, Italy. RP Zanussi, S (reprint author), CRO Natl Canc Inst, Microbiol Immunol & Virol Unit, Via F Gallini 2, I-33081 Aviano, PN, Italy. EM szanussi@cro.it OI Bortolin, Maria Teresa/0000-0003-0589-1669; Mazzucato, Mario/0000-0001-8319-053X; De Paoli, Paolo/0000-0002-9502-1781 FU Ministero del lavoro, della salute e delle politiche sociali [40H73] FX We thank Luigina Mei for editorial assistance. This work was supported by grants from "Ministero del lavoro, della salute e delle politiche sociali" (grant 40H73). The content of this article has been presented as an oral communication to the VI Italian Conference on AIDS and Retroviruses, Rome, May 25-27, 2014. NR 47 TC 4 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 1 PY 2015 VL 31 IS 1 SI SI BP 150 EP 159 DI 10.1089/aid.2014.0157 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AY8DO UT WOS:000347784900021 PM 25581618 ER PT J AU Choi, HW Kim, HR Baek, HJ Kook, H Cho, D Shin, JH Suh, SP Ryang, DW Shin, MG AF Choi, Hyun-Woo Kim, Hye-Ran Baek, Hee-Jo Kook, Hoon Cho, Duck Shin, Jong-Hee Suh, Soon-Pal Ryang, Dong-Wook Shin, Myung-Geun TI Alteration of the SETBP1 Gene and Splicing Pathway Genes SF3B1, U2AF1, and SRSF2 in Childhood Acute Myeloid Leukemia SO ANNALS OF LABORATORY MEDICINE LA English DT Article DE SETBP1; SF3B1; U2AF1; SRSF2; AML; Childhood ID MUTATIONS; MACHINERY; MYELODYSPLASIA; MANAGEMENT; PREDICTS; IDH1 AB Background: Recurrent somatic SET-binding protein 1 (SETBP1) and splicing pathway gene mutations have recently been found in atypical chronic myeloid leukemia and other hematologic malignancies. These mutations have been comprehensively analyzed in adult AML, but not in childhood AML. We investigated possible alteration of the SETBPI, splicing factor 31 subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor I (U2AF1), and serine/arginine-rich splicing factor 2 (SRSF2) genes in childhood AML. Methods: Cytogenetic and molecular analyses were performed to reveal chromosomal and genetic alterations. Sequence alterations in the SETBPI, SF3B1, U2AF1, and SRSF2 genes were examined by using direct sequencing in a cohort of 53 childhood AML patients. Results: Childhood AML patients did not harbor any recurrent SETBPI gene mutations, although our study did identify a synonymous mutation in one patient. None of the previously reported aberrations in the mutational hotspot of SF3B1, U2AF1, and SRSF2 were identified in any of the 53 patients. Conclusions: Alterations of the SETBPI gene or SF3B1, U2AF1, and SRSF2 genes are not common genetic events in childhood AML, implying that the mutations are unlikely to exert a driver effect in myeloid leukemogenesis during childhood. C1 [Choi, Hyun-Woo; Cho, Duck; Shin, Jong-Hee; Suh, Soon-Pal; Ryang, Dong-Wook; Shin, Myung-Geun] Chonnam Natl Univ, Hwasun Hosp, Dept Lab Med, Hwasun 519763, South Korea. [Kim, Hye-Ran; Shin, Myung-Geun] Chonnam Natl Univ, Sch Med, Brain Korea Plus Project 21, Kwangju, South Korea. [Kim, Hye-Ran] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Baek, Hee-Jo; Kook, Hoon] Chonnam Natl Univ, Hwasun Hosp, Dept Pediat, Hwasun 519763, South Korea. [Baek, Hee-Jo; Kook, Hoon; Shin, Myung-Geun] Chonnam Natl Univ, Hwasun Hosp, Environm Hlth Ctr Childhood Leukemia & Canc, Hwasun 519763, South Korea. RP Shin, MG (reprint author), Chonnam Natl Univ, Sch Med, Dept Lab Med, 322 Seoyang Ro, Hwasun 519763, South Korea. EM mgshin@chonnam.ac.kr FU National Research Foundation of Korea (NRF) [2011-0015304]; NRF Basic Science Research Program [2010-0024326]; Leading Foreign Research Institute Recruitment Program through the NRF - Ministry of Education, Science and Technology (MEST) [20110030034]; National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [2013-1320070] FX This study was supported by the National Research Foundation of Korea (NRF) and grants (No. 2011-0015304), the NRF Basic Science Research Program (grant 2010-0024326), the Leading Foreign Research Institute Recruitment Program (No. 20110030034) through the NRF funded by the Ministry of Education, Science and Technology (MEST), and a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (No. 2013-1320070). NR 21 TC 0 Z9 0 U1 1 U2 4 PU KOREAN SOC LABORATORY MEDICINE PI SEOUL PA KOREAN MEDICAL ASSOC BLDG, RM 602,302-75 ICHON 1-DONG, YONGSAN-GU, SEOUL, 140-721, SOUTH KOREA SN 2234-3806 EI 2234-3814 J9 ANN LAB MED JI Ann. Lab. Med. PD JAN PY 2015 VL 35 IS 1 BP 118 EP 122 DI 10.3343/alm.2015.35.1.118 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AY7MW UT WOS:000347745100018 PM 25553291 ER PT J AU Krenz, JE Hofmann, JN Smith, TR Cunningham, RN Fenske, RA Simpson, CD Keifer, M AF Krenz, Jennifer E. Hofmann, Jonathan N. Smith, Theresa R. Cunningham, Rad N. Fenske, Richard A. Simpson, Christopher D. Keifer, Matthew TI Determinants of Butyrylcholinesterase Inhibition Among Agricultural Pesticide Handlers in Washington State: An Update SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE agriculture; biological monitoring; cholinesterase; determinants of exposure; occupational exposure; organophosphorus compounds; pesticide; pesticide handler ID ORGANOPHOSPHATE PESTICIDES; ACETYLCHOLINESTERASE ACTIVITY; PRENATAL EXPOSURE; WORKERS; HEALTH; CHOLINESTERASE; CHLORPYRIFOS; BIOMARKER; CHILDREN; PLASMA AB Organophosphate (OP) and N-methyl-carbamate (CB) insecticides are used widely in agriculture to manage insect pests of economic importance. Agricultural workers are more likely to suffer exposure because of the widespread use of OP/CBs in agriculture, and pesticide-related illnesses among handlers may be more severe when compared to other farm workers. The goal of this study was to identify occupational and personal characteristics associated with butyrylcholinesterase (BuChE) inhibition in participants recruited from the Washington State Cholinesterase Monitoring Program from 2006 to 2011. We conducted a longitudinal study among agricultural pesticide handlers in Washington State during the OP/CB spray season (March-July) over a 6-year period (2006-2011). Linear mixed effects regression models were used to evaluate BuChE inhibition in relation to self-reported occupational and personal characteristics. Relative to pre-season baseline levels, the mean decrease in BuChE activity during the OP/CB spray season over all years of the study period was 3.77% (P < 0.001). Greater BuChE inhibition was observed among handlers who reported using multiple OP/CBs (beta = -2.70, P = 0.045), mixed or loaded OP/CBs (beta = -3.97, P = 0.002), did not store personal protective equipment (PPE) in a locker at work (beta = -3.4, P = 0.014), or did not wear chemical-resistant boots (beta = -16.6, P < 0.001). The Washington State Cholinesterase Monitoring Program has provided a valuable opportunity to evaluate potential sources of OP/CB exposure among agricultural pesticide handlers. Several previously reported associations were confirmed in the current analysis, which included a larger number of pesticide handlers enrolled over a longer time period. The use of multiple OP/CBs and mixing/loading activities were significant risk factors, and the use of chemical-resistant boots and lockers for PPE storage were protective factors. Our findings point toward logical interventions to reduce exposure such as the implementation of engineering controls for mixing/loading activities, requirements for appropriate footwear, and the regular use of lockers for PPE storage. C1 [Krenz, Jennifer E.; Cunningham, Rad N.; Fenske, Richard A.; Simpson, Christopher D.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Hofmann, Jonathan N.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Smith, Theresa R.] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Keifer, Matthew] Marshfield Clin Res Fdn, Natl Farm Med Ctr, Marshfield, WI 54449 USA. RP Simpson, CD (reprint author), Univ Washington, Dept Environm & Occupat Hlth Sci, Box 357234, Seattle, WA 98195 USA. EM simpson1@uw.edu FU United States Centers for Disease Control, National Institute of Occupational Safety and health (CDC/NIOSH) [2 U50 OH07544-07, 1 T42 OH008433-01]; United States National Institute of Environmental Health Sciences (NIEHS) [P30 ES07033, P42 ES04696-22, T32 ES07262] FX United States Centers for Disease Control, National Institute of Occupational Safety and health (CDC/NIOSH) (2 U50 OH07544-07, 1 T42 OH008433-01); United States National Institute of Environmental Health Sciences (NIEHS) (P30 ES07033, P42 ES04696-22, T32 ES07262). NR 41 TC 2 Z9 2 U1 2 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 EI 1475-3162 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JAN PY 2015 VL 59 IS 1 BP 25 EP 40 DI 10.1093/annhyg/meu072 PG 16 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA AY8ZS UT WOS:000347839800004 PM 25261454 ER PT J AU Friesen, MC Locke, SJ Chen, YC Coble, JB Stewart, PA Ji, BT Bassig, B Lu, W Xue, SZ Chow, WH Lan, Q Purdue, MP Rothman, N Vermeulen, R AF Friesen, Melissa C. Locke, Sarah J. Chen, Yu-Cheng Coble, Joseph B. Stewart, Patricia A. Ji, Bu-Tian Bassig, Bryan Lu, Wei Xue, Shouzheng Chow, Wong-Ho Lan, Qing Purdue, Mark P. Rothman, Nathaniel Vermeulen, Roel TI Historical Occupational Trichloroethylene Air Concentrations Based on Inspection Measurements From Shanghai, China SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE China; occupational exposures; population-based studies; statistical model; trichloroethylene ID JOB-EXPOSURE MATRIX; LONG-TERM TRENDS; HYPERSENSITIVITY DERMATITIS; COMPREHENSIVE EVALUATION; PERCHLOROETHYLENE; EPIDEMIOLOGY; INDUSTRY; WORKERS; HEALTH; COHORT AB Trichloroethylene (TCE) is a carcinogen that has been linked to kidney cancer and possibly other cancer sites including non-Hodgkin lymphoma. Its use in China has increased since the early 1990s with China's growing metal, electronic, and telecommunications industries. We examined historical occupational TCE air concentration patterns in a database of TCE inspection measurements collected in Shanghai, China to identify temporal trends and broad contrasts among occupations and industries. Using a database of 932 short-term, area TCE air inspection measurements collected in Shanghai worksites from 1968 through 2000 (median year 1986), we developed mixed-effects models to evaluate job-, industry-, and time-specific TCE air concentrations. Models of TCE air concentrations from Shanghai work sites predicted that exposures decreased 5-10% per year between 1968 and 2000. Measurements collected near launderers and dry cleaners had the highest predicted geometric means (GM for 1986 = 150-190mg m(-3)). The majority (53%) of the measurements were collected in metal treatment jobs. In a model restricted to measurements in metal treatment jobs, predicted GMs for 1986 varied 35-fold across industries, from 11mg m(-3) in 'other metal products/repair' industries to 390mg m(-3) in 'ships/aircrafts' industries. TCE workplace air concentrations appeared to have dropped over time in Shanghai, China between 1968 and 2000. Understanding differences in TCE concentrations across time, occupations, and industries may assist future epidemiologic studies in China. C1 [Friesen, Melissa C.; Locke, Sarah J.; Chen, Yu-Cheng; Coble, Joseph B.; Stewart, Patricia A.; Ji, Bu-Tian; Bassig, Bryan; Xue, Shouzheng; Chow, Wong-Ho; Lan, Qing; Purdue, Mark P.; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA 22207 USA. [Lu, Wei] Shanghai Municipal Ctr Dis Control, Shanghai, Peoples R China. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, Utrecht, Netherlands. RP Friesen, MC (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Purdue, Mark/C-9228-2016; Friesen, Melissa/A-5362-2009; Vermeulen, Roel/F-8037-2011 OI Purdue, Mark/0000-0003-1177-3108; Vermeulen, Roel/0000-0003-4082-8163 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01 CP10122-19] FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Z01 CP10122-19). NR 33 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 EI 1475-3162 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JAN PY 2015 VL 59 IS 1 BP 62 EP 78 DI 10.1093/annhyg/meu066 PG 17 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA AY8ZS UT WOS:000347839800007 PM 25180291 ER PT J AU Cuzick, J Thorat, MA Bosetti, C Brown, PH Burn, J Cook, NR Ford, LG Jacobs, EJ Jankowski, JA La Vecchia, C Law, M Meyskens, F Rothwell, PM Senn, HJ Umar, A AF Cuzick, J. Thorat, M. A. Bosetti, C. Brown, P. H. Burn, J. Cook, N. R. Ford, L. G. Jacobs, E. J. Jankowski, J. A. La Vecchia, C. Law, M. Meyskens, F. Rothwell, P. M. Senn, H. J. Umar, A. TI Estimates of benefits and harms of prophylactic use of aspirin in the general population SO ANNALS OF ONCOLOGY LA English DT Review DE aspirin; prevention; benefit-harm; cancer; cardiovascular disease; gastrointestinal bleeding ID LOW-DOSE ASPIRIN; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RANDOMIZED CONTROLLED-TRIALS; PEPTIC-ULCER DISEASE; HELICOBACTER-PYLORI; PRIMARY PREVENTION; COLORECTAL-CANCER; COST-EFFECTIVENESS; HEART-DISEASE; FOLLOW-UP AB .Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer. The effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period. Prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit-harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening-eradication before starting aspirin prophylaxis. C1 [Cuzick, J.; Thorat, M. A.] Queen Mary Univ London, Ctr Canc Prevent, Wolfson Inst Prevent Med, London EC1M 6BQ, England. [Bosetti, C.; La Vecchia, C.] IRCCS Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Brown, P. H.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Burn, J.] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Cook, N. R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Ford, L. G.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Jacobs, E. J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Jankowski, J. A.] Univ Plymouth, Ctr Biomed Res Translat & Stratified Med, Peninsula Sch Med, Plymouth PL4 8AA, Devon, England. [Jankowski, J. A.] Univ Plymouth, Ctr Biomed Res Translat & Stratified Med, Peninsula Sch Dent, Plymouth PL4 8AA, Devon, England. [Jankowski, J. A.] Queen Mary Univ London, Blizard Inst Cell & Mol Sci, Ctr Digest Dis, London, England. [La Vecchia, C.] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Law, M.] Queen Mary Univ London, Ctr Environm & Prevent Med, Wolfson Inst Prevent Med, London EC1M 6BQ, England. [Meyskens, F.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Rothwell, P. M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Senn, H. J.] Tumor & Breast Ctr ZeTuP, St Gallen, Switzerland. [Umar, A.] NCI, Gastrointestinal & Other Cancers Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Cuzick, J (reprint author), Queen Mary Univ London, Ctr Canc Prevent, Wolfson Inst Prevent Med, Charterhouse Sq, London EC1M 6BQ, England. EM j.cuzick@qmul.ac.uk RI Jankowski, Janusz/H-2706-2012; Thorat, Mangesh/A-9787-2008; OI Jankowski, Janusz/0000-0003-2130-9181; Thorat, Mangesh/0000-0001-8673-5320; La Vecchia, Carlo/0000-0003-1441-897X; Burn, John/0000-0002-9823-2322 FU International Society of Cancer Prevention (ISCaP); Cancer Research UK (CRUK); British Heart Foundation (BHF); American Cancer Society (ACS); CRUK; BHF; ACS FX This evidence review meeting was sponsored by International Society of Cancer Prevention (ISCaP), Cancer Research UK (CRUK), British Heart Foundation (BHF) and American Cancer Society (ACS) and received funding from CRUK, BHF and ACS. Sponsors and funding sources had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 52 TC 80 Z9 83 U1 7 U2 30 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 JAN PY 2015 VL 26 IS 1 BP 47 EP 57 DI 10.1093/annonc/mdu225 PG 11 WC Oncology SC Oncology GA AY2JP UT WOS:000347416300008 PM 25096604 ER PT J AU Qiang, W Yau, WM Schulte, J AF Qiang, Wei Yau, Wai-Ming Schulte, Juergen TI Fibrillation of beta amyloid peptides in the presence of phospholipid bilayers and the consequent membrane disruption SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Alzheimer's disease; Neurotoxicity mechanism; Membrane disruption; amyloid fibril; Solid state NMR ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; SYNAPTIC PLASMA-MEMBRANES; HIV FUSION PEPTIDE; ALZHEIMERS-DISEASE; A-BETA; LIPID-MEMBRANES; PRECURSOR PROTEIN; THIOFLAVIN-T; METAL-IONS AB Fibrillation of beta amyloid (A beta) peptides and the accumulation of amyloid plaques are considered as an important clinical hallmark to identify Alzheimer's disease (AD). The physiological connection between A beta plaques and the disruption of neuronal cells has not been clearly understood. One hypothesis to explain the A beta neurotoxicity is that the fibrillation process induces disruption to the cellular membrane. We studied the A beta fibrillation process in two biologically relevant conditions with the peptide either pre-incorporated into or externally added to the synthetic phospholipid bilayers. These two sample preparation conditions mimic the physiological membrane proximities of A beta peptides before and after the enzymatic cleavage of amyloid precursor protein (APP). Using thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM), we were able to monitor the kinetics and morphological evolution of fibril formation, which was highly sensitive to the two sample preparation protocols. While the external addition protocol generates long and mature fibrils through normal fibrillation process, the pre-incubation protocol was found to stabilize the immature protofibrils. Fluorescence spectroscopy studies with doubly-labeled phospholipids indicated that there may be a lipid uptake process associated with the fibril formation. Solid state nuclear magnetic resonance (NMR) spectroscopy provided evidence for high resolution structural variations in fibrils formed with different protocols, and in particular the stabilization of long-range contact between N- and C-terminal beta strands. In addition, disruption of phospholipid bilayers was supported by measurements with P-31 chemical shifts and relaxation time constants. This article is part of a Special Issue entitled: NMR Spectroscopy for Atomistic Views of Biomembranes and Cell Surfaces. Guest Editors: Lynette Cegelski and David P. Weliky. (C) 2014 Elsevier B.V. All rights reserved. C1 [Qiang, Wei; Schulte, Juergen] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Qiang, Wei; Yau, Wai-Ming] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Qiang, W (reprint author), SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. EM wqiang@binghamton.edu FU National Institutes of Health; Binghamton University, State University of New York; NSF Major Research Instrumentation Program [NSF 0922815] FX This work was supported by the intramural research program at the National Institutes of Health and the startup research funding from Binghamton University, State University of New York. The NMR experiments on the 600 MHz spectrometer were funded by the NSF Major Research Instrumentation Program (NSF 0922815). We greatly thank Dr. Robert Tycko for his support on using materials and instruments, as well as helpful discussion of the results. NR 72 TC 8 Z9 8 U1 7 U2 57 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JAN PY 2015 VL 1848 IS 1 SI SI BP 266 EP 276 DI 10.1016/j.bbamem.2014.04.011 PN B PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AY7NQ UT WOS:000347747100008 PM 24769158 ER PT J AU Huynh, N Beutler, JA Shulkes, A Baldwin, GS He, H AF Nhi Huynh Beutler, John A. Shulkes, Arthur Baldwin, Graham S. He, Hong TI Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1 alpha and beta-catenin via a p-21 activated kinase 1-dependent pathway SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Glaucarubinone; PAK1; HIF-1 alpha; beta-Catenin; CRC ID P21-ACTIVATED KINASES; PROTEIN-SYNTHESIS; QUASSINOIDS; CELLS; FACTOR-1-ALPHA; SURVIVAL; APC AB p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/beta-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [H-3]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1 alpha and beta-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1 alpha or. and beta-catenin via a PAK1-dependent pathway. (C) 2014 Elsevier B.V. All rights reserved. C1 [Nhi Huynh; Shulkes, Arthur; Baldwin, Graham S.; He, Hong] Univ Melbourne, Austin Hlth, Dept Surg, Heidelberg, Vic 3084, Australia. [Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP He, H (reprint author), Univ Melbourne, Austin Hlth, Dept Surg, Studley Rd, Heidelberg, Vic 3084, Australia. EM hong.he@unimelb.edu.au OI Baldwin, Graham/0000-0002-0944-8747 FU National Health and Medical Research Council (NHMRC) of Australia [508908, 1041831]; Austin Hospital Medical Research Foundation [2-1281]; Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research [1 ZIA BC011470 02] FX This work was supported by the National Health and Medical Research Council (NHMRC) of Australia grants 508908 (HH) and 1041831 (GB & AS), by the Austin Hospital Medical Research Foundation 2-1281 (HH), and by the Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research 1 ZIA BC011470 02 (JB). NR 32 TC 4 Z9 4 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN PY 2015 VL 1853 IS 1 BP 157 EP 165 DI 10.1016/j.bbamcr.2014.10.013 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AY5FJ UT WOS:000347598100015 PM 25409929 ER PT J AU Song, CC Wang, Q Song, CZ Lockett, SJ Colburn, NH Li, CCH Wang, JM Rogers, TJ AF Song, Changcheng Wang, Qing Song, Changzheng Lockett, Stephen J. Colburn, Nancy H. Li, Chou-Chi H. Wang, Ji Ming Rogers, Thomas J. TI Nucleocytoplasmic shuttling of valosin-containing protein (VCP/p97) regulated by its N domain and C-terminal region SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Valosin containing protein; Nucleocytoplasmic shuttling; Nuclear export signal; Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) ID AAA-ATPASE P97/VCP; NUCLEAR EXPORT SIGNAL; P97/VALOSIN-CONTAINING PROTEIN; FRONTOTEMPORAL DEMENTIA; PAGET-DISEASE; D1 RING; NUCLEOLAR; P97; LOCALIZATION; P97-VCP AB Valosin-containing protein (VCP or p97), a member of the AAA family (ATPases associated with diverse cellular activities), plays a key role in many important cellular activities. A genetic deficiency of VCP can cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). Previous studies showed that the VCP N domain is essential for the regulation of nuclear entry of VCP. Here we report that IBMPFD mutations, which are mainly located in the N domain, suppress the nuclear entry of VCP. Moreover, the peptide sequence G(780)AGPSQ in the C-terminal region regulates the retention of VCP in the nucleus. A mutant lacking this sequence can increase the nuclear distribution of IBMPFD VCP, suggesting that this sequence is a potential molecular target for correcting the deficient nucleocytoplasmic shuttling of IBMPFD VCP proteins. (C) 2014 Elsevier B.V. All rights reserved. C1 [Song, Changcheng; Rogers, Thomas J.] Temple Univ, Ctr Inflammat Translat & Clin Res, Sch Med, Philadelphia, PA 19140 USA. [Wang, Ji Ming] NCI, Ctr Canc Res, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Lockett, Stephen J.] NCI, Opt Microscopy & Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. [Colburn, Nancy H.; Li, Chou-Chi H.] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. [Li, Chou-Chi H.] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. [Song, Changzheng] Shandong Acad Med Sci, Erythrocrine Project Translat Med, Jinan 250062, Peoples R China. [Wang, Qing] Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40536 USA. RP Song, CC (reprint author), Temple Univ, Ctr Inflammat Translat & Clin Res, Sch Med, MERB 1183H,3500 N Broad St, Philadelphia, PA 19140 USA. EM songc@temple.edu FU NIEHS [1R21ES023051]; NCI [NO1CO56000, HHSN261200800001E]; Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research [N01-CO-12400]; National Natural Science Foundation of China [30672433, 30271215]; Natural Science Foundation of Shandong Province [1872010ZRE27212] FX We thank Drs. Carlos Barrero, Ying Wang and Ren-Ming Dai for technical support, and Dr. Madesh Muniswamy for providing the confocal imaging facility. 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 publisher or recipient acknowledges the right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the manuscript. This research was funded by NIEHS 1R21ES023051 for C.S. Other supports include: DA-14230, DA-25532, and DA-13429 for T.J.R.; NCI Contract Nos. NO1CO56000 and HHSN261200800001E for S.L.; Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research under contract N01-CO-12400 for N.C., C.C.L. and J.M.W.; National Natural Science Foundation of China Nos. 30672433 and 30271215 and Natural Science Foundation of Shandong Province No. 1872010ZRE27212 for S.C.Z. NR 31 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN PY 2015 VL 1853 IS 1 BP 222 EP 232 DI 10.1016/j.bbamcr.2014.10.019 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AY5FJ UT WOS:000347598100021 PM 25447673 ER PT J AU Zhao, HB Peddada, SD Cui, XP AF Zhao, Haibing Peddada, Shyamal D. Cui, Xinping TI Mixed directional false discovery rate control in multiple pairwise comparisons using weighted p-values SO BIOMETRICAL JOURNAL LA English DT Article; Proceedings Paper CT 8th International Conference on Multiple Comparison Procedures (MCP2013) CY JUL 08-11, 2013 CL Univ Southampton, Southampton, UNITED KINGDOM HO Univ Southampton DE Benjamini Hochberg procedure; Microarray; Mixed directional false discovery rate; Multiple pairwise comparison; Weighted p-value ID LIVER-CANCER; ACETAMINOPHEN; PROPORTION; LANDSCAPE; TUMORS; NULL AB In many applications, researchers are interested in making q pairwise comparisons among k test groups on the basis of m outcome variables. Often, m is very large. For example, such situations arise in gene expression microarray studies involving several experimental groups. Researchers are often not only interested in identifying differentially expressed genes between a given pair of experimental groups, but are also interested in making directional inferences such as whether a gene is up-or downregulated in one treatment group relative to another. In such situations, in addition to the usual errors such as false positive (Type I error) and false negative (Type II error), one may commit directional error (Type III error). For example, in a dose response microarray study, a gene may be declared to be upregulated in the high dose group compared to the low dose group when it is not. In this paper, we introduce a mixed directional false discovery rate (mdFDR) controlling procedure using weighted p-values to select positives in different directions. The weights are defined as the inverse of two times the proportion of either positive or negative discoveries. The proposed procedure has been proved mathematically to control the mdFDR at level a and to have a larger power (which is defined as the expected proportion of nontrue null hypotheses) than the GSP10 procedure proposed by Guo et al. (2010). Simulation studies and real data analysis are also conducted to show the outperformance of the proposed procedure than the GSP10 procedure. C1 [Zhao, Haibing] Shanghai Univ Finance & Econ, Sch Stat & Management, Shanghai 200433, Peoples R China. [Peddada, Shyamal D.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Cui, Xinping] Univ Calif Riverside, Dept Stat, Ctr Plant Cell Biol, Riverside, CA 92521 USA. RP Cui, XP (reprint author), Univ Calif Riverside, Dept Stat, Ctr Plant Cell Biol, Riverside, CA 92521 USA. EM xinping.cui@ucr.edu FU National Natural Science Foundation of China (NSFC) [11101255]; University of California AES-CE RSAP grant [A01869]; NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX The research of H.Z. was supported by a grant from the National Natural Science Foundation of China (NSFC) [No. 11101255]. The research of XC was supported, in part, by University of California AES-CE RSAP grant [A01869]. The research of SDP was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04]. NR 30 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD JAN PY 2015 VL 57 IS 1 SI SI BP 144 EP 158 DI 10.1002/bimj.201300242 PG 15 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY4GO UT WOS:000347536500011 PM 25410394 ER PT J AU Stratton, P AF Stratton, P. TI Gynecologic care after hematopoietic cell transplantation: a call to action to include gynecologists in the transplant team SO BONE MARROW TRANSPLANTATION LA English DT Editorial Material ID PROGRESS C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Consult Serv, Program Reprod & Adult Endocrinol, Bethesda, MD USA. RP Stratton, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Gynecol Consult Serv, Program Reprod & Adult Endocrinol, Bethesda, MD USA. EM ps79c@nih.gov NR 8 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JAN PY 2015 VL 50 IS 1 BP 1 EP 2 DI 10.1038/bmt.2014.247 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AY8MD UT WOS:000347806800001 PM 25365065 ER PT J AU Shah, NN Wayne, AS Grady, C Fry, T Wendler, D AF Shah, N. N. Wayne, A. S. Grady, C. Fry, T. Wendler, D. TI Children as hematopoietic cell donors in research: when is it approvable? SO BONE MARROW TRANSPLANTATION LA English DT Article ID G-CSF; MARROW; DONATION; BLOOD; TRANSPLANTATION; STATEMENT; RISK AB With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor-derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations. C1 [Shah, N. N.; Wayne, A. S.; Fry, T.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, A. S.] Univ So Calif, Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA USA. [Grady, C.; Wendler, D.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Warren Grant Magnuson Clinical Center FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Warren Grant Magnuson Clinical Center. NR 13 TC 2 Z9 2 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JAN PY 2015 VL 50 IS 1 BP 15 EP 19 DI 10.1038/bmt.2014.224 PG 5 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AY8MD UT WOS:000347806800004 PM 25330224 ER PT J AU Engels, EA Landgren, O Costello, R Burton, D Mailankody, S Storek, J AF Engels, E. A. Landgren, O. Costello, R. Burton, D. Mailankody, S. Storek, J. TI Serum immunoglobulin free light chains and post-transplant lymphoproliferative disorder among allogeneic hematopoietic stem cell transplant recipients SO BONE MARROW TRANSPLANTATION LA English DT Letter C1 [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Landgren, O.] Mem Sloan Kettering Canc Ctr, Myeloma Serv, New York, NY 10021 USA. [Costello, R.; Burton, D.; Mailankody, S.] NCI, Multiple Myeloma Sect, Bethesda, MD 20892 USA. [Storek, J.] Univ Calgary, Calgary, AB, Canada. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU Intramural NIH HHS NR 10 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JAN PY 2015 VL 50 IS 1 BP 146 EP 147 DI 10.1038/bmt.2014.213 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AY8MD UT WOS:000347806800028 PM 25265459 ER PT J AU Sprung, CN Ivashkevich, A Forrester, HB Redon, CE Georgakilas, A Martin, OA AF Sprung, Carl N. Ivashkevich, Alesia Forrester, Helen B. Redon, Christophe E. Georgakilas, Alexandros Martin, Olga A. TI Oxidative DNA damage caused by inflammation may link to stress-induced non-targeted effects SO CANCER LETTERS LA English DT Review DE Bystander effect; Non-targeted effects; Abscopal effects; Radiation induced bystander effects; DNA damage; Ionizing radiation ID RAT LUNG IRRADIATION; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INDUCED ADAPTIVE RESPONSE; PRIMARY HUMAN FIBROBLASTS; DOUBLE-STRAND BREAKS; MEDIATED INTERCELLULAR COMMUNICATION; HUMAN TISSUE MODELS; LOW-DOSE RADIATION; EFFECTS IN-VIVO; FACTOR-KAPPA-B AB A spectrum of radiation-induced non-targeted effects has been reported during the last two decades since Nagasawa and Little first described a phenomenon in cultured cells that was later called the "bystander effect". These non-targeted effects include radiotherapy-related abscopal effects, where changes in organs or tissues occur distant from the irradiated region. The spectrum of non-targeted effects continue to broaden over time and now embrace many types of exogenous and endogenous stressors that induce a systemic genotoxic response including a widely studied tumor microenvironment. Here we discuss processes and factors leading to DNA damage induction in non-targeted cells and tissues and highlight similarities in the regulation of systemic effects caused by different stressors. Crown Copyright (C) 2013 Published by Elsevier Ireland Ltd. All rights reserved. C1 [Sprung, Carl N.; Ivashkevich, Alesia; Forrester, Helen B.] Monash Univ, Ctr Innate Immun & Infect Dis, Monash Inst Med Res, Clayton, Vic 3168, Australia. [Redon, Christophe E.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Georgakilas, Alexandros] Natl Tech Univ Athens, Dept Phys, Sch Appl Math & Phys Sci, GR-15773 Athens, Greece. [Martin, Olga A.] Peter MacCallum Canc Ctr, Dept Radiat Oncol, Melbourne, Vic, Australia. [Martin, Olga A.] Peter MacCallum Canc Ctr, Mol Radiat Biol Lab, Melbourne, Vic, Australia. [Martin, Olga A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3010, Australia. RP Sprung, CN (reprint author), Monash Univ, Ctr Innate Immunol & Infect Dis, Monash Inst Med Res, 27-31 Wright St, Clayton, Vic 3168, Australia. EM carl.sprung@monash.edu FU National Institute of Health [5U19AI067773-07]; round of the priority-driven Collaborative Cancer Research Scheme [1002743]; Australian Government Department of Health and Ageing; Cancer Australia; Australian National Health and Medical Research Council [10275598]; Australian National Breast Cancer Foundation [PG-08-06]; Victorian Government's Operational Infrastructure Support Program; EU [MC-CIG-303514]; COST ACTION [CM1202] FX We thank Pavel Lobachevsky and Roger Martin for critical reading of the manuscript. This project was supported through the National Institute of Health (Grant 5U19AI067773-07) and the 2010 round of the priority-driven Collaborative Cancer Research Scheme (Grant 1002743) and funded by the Australian Government Department of Health and Ageing with the assistance of Cancer Australia. Also, this work was supported by the Australian National Health and Medical Research Council (Grant 10275598) and the Australian National Breast Cancer Foundation (Grant PG-08-06; http://www.nbcf.org.au/). Support was also provided by the Victorian Government's Operational Infrastructure Support Program and A. Georgakilas's funding is from EU grant MC-CIG-303514 and COST ACTION CM1202 'Biomimetic Radical Chemistry'. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 175 TC 14 Z9 14 U1 0 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD JAN 1 PY 2015 VL 356 IS 1 SI SI BP 72 EP 81 DI 10.1016/j.canlet.2013.09.008 PG 10 WC Oncology SC Oncology GA AY4ZP UT WOS:000347583700010 PM 24041866 ER PT J AU Dabydeen, SA Kang, K Diaz-Cruz, ES Alamri, A Axelrod, ML Bouker, KB Al-Kharboosh, R Clarke, R Hennighausen, L Furth, PA AF Dabydeen, Sarah A. Kang, Keunsoo Diaz-Cruz, Edgar S. Alamri, Ahmad Axelrod, Margaret L. Bouker, Kerrie B. Al-Kharboosh, Rawan Clarke, Robert Hennighausen, Lothar Furth, Priscilla A. TI Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance SO CARCINOGENESIS LA English DT Article ID BREAST-CANCER CELLS; ESTROGEN-RECEPTOR-ALPHA; EPITHELIAL-CELLS; PATHWAYS; PREVENTION; NETWORKS; THERAPY; PROTEIN; HYPERPLASIA; METASTASIS AB Differential responses to tamoxifen and letrozole shown with two different lesions in the estrogen-ER pathway in genetically engineered mice, RNA-seq demonstrated an association of immune-related gene expression with tamoxifen resistance, and letrozole was an effective alternative when tamoxifen resistance was present.Response to breast cancer chemoprevention can depend upon host genetic makeup and initiating events leading up to preneoplasia. Increased expression of aromatase and estrogen receptor (ER) is found in conjunction with breast cancer. To investigate response or resistance to endocrine therapy, mice with targeted overexpression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 overexpressing mice responded to letrozole with reduced hyperplastic alveolar nodule prevalence and decreased mammary epithelial cell proliferation. CYP19A1 overexpressing mice were tamoxifen sensitive but Esr1 overexpressing mice were tamoxifen resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance were found. RNA-sequencing (RNA-seq) was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1- and Brca1-deficient mice, whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon regulatory factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human immunoglobulin lambda-like polypeptide 1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies. C1 [Dabydeen, Sarah A.; Diaz-Cruz, Edgar S.; Alamri, Ahmad; Axelrod, Margaret L.; Bouker, Kerrie B.; Al-Kharboosh, Rawan; Clarke, Robert; Furth, Priscilla A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. [Kang, Keunsoo] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Kang, Keunsoo] Dankook Univ, Dept Microbiol, Cheonan 330714, South Korea. [Diaz-Cruz, Edgar S.] Belmont Univ, Coll Pharm, Dept Pharmaceut Social & Adm Sci, Nashville, TN 37212 USA. [Alamri, Ahmad] King Khalid Univ, Coll Appl Med Sci, Clin Sci Lab, Abha 62529, Saudi Arabia. [Furth, Priscilla A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Med, Washington, DC 20057 USA. RP Furth, PA (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd NW,Res Bldg,Room 520A, Washington, DC 20057 USA. EM paf3@georgetown.edu RI Clarke, Robert/A-6485-2008 OI Clarke, Robert/0000-0002-9278-0854 FU National Institutes of Health (NIH) National Cancer Institute (NCI) [RO1 CA112176]; NIH NCI 'Research Supplements to Promote Diversity in Health-Related Research' [CA112176]; Susan G. Komen for the Cure Postdoctoral Fellowship grant [KG080359]; NIH T32 Ruth L. Kirschstein National Research Service Award Institutional Training grant [5T32CA009686-15]; Department of Defense Breast Cancer Postdoctoral Fellowship Award [BC130883]; NIH, NCI [U54CA149147]; Saudi Arabian Cultural Mission-King Abdullah Scholarship; NIH [IG20RR025828]; NIH NCI [5P30CA051008]; Intramural Research Program (IRP) of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX National Institutes of Health (NIH) National Cancer Institute (NCI) (RO1 CA112176 to P.A.F.); NIH NCI 'Research Supplements to Promote Diversity in Health-Related Research' (CA112176 to support E.S.D.-C.); Susan G. Komen for the Cure Postdoctoral Fellowship grant (KG080359 to support E.S.D.-C.); NIH T32 Ruth L. Kirschstein National Research Service Award Institutional Training grant (5T32CA009686-15 to support S.A.D. and E.S.D.-C.); Department of Defense Breast Cancer Postdoctoral Fellowship Award BC130883 (to K.B.B.); NIH, NCI U54CA149147 (to R.C.); Saudi Arabian Cultural Mission-King Abdullah Scholarship (R.A.-K.); NIH IG20RR025828 (Rodent Barrier Facility Equipment); NIH NCI 5P30CA051008 (Histology and Tissue, Tissue Culture and Animal Shared Resources). The Intramural Research Program (IRP) of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) funded part of this research. NR 50 TC 4 Z9 4 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JAN PY 2015 VL 36 IS 1 BP 122 EP 132 DI 10.1093/carcin/bgu237 PG 11 WC Oncology SC Oncology GA AY9BM UT WOS:000347844700017 PM 25421723 ER PT J AU Lan, Q Smith, MT Tang, XJ Guo, WH Vermeulen, R Ji, ZY Hu, W Hubbard, AE Shen, M McHale, CM Qiu, CY Liu, SW Reiss, B Beane-Freeman, L Blair, A Ge, YC Xiong, J Li, LY Rappaport, SM Huang, HL Rothman, N Zhang, LP AF Lan, Qing Smith, Martyn T. Tang, Xiaojiang Guo, Weihong Vermeulen, Roel Ji, Zhiying Hu, Wei Hubbard, Alan E. Shen, Min McHale, Cliona M. Qiu, Chuangyi Liu, Songwang Reiss, Boris Beane-Freeman, Laura Blair, Aaron Ge, Yichen Xiong, Jun Li, Laiyu Rappaport, Stephen M. Huang, Hanlin Rothman, Nathaniel Zhang, Luoping TI Chromosome-wide aneuploidy study of cultured circulating myeloid progenitor cells from workers occupationally exposed to formaldehyde SO CARCINOGENESIS LA English DT Article ID IN-SITU HYBRIDIZATION; LONG ARM DELETION; INHALED FORMALDEHYDE; POTENTIAL MECHANISMS; HEMATOPOIETIC STEM; OXIDATIVE STRESS; RISK-ASSESSMENT; LEUKEMIA; BENZENE; LYMPHOCYTES AB Formaldehyde (FA) is an economically important industrial chemical to which millions of people worldwide are exposed environmentally and occupationally. Recently, the International Agency for Cancer Research concluded that there is sufficient evidence that FA causes leukemia, particularly myeloid leukemia. To evaluate the biological plausibility of this association, we employed a chromosome-wide aneuploidy study approach, which allows the evaluation of aneuploidy and structural chromosome aberrations (SCAs) of all 24 chromosomes simultaneously, to analyze cultured myeloid progenitor cells from 29 workers exposed to relatively high levels of FA and 23 unexposed controls. We found statistically significant increases in the frequencies of monosomy, trisomy, tetrasomy and SCAs of multiple chromosomes in exposed workers compared with controls, with particularly notable effects for monosomy 1 [P = 6.02E-06, incidence rate ratio (IRR) = 2.31], monosomy 5 (P = 9.01E-06; IRR = 2.24), monosomy 7 (P = 1.57E-05; IRR = 2.17), trisomy 5 (P = 1.98E-05; IRR = 3.40) and SCAs of chromosome 5 (P = 0.024; IRR = 4.15). The detection of increased levels of monosomy 7 and SCAs of chromosome 5 is particularly relevant as they are frequently observed in acute myeloid leukemia. Our findings provide further evidence that leukemia-related cytogenetic changes can occur in the circulating myeloid progenitor cells of healthy workers exposed to FA, which may be a potential mechanism underlying FA-induced leukemogenesis. C1 [Lan, Qing; Hu, Wei; Shen, Min; Beane-Freeman, Laura; Blair, Aaron; Rothman, Nathaniel] NIH, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Smith, Martyn T.; Guo, Weihong; Ji, Zhiying; Hubbard, Alan E.; McHale, Cliona M.; Rappaport, Stephen M.; Zhang, Luoping] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Tang, Xiaojiang; Qiu, Chuangyi; Ge, Yichen; Li, Laiyu; Huang, Hanlin] Guangdong Poisoning Control Ctr, Sci & Educ Dept, Guangzhou 510300, Guangdong, Peoples R China. [Vermeulen, Roel; Reiss, Boris] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3508 Utrecht, Netherlands. [Liu, Songwang] Qiaotou Hosp, Dept Occupat Hlth, Dongguan 523323, Guangdong, Peoples R China. [Xiong, Jun] Dongguan Ctr Dis Control & Prevent, Dept Occupat Hlth, Guangzhou 523129, Guangdong, Peoples R China. RP Zhang, LP (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. EM qingl@mail.nih.gov; luoping@berkeley.edu RI Beane Freeman, Laura/C-4468-2015; Vermeulen, Roel/F-8037-2011 OI Beane Freeman, Laura/0000-0003-1294-4124; Vermeulen, Roel/0000-0003-4082-8163 FU National Cancer Institute; National Institute of Environmental Health Sciences [R01ES017452, P42ES004705] FX Intramural funds from the National Cancer Institute and National Institute of Environmental Health Sciences (R01ES017452 to L.Z. and P42ES004705 to M.T.S.). NR 54 TC 8 Z9 9 U1 1 U2 6 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 JAN PY 2015 VL 36 IS 1 BP 160 EP 167 DI 10.1093/carcin/bgu229 PG 8 WC Oncology SC Oncology GA AY9BM UT WOS:000347844700021 PM 25391402 ER PT J AU Galluzzi, L Bravo-San Pedro, JM Vitale, I Aaronson, SA Abrams, JM Adam, D Alnemri, ES Altucci, L Andrews, D Annicchiarico-Petruzzelli, M Baehrecke, EH Bazan, NG Bertrand, MJ Bianchi, K Blagosklonny, MV Blomgren, K Borner, C Bredesen, DE Brenner, C Campanella, M Candi, E Cecconi, F Chan, FK Chandel, NS Cheng, EH Chipuk, JE Cidlowski, JA Ciechanover, A Dawson, TM Dawson, VL De Laurenzi, V De Maria, R Debatin, KM Di Daniele, N Dixit, VM Dynlacht, BD El-Deiry, WS Fimia, GM Flavell, RA Fulda, S Garrido, C Gougeon, ML Green, DR Gronemeyer, H Hajnoczky, G Hardwick, JM Hengartner, MO Ichijo, H Joseph, B Jost, PJ Kaufmann, T Kepp, O Klionsky, DJ Knight, RA Kumar, S Lemasters, JJ Levine, B Linkermann, A Lipton, SA Lockshin, RA Lopez-Otin, C Lugli, E Madeo, F Malorni, W Marine, JC Martin, SJ Martinou, JC Medema, JP Meier, P Melino, S Mizushima, N Moll, U Munoz-Pinedo, C Nunez, G Oberst, A Panaretakis, T Penninger, JM Peter, ME Piacentini, M Pinton, P Prehn, JH Puthalakath, H Rabinovich, GA Ravichandran, KS Rizzuto, R Rodrigues, CM Rubinsztein, DC Rudel, T Shi, Y Simon, HU Stockwell, BR Szabadkai, G Tait, SW Tang, HL Tavernarakis, N Tsujimoto, Y Vanden Berghe, T Vandenabeele, P Villunger, A Wagner, EF Walczak, H White, E Wood, WG Yuan, J Zakeri, Z Zhivotovsky, B Melino, G Kroemer, G AF Galluzzi, L. Bravo-San Pedro, J. M. Vitale, I. Aaronson, S. A. Abrams, J. M. Adam, D. Alnemri, E. S. Altucci, L. Andrews, D. Annicchiarico-Petruzzelli, M. Baehrecke, E. H. Bazan, N. G. Bertrand, M. J. Bianchi, K. Blagosklonny, M. V. Blomgren, K. Borner, C. Bredesen, D. E. Brenner, C. Campanella, M. Candi, E. Cecconi, F. Chan, F. K. Chandel, N. S. Cheng, E. H. Chipuk, J. E. Cidlowski, J. A. Ciechanover, A. Dawson, T. M. Dawson, V. L. De laurenzi, V. De Maria, R. Debatin, K-M Di Daniele, N. Dixit, V. M. Dynlacht, B. D. El-Deiry, W. S. Fimia, G. M. Flavell, R. A. Fulda, S. Garrido, C. Gougeon, M-L Green, D. R. Gronemeyer, H. Hajnoczky, G. Hardwick, J. M. Hengartner, M. O. Ichijo, H. Joseph, B. Jost, P. J. Kaufmann, T. Kepp, O. Klionsky, D. J. Knight, R. A. Kumar, S. Lemasters, J. J. Levine, B. Linkermann, A. Lipton, S. A. Lockshin, R. A. Lopez-Otin, C. Lugli, E. Madeo, F. Malorni, W. Marine, J-C Martin, S. J. Martinou, J-C Medema, J. P. Meier, P. Melino, S. Mizushima, N. Moll, U. Munoz-Pinedo, C. Nunez, G. Oberst, A. Panaretakis, T. Penninger, J. M. Peter, M. E. Piacentini, M. Pinton, P. Prehn, J. H. Puthalakath, H. Rabinovich, G. A. Ravichandran, K. S. Rizzuto, R. Rodrigues, C. M. Rubinsztein, D. C. Rudel, T. Shi, Y. Simon, H-U Stockwell, B. R. Szabadkai, G. Tait, S. W. Tang, H. L. Tavernarakis, N. Tsujimoto, Y. Vanden Berghe, Tom Vandenabeele, P. Villunger, A. Wagner, E. F. Walczak, H. White, E. Wood, W. G. Yuan, J. Zakeri, Z. Zhivotovsky, B. Melino, G. Kroemer, G. TI Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 SO CELL DEATH AND DIFFERENTIATION LA English DT Review ID MITOCHONDRIAL PERMEABILITY TRANSITION; TUMOR-NECROSIS-FACTOR; APOPTOSIS-INDUCING FACTOR; MIXED LINEAGE KINASE; CYTOCHROME-C RELEASE; ISCHEMIA-REPERFUSION INJURY; DOMAIN-LIKE PROTEIN; Q-VD-OPH; OUTER-MEMBRANE PERMEABILIZATION; CASPASE INHIBITION SWITCHES AB Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death. C1 [Galluzzi, L.; Bravo-San Pedro, J. M.] Gustave Roussy Canc Ctr, Villejuif, France. [Galluzzi, L.; Bravo-San Pedro, J. M.; Kepp, O.; Kroemer, G.] Ctr Rech Cordeliers, Equipe Labellisee Ligue Natl Contre Canc 11, F-75006 Paris, France. [Galluzzi, L.; Kroemer, G.] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Bravo-San Pedro, J. M.; Kepp, O.; Kroemer, G.] Gustave Roussy, INSERM, U1138, Paris, France. [Vitale, I.; De Maria, R.] Regina Elena Inst Canc Res, Rome, Italy. [Aaronson, S. A.; Chipuk, J. E.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA. [Abrams, J. M.] UT Southwestrn Med Ctr, Dept Cell Biol, Dallas, TX USA. [Adam, D.] Univ Kiel, Inst Immunol, Kiel, Germany. [Alnemri, E. S.] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Altucci, L.] Seconda Univ Napoli, Dipartimento Biochim Biofis & Patol Gen, Naples, Italy. [Andrews, D.] Univ Toronto, Dept Biochem & Med Biophys, Toronto, ON, Canada. [Annicchiarico-Petruzzelli, M.] IRCCS, IDI, Biochem Lab, Rome, Italy. [Baehrecke, E. H.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA. [Bazan, N. G.] Sch Med, Neurosci Ctr Excellence, New Orleans, LA USA. [Bertrand, M. J.; Vanden Berghe, Tom; Vandenabeele, P.] VIB, Inflammat Res Ctr, Ghent, Belgium. [Bertrand, M. J.; Vanden Berghe, Tom; Vandenabeele, P.] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Bianchi, K.] Canc Res UK Ctr Excellence, Barts Canc Inst, London, England. [Bianchi, K.] Queen Mary Univ London, John Vane Sci Ctr, London, England. [Blagosklonny, M. V.] Roswell Pk Canc Inst, Dept Cell Stress Biol, Buffalo, NY 14263 USA. [Blomgren, K.] Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden. [Borner, C.] Univ Freiburg, Inst Mol Med, D-79106 Freiburg, Germany. [Borner, C.] Univ Freiburg, Spemann Grad Sch Biol & Med, D-79106 Freiburg, Germany. [Bredesen, D. E.] Buck Inst Res Aging, Novato, CA USA. [Bredesen, D. E.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Brenner, C.] INSERM, UMRS769, Chatenay Malabry, France. [Brenner, C.] LabEx LERMIT, Chatenay Malabry, France. [Brenner, C.] Univ Paris 11, Orsay, France. [Campanella, M.] UCL, Dept Comparat Biomed Sci, London, England. [Campanella, M.] UCL, Consortium Mitochondrial Res, London, England. [Candi, E.; Melino, G.] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. [Cecconi, F.] IRCCS Fdn Santa Lucia, Lab Mol Neuroembryol, Rome, Italy. [Cecconi, F.; Piacentini, M.] Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy. [Cecconi, F.] Danish Canc Soc Res Ctr, Unit Cell Stress & Survival, Copenhagen, Denmark. [Chan, F. K.] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Chandel, N. S.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Cheng, E. H.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Cheng, E. H.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Cidlowski, J. A.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. [Ciechanover, A.] Technion Israel Inst Technol, Rappaport Fac Med & Res Inst, Tumor & Vasc Biol Res Ctr, Haifa, Israel. [Dawson, T. M.; Dawson, V. L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Solomon H Snyder Dept Neurosci,Dept Neurol Pharma, Baltimore, MD USA. [Dawson, T. M.; Dawson, V. L.] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA USA. [De laurenzi, V.] Gabriele Annunzio Univ, Dept Expt & Clin Sci, Chieti, Italy. [Debatin, K-M] Ulm Univ Med Ctr, Dept Pediat & Adolescent Med, Ulm, Germany. [Di Daniele, N.] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy. [Dixit, V. M.] Genentech Inc, Dept Physiol Chem, South San Francisco, CA USA. [Dynlacht, B. D.] NYU, Sch Med, Smilow Res Ctr, Dept Pathol, New York, NY USA. [Dynlacht, B. D.] NYU, Sch Med, Smilow Res Ctr, Inst Canc, New York, NY USA. [El-Deiry, W. S.] Penn State Coll Med, Penn State Hershey Canc Inst, Dept Med Hematol Oncol, Lab Translat Oncol & Expt Canc Therapeut, Hershey, PA USA. [Fimia, G. M.] Univ Salento, Dept Biol & Environm Sci & Technol DiSTeBA, Lecce, Italy. [Fimia, G. M.] IRCCS, Natl Inst Infect Dis Lazzaro Spallanzani, Dept Epidemiol & Preclin Res, Rome, Italy. [Flavell, R. A.] Yale Sch Med, Dept Immunobiol, New Haven, CT USA. [Fulda, S.] Goethe Univ Frankfurt, Inst Expt Canc Res Pediat, Frankfurt, Germany. [Garrido, C.] INSERM, U866, Dijon, France. [Garrido, C.] Univ Burgundy, Fac Med, Dijon, France. [Gougeon, M-L] Inst Pasteur, Infect & Epidemiol Dept, Antiviral Immun Biotherapy & Vaccine Unit, Paris, France. [Green, D. R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Gronemeyer, H.] IGBMC, Dept Funct Genom & Canc, Illkirch Graffenstaden, France. [Hajnoczky, G.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Hardwick, J. M.; Tang, H. L.] Johns Hopkins Univ, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Hengartner, M. O.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Ichijo, H.] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Cell Signaling, Tokyo, Japan. [Joseph, B.; Panaretakis, T.] Canc Centrum Karolinska CCK, Dept Oncol Pathol, Stockholm, Sweden. [Jost, P. J.] Tech Univ Munich, Dept Med Hematol, D-80290 Munich, Germany. [Kaufmann, T.] Univ Bern, Fac Med, Inst Pharmacol, Bern, Switzerland. [Knight, R. A.] UCL, Inst Child Hlth, Med Mol Biol Unit, London, England. [Knight, R. A.; Melino, G.] Med Res Council Toxicol Unit, Leicester, Leics, England. [Kumar, S.] Univ S Australia, Ctr Canc Biol, Adelaide, SA 5001, Australia. [Kumar, S.] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Kumar, S.] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA, Australia. [Lemasters, J. J.] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci & Biochem & Mol, Charleston, SC 29425 USA. [Levine, B.] Univ Texas SW Med Ctr Dallas, Ctr Autophagy Res, Dallas, TX 75390 USA. [Linkermann, A.] Univ Kiel, Div Nephrol & Hypertens, Kiel, Germany. [Lipton, S. A.] Scripps Res Inst, La Jolla, CA 92037 USA. [Lipton, S. A.] Sanford Burnham Ctr Neurosci Aging & Stem Cel Res, La Jolla, CA USA. [Lipton, S. A.] Salk Inst Biol Studies, La Jolla, CA 92037 USA. [Lipton, S. A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Lockshin, R. A.] St Johns Univ, Dept Biol Sci, Queens, NY USA. [Lopez-Otin, C.] Univ Oviedo, Inst Univ Oncol IUOPA, Fac Med, Dept Biochem & Mol Biol, Oviedo, Spain. [Lugli, E.] Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. [Madeo, F.] Graz Univ, Inst Mol Biosci, Graz, Austria. [Malorni, W.] Ist Superiore Sanita, Dept Therapeut Res & Med Evaluat, Rome, Italy. [Malorni, W.] San Raffaele Inst, Sulmona, Italy. [Marine, J-C] Ctr Biol Dis, Lab Mol Canc Biol, Leuven, Belgium. [Marine, J-C] Ctr Human Genet, Lab Mol Canc Biol, Leuven, Belgium. [Martin, S. J.] Trinity Coll Dublin, Smurfit Inst, Dept Genet, Dublin, Ireland. [Martinou, J-C] Univ Geneva, Dept Cell Biol, Geneva, Switzerland. [Medema, J. P.] Univ Amsterdam, Acad Med Ctr, Lab Experiments Oncol & Radiobiol LEXOR, NL-1105 AZ Amsterdam, Netherlands. [Meier, P.] Breakthrough Toby Robins Breast Canc Res Ctr, Inst Canc Res, London, England. [Melino, S.] Univ Roma Tor Vergata, Dept Chem Sci & Technol, Rome, Italy. [Mizushima, N.; Munoz-Pinedo, C.] Univ Tokyo, Fac Med, Cell Death Regulat Grp, Tokyo 113, Japan. [Moll, U.] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA. [Munoz-Pinedo, C.] Bellvitge Biomed Res Inst IDIBELL, Cell Death Regulat Grp, Barcelona, Spain. [Nunez, G.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [Nunez, G.] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA. [Oberst, A.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Penninger, J. M.] Austrian Acad Sci, Inst Mol Biotechnol, A-1010 Vienna, Austria. [Peter, M. E.] Northwestern Univ, Feinberg Sch Med, Dept Hematol Oncol, Chicago, IL 60611 USA. [Pinton, P.] Univ Ferrara, Dept Morphol Surg & Expt Med, Sect Pathol Oncol & Expt Biol, I-44100 Ferrara, Italy. [Pinton, P.] Univ Ferrara, LTTA Ctr, I-44100 Ferrara, Italy. [Prehn, J. H.] Royal Coll Surg, Dept Physiol & Med Phys, Dublin, Ireland. [Puthalakath, H.] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem, Melbourne, Vic, Australia. [Rabinovich, G. A.] Consejo Nacl Invest Cient & Tecn, Inst Biol Med Expt IBYME, Immunopathol Lab, RA-1033 Buenos Aires, DF, Argentina. [Ravichandran, K. S.] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA USA. [Rizzuto, R.; Szabadkai, G.] Univ Padua, Dept Biomed Sci, Padua, Italy. [Rodrigues, C. M.] Univ Lisbon, Fac Pharm, Res Inst Med, P-1699 Lisbon, Portugal. [Rubinsztein, D. C.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Rudel, T.] Univ Wurzburg, Dept Microbiol, D-97070 Wurzburg, Germany. [Shi, Y.] Soochow Univ, Soochow Inst Translat Med, Suzhou, Peoples R China. [Simon, H-U] Univ Bern, Inst Pharmacol, Bern, Switzerland. [Stockwell, B. R.] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Stockwell, B. R.] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Szabadkai, G.] UCL, Dept Cell & Dev Biol, London, England. [Szabadkai, G.] UCL, Consortium Mitochondrial Res, London, England. [Tait, S. W.] Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland. [Tait, S. W.] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Tavernarakis, N.] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion, Crete, Greece. [Tavernarakis, N.] Univ Crete, Fac Med, Dept Basic Sci, Iraklion, Crete, Greece. [Tsujimoto, Y.] Osaka Med Ctr Canc & Cardiovasc Dis, Osaka, Japan. [Vandenabeele, P.] Univ Ghent, Methusalem Program, B-9000 Ghent, Belgium. [Villunger, A.] Med Univ Innsbruck, Bioctr, Div Dev Immunol, A-6020 Innsbruck, Austria. [Wagner, E. F.] Spanish Natl Canc Res Ctr CNIO, Canc Cell Biol Program, Madrid, Spain. [Walczak, H.] UCL, Inst Canc, Ctr Cell Death Canc & Inflammat CCCI, London, England. [White, E.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Wood, W. G.] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA. [Wood, W. G.] VA Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN USA. [Yuan, J.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Zakeri, Z.] Queens Coll, Dept Biol, Queens, NY USA. [Zakeri, Z.] CUNY, Grad Ctr, Queens, NY USA. [Zhivotovsky, B.] Karolinska Inst, Inst Environm Med, Div Toxicol, S-10401 Stockholm, Sweden. [Zhivotovsky, B.] Moscow MV Lomonosov State Univ, Fac Fundamental Med, Moscow, Russia. [Kroemer, G.] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France. RP Galluzzi, L (reprint author), Ctr Rech Cordeliers, Equipe Apoptose Canc & Immun 11, 15 Rue Ecole Med, F-75006 Paris, France. EM deadoc@vodafone.it; kroemer@orange.fr RI Piacentini, Mauro/I-2411-2016; Lopez-Otin, Carlos/C-6657-2013; Tavernarakis, Nektarios/B-9684-2013; Pinton, Paolo/J-8025-2012; Bertrand, Mathieu/P-6465-2016; Prehn, Jochen/A-3928-2010; Jost, Philipp/S-4962-2016; iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, CellFun /A-4244-2014; Gronemeyer, Hinrich/H-7002-2016; Marine, Jean-Christophe/K-3292-2016; Chan, Francis/E-9647-2014; Vandenabeele, Peter/C-8597-2009; Debatin, Klaus-Michael/J-9704-2014; Bravo San Pedro, Jose Manuel/F-1680-2015; Penninger, Josef/I-6860-2013; Wagner, Erwin/G-9637-2012; Marine, Jean Christophe/J-2237-2015; Gronemeyer, Hinrich/G-6240-2011; Rodrigues, Cecilia/M-3572-2013; Munoz-Pinedo, Cristina/B-6118-2008; Malorni, Walter/G-5874-2016; Adam, Dieter/E-9763-2010; OI Piacentini, Mauro/0000-0003-2919-1296; Lopez-Otin, Carlos/0000-0001-6964-1904; Tavernarakis, Nektarios/0000-0002-5253-1466; Pinton, Paolo/0000-0001-7108-6508; Prehn, Jochen/0000-0003-3479-7794; Jost, Philipp/0000-0003-2454-0362; Gronemeyer, Hinrich/0000-0001-9454-2449; Panaretakis, Theocharis/0000-0001-5754-6950; Kaufmann, Thomas/0000-0001-9906-874X; VITALE, ILIO/0000-0002-5918-1841; malorni, walter/0000-0002-1223-7000; Zhivotovsky, Boris/0000-0002-2238-3482; Flavell, Richard/0000-0003-4461-0778; Dawson, Valina/0000-0002-2915-3970; Marine, Jean-Christophe/0000-0003-2433-9837; Chan, Francis/0000-0002-4803-8353; Debatin, Klaus-Michael/0000-0002-8397-1886; Penninger, Josef/0000-0002-8194-3777; Wagner, Erwin/0000-0001-7872-0196; Gronemeyer, Hinrich/0000-0001-9454-2449; Rodrigues, Cecilia/0000-0002-4829-754X; Munoz-Pinedo, Cristina/0000-0002-9120-664X; Adam, Dieter/0000-0002-5668-5032; Linkermann, Andreas/0000-0001-6287-9725; Cecconi, Francesco/0000-0002-5614-4359; Andrews, David/0000-0002-9266-7157; Bravo-San Pedro, Jose Manuel/0000-0002-5781-1133; MELINO, SONIA MICHAELA/0000-0001-7694-5279; Blomgren, Klas/0000-0002-0476-7271; Kumar, Sharad/0000-0001-7126-9814; Chipuk, Jerry Edward/0000-0002-1337-842X FU European Research Council [233294]; Medical Research Council [MC_U132670600]; NCI NIH HHS [R01 CA097061, R01 CA130893, R01 CA163591, R01 CA169291, R01 CA170702]; NIAAA NIH HHS [R01 AA021191]; NIAID NIH HHS [R01 AI044828]; NICHD NIH HHS [P01 HD029587, R01 HD066319]; NIDA NIH HHS [P50 DA000266]; NIDDK NIH HHS [R01 DK073336, R56 DK037034]; NIGMS NIH HHS [R01 GM053396, R01 GM072124, R01 GM096208]; NINDS NIH HHS [P50 NS038377, R01 NS086890]; Wellcome Trust [095317, 100140] NR 336 TC 181 Z9 184 U1 12 U2 92 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JAN PY 2015 VL 22 IS 1 SI SI BP 58 EP 73 DI 10.1038/cdd.2014.137 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AY9AJ UT WOS:000347841600008 PM 25236395 ER PT J AU Ursano, RJ Heeringa, SG Stein, MB Jain, S Raman, R Sun, XY Chiu, WT Colpe, LJ Fullerton, CS Gilman, SE Hwang, I Naifeh, JA Nock, MK Rosellini, AJ Sampson, NA Schoenbaum, M Zaslavsky, AM Kessler, RC AF Ursano, Robert J. Heeringa, Steven G. Stein, Murray B. Jain, Sonia Raman, Rema Sun, Xiaoying Chiu, Wai Tat Colpe, Lisa J. Fullerton, Carol S. Gilman, Stephen E. Hwang, Irving Naifeh, James A. Nock, Matthew K. Rosellini, Anthony J. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Kessler, Ronald C. TI PREVALENCE AND CORRELATES OF SUICIDAL BEHAVIOR AMONG NEW SOLDIERS IN THE US ARMY: RESULTS FROM THE ARMY STUDY TO ASSESS RISK AND RESILIENCE IN SERVICEMEMBERS (ARMY STARRS) SO DEPRESSION AND ANXIETY LA English DT Article DE military personnel; prevalence; suicide; suicide ideation; suicide attempt ID RANDOMIZED CONTROLLED-TRIAL; NATIONAL-COMORBIDITY-SURVEY; PSYCHOLOGICAL DISORDERS; ADOLESCENTS; MILITARY; THERAPY; DESIGN; RATES AB BackgroundThe prevalence of suicide among U.S. Army soldiers has risen dramatically in recent years. Prior studies suggest that most soldiers with suicidal behaviors (i.e., ideation, plans, and attempts) had first onsets prior to enlistment. However, those data are based on retrospective self-reports of soldiers later in their Army careers. Unbiased examination of this issue requires investigation of suicidality among new soldiers. MethodThe New Soldier Study (NSS) of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) used fully structured self-administered measures to estimate preenlistment histories of suicide ideation, plans, and attempts among new soldiers reporting for Basic Combat Training in 2011-2012. Survival models examined sociodemographic correlates of each suicidal outcome. ResultsLifetime prevalence estimates of preenlistment suicide ideation, plans, and attempts were 14.1, 2.3, and 1.9%, respectively. Most reported onsets of suicide plans and attempts (73.3-81.5%) occurred within the first year after onset of ideation. Odds of these lifetime suicidal behaviors among new soldiers were positively, but weakly associated with being female, unmarried, religion other than Protestant or Catholic, and a race/ethnicity other than non-Hispanic White, non-Hispanic Black, or Hispanic. ConclusionsLifetime prevalence estimates of suicidal behaviors among new soldiers are consistent with retrospective reports of preenlistment prevalence obtained from soldiers later in their Army careers. Given that prior suicidal behaviors are among the strongest predictors of later suicides, consideration should be given to developing methods of obtaining valid reports of preenlistment suicidality from new soldiers to facilitate targeting of preventive interventions. (C) 2014 Wiley Periodicals, Inc. C1 [Ursano, Robert J.; Fullerton, Carol S.; Naifeh, James A.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.; Jain, Sonia; Raman, Rema; Sun, Xiaoying] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Raman, Rema] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Chiu, Wai Tat; Hwang, Irving; Rosellini, Anthony J.; Sampson, Nancy A.; Zaslavsky, Alan M.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MD USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MD USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA USA. RP Ursano, RJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM robert.ursano@usuhs.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; U.S. Department of Health and Human Services; NIH/NIMH [U01MH087981] FX Contract grant sponsor: Department of the Army, U.S. Department of Health and Human Services, and NIH/NIMH; Contract grant number: U01MH087981. NR 29 TC 10 Z9 10 U1 5 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JAN PY 2015 VL 32 IS 1 BP 3 EP 12 DI 10.1002/da.22317 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AY9MI UT WOS:000347874800002 PM 25338964 ER PT J AU Rosellini, AJ Heeringa, SG Stein, MB Ursano, RJ Chiu, WT Colpe, LJ Fullerton, CS Gilman, SE Hwang, I Naifeh, JA Nock, MK Petukhova, M Sampson, NA Schoenbaum, M Zaslavsky, AM Kessler, RC AF Rosellini, Anthony J. Heeringa, Steven G. Stein, Murray B. Ursano, Robert J. Chiu, Wai Tat Colpe, Lisa J. Fullerton, Carol S. Gilman, Stephen E. Hwang, Irving Naifeh, James A. Nock, Matthew K. Petukhova, Maria Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Kessler, Ronald C. TI LIFETIME PREVALENCE OF DSM-IV MENTAL DISORDERS AMONG NEW SOLDIERS IN THE US ARMY: RESULTS FROM THE ARMY STUDY TO ASSESS RISK AND RESILIENCE IN SERVICEMEMBERS (ARMY STARRS) SO DEPRESSION AND ANXIETY LA English DT Article DE military personnel; mental disorders; prevalence; epidemiology; demographics ID COMORBIDITY SURVEY REPLICATION; AGE-OF-ONSET; POSTTRAUMATIC-STRESS-DISORDER; HEALTH-CARE; PSYCHIATRIC-DISORDERS; MILITARY PERSONNEL; COMBAT EXPOSURE; SUBSTANCE USE; EVENTS; CIDI AB BackgroundThe prevalence of 30-day mental disorders with retrospectively reported early onsets is significantly higher in the U.S. Army than among socio-demographically matched civilians. This difference could reflect high prevalence of preenlistment disorders and/or high persistence of these disorders in the context of the stresses associated with military service. These alternatives can to some extent be distinguished by estimating lifetime disorder prevalence among new Army recruits. MethodsThe New Soldier Study (NSS) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) used fully structured measures to estimate lifetime prevalence of 10 DSM-IV disorders in new soldiers reporting for Basic Combat Training in 2011-2012 (n = 38,507). Prevalence was compared to estimates from a matched civilian sample. Multivariate regression models examined socio-demographic correlates of disorder prevalence and persistence among new soldiers. ResultsLifetime prevalence of having at least one internalizing, externalizing, or either type of disorder did not differ significantly between new soldiers and civilians, although three specific disorders (generalized anxiety, posttraumatic stress, and conduct disorders) and multimorbidity were significantly more common among new soldiers than civilians. Although several socio-demographic characteristics were significantly associated with disorder prevalence and persistence, these associations were uniformly weak. ConclusionsNew soldiers differ somewhat, but not consistently, from civilians in lifetime preenlistment mental disorders. This suggests that prior findings of higher prevalence of current disorders with preenlistment onsets among soldiers than civilians are likely due primarily to a more persistent course of early-onset disorders in the context of the special stresses experienced by Army personnel. (C) 2014 Wiley Periodicals, Inc. C1 [Rosellini, Anthony J.; Chiu, Wai Tat; Hwang, Irving; Petukhova, Maria; Sampson, Nancy A.; Zaslavsky, Alan M.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Ursano, Robert J.; Fullerton, Carol S.; Naifeh, James A.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM Kessler@hcp.med.harvard.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; U.S. Department of Health and Human Services; NIH/NIMH [U01MH087981] FX Contract grant sponsor: Department of the Army, U.S. Department of Health and Human Services, and NIH/NIMH; contract grant number: U01MH087981. NR 52 TC 11 Z9 11 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JAN PY 2015 VL 32 IS 1 BP 13 EP 24 DI 10.1002/da.22316 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AY9MI UT WOS:000347874800003 PM 25338841 ER PT J AU Van, C Williams, JS Kunkel, TA Peterson, CL AF Van, Christopher Williams, Jessica S. Kunkel, Thomas A. Peterson, Craig L. TI Deposition of histone H2A.Z by the SWR-C remodeling enzyme prevents genome instability SO DNA REPAIR LA English DT Article DE Chromatin remodeling; Genome instability; Mismatch repair; Exonuclease 1; H2A.Z ID DNA-POLYMERASE-EPSILON; MISMATCH REPAIR; CHROMATIN; REPLICATION; MUTATIONS; DYNAMICS; ERRORS; ALPHA; DELTA AB The yeast SWR-C chromatin remodeling enzyme catalyzes chromatin incorporation of the histone variant H2A.Z which plays roles in transcription, DNA repair, and chromosome segregation. Dynamic incorporation of H2A.Z by SWR-C also enhances the ability of exonuclease I (Exo1) to process DNA ends during repair of double strand breaks. Given that Exo1 also participates in DNA replication and mismatch repair, here we test whether SWR-C influences DNA replication fidelity. We find that inactivation of SWR-C elevates the spontaneous mutation rate of a strain encoding a L612M variant of DNA polymerase (Pol) delta, with a single base mutation signature characteristic of lagging strand replication errors. However, this genomic instability does not solely result from reduced Exo1 function, because single base mutator effects are seen in both Exo1-proficient and Exo1-deficient po13-L612M swr1 Delta strains. The data are consistent with the possibility that incorporation of the H2A.Z variant by SWR-C may stimulate Exo1 activity, as well as enhance the fidelity of replication by Pol delta, the repair of mismatches generated by Pol delta, or both. (C) 2014 Elsevier B.V. All rights reserved. C1 [Van, Christopher; Peterson, Craig L.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Williams, Jessica S.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Williams, Jessica S.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Struct Biol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM Craig.Peterson@umassmed.edu FU Division of Intramural Research of the NIH, NIEHS [Z01 ES065070]; NIH [GM054096]; American Cancer Society - Lakeshore Division Postdoctoral Fellowship FX We thank Alan Clark and Scott Lujan for helpful comments on the manuscript and Kunkel lab members for data previously generated in the lab. We are grateful to Grace Kissling for statistical expertise and the NIEHS Molecular Genetics Core Facility for sequencing of 5-FOA-resistant mutants. This work was supported by Project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the NIH, NIEHS, and by a grant from the NIH (GM054096) to C.L.P. C.V. was supported by an American Cancer Society - Lakeshore Division Postdoctoral Fellowship. NR 26 TC 3 Z9 3 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JAN PY 2015 VL 25 BP 9 EP 14 DI 10.1016/j.dnarep.2014.10.010 PG 6 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AY9KA UT WOS:000347867600002 PM 25463393 ER PT J AU Siebrasse, EA Pastrana, DV Nguyen, NL Wang, A Roth, MJ Holland, SM Freeman, AF McDyer, J Buck, CB Wang, D AF Siebrasse, Erica A. Pastrana, Diana V. Nguyen, Nang L. Wang, Annie Roth, Mark J. Holland, Steven M. Freeman, Alexandra F. McDyer, John Buck, Christopher B. Wang, David TI WU Polyomavirus in Respiratory Epithelial Cells from Lung Transplant Patient with Job Syndrome SO EMERGING INFECTIOUS DISEASES LA English DT Article ID KI; INFECTION; UPDATE AB We detected WU polyomavirus (WUPyV) in a bronchoalveolar lavage sample from lungs transplanted into a recipient with Job syndrome by using immunoassays specific for the WUPyV viral protein 1. Co-staining for an epithelial cell marker identified most WUPyV viral protein 1 positive cells as respiratory epithelial cells. C1 [Siebrasse, Erica A.; Nguyen, Nang L.; Wang, Annie; Wang, David] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Pastrana, Diana V.; Roth, Mark J.; Holland, Steven M.; Freeman, Alexandra F.; Buck, Christopher B.] NIH, Bethesda, MD 20892 USA. [McDyer, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Wang, D (reprint author), Washington Univ, Dept Mol Microbiol, Sch Med, Campus Box 8230,660 S Euclid Ave, St Louis, MO 63110 USA. EM davewang@borcim.wustl.edu OI Buck, Christopher/0000-0003-3165-8094 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH [P30AR048335]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH [R21AI095922]; Children's Discovery Institute at Washington University in St. Louis; NIH Intramural Research Program; Center for Cancer Research; Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program; National Institute of Allergy and Infectious Diseases FX Experimental support was provided by the Hybridoma Facility of the Rheumatic Diseases Core Center. This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (award no. P30AR048335); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; grant R21AI095922 to D.W.; the Children's Discovery Institute at Washington University in St. Louis; and the NIH Intramural Research Program, with support from the Center for Cancer Research and National Institute of Allergy and Infectious Diseases. E.A.S. was supported by the Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program. NR 12 TC 7 Z9 7 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JAN PY 2015 VL 21 IS 1 BP 103 EP 106 DI 10.3201/eid2101.140855 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AY3SW UT WOS:000347503700017 PM 25531075 ER PT J AU Kenyon, N Wang, L Spornick, N Khaibullina, A Almeida, LEF Cheng, Y Wang, JC Guptill, V Finkel, JC Quezado, ZMN AF Kenyon, Nicholas Wang, Li Spornick, Nicholas Khaibullina, Alfia Almeida, Luis E. F. Cheng, Yao Wang, Jichuan Guptill, Virginia Finkel, Julia C. Quezado, Zenaide M. N. TI Sickle cell disease in mice is associated with sensitization of sensory nerve fibers SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Sickle cell; pain; nociception; sine wave; somatosensory; fetal hemoglobin ID CURRENT VOCALIZATION THRESHOLD; WAVE ELECTRICAL-STIMULATION; NOCICEPTION ASSAY; NEUROPATHIC PAIN; MOUSE MODELS; RAT MODEL; ANEMIA; COLD; HEMOGLOBIN; ACTIVATION AB The pain phenotype in sickle cell disease (SCD) patients is highly variable. A small percentage of SCD patients experience many vaso-occlusive crises/year, 5% of patients account for over 30% of pain episodes, while 39% report few episodes of severe pain. Clearly, a better understanding of the pathobiology of SCD is needed to improve its therapy. Humanized sickle cell mice recapitulate several phenotypes of SCD patients and provide a model for the study of SCD pain. Researchers have shown that one strain of humanized SCD mice, the BERK strain, has abnormal pain phenotype. However, the nociception phenotype of another humanized SCD mouse strain, the Townes strain, has not been described. In a large cross-sectional study of BERK and Townes SCD mice, we examined thermosensory response and sensory nerve fiber function using sine-wave electrical stimulation at 2000, 250, and 5Hz to stimulate preferentially A, A, and C sensory nerve fibers, respectively. We found that BERK and Townes mice, compared to respective controls, had decreases in 2000, 250, and 5Hz current vocalization thresholds in patterns that suggest sensitization of a broad spectrum of sensory nerve fibers. In addition, the pattern of sensitization of sensory fibers varied according to strain, sex, age, and mouse genotype. In a similarly variable pattern, Townes and BERKs also had significantly altered sensitivity to noxious thermal stimuli in agreement with what has been shown by others. In summary, the analysis of somatosensory function using sine-wave electrical stimulation in humanized sickle cell mice suggests that in SCD, both myelinated and unmyelinated, fibers are sensitized. The pattern of sensory fiber sensitization is distinct from that observed in pain models of neuropathic and inflammatory pain. These findings raise the possibility that sensitization of a broad spectrum of sensory fibers might contribute to the altered and variable nociception phenotype in SCD. C1 [Kenyon, Nicholas; Wang, Li; Spornick, Nicholas; Khaibullina, Alfia; Almeida, Luis E. F.; Finkel, Julia C.; Quezado, Zenaide M. N.] George Washington Univ, Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Childrens Res Inst,Div Pain Med,Sch Med & Hlth Sc, Washington, DC 20010 USA. [Cheng, Yao; Wang, Jichuan] Childrens Natl Med Ctr, Ctr Translat Sci, Div Biostat & Study Methodol, Washington, DC 20010 USA. [Guptill, Virginia] NIH, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. RP Quezado, ZMN (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Childrens Res Inst,Div Pain Med,Sch Med & Hlth Sc, Washington, DC 20010 USA. EM zquezado@childrensnational.org RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU National Institutes of Health Clinical Center, NIH; Sheikh Zayed Institute for Pediatric Surgical Innovation FX The authors are grateful to LaShon Middleton and Sayuri Kamimura for expert technical support during experiments, to Aral C. Greene and Nina Afsar for editorial help, and to Edward C.C. Wong, MD and Nannette Poidven for measurements of fetal hemoglobin concentration. This work was supported by the Intramural Program from the National Institutes of Health Clinical Center, NIH and the Sheikh Zayed Institute for Pediatric Surgical Innovation. NR 48 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD JAN PY 2015 VL 240 IS 1 BP 87 EP 98 DI 10.1177/1535370214544275 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AZ1CH UT WOS:000347977400010 PM 25070860 ER PT J AU Lessard, JC Kalinin, A Bible, PW Morasso, MI AF Lessard, Juliane C. Kalinin, Alexandr Bible, Paul W. Morasso, Maria I. TI Calmodulin 4 is dispensable for epidermal barrier formation and wound healing in mice SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE calcium-binding protein; epidermis; skin barrier; wound repair ID DIFFERENTIATION; PROTEIN; SCARF; EXPRESSION AB Calcium-mediated signals play important roles in epidermal barrier formation, skin homoeostasis and wound repair. Calmodulin 4 (Calm4) is a small, Ca2+-binding protein with strong expression in suprabasal keratinocytes. In mice, Calm4 first appears in the skin at the time of barrier formation, and its expression increases in response to epidermal barrier challenges. In this study, we report the generation of Calm4 knockout mice and provide evidence that Calm4 is dispensable for epidermal barrier formation, maintenance and repair. C1 [Lessard, Juliane C.; Kalinin, Alexandr; Bible, Paul W.; Morasso, Maria I.] NIAMSD, Skin Biol Lab, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMSD, Skin Biol Lab, Bldg 50,Room 1523, Bethesda, MD 20892 USA. EM morasso@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH [ZIA AR041124-15] FX The authors thank Dr. Gustavo Gutierrez-Cruz and Dr. Hong-Wei Sun for help with the RNAseq experiments, Kimberly Hilsen for assistance with mouse breeding and Dr. Mary Ann Stepp for input relating to the wound healing studies. This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (ZIA AR041124-15 to M.I. Morasso). NR 9 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD JAN PY 2015 VL 24 IS 1 BP 55 EP 57 DI 10.1111/exd.12568 PG 3 WC Dermatology SC Dermatology GA AY6WP UT WOS:000347703900012 PM 25316000 ER PT J AU Stephenson, D Perry, D Bens, C Bain, LJ Berry, D Krams, M Sperling, R Dilts, D Luthman, J Hanna, D McKew, J Temple, R Fields, FO Salloway, S Katz, R AF Stephenson, Diane Perry, Dan Bens, Cynthia Bain, Lisa J. Berry, Donald Krams, Michael Sperling, Reisa Dilts, David Luthman, Johan Hanna, Debra McKew, John Temple, Robert Fields, F. Owen Salloway, Stephen Katz, Russell TI Charting a path toward combination therapy for Alzheimer's disease SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Alzheimer's disease; combination therapy; collaboration; novel therapy; co-development ID DRUG DEVELOPMENT; BREAST-CANCER; CLINICAL-TRIALS; MAJOR DISEASES; BIOMARKERS; CHEMOTHERAPY; MEMANTINE; RECOMMENDATIONS; PERSPECTIVES; COALITION AB It is acknowledged that progress in combined therapeutic approaches for Alzheimer's disease (AD) will require an unprecedented level of collaboration. At a meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition and the Critical Path Institute, investigators from industry, academia and regulatory agencies agreed on the need for combinatorial approaches to treating AD. The need for advancing multiple targets includes recognition for novel adaptive trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination. A combination trial now being planned may test drugs targeting different pathogenic pathways or multiple targets along a common pathway. Collaborations and consortia-based strategies are pivotal for success and a regulatory framework is recommended for success. C1 [Stephenson, Diane] Crit Path Inst, CAMD, Tucson, AZ 85718 USA. [Perry, Dan; Bens, Cynthia] Alliance Aging Res, Accelerate Cure Treatments Alzheimers Dis ACT AD, Washington, DC USA. [Berry, Donald] Berry Consultants LLC, Austin, TX 78746 USA. [Krams, Michael] Janssen Pharmaceut, Neurol Franchise, Titusville, NJ USA. [Sperling, Reisa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Dilts, David] OHSU Knight Canc Inst, Div Management, Ctr Management Res Healthcare, Portland, OR USA. [Luthman, Johan] Eisai Pharmaceut, Visakhapatnam, Andhra Pradesh, India. [Hanna, Debra] Crit Path TB Drug Regimens Regulatory Sci Consort, Tucson, AZ USA. [McKew, John] NIH, Therapeut Dev Branch, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Fields, F. Owen] Pfizer, Worldwide Res & Dev, Regulatory Strategy, New York, NY USA. [Salloway, Stephen] Butler Hosp, Memory & Aging Program, Providence, RI 02906 USA. RP Stephenson, D (reprint author), Crit Path Inst, CAMD, Tucson, AZ 85718 USA. EM DStephenson@c-path.org RI Akbar, Afrah/C-2001-2016 FU Eli Lily; Eisai; Avid; Janssen; Biogen Idec; Merck Lilly; Roche Genentech FX M Krams is an employee of Janssen R&D. R Sperling is a consultant to Roche, Isis, Genentech, Janssen and has received research support from Eli Lily, Eisai, Avid and Janssen. J Luthman is an employee of Eisai Inc and owns shares in AstraZeneca & Merck Inc. F Owen Fields is employed by Pfizer and has stock options in Pfizer. S Salloway has received research support from Biogen Idec, Merck Lilly, Roche & Genentech. 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 30 TC 10 Z9 10 U1 1 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD JAN PY 2015 VL 15 IS 1 SI SI BP 107 EP 113 DI 10.1586/14737175.2015.995168 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AY8KQ UT WOS:000347802800009 PM 25540951 ER PT J AU Bergamaschi, C Kulkarni, V Rosati, M Alicea, C Jalah, R Chen, S Bear, J Sardesai, NY Valentin, A Felber, BK Pavlakis, GN AF Bergamaschi, C. Kulkarni, V. Rosati, M. Alicea, C. Jalah, R. Chen, S. Bear, J. Sardesai, N. Y. Valentin, A. Felber, B. K. Pavlakis, G. N. TI Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells SO GENE THERAPY LA English DT Article ID NATURAL-KILLER-CELLS; HUMORAL IMMUNE-RESPONSES; SIV-INFECTED MACAQUES; PHASE-I TRIAL; NONHUMAN-PRIMATES; RHESUS MACAQUES; RECEPTOR-ALPHA; SOLUBLE IL-15R-ALPHA; INTERLEUKIN (IL)-15; TRANS PRESENTATION AB Interleukin-15 (IL-15) is a common.-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15R alpha) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL-15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8(+)NK cells, all memory CD8(+) T-cell subsets and effector memory CD4(+) T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection. C1 [Bergamaschi, C.; Kulkarni, V.; Alicea, C.; Jalah, R.; Bear, J.; Felber, B. K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Rosati, M.; Chen, S.; Valentin, A.; Pavlakis, G. N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Sardesai, N. Y.] Inovio Pharmaceut, Plymouth Meeting, PA USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. EM george.pavlakis@nih.gov FU National Cancer Institute, National Institutes of Health (NCI/NIH) FX This work was funded in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). We thank GR Pilkington for discussions and assistance and KA Goetz for technical assistance; D Weiss, J Treece, A Cristillo, M Ferrari and staff at Advanced Bioscience Laboratory for support; and T Jones for editorial assistance. NR 63 TC 4 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD JAN PY 2015 VL 22 IS 1 BP 76 EP 86 DI 10.1038/gt.2014.84 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AY8FN UT WOS:000347790000009 PM 25273353 ER PT J AU Teixeira, AL de Souza, RT Zanetti, MV Brunoni, AR Busatto, GF Zarate, CA Gattaz, WF Machado-Vieira, R AF Teixeira, Antonio L. de Souza, Rafael T. Zanetti, Marcus V. Brunoni, Andre R. Busatto, Geraldo F. Zarate, Carlos A., Jr. Gattaz, Wagner F. Machado-Vieira, Rodrigo TI Increased plasma levels of soluble TNF receptors 1 and 2 in bipolar depression and impact of lithium treatment SO HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL LA English DT Article DE bipolar disorder; bipolar depression; lithium; sTNFR1; sTNFR2 ID TUMOR-NECROSIS-FACTOR; INFLAMMATORY MARKERS; RATING-SCALE; SERUM-LEVELS; DISORDER; CYTOKINES; METAANALYSIS; SCHIZOPHRENIA; BIOMARKERS; ALPHA AB ObjectiveTNF system (TNF and its soluble receptors sTNFR1 and 2) has been investigated as a potential molecular target in bipolar disorder. The aim of the study was to compare plasma levels of these receptors in unmedicated bipolar depressed patients compared with healthy controls, and to evaluate the effects of a 6-week lithium treatment on sTNFR1 and sTNFR2 levels. MethodsThe study enrolled 29 patients with unmedicated bipolar disorder in a major depressive episode and 27 matched controls. Patients had blood collected at baseline and after 6weeks of lithium treatment. The concentration of sTNFRs was measured by ELISA. ResultssTNFR1 and sTNFR2 levels were significantly increased in bipolar depression in comparison with healthy subjects. Lithium treatment did not significantly change sTNFR1 and sTNFR2 levels from baseline to endpoint. There was no correlation between improvement in depressive symptoms and the change in sTNFR1 or sTNFR1 levels. ConclusionThese results reinforce the involvement of an activated immune response system in the pathophysiology of bipolar disorder, with no impact of lithium treatment on the related biomarkers. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Teixeira, Antonio L.] Univ Fed Minas Gerais, Sch Med, Interdisciplinary Lab Med Investigat, Belo Horizonte, MG, Brazil. [de Souza, Rafael T.; Zanetti, Marcus V.; Brunoni, Andre R.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Neurosci Lab, LIM 27, Sao Paulo, Brazil. [Zanetti, Marcus V.; Busatto, Geraldo F.] Univ Sao Paulo, Inst & Dept Psychiat, Lab Psychiat Neuroimaging, LIM 21, Sao Paulo, Brazil. [Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Teixeira, AL (reprint author), Univ Fed Minas Gerais, Fac Med, Lab Interdisciplinar Invest Med, Sala 281,Av Alfredo Balena,190 Santa Efigenia, BR-30130100 Belo Horizonte, MG, Brazil. EM altexr@gmail.com RI Brunoni, Andre/H-8394-2012; Busatto, Geraldo/D-4431-2009; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Brunoni, Andre/0000-0002-6310-3571; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU CNPq; Minas Gerais Research Foundation (Fapemig); Sao Paulo Research Foundation (Fapesp, Brazil) [2009/14891-9] FX This work was funded by CNPq, Minas Gerais Research Foundation (Fapemig), and Sao Paulo Research Foundation (Fapesp, Brazil 2009/14891-9). NR 31 TC 7 Z9 7 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6222 EI 1099-1077 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD JAN PY 2015 VL 30 IS 1 BP 52 EP 56 DI 10.1002/hup.2450 PG 5 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA AY6XA UT WOS:000347704900006 PM 25572309 ER PT J AU Traynor, BJ Renton, AE AF Traynor, Bryan J. Renton, Alan E. TI Exploring the Epigenetics of Alzheimer Disease SO JAMA NEUROLOGY LA English DT Editorial Material ID DNA METHYLATION; BRAIN; SORL1; LOCI C1 [Traynor, Bryan J.; Renton, Alan E.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, 35 Convent Dr,Porter Neurosci Bldg,Room 1A-110, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov FU Intramural NIH HHS; NIA NIH HHS [Z01-AG000949-02] NR 9 TC 3 Z9 3 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD JAN PY 2015 VL 72 IS 1 BP 8 EP 9 DI 10.1001/jamaneurol.2014.3057 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AY8PI UT WOS:000347815300002 PM 25365705 ER PT J AU Christen, WG Glynn, RJ Gaziano, JM Darke, AK Crowley, JJ Goodman, PJ Lippman, SM Lad, TE Bearden, JD Goodman, GE Minasian, LM Thompson, IM Blanke, CD AF Christen, William G. Glynn, Robert J. Gaziano, J. Michael Darke, Amy K. Crowley, John J. Goodman, Phyllis J. Lippman, Scott M. Lad, Thomas E. Bearden, James D. Goodman, Gary E. Minasian, Lori M. Thompson, Ian M., Jr. Blanke, Charles D. TI Age-Related Cataract in Men in the Selenium and Vitamin E Cancer Prevention Trial Eye Endpoints Study A Randomized Clinical Trial SO JAMA OPHTHALMOLOGY LA English DT Article ID GLUTATHIONE-PEROXIDASE ACTIVITY; SENILE CATARACT; ANTIOXIDANT VITAMINS; PROSTATE-CANCER; PROTECTIVE ROLE; LENS OPACITIES; BETA-CAROTENE; FINNISH MEN; SUPPLEMENTATION; SELECT AB IMPORTANCE Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium. OBJECTIVE To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men. DESIGN, SETTING, AND PARTICIPANTS The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35 533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11 267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study. INTERVENTIONS Individual supplements of selenium (200 mu g per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-a-tocopheryl acetate). MAIN OUTCOMES AND MEASURES Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract. RESULTS During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95% CI, 0.75-1.11; P =.37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95% CI, 0.84-1.25; P =.81). Similar results were observed for cataract extraction. CONCLUSIONS AND RELEVANCE These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract. C1 [Christen, William G.; Glynn, Robert J.; Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Prevent Med, Boston, MA 02215 USA. [Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Aging, Boston, MA 02215 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Darke, Amy K.; Crowley, John J.; Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, Southwest Oncol Grp Stat Ctr, Seattle, WA 98104 USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, Off Director, San Diego, CA 92103 USA. [Lad, Thomas E.] Jesse Brown VA Med Ctr, Chicago, IL USA. [Bearden, James D.] Spartanburg Reg Med Ctr, Upstate Carolina Community Clin Oncol Program, Spartanburg, SC USA. [Goodman, Gary E.] Swedish Med Ctr, Washington, DC USA. [Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Urol, San Antonio, TX 78229 USA. [Blanke, Charles D.] Oregon Hlth & Sci Univ, Knight Canc Inst, Southwest Oncol Grp Chairs Off, Portland, OR 97201 USA. [Blanke, Charles D.] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. RP Christen, WG (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM wchristen@rics.bwh.harvard.edu FU Public Health Service - National Cancer Institute, National Institutes of Health, Department of Health and Human Services [CA37429]; National Center for Complementary and Alternative Medicine; [EY014418] FX This work was supported by grant EY014418 and in part by grant CA37429 from the Public Health Service Cooperative Agreement awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and the National Center for Complementary and Alternative Medicine. NR 43 TC 10 Z9 10 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JAN PY 2015 VL 133 IS 1 BP 17 EP 24 DI 10.1001/jamaophthalmol.2014.3478 PG 8 WC Ophthalmology SC Ophthalmology GA AZ1AJ UT WOS:000347972500003 PM 25232809 ER PT J AU Kessler, RC Warner, CH Ivany, C Petukhova, MV Rose, S Bromet, EJ Brown, M Cai, TX Colpe, LJ Cox, KL Fullerton, CS Gilman, SE Gruber, MJ Heeringa, SG Lewandowski-Romps, L Li, JL Millikan-Bell, A Naifeh, JA Nock, MK Rosellini, AJ Sampson, NA Schoenbaum, M Stein, MB Wessely, S Zaslavsky, AM Ursano, RJ AF Kessler, Ronald C. Warner, Christopher H. Ivany, Christopher Petukhova, Maria V. Rose, Sherri Bromet, Evelyn J. Brown, Millard, III Cai, Tianxi Colpe, Lisa J. Cox, Kenneth L. Fullerton, Carol S. Gilman, Stephen E. Gruber, Michael J. Heeringa, Steven G. Lewandowski-Romps, Lisa Li, Junlong Millikan-Bell, Amym. Naifeh, James A. Nock, Matthew K. Rosellini, Anthony J. Sampson, Nancy A. Schoenbaum, Michael Stein, Murray B. Wessely, Simon Zaslavsky, Alan M. Ursano, Robert J. CA Army STARRS Collaborators TI Predicting Suicides After Psychiatric Hospitalization in US Army Soldiers The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO JAMA PSYCHIATRY LA English DT Article ID DECISION-SUPPORT-SYSTEMS; INPATIENT CARE; PREVENTION; DISCHARGE; METAANALYSIS; REGRESSION; DEPRESSION; ATTEMPTORS; BEHAVIOR; PERIODS AB IMPORTANCE The US Army experienced a sharp increase in soldier suicides beginning in 2004. Administrative data reveal that among those at highest risk are soldiers in the 12 months after inpatient treatment of a psychiatric disorder. OBJECTIVE To develop an actuarial risk algorithm predicting suicide in the 12 months after US Army soldier inpatient treatment of a psychiatric disorder to target expanded posthospitalization care. DESIGN, SETTING, AND PARTICIPANTS There were 53 769 hospitalizations of active duty soldiers from January 1, 2004, through December 31, 2009, with International Classification of Diseases, Ninth Revision, Clinical Modification psychiatric admission diagnoses. Administrative data available before hospital discharge abstracted from a wide range of data systems (sociodemographic, US Army career, criminal justice, and medical or pharmacy) were used to predict suicides in the subsequent 12 months using machine learning methods (regression trees and penalized regressions) designed to evaluate cross-validated linear, nonlinear, and interactive predictive associations. MAIN OUTCOMES AND MEASURES Suicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge. RESULTS Sixty-eight soldiers died by suicide within 12 months of hospital discharge (12.0% of all US Army suicides), equivalent to 263.9 suicides per 100 000 person-years compared with 18.5 suicides per 100 000 person-years in the total US Army. The strongest predictors included sociodemographics (male sex [odds ratio (OR), 7.9; 95% CI, 1.9-32.6] and late age of enlistment [OR, 1.9; 95% CI, 1.0-3.5]), criminal offenses (verbal violence [OR, 2.2; 95% CI, 1.2-4.0] and weapons possession [OR, 5.6; 95% CI, 1.7-18.3]), prior suicidality [OR, 2.9; 95% CI, 1.7-4.9], aspects of prior psychiatric inpatient and outpatient treatment (eg, number of antidepressant prescriptions filled in the past 12 months [OR, 1.3; 95% CI, 1.1-1.7]), and disorders diagnosed during the focal hospitalizations (eg, nonaffective psychosis [OR, 2.9; 95% CI, 1.2-7.0]). A total of 52.9% of posthospitalization suicides occurred after the 5% of hospitalizations with highest predicted suicide risk (3824.1 suicides per 100 000 person-years). These highest-risk hospitalizations also accounted for significantly elevated proportions of several other adverse posthospitalization outcomes (unintentional injury deaths, suicide attempts, and subsequent hospitalizations). CONCLUSIONS AND RELEVANCE The high concentration of risk of suicide and other adverse outcomes might justify targeting expanded posthospitalization interventions to soldiers classified as having highest posthospitalization suicide risk, although final determination requires careful consideration of intervention costs, comparative effectiveness, and possible adverse effects. C1 [Kessler, Ronald C.; Petukhova, Maria V.; Rose, Sherri; Gruber, Michael J.; Rosellini, Anthony J.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Warner, Christopher H.] Blanchfield Army Community Hosp, Dept Behav Med, Ft Campbell, KY USA. [Ivany, Christopher; Brown, Millard, III] US Army Off Surg Gen, Falls Church, VA USA. [Bromet, Evelyn J.] SUNY Stony Brook, Sch Med, Dept Psychiat, Stony Brook, NY 11794 USA. [Cai, Tianxi; Li, Junlong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Cox, Kenneth L.; Millikan-Bell, Amym.] US Army Publ Hlth Command, Aberdeen Proving Ground, MD USA. [Fullerton, Carol S.; Naifeh, James A.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Heeringa, Steven G.; Lewandowski-Romps, Lisa] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Deapartment Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Wessely, Simon] Kings Coll London, Kings Ctr Mil Hlth Res, London WC2R 2LS, England. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave,Ste 215, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu RI Gilman, Stephen/E-7632-2010; Wessely, Simon/A-8713-2008 OI Gilman, Stephen/0000-0002-8331-6419; FU US Department of the Army; National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services; [U01MH087981] FX The Army STARRS was sponsored by the US Department of the Army and funded under cooperative agreement U01MH087981 with the National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services. NR 48 TC 28 Z9 28 U1 6 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2015 VL 72 IS 1 BP 49 EP 57 DI 10.1001/jamapsychiatry.2014.1754 PG 9 WC Psychiatry SC Psychiatry GA AY5KJ UT WOS:000347610700007 PM 25390793 ER PT J AU Zeitler, EP Piccini, JP Hellkamp, AS Whellan, DJ Jackson, KP Ellis, SJ Kraus, WE Keteyian, SJ Kitzman, DW Ewald, GA Fleg, JL Pina, IL O'Connor, CM AF Zeitler, Emily P. Piccini, Jonathan P. Hellkamp, Anne S. Whellan, David J. Jackson, Kevin P. Ellis, Stephen J. Kraus, William E. Keteyian, Steven J. Kitzman, Dalane W. Ewald, Gregory A. Fleg, Jerome L. Pina, Ileana L. O'Connor, Christopher M. CA HF-ACTION Investigators TI Exercise Training and Pacing Status in Patients With Heart Failure: Results From HF-ACTION SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; exercise; implanted cardiac pacemaker; mortality ID RANDOMIZED CONTROLLED-TRIAL; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; CARDIAC RESYNCHRONIZATION THERAPY; INVESTIGATING OUTCOMES; PERFORMANCE; BENEFIT; DISEASE; UPDATE AB Background: We sought to determine if outcomes with exercise training in heart failure (HF) vary according to ventricular pacing type. Methods and Results: Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized 2,331 outpatients with HF and left ventricular ejection fraction <= 35% to usual care plus exercise training or usual care alone. We examined the relationship between outcomes and randomized treatment according to ventricular pacing status with the use of Cox proportional hazards modeling. In HF-ACTION 1,118 patients (48%) had an implanted cardiac rhythm device: 683 with right ventricular (RV) and 435 with biventricular (BiV) pacemakers. Patients with pacing devices were older, more frequently white, and had lower peak VO2 (P < .001 for all). Peak VO2 improved similarly with training in groups with and without pacing devices. The primary composite end point-all-cause death or hospitalization was reduced only in patients randomized to exercise training without a device (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67-0.93 [P = .004]; RV lead: HR 1.04, 95% CI 0.84-1.28 [P = .74]; BiV pacing: HR 1.05, 95% CI 0.82-1.34 [P = .72]; interaction P = .058). Conclusions: Exercise training may improve exercise capacity in patients with implanted cardiac devices. However, the apparent beneficial effects of exercise on hospitalization or death may be attenuated in patients with implanted cardiac devices and requires further study. C1 [Zeitler, Emily P.; Piccini, Jonathan P.; Jackson, Kevin P.; Ellis, Stephen J.; Kraus, William E.; O'Connor, Christopher M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Div Cardiol,Dept Med, Durham, NC 27710 USA. [Hellkamp, Anne S.] Duke Clin Res Inst, Durham, NC USA. [Whellan, David J.] Thomas Jefferson Univ, Dept Med, Div Cardiol, Philadelphia, PA 19107 USA. [Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Kitzman, Dalane W.] Wake Forest Univ, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27109 USA. [Ewald, Gregory A.] Washington Univ, Div Cardiovasc Dis, St Louis, MO USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Dept Med, Div Cardiol, New York, NY USA. RP Piccini, JP (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Div Cardiol, POB 17969, Durham, NC 27710 USA. EM jonathan.piccini@duke.edu OI Hellkamp, Anne/0000-0003-0919-4502 FU National Institutes of Health [5U01HL063747, RU01HL066482, 5UO1HL06694]; Boston Scientific FX HF-ACTION was funded by the National Institutes of Health (5U01HL063747 to C.M.O., RU01HL066482 to I.L.P., and 5UO1HL06694 to S.J.K.). The present work was supported by a grant from Boston Scientific to J.P.P., D.J.W., and C.M.O. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, NIH, or the Department of Health and Human Services. NR 16 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD JAN PY 2015 VL 21 IS 1 BP 60 EP 67 DI 10.1016/j.cardfail.2014.10.004 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AY9KR UT WOS:000347869300009 PM 25463413 ER PT J AU Jiang, CT Xie, C Li, F Zhang, LM Nichols, RG Krausz, KW Cai, JW Qi, YP Fang, ZZ Takahashi, S Tanaka, N Desai, D Amin, SG Albert, I Patterson, AD Gonzalez, FJ AF Jiang, Changtao Xie, Cen Li, Fei Zhang, Limin Nichols, Robert G. Krausz, Kristopher W. Cai, Jingwei Qi, Yunpeng Fang, Zhong-Ze Takahashi, Shogo Tanaka, Naold Desai, Dhimant Amin, Shantu G. Albert, Istvan Patterson, Andrew D. Gonzalez, Frank J. TI Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID INDUCED INSULIN-RESISTANCE; BILE-ACID-HOMEOSTASIS; HUMAN GUT MICROBIOTA; DIET-INDUCED OBESITY; CHOLESTEROL 7-ALPHA-HYDROXYLASE; HEPATIC STEATOSIS; GENE-EXPRESSION; MICE; FXR; METABOLISM AB Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment. C1 [Jiang, Changtao; Xie, Cen; Li, Fei; Krausz, Kristopher W.; Qi, Yunpeng; Fang, Zhong-Ze; Tanaka, Naold; Desai, Dhimant; Amin, Shantu G.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jiang, Changtao] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100871, Peoples R China. [Zhang, Limin; Nichols, Robert G.; Cai, Jingwei; Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Zhang, Limin; Nichols, Robert G.; Cai, Jingwei; Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Zhang, Limin] Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance, CAS Key Lab Magnet Resonance Biol Syst, Wuhan, Peoples R China. [Desai, Dhimant; Amin, Shantu G.] Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA USA. [Albert, Istvan] Penn State Univ, Bioinformat Consulting Ctr, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM adp117@psu.edu; gonzalef@mail.nih.gov RI limin, zhang/O-8208-2016; Patterson, Andrew/G-3852-2012 OI limin, zhang/0000-0001-5689-948X; Patterson, Andrew/0000-0003-2073-0070 FU Intramural Research Program of the Center for Cancer Research, NCI, NIH; National Institutes of Environmental Health Sciences [ES022186]; Pennsylvania Department of Health using Tobacco CURE Funds FX We thank Xin Pan and Jie Liu for help with analysis of mitochondrial isolation and functional studies, Toren Finkel for use of the Seahorse XF 96 analyzer, and Linda G. Byrd and John Buckley for technical assistance with the mouse studies. This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH and by the National Institutes of Environmental Health Sciences (ES022186, to A.D. Patterson). Sequencing was provided by the Penn State Genomics Core Facility (University Park, Pennsylvania, USA). This project is funded in part by a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions of this work. NR 68 TC 72 Z9 73 U1 7 U2 45 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 JAN PY 2015 VL 125 IS 1 BP 386 EP 402 DI 10.1172/JCI76738 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AY7NS UT WOS:000347747300040 PM 25500885 ER PT J AU Grahnemo, L Jochems, C Andersson, A Engdahl, C Ohlsson, C Islander, U Carlsten, H AF Grahnemo, Louise Jochems, Caroline Andersson, Annica Engdahl, Cecilia Ohlsson, Claes Islander, Ulrika Carlsten, Hans TI Possible role of lymphocytes in glucocorticoid-induced increase in trabecular bone mineral density SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; POSTMENOPAUSAL WOMEN; ESTROGEN DEFICIENCY; IN-VIVO; DEXAMETHASONE TREATMENT; CORTICOSTEROID ACTION; RHEUMATOID-ARTHRITIS; ORAL CORTICOSTEROIDS; JOINT DESTRUCTION; T-LYMPHOCYTES AB Treatment with anti-inflammatory glucocorticoids is associated with osteoporosis. Many of the treated patients are postmenopausal women, who even without treatment have an increased risk of osteoporosis. Lymphocytes have been shown to play a role in postmenopausal and arthritis-induced osteoporosis, and they are targeted by glucocorticoids. The aim of this study was to investigate the mechanisms behind effects of glucocorticoids on bone during health and menopause, focusing on lymphocytes. Female C57BL/6 or SCID mice were therefore sham-operated or ovariectomized and 2 weeks later treatment with dexamethasone (dex), the nonsteroidal anti-inflammatory drug carprofen, or vehicle was started and continued for 2.5 weeks. At the termination of experiments, femurs were phenotyped using peripheral quantitative computed tomography and high-resolution micro-computed tomography, and markers of bone turnover were analyzed in serum. Tand B lymphocyte populations in bone marrow and spleen were analyzed by flow cytometry. Dex-treated C57BL/6 mice had increased trabecular bone mineral density, but lower cortical content and thickness compared with vehicle-treated mice. The dex-treated mice also had lower levels of bone turnover markers and markedly decreased numbers of spleen T and B lymphocytes. In contrast, these effects could not be repeated when mice were treated with the nonsteroidal anti-inflammatory drug carprofen. In addition, dex did not increase trabecular bone in ovariectomized SCID mice lacking functional Tand B lymphocytes. In contrast to most literature, the results from this study indicate that treatment with dex increased trabecular bone density, which may indicate that this effect is associated with corticosteroid-induced alterations of the lymphocyte populations. C1 [Grahnemo, Louise; Jochems, Caroline; Andersson, Annica; Engdahl, Cecilia; Islander, Ulrika; Carlsten, Hans] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Rheumatol & Inflammat, S-40530 Gothenburg, Sweden. [Grahnemo, Louise; Jochems, Caroline; Andersson, Annica; Engdahl, Cecilia; Islander, Ulrika; Carlsten, Hans] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, S-40530 Gothenburg, Sweden. [Jochems, Caroline] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Grahnemo, L (reprint author), Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Rheumatol & Inflammat, Box 480, S-40530 Gothenburg, Sweden. EM louise.grahnemo@gu.se RI Andersson, Annica/B-4424-2015; OI Andersson, Annica/0000-0002-3333-8687; Grahnemo, Louise/0000-0001-5276-6612; Engdahl, Cecilia/0000-0002-8914-0178 FU Medical Faculty of Goteborg University (ALF); Goteborg Medical Society; King Gustav V's 80 years' Foundation; Sahlgrenska Foundation; NovoNordic Foundation; Borje Dahlin foundation; Association against Rheumatism; Reumaforskningsfond Margareta; Swedish Research Council FX This study was supported by grants from the Medical Faculty of Goteborg University (ALF), The Goteborg Medical Society, King Gustav V's 80 years' Foundation, the Sahlgrenska Foundation, the NovoNordic Foundation, the Borje Dahlin foundation, the Association against Rheumatism, Reumaforskningsfond Margareta, and the Swedish Research Council. The FACS Canto II was purchased thanks to generous support from the Inga-Britt and Arne Lundberg Foundation. NR 53 TC 6 Z9 8 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD JAN PY 2015 VL 224 IS 1 BP 97 EP 108 DI 10.1530/JOE-14-0508 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY9OW UT WOS:000347881200012 PM 25359897 ER PT J AU Guevara, AB Demonet, JF Polejaeva, E Knutson, KM Wassermann, EM Krueger, F Grafman, J AF Guevara, Andrea Brioschi Demonet, Jean-Francois Polejaeva, Elena Knutson, Kristine M. Wassermann, Eric M. Krueger, Frank Grafman, Jordan TI Association Between Long-Term Cognitive Decline in Vietnam Veterans With TBI and Caregiver Attachment Style SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Article DE attachment style (AS); caregiver; cognitive reserve; fearful; neural plasticity; traumatic brain injury (TBI) ID TRAUMATIC BRAIN-INJURY; PENETRATING HEAD-INJURY; ADULT ATTACHMENT; SYNAPTIC PLASTICITY; COPING STRATEGIES; FOLLOW-UP; DEMENTIA; ENVIRONMENT; ENRICHMENT; STABILITY AB Objective: To examine whether a caregiver's attachment style is associated with patient cognitive trajectory after traumatic brain injury (TBI). Setting: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. Participants: Forty Vietnam War veterans with TBI and their caregivers. Main Outcome Measure: Cognitive performance, measured by the Armed Forces Qualification Test percentile score, completed at 2 time points: preinjury and 40 years postinjury. Design: On the basis of caregivers' attachment style (secure, fearful, preoccupied, dismissing), participants with TBI were grouped into a high or low group. To examine the association between cognitive trajectory of participants with TBI and caregivers' attachment style, we ran four 2 x 2 analysis of covariance on cognitive performances. Results: After controlling for other factors, cognitive decline was more pronounced in participants with TBI with a high fearful caregiver than among those with a low fearful caregiver. Other attachment styles were not associated with decline. Conclusion and Implication: Caregiver fearful attachment style is associated with a significant decline in cognitive status after TBI. We interpret this result in the context of the neural plasticity and cognitive reserve literatures. Finally, we discuss its impact on patient demand for healthcare services and potential interventions. C1 [Guevara, Andrea Brioschi; Polejaeva, Elena; Knutson, Kristine M.; Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Guevara, Andrea Brioschi; Demonet, Jean-Francois] Univ Lausanne, Fac Biol & Med, Lausanne, VD, Switzerland. [Demonet, Jean-Francois] Univ Lausanne Hosp, Dept Clin Neurosci, Memory Ctr, CHUV, Lausanne, Switzerland. [Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Grafman, Jordan] Rehabil Inst Chicago, Chicago, IL 60611 USA. RP Grafman, J (reprint author), Rehabil Inst Chicago, 345 E Super St,Ste 1796, Chicago, IL 60611 USA. EM jgrafman@ric.org OI Grafman, Jordan H./0000-0001-8645-4457; Demonet, Jean-Francois/0000-0003-0100-6175 NR 65 TC 1 Z9 1 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-9701 EI 1550-509X J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD JAN-FEB PY 2015 VL 30 IS 1 BP E26 EP E33 DI 10.1097/HTR.0000000000000046 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA AY8BW UT WOS:000347780400004 ER PT J AU Nguyen, R Dombi, E Akshintala, S Baldwin, A Widemann, BC AF Nguyen, Rosa Dombi, Eva Akshintala, Srivandana Baldwin, Andrea Widemann, Brigitte C. TI Characterization of spinal findings in children and adults with neurofibromatosis type 1 enrolled in a natural history study using magnetic resonance imaging SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Neurofibromatosis type 1; Plexiform neurofibroma; Spinal MRI; Spinal neurofibroma ID MRI; TUMORS; SCOLIOSIS; STENOSIS; AGE AB To characterize spinal abnormalities in patients with neurofibromatosis type 1 (NF1) using magnetic resonance imaging (MRI). NF1 patients with at least one spine MRI were selected from participants prospectively enrolled in the National Cancer Institute NF1 Natural History Study. Data were analyzed retrospectively. Ninety-seven patients (38 females, median age 14.2 years, standard deviation [SD] 7.6) had baseline imaging of the spine, and 26 patients (27 %) had one follow-up spine MRI (follow up time 2.5 years, SD 1.1, range 0.7-4.7). Seventy-eight patients (80 %) had spinal neurofibromas, with rising frequency from 70 % in patients younger than 10 years to 80 % in patients aged 10-18 years to 89 % in individuals older than 18 years of age. At baseline, 33/97 patients (34 %) had MRI changes consistent with spinal cord compression that was most prevalent at the cervical (43 %) and lumbar spine region (40 %). Seven of nine patients with progression of their spinal neurofibromas developed cord compression. Paraspinal plexiform neurofibromas (PNs) were present in 77/97 patients (79 %), of which 68 patients (88 %) had concomitant spinal neurofibromas. Spinal curvature abnormality was present in 50/97 patients (51 %, 20 females, median age 14.6 years, SD 7.6). Patients with paraspinal PNs had six-fold higher odds of developing spinal curvature abnormalities compared to patients without PN (OR = 5.9, 95 % CI 1.81 to 19.44, p = 0.0033). A total of 58/97 patients (60 %, median age 16.1 years, SD 7.8, range 4.8-48.2 years) presented with neurologic abnormalities that progressed in 12/26 patients (46 %). Substantial spinal neurofibroma and paraspinal PN burden was observed in our study population, which represents a selective group of patients with specifically more severe tumor involvement than the general NF1 population. Occurrence and progression of spinal neurofibromas on repeat evaluations highlight the need for longitudinal clinical monitoring in patients with known spinal disease. C1 [Nguyen, Rosa] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Nguyen, Rosa] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. [Nguyen, Rosa; Dombi, Eva; Akshintala, Srivandana; Baldwin, Andrea; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Nguyen, R (reprint author), St Jude Childrens Res Hosp, Dept Oncol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM rosi.nguyen@gmail.com FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank the patients and their families for participating in the NF1 natural history study and Natasha Brunson for her assistance with the data management. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2015 VL 121 IS 1 BP 209 EP 215 DI 10.1007/s11060-014-1629-5 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AY9UE UT WOS:000347895100024 PM 25293439 ER PT J AU Romero, R Miranda, J Kusanovic, JP Chaiworapongsa, T Chaemsaithong, P Martinez, A Gotsch, F Dong, Z Ahmed, AI Shaman, M Lannaman, K Yoon, BH Hassan, SS Kim, CJ Korzeniewski, SJ Yeo, LM Kim, YM AF Romero, Roberto Miranda, Jezid Kusanovic, Juan P. Chaiworapongsa, Tinnakorn Chaemsaithong, Piya Martinez, Alicia Gotsch, Francesca Dong, Zhong Ahmed, Ahmed I. Shaman, Majid Lannaman, Kia Yoon, Bo Hyun Hassan, Sonia S. Kim, Chong J. Korzeniewski, Steven J. Yeo, Lami Kim, Yeon Mee TI Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE funisitis; Gardnerella vaginalis; histologic chorioamnionitis; intra-amniotic infection/inflammation; microbial invasion of the amniotic cavity (MIAC); PCR/ESI-MS; pregnancy; sterile inflammation; ureaplasma urealyticum ID PRETERM PREMATURE RUPTURE; POLYMERASE-CHAIN-REACTION; FLUID INTERLEUKIN-6 LEVELS; BLOOD-CELL COUNT; POSTCESAREAN DELIVERY ENDOMETRITIS; INFLAMMATORY RESPONSE SYNDROME; UREAPLASMA-UREALYTICUM; INTRAAMNIOTIC INFECTION; MYCOPLASMA-HOMINIS; INTACT MEMBRANES AB Introduction: The objectives of this study were: 1) to determine the amniotic fluid (AF) microbiology of patients with the diagnosis of clinical chorioamnionitis at term using both cultivation and molecular techniques; and 2) to examine the relationship between intra-amniotic inflammation with and without microorganisms and placental lesions consistent with acute AF infection. Methods: The AF samples obtained by transabdominal amniocentesis from 46 women with clinical signs of chorioamnionitis at term were analyzed using cultivation techniques (for aerobic and anerobic bacteria as well as genital mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). The frequency of microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation [defined as an AF interleukin 6 (IL-6) concentration = 2.6 ng/mL], and placental lesions consistent with acute AF infection (acute histologic chorioamnionitis and/or acute funisitis) were examined according to the results of AF cultivation and PCR/ESI-MS as well as AF IL-6 concentrations. Results: 1) Culture identified bacteria in AF from 46% (21/46) of the participants, whereas PCR/ESI-MS was positive for microorganisms in 59% (27/46) - combining these two tests, microorganisms were detected in 61% (28/46) of patients with clinical chorioamnionitis at term. Eight patients had discordant test results; one had a positive culture and negative PCR/ESI-MS result, whereas seven patients had positive PCR/ESI-MS results and negative cultures. 2) Ureaplasma urealyticum (n = 8) and Gardnerella vaginalis (n = 10) were the microorganisms most frequently identified by cultivation and PCR/ESI-MS, respectively. 3) When combining the results of AF culture, PCR/ESI-MS and AF IL-6 concentrations, 15% (7/46) of patients did not have intra-amniotic inflammation or infection, 6.5% (3/46) had only MIAC, 54% (25/46) had microbial-associated intra-amniotic inflammation, and 24% (11/46) had intra-amniotic inflammation without detectable microorganisms. 4) Placental lesions consistent with acute AF infection were significantly more frequent in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [70.8% (17/24) vs. 28.6% (2/7); P = 0.04]. Conclusion: Microorganisms in the AF were identified in 61% of patients with clinical chorioamnionitis at term; 54% had microbial-associated intra-amniotic inflammation, whereas 24% had intra-amniotic inflammation without detectable microorganisms. C1 [Miranda, Jezid; Kusanovic, Juan P.; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Martinez, Alicia; Gotsch, Francesca; Dong, Zhong; Ahmed, Ahmed I.; Shaman, Majid; Lannaman, Kia; Hassan, Sonia S.; Kim, Chong J.; Korzeniewski, Steven J.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Miranda, Jezid; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Martinez, Alicia; Dong, Zhong; Ahmed, Ahmed I.; Shaman, Majid; Lannaman, Kia; Hassan, Sonia S.; Korzeniewski, Steven J.; Yeo, Lami] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan P.] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Santiago, Chile. [Kusanovic, Juan P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Chaiworapongsa, Tinnakorn; Gotsch, Francesca; Hassan, Sonia S.; Kim, Chong J.; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Yeo, Lami] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA. [Gotsch, Francesca] Azienda Osped Univ, Integrata Verona, Verona, Italy. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Kim, Chong J.] Univ Ulsan, Coll Med, Dept Pathol, Asan Med Ctr, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; ykim.haeundae@gmail.com NR 229 TC 26 Z9 27 U1 0 U2 9 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JAN PY 2015 VL 43 IS 1 BP 19 EP 36 DI 10.1515/jpm-2014-0249 PG 18 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AZ0TN UT WOS:000347957900004 PM 25720095 ER PT J AU Solomon, SS Mehta, SH SriKrishnan, AK Solomon, S McFall, AM Laeyendecker, O Celentano, DD Iqbal, SH Anand, S Vasudevan, CK Saravanan, S Lucas, GM Kumar, MS Sulkowski, MS Quinn, TC AF Solomon, Sunil Suhas Mehta, Shruti H. SriKrishnan, Aylur K. Solomon, Suniti McFall, Allison M. Laeyendecker, Oliver Celentano, David D. Iqbal, Syed H. Anand, Santhanam Vasudevan, Canjeevaram K. Saravanan, Shanmugam Lucas, Gregory M. Kumar, Muniratnam S. Sulkowski, Mark S. Quinn, Thomas C. TI Burden of hepatitis C virus disease and access to hepatitis C virus services in people who inject drugs in India: a cross-sectional study SO LANCET INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; ANTIVIRAL THERAPY; HCV INFECTION; SOFOSBUVIR; USERS; EPIDEMIOLOGY; PREVALENCE; PREVENTION; MORTALITY; BARRIERS AB Background 90% of individuals infected with hepatitis C virus (HCV) worldwide reside in resource-limited settings. We aimed to characterise the prevalence of HCV, HIV/HCV co-infection, and the HCV care continuum in people who inject drugs in India. Methods 14 481 people (including 31 seeds individuals selected as the starting point for sampling because they were well connected in the drug using community) who inject drugs were sampled from 15 cities throughout India using respondent-driven sampling from Jan 2, 2013 to Dec 19, 2013. Data from seeds were excluded from all analyses. HCV prevalence was estimated by the presence of anti-HCV antibodies incorporating respondent-driven sampling weights. HCV care continuum outcomes were self-reported except for viral clearance in treatment-experienced participants. Findings The median age of participants was 30 years (IQR 24-36) and 13 608 (92.4%) of 14 449 were men (data were missing for some variables). Weighted HCV prevalence was 5777 (37.2%) of 14447; HIV/HCV co-infection prevalence was 2085 (13-2%) of 14435. Correlates of HCV infection included high lifetime injection frequency, HIV positivity, and a high prevalence of people with HIV RNA (more than 1000 copies per mL) in the community. Of the 5777 people who inject drugs that were HCV antibody positive, 440 (5.5%) were aware of their status, 225 (3.0%) had seen a doctor for their HCV, 79 (1.4%) had taken HCV treatment, and 18 (0.4%) had undetectable HCV RNA. Of 12 128 participants who had not previously been tested for HCV, 6138 (50.5%) did not get tested because they had not heard of HCV. In the 5777 people who were HCV antibody positive, 2086 (34.4%) reported harmful or hazardous alcohol use, of whom 1082 (50.4%) were dependent, and 3821 (65.3%) reported needle sharing. Awareness of HCV positive status was significantly associated with higher education, HIV testing history, awareness of HIV positive status, and higher community antiretroviral therapy coverage. Interpretation The high burden of HCV and HIV/HCV co-infection coupled with low-access to HCV services emphasises an urgent need to include resource-limited settings in the global HCV agenda. Although new treatments will become available worldwide in the near future, programmes to improve awareness and reduce disease progression and transmission need to be scaled up without further delay. Failure to do so could result in patterns of rising mortality, undermining advances in survival attributed to widespread HIV treatment. C1 [Solomon, Sunil Suhas; Laeyendecker, Oliver; Lucas, Gregory M.; Sulkowski, Mark S.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Solomon, Sunil Suhas; Mehta, Shruti H.; McFall, Allison M.; Celentano, David D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Solomon, Sunil Suhas; SriKrishnan, Aylur K.; Solomon, Suniti; Iqbal, Syed H.; Anand, Santhanam; Vasudevan, Canjeevaram K.; Saravanan, Shanmugam; Kumar, Muniratnam S.] YR Gaitonde Ctr AIDS Res & Educ, Madras, Tamil Nadu, India. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Solomon, SS (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. EM sss@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU US National Institutes of Health FX Funding US National Institutes of Health NR 32 TC 24 Z9 24 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JAN PY 2015 VL 15 IS 1 BP 36 EP 45 DI 10.1016/S1473-3099(14)71045-X PG 10 WC Infectious Diseases SC Infectious Diseases GA AY9GD UT WOS:000347857900026 PM 25486851 ER PT J AU Checkley, W White, AC Jaganath, D Arrowood, MJ Chalmers, RM Chen, XM Fayer, R Griffiths, JK Guerrant, RL Hedstrom, L Huston, CD Kotloff, KL Kang, G Mead, JR Miller, M Petri, WA Priest, JW Roos, DS Striepen, B Thompson, RCA Ward, HD Van Voorhis, WA Xiao, LH Zhu, G Houpt, ER AF Checkley, William White, A. Clinton, Jr. Jaganath, Devon Arrowood, Michael J. Chalmers, Rachel M. Chen, Xian-Ming Fayer, Ronald Griffiths, Jeffrey K. Guerrant, Richard L. Hedstrom, Lizbeth Huston, Christopher D. Kotloff, Karen L. Kang, Gagandeep Mead, Jan R. Miller, Mark Petri, William A., Jr. Priest, Jeffrey W. Roos, David S. Striepen, Boris Thompson, R. C. Andrew Ward, Honorine D. Van Voorhis, Wesley A. Xiao, Lihua Zhu, Guan Houpt, Eric R. TI A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium SO LANCET INFECTIOUS DISEASES LA English DT Review ID INOSINE 5'-MONOPHOSPHATE DEHYDROGENASE; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; SYSTEMIC ANTIBODY-RESPONSES; INTESTINAL EPITHELIAL-CELLS; RANDOMIZED CONTROLLED-TRIAL; EARLY-CHILDHOOD DIARRHEA; MANNOSE-BINDING LECTIN; NATURAL-KILLER-CELLS; TIME PCR DETECTION; PARVUM INFECTION AB Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances. C1 [Checkley, William; Jaganath, Devon] Johns Hopkins Univ, Dept Int Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. [Checkley, William; Miller, Mark] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [White, A. Clinton, Jr.] Univ Texas Med Branch, Div Infect Dis, Galveston, TX 77555 USA. [Arrowood, Michael J.; Priest, Jeffrey W.; Xiao, Lihua] Ctr Dis Control & Prevent, Atlanta, GA USA. [Chalmers, Rachel M.] Publ Hlth Wales, Natl Cryptosporidium Reference Unit, Swansea, W Glam, Wales. [Chen, Xian-Ming] Creighton Univ, Dept Med Microbiol & Immunol, Omaha, NE 68178 USA. [Fayer, Ronald] USDA, Environm Microbial Food Safety Lab, Beltsville, MD 20705 USA. [Griffiths, Jeffrey K.] Tufts Univ, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Guerrant, Richard L.; Petri, William A., Jr.; Houpt, Eric R.] Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA. [Hedstrom, Lizbeth] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. [Hedstrom, Lizbeth] Brandeis Univ, Dept Chem, Waltham, MA 02254 USA. [Huston, Christopher D.] Univ Vermont, Div Infect Dis, Burlington, VT USA. [Kotloff, Karen L.] Univ Maryland, Sch Med, Div Infect Dis & Trop Pediat, Dept Pediat,Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Kang, Gagandeep] Christian Med Coll & Hosp, Div Gastrointestinal Sci, Vellore, Tamil Nadu, India. [Mead, Jan R.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Mead, Jan R.] Atlanta VA Med Ctr, Decatur, GA USA. [Roos, David S.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Striepen, Boris] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA. [Thompson, R. C. Andrew] Murdoch Univ, Sch Vet & Life Sci, Perth, WA, Australia. [Ward, Honorine D.] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA USA. [Van Voorhis, Wesley A.] Univ Washington, Dept Med, Allergy & Infect Dis Div, Seattle, WA USA. [Van Voorhis, Wesley A.] Univ Washington, Allergy & Infect Dis Div, Dept Global Hlth, Seattle, WA 98195 USA. [Van Voorhis, Wesley A.] Univ Washington, Dept Microbiol, Allergy & Infect Dis Div, Seattle, WA 98195 USA. [Zhu, Guan] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX USA. RP Checkley, W (reprint author), Johns Hopkins Univ, Sch Med, Suite 9121,1800 Orleans Ave, Baltimore, MD 21205 USA. EM wcheckl1@jhmi.edu RI Xiao, Lihua/B-1704-2013; OI Xiao, Lihua/0000-0001-8532-2727; White, A Clinton/0000-0002-9668-4632; Striepen, Boris/0000-0002-7426-432X FU Bill & Melinda Gates Foundation FX We acknowledge all speakers who attended the meeting Cryptosporidium: Global Burden, Novel Diagnostics, Therapeutics and Vaccine Targets, held in Philadelphia, PA, USA, in December, 2011. We received financial support from the Bill & Melinda Gates Foundation; our funding source did not have a role in the development of this Review. The findings and conclusions in this Review are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 148 TC 72 Z9 74 U1 15 U2 64 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JAN PY 2015 VL 15 IS 1 BP 85 EP 94 DI 10.1016/S1473-3099(14)70772-8 PG 10 WC Infectious Diseases SC Infectious Diseases GA AY9GD UT WOS:000347857900031 PM 25278220 ER PT J AU Rosean, TR Tompkins, VS Olivier, AK Sompallae, R Norian, LA Morse, HC Waldschmidt, TJ Janz, S AF Rosean, T. R. Tompkins, V. S. Olivier, A. K. Sompallae, R. Norian, L. A. Morse, H. C., III Waldschmidt, T. J. Janz, S. TI The tumor microenvironment is the main source of IL-6 for plasma cell tumor development in mice SO LEUKEMIA LA English DT Letter ID BONE-MARROW MICROENVIRONMENT; MULTIPLE-MYELOMA; MONOCLONAL GAMMOPATHY; PLASMACYTOMAS; INTERLEUKIN-6; INHIBITION; MYC C1 [Rosean, T. R.; Norian, L. A.; Waldschmidt, T. J.; Janz, S.] Univ Iowa, Interdisciplinary Grad Program Immunol, Iowa City, IA 52242 USA. [Tompkins, V. S.; Olivier, A. K.; Sompallae, R.; Waldschmidt, T. J.; Janz, S.] UI Carver Coll Med, Dept Pathol, Iowa City, IA USA. [Sompallae, R.] UI Carver Coll Med, Bioinformat Core Facil, Iowa City, IA USA. [Norian, L. A.] UI Carver Coll Med, Dept Urol, Iowa City, IA USA. [Morse, H. C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rosean, TR (reprint author), Univ Iowa, Interdisciplinary Grad Program Immunol, Iowa City, IA 52242 USA. EM siegfried-janz@uiowa.edu OI Tompkins, Van/0000-0003-1279-8075 FU NCI NIH HHS [P30 CA086862, P30CA086862, P50 CA097274, P50CA097274, R01 CA151354, R01CA151354]; NHLBI NIH HHS [T32 HL007344]; NIAID NIH HHS [T32 AI007485, 5T32 AI007485] NR 15 TC 10 Z9 10 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2015 VL 29 IS 1 BP 233 EP 237 DI 10.1038/leu.2014.260 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AY6JX UT WOS:000347673700026 PM 25257990 ER PT J AU Tomei, S Bedognetti, D De Giorgi, V Sommariva, M Civini, S Reinboth, J Al Hashmi, M Ascierto, ML Liu, QZ Ayotte, BD Worschech, A Uccellini, L Ascierto, PA Stroncek, D Palmieri, G Chouchane, L Wang, E Marincola, FM AF Tomei, Sara Bedognetti, Davide De Giorgi, Valeria Sommariva, Michele Civini, Sara Reinboth, Jennifer Al Hashmi, Muna Ascierto, Maria Libera Liu, Qiuzhen Ayotte, Ben D. Worschech, Andrea Uccellini, Lorenzo Ascierto, Paolo A. Stroncek, David Palmieri, Giuseppe Chouchane, Lotfi Wang, Ena Marincola, Francesco M. TI The immune-related role of BRAF in melanoma SO MOLECULAR ONCOLOGY LA English DT Article DE BRAF; NRAS; Melanoma; Immune phenotype ID PROTEIN-KINASE ACTIVATION; GENE-EXPRESSION SIGNATURE; N-RAS ONCOGENE; METASTATIC MELANOMA; TARGETED THERAPY; B-RAF; CANCER-IMMUNOTHERAPY; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; SIGNALING PATHWAY AB Background: The existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NAAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAP and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group. Methods: One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. Results: Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy,such association was stronger in samples displaying low BRAY mRNA expression. However, when testing NAAS mutations, we were not able to find the same association. Conclusion: This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Tomei, Sara; Bedognetti, Davide; De Giorgi, Valeria; Sommariva, Michele; Reinboth, Jennifer; Ascierto, Maria Libera; Liu, Qiuzhen; Uccellini, Lorenzo; Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Tomei, Sara; Bedognetti, Davide; De Giorgi, Valeria; Sommariva, Michele; Reinboth, Jennifer; Ascierto, Maria Libera; Liu, Qiuzhen; Uccellini, Lorenzo; Wang, Ena; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Tomei, Sara; Worschech, Andrea; Chouchane, Lotfi] Weill Cornell Med Coll Qatar, Dept Genet Med, Doha, Qatar. [Tomei, Sara; Bedognetti, Davide; Al Hashmi, Muna; Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Sommariva, Michele] Univ Milan, Dept Biomed Sci & Hlth, Milan, Italy. [Civini, Sara; Stroncek, David] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Civini, Sara; Stroncek, David] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Reinboth, Jennifer] Univ Wurzburg, Dept Biochem, Bioctr, D-97074 Wurzburg, Germany. [Reinboth, Jennifer] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. [Ascierto, Maria Libera] Univ Genoa, CEBR, I-16126 Genoa, Italy. [Ayotte, Ben D.] No Michigan Univ, Dept Biol, Marquette, MI 49855 USA. [Uccellini, Lorenzo] Univ Milan, Inst Infect & Trop Dis, L Sacco Hosp, Milan, Italy. [Ascierto, Paolo A.] Ist Nazl Tumori Fdn G Pascale, Naples, Italy. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Sassari, Italy. RP Tomei, S (reprint author), Qatar Fdn, Sidra Med & Res Ctr, Al Nasr Tower,Al Corniche St,PO 26999, Doha, Qatar. EM stomei@sidra.org RI De Giorgi, Valeria/D-4582-2017; Sommariva, Michele/C-1174-2017 OI Bedognetti, Davide/0000-0002-5857-773X; Palmieri, Giuseppe/0000-0002-4350-2276; Sommariva, Michele/0000-0002-7622-0996 FU Intramural Research Program of the National Institutes of Health (NIH); Fondazione Melanoma Onlus, Naples, Italy; Sidra Medical and Research Center, Doha, Qatar FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH); all NIH affiliated authors performed this work as part of their official duties. The study was supported in part by Fondazione Melanoma Onlus, Naples, Italy and Sidra Medical and Research Center, Doha, Qatar. NR 55 TC 10 Z9 10 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD JAN PY 2015 VL 9 IS 1 BP 93 EP 104 DI 10.1016/j.molonc.2014.07.014 PG 12 WC Oncology SC Oncology GA AY9IL UT WOS:000347863700008 PM 25174651 ER PT J AU Fratta, P Polke, JM Newcombe, J Mizielinska, S Lashley, T Poulter, M Beck, J Preza, E Devoy, A Sidle, K Howard, R Malaspina, A Orrell, RW Clarke, J Lu, CH Mokj, K Collins, T Shoaii, M Nanji, T Wray, S Adamson, G Pittman, A Renton, AE Traynor, BJ Sweeney, MG Revesz, T Houlden, H Mead, S Isaacs, AM Fisher, EMC AF Fratta, Pietro Polke, James M. Newcombe, Jia Mizielinska, Sarah Lashley, Tammaryn Poulter, Mark Beck, Jon Preza, Elisavet Devoy, Anny Sidle, Katie Howard, Robin Malaspina, Andrea Orrell, Richard W. Clarke, Jan Lu, Ching-Hua Mok, Kin Collins, Toby Shoaii, Maryam Nanji, Tina Wray, Selina Adamson, Gary Pittman, Alan Renton, Alan E. Traynor, Bryan J. Sweeney, Mary G. Revesz, Tamas Houlden, Henry Mead, Simon Isaacs, Adrian M. Fisher, Elizabeth M. C. TI Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion SO NEUROBIOLOGY OF AGING LA English DT Article DE Frontotemporal dementia; Somatic instability; Amyotrophic lateral sclerosis ID FRONTOTEMPORAL LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT EXPANSIONS; DEMENTIA; MUTATION; ALS; DISEASE; FTD; FREQUENT; RNA AB An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions > 500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD. (C) 2015 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Fratta, Pietro; Mizielinska, Sarah; Poulter, Mark; Beck, Jon; Devoy, Anny; Collins, Toby; Adamson, Gary; Mead, Simon; Isaacs, Adrian M.; Fisher, Elizabeth M. C.] UCL, Dept Neurodegenerat Dis, London WC1N 3BG, England. [Fratta, Pietro; Orrell, Richard W.; Fisher, Elizabeth M. C.] UCL, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Polke, James M.; Nanji, Tina; Sweeney, Mary G.; Houlden, Henry] Neurogenet Unit, London, England. [Newcombe, Jia] UCL, Inst Neurol, NeuroResource, London WC1N 3BG, England. [Lashley, Tammaryn; Revesz, Tamas] UCL, Queen Sq Brain Bank Neurol Disorders, London WC1N 3BG, England. [Poulter, Mark; Beck, Jon; Adamson, Gary] UCL, MRC Prion Unit, London WC1N 3BG, England. [Preza, Elisavet; Sidle, Katie; Orrell, Richard W.; Shoaii, Maryam; Wray, Selina; Pittman, Alan; Houlden, Henry] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Sidle, Katie; Howard, Robin; Malaspina, Andrea; Orrell, Richard W.; Clarke, Jan] Natl Hosp Neurol & Neurosurg, London WC1N 3BG, England. [Lu, Ching-Hua] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Neurosci & Trauma, London, England. [Lu, Ching-Hua; Mok, Kin] UCL, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Renton, Alan E.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Fratta, P (reprint author), UCL, Dept Neurodegenerat Dis, Queen Sq, London WC1N 3BG, England. EM p.fratta@ucl.ac.uk; James.Polke@uclh.nhs.uk; e.fisher@prion.ucl.ac.uk RI Pittman, Alan/D-6231-2012; Lashley, Tammaryn/D-2583-2009; Mok, Kin/F-5860-2012; Houlden, Henry/C-1532-2008; Revesz, Tamas/A-8732-2010; OI Houlden, Henry/0000-0002-2866-7777; Revesz, Tamas/0000-0003-2501-0259; Devoy, Anny/0000-0002-1293-0630; Wray, Selina/0000-0003-3062-7050 FU Medical Research Council; Medical Research Council/Motor Neurone Disease Association LEW Fellowship; NIHR-UCLH-Biomedical Research Centre; Thierry Latran Foundation; Motor Neurone Disease Association; Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme; Alzheimer's Research Fellowship FX This work was supported by the Medical Research Council (Mark Poulter, Simon Mead, and Elizabeth M. C. FIsher), Medical Research Council/Motor Neurone Disease Association LEW Fellowship (Pietro Fratta), NIHR-UCLH-Biomedical Research Centre (Pietro Fratta), Thierry Latran Foundation (Elizabeth Fisher), Motor Neurone Disease Association (Adrian M. Isaacs, Elizabeth Fisher, and Richard Orrell). Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. Tammaryn Lashley is funded by an Alzheimer's Research Fellowship. NR 33 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2015 VL 36 IS 1 AR 546.e1 DI 10.1016/j.neurobiolaging.2014.07.037 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AY2HD UT WOS:000347408600059 PM 25179228 ER PT J AU Ghani, M Lang, AE Zinman, L Nacmias, B Sorbi, S Bessi, V Tedde, A Tartaglia, MC Surace, EI Sato, C Moreno, D Xi, ZR Hung, R Nalls, MA Singleton, A St George-Hyslop, P Rogaeva, E AF Ghani, Mahdi Lang, Anthony E. Zinman, Lorne Nacmias, Benedetta Sorbi, Sandro Bessi, Valentina Tedde, Andrea Tartaglia, Maria Carmela Surace, Ezequiel I. Sato, Christine Moreno, Danielle Xi, Zhengrui Hung, Rachel Nalls, Mike A. Singleton, Andrew St George-Hyslop, Peter Rogaeva, Ekaterina TI Mutation analysis of patients with neurodegenerative disorders using NeuroX array SO NEUROBIOLOGY OF AGING LA English DT Article DE NeuroX; Mutation; Neurodegenerative disorder ID ONSET ALZHEIMERS-DISEASE; AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONS-DISEASE; GENE-MUTATIONS; SOD1 MUTATION; ASSOCIATION; PHENOTYPE; VARIANTS; GENOME; TREM2 AB Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e. g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p. M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p. A4V and p. I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency < 1%), including ABCA7 p. L400V in a family with Alzheimer's disease and LRRK2 p. R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ghani, Mahdi; Lang, Anthony E.; Tartaglia, Maria Carmela; Sato, Christine; Moreno, Danielle; Xi, Zhengrui; Hung, Rachel; St George-Hyslop, Peter; Rogaeva, Ekaterina] Univ Toronto, Tanz Ctr Neurodegenerat Dis, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Univ Toronto, Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Ctr, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Univ Toronto, Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.; Zinman, Lorne; Tartaglia, Maria Carmela; St George-Hyslop, Peter; Rogaeva, Ekaterina] Univ Toronto, Dept Med, Div Neurol, Toronto, ON M5T 2S8, Canada. [Zinman, Lorne] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Nacmias, Benedetta; Sorbi, Sandro; Bessi, Valentina; Tedde, Andrea] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth NEURO, Florence, Italy. [Surace, Ezequiel I.] Consejo Nacl Invest Cient & Tecn CONICET, Mol Biol Lab, Inst Invest Neurol Dr Raul Carrea FLENI, Buenos Aires, DF, Argentina. [Nalls, Mike A.; Singleton, Andrew] NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge, England. RP St George-Hyslop, P (reprint author), Univ Toronto, Tanz Ctr Neurodegenerat Dis, 60 Leonard Ave, Toronto, ON M5T 2S8, Canada. EM p.hyslop@utoronto.ca; ekaterina.rogaeva@utoronto.ca RI Singleton, Andrew/C-3010-2009; OI NACMIAS, Benedetta/0000-0001-9338-9040; sorbi, sandro/0000-0002-0380-6670 FU Canadian Institutes of Health Research; Ontario Research Fund; W. Garfield Weston Foundation; Intramural Research Program of the National Institute on Aging; National Institutes of Health (NIH), part of the Department of Health and Human Services [ZO1 AG000958-11]; Cassa di Risparmio di Pistoia e Pescia [CRPT 2013/0347]; Cassa di Risparmio di Firenze [CRF 2013/0199]; Ministry of Health [RF-2010-2319722]; PRIN [2010PWNJXK] FX This work was supported by grants from the Canadian Institutes of Health Research, Ontario Research Fund, the W. Garfield Weston Foundation (Ekaterina Rogaeva and Peter St George-Hyslop); the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH), part of the Department of Health and Human Services; project number ZO1 AG000958-11 (Andrew Singleton); the Cassa di Risparmio di Pistoia e Pescia # CRPT 2013/0347, the Cassa di Risparmio di Firenze # CRF 2013/0199, Ministry of Health # RF-2010-2319722 and # PRIN 2010PWNJXK (Benedetta Nacmias and Sandro Sorbi). NR 40 TC 5 Z9 5 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2015 VL 36 IS 1 DI 10.1016/j.neurobiolaging.2014.07.038 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AY2HD UT WOS:000347408600058 ER PT J AU Massey, SH Estabrook, R O'Brien, TC Pine, DS Burns, JL Jacob, S Cook, EH Wakschlag, LS AF Massey, Suena H. Estabrook, Ryne O'Brien, T. Caitlin Pine, Daniel S. Burns, James L. Jacob, Suma Cook, Edwin H. Wakschlag, Lauren S. TI Preliminary evidence for the interaction of the oxytocin receptor gene (oxtr) and face processing in differentiating prenatal smoking patterns SO NEUROSCIENCE LETTERS LA English DT Article DE Pregnancy smoking; Oxytocin receptor gene; Social cognition; Nonverbal accuracy; Cognitive empathy; Differential susceptibility ID MATERNAL SMOKING; FACIAL EXPRESSIONS; PREGNANCY SMOKING; LUNG-FUNCTION; METAANALYSIS; CESSATION; BEHAVIOR; PSYCHOPATHOLOGY; SUSCEPTIBILITY; POLYMORPHISM AB Prenatal smoking cessation has been described as an empathic action "for the baby," but this has not been empirically demonstrated. We capitalized on a genetically-characterized extant dataset with outstanding measurement of prenatal smoking patterns and maternal face processing data (as an indicator of empathy) to test this hypothesis, and explore how empathy and smoking patterns may be moderated by a genetic substrate of empathy, the oxytocin receptor gene (OXTR). Participants were 143Caucasian women from the East Boston family study with repeated prospective reports of smoking level, adjusted based on repeated cotinine bioassays. Salivary DNA and face processing (Diagnostic Analysis of Nonverbal Accuracy-2) were assessed 14 years later at an adolescent follow-up of offspring. Two-thirds of participants reported smoking prior to pregnancy recognition. Of these, 21% quit during pregnancy; 56% reduced smoking, and 22% smoked persistently at the same level. A significant interaction between face processing and OXTR variants previously associated with increased sensitivity to social context, rs53576GG and rs2254298A, was found (beta =-.181; p =.015); greater ability to identify distress in others was associated with lower levels of smoking during pregnancy for rs53576(GG)/rs2254298(A) individuals (p = .013), but not for other genotypes (p = .892). Testing this "empathy hypothesis of prenatal smoking cessation" in larger studies designed to examine this question can elucidate whether interventions to enhance empathy can improve prenatal smoking cessation rates. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Massey, Suena H.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Massey, Suena H.; Estabrook, Ryne; Burns, James L.; Wakschlag, Lauren S.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [O'Brien, T. Caitlin] Illinois Coll, Dept Psychol, Jacksonville, IL 62650 USA. [Pine, Daniel S.] NIMH, Lab Affect & Dev Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. [Jacob, Suma] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55454 USA. [Cook, Edwin H.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Wakschlag, Lauren S.] Northwestern Univ, Inst Policy Res, Evanston, IL 60208 USA. RP Massey, SH (reprint author), 676 North St Clair St,Suite 1000, Chicago, IL 60611 USA. EM suena.massey@northwestern.edu; restabrook@northwestern.edu; tcobrien@northwestern.edu; pined@mail.nih.gov; james-l-burns@northwestern.edu; sjacob@umn.edu; edcook@uic.edu; lauriew@northwestern.edu OI Cook, Edwin/0000-0002-5848-5114; Jacob, Suma/0000-0001-7434-7398 FU National Institute on Drug Abuse (NIDA) [R01 DA015223, R01 DA023653-01A2, R01 DA023653-03S1]; Walden & Jean Young Shaw Foundation; Northwestern Memorial Foundation FX Work was supported by grants R01 DA015223, R01 DA023653-01A2, and R01 DA023653-03S1 from the National Institute on Drug Abuse (NIDA) (PI: Lauren Wakschlag), the Walden & Jean Young Shaw Foundation (PI: Lauren Wakschlag), and the Northwestern Memorial Foundation (PI: Suena Massey). Funding sources had no role in the design, collection, analysis or interpretation of data, writing the manuscript, or the decision to submit results for publication. We are deeply appreciative of the expertise provided by Vanja Dukic, PhD, and Kate Pickett, PhD, and editorial assistance by Stephanie Schuette, BA. NR 46 TC 5 Z9 5 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 1 PY 2015 VL 584 BP 259 EP 264 DI 10.1016/j.neulet.2014.10.049 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AY4XS UT WOS:000347579000049 PM 25450139 ER PT J AU Raineri, M Gonzalez, B Rivero-Echeto, C Muniz, JA Gutierrez, ML Ghanem, CI Cadet, JL Garcia-Rill, E Urbano, FJ Bisagno, V AF Raineri, Mariana Gonzalez, Betina Rivero-Echeto, Celeste Muniz, Javier A. Laura Gutierrez, Maria Ghanem, Carolina I. Cadet, Jean Lud Garcia-Rill, Edgar Urbano, Francisco J. Bisagno, Veronica TI Differential Effects of Environment-Induced Changes in Body Temperature on Modafinil's Actions Against Methamphetamine-Induced Striatal Toxicity in Mice SO NEUROTOXICITY RESEARCH LA English DT Article DE Modafinil; Methamphetamine; Dopamine; Astroglia; Striatum; Toxicity ID INDUCED DOPAMINERGIC NEUROTOXICITY; SUBSTANCE USE DISORDERS; SUBSTITUTED AMPHETAMINES; CAUDATE-PUTAMEN; C57BL/6J MOUSE; NULL MUTATION; RAT STRIATUM; IN-VIVO; BRAIN; TRANSPORTER AB Methamphetamine (METH) exposure can produce hyperthermia that might lead to toxicity and death. Modafinil is a wake-promoting compound that is also been prescribed off-label to treat METH dependence. Modafinil has shown neuroprotective properties against METH harmful effects in animal models. The goal of the present study was to test if the prevention of hyperthermia might play a role on the neuroprotective actions of modafinil against METH toxicity using various ambient temperatures. METH was administered to female C57BL/6 mice in a binge regimen: 4 x 5 mg/kg, 2 h apart; modafinil (90 mg/kg) was injected twice, 1 h before first and fourth METH injections. Drugs were given at cold ambient temperature (14 A degrees C) or hot ambient temperature (29 A degrees C). Body temperature was measured during treatments. Brains were dissected out 6 days after treatments and processed for tyrosine hydroxylase (TH), dopamine transporter (DAT), GFAP and c-Fos immunohistochemistry. Exposure to hot ambient temperature exacerbated METH toxicity evidenced by striatal reductions in TH and DAT and increased GFAP immmunoreactivity. Modafinil counteracted reductions in TH and DAT, but failed to block astroglial activation. At both ambient temperatures tested modafinil did induce increments in GFAP, but the magnitude was significantly lower than the one induced by METH. Both drugs induced increases in c-Fos positive nuclei; modafinil did not block this effect. Our results suggest that protective effects of modafinil against METH-induced neurotoxicity may be dependent, in part, to its hypothermic effects. Nevertheless, modafinil maintained some protective properties on METH-induced alterations in the striatum at different ambient temperatures. C1 [Raineri, Mariana; Gonzalez, Betina; Muniz, Javier A.; Laura Gutierrez, Maria; Ghanem, Carolina I.; Bisagno, Veronica] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn ININFA UBA CONIC, Inst Invest Farmacol, RA-1113 Buenos Aires, DF, Argentina. [Rivero-Echeto, Celeste; Urbano, Francisco J.] Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn, Inst Fisiol Biol Mol & Neurociencias, Lab Fisiol & Biol Mol, RA-1113 Buenos Aires, DF, Argentina. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, Baltimore, MD USA. [Garcia-Rill, Edgar] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA. RP Bisagno, V (reprint author), Univ Buenos Aires, Consejo Nacl Invest Cient & Tecn ININFA UBA CONIC, Inst Invest Farmacol, Junin 956,Piso 5, RA-1113 Buenos Aires, DF, Argentina. EM vbisagno@ffyb.uba.ar OI Garcia-Rill, Edgar/0000-0003-1367-3071 FU Fundacion Bunge y Born; PIP, Argentina [11420100100072]; PICT, Argentina [2012-0924, 2012-1769]; NIH [P20 GM103425, P230 GM110702] FX Dr. Bisagno has been authorized to study drug abuse substances in animal models by A.N.M.A.T. (National Board of Medicine Food and Medical Technology, Ministerio de Salud, Argentina). Dr. Betina Gonzalez is a recipient of a Postdoctoral Award from Fundacion Bunge y Born. This work is supported by Grants PIP 11420100100072, PICT 2012-0924, PICT 2012-1769, Argentina, and by NIH awards P20 GM103425 and P230 GM110702 to the Center for Translational Neuroscience. NR 54 TC 1 Z9 1 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 EI 1476-3524 J9 NEUROTOX RES JI Neurotox. Res. PD JAN PY 2015 VL 27 IS 1 BP 71 EP 83 DI 10.1007/s12640-014-9493-9 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AY4NO UT WOS:000347555800007 PM 25261212 ER PT J AU Bouchard, C Antunes-Correa, LM Ashley, EA Franklin, N Hwang, PM Mattsson, CM Negrao, CE Phillips, SA Sarzynski, MA Wang, PY Wheeler, MT AF Bouchard, Claude Antunes-Correa, Ligia M. Ashley, Euan A. Franklin, Nina Hwang, Paul M. Mattsson, C. Mikael Negrao, Carlos E. Phillips, Shane A. Sarzynski, Mark A. Wang, Ping-yuan Wheeler, Matthew T. TI Personalized Preventive Medicine: Genetics and the Response to Regular Exercise in Preventive Interventionse SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Personalized medicine; Individual differences; Genetics; Mitochondria; Endothelium ID CHRONIC HEART-FAILURE; ALL-CAUSE MORTALITY; RANDOMIZED CONTROLLED-TRIAL; CORONARY-ARTERY-DISEASE; FLOW-MEDIATED DILATION; MAXIMAL AEROBIC POWER; WIDE LINKAGE SCAN; PHYSICAL-ACTIVITY; SKELETAL-MUSCLE; HERITAGE FAMILY AB Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bouchard, Claude; Sarzynski, Mark A.] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70806 USA. [Antunes-Correa, Ligia M.; Negrao, Carlos E.] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil. [Ashley, Euan A.; Mattsson, C. Mikael; Wheeler, Matthew T.] Stanford Univ, Div Cardiovasc Med, Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA. [Ashley, Euan A.; Wheeler, Matthew T.] Stanford Univ, Sch Med, Cardiovasc Inst, Stanford, CA 94305 USA. [Franklin, Nina; Phillips, Shane A.] Univ Illinois, Dept Med, Integrat Physiol Lab, Dept Phys Therapy, Chicago, IL USA. [Hwang, Paul M.; Wang, Ping-yuan] NHLBI, NIH, Bethesda, MD 20892 USA. [Mattsson, C. Mikael] Swedish Sch Sport & Hlth Sci, Stockholm, Sweden. [Negrao, Carlos E.] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo, Brazil. RP Bouchard, C (reprint author), Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70806 USA. EM claude.bouchard@pbrc.edu RI OCRC, FAPESP/K-1312-2015; Sarzynski, Mark/A-9798-2014; Bouchard, Claude/A-7637-2009; Negrao, Carlos /C-4281-2012 OI OCRC, FAPESP/0000-0003-4596-1043; FU National Institutes of Health [HL-45670]; Division of Intramural Research, National Heart, Lung, and Blood Institutes (NHLBI); Bench-to-Bedside of the National Institutes of Health; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo FAPESP [2013/15651-7, 2013/07607-8]; CNPq [301867/2010-0]; FAPESP [2013/07607-8, 2010/50048-1]; Fundacao Zerbini FX C Bouchard is partially supported by the John W. Barton, Sr. Chair in Genetics and Nutrition. Research on the HERITAGE Family Study was supported for over 20 years by the National Institutes of Health (HL-45670). PY Wang and PM Hwang are supported by the Division of Intramural Research, National Heart, Lung, and Blood Institutes (NHLBI) and by a Bench-to-Bedside of the National Institutes of Health. LM Antunes-Correa was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo FAPESP (2013/15651-7 and 2013/07607-8). CE Negrao was supported by CNPq (301867/2010-0), FAPESP (2010/50048-1 and 2013/07607-8), and, in part, by Fundacao Zerbini. NR 92 TC 8 Z9 8 U1 3 U2 18 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD JAN-FEB PY 2015 VL 57 IS 4 BP 337 EP 346 DI 10.1016/j.pcad.2014.08.005 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AZ1MU UT WOS:000348003900008 PM 25559061 ER PT J AU Zhang, X Belkina, N Jacob, HKC Maity, T Biswas, R Venugopalan, A Shaw, PG Kim, MS Chaerkady, R Pandey, A Guha, U AF Zhang, Xu Belkina, Natalya Jacob, Harrys Kishore Charles Maity, Tapan Biswas, Romi Venugopalan, Abhilash Shaw, Patrick G. Kim, Min-Sik Chaerkady, Raghothama Pandey, Akhilesh Guha, Udayan TI Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics SO PROTEOMICS LA English DT Article DE Autophagy; EGFR; Erlotinib; Mass spectrometry; NSCLC; Phosphoproteomics; SILAC ID HIGHLY SELECTIVE ENRICHMENT; PROTEIN PHOSPHATASE 2A; TITANIUM-DIOXIDE; POSTTRANSLATIONAL MODIFICATIONS; PHOSPHORYLATED PEPTIDES; CELL-CULTURE; AMINO-ACIDS; GEFITINIB; KINASE; RESISTANCE AB Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10-30% of lung adenocarcinoma and are associated with tyrosine kinase inhibitor (TKI) sensitivity. We sought to identify the immediate direct and indirect phosphorylation targets of mutant EGFRs in lung adenocarcinoma. We undertook SILAC strategy, phosphopeptide enrichment, and quantitative MS to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring EGFR(L858R) and EGFR(L858R/T790M), the TKI-sensitive, and TKI-resistant mutations, respectively. Top canonical pathways that were inhibited upon erlotinib treatment in sensitive cells, but not in the resistant cells include EGFR, insulin receptor, hepatocyte growth factor, mitogen-activated protein kinase, mechanistic target of rapamycin, ribosomal protein S6 kinase beta 1, and Janus kinase/signal transducer and activator of transcription signaling. We identified phosphosites in proteins of the autophagy network, such as ULK1 (S623) that is constitutively phosphorylated in these lung adenocarcinoma cells; phosphorylation is inhibited upon erlotinib treatment in sensitive cells, but not in resistant cells. Finally, kinase-substrate prediction analysis from our data indicated that substrates of basophilic kinases from, AGC and Calcium and calmodulin-dependent kinase groups, as well as STE group kinases were significantly enriched and those of proline-directed kinases from, CMGC and Casein kinase groups were significantly depleted among substrates that exhibited increased phosphorylation upon EGF stimulation and reduced phosphorylation upon TKI inhibition. This is the first study to date to examine global phosphorylation changes upon erlotinib treatment of lung adenocarcinoma cells and results from this study provide new insights into signaling downstream of mutant EGFRs in lung adenocarcinoma. All MS data have been deposited in the ProteomeXchange with identifier PXD001101 (http://proteomecentral.proteomexchange.org/dataset/PXD001101). C1 [Zhang, Xu; Belkina, Natalya; Maity, Tapan; Biswas, Romi; Venugopalan, Abhilash; Guha, Udayan] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Jacob, Harrys Kishore Charles] Inst Bioinformat, Bangalore, Karnataka, India. [Jacob, Harrys Kishore Charles; Shaw, Patrick G.; Kim, Min-Sik; Chaerkady, Raghothama; Pandey, Akhilesh] Johns Hopkins Univ, Dept Biol Chem, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Jacob, Harrys Kishore Charles] Manipal Univ, Manipal, Karnataka, India. [Pandey, Akhilesh] Johns Hopkins Univ, Dept Pathol, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Pandey, Akhilesh] Johns Hopkins Univ, Dept Oncol, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Guha, U (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM udayan.guha@nih.gov FU U.S. National Cancer Institute Center for Cancer Research (NCI-CCR) [ZIA BC 011410]; K99 Career Transition award [K99CA140792]; NIH [U54GM103520]; NCI's Clinical Proteomic Tumor Analysis Consortium initiative [U24CA160036]; National Heart, Lung and Blood Institute [HHSN268201000032C]; Council of Scientific and Industrial Research (CSIR), India FX This work was supported by U.S. National Cancer Institute Center for Cancer Research (NCI-CCR) Intramural Research Program ZIA BC 011410 (U.G.) and K99 Career Transition award (K99CA140792) (U.G.). The work was also supported in part by an NIH roadmap grant for Technology Centers of Networks and Pathways (U54GM103520), NCI's Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036), and a contract (HHSN268201000032C) from the National Heart, Lung and Blood Institute (A.P.). H.K.C.J. was a recipient of a Senior Research Fellowship from Council of Scientific and Industrial Research (CSIR), India. NR 58 TC 11 Z9 11 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD JAN PY 2015 VL 15 IS 2-3 SI SI BP 340 EP 355 DI 10.1002/pmic.201400315 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY9UI UT WOS:000347895500017 PM 25404012 ER PT J AU Kim, Y van Ryn, M Jensen, RE Griffin, JM Potosky, A Rowland, J AF Kim, Youngmee van Ryn, Michelle Jensen, Roxanne E. Griffin, Joan M. Potosky, Arnold Rowland, Julia TI Effects of gender and depressive symptoms on quality of life among colorectal and lung cancer patients and their family caregivers SO PSYCHO-ONCOLOGY LA English DT Article DE depressive symptoms; quality of life; dyadic adjustment; gender; cancer; oncology ID PSYCHOLOGICAL DISTRESS; SPOUSE CAREGIVERS; PSYCHOSOCIAL CARE; BREAST-CANCER; HEALTH; COMORBIDITY; TRAJECTORIES; METAANALYSIS; SURVIVORS; OUTCOMES AB ObjectiveCancer patients and their family caregivers often report elevated levels of depressive symptoms, along with poorer mental and physical health (quality of life: QOL). Although the mutuality in distress between patients and their caregivers is relatively well known, unknown are the degree to which caregivers' depressive symptoms independently predict their patient's QOL and vice versa, and whether the relations vary by cancer type or gender. MethodsColorectal or lung cancer patients and their caregivers (398 dyads) provided complete data for study variables (212 colorectal cancer patient dyads, 186 lung cancer patient dyads; 257 male patient dyads, 141 female patient dyads). Patients' depressive symptoms and QOL were measured approximately 4 and 12months post-diagnosis; caregivers' depressive symptoms and QOL were measured approximately 5months post-diagnosis. ResultsThe actor-partner interdependence model confirmed that each person's depressive symptom level was uniquely associated with his/her own concurrent QOL. Female patients' depressive symptoms were also related to their caregivers' poorer physical and better mental health, particularly when the pair's depressive symptoms were at similarly elevated level. On the other hand, male patients' elevated depressive symptoms were related to their caregivers' poorer mental health. ConclusionsFindings suggest that QOL among patients and their family caregivers is interdependent. In light of this interdependency, psychosocial interventions for managing depressive symptoms should target both patients and their family caregivers, from which both may benefit by not only alleviating depressive symptoms but also improving QOL. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Kim, Youngmee] Univ Miami, Coral Gables, FL 33124 USA. [van Ryn, Michelle] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Jensen, Roxanne E.; Potosky, Arnold] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Griffin, Joan M.] Minneapolis VA Med Ctr, Minneapolis, MN USA. [Rowland, Julia] NCI, Bethesda, MD 20892 USA. RP Kim, Y (reprint author), Univ Miami, Dept Psychol, 5665 Ponce de Leon Blvd, Coral Gables, FL 33124 USA. EM ykim@miami.edu OI Kim, Youngmee/0000-0002-3109-6362 FU National Cancer Institute [U01 CA93324, U01 CA93326, U01 CA93329, U01 CA93332, U01 CA93339, U01 CA93344, U01 CA93348]; Department of Veterans Affairs [CRS 02-164]; Sylvester Comprehensive Cancer Center, University of Miami, FL FX This study was supported by grants from the National Cancer Institute (U01 CA93324, U01 CA93326, U01 CA93329, U01 CA93332, U01 CA93339, U01 CA93344, and U01 CA93348) and the Department of Veterans Affairs (CRS 02-164). Writing of this manuscript was supported by the Sylvester Comprehensive Cancer Center, University of Miami, FL, to the first author. The first author dedicates this research to the memory of Heekyoung Kim. NR 39 TC 10 Z9 10 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JAN PY 2015 VL 24 IS 1 BP 95 EP 105 DI 10.1002/pon.3580 PG 11 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AY9TY UT WOS:000347894500013 PM 24831223 ER PT J AU Fleming, SM Maniscalco, B Ko, Y Amendi, N Ro, T Lau, H AF Fleming, Stephen M. Maniscalco, Brian Ko, Yoshiaki Amendi, Namema Ro, Tony Lau, Hakwan TI Action-Specific Disruption of Perceptual Confidence SO PSYCHOLOGICAL SCIENCE LA English DT Article DE perception; motor processes; monitoring; open data ID TRANSCRANIAL MAGNETIC STIMULATION; DORSAL PREMOTOR CORTEX; FRONTAL EYE FIELDS; DECISION-MAKING; SIGNAL-DETECTION; PARIETAL CORTEX; NEURAL BASIS; SELECTION; MOVEMENT; METACOGNITION AB Theoretical models of perception assume that confidence is related to the quality or strength of sensory processing. Counter to this intuitive view, we showed in the present research that the motor system also contributes to judgments of perceptual confidence. In two experiments, we used transcranial magnetic stimulation (TMS) to manipulate response-specific representations in the premotor cortex, selectively disrupting postresponse confidence in visual discrimination judgments. Specifically, stimulation of the motor representation associated with the unchosen response reduced confidence in correct responses, thereby reducing metacognitive capacity without changing visual discrimination performance. Effects of TMS on confidence were observed when stimulation was applied both before and after the response occurred, which suggests that confidence depends on late-stage metacognitive processes. These results place constraints on models of perceptual confidence and metacognition by revealing that action-specific information in the premotor cortex contributes to perceptual confidence. C1 [Fleming, Stephen M.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Fleming, Stephen M.] Univ Oxford, Dept Expt Psychol, Oxford OX1 2JD, England. [Maniscalco, Brian; Ko, Yoshiaki; Amendi, Namema; Lau, Hakwan] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Maniscalco, Brian] NINDS, NIH, Bethesda, MD 20892 USA. [Ro, Tony] CUNY City Coll, Dept Psychol, New York, NY 10031 USA. [Lau, Hakwan] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Fleming, SM (reprint author), NYU, Ctr Neural Sci, 6 Washington Pl, New York, NY 10003 USA. EM sf102@nyu.edu RI Trivedi, Kruti/E-7558-2015 FU NINDS NIH HHS [R01 NS088628, R01NS088628]; Wellcome Trust [091593, WT096185] NR 41 TC 19 Z9 19 U1 3 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 EI 1467-9280 J9 PSYCHOL SCI JI Psychol. Sci. PD JAN PY 2015 VL 26 IS 1 BP 89 EP 98 DI 10.1177/0956797614557697 PG 10 WC Psychology, Multidisciplinary SC Psychology GA AZ0RW UT WOS:000347953200009 PM 25425059 ER PT J AU Peprah, E Xu, HC Tekola-Ayele, F Royal, CD AF Peprah, Emmanuel Xu, Huichun Tekola-Ayele, Fasil Royal, Charmaine D. TI Genome-Wide Association Studies in Africans and African Americans: Expanding the Framework of the Genomics of Human Traits and Disease SO PUBLIC HEALTH GENOMICS LA English DT Review DE African American; African ancestry; African populations; Genetic conditions; Genome-wide association studies; Genomics; Global health; Health ID FRAGILE-X-SYNDROME; SICKLE-CELL-DISEASE; PROSTATE-CANCER; WHOLE-GENOME; COMMUNITY ENGAGEMENT; ALCOHOL DEPENDENCE; EUROPEAN-AMERICAN; GENETIC DIVERSITY; COMPLEX DISEASE; VARIANTS AB Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions. (C) 2014 S. Karger AG, Basel C1 [Peprah, Emmanuel] NHLBI, Ctr Translat Res & Implementat Sci, Bethesda, MD 20817 USA. [Tekola-Ayele, Fasil] NIH, Ctr Res Genom & Global Hlth, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Xu, Huichun] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Royal, Charmaine D.] Duke Univ, Dept African & African Amer Studies, Durham, NC USA. RP Peprah, E (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, 6705 Rockledge Dr,Suite 6070, Bethesda, MD 20817 USA. EM peprahek@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU NIA [T32-AG000219] FX The authors kindly acknowledge and also thank Dr. Daniel Shriner at the Center for Research on Genomics and Global Health (CRGGH), and the NIH Fellows Editorial Board for editorial advice and careful reading of the manuscript. This research was supported in part by an NIA training grant to the University of Maryland (T32-AG000219). NR 112 TC 6 Z9 6 U1 0 U2 10 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-4246 EI 1662-8063 J9 PUBLIC HEALTH GENOM JI Pub. Health Genomics PY 2015 VL 18 IS 1 BP 40 EP 51 DI 10.1159/000367962 PG 12 WC Genetics & Heredity; Public, Environmental & Occupational Health SC Genetics & Heredity; Public, Environmental & Occupational Health GA AY6YH UT WOS:000347708100005 PM 25427668 ER PT J AU Wendler, DS Rid, A AF Wendler, David S. Rid, Annette TI Genetic research on biospecimens poses minimal risk SO TRENDS IN GENETICS LA English DT Review DE minimal risk; genetic research; confidentiality ID GENOMICS; IDENTIFIABILITY; FRAMEWORK; ATTITUDES; STANDARD; SAMPLES AB Genetic research on human biospecimens is increasingly common. However, debate continues over the level of risk that this research poses to sample donors. Some argue that genetic research on biospecimens poses minimal risk; others argue that it poses greater than minimal risk and therefore needs additional requirements and limitations. This debate raises concern that some donors are not receiving appropriate protection or, conversely, that valuable research is being subject to unnecessary requirements and limitations. The present paper attempts to resolve this debate using the widely-endorsed 'risks of daily life' standard. The three extant versions of this standard all suggest that, with proper measures in place to protect confidentiality, most genetic research on human biospecimens poses minimal risk to donors. C1 [Wendler, David S.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Rid, Annette] Kings Coll London, Dept Social Sci Hlth & Med, London, England. RP Wendler, DS (reprint author), NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Intramural Research Program, NIH Clinical Center; University of Zurich (Nachwuchsforderungskredit); European Commission [FP7-PEOPLE-2011-IEF-301816] FX Thanks to Ben Berkman JD, NIH, Christine Grady PhD, NIH, Sara Hull PhD, NIH and Barbara Prainsack PhD, King's College London for their helpful comments on previous drafts of the manuscript. This work was supported by the Intramural Research Program, NIH Clinical Center. However, the opinions expressed are the authors' own. They do not represent the position or policy of the NIH. Annette Rid received funding from the University of Zurich (Nachwuchsforderungskredit) and the European Commission (FP7-PEOPLE-2011-IEF-301816). NR 34 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2015 VL 31 IS 1 BP 11 EP 15 DI 10.1016/j.tig.2014.10.003 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AY9JW UT WOS:000347867200004 PM 25530152 ER PT J AU Lopez, MA Basco, MA AF Lopez, Molly A. Basco, Monica A. TI Effectiveness of Cognitive Behavioral Therapy in Public Mental Health: Comparison to Treatment as Usual for Treatment-Resistant Depression SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Cognitive behavioral therapy; Depression; Evidence-based practices; Effectiveness ID RANDOMIZED CLINICAL-TRIAL; PSYCHOLOGISTS ATTITUDES; TREATING DEPRESSION; COST-EFFECTIVENESS; FLUOXETINE PROZAC; EXPOSURE THERAPY; MAJOR DEPRESSION; NATIONAL-SURVEY; PSYCHOTHERAPY; DISSEMINATION AB State mental health systems have been leaders in the implementation of evidence-based approaches to care for individuals with severe mental illness. Numerous case studies of the wide-scale implementation of research-supported models such as integrated dual diagnosis treatment and assertive community treatment are documented. However, relatively few dissemination efforts have focused on cognitive behavioral therapy (CBT) for individuals with major depression despite evidence indicating its efficacy with this population. A multi-site effectiveness trial of CBT was conducted within the Texas public mental health system. Eighty-three adults with major depression received CBT from community clinicians trained through a workshop and regular consultation with a master clinician. Outcomes were compared to a matched sample of individuals receiving pharmacotherapy. Outcome measures used included the quick inventory of depressive symptomatology and beck depression inventory. Individuals receiving CBT showed greater improvements in depression symptoms than those in the comparison group. Greater pre-treatment symptom severity predicted better treatment response, while the presence of comorbid personality disorders was associated with poorer outcomes. C1 [Lopez, Molly A.] Univ Texas Austin, Sch Social Work, Austin, TX 78703 USA. [Basco, Monica A.] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Lopez, MA (reprint author), Univ Texas Austin, Sch Social Work, 1717 West 6th St,Suite 335, Austin, TX 78703 USA. EM mlopez@mail.utexas.edu FU NIMH NIH HHS [R34 MH074749, R34MH074749] NR 57 TC 4 Z9 4 U1 4 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JAN PY 2015 VL 42 IS 1 BP 87 EP 98 DI 10.1007/s10488-014-0546-4 PG 12 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AY2EK UT WOS:000347401200010 PM 24692026 ER PT J AU Aoun, EG Lee, MR Haass-Koffler, CL Swift, RM Addolorato, G Kenna, GA Leggio, L AF Aoun, Elie G. Lee, Mary R. Haass-Koffler, Carolina L. Swift, Robert M. Addolorato, Giovanni Kenna, George A. Leggio, Lorenzo TI Relationship Between the Thyroid Axis and Alcohol Craving SO ALCOHOL AND ALCOHOLISM LA English DT Article ID THYROTROPIN-RELEASING-HORMONE; COMPULSIVE DRINKING SCALE; DEPENDENT PATIENTS; RAT-BRAIN; ETHANOL; BACLOFEN; SYSTEM; STIMULATION; AGGRESSION; VALIDATION AB Aims: A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients. Methods: Forty-two treatment-seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]. Results: At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029). Conclusion: If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking. C1 [Aoun, Elie G.; Lee, Mary R.; Haass-Koffler, Carolina L.; Swift, Robert M.; Addolorato, Giovanni; Kenna, George A.; Leggio, Lorenzo] Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Baltimore, MD 21224 USA. RP Leggio, L (reprint author), Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Baltimore, MD 21224 USA. EM lorenzo.leggio@nih.gov RI Leggio, Lorenzo/M-2972-2016 FU European Foundation for Alcohol Research (ERAB); Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA); Brown University - National Institute of Mental Health (NIMH) [R25MH101076]; Brown University - NIAAA [5T32AA007459-28]; NIAAA [R21AA021128] FX Support for this study was partially provided by an Exchange Award from the European Foundation for Alcohol Research (ERAB) to L.L. when he was working at Brown University, Providence, RI. At present, L.L. and M.R.L. are federal employees in the Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, which is supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). E.G.A.'s work is supported by a Brown University research education grant funded by the National Institute of Mental Health (NIMH; R25MH101076). C.L.H.-K.'s work is supported by a Brown University training grant funded by NIAAA (5T32AA007459-28). G.A.K.'s work is supported by R21AA021128 from NIAAA. NR 36 TC 1 Z9 1 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD JAN-FEB PY 2015 VL 50 IS 1 BP 24 EP 29 DI 10.1093/alcalc/agu085 PG 6 WC Substance Abuse SC Substance Abuse GA AY2JL UT WOS:000347415400004 PM 25433251 ER PT J AU Mannisto, T Mendola, P Liu, DP Leishear, K Sherman, S Laughon, SK AF Maennistoe, Tuija Mendola, Pauline Liu, Danping Leishear, Kira Sherman, Seth Laughon, S. Katherine TI Acute Air Pollution Exposure and Blood Pressure at Delivery Among Women With and Without Hypertension SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE air pollution; blood pressure; epidemiology; hypertension; pregnancy ID PARTICULATE MATTER; PREGNANT-WOMEN; PULSE PRESSURE; DISEASE; COHORT; ADULTS; NONSMOKING; MORTALITY; RISK AB BACKGROUND Chronic air pollution exposure increases risk for hypertensive disorders of pregnancy, but the effect of acute air pollution exposure on blood pressure during pregnancy is less well known. METHODS We studied 151,276 singleton term deliveries from the Consortium on Safe Labor (2002-2008) with clinical blood pressure measured at admission to labor/delivery and diagnoses of hypertensive disorders collected from electronic medical records and hospital discharge summaries. Air pollution exposures were estimated for the admission hour and the 4 hours preceding admission using a modified version of the Community Multiscale Air Quality models and observed air monitoring data. Blood pressure was categorized as normal; high normal; and mild, moderate, or severe hypertension based on pregnancy cut points. Adjusted ordinal logistic regression estimated the odds of women having a higher admission blood pressure category as a function of air pollutant, hypertensive disorders, and their interaction effect. RESULTS Odds of high blood pressure at admission to labor/delivery were increased in normotensive women after exposure to nitrogen oxides (by 0.2%/5 units), sulfur dioxide (by 0.3%/1 unit), carbon monoxide and several air toxics (by 3%-4%/high exposure). The effects were often similar or stronger among women with gestational hypertension and preeclampsia. Exposure to particulate matter < 10 mu m increased odds of high blood pressure in women with preeclampsia by 3%/5 units. CONCLUSIONS Air pollution can influence admission blood pressure in term deliveries and may increase likelihood of preeclampsia screening at delivery admission. C1 [Maennistoe, Tuija; Mendola, Pauline; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Leishear, Kira] Glotech, Rockville, MD USA. [Sherman, Seth] EMMES Corp, Rockville, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 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 of Child Health and Human Development, National Institutes of Health [HHSN267200603425C, HHSN275200800002I, HHSN27500008] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; including Contract No. HHSN267200603425C (Consortium on Safe Labor) and Contract No. HHSN275200800002I; Task Order No. HHSN27500008 (Air Quality and Reproductive Health). Institutions involved in the consortium include: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville, MD (Data Coordinating Center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Houston, Houston, Texas. The Texas A&M Supercomputing Facility (http://sc.tamu.edu) and the Texas Advanced Computing Center (http://www.tacc.utexas.edu/) provided computing resources essential for completing the air quality simulations for exposure estimations in this study. NR 32 TC 8 Z9 8 U1 0 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JAN PY 2015 VL 28 IS 1 BP 58 EP 72 DI 10.1093/ajh/hpu077 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AY2JI UT WOS:000347415100009 PM 24795401 ER PT J AU Cheresh, P Morales-Nebreda, L Kim, SJ Yeldandi, A Williams, DB Cheng, Y Mutlu, GM Budinger, GRS Ridge, K Schumacker, PT Bohr, VA Kamp, DW AF Cheresh, Paul Morales-Nebreda, Luisa Kim, Seok-Jo Yeldandi, Anjana Williams, David B. Cheng, Yuan Mutlu, Goekhan M. Budinger, G. R. Scott Ridge, Karen Schumacker, Paul T. Bohr, Vilhelm A. Kamp, David W. TI Asbestos-Induced Pulmonary Fibrosis Is Augmented in 8-Oxoguanine DNA Glycosylase Knockout Mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asbestosis; pulmonary fibrosis; mitochondria; 8-oxyguanosine DNA glycosylase ID ENDOPLASMIC-RETICULUM STRESS; EPITHELIAL-CELL APOPTOSIS; MITOCHONDRIA-REGULATED APOPTOSIS; OXIDATIVE STRESS; REPAIR ENZYME; GENE-EXPRESSION; LUNG CARCINOMAS; 1 PROTECTS; OGG1 GENE; DAMAGE AB Asbestos causes asbestosis and malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as asbestos. We previously showed that mitochondrial reactive oxygen species mediate asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme, prevents oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments asbestos-induced pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 mu l) or titanium dioxide (100 mu g/50 mu l), crocidolite or Libby amphibole asbestos (100 mu g/50 mu l) each augmented pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology, fibrosis score, lung collagen via Sircol, and type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased pulmonary fibrosis after crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved caspase-3 immunostaining. AEC involvement was verified by colocalization studies using surfactant protein C. Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased mtDNA damage, reduced mitochondrial aconitase expression, and increased P53 and cleaved caspase-9 expression, and these changes were enhanced 3 weeks after crocidolite exposure. These findings suggest an important role for AEC mtDNA integrity maintained by OGG1 in the pathogenesis of pulmonary fibrosis that may represent a novel therapeutic target. C1 [Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo; Williams, David B.; Cheng, Yuan; Mutlu, Goekhan M.; Budinger, G. R. Scott; Ridge, Karen; Kamp, David W.] Jesse Brown VA Med Ctr, Dept Med, Div Pulm & Crit Care Med, Chicago, IL USA. [Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo; Williams, David B.; Cheng, Yuan; Mutlu, Goekhan M.; Budinger, G. R. Scott; Ridge, Karen; Kamp, David W.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Yeldandi, Anjana] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Schumacker, Paul T.] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Kamp, DW (reprint author), Northwestern Univ, Feinberg Sch Med Pulm & Crit Care Med, Mc Gaw M-330,240 E Huron St, Chicago, IL 60611 USA. EM d-kamp@northwestern.edu FU National Institutes of Health grants [RO1ES020357, R01HL071643, NCICA0605531]; VA Merit award FX This work was supported by National Institutes of Health grants RO1ES020357 (D. W. K.), R01HL071643 (K. R.), and NCICA0605531 and by a VA Merit award (D. W. K.). NR 66 TC 7 Z9 7 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JAN PY 2015 VL 52 IS 1 BP 25 EP 36 DI 10.1165/rcmb.2014-0038OC PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AY2KY UT WOS:000347420300003 PM 24918270 ER PT J AU Malve, M Gharib, AM Yazdani, SK Finet, G Martinez, MA Pettigrew, R Ohayon, J AF Malve, M. Gharib, A. M. Yazdani, S. K. Finet, G. Martinez, M. A. Pettigrew, R. Ohayon, J. TI Tortuosity of Coronary Bifurcation as a Potential Local Risk Factor for Atherosclerosis: CFD Steady State Study Based on In Vivo Dynamic CT Measurements SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE CFD; Wall shear stress; Hemodynamics; Tortuosity; Coronary bifurcation; Atherosclerosis ID WALL SHEAR-STRESS; NEWTONIAN BLOOD-FLOW; INTRAVASCULAR ULTRASOUND; CAROTID BIFURCATION; ARTERY-DISEASE; COMPUTED-TOMOGRAPHY; FOLLOW-UP; PATTERNS; PLAQUE; HEMODYNAMICS AB The purpose of the present study was to determine whether in vivo bifurcation geometric factors would permit prediction of the risk of atherosclerosis. It is worldwide accepted that low or oscillatory wall shear stress (WSS) is a robust hemodynamic factor in the development of atherosclerotic plaque and has a strong correlation with the local site of plaque deposition. However, it still remains unclear how coronary bifurcation geometries are correlated with such hemodynamic forces. Computational fluid dynamics simulations were performed on left main (LM) coronary bifurcation geometries derived from CT of eight patients without significant atherosclerosis. WSS amplitudes were accurately quantified at two high risk zones of atherosclerosis, namely at proximal left anterior descending artery (LAD) and at proximal left circumflex artery (LCx), and also at three high WSS concentration sites near the bifurcation. Statistical analysis was used to highlight relationships between WSS amplitudes calculated at these five zones of interest and various geometric factors. The tortuosity index of the LM-LAD segment appears to be an emergent geometric factor in determining the low WSS amplitude at proximal LAD. Strong correlations were found between the high WSS amplitudes calculated at the endothelial regions close to the flow divider. This study not only demonstrated that CT imaging studies of local risk factor for atherosclerosis could be clinically performed, but also showed that tortuosity of LM-LAD coronary branch could be used as a surrogate marker for the onset of atherosclerosis. C1 [Malve, M.] Univ Publ Navarra, Dept Mech Engn Energet & Mat, Pamplona 31006, Spain. [Malve, M.; Martinez, M. A.] Univ Zaragoza, Aragon Inst Engn Res, Zaragoza, Spain. [Malve, M.; Martinez, M. A.] CIBER BBN, Madrid, Spain. [Gharib, A. M.; Pettigrew, R.] NIDDK, Lab Integrat Cardiovasc Imaging Sci, NIH, Bethesda, MD 20892 USA. [Yazdani, S. K.] Univ S Alabama, Dept Mech Engn, Mobile, AL 36688 USA. [Finet, G.] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Finet, G.] Univ Lyon 1, INSERM, U886, F-69365 Lyon, France. [Ohayon, J.] In3S, CNRS UMR 5525, UJF, Lab TIMC DyCTiM, Grenoble, France. [Ohayon, J.] Univ Savoie, Engn Sch Polytech Annecy Chambery, Chambery, France. RP Malve, M (reprint author), Univ Publ Navarra, Dept Mech Engn Energet & Mat, Campus Arrosadia, Pamplona 31006, Spain. EM mauro.malve@unavarra.es; jacques.ohayon@imag.fr RI Martinez, Miguel Angel/F-5903-2011; Malve, Mauro/A-5516-2013; Gharib, Ahmed/O-2629-2016 OI Martinez, Miguel Angel/0000-0002-8375-0354; Malve, Mauro/0000-0002-0116-2736; Gharib, Ahmed/0000-0002-2476-481X FU Spanish Ministry of Science and Technology [DPI-2010-20746-C03-01]; Instituto de Salud Carlos III (ISCIII) through the CIBER-BBN initiative; National Institutes of Health (NIH) FX M. Malve and M.A. Martinez are supported by the Spanish Ministry of Science and Technology through research project DPI-2010-20746-C03-01 and the Instituto de Salud Carlos III (ISCIII) through the CIBER-BBN initiative. This research was supported in part by an appointment (J. Ohayon) to the Senior Fellow Program at the National Institutes of Health (NIH). This program is administered by Oak Ridge Institute for Science and Education through an inter-agency agreement between the NIH and the U.S. Department of Energy. NR 50 TC 6 Z9 7 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD JAN PY 2015 VL 43 IS 1 BP 82 EP 93 DI 10.1007/s10439-014-1056-y PG 12 WC Engineering, Biomedical SC Engineering GA AY6QC UT WOS:000347689700008 PM 24986333 ER PT J AU Morris, JH Wu, A Yamashita, RA Marchler-Bauer, A Ferrin, TE AF Morris, John H. Wu, Allan Yamashita, Roxanne A. Marchler-Bauer, Aron Ferrin, Thomas E. TI cddApp: a Cytoscape app for accessing the NCBI conserved domain database SO BIOINFORMATICS LA English DT Article ID UCSF-CHIMERA; VISUALIZATION; NETWORKS AB Motivation: cddApp is a Cytoscape extension that supports the annotation of protein networks with information about domains and specific functional sites from the National Center for Biotechnology Information's conserved domain database (CDD). CDD information is loaded for nodes annotated with NCBI numbers or UniProt identifiers and (optionally) Protein Data Bank structures. cddApp integrates with the Cytoscape apps structureViz2 and enhancedGraphics. Together, these three apps provide powerful tools to annotate nodes with CDD domain and site information and visualize that information in both network and structural contexts. C1 [Morris, John H.; Wu, Allan; Ferrin, Thomas E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yamashita, Roxanne A.; Marchler-Bauer, Aron] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Morris, JH (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM scooter@cgl.ucsf.edu FU Intramural Research Program of the U.S. National Institutes of Health (NIH); National Library of Medicine; NIH National Institute of General Medical Science [P41-GM103311] FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health (NIH); National Library of Medicine; and by NIH National Institute of General Medical Science Grant [P41-GM103311]. NR 10 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JAN 1 PY 2015 VL 31 IS 1 BP 134 EP 136 DI 10.1093/bioinformatics/btu605 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AY2JU UT WOS:000347417000025 PM 25212755 ER PT J AU Samish, I Bourne, PE Najmanovich, RJ AF Samish, Ilan Bourne, Philip E. Najmanovich, Rafael J. TI Achievements and challenges in structural bioinformatics and computational biophysics SO BIOINFORMATICS LA English DT Article ID PROTEIN-STRUCTURE PREDICTION; MOLECULAR RECOGNITION; DRUG DISCOVERY; SIMULATION; DESIGN; 3D; PRINCIPLES; DOCKING; BIOLOGY; SIMILARITIES AB Motivation: The field of structural bioinformatics and computational biophysics has undergone a revolution in the last 10 years. Developments that are captured annually through the 3DSIG meeting, upon which this article reflects. Results: An increase in the accessible data, computational resources and methodology has resulted in an increase in the size and resolution of studied systems and the complexity of the questions amenable to research. Concomitantly, the parameterization and efficiency of the methods have markedly improved along with their cross-validation with other computational and experimental results. Conclusion: The field exhibits an ever-increasing integration with biochemistry, biophysics and other disciplines. In this article, we discuss recent achievements along with current challenges within the field. C1 [Samish, Ilan] Weizmann Inst Sci, Dept Plant Sci, IL-76100 Rehovot, Israel. [Samish, Ilan] Ort Braude Coll, IL-2161002 Karmiel, Israel. [Bourne, Philip E.] NIH, Bethesda, MD 20814 USA. [Najmanovich, Rafael J.] Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ J1H 5N4, Canada. RP Najmanovich, RJ (reprint author), Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ J1H 5N4, Canada. EM Rafael.Najmanovich@USherbrooke.ca RI samish, ilan/B-7980-2016; OI samish, ilan/0000-0002-0299-9124; Najmanovich, Rafael/0000-0002-6971-7224 NR 77 TC 6 Z9 6 U1 3 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JAN 1 PY 2015 VL 31 IS 1 BP 146 EP 150 DI 10.1093/bioinformatics/btu769 PG 5 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 AY2JU UT WOS:000347417000029 PM 25488929 ER PT J AU Elliott, KC Resnik, DB AF Elliott, Kevin C. Resnik, David B. TI Scientific Reproducibility, Human Error, and Public Policy SO BIOSCIENCE LA English DT Editorial Material C1 [Elliott, Kevin C.] Michigan State Univ, Lyman Briggs Coll, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. [Elliott, Kevin C.] Michigan State Univ, Dept Philosophy, E Lansing, MI 48824 USA. [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Elliott, KC (reprint author), Michigan State Univ, Lyman Briggs Coll, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. EM kce@msu.edu NR 11 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3568 EI 1525-3244 J9 BIOSCIENCE JI Bioscience PD JAN PY 2015 VL 65 IS 1 BP 5 EP 6 DI 10.1093/biosci/biu197 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AY2KF UT WOS:000347418200002 ER PT J AU Yu, K Zhang, H Wheeler, W Horne, HN Chen, JB Figueroa, JD AF Yu, Kai Zhang, Han Wheeler, William Horne, Hisani N. Chen, Jinbo Figueroa, Jonine D. TI A robust association test for detecting genetic variants with heterogeneous effects SO BIOSTATISTICS LA English DT Article DE Breast cancer; Etiology heterogeneity; Genetic association study; Multiple-comparison adjustment; Tree-based model ID BREAST-CANCER RISK; REGRESSION-MODEL; CONSORTIUM; LOCI AB One common strategy for detecting disease-associated genetic markers is to compare the genotype distributions between cases and controls, where cases have been diagnosed as having the disease condition. In a study of a complex disease with a heterogeneous etiology, the sampled case group most likely consists of people having different disease subtypes. If we conduct an association test by treating all cases as a single group, we maximize our chance of finding genetic risk factors with a homogeneous effect, regardless of the underlying disease etiology. However, this strategy might diminish the power for detecting risk factors whose effect size varies by disease subtype. We propose a robust statistical procedure to identify genetic risk factors that have either a uniform effect for all disease subtypes or heterogeneous effects across different subtypes, in situations where the subtypes are not predefined but can be characterized roughly by a set of clinical and/or pathologic markers. We demonstrate the advantage of the new procedure through numeric simulation studies and an application to a breast cancer study. C1 [Yu, Kai; Zhang, Han; Horne, Hisani N.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD 20892 USA. [Chen, Jinbo] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Yu, K (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM yuka@mail.nih.gov RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 FU Intramural Program of the NIH; National Cancer Institute; [R01-ES016626] FX The work of Kai Yu, Han Zhang, Hisani N. Horne, and Jinbo Chen was supported in part by the Intramural Program of the NIH and the National Cancer Institute. The work of Jinbo Chen was supported by R01-ES016626. The authors of the study thank Pei Chao and Michael Stagner from Information Management Services (Silver Spring, MD, USA) for data management support; the participants, physicians, pathologists, nurses, and interviewers from participating centers in Poland for their efforts during field work; and Drs. Montse Garcia-Closas, Louise Brinton, Mark Sherman, Beata Peplonska, and Jolanta Lissowska for their contributions to the study design of the NCI Polish Breast Cancer Study. NR 16 TC 0 Z9 0 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2015 VL 16 IS 1 BP 5 EP 16 DI 10.1093/biostatistics/kxu036 PG 12 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY2JZ UT WOS:000347417500003 PM 25057183 ER PT J AU Lum, KJ Sundaram, R Louis, TA AF Lum, Kirsten J. Sundaram, Rajeshwari Louis, Thomas A. TI Accounting for length-bias and selection effects in estimating the distribution of menstrual cycle length SO BIOSTATISTICS LA English DT Article DE Backward recurrence time; Length-bias; Menstrual cycle length; Renewal process; Selection effects; Survival analysis ID NONPARAMETRIC-ESTIMATION; CONFIDENCE-INTERVALS; RENEWAL PROCESSES; RANDOM TRUNCATION; ESTIMATING TIME; PREGNANCY; MODEL; PATTERNS; LIFE AB Prospective pregnancy studies are a valuable source of longitudinal data on menstrual cycle length. However, care is needed when making inferences of such renewal processes. For example, accounting for the sampling plan is necessary for unbiased estimation of the menstrual cycle length distribution for the study population. If couples can enroll when they learn of the study as opposed to waiting for the start of a new menstrual cycle, then due to length-bias, the enrollment cycle will be stochastically larger than the general run of cycles, a typical property of prevalent cohort studies. Furthermore, the probability of enrollment can depend on the length of time since a woman's last menstrual period (a backward recurrence time), resulting in selection effects. We focus on accounting for length-bias and selection effects in the likelihood for enrollment menstrual cycle length, using a recursive two-stage approach wherein we first estimate the probability of enrollment as a function of the backward recurrence time and then use it in a likelihood with sampling weights that account for length-bias and selection effects. To broaden the applicability of our methods, we augment our model to incorporate a couple-specific random effect and time-independent covariate. A simulation study quantifies performance for two scenarios of enrollment probability when proper account is taken of sampling plan features. In addition, we estimate the probability of enrollment and the distribution of menstrual cycle length for the study population of the Longitudinal Investigation of Fertility and the Environment Study. C1 [Lum, Kirsten J.; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, DHHS, Rockville, MD 20852 USA. [Lum, Kirsten J.; Louis, Thomas A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Louis, Thomas A.] US Bur Census, Suitland, MD 20746 USA. RP Louis, TA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. EM tlouis@jhu.edu OI Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the U.S., National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; U.S., National Institutes of Health, National Institute of Environmental Health Sciences [Training Grant] [2T32ES012871] FX This work was supported by the Intramural Research Program of the U.S., National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [Contracts N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] and by the U.S., National Institutes of Health, National Institute of Environmental Health Sciences [Training Grant 2T32ES012871]. NR 26 TC 3 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2015 VL 16 IS 1 BP 113 EP 128 DI 10.1093/biostatistics/kxu035 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY2JZ UT WOS:000347417500011 PM 25027273 ER PT J AU Song, MS Kraft, P Joshi, AD Barrdahl, M Chatterjee, N AF Song, Minsun Kraft, Peter Joshi, Amit D. Barrdahl, Myrto Chatterjee, Nilanjan TI Testing calibration of risk models at extremes of disease risk SO BIOSTATISTICS LA English DT Article DE Case-control studies; Gene-gene and gene-environment interactions; Genome-wide association studies; Goodness-of-fit tests; Polygenic score; Risk stratification ID ASSOCIATION; PERFORMANCE; PREDICTION; VARIANTS; BREAST AB Risk-prediction models need careful calibration to ensure they produce unbiased estimates of risk for subjects in the underlying population given their risk-factor profiles. As subjects with extreme high or low risk may be the most affected by knowledge of their risk estimates, checking the adequacy of risk models at the extremes of risk is very important for clinical applications. We propose a new approach to test model calibration targeted toward extremes of disease risk distribution where standard goodness-of-fit tests may lack power due to sparseness of data. We construct a test statistic based on model residuals summed over only those individuals who pass high and/or low risk thresholds and then maximize the test statistic over different risk thresholds. We derive an asymptotic distribution for the max-test statistic based on analytic derivation of the variance-covariance function of the underlying Gaussian process. The method is applied to a large case-control study of breast cancer to examine joint effects of common single nucleotide polymorphisms (SNPs) discovered through recent genome-wide association studies. The analysis clearly indicates a non-additive effect of the SNPs on the scale of absolute risk, but an excellent fit for the linear-logistic model even at the extremes of risks. C1 [Song, Minsun; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Kraft, Peter; Joshi, Amit D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Barrdahl, Myrto] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM chattern@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; U.S. National Institutes of Health, National Cancer Institute [U01-CA98233, U19-CA148065, U01-CA98710, U01-CA98216, U01-CA98758]; U.S. National Institutes of Health, National Cancer Institute (Intramural Research Program of NIH/NCI, Division of Cancer Epidemiology and Genetics) FX Drs M.S. and N.C.'s research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. The breast cancer dataset was funded by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 and U19-CA148065 to David J. Hunter, U01-CA98710 to Michael J. Thun, U01-CA98216 to Elio Riboli and Rudolf Kaaks, and U01-CA98758 to Brian E. Henderson, and Intramural Research Program of NIH/NCI, Division of Cancer Epidemiology and Genetics). NR 16 TC 5 Z9 5 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2015 VL 16 IS 1 BP 143 EP 154 DI 10.1093/biostatistics/kxu034 PG 12 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY2JZ UT WOS:000347417500013 PM 25027274 ER PT J AU Shardell, M Hicks, GE Ferrucci, L AF Shardell, Michelle Hicks, Gregory E. Ferrucci, Luigi TI Doubly robust estimation and causal inference in longitudinal studies with dropout and truncation by death SO BIOSTATISTICS LA English DT Article DE Causal inference; Longitudinal data analysis; Missing data; Observational studies ID MARGINAL STRUCTURAL MODELS; VITAMIN-D DEFICIENCY; MISSING DATA; HYPOTHETICAL INTERVENTIONS; PRINCIPAL STRATIFICATION; POST-RANDOMIZATION; OUTCOMES; MORTALITY; EPIDEMIOLOGY; GUIDELINE AB Motivated by aging research, we propose an estimator of the effect of a time-varying exposure on an outcome in longitudinal studies with dropout and truncation by death. We use an inverse-probability weighted (IPW) estimator to derive a doubly robust augmented inverse-probability weighted (AIPW) estimator. IPW estimation involves weights for the exposure mechanism, dropout, and mortality; AIPW estimation additionally involves estimating data-generating models via regression. We demonstrate that the estimators identify a causal contrast that is a function of principal strata effects under a set of assumptions. Simulations show that AIPW estimation is unbiased when weights or outcome regressions are correct, and that AIPW estimation is more efficient than IPW estimation when all models are correct. We apply the method to a study of vitamin D and gait speed among older adults. C1 [Shardell, Michelle] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21225 USA. RP Shardell, M (reprint author), Univ Maryland, Dept Epidemiol & Publ Hlth, 660 West Redwood St, Baltimore, MD 21201 USA. EM mshardel@epi.umaryland.edu FU National Institutes of Health [K25AG034216, R01AG041202] FX This work was supported by the National Institutes of Health (K25AG034216, R01AG041202). NR 46 TC 4 Z9 4 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2015 VL 16 IS 1 BP 155 EP 168 DI 10.1093/biostatistics/kxu032 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY2JZ UT WOS:000347417500014 PM 24997309 ER PT J AU Li, Y Safaeian, M Robbins, HA Graubard, BI AF Li, Yan Safaeian, Mahboobeh Robbins, Hilary A. Graubard, Barry I. TI Logistic analysis of epidemiologic studies with augmentation sampling involving re-stratification and population expansion SO BIOSTATISTICS LA English DT Article DE Pseudo-likelihood function; Sample weighting; Taylor linearization variance estimation; Two-stage stratified sampling ID DUAL FRAME SURVEYS; HUMAN-PAPILLOMAVIRUS; COSTA-RICA; DESIGN; INFECTION AB Epidemiologic cross-sectional, case-cohort, or case-control studies often select augmentation samples to supplement an existing (baseline) sample, primarily for the two reasons: (1) to increase the sample sizes from certain subdomains of interest that were not originally considered in the design of the baseline study and (2) to obtain samples from an extension of the target population. To address these two objectives, two-stage stratified sample designs are considered, where the stratification based on the expanded population at the second stage is not nested in the first stage strata. The sample weighting and Taylor linearization variance estimation for the two-stage stratified sample designs, involving re-stratification and population expansion, are provided for estimating population totals and logistic regression coefficients. Results from limited simulation studies and a logistic regression analysis of a study of human papillomavirus serology are provided. C1 [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Safaeian, Mahboobeh; Robbins, Hilary A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. EM yli6@umd.edu FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 17 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2015 VL 16 IS 1 BP 169 EP 178 DI 10.1093/biostatistics/kxu024 PG 10 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AY2JZ UT WOS:000347417500015 PM 24907707 ER PT J AU Markt, SC Valdimarsdottir, UA Shui, IM Sigurdardottir, LG Rider, JR Tamimi, RM Batista, JL Haneuse, S Flynn-Evans, E Lockley, SW Czeisler, CA Stampfer, MJ Launer, L Harris, T Smith, AV Gudnason, V Lindstrom, S Kraft, P Mucci, LA AF Markt, Sarah C. Valdimarsdottir, Unnur A. Shui, Irene M. Sigurdardottir, Lara G. Rider, Jennifer R. Tamimi, Rulla M. Batista, Julie L. Haneuse, Sebastien Flynn-Evans, Erin Lockley, Steven W. Czeisler, Charles A. Stampfer, Meir J. Launer, Lenore Harris, Tamara Smith, Albert Vernon Gudnason, Vilmundur Lindstrom, Sara Kraft, Peter Mucci, Lorelei A. TI Circadian clock genes and risk of fatal prostate cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Circadian genes; Prostate cancer; Genetic polymorphisms ID GENOME-WIDE ASSOCIATION; SHIFT-WORK; GENOTOXIC STRESS; TUMOR-SUPPRESSOR; DISRUPTION; VARIANTS; NPAS2; MEN; EPIDEMIOLOGY; CYCLE AB Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels. We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes. None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels. We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels. C1 [Markt, Sarah C.; Valdimarsdottir, Unnur A.; Shui, Irene M.; Rider, Jennifer R.; Tamimi, Rulla M.; Batista, Julie L.; Stampfer, Meir J.; Lindstrom, Sara; Kraft, Peter; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Valdimarsdottir, Unnur A.; Sigurdardottir, Lara G.; Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Valdimarsdottir, Unnur A.; Sigurdardottir, Lara G.; Mucci, Lorelei A.] Univ Iceland, Ctr Publ Hlth Sci, Reykjavik, Iceland. [Sigurdardottir, Lara G.] Iceland Canc Soc, Reykjavik, Iceland. [Rider, Jennifer R.; Tamimi, Rulla M.; Batista, Julie L.; Stampfer, Meir J.; Mucci, Lorelei A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Haneuse, Sebastien; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Flynn-Evans, Erin; Lockley, Steven W.; Czeisler, Charles A.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA 02115 USA. [Flynn-Evans, Erin; Lockley, Steven W.; Czeisler, Charles A.] Brigham & Womens Hosp, Dept Med, Div Sleep Med, Boston, MA 02115 USA. [Launer, Lenore; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Lindstrom, Sara; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. RP Markt, SC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM sec110@mail.harvard.edu RI Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Rider, Jennifer/0000-0002-2637-6036 FU National Institutes on Aging Intramural Research Program [N01-AG-12100]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Harvard Catalyst Award; Icelandic Cancer Society; National Cancer Institute at the National Institutes of Health [P01 CA055075, CA133891, CA42182, CA34944, CA40360, CA141298, CA98233, CA097193]; National Heart, Lung, and Blood Institute at the National Institutes of Health [HL26490, HL34595]; National Cancer Institute at the National Institutes of Health Training Grant [R25 CA098566, T32 CA09001-35]; US Army Department of Defense Prostate Cancer Research Program Fellowship; NIH NIA [P01-AG-009975] FX We thank the study participants and the Icelandic Heart Association clinic staff for their invaluable contribution. We are grateful to the ongoing participation of men in the Health Professionals Follow-up Study (UM1 CA167552) and would like to acknowledge our colleagues (Lauren McLaughlin and Siobhan Saint-Surin) working on these studies for their valuable help. In addition, we would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The AGES-Reykjavik is supported by Contract N01-AG-12100 from the National Institutes on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). In addition, this study was supported by funding from the Harvard Catalyst Award, the Icelandic Cancer Society, the National Cancer Institute at the National Institutes of Health (P01 CA055075, CA133891, CA42182, CA34944, CA40360, CA141298, CA98233 and CA097193); the National Heart, Lung, and Blood Institute at the National Institutes of Health (HL26490, HL34595). National Cancer Institute at the National Institutes of Health Training Grant (R25 CA098566 and T32 CA09001-35 to SCM); and the Prostate Cancer Foundation (to LAM and JRR); US Army Department of Defense Prostate Cancer Research Program Fellowship (to IMS). CAC was supported in part by NIH NIA Grant P01-AG-009975. NR 40 TC 5 Z9 5 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JAN PY 2015 VL 26 IS 1 BP 25 EP 33 DI 10.1007/s10552-014-0478-z PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AY0JA UT WOS:000347281800003 PM 25388799 ER PT J AU Nyante, SJ Gammon, MD Kaufman, JS Bensen, JT Lin, DY Barnholtz-Sloan, JS Hu, YJ He, QC Luo, JC Millikan, RC AF Nyante, Sarah J. Gammon, Marilie D. Kaufman, Jay S. Bensen, Jeannette T. Lin, Dan Yu Barnholtz-Sloan, Jill S. Hu, Yijuan He, Qianchuan Luo, Jingchun Millikan, Robert C. TI Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Single nucleotide polymorphisms; Estrogen receptor; Progesterone receptor; Cytochrome P450 family 19 subfamily A polypeptide 1; 17-Beta hydroxysteroid dehydrogenase type II; Sex hormone-binding globulin; 3-Beta hydroxysteroid dehydrogenase type I ID GENOME-WIDE ASSOCIATION; BASAL-LIKE SUBTYPE; SUSCEPTIBILITY LOCI; POPULATION STRATIFICATION; LINKAGE DISEQUILIBRIUM; COMMON VARIANTS; HUMAN AROMATASE; RECEPTOR; POLYMORPHISM; CELLS AB To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina. Cases (n = 1,972) were women 20-74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r (2) statistic. Odds ratios (ORs) and 95 % confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values < 3.3 x 10(-4) were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n = 679) and basal-like (n = 200), were based on the Wald statistic. ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95 % CI 1.51-3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95 % CI 1.43-3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95 % CI 1.14-1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r (2) = 0.70; whites r (2) = 0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER-, and unclassified subtypes. ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes. C1 [Nyante, Sarah J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gammon, Marilie D.; Bensen, Jeannette T.; Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Gammon, Marilie D.; Bensen, Jeannette T.; Lin, Dan Yu; Luo, Jingchun; Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Kaufman, Jay S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Lin, Dan Yu; Hu, Yijuan] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Barnholtz-Sloan, Jill S.] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. [He, Qianchuan] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Nyante, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM nyantesj@mail.nih.gov OI Kaufman, Jay/0000-0003-1606-401X FU National Institutes of Health [P50-CA58223, P30-CA16086, R25-CA57726, P30ES10126] FX This work was supported by funding from the National Institutes of Health [P50-CA58223, P30-CA16086, R25-CA57726 to S.J.N., P30ES10126 to M. D. G. and R. C. M.]. The authors wish to thank Patricia Basta of the University of North Carolina at Chapel Hill Epidemiology Department, and Michael Andre and Amanda Beaty of the University of North Carolina Lineberger Comprehensive Cancer Center for their work preparing the DNA samples and conducting the genotyping. The authors also thank Jessica Tse of the University of North Carolina at Chapel Hill Epidemiology Department for advice and statistical support. NR 62 TC 1 Z9 1 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JAN PY 2015 VL 26 IS 1 BP 121 EP 131 DI 10.1007/s10552-014-0491-2 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AY0JA UT WOS:000347281800012 PM 25421376 ER PT J AU Warrington, NM Sun, T Luo, JQ McKinstry, RC Parkin, PC Ganzhorn, S Spoljaric, D Albers, AC Merkelson, A Stewart, DR Stevenson, DA Viskochil, D Druley, TE Forys, JT Reilly, KM Fisher, MJ Tabori, U Allen, JC Schiffman, JD Gutmann, DH Rubin, JB AF Warrington, Nicole M. Sun, Tao Luo, Jingqin McKinstry, Robert C. Parkin, Patricia C. Ganzhorn, Sara Spoljaric, Debra Albers, Anne C. Merkelson, Amanda Stewart, Douglas R. Stevenson, David A. Viskochil, David Druley, Todd E. Forys, Jason T. Reilly, Karlyne M. Fisher, Michael J. Tabori, Uri Allen, Jeffrey C. Schiffman, Joshua D. Gutmann, David H. Rubin, Joshua B. TI The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients SO CANCER RESEARCH LA English DT Article ID VISUAL-ACUITY; FOLLOW-UP; CHILDREN; TUMORS; MANIFESTATIONS; ASSOCIATION; EXPRESSION; BRAIN; MODEL AB Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1. (C)2014 AACR. C1 [Warrington, Nicole M.; Sun, Tao; McKinstry, Robert C.; Ganzhorn, Sara; Spoljaric, Debra; Druley, Todd E.; Forys, Jason T.; Rubin, Joshua B.] Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Luo, Jingqin] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [McKinstry, Robert C.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Parkin, Patricia C.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Albers, Anne C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Merkelson, Amanda] NYU, Langone Med Ctr, Dept Pediat, New York, NY USA. [Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Stewart, Douglas R.] Univ Utah, Div Med Genet, Salt Lake City, UT USA. [Stevenson, David A.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Reilly, Karlyne M.] NCI, Ctr Canc Res, Off Director, Rare Tumors Initiat, Bethesda, MD USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA. [Rubin, Joshua B.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Rubin, Joshua B.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. RP Rubin, JB (reprint author), Washington Univ, Sch Med, Campus Box 8208,660 South Euclid Ave, St Louis, MO 63110 USA. EM rubin_j@kids.wustl.edu FU Children's Discovery Institute of Washington University; NCI [RO1-CA136573, UO1-CA141549]; NIH [UL1RR025764]; DOD [W81XWH-11-1-0250]; Children's Tumor Foundation; Hospital for Sick Children Research Institute; University of Utah; Division of Cancer Epidemiology and Genetics of the National Cancer Institute; NCI Cancer Center [P30 CA91842]; ICTS/CTSA from the National Center for Research Resources (NCRR), a component of the NIH [UL1TR000448]; NIH, NCI [IRP ZIA BC 010539]; NIH Roadmap for Medical Research FX This work was supported by grants from The Children's Discovery Institute of Washington University (J.B. Rubin and D.H. Gutmann), the NCI RO1-CA136573 (J.B. Rubin and D.H. Gutmann), UO1-CA141549 (D.H. Gutmann), the NIH UL1RR025764 (D.A. Stevenson), The DOD W81XWH-11-1-0250 (D.A. Stevenson), Children's Tumor Foundation Young Investigator Award (T. Sun), IRP ZIA BC 010539 of the NIH, NCI (K.M. Reilly), The Hospital for Sick Children Research Institute (P.C. Parkin), the University of Utah Clinical Genetics Research Program (D.A. Stevenson). D.R. Stewart was supported, in part, by the intramural program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine helped with genomic analysis and is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. NR 29 TC 13 Z9 13 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 1 PY 2015 VL 75 IS 1 BP 16 EP 21 DI 10.1158/0008-5472.CAN-14-1891 PG 6 WC Oncology SC Oncology GA AY1XN UT WOS:000347383000004 PM 25381154 ER PT J AU Boggs, AE Vitolo, MI Whipple, RA Charpentier, MS Goloubeva, OG Ioffe, OB Tuttle, KC Slovic, J Lu, YL Mills, GB Martin, SS AF Boggs, Amanda E. Vitolo, Michele I. Whipple, Rebecca A. Charpentier, Monica S. Goloubeva, Olga G. Ioffe, Olga B. Tuttle, Kimberly C. Slovic, Jana Lu, Yiling Mills, Gordon B. Martin, Stuart S. TI alpha-Tubulin Acetylation Elevated in Metastatic and Basal-like Breast Cancer Cells Promotes Microtentacle Formation, Adhesion, and Invasive Migration SO CANCER RESEARCH LA English DT Article ID CIRCULATING TUMOR-CELLS; ACETYLTRANSFERASE; EXPRESSION; CYTOSKELETON; HDAC6; MICROTUBULES; SUBTYPES; SURVIVAL; MEC-17; REATTACHMENT AB Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of alpha-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high alpha-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation of the acetylation site on alpha-tubulin and enzymatic modulation of this posttranslational modification exerted a significant impact on McTN frequency and the reattachment of suspended tumor cells. Reducing alpha-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of more than 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared with primary tumors. Proteomic analysis of an independent cohort of more than 390 patient specimens further documented the relationship between increased alpha-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high-intensity alpha-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated alpha-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in patients with breast cancer. (C) 2014 AACR. C1 [Boggs, Amanda E.; Vitolo, Michele I.; Charpentier, Monica S.; Slovic, Jana; Martin, Stuart S.] Univ Maryland, Grad Program Life Sci, Baltimore, MD 21201 USA. [Boggs, Amanda E.; Vitolo, Michele I.; Whipple, Rebecca A.; Charpentier, Monica S.; Slovic, Jana; Martin, Stuart S.] Univ Maryland, Marlene & Stewart Greenebaum NCI Canc Ctr, Baltimore, MD 21201 USA. [Vitolo, Michele I.; Martin, Stuart S.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Goloubeva, Olga G.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Ioffe, Olga B.; Tuttle, Kimberly C.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. RP Martin, SS (reprint author), Univ Maryland, Sch Med, Dept Physiol, Marlene & Stewart Greenebaum NCI Canc Ctr, 655 W Baltimore St,Bressler Bldg,Room 10-029, Baltimore, MD 21201 USA. EM ssmartin@som.umaryland.edu FU National Cancer Institute [R01-CA154624, R01-124704]; Susan G. Komen Foundation [KG100240]; Department of Defense [BC100675]; NIH grant [K01-CA166576] FX This research is supported by R01-CA154624 and R01-124704 from the National Cancer Institute, KG100240 from the Susan G. Komen Foundation, and an Era of Hope Scholar Award from the Department of Defense (BC100675). M.I. Vitolo is supported by NIH grant K01-CA166576. NR 57 TC 15 Z9 15 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 1 PY 2015 VL 75 IS 1 BP 203 EP 215 DI 10.1158/0008-5472.CAN-13-3563 PG 13 WC Oncology SC Oncology GA AY1XN UT WOS:000347383000021 PM 25503560 ER PT J AU Raft, S Groves, AK AF Raft, Steven Groves, Andrew K. TI Segregating neural and mechanosensory fates in the developing ear: patterning, signaling, and transcriptional control SO CELL AND TISSUE RESEARCH LA English DT Review DE Inner ear; Neurogenesis; Sensory cells; Transcription factors; Induction ID MAMMALIAN INNER-EAR; HAIR-CELL-DIFFERENTIATION; DEVELOPING NERVOUS-SYSTEM; DEVELOPING DROSOPHILA EYE; SENSORY ORGAN DEVELOPMENT; ADULT ABDOMINAL SEGMENTS; MIND-BOMB MUTANT; OTIC PLACODE; IN-VIVO; SUPPORTING CELLS AB The vertebrate inner ear is composed of multiple sensory receptor epithelia, each of which is specialized for detection of sound, gravity, or angular acceleration. Each receptor epithelium contains mechanosensitive hair cells, which are connected to the brainstem by bipolar sensory neurons. Hair cells and their associated neurons are derived from the embryonic rudiment of the inner ear epithelium, but the precise spatial and temporal patterns of their generation, as well as the signals that coordinate these events, have only recently begun to be understood. Gene expression, lineage tracing, and mutant analyses suggest that both neurons and hair cells are generated from a common domain of neural and sensory competence in the embryonic inner ear rudiment. Members of the Shh, Wnt, and FGF families, together with retinoic acid signals, regulate transcription factor genes within the inner ear rudiment to establish the axial identity of the ear and regionalize neurogenic activity. Close-range signaling, such as that of the Notch pathway, specifies the fate of sensory regions and individual cell types. We also describe positive and negative interactions between basic helix-loop-helix and SoxB family transcription factors that specify either neuronal or sensory fates in a context-dependent manner. Finally, we review recent work on inner ear development in zebrafish, which demonstrates that the relative timing of neurogenesis and sensory epithelial formation is not phylogenetically constrained. C1 [Raft, Steven] NIDCD, Sect Sensory Cell Regenerat & Dev, NIH, Bethesda, MD 20892 USA. [Groves, Andrew K.] Baylor Coll Med, Program Dev Biol, Dept Neurosci, Houston, TX 77030 USA. [Groves, Andrew K.] Baylor Coll Med, Program Dev Biol, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Groves, AK (reprint author), Baylor Coll Med, Program Dev Biol, Dept Neurosci, 1 Baylor Plaza, Houston, TX 77030 USA. EM rafts@nidcd.nih.gov; akgroves@bcm.edu OI Groves, Andrew/0000-0002-0784-7998 FU NIDCD NIH HHS [R01 DC006185] NR 173 TC 12 Z9 12 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD JAN PY 2015 VL 359 IS 1 BP 315 EP 332 DI 10.1007/s00441-014-1917-6 PG 18 WC Cell Biology SC Cell Biology GA AY2FJ UT WOS:000347403700023 PM 24902666 ER PT J AU Gamrekelashvili, J Greten, TF Korangy, F AF Gamrekelashvili, Jaba Greten, Tim F. Korangy, Firouzeh TI Immunogenicity of necrotic cell death SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Cell death; Peptidase; Immunogenic cell death; Cancer vaccine; CD8(+) T cell ID MHC CLASS-I; HEAT-SHOCK PROTEINS; CD8(+) T-CELLS; ANTIGEN-PROCESSING PATHWAY; INNATE IMMUNE-RESPONSES; APOPTOTIC TUMOR-CELLS; THIMET OLIGOPEPTIDASE; DENDRITIC CELLS; PROINFLAMMATORY CYTOKINE; CALRETICULIN EXPOSURE AB The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity. C1 [Gamrekelashvili, Jaba] Hannover Med Sch, Dept Nephrol, D-30623 Hannover, Germany. [Greten, Tim F.; Korangy, Firouzeh] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH,CCR, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH,CCR, Bldg 10 Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov; firouzeh.korangy@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU NCI, NIH FX This work was supported by the Intramural Research Program of the NCI, NIH. NR 116 TC 1 Z9 2 U1 2 U2 8 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JAN PY 2015 VL 72 IS 2 BP 273 EP 283 DI 10.1007/s00018-014-1741-x PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AY2FL UT WOS:000347404000005 PM 25274062 ER PT J AU Reis, J Fischer, JT Prichard, G Weiller, C Cohen, LG Fritsch, B AF Reis, Janine Fischer, Jan Torben Prichard, George Weiller, Cornelius Cohen, Leonardo G. Fritsch, Brita TI Time- but Not Sleep-Dependent Consolidation of tDCS-Enhanced Visuomotor Skills SO CEREBRAL CORTEX LA English DT Article DE cortical excitability; motor skill learning; noninvasive brain stimulation; warm-up decrement ID DIRECT-CURRENT STIMULATION; WARM-UP DECREMENT; PRIMARY MOTOR CORTEX; PROCEDURAL CONSOLIDATION; PREMOTOR CORTEX; SEQUENCE; PLASTICITY; MEMORY; PERFORMANCE; HUMANS AB Consolidation of motor skills after training can occur in a time- or sleep-dependent fashion. Recent studies revealed time-dependent consolidation as a common feature of visuomotor tasks. We have previously shown that anodal transcranial direct current stimulation (tDCS) in combination with repeated motor training benefits consolidation by the induction of offline skill gains in a complex visuomotor task, preventing the regular occurrence of skill loss between days. Here, we asked 2 questions: What is the time course of consolidation between days for this task and do exogenously induced offline gains develop as a function of time or overnight sleep? We found that both the development of offline skill loss in sham-stimulated subjects and offline skill gains induced by anodal tDCS critically depend on the passage of time after training, but not on overnight sleep. These findings support the view that tDCS interacts directly with the physiological consolidation process. However, in a control experiment, anodal tDCS applied after the training did not induce skill gains, implying that coapplication of tDCS and training is required to induce offline skill gains, pointing to the initiation of consolidation already during training. C1 [Reis, Janine; Fischer, Jan Torben; Prichard, George; Weiller, Cornelius; Fritsch, Brita] Univ Freiburg, Dept Neurol, D-79106 Freiburg, Germany. [Prichard, George] UCL London, Inst Cognit Neurosci, London, England. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Reis, J (reprint author), Univ Freiburg, Dept Neurol, Breisacher Str 64, D-79106 Freiburg, Germany. EM janine.reis@uniklinik-freiburg.de OI Fritsch, Brita/0000-0003-4884-9049 FU Alexander-von-Humboldt-Foundation; NINDS Intramural Program; Neurex Support Program for welcome/coming back of researchers FX This work was supported by a personal grant of the Alexander-von-Humboldt-Foundation and the NINDS Intramural Program (J.R. and L.G.C.) as well as the Neurex Support Program for welcome/coming back of researchers (J.R. and B.F.). NR 53 TC 19 Z9 20 U1 1 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JAN PY 2015 VL 25 IS 1 BP 109 EP 117 DI 10.1093/cercor/bht208 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AY2KA UT WOS:000347417600011 PM 23960213 ER PT J AU Taveira-DaSilva, AM Jones, AM Julien-Williams, PA Stylianou, M Moss, J AF Taveira-DaSilva, Angelo M. Jones, Amanda M. Julien-Williams, Patricia A. Stylianou, Mario Moss, Joel TI Retrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis SO CHEST LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; GIANT-CELL ASTROCYTOMAS; GROWTH CONTROL; GENE-PRODUCTS; LUNG-FUNCTION; ATORVASTATIN; EVEROLIMUS; MTOR; RHEB; TSC2 AB BACKGROUND: Combined simvastatin and sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. METHODS: To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus sirolimus (n = 14), sirolimus alone (n = 44), or simvastatin alone (n = 20). RESULTS: Sirolimus-related adverse events in the simvastatin plus sirolimus and sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (D-LCO) yearly rates of change were, respectively, -1.4 +/- 0.2 and -1.8 +/- 0.2% predicted. After simvastatin plus sirolimus therapy, these rates changed to +1.2 +/- 0.5 (P = .635) and +0.3 +/- 0.4% predicted (P = .412), respectively. In 44 patients treated with sirolimus alone, FEV1 and D-LCO rates of change were -1.7 +/- 0.1 and -2.2 +/- 0.1% predicted before treatment and +1.7 +/- 0.3 and +0.7 +/- 0.3% predicted after treatment (P<.001). CONCLUSIONS: Therapy with sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of sirolimus. C1 [Taveira-DaSilva, Angelo M.; Jones, Amanda M.; Julien-Williams, Patricia A.; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Stylianou, Mario] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Taveira-DaSilva, AM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute FX This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 32 TC 4 Z9 5 U1 0 U2 5 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2015 VL 147 IS 1 BP 180 EP 187 DI 10.1378/chest.14-0758 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AY3AH UT WOS:000347456500037 PM 25167325 ER PT J AU Hughes, DPM Kummar, S Lazar, AJ AF Hughes, Dennis P. M. Kummar, Shivaani Lazar, Alexander J. TI New, Tolerable gamma-Secretase Inhibitor Takes Desmoid Down a Notch SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID ADVANCED SOLID TUMORS; SIGNALING PATHWAY; PHASE-I; CANCER AB A phase I trial of PF-03084014, an oral reversible gamma-secretase inhibitor, in solid tumor malignancies shows drug tolerability in patients. Evidence of Notch pathway inhibition was demonstrated in peripheral blood. A surprisingly high rate of response was seen in desmoid tumors, a rare but sometimes locally aggressive sarcoma. (C) 2014 AACR. C1 [Hughes, Dennis P. M.] Univ Texas MD Anderson Canc Ctr, Childrens Canc Hosp, Dept Pediat Res, Houston, TX 77030 USA. [Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Lazar, Alexander J.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Lazar, Alexander J.] Univ Texas MD Anderson Canc Ctr, Sarcoma Res Ctr, Houston, TX 77030 USA. RP Lazar, AJ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Pathol, 1515 Holcombe Blvd,Unit 85, Houston, TX 77030 USA. EM alazar@mdanderson.org RI Lazar, Alexander/A-3416-2008 OI Lazar, Alexander/0000-0002-6395-4499 FU NCI NIH HHS [R01 CA141208, P30 CA016672, R01 CA149501, R01CA141208, R01CA149501] NR 11 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2015 VL 21 IS 1 BP 7 EP 9 DI 10.1158/1078-0432.CCR-14-1660 PG 3 WC Oncology SC Oncology GA AY3CQ UT WOS:000347462600003 PM 25336699 ER PT J AU Srinivasan, R Ricketts, CJ Sourbier, C Linehan, WM AF Srinivasan, Ramaprasad Ricketts, Christopher J. Sourbier, Carole Linehan, W. Marston TI New Strategies in Renal Cell Carcinoma: Targeting the Genetic and Metabolic Basis of Disease SO CLINICAL CANCER RESEARCH LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; KIDNEY CANCER; FUMARATE-HYDRATASE; HEREDITARY LEIOMYOMATOSIS; REDUCTIVE CARBOXYLATION; MET PROTOONCOGENE; POOR-PROGNOSIS; FACTOR 1-ALPHA; HIF-ALPHA; MUTATIONS AB The development of new forms of treatment of advanced renal cell carcinoma over the past two decades has been primarily focused on targeting the VHL/HIF pathway. The recent identification of mutations of chromatin-remodeling genes in clear-cell renal carcinoma (ccRCC), of genomic heterogeneity, and of a Warburg-like metabolic phenotype in advanced disease has had a profound effect on our understanding of the evolution of ccRCC and on potential approaches to personalized therapy. Early approaches to therapy for patients with advanced type I papillary RCC that have centered around the MET/HGF pathway will expand as more genomic information becomes available. Sporadic and familial type II papillary renal cell carcinoma are characterized by enhanced aerobic glycolysis and share an antioxidant response phenotype. In fumarate hydratase-deficient RCC, fumarate-induced succination of KEAP1 activates Nrf2 signaling. CUL3 and Nrf2 mutations as well as an Nrf2 activation phenotype are found in sporadic type II papillary RCC. Therapeutic approaches designed to target the Nrf2 pathway as well as to impair blood flow and glucose delivery in these cancers that are highly dependent on a robust tumor vasculature and on ready availability of glucose for energy production and glycolysis are in development. (C) 2015 AACR. C1 [Srinivasan, Ramaprasad; Ricketts, Christopher J.; Sourbier, Carole; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr MSC 1107,CRC Room 1W-5940, Bethesda, MD 20892 USA. EM WML@nih.gov FU NCI NIH HHS [Z01 BC011028-01, Z01 BC011038-01] NR 74 TC 20 Z9 20 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2015 VL 21 IS 1 BP 10 EP 17 DI 10.1158/1078-0432.CCR-13-2993 PG 8 WC Oncology SC Oncology GA AY3CQ UT WOS:000347462600004 PM 25564569 ER PT J AU Reiss, KA Herman, JM Zahurak, M Brade, A Dawson, LA Scardina, A Joffe, C Petito, E Hacker-Prietz, A Kinders, RJ Wang, LH Chen, A Temkin, S Horiba, N Siu, LL Azad, NS AF Reiss, Kim A. Herman, Joseph M. Zahurak, Marianna Brade, Anthony Dawson, Laura A. Scardina, Angela Joffe, Caitlin Petito, Emily Hacker-Prietz, Amy Kinders, Robert J. Wang, Lihua Chen, Alice Temkin, Sarah Horiba, Naomi Siu, Lillian L. Azad, Nilofer S. TI A Phase I Study of Veliparib (ABT-888) in Combination with Low-Dose Fractionated Whole Abdominal Radiation Therapy in Patients with Advanced Solid Malignancies and Peritoneal Carcinomatosis SO CLINICAL CANCER RESEARCH LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; PARP INHIBITOR; OVARIAN-CANCER; COLORECTAL ORIGIN; TREATMENT OPTIONS; TUMORS; RADIOTHERAPY; IRINOTECAN; MODELS; RADIOSENSITIZATION AB Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies. Experimental Design: Patients were treated with veliparib (80320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3of each cycle. Circulating tumor cells (CTC) were collected and evaluated for gamma-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (>= 24 weeks) was observed in 7 patients (33%). Median progressionfree survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of gamma-H2AX-positive CTCs was observed in a subset of patients (3/6 with > 2 CTCs at baseline). Conclusions: Combined veliparib and LDFWAR is a welltolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation. C1 [Reiss, Kim A.; Scardina, Angela; Joffe, Caitlin; Petito, Emily; Azad, Nilofer S.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Med Oncol, Baltimore, MD 21287 USA. [Herman, Joseph M.; Hacker-Prietz, Amy] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Radiat Oncol, Baltimore, MD 21287 USA. [Zahurak, Marianna] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Stat, Baltimore, MD USA. [Brade, Anthony; Dawson, Laura A.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON M5S 1A1, Canada. [Kinders, Robert J.; Wang, Lihua] NCI, Off Director, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Temkin, Sarah; Horiba, Naomi] Univ Maryland, Sch Med, Dept Obstet Gynecol & Reprod Sci, Baltimore, MD 21201 USA. [Siu, Lillian L.] Univ Toronto, Dept Med Oncol & Hematol, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5S 1A1, Canada. RP Azad, NS (reprint author), Johns Hopkins Univ, Sch Med, 1650 Orleans St,Suite 4M10, Baltimore, MD 21287 USA. EM nazad2@jhmi.edu FU Princess Margaret Phase I Consortium [U01-CA-132123]; Cancer Center support grant [P30 UMGCC]; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins [UO1CA070095] FX This study was supported by the following grants: U01-CA-132123 (Princess Margaret Phase I Consortium), the P30 UMGCC Cancer Center support grant, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, grant UO1CA070095. NR 47 TC 19 Z9 21 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2015 VL 21 IS 1 BP 68 EP 76 DI 10.1158/1078-0432.CCR-14-1552 PG 9 WC Oncology SC Oncology GA AY3CQ UT WOS:000347462600011 PM 25355929 ER PT J AU Baranello, RJ Bharani, KL Padmaraju, V Chopra, N Lahiri, DK Greig, NH Pappolla, MA Sambamurti, K AF Baranello, Robert J. Bharani, Krishna L. Padmaraju, Vasudevaraju Chopra, Nipun Lahiri, Debomoy K. Greig, Nigel H. Pappolla, Miguel A. Sambamurti, Kumar TI Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer's Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; amyloid beta degradation; amyloid beta peptide; endothelin-converting enzyme; insulin-degrading enzyme; neprilysin; neurodegeneration ID INSULIN-DEGRADING ENZYME; ANGIOTENSIN-CONVERTING ENZYME; RECEPTOR-RELATED PROTEIN; UBIQUITIN-PROTEASOME PATHWAY; N-END RULE; PRECURSOR PROTEIN; A-BETA; APOLIPOPROTEIN-E; MATRIX METALLOPROTEINASES; GAMMA-SECRETASE AB Amyloid-beta proteins (A beta) of 42 (A beta 42) and 40 aa (A beta 40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the A beta precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the epsilon 4 allele of Apolipoprotein E (ApoE-epsilon 4) foster the accumulation of A beta and also induce the entire spectrum of pathology associated with the disease. A beta accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by beta-site APP cleaving enzyme (BACE1) and gamma-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate A beta. Although A beta accumulates in all forms of AD, the only pathways known to be affected in FAD increase A beta production by APP gene duplication or via base substitutions on APP and gamma-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer A beta 42 or both A beta 40 and A beta 42. However, the vast majority of AD patients accumulate A beta without these known mutations. This led to proposals that impairment of A beta degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of gamma-secretase inhibitors to paradoxically increase the yield of A beta and we have recently established that the mechanism is by skirting A beta degradation. This review outlines major cellular pathways of A beta degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for A beta turnover. C1 [Baranello, Robert J.; Bharani, Krishna L.; Padmaraju, Vasudevaraju; Sambamurti, Kumar] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Chopra, Nipun; Lahiri, Debomoy K.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Pappolla, Miguel A.] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA. RP Sambamurti, K (reprint author), Med Univ S Carolina, Dept Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM sambak@musc.edu RI Bharani, Krishna/D-4179-2016 OI Bharani, Krishna/0000-0002-5441-4423 FU Alzheimer Association IIRG [10-173-180]; Alzheimer Association NIH [AG046200, AG042804]; Alzheimer's Association [IIRG-11-206418]; NIA; MSTP grant [NIH T32 GM08716-13] FX The authors thank the Alzheimer's Association IIRG 10-173-180 and NIH AG046200 to KS, Alzheimer's Association IIRG-11-206418 and NIH AG042804 to DKL and Intramural NIA to NHG supported this work. KLB was supported by an MSTP grant - NIH T32 GM08716-13. The authors thank Ms. Meera Parasuraman for reading and editing the manuscript. NR 196 TC 30 Z9 30 U1 3 U2 27 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PY 2015 VL 12 IS 1 BP 32 EP 46 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AY0PS UT WOS:000347299500004 PM 25523424 ER PT J AU El Meskini, R Iacovelli, AJ Kulaga, A Gumprecht, M Martin, PL Baran, M Householder, DB Van Dyke, T Ohler, ZW AF El Meskini, Rajaa Iacovelli, Anthony J. Kulaga, Alan Gumprecht, Michelle Martin, Philip L. Baran, Maureen Householder, Deborah B. Van Dyke, Terry Ohler, Zoe Weaver TI A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors SO DISEASE MODELS & MECHANISMS LA English DT Article DE Glioblastoma; Mouse model; PI3K and MEK inhibition; Apoptosis ID HIGH-GRADE ASTROCYTOMAS; IN-VIVO; MALIGNANT ASTROCYTOMAS; RADIATION-THERAPY; MOUSE MODELS; BRAIN-TUMORS; PHASE-I; ACTIVATION; GLIOMAS; PI3K/MTOR AB Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. C1 [El Meskini, Rajaa; Iacovelli, Anthony J.; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L.; Baran, Maureen; Householder, Deborah B.; Van Dyke, Terry; Ohler, Zoe Weaver] Leidos Biomed Res Inc, Ctr Adv Preclin Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Van Dyke, Terry] Frederick Natl Lab Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Ohler, ZW (reprint author), Leidos Biomed Res Inc, Ctr Adv Preclin Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM zweaverohler@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work has been funded with federal funds from the National Cancer Institute, National Institutes of Health under Contract No. HHSN261200800001E. NR 58 TC 5 Z9 5 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JAN PY 2015 VL 8 IS 1 BP 45 EP 56 DI 10.1242/dmm.018168 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AY1XI UT WOS:000347382400004 PM 25431423 ER PT J AU Attene-Ramos, MS Huang, RL Michael, S Witt, KL Richard, A Tice, RR Simeonov, A Austin, CP Xia, MH AF Attene-Ramos, Matias S. Huang, Ruili Michael, Sam Witt, Kristine L. Richard, Ann Tice, Raymond R. Simeonov, Anton Austin, Christopher P. Xia, Menghang TI Profiling of the Tox21 Chemical Collection for Mitochondrial Function to Identify Compounds that Acutely Decrease Mitochondrial Membrane Potential SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID CYTOCHROME-C RELEASE; OXIDATIVE-PHOSPHORYLATION; ENVIRONMENTAL CHEMICALS; LEUKEMIA-CELLS; DYSFUNCTION; MECHANISM; TOXICITY; APOPTOSIS; BRYOSTATIN-1; CYTOTOXICITY AB BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases. OBJECTIVES: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP). Methods: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (similar to 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. RESULTS: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cyto-toxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay <= 3; p < 0.05]. More than 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP. CONCLUSIONS: Our multiplexed qHTS approach allowed us to generate a robust and reliable data set to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity. C1 [Attene-Ramos, Matias S.; Huang, Ruili; Michael, Sam; Simeonov, Anton; Austin, Christopher P.; Xia, Menghang] NIH, Natl Ctr Advancing Translat Sci, US Dept HHS, Bethesda, MD 20892 USA. [Witt, Kristine L.; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Richard, Ann] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Xia, MH (reprint author), NIH, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU National Institute of Environmental Health Sciences (NIEHS)/Division of the National Toxicology Program [IAG Y2-ES-7020-01] FX This work was supported through interagency agreement IAG Y2-ES-7020-01 from the National Institute of Environmental Health Sciences (NIEHS)/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences, NIH. NR 45 TC 13 Z9 13 U1 5 U2 21 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 JAN PY 2015 VL 123 IS 1 BP 49 EP 56 DI 10.1289/ehp.1408642 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AY1YF UT WOS:000347385000013 PM 25302578 ER PT J AU Louis, GMB Chen, Z Schisterman, EF Kim, S Sweeney, AM Sundaram, R Lynch, CD Gore-Langton, RE Barr, DB AF Louis, Germaine M. Buck Chen, Zhen Schisterman, Enrique F. Kim, Sungduk Sweeney, Anne M. Sundaram, Rajeshwari Lynch, Courtney D. Gore-Langton, Robert E. Barr, Dana Boyd TI Perfluorochemicals and Human Semen Quality: The LIFE Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID MALE REPRODUCTIVE HEALTH; SPERM DNA FRAGMENTATION; IN-VITRO; PERFLUORINATED COMPOUNDS; ENDOCRINE DISRUPTERS; SERUM COTININE; EXPOSURE; MEN; PERFLUOROOCTANOATE; PFOS AB BACKGROUND: The relation between persistent environmental chemicals and semen quality is evolving, although limited data exist for men recruited from general populations. Objectives: We examined the relation between perfluorinated chemicals (PFCs) and semen quality among 501 male partners of couples planning pregnancy. METHODS: Using population-based sampling strategies, we recruited 501 couples discontinuing contraception from two U.S. geographic regions from 2005 through 2009. Baseline interviews and anthropometric assessments were conducted, followed by blood collection for the quantification of seven serum PFCs (perfluorosulfonates, perfluorocarboxylates, and perfluoro-sulfonamides) using tandem mass spectrometry. Men collected a baseline semen sample and another approximately 1 month later. Semen samples were shipped with freezer packs, and analyses were performed on the day after collection. We used linear regression to estimate the difference in each semen parameter associated with a one unit increase in the natural log-transformed PFC concentration after adjusting for confounders and modeling repeated semen samples. Sensitivity analyses included optimal Box-Cox transformation of semen quality end points. RESULTS: Six PFCs [2-(N-methyl-perfluorooctane sulfonamido) acetate (Me-PFOSA-AcOH), perfluoro-decanoate (PFDeA), perfluoro-nonanoate (PFNA), perfluorooctane sulfonamide (PFOSA), perfluoro-octane sulfonate (PFOS), and perfluoro-octanoic acid (PFOA)] were associated with 17 semen quality end points before Box-Cox transformation. PFOSA was associated with smaller sperm head area and perimeter, a lower percentage of DNA stainability, and a higher percentage of bicephalic and immature sperm. PFDeA, PFNA, PFOA, and PFOS were associated with a lower percentage of sperm with coiled tails. CONCLUSIONS: Select PFCs were associated with certain semen end points, with the most significant associations observed for PFOSA but with results in varying directions. C1 [Louis, Germaine M. Buck; Chen, Zhen; Schisterman, Enrique F.; Kim, Sungduk; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, US Dept HHS, Rockville, MD 20852 USA. [Sweeney, Anne M.] Univ Texas Rural Sch Publ Hlth, Dept Epidemiol & Biostat, College Stn, TX USA. [Lynch, Courtney D.] Ohio State Univ, Dept Obstet & Gynecol, Coll Med, Columbus, OH 43210 USA. [Gore-Langton, Robert E.] EMMES Corp, Rockville, MD USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01-HD-3-3355, N01-HD-3-3356, and NOH-HD-3-3358). NR 68 TC 10 Z9 13 U1 4 U2 32 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 JAN PY 2015 VL 123 IS 1 BP 57 EP 63 DI 10.1289/ehp.1307621 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AY1YF UT WOS:000347385000014 PM 25127343 ER PT J AU Whirledge, S Senbanjo, LT Cidlowski, JA AF Whirledge, Shannon Senbanjo, Linda T. Cidlowski, John A. TI Genistein Disrupts Glucocorticoid Receptor Signaling in Human Uterine Endometrial Ishikawa Cells SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID GENE-EXPRESSION; ESTROGEN; DISEASE; BINDING; BETA; SOY; ISOFLAVONES; INFERTILITY; INVITRO; CANCER AB BACKGROUND: The link between environmental estrogen exposure and defects in the female reproductive tract is well established. The phytoestrogen genistein is able to modulate uterine estrogen receptor (ER) activity, and dietary exposure is associated with uterine pathologies. Regulation of stress and immune functions by the glucocorticoid receptor (GR) is also an integral part of maintaining reproductive tract function; disruption of GR signaling by genistein may also have a role in the adverse effects of genistein. OBJECTIVE: We evaluated the transcriptional response to genistein in Ishikawa cells and investigated the effects of genistein on GR-mediated target genes. METHODS: We used Ishikawa cells as a model system to identify novel targets of genistein and the synthetic gluco-corticoid dexamethasone through whole genome microarray analysis. Common gene targets were defined and response patterns verified by quantitative real-time reverse-transcription polymerase chain reaction. The mechanism of transcriptional antagonism was determined for select genes. RESULTS: Genistein regulated numerous genes in Ishikawa cells independently of estradiol, and the response to coadministration of genistein and dexamethasone was unique compared with the response to either estradiol or dexamethasone alone. Furthermore, genistein altered gluco-corticoid regulation of GR target genes. In a select set of genes, co-regulation by dexamethasone and genistein was found to require both GR and ER alpha signaling, respectively. CONCLUSIONS: Using Ishikawa cells, we observed that exposure to genistein resulted in distinct changes in gene expression and unique differences in the GR transcriptome. C1 [Whirledge, Shannon; Senbanjo, Linda T.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the NIEHS, NIH FX This research was supported by the Intramural Research Program of the NIEHS, NIH. NR 34 TC 3 Z9 3 U1 1 U2 7 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 JAN PY 2015 VL 123 IS 1 BP 80 EP 87 DI 10.1289/ehp.1408437 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AY1YF UT WOS:000347385000017 PM 25136773 ER PT J AU Robledo, CA Yeung, E Mendola, P Sundaram, R Maisog, J Sweeney, AM Barr, DB Louis, GMB AF Robledo, Candace A. Yeung, Edwina Mendola, Pauline Sundaram, Rajeshwari Maisog, Jose Sweeney, Anne M. Barr, Dana Boyd Louis, Germaine M. Buck TI Preconception Maternal and Paternal Exposure to Persistent Organic Pollutants and Birth Size: The LIFE Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID POLYBROMINATED DIPHENYL ETHERS; UMBILICAL-CORD BLOOD; SOLID-PHASE EXTRACTION; POLYCHLORINATED-BIPHENYLS; GESTATIONAL-AGE; DEVELOPMENTAL TOXICITY; HUMAN-SERUM; PRENATAL EXPOSURE; PREGNANT-WOMEN; FETAL-GROWTH AB BACKGROUND: Persistent organic pollutants (POPs) are developmental toxicants, but the impact of both maternal and paternal exposures on offspring birth size is largely unexplored. OBJECTIVE: We examined associations between maternal and paternal serum concentrations of 63 POPs, comprising five major classes of pollutants, with birth size measures. METHODS: Parental serum concentrations of 9 organo-chlorine pesticides, 1 polybrominated biphenyl (PBB), 7 perfluoroalkyl chemicals (PFCs), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs) were measured before conception for 234 couples. Differences in birth weight, length, head circumference, and ponderal index were estimated using multiple linear regression per 1-SD increase in natural log-transformed (ln-transformed) chemicals. Models were estimated separately for each parent and adjusted for maternal age, maternal pre-pregnancy body mass index (kilograms per meter squared) and other confounders, and all models included an interaction term between infant sex and each chemical. RESULTS: Among girls (n = 117), birth weight was significantly lower (range, 84-195 g) in association with a 1-SD increase in ln-transformed maternal serum concentrations of DDT, PBDE congeners 28 and 183, and paternal serum concentrations of PBDE-183 and PCB-167. Among boys (n = 113), maternal (PCBs 138, 153, 167, 170, 195, and 209 and perfluorooctane sulfonamide) and paternal (PCBs 172 and 195) serum concentrations of several POPs were statistically associated with lower birth weight (range, 98-170 g), whereas paternal concentrations of PBDEs (66, 99) were associated with higher birth weight. Differences in offspring head circumference, length, and ponderal index were also associated with parental exposures. CONCLUSIONS: Preconceptional maternal and paternal concentrations of several POPs were associated with statistically significant differences in birth size among offspring. C1 [Robledo, Candace A.; Yeung, Edwina; Mendola, Pauline; Sundaram, Rajeshwari; Maisog, Jose; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Sweeney, Anne M.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, Dept Epidemiol & Biostat, College Stn, TX USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Robledo, CA (reprint author), Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Dept Behav & Community Hlth, 3500 Camp Bowie,EAD 709H, Ft Worth, TX 76107 USA. EM candace.robledo@unthsc.edu RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358). The CDC staff performed the analytic chemistry work for this study under a Memorandum of Understanding with the NICHD. NR 61 TC 12 Z9 12 U1 2 U2 30 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 JAN PY 2015 VL 123 IS 1 BP 88 EP 94 DI 10.1289/ehp.1308016 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AY1YF UT WOS:000347385000018 PM 25095280 ER PT J AU Rodriguez-Contreras, D Aslan, H Feng, XH Tran, K Yates, PA Kamhawi, S Landfear, SM AF Rodriguez-Contreras, Dayana Aslan, Hamide Feng, Xiuhong Tran, Khoa Yates, Phillip A. Kamhawi, Shaden Landfear, Scott M. TI Regulation and biological function of a flagellar glucose transporter in Leishmania mexicana: a potential glucose sensor SO FASEB JOURNAL LA English DT Article DE environmental sensing; Leishmania parasites; protein expression; transceptor; TaV2A peptide ID NUCLEOSIDE TRANSPORTER; TRYPANOSOMA-CRUZI; PRIMARY CILIUM; EXPRESSION; SEQUENCE; NUTRIENT; PROTEIN; HEXOSE; GENE; PROMASTIGOTES AB In Leishmania mexicana parasites, a unique glucose transporter, LmxGT1, is selectively targeted to the flagellar membrane, suggesting a possible sensory role that is often associated with ciliary membrane proteins. Expression of LmxGT1 is down-regulated similar to 20-fold by increasing cell density but is up-regulated similar to 50-fold by depleting glucose from the medium, and the permease is strongly down-regulated when flagellated insect-stage promastigotes invade mammalian macrophages and transform into intracellular amastigotes. Regulation of LmxGT1 expression by glucose and during the lifecycle operates at the level of protein stability. Significantly, Delta lmxgt1 null mutant, grown in abundant glucose, undergoes catastrophic loss of viability when parasites deplete glucose from the medium, a property not exhibited by wild-type or add-back lines. These results suggest that LmxGT1 may function as a glucose sensor that allows parasites to enter the stationary phase when they deplete glucose and that in the absence of this sensor, parasites do not maintain viability when they run out of glucose. However, alternate roles for LmxGT1 in monitoring glucose availability are considered. The absence of known sensory receptors with defined ligands and biologic functions in Leishmania and related kinetoplastid parasites underscores the potential significance of these observations. C1 [Rodriguez-Contreras, Dayana; Feng, Xiuhong; Tran, Khoa; Landfear, Scott M.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Yates, Phillip A.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Aslan, Hamide; Kamhawi, Shaden] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Landfear, SM (reprint author), Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM landfear@ohsu.edu FU Intramural NIH HHS; NCRR NIH HHS [S10 RR023432, S10-RR023432]; NIAID NIH HHS [AI023682, AI25920, F32 AI096854, R01 AI023682, R01 AI025920, R37 AI023682] NR 49 TC 6 Z9 6 U1 0 U2 9 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 JAN PY 2015 VL 29 IS 1 BP 11 EP 24 DI 10.1096/fj.14-251991 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AY1UX UT WOS:000347378600003 PM 25300620 ER PT J AU Csoka, B Nemeth, ZH Toro, G Koscso, B Kokai, E Robson, SC Enjyoji, K Rolandelli, RH Erdelyi, K Pacher, P Hasko, G AF Csoka, Balazs Nemeth, Zoltan H. Toero, Gabor Koscso, Balazs Kokai, Endre Robson, Simon C. Enjyoji, Keiichi Rolandelli, Rolando H. Erdelyi, Katalin Pacher, Pal Hasko, Gyoergy TI CD39 improves survival in microbial sepsis by attenuating systemic inflammation SO FASEB JOURNAL LA English DT Article DE interleukin; TNF; MIP; lung; kidney ID ISCHEMIA-REPERFUSION INJURY; A(2B) ADENOSINE RECEPTORS; MURINE SEPTIC PERITONITIS; ECTO-5'-NUCLEOTIDASE CD73; POLYMICROBIAL SEPSIS; TRIPHOSPHATE DIPHOSPHOHYDROLASE-1; DECREASES MORTALITY; HEPATIC-INJURY; MACROPHAGES; DYSFUNCTION AB Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Excessive inflammation is a major cause of organ failure and mortality in sepsis. Ectonucleoside triphosphate diphosphohydrolase 1, ENTPDase1 (CD39) is a cell surface nucleotide-metabolizing enzyme, which degrades the extracellular purines ATP and ADP, thereby regulating purinergic receptor signaling. Although the role of purinergic receptor signaling in regulating inflammation and sepsis has been addressed previously, the role of CD39 in regulating the host's response to sepsis is unknown. We found that the CD39 mimic apyrase (250 U/kg) decreased and knockout or pharmacologic blockade with sodium polyoxotungstate (5 mg/kg; IC50 approximate to 10 mu M) of CD39 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture. CD39 decreased inflammation, organ damage, immune cell apoptosis, and bacterial load. Use of bone marrow chimeric mice revealed that CD39 expression on myeloid cells decreases inflammation in septic mice. CD39 expression is upregulated during sepsis in mice, as well as in both murine and human macrophages stimulated with Escherichia coli. Moreover, E. coli increases CD39 promoter activity in macrophages. Altogether, these data indicate CD39 as an evolutionarily conserved inducible protective pathway during sepsis. We propose CD39 as a novel therapeutic target in the management of sepsis. C1 [Csoka, Balazs; Nemeth, Zoltan H.; Koscso, Balazs; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Csoka, Balazs; Koscso, Balazs; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ 07103 USA. [Nemeth, Zoltan H.; Rolandelli, Rolando H.] Morristown Med Ctr, Dept Surg, Morristown, NJ USA. [Toero, Gabor; Kokai, Endre; Hasko, Gyoergy] Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, H-4012 Debrecen, Hungary. [Robson, Simon C.; Enjyoji, Keiichi] Beth Israel Deaconess Med Ctr, Dept Med, Gastroenterol & Transplant Inst, Boston, MA 02215 USA. [Robson, Simon C.; Enjyoji, Keiichi] Harvard Univ, Sch Med, Boston, MA USA. [Erdelyi, Katalin; Pacher, Pal] NIAAA, Bethesda, MD USA. RP Hasko, G (reprint author), Rutgers New Jersey Med Sch, Dept Surg, 185 South Orange Ave, Newark, NJ 07103 USA. EM haskoge@njms.rutgers.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS; NIGMS NIH HHS [R01GM66189, R01 GM066189] NR 55 TC 7 Z9 7 U1 5 U2 12 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 JAN PY 2015 VL 29 IS 1 BP 25 EP 36 DI 10.1096/fj.14-253567 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AY1UX UT WOS:000347378600004 PM 25318479 ER PT J AU House, JS Li, HL DeGraff, LM Flake, G Zeldin, DC London, SJ AF House, John S. Li, Huiling DeGraff, Laura M. Flake, Gordon Zeldin, Darryl C. London, Stephanie J. TI Genetic variation in HTR4 and lung function: GWAS follow-up in mouse SO FASEB JOURNAL LA English DT Article DE pulmonary function; airway hyperresponsiveness; mouse models ID GENOME-WIDE ASSOCIATION; OBSTRUCTIVE PULMONARY-DISEASE; SEROTONIN 5-HT4 RECEPTORS; AIRWAY HYPERRESPONSIVENESS; ASTHMA; EXPRESSION; KNOCK; IDENTIFICATION; HIPPOCAMPUS; VARIANTS AB Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung resistance and also increased methacholine-induced airway hyper responsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitiveto serotonin-induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS. C1 [House, John S.; Li, Huiling; DeGraff, Laura M.; Zeldin, Darryl C.; London, Stephanie J.] NIEHS, Div Intramural Res, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Flake, Gordon] US Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Res Triangle Pk, NC USA. RP London, SJ (reprint author), NIEHS, NIH, 111 TW Alexander Dr,POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM london2@niehs.nih.gov OI House, John S./0000-0002-8447-7871; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS; NIBIB NIH HHS [P41 EB015897]; NIEHS NIH HHS [Z01 ES025045, Z01 ES043012]; PHS HHS [Z01 025043] NR 54 TC 1 Z9 1 U1 1 U2 6 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 JAN PY 2015 VL 29 IS 1 BP 323 EP 335 DI 10.1096/fj.14-253898 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AY1UX UT WOS:000347378600030 PM 25342126 ER PT J AU Markland, A Wang, L Jelovsek, JE Brubaker, L Tuteja, A Weidner, AC LoSavio, A Corton, M Meikle, S Richter, HE AF Markland, Alayne Wang, Lu Jelovsek, J. Eric Brubaker, Linda Tuteja, Ashook Weidner, Alison C. LoSavio, Andelka Corton, Marlene Meikle, Susan Richter, Holly E. TI Symptom Improvement in Women After Fecal Incontinence Treatments: A Multicenter Cohort Study of the Pelvic Floor Disorders Network SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE fecal incontinence; cohort study; surgical treatment; nonsurgical treatment; quality of life ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; BIOFEEDBACK; QUESTIONNAIRE; EPIDEMIOLOGY; POPULATION; OUTCOMES; PATIENT; ADULTS AB Objectives: The study aims were to characterize women with fecal incontinence (FI) and measure changes in FI severity and quality of life 3 and 12 months after treatment. Methods: This study is a secondary analysis of a multicenter study measuring adaptive behaviors among women with FI. Women included had a primary complaint of at least monthly FI over 3 consecutive months and planned FI treatment. Demographic and medical history data were obtained at baseline. Data were collected at baseline, 3 months, and 12 months after clinically selected, nonstandardized treatment. Validated questionnaires were as follows: Fecal Incontinence Severity Index, Modified Manchester Health Questionnaire, Pelvic Floor Disorders Inventory's Colorectal and Anal Distress Inventory, Pelvic Floor Impact Questionnaire's Colorectal and Anal Impact Questionnaire, and Medical Outcomes Study Short Form. Questionnaire score changes from baseline were compared using paired t tests at 3 and 12 months after treatment. Results: Of the 133 women enrolled, 90 women had treatment data at 3 months and 77 at 12 months. Nonsurgical therapies were the most common (78%) with anal sphincter repair in 22%. Fecal Incontinence Severity Index scores and Modified Manchester Health Questionnaire scores significantly improved 3 months after nonsurgical and surgical treatments (-8.8 +/- 12.0 and -12.6 +/- 19.2, respectively, P < 0.001), as did Colorectal-Anal Distress Inventory and Colorectal-Anal Impact Questionnaire scores (-52.7 +/- 70.0 and -60.6 +/- 70.0, respectively, P < 0.001) and Medical Outcomes Study Short Form mental health scores (4.2 +/- 9.4, P = 0.001). Improvement persisted 12 months posttreatment. Conclusions: In women seeking care for FI, symptom severity and condition-specific quality of life significantly improve within the first 3 months after FI treatment and are maintained up to 12 months. C1 [Markland, Alayne] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Wang, Lu] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jelovsek, J. Eric] Cleveland Clin, Dept Obstet Gynecol, Cleveland, OH 44106 USA. [Jelovsek, J. Eric] Cleveland Clin, Womens Hlth Inst, Cleveland, OH 44106 USA. [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL USA. [Tuteja, Ashook] Univ Utah, Salt Lake City Vet Affairs Med Ctr, Dept Med, Salt Lake City, UT USA. [Weidner, Alison C.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [LoSavio, Andelka] Loyola Univ Chicago, Stritch Sch Med, Dept Med, Chicago, IL USA. [Corton, Marlene] Univ Texas Southwestern, Dept Obstet & Gynecol, Dallas, TX USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL USA. RP Markland, A (reprint author), Birmingham Vet Affairs Med Ctr, Dept Med, Div Gerontol Geriatr & Palliat Care, GRECC 11-G,Room 8220,700 South 19th St, Birmingham, AL 35233 USA. EM amarkland@uabmc.edu OI Markland, Alayne/0000-0002-6567-6744 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health Office of Research on Women's Health [U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health (U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, and U10 HD54241). NR 29 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 EI 2154-4212 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD JAN-FEB PY 2015 VL 21 IS 1 BP 46 EP 52 DI 10.1097/SPV.0000000000000099 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AY3DN UT WOS:000347464800015 PM 25185613 ER PT J AU Reinhold, WC Varma, S Rajapakse, VN Luna, A Sousa, FG Kohn, KW Pommier, YG AF Reinhold, William C. Varma, Sudhir Rajapakse, Vinodh N. Luna, Augustin Sousa, Fabricio Garmus Kohn, Kurt W. Pommier, Yves G. TI Using drug response data to identify molecular effectors, and molecular "omic" data to identify candidate drugs in cancer SO HUMAN GENETICS LA English DT Review ID TUMOR-CELL-LINES; MICRORNA EXPRESSION PROFILES; GENE-EXPRESSION; VARIABLE SELECTION; MESSENGER-RNA; PANEL; SENSITIVITY; SCREEN; IDENTIFICATION; MUTATIONS AB The current convergence of molecular and pharmacological data provides unprecedented opportunities to gain insights into the relationships between the two types of data. Multiple forms of large-scale molecular data, including but not limited to gene and microRNA transcript expression, DNA somatic and germline variations from next-generation DNA and RNA sequencing, and DNA copy number from array comparative genomic hybridization are all potentially informative when one attempts to recognize the panoply of potentially influential events both for cancer progression and therapeutic outcome. Concurrently, there has also been a substantial expansion of the pharmacological data being accrued in a systematic fashion. For cancer cell lines, the National Cancer Institute cell line panel (NCI-60), the Cancer Cell Line Encyclopedia (CCLE), and the collaborative Genomics of Drug Sensitivity in Cancer (GDSC) databases all provide subsets of these forms of data. For the patient-derived data, The Cancer Genome Atlas (TCGA) provides analogous forms of genomic information along with treatment histories. Integration of these data in turn relies on the fields of statistics and statistical learning. Multiple algorithmic approaches may be chosen, depending on the data being considered, and the nature of the question being asked. Combining these algorithms with prior biological knowledge, the results of molecular biological studies, and the consideration of genes as pathways or functional groups provides both the challenge and the potential of the field. The ultimate goal is to provide a paradigm shift in the way that drugs are selected to provide a more targeted and efficacious outcome for the patient. C1 [Reinhold, William C.; Varma, Sudhir; Rajapakse, Vinodh N.; Luna, Augustin; Sousa, Fabricio Garmus; Kohn, Kurt W.; Pommier, Yves G.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD 20707 USA. [Luna, Augustin] Mem Sloan Kettering Canc Ctr, Comp Biol Program, New York, NY 10021 USA. [Sousa, Fabricio Garmus] Univ Fed Mato Grosso do Sul, CETROGEN, PPGFARM, BR-79070900 Campo Grande, MS, Brazil. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD 20707 USA. RP Reinhold, WC (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 5041, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov; pommier@nih.gov RI Sousa, Fabricio/O-8878-2015 OI Sousa, Fabricio/0000-0003-0444-754X FU Center for Cancer Research, Intramural Program of the National Cancer Institute [Z01 BC 006150]; MSKCC Genome Data Analysis Center [U24 CA143840]; National Cancer Institute (NCI)/National Human Genome Research Institute (NHGRI) FX Our studies are supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute (Z01 BC 006150). This work was also supported in part by a MSKCC Genome Data Analysis Center Grant (U24 CA143840) awarded as part of the National Cancer Institute (NCI)/National Human Genome Research Institute (NHGRI). NR 71 TC 8 Z9 8 U1 2 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JAN PY 2015 VL 134 IS 1 BP 3 EP 11 DI 10.1007/s00439-014-1482-9 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AY0NW UT WOS:000347294000002 PM 25213708 ER PT J AU Davis, JM Searles, VB Anderson, N Keeney, J Raznahan, A Horwood, LJ Fergusson, DM Kennedy, MA Giedd, J Sikela, JM AF Davis, Jonathon M. Searles, Veronica B. Anderson, Nathan Keeney, Jonathon Raznahan, Armin Horwood, L. John Fergusson, David M. Kennedy, Martin A. Giedd, Jay Sikela, James M. TI DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores SO HUMAN GENETICS LA English DT Article ID GENERAL INTELLIGENCE; CHILDREN; HERITABILITY; EVOLUTION; DOMAINS; CORTEX; SIZE AB DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts. C1 [Davis, Jonathon M.; Searles, Veronica B.; Anderson, Nathan; Keeney, Jonathon; Sikela, James M.] Univ Colorado, Dept Biochem & Mol Genet & Human Med Genet, Med Scientist Training Program, Sch Med, Aurora, CO 80045 USA. [Davis, Jonathon M.; Searles, Veronica B.; Anderson, Nathan; Keeney, Jonathon; Sikela, James M.] Univ Colorado, Dept Biochem & Mol Genet & Human Med Genet, Med Scientist Neurosci Program, Sch Med, Aurora, CO 80045 USA. [Raznahan, Armin; Giedd, Jay] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Horwood, L. John; Fergusson, David M.] Univ Otago, Dept Psychol Med, Christchurch Hlth & Dev Study, Christchurch 8140, New Zealand. [Kennedy, Martin A.] Univ Otago, Dept Pathol, Gene Struct & Funct Lab, Christchurch 8140, New Zealand. RP Sikela, JM (reprint author), Univ Colorado, Dept Biochem & Mol Genet & Human Med Genet, Med Scientist Training Program, Sch Med, Anschutz Med Campus,RC1-S,L18-10125, Aurora, CO 80045 USA. EM james.sikela@ucdenver.edu RI Giedd, Jay/J-9644-2015; Kennedy, Martin/A-4942-2008 OI Giedd, Jay/0000-0003-2002-8978; Kennedy, Martin/0000-0002-6445-8526 FU NIH [R01 MH081203]; Colorado Clinical and Translational Science Institute [TL1 TR001081]; Coleman Institute for Cognitive Disabilities; Health Research Council of New Zealand; National Child Health Research Foundation; Canterbury Medical Research Foundation; New Zealand Lottery Grants Board; Marsden Fund; James Hume Bequest Fund FX Funding for this work was provided by NIH R01 MH081203 (JMS), Colorado Clinical and Translational Science Institute TL1 TR001081 (VBS), and a Graduate Assistantship from the Coleman Institute for Cognitive Disabilities (JK). CHDS was funded by Grants from the Health Research Council of New Zealand, the National Child Health Research Foundation, the Canterbury Medical Research Foundation, the New Zealand Lottery Grants Board, the Marsden Fund, and the James Hume Bequest Fund. We thank Allison Miller for preparation of DNA samples. NR 29 TC 5 Z9 6 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JAN PY 2015 VL 134 IS 1 BP 67 EP 75 DI 10.1007/s00439-014-1489-2 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AY0NW UT WOS:000347294000008 PM 25287832 ER PT J AU Mansoor, A Patsekin, V Scherl, D Robinson, JP Rajwa, B AF Mansoor, Awais Patsekin, Valery Scherl, Dale Robinson, J. Paul Rajwa, Bartlomiej TI A Statistical Modeling Approach to Computer-Aided Quantification of Dental Biofilm SO IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS LA English DT Article DE Biofilm; dental plaque; Gaussian Markov random field (GMRF); quantitative fluorescence; superpixelization ID LIGHT-INDUCED FLUORESCENCE; IMAGE SEGMENTATION; PLAQUE; CLASSIFICATION; RELIABILITY; VALIDATION; CARIES; QLF AB Biofilm is a formation of microbial material on tooth substrata. Several methods to quantify dental biofilm coverage have recently been reported in the literature, but at best they provide a semiautomated approach to quantification with significant input from a human grader that comes with the grader's bias of what is foreground, background, biofilm, and tooth. Additionally, human assessment indices limit the resolution of the quantification scale; most commercial scales use five levels of quantification for biofilm coverage (0%, 25%, 50%, 75%, and 100%). On the other hand, current state-of-the-art techniques in automatic plaque quantification fail to make their way into practical applications owing to their inability to incorporate human input to handle misclassifications. This paper proposes a new interactive method for biofilm quantification in Quantitative light-induced fluorescence (QLF) images of canine teeth that is independent of the perceptual bias of the grader. The method partitions a QLF image into segments of uniform texture and intensity called superpixels; every superpixel is statistically modeled as a realization of a single 2-D Gaussian Markov random field (GMRF) whose parameters are estimated; the superpixel is then assigned to one of three classes (background, biofilm, tooth substratum) based on the training set of data. The quantification results show a high degree of consistency and precision. At the same time, the proposed method gives pathologists full control to postprocess the automatic quantification by flipping misclassified superpixels to a different state (background, tooth, biofilm) with a single click, providing greater usability than simply marking the boundaries of biofilm and tooth as done by current state-of-the-art methods. C1 [Mansoor, Awais] Purdue Univ, Dept Elect & Comp Engn, W Lafayette, IN 47906 USA. [Mansoor, Awais] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Patsekin, Valery; Rajwa, Bartlomiej] Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47906 USA. [Robinson, J. Paul] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47906 USA. [Scherl, Dale] Hills Pet Nutr, Topeka, KS 66603 USA. RP Mansoor, A (reprint author), Purdue Univ, Dept Elect & Comp Engn, W Lafayette, IN 47906 USA. EM awais.mansoor@gmail.com; vpatseki@purdue.edu; DaleScherl@hillpet.com; wombat@purdue.edu; brajwa@purdue.edu RI Rajwa, Bartek/B-3169-2009 OI Rajwa, Bartek/0000-0001-7540-8236 NR 39 TC 1 Z9 1 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2194 J9 IEEE J BIOMED HEALTH JI IEEE J. Biomed. Health Inform. PD JAN PY 2015 VL 19 IS 1 BP 358 EP 366 DI 10.1109/JBHI.2014.2310204 PG 9 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA AY1GP UT WOS:000347342300043 PM 25710065 ER PT J AU Williamson, JD Launer, LJ Miller, ME AF Williamson, Jeff D. Launer, Lenore J. Miller, Michael E. CA ACCORD MIND Investigators TI Faster Brain Shrinkage in the ACCORD MIND Study: An Unexpected Result? Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Williamson, Jeff D.] Wake Forest Univ, Dept Internal Med, Roena B Kulynych Ctr Memory & Cognit Res, Winston Salem, NC 27109 USA. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Miller, Michael E.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. RP Williamson, JD (reprint author), Wake Forest Sch Med, Dept Internal Med, Roena B Kulynych Ctr Memory & Cognit Res, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jwilliam@wakehealth.edu NR 1 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2015 VL 175 IS 1 BP 144 EP 145 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AY1BM UT WOS:000347328500040 PM 25560951 ER PT J AU Williams, PL Crain, MJ Yildirim, C Hazra, R Van Dyke, RB Rich, K Read, JS Stuard, E Rathore, M Mendez, HA Watts, DH AF Williams, Paige L. Crain, Marilyn J. Yildirim, Cenk Hazra, Rohan Van Dyke, Russell B. Rich, Kenneth Read, Jennifer S. Stuard, Emma Rathore, Mobeen Mendez, Hermann A. Watts, D. Heather CA Pediat HIV AIDS Cohort Study TI Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus-Exposed Uninfected Infants SO JAMA PEDIATRICS LA English DT Article ID HIV-INFECTED WOMEN; BIRTH-DEFECTS; 1ST TRIMESTER; PREGNANCY; RISK; THERAPY; CHILDREN; SAFETY; BORN; ABNORMALITIES AB IMPORTANCE Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents. OBJECTIVE To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012. EXPOSURES First-trimester exposure to any ARV and to specific ARV medications. MAIN OUTCOMES AND MEASURES The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics. RESULTS Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78%(95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs. CONCLUSIONS AND RELEVANCE Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted. C1 [Williams, Paige L.; Yildirim, Cenk] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Crain, Marilyn J.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Rich, Kenneth] Univ Illinois, Dept Pediat, Chicago, IL USA. [Read, Jennifer S.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Stuard, Emma] Bronx Lebanon Hosp Ctr, Dept Pediat Infect Dis, Bronx, NY USA. [Rathore, Mobeen] Univ Florida, Ctr HIV AIDS Res Educ & Serv, Jacksonville, FL USA. [Mendez, Hermann A.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Watts, D. Heather] US Dept State, Off US Global AIDS Coordinator, Washington, DC 20520 USA. RP Williams, PL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM paige@sdac.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse FX The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard School of Public Health (HD052102, 3 U01 HD052102-05S1, and 3 U01 HD052102-06S3) (principal investigator George Seage and project director Julie Alperen) and the Tulane University School of Medicine (HD052104 and 3U01HD052104-06S1) (principal investigator Russell B. Van Dyke, coprincipal investigator Kenneth Rich, and project director Patrick Davis). Data management services were provided by the Frontier Science and Technology Research Foundation, Inc (principal investigator Suzanne Siminski), and regulatory services and logistical support were provided byWestat, Inc (principal investigator Julie Davidson). NR 32 TC 11 Z9 11 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD JAN PY 2015 VL 169 IS 1 BP 48 EP 55 DI 10.1001/jamapediatrics.2014.1889 PG 8 WC Pediatrics SC Pediatrics GA AY1JI UT WOS:000347349300014 PM 25383770 ER PT J AU McGowan, EC Bloomberg, GR Gergen, PJ Visness, CM Jaffee, KF Sandel, M O'Connor, G Kattan, M Gern, J Wood, RA AF McGowan, Emily C. Bloomberg, Gordon R. Gergen, Peter J. Visness, Cynthia M. Jaffee, Katy F. Sandel, Megan O'Connor, George Kattan, Meyer Gern, James Wood, Robert A. TI Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Food allergy; inner city; Urban Environment and Childhood Asthma cohort; specific IgE ID PEANUT-SPECIFIC IGG; EGG ALLERGY; NATIONAL-HEALTH; EARLY-CHILDHOOD; UNITED-STATES; PREVALENCE; CHILDREN; ASTHMA; ENDOTOXIN; URBAN AB Objective: Previous data suggest that food allergy (FA) might be more common in inner-city children; however, these studies have not collected data on both sensitization and clinical reactivity or early-life exposures. Methods: Children in the Urban Environment and Childhood Asthma birth cohort were followed through age 5 years. Household exposures, diet, clinical history, and physical examinations were assessed yearly; levels of specific IgE to milk, egg, and peanut were measured at 1, 2, 3, and 5 years of age. On the basis of sensitization (IgE >= 0.35 kU/L) and clinical history over the 5-year period, children were classified as having FA or being possibly allergic, sensitized but tolerant, or not allergic/not sensitized. Results: Five hundred sixteen children were included. Overall, 55.4% were sensitized (milk, 46.7%; egg, 31.0%; and peanut, 20.9%), whereas 9.9% were categorized as having FA (peanut, 6.0%; egg, 4.3%; andmilk, 2.7%; 2.5% to > 1 food). The remaining children were categorized as possibly allergic (17.0%), sensitized but tolerant (28.5%), and not sensitized (44.6%). Eighteen (3.5%) reported reactions to foods forwhich IgElevelswere not measured. Food-specific IgE levels were similar in children with FA versus sensitized but tolerant children, except for egg, levels ofwhich were higher in patients with FA at ages 1 and 2 years. FA was associated with recurrent wheeze, eczema, aeroallergen sensitization, male sex, breast-feeding, and lower endotoxin exposure in year 1 but not with race/ethnicity, income, tobacco exposure, maternal stress, or early introduction of solid foods. Conclusions: Even given that this was designed to be a high-risk cohort, the cumulative incidence of FA is extremely high, especially considering the strict definition of FA that was applied and that only 3 common allergens were included. C1 [McGowan, Emily C.] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Dept Med, Baltimore, MD 21287 USA. [McGowan, Emily C.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bloomberg, Gordon R.] Washington Univ, Sch Med, Div Allergy Immunol & Pulm Med, St Louis, MO 63130 USA. [Gergen, Peter J.] NIAID, NIH, Bethesda, MD 20892 USA. [Visness, Cynthia M.; Jaffee, Katy F.] Rho Inc, Chapel Hill, NC USA. [Sandel, Megan] Boston Univ, Sch Med, Dept Med, Div Pediat Primary Care, Boston, MA 02118 USA. [O'Connor, George] Boston Univ, Sch Med, Dept Med, Div Pulm Allergy Sleep & Crit Care Med, Boston, MA 02118 USA. [Kattan, Meyer] New York Presbyterian Columbia Univ, Med Ctr, Div Pediat Pulmonol, Dept Pediat, New York, NY USA. [Gern, James] Univ Wisconsin, Sch Med, Dept Pediat, Div Allergy & Immunol, Madison, WI 53706 USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Div Allergy & Immunol, Baltimore, MD 21287 USA. RP Wood, RA (reprint author), Johns Hopkins Univ, Sch Med, 600 North Wolfe St,CMSC 1102, Baltimore, MD 21287 USA. EM rwood@jhmi.edu FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; Department of Health and Human Services [NO1-AI-25496, NO1-AI-25482, HHSN2722 00900052C, HHSN272201000052I] FX Supported in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract nos. NO1-AI-25496, NO1-AI-25482, HHSN2722 00900052C, and HHSN272201000052I. Additional support was provided under grants RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, and 5UL1RR024992-02. NR 37 TC 12 Z9 12 U1 5 U2 27 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2015 VL 135 IS 1 BP 171 EP U261 DI 10.1016/j.jaci.2014.06.033 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA AY0PG UT WOS:000347298200021 PM 25129677 ER PT J AU Pino-Yanes, M Thakur, N Gignoux, CR Galanter, JM Roth, LA Eng, C Nishimura, KK Oh, SS Vora, H Huntsman, S Nguyen, EA Hu, DL Drake, KA Conti, DV Moreno-Estrada, A Sandoval, K Winkler, CA Borrell, LN Lurmann, F Islam, TS Davis, A Farber, HJ Meade, K Avila, PC Serebrisky, D Bibbins-Domingo, K Lenoir, MA Ford, JG Brigino-Buenaventura, E Rodriguez-Cintron, W Thyne, SM Sen, S Rodriguez-Santana, JR Bustamante, CD Williams, LK Gilliland, FD Gauderman, WJ Kumar, R Torgerson, DG Burchard, EG AF Pino-Yanes, Maria Thakur, Neeta Gignoux, Christopher R. Galanter, Joshua M. Roth, Lindsey A. Eng, Celeste Nishimura, Katherine K. Oh, Sam S. Vora, Hita Huntsman, Scott Nguyen, Elizabeth A. Hu, Donglei Drake, Katherine A. Conti, David V. Moreno-Estrada, Andres Sandoval, Karla Winkler, Cheryl A. Borrell, Luisa N. Lurmann, Fred Islam, Talat S. Davis, Adam Farber, Harold J. Meade, Kelley Avila, Pedro C. Serebrisky, Denise Bibbins-Domingo, Kirsten Lenoir, Michael A. Ford, Jean G. Brigino-Buenaventura, Emerita Rodriguez-Cintron, William Thyne, Shannon M. Sen, Saunak Rodriguez-Santana, Jose R. Bustamante, Carlos D. Williams, L. Keoki Gilliland, Frank D. Gauderman, W. James Kumar, Rajesh Torgerson, Dara G. Burchard, Esteban G. TI Genetic ancestry influences asthma susceptibility and lung function among Latinos SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; PUERTO-RICAN CHILDREN; NATIVE-AMERICAN ANCESTRY; CHILDHOOD ASTHMA; AFRICAN ANCESTRY; UNITED-STATES; SOCIOECONOMIC-STATUS; ADMIXED POPULATIONS; LOCAL ANCESTRY; SKIN COLOR AB Background: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. Objective: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. Methods: We analyzed 5493 Latinos with and without asthma from3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios ( OR) and effect sizes were assessed for every 20% increase in each ancestry. Results: Native American ancestry was associated with lower odds of asthma ( OR 5 0.72, 95% CI: 0.66-0.78, P 5 8.0 3 10 215), while African ancestry was associated with higher odds of asthma ( OR 5 1.40, 95% CI: 1.14-1.72, P 5.001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre-and postbronchodilator measures of FEV1 ( 277 6 19 mL; P 5 5.8 3 10 25 and 283 6 19 mL; P 5 1.1 x 10 25, respectively) and forced vital capacity ( 2100 6 21 mL; P 5 2.7 3 10 26 and 2107 6 22 mL; P 5 1.0 x 10 26, respectively). Conclusion: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos. ( J Allergy Clin Immunol 2015; 135: 228-35.) C1 [Pino-Yanes, Maria; Thakur, Neeta; Galanter, Joshua M.; Roth, Lindsey A.; Eng, Celeste; Nishimura, Katherine K.; Oh, Sam S.; Huntsman, Scott; Nguyen, Elizabeth A.; Hu, Donglei; Torgerson, Dara G.; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pino-Yanes, Maria; Burchard, Esteban G.] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Gignoux, Christopher R.; Galanter, Joshua M.; Drake, Katherine A.; Burchard, Esteban G.] UCSF, Dept Bioengn & Therapeut Sci, San Francisco, CA USA. [Vora, Hita; Conti, David V.; Islam, Talat S.; Gilliland, Frank D.; Gauderman, W. James] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Moreno-Estrada, Andres; Sandoval, Karla; Bustamante, Carlos D.] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Winkler, Cheryl A.] NCI, Basic Res Lab, SAIC Frederick Inc, Ctr Canc Res, Frederick, MD 21701 USA. [Borrell, Luisa N.] CUNY, Dept Hlth Sci, Grad Program Publ Hlth, Bronx, NY USA. [Lurmann, Fred] Sonoma Technol Inc, Petaluma, CA USA. [Davis, Adam; Meade, Kelley] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Farber, Harold J.] Baylor Coll Med, Dept Pediat, Sect Pulmonol, Houston, TX 77030 USA. [Farber, Harold J.] Texas Childrens Hosp, Houston, TX 77030 USA. [Avila, Pedro C.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Serebrisky, Denise] Jacobi Med Ctr, Pediat Pulm Div, Bronx, NY USA. [Bibbins-Domingo, Kirsten] UCSF, Div Gen Internal Med, San Francisco, CA USA. [Lenoir, Michael A.] Bay Area Pediat, Oakland, CA USA. [Ford, Jean G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Brigino-Buenaventura, Emerita] Kaiser Permanente Vallejo Med Ctr, Dept Allergy & Immunol, Vallejo, CA USA. [Rodriguez-Cintron, William] Vet Caribbean Hlth Care Syst, San Juan, PR USA. [Thyne, Shannon M.] UCSF, San Francisco Gen Hosp, Dept Pediat, San Francisco, CA USA. [Sen, Saunak] UCSF, Dept Epidemiol & Biostat, San Francisco, CA USA. [Rodriguez-Santana, Jose R.] Ctr Neumol Pediat, San Juan, PR USA. [Williams, L. Keoki] Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Kumar, Rajesh] Northwestern Univ, Childrens Mem Hosp, Chicago, IL 60614 USA. [Kumar, Rajesh] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Pino-Yanes, M (reprint author), Univ Calif San Francisco, Dept Med, 1550 4th St,Rock Hall Room 582,UCSF Box 2911, San Francisco, CA 94143 USA. EM mdelpino@ull.edu.es RI Pino-Yanes, Maria/C-8498-2017; OI Pino-Yanes, Maria/0000-0003-0332-437X; Nguyen, Elizabeth/0000-0002-8070-6382 FU National Institutes of Health (NIH) [R01-ES015794, U19-AI077439, R01-HL088133, R01-HL078885, R25-CA113710, T32-GM007546, R01-HL004464, R01-HL104608, R01AI079139, R01AI061774, P30ES007048, P01ES011627, R01ES023262, R01ES021801, K23-HL093023]; National Institute onMinorityHealthAndHealth Disparities [P60MD006902, M01-RR00188]; NationalCancer Institute, National Institutes ofHealth [HHSN26120080001E] FX This study was supported in part by National Institutes of Health (NIH) R01-ES015794, U19-AI077439, R01-HL088133, R01-HL078885, R25-CA113710, T32-GM007546, R01-HL004464, R01-HL104608 to E. G. B., R01AI079139 and R01AI061774 to L. K. W., P30ES007048, P01ES011627, R01ES023262, R01ES021801 to F. G., and K23-HL093023 to R. K.; the National Institute onMinorityHealthAndHealth Disparities under award number P60MD006902 to K. B. D and E. G. B. and M01-RR00188 to the Texas Children's Hospital General Clinical Research Center; Flight Attendant Medical Research Institute, RWJFAmosMedical FacultyDevelopmentAward, the Sandler Foundation to E. G. B.; theAmerican Asthma Foundation to L. K. W. and E. G. B.; Ernest S. BazleyGrant to P. C. A.; and theNationalCancer Institute, National Institutes ofHealth, under contract HHSN26120080001E by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research to C. A. W. C. R. G. was supported in part by the UCSF Chancellor's Research Fellowship, Dissertation Year Fellowship, and National Institutes of Health Training Grant T32 GM007175. J. M. G. was supported in part by National Institutes of Health Training Grant T32 (GM007546) and career development awards from the NHLBI K23 (K23HL111636) and NCATS KL2 (KL2TR000143), aswell as the Hewett Fellowship. M. P. Y. was funded by a postdoctoral fellowship from Fundaci ~ on Ram ~ on Areces, Madrid, Spain. NR 53 TC 18 Z9 18 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2015 VL 135 IS 1 BP 228 EP 235 DI 10.1016/j.jaci.2014.07.053 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA AY0PG UT WOS:000347298200027 PM 25301036 ER PT J AU Powell-Wiley, TM AF Powell-Wiley, Tiffany M. TI Capsule Commentary on Paul et al., Size Misperception Among Overweight and Obese Families SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM Tiffany.powell@nih.gov FU Intramural NIH HHS NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JAN PY 2015 VL 30 IS 1 BP 95 EP 95 DI 10.1007/s11606-014-3040-5 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AY2JG UT WOS:000347414800019 PM 25277879 ER PT J AU Wu, J Zhang, RH Tang, N Gong, ZZ Zhou, JF Chen, YW Chen, K Cai, W AF Wu, Jin Zhang, Ruihua Tang, Ning Gong, Zizhen Zhou, Jiefei Chen, Yingwei Chen, Kang Cai, Wei TI Dopamine inhibits the function of Gr-1(+)CD115(+) myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE iNOS; nitric oxide; MDSC; neurotransmitter; cancer; immune suppression ID REGULATORY T-CELLS; TUMOR-BEARING MICE; NITRIC-OXIDE; PARKINSONS-DISEASE; SIGNALING PATHWAY; CANCER-PATIENTS; INFLAMMATION; LYMPHOCYTE; ACTIVATION; MECHANISM AB MDSCs accumulate in tumor-bearing animals and cancer patients and are a major factor responsible for cancer-induced immunosuppression that limits effective cancer immunotherapy. Strategies aimed at effectively inhibiting the function of MDSCs are expected to enhance host anti-tumor immunity and improve cancer immunotherapy significantly. The neurotransmitter DA has been found to have anti-cancer activity, but the underlying mechanism is poorly understood. In this study, we sought to investigate the therapeutic mechanism and efficacy of DA on the inhibition of cancer development via the regulation of MDSC functions. The regulation of the suppressive function of Gr-1(+)CD115(+) MDSCs by DA was determined by use of murine syngeneic LLC and B16 graft models treated with DA in vivo, as well as Gr-1(+)CD115(+) MDSCs isolated from these model treated with DA ex vivo. Here, we show that Gr-1(+)CD115(+) monocytic MDSCs express D1-like DA receptors. DA dramatically attenuated the inhibitory function of tumor-induced monocytic MDSCs on T cell proliferation and IFN-gamma production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-gamma-induced NO production by MDSCs from tumor-bearing mice and cancer patients. Decreased NO production was, in part, mediated via the suppression of p-ERK and p-JNK. In conclusion, the neurotransmitter DA potently inhibits the suppressive function of MDSC and enhances anti-tumor immunity. Our finding provides a mechanistic basis for the use of DA or D1-like receptor agonists to overcome tumor-induced immunosuppression in cancer immunotherapy. C1 [Wu, Jin; Tang, Ning; Gong, Zizhen; Zhou, Jiefei; Chen, Yingwei; Cai, Wei] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Shanghai Inst Pediat Res, Shanghai, Peoples R China. [Chen, Yingwei] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Gastroenterol, Shanghai, Peoples R China. [Wu, Jin; Tang, Ning; Gong, Zizhen; Zhou, Jiefei; Chen, Yingwei; Cai, Wei] Shanghai Key Lab Pediat Gastroenterol & Nutr, Shanghai, Peoples R China. [Zhang, Ruihua] Icahn Sch Med Mt Sinai, Dept Med, Inst Immunol, New York, NY 10029 USA. [Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Immunol & Microbiol, Detroit, MI USA. [Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, US Natl Inst Hlth, Detroit, MI USA. [Chen, Kang] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wu, J (reprint author), Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China. EM wujin51@yahoo.com; caiw1978@163.com FU National Natural Science Foundation of China [81201602]; Shanghai Pujiang Program [12PJ1407600]; Scientific Foundation of Shanghai Health Bureau [20114138]; Scientific Research Foundation for Returned Scholars (Ministry of Education of China); Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition [11DZ2260500] FX This work was supported by grants from National Natural Science Foundation of China (81201602), Shanghai Pujiang Program (12PJ1407600), Scientific Foundation of Shanghai Health Bureau (20114138), and Scientific Research Foundation for Returned Scholars (Ministry of Education of China; to J.W.) and Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition (11DZ2260500; to W.C.). NR 55 TC 6 Z9 8 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 JAN PY 2015 VL 97 IS 1 BP 191 EP 200 DI 10.1189/jlb.5A1113-626RR PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AY3CZ UT WOS:000347463400021 PM 25341727 ER PT J AU Lockey, JE Redlich, CA Streicher, R Pfahles-Hutchens, A Hakkinen, PJ Ellison, GL Harber, P Utell, M Holland, J Comai, A White, M AF Lockey, James E. Redlich, Carrie A. Streicher, Robert Pfahles-Hutchens, Andrea Hakkinen, Pertti (Bert) J. Ellison, Gary L. Harber, Philip Utell, Mark Holland, John Comai, Andrew White, Marc TI Isocyanates and Human Health Multistakeholder Information Needs and Research Priorities SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID METHYLENE DIPHENYL DIISOCYANATE; COLLISION REPAIR INDUSTRY; OCCUPATIONAL ASTHMA; TOLUENE DIISOCYANATE; EXPOSURE LIMITS; SKIN EXPOSURE; POLYURETHANE; SURVEILLANCE AB Objectives: To outline the knowledge gaps and research priorities identified by a broad base of stakeholders involved in the planning and participation of an international conference and research agenda workshop on isocyanates and human health held in Potomac, Maryland, in April 2013. Methods: A multimodal iterative approach was used for data collection including preconference surveys, review of a 2001 consensus conference on isocyanates, oral and poster presentations, focused break-out sessions, panel discussions, and postconference research agenda workshop. Results: Participants included representatives of consumer and worker health, health professionals, regulatory agencies, academic and industry scientists, labor, and trade associations. Conclusions: Recommendations were summarized regarding knowledge gaps and research priorities in the following areas: worker and consumer exposures; toxicology, animal models, and biomarkers; human cancer risk; environmental exposure and monitoring; and respiratory epidemiology and disease, and occupational health surveillance. C1 [Lockey, James E.] Univ Cincinnati, Div Occupat & Environm Med, Dept Environm Hlth, Pulm Div,Dept Internal Med,Coll Med, Cincinnati, OH 45267 USA. [Redlich, Carrie A.] Yale Univ, Sch Med, Yale Occupat & Environm Med, New Haven, CT USA. [Streicher, Robert] NIOSH, Div Appl Res & Technol, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Pfahles-Hutchens, Andrea] US EPA, Risk Assessment Div, Off Chem Safety & Pollut Prevent, Washington, DC 20460 USA. [Hakkinen, Pertti (Bert) J.] NIH, Off Clin Toxicol, Specialized Informat Serv, Natl Lib Med, Bethesda, MD 20892 USA. [Ellison, Gary L.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Harber, Philip] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Utell, Mark] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Holland, John] Holland Associates, Palo Alto, CA USA. [Comai, Andrew] UAW Hlth & Safety, Int Union, Detroit, MI USA. [White, Marc] Univ British Columbia, Dept Family Practice, Vancouver, BC V5Z 1M9, Canada. [White, Marc] Canadian Inst Relief Pain & Disabil, Vancouver, BC, Canada. RP Lockey, JE (reprint author), Univ Cincinnati, Coll Med, Div Occupat & Environm Med, Dept Environm Hlth, 3223 Eden Ave, Cincinnati, OH 45267 USA. EM lockeyje@ucmail.uc.edu RI White, Marc/N-8404-2015; Hakkinen, Pertti/G-4803-2016; OI Hakkinen, Pertti/0000-0002-8295-9738; White, Marc/0000-0001-7623-1268 FU National Institutes of Health, National Cancer Institute; Canadian Institutes for Health Research-Institute of Cancer Research; University of Cincinnati College of Medicine FX National Institutes of Health, National Cancer Institute; Canadian Institutes for Health Research-Institute of Cancer Research; and University of Cincinnati College of Medicine. NR 30 TC 3 Z9 3 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JAN PY 2015 VL 57 IS 1 BP 44 EP 51 DI 10.1097/JOM.0000000000000278 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AY3IP UT WOS:000347477900010 PM 25563538 ER PT J AU Wigton, R Radua, J Allen, P Averbeck, B Meyer-Lindenberg, A McGuire, P Shergill, SS Fusar-Poli, P AF Wigton, Rebekah Radua, Jocham Allen, Paul Averbeck, Bruno Meyer-Lindenberg, Andreas McGuire, Philip Shergill, Sukhi S. Fusar-Poli, Paolo TI Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Review ID SOCIAL ANXIETY DISORDER; ASSOCIATIVE LEARNING-TASK; HUMAN BRAIN; EMOTIONAL FACES; DOPAMINE INTERACTIONS; INTRANASAL OXYTOCIN; AMYGDALA REACTIVITY; PREFRONTAL CORTEX; INSULA ACTIVATION; NEURAL CIRCUITRY AB Background: Oxytocin (OXT) plays a prominent role in social cognition and may have clinical applications for disorders such as autism, schizophrenia and social anxiety. The neural basis of its mechanism of action remains unclear. Methods: We conducted a systematic literature review of placebo-controlled imaging studies using OXT as a pharmacological manipulator of brain activity. Results: We identified a total of 21 studies for inclusion in our review, and after applying additional selection criteria, 11 of them were included in our fMRI voxel-based meta-analysis. The results demonstrate consistent alterations in activation of brain regions, including the temporal lobes and insula, during the processing of social stimuli, with some variation dependent on sex and task. The meta-analysis revealed significant left insular hyperactivation after OXT administration, suggesting a potential modulation of neural circuits underlying emotional processing. Limitations: This quantitative review included only a limited number of studies, thus the conclusions of our analysis should be interpreted cautiously. This limited sample size precluded a more detailed exploration of potential confounding factors, such as sex or other demographic factors, that may have affected our meta-analysis. Conclusion: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity. The magnitude of this neural activation is largest in the temporal lobes, and a meta-analysis across all tasks and both sexes showed that the left insula demonstrated the most robust activation to OXT administration. C1 [Wigton, Rebekah; Radua, Jocham; Allen, Paul; McGuire, Philip; Shergill, Sukhi S.; Fusar-Poli, Paolo] Kings Coll London, Inst Psychiat, Dept Psychosis Studies, London SE5 8AF, England. [Radua, Jocham] Cibersam, Fidmag, Barcelona, Spain. [Averbeck, Bruno] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany. RP Wigton, R (reprint author), Kings Coll London, Inst Psychiat, Cognit & Schizophrenia Imaging Lab, De Crespigny Pk Rd, London SE5 8AF, England. EM rebekah.wigton@kcl.ac.uk RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU NARSAD Young Investigator Award FX P. Fusar-Poli was supported in part by a 2014 NARSAD Young Investigator Award. NR 133 TC 23 Z9 23 U1 1 U2 29 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 1180-4882 EI 1488-2434 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JAN PY 2015 VL 40 IS 1 BP E1 EP E22 DI 10.1503/jpn.130289 PG 22 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AY4KA UT WOS:000347545500001 PM 25520163 ER PT J AU Starke, C Betz, H Hickmann, L Lachmann, P Neubauer, B Kopp, JB Sequeira-Lopez, MLS Gomez, RA Hohenstein, B Todorov, VT Hugo, CPM AF Starke, Charlotte Betz, Hannah Hickmann, Linda Lachmann, Peter Neubauer, Bjoern Kopp, Jeffrey B. Sequeira-Lopez, Maria Luisa S. Gomez, R. Ariel Hohenstein, Bernd Todorov, Vladimir T. Hugo, Christian P. M. TI Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID EXPRESSION; MICE; GLOMERULONEPHRITIS; NEPHRITIS; PHENOTYPE AB Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reportermice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers alpha 8-integrin and PDGF receptor-beta but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury. C1 [Starke, Charlotte; Betz, Hannah; Hickmann, Linda; Lachmann, Peter; Hohenstein, Bernd; Todorov, Vladimir T.; Hugo, Christian P. M.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Div Nephrol, Dept Internal Med 3, D-01307 Dresden, Germany. [Neubauer, Bjoern] Univ Regensburg, Inst Physiol, D-93053 Regensburg, Germany. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Sequeira-Lopez, Maria Luisa S.; Gomez, R. Ariel] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA. RP Todorov, VT (reprint author), Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Div Nephrol, Dept Internal Med 3, Fetscherstr 74, D-01307 Dresden, Germany. EM vladimir.todorov@uniklinikum-dresden.de; christian.hugo@uniklinikum-dresden.de OI Kopp, Jeffrey/0000-0001-9052-186X FU German Research Foundation [HU-600/6-1, TO 679/1-1, SFB 699/B1, HO-2522/6-1]; Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by grants from the German Research Foundation(HU-600/6-1 to C.H., TO 679/1-1 and SFB 699/B1 to V.T.T., and HO-2522/6-1 to B.H.) and the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (to J.B.K.). NR 18 TC 14 Z9 14 U1 2 U2 6 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 JAN PY 2015 VL 26 IS 1 BP 48 EP 54 DI 10.1681/ASN.2014030265 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AY4QS UT WOS:000347564000009 PM 24904091 ER PT J AU Yoo, TH Pedigo, CE Guzman, J Correa-Medina, M Wei, CL Villarreal, R Mitrofanova, A Leclercq, F Faul, C Li, J Kretzler, M Nelson, RG Lehto, M Forsblom, C Groop, PH Reiser, J Burke, GW Fornoni, A Merscher, S AF Yoo, Tae-Hyun Pedigo, Christopher E. Guzman, Johanna Correa-Medina, Mayrin Wei, Changli Villarreal, Rodrigo Mitrofanova, Alla Leclercq, Farah Faul, Christian Li, Jing Kretzler, Matthias Nelson, Robert G. Lehto, Markku Forsblom, Carol Groop, Per-Henrik Reiser, Jochen Burke, George William Fornoni, Alessia Merscher, Sandra TI Sphingomyelinase-Like Phosphodiesterase 3b Expression Levels Determine Podocyte Injury Phenotypes in Glomerular Disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HUMAN DIABETIC-NEPHROPATHY; TNF RECEPTORS 1; UROKINASE RECEPTOR; KIDNEY-DISEASE; SUPAR LEVELS; ACTIVATOR; PERMEABILITY; KINASE; CELLS AB Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte alpha V beta(3) integrin-dependent migration in vitro. Furthermore, alpha V beta(3) integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent alpha V beta(3) integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented alpha V beta(3) integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target. C1 [Yoo, Tae-Hyun; Pedigo, Christopher E.; Guzman, Johanna; Correa-Medina, Mayrin; Villarreal, Rodrigo; Mitrofanova, Alla; Leclercq, Farah; Faul, Christian; Fornoni, Alessia; Merscher, Sandra] Univ Miami, Miller Sch Med, Peggy & Harold Katz Family Drug Discovery Ctr, Dept Med,Div Nephrol & Hypertens, Miami, FL 33136 USA. [Burke, George William] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Yoo, Tae-Hyun] Yonsei Univ, Coll Med, Div Nephrol, Dept Internal Med, Seoul, South Korea. [Guzman, Johanna; Fornoni, Alessia; Merscher, Sandra] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Wei, Changli; Li, Jing; Reiser, Jochen] Rush Univ, Div Nephrol, Dept Internal Med, Chicago, IL 60612 USA. [Kretzler, Matthias] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Lehto, Markku; Forsblom, Carol; Groop, Per-Henrik] Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Lehto, Markku; Forsblom, Carol; Groop, Per-Henrik] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, Helsinki, Finland. [Lehto, Markku; Forsblom, Carol; Groop, Per-Henrik] Univ Helsinki, Diabet & Obes Res Program, Res Programs Unit, Helsinki, Finland. [Groop, Per-Henrik] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. RP Fornoni, A (reprint author), Univ Miami, Div Nephrol & Hypertens, 1580 NW 10th Ave, Miami, FL 33136 USA. EM afornoni@med.miami.edu; smerscher@med.miami.edu FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; (University of Miami Clinical and Translational Science Institute) from the National Center for Advancing Translational Sciences [1UL-1TR00046]; National Institute on Minority Health and Health Disparities; Yonsei University College of Medicine Faculty Research Grant [6-2013-0143]; Wilhelm and Else Stockmann Foundation; Novo Nordisk Foundation; Folkhalsan Research Foundation; Nordisk Foundation; Academy of Finland [134379]; National Institutes of Health [R01-DK089394, R01-DK073495, R01-DK101350, DK090316]; Diabetes Research Institute Foundation; Nephcure Foundation; Peggy and Harold Katz Family Foundation; Diabetic Complications Consortium (DiaComp); Stanley J. Glaser Foundation Research Award FX This study was supported, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Part of this project was supported by Grant 1UL-1TR00046 (University of Miami Clinical and Translational Science Institute) from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. This study was supported by Yonsei University College of Medicine Faculty Research Grant 6-2013-0143 (to T.-H.Y.) for 2013. The study was also supported by the Wilhelm and Else Stockmann Foundation (M.L. and P.-H.G.), the Novo Nordisk Foundation (M.L. and P.-H.G.), the Folkhalsan Research Foundation (P.-H.G.), and Academy of Finland Grant 134379 (to P.-H.G.). J.R. is supported by National Institutes of Health Grants R01-DK089394, R01-DK073495, and R01-DK101350. G.W.B., A.F., and S.M. are supported by National Institutes of Health Grant DK090316. A.F. and S.M. are supported by the Diabetes Research Institute Foundation, the Nephcure Foundation, the Peggy and Harold Katz Family Foundation, and the Diabetic Complications Consortium (DiaComp). S.M. is supported by a Stanley J. Glaser Foundation Research Award. NR 46 TC 20 Z9 22 U1 2 U2 7 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 JAN PY 2015 VL 26 IS 1 BP 133 EP 147 DI 10.1681/ASN.2013111213 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA AY4QS UT WOS:000347564000016 PM 24925721 ER PT J AU Rebholz, CM Grams, ME Coresh, J Selvin, E Inker, LA Levey, AS Kimmel, PL Vasan, RS Eckfeldt, JH Feldman, HI Hsu, CY Lutsey, PL AF Rebholz, Casey M. Grams, Morgan E. Coresh, Josef Selvin, Elizabeth Inker, Lesley A. Levey, Andrew S. Kimmel, Paul L. Vasan, Ramachandran S. Eckfeldt, John H. Feldman, Harold I. Hsu, Chi-yuan Lutsey, Pamela L. CA Chronic Kidney Dis Biomarkers TI Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; PARATHYROID-HORMONE; PROGRESSION; MORTALITY; FGF23; RISK; PHOSPHATE; HEART; FIBROBLAST-GROWTH-FACTOR-23 AB Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990-1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73m(2). During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (>54.6 pg/ml) compared with the lowest quintile (<32.0 pg/ml) was associated with risk of developing ESRD (hazard ratio, 2.10; 95% confidence interval, 1.31 to 3.36; trend P<0.001). In a large, community-based study comprising a broad range of kidney function, higher baseline fibroblast growth factor-23 levels were associated with increased risk of incident ESRD independent of the baseline level of kidney function and a number of other risk factors. C1 [Rebholz, Casey M.; Grams, Morgan E.; Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Rebholz, Casey M.; Grams, Morgan E.; Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Grams, Morgan E.] Johns Hopkins Sch Med, Div Nephrol, Dept Med, Baltimore, MD USA. [Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Sch Med, Div Gen Internal Med, Dept Med, Baltimore, MD USA. [Inker, Lesley A.; Levey, Andrew S.] Tufts Med Ctr, Dept Med, William B Schwartz Div Nephrol, Boston, MA USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol & Cardiol, Boston, MA 02118 USA. [Eckfeldt, John H.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Feldman, Harold I.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Feldman, Harold I.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Sch Med, Dept Med, Div Nephrol, San Francisco, CA USA. [Lutsey, Pamela L.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Rebholz, CM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 2024 E Monument St,Suite 2-600, Baltimore, MD 21287 USA. EM crebhol1@jhu.edu OI Grams, Morgan/0000-0002-4430-6023; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NHLBI [R01-HL103706, T32-HL007024]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK089174]; NIDDK [U01-DK085649, U01-DK085673, U01-DK085660, U01-DK085688, U01-DK085651, U01-DK085689] FX The ARIC study is conducted as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Measurement of the main analytes in this article was supported by grants from the NHLBI (R01-HL103706 to P.L.) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01-DK089174 to E.S.). C.M.R. is supported in part by an NHLBI cardiovascular epidemiology training grant (T32-HL007024). This study was partially supported by grants from the NIDDK (U01-DK085649, U01-DK085673, U01-DK085660, U01-DK085688, U01-DK085651, and U01-DK085689 to the Chronic Kidney Disease Biomarkers Consortium). NR 42 TC 13 Z9 13 U1 1 U2 6 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 JAN PY 2015 VL 26 IS 1 BP 192 EP 200 DI 10.1681/ASN.2014020218 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AY4QS UT WOS:000347564000021 PM 25060052 ER PT J AU Cuburu, N Wang, KN Goodman, KN Pang, YY Thompson, CD Lowy, DR Cohen, JI Schiller, JT AF Cuburu, Nicolas Wang, Kening Goodman, Kyle N. Pang, Yuk Ying Thompson, Cynthia D. Lowy, Douglas R. Cohen, Jeffrey I. Schiller, John T. TI Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8(+) T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge SO JOURNAL OF VIROLOGY LA English DT Article ID PLASMID DNA VACCINE; IMMUNE-RESPONSES; GLYCOPROTEIN-B; GUINEA-PIGS; INTRANASAL IMMUNIZATION; PROTECTIVE IMMUNITY; TYPE-2 INFECTION; SENSORY GANGLIA; SUBUNIT VACCINE; DENDRITIC CELLS AB No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8(+) T cells that were able to secrete gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8(+) T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. IMPORTANCE Genital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection. C1 [Cuburu, Nicolas; Pang, Yuk Ying; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Kening; Goodman, Kyle N.; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM schillej@dc37a.nci.nih.gov FU National Institute of Allergy and Infectious Diseases; National Cancer Institute, Center for Cancer Research, NIH FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, Center for Cancer Research, NIH. NR 66 TC 5 Z9 5 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2015 VL 89 IS 1 BP 83 EP 96 DI 10.1128/JVI.02380-14 PG 14 WC Virology SC Virology GA AX8RL UT WOS:000347176100008 PM 25320297 ER PT J AU Weiskopf, D Angelo, MA Bangs, DJ Sidney, J Paul, S Peters, B de Silva, AD Lindow, JC Diehl, SA Whitehead, S Durbin, A Kirkpatrick, B Sette, A AF Weiskopf, Daniela Angelo, Michael A. Bangs, Derek J. Sidney, John Paul, Sinu Peters, Bjoern de Silva, Aruna D. Lindow, Janet C. Diehl, Sean A. Whitehead, Stephen Durbin, Anna Kirkpatrick, Beth Sette, Alessandro TI The Human CD8(+) T Cell Responses Induced by a Live Attenuated Tetravalent Dengue Vaccine Are Directed against Highly Conserved Epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID ANTIGEN PRESENTATION; CLASS-I; VIRUS; INFLUENZA; INFECTION; SEROTYPE; TRIAL AB The incidence of infection with any of the four dengue virus serotypes (DENV1 to -4) has increased dramatically in the last few decades, and the lack of a treatment or vaccine has contributed to significant morbidity and mortality worldwide. A recent comprehensive analysis of the human T cell response against wild-type DENV suggested an human lymphocyte antigen (HLA)linked protective role for CD8(+) T cells. We have collected one-unit blood donations from study participants receiving the monovalent or tetravalent live attenuated DENV vaccine (DLAV), developed by the U.S. National Institutes of Health. Peripheral blood mononuclear cells from these donors were screened in gamma interferon enzyme-linked immunosorbent spot assays with pools of predicted, HLA-matched, class I binding peptides covering the entire DENV proteome. Here, we characterize for the first time CD8(+) T cell responses after live attenuated dengue vaccination and show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue infection. Interestingly, whereas broad responses to structural and nonstructural (NS) proteins were observed after monovalent vaccination, T cell responses following tetravalent vaccination were, dramatically, focused toward the highly conserved NS proteins. Epitopes were highly conserved in a vast variety of field isolates and able to elicit multifunctional T cell responses. Detailed knowledge of the T cell response will contribute to the identification of robust correlates of protection in natural immunity and following vaccination against DENV. IMPORTANCE The development of effective vaccination strategies against dengue virus (DENV) infection and clinically significant disease is a task of high global public health value and significance, while also being a challenge of significant complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results challenge the hypothesis that seroconversion is the only reliable correlate of protection. Here, we show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV. C1 [Weiskopf, Daniela; Angelo, Michael A.; Bangs, Derek J.; Sidney, John; Paul, Sinu; Peters, Bjoern; de Silva, Aruna D.; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Lindow, Janet C.; Diehl, Sean A.; Kirkpatrick, Beth] Univ Vermont, Coll Med, Burlington, VT USA. [Lindow, Janet C.; Diehl, Sean A.; Kirkpatrick, Beth] Univ Vermont, Vaccine Testing Ctr, Burlington, VT USA. [Whitehead, Stephen] NIAID, NIH, Bethesda, MD 20892 USA. [Durbin, Anna] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [de Silva, Aruna D.] Genetech Res Inst, Colombo, Sri Lanka. RP Weiskopf, D (reprint author), La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. EM daniela@liai.org OI Diehl, Sean/0000-0001-9700-235X; Lindow, Janet/0000-0003-3235-3698 FU National Institutes of Health [HHSN272200900042C, HHSN27220140045C]; NIH National Institute of Allergy and Infectious Diseases FX This study was supported by National Institutes of Health contracts HHSN272200900042C and HHSN27220140045C (to A.S.) and in part by the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases. The hinders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 22 Z9 22 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2015 VL 89 IS 1 BP 120 EP 128 DI 10.1128/JVI.02129-14 PG 9 WC Virology SC Virology GA AX8RL UT WOS:000347176100011 PM 25320311 ER PT J AU Kurup, D Wirblich, C Feldmann, H Marzi, A Schnell, MJ AF Kurup, Drishya Wirblich, Christoph Feldmann, Heinz Marzi, Andrea Schnell, Matthias J. TI Rhabdovirus-Based Vaccine Platforms against Henipaviruses SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; RECOMBINANT RABIES VIRUS; NIPAH-VIRUS; HENDRA-VIRUS; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; ENVELOPE PROTEINS; G-GLYCOPROTEIN; SARS-COV; PROTECTION AB The emerging zoonotic pathogens Hendra virus (HeV) and Nipah virus (NiV) are in the genus Henipavirus in the family Paramyxoviridae. HeV and NiV infections can be highly fatal to humans and livestock. The goal of this study was to develop candidate vaccines against henipaviruses utilizing two well-established rhabdoviral vaccine vector platforms, recombinant rabies virus (RABV) and recombinant vesicular stomatitis virus (VSV), expressing either the codon-optimized or the wild-type (wt) HeV glycoprotein (G) gene. The RABV vector expressing the codon-optimized HeV G showed a 2- to 3-fold increase in incorporation compared to the RABV vector expressing wt HeV G. There was no significant difference in HeV G incorporation in the VSV vectors expressing either wt or codon-optimized HeV G. Mice inoculated intranasally with any of these live recombinant viruses showed no signs of disease, including weight loss, indicating that HeV G expression and incorporation did not increase the neurotropism of the vaccine vectors. To test the immunogenicity of the vaccine candidates, we immunized mice intramuscularly with either one dose of the live vaccines or 3 doses of 10 mu g chemically inactivated viral particles. Increased codon-optimized HeV G incorporation into RABV virions resulted in higher antibody titers against HeV G compared to inactivated RABV virions expressing wt HeV G. The live VSV vectors induced more HeV G-specific antibodies as well as higher levels of HeV neutralizing antibodies than the RABV vectors. In the case of killed particles, HeV neutralizing serum titers were very similar between the two platforms. These results indicated that killed RABV with codon-optimized HeV G should be the vector of choice as a dual vaccine in areas where rabies is endemic. IMPORTANCE Scientists have been tracking two new viruses carried by the Pteropid fruit bats: Hendra virus (HeV) and Nipah virus (NiV). Both viruses can be fatal to humans and also pose a serious risk to domestic animals. A recent escalation in the frequency of outbreaks has increased the need for a vaccine that prevents HeV and NiV infections. In this study, we performed an extensive comparison of live and killed particles of two recombinant rhabdoviral vectors, rabies virus and vesicular stomatitis virus (VSV), expressing wild-type or codon-optimized HeV glycoprotein, with the goal of developing a candidate vaccine against HeV. Based on our data from the presented mouse immunogenicity studies, we conclude that a killed RABV vaccine would be highly effective against HeV infections and would make an excellent vaccine candidate in areas where both RABV and henipaviruses pose a threat to human health. C1 [Kurup, Drishya; Wirblich, Christoph; Schnell, Matthias J.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Feldmann, Heinz; Marzi, Andrea] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. RP Schnell, MJ (reprint author), Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. EM Matthias.Schnell@jefferson.edu FU NIAID Division of Intramural Research, NIAID [R01AI105204]; Jefferson Vaccine Center FX This work was supported in part by the NIAID Division of Intramural Research, NIAID grant R01AI105204 to M.J.S., and the Jefferson Vaccine Center. NR 63 TC 12 Z9 12 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2015 VL 89 IS 1 BP 144 EP 154 DI 10.1128/JVI.02308-14 PG 11 WC Virology SC Virology GA AX8RL UT WOS:000347176100013 PM 25320306 ER PT J AU Matsuno, K Weisend, C Kajihara, M Matysiak, C Williamson, BN Simuunza, M Mweene, AS Takada, A Tesh, RB Ebihara, H AF Matsuno, Keita Weisend, Carla Kajihara, Masahiro Matysiak, Colette Williamson, Brandi N. Simuunza, Martin Mweene, Aaron S. Takada, Ayato Tesh, Robert B. Ebihara, Hideki TI Comprehensive Molecular Detection of Tick-Borne Phleboviruses Leads to the Retrospective Identification of Taxonomically Unassigned Bunyaviruses and the Discovery of a Novel Member of the Genus Phlebovirus SO JOURNAL OF VIROLOGY LA English DT Article ID THROMBOCYTOPENIA SYNDROME VIRUS; TO-PERSON TRANSMISSION; SEVERE FEVER; BHANJA VIRUS; GENETIC-CHARACTERIZATION; SEROLOGICAL SURVEY; HEARTLAND VIRUS; CHINA; ANT