FN Thomson Reuters Web of Science™ VR 1.0 PT J AU De Sancho, D Kubas, A Wang, PH Blumberger, J Best, RB AF De Sancho, David Kubas, Adam Wang, Po-Hung Blumberger, Jochen Best, Robert B. TI Identification of Mutational Hot Spots for Substrate Diffusion: Application to Myoglobin SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; SPERM-WHALE MYOGLOBIN; LIGAND MIGRATION; CARBON-MONOXIDE; STRUCTURAL DYNAMICS; FOLDING KINETICS; CO DIFFUSION; PATHWAYS; BINDING; PROTEIN AB The pathways by which small molecules (substrates or inhibitors) access active sites are a key aspect of the function of enzymes and other proteins. A key problem in designing or altering such proteins is to identify sites for mutation that will have the desired effect on the substrate transport properties. While specific access channels have been invoked in the past, molecular simulations suggest that multiple routes are possible, complicating the analysis. This complexity, however, can be captured by a Markov State Model (MSM) of the ligand diffusion process. We have developed a sensitivity analysis of the resulting rate matrix, which identifies the locations where mutations should have the largest effect on the diffusive on rate. We apply this method to myoglobin, which is the best characterized example both from experiment and simulation. We validate the approach by translating the sensitivity parameter obtained from this method into the CO binding rates in myoglobin upon mutation, resulting in a semi-quantitative correlation with experiments. The model is further validated against an explicit simulation for one of the experimental mutants. C1 [De Sancho, David] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Kubas, Adam; Wang, Po-Hung; Blumberger, Jochen] UCL, Dept Phys & Astron, London WC1E 6BT, England. [Best, Robert B.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [De Sancho, David] CIC NanoGUNE, Donostia San Sebastian 20018, Spain. [De Sancho, David] Ikerbasque, Basque Fdn Sci, Bilbao 48013, Spain. [Wang, Po-Hung] Theoret Mol Sci Lab, Wako, Saitama 3510198, Japan. RP Best, RB (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI nanoGUNE, CIC/A-2623-2015; Wang, Po-hung/G-9962-2012; De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016 OI Wang, Po-hung/0000-0001-6770-1918; De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543 FU EPSRC [EP/J016764/1, EP/J015571/1]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Royal Society; Materials Chemistry Consortium (EPSRC) [EP/F067496, EP/L000202] FX D.D.S. was supported by EPSRC Grant EP/J016764/1 and A.K. by EPSRC Grant EP/J015571/1. R.B.B. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. J.B. thanks the Royal Society for a University Research Fellowship. This work was carried out on the HECToR and Archer computing facilities (Edinburgh), access to which was granted through the Materials Chemistry Consortium (EPSRC Grants EP/F067496 and EP/L000202). 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). The authors acknowledge the use of the UCL Legion High Performance Computing Facility (Legion@UCL) and associated support services in the completion of this work D.D. acknowledges Jacob Stevenson for useful discussions. NR 62 TC 4 Z9 4 U1 4 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD APR PY 2015 VL 11 IS 4 BP 1919 EP 1927 DI 10.1021/ct5011455 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CG3JM UT WOS:000353176500056 PM 26574395 ER PT J AU Trasande, L Zoeller, RT Hass, U Kortenkamp, A Grandjean, P Myers, JP DiGangi, J Bellanger, M Hauser, R Legler, J Skakkebaek, NE Heindel, JJ AF Trasande, Leonardo Zoeller, R. Thomas Hass, Ulla Kortenkamp, Andreas Grandjean, Philippe Myers, John Peterson DiGangi, Joseph Bellanger, Martine Hauser, Russ Legler, Juliette Skakkebaek, Niels E. Heindel, Jerrold J. TI Estimating Burden and Disease Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID WILLINGNESS-TO-PAY; PERSISTENT ORGANIC POLLUTANTS; URINARY BISPHENOL-A; DIPHENYL ETHER PBDE; THYROID-HORMONE; UNITED-STATES; QUALITY INDICATORS; GRADING QUALITY; HEALTH; RECOMMENDATIONS AB Context: Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. Objective: The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). Design: A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. Results: Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of (sic)157 billion (or $ 209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of (sic)109 billion that differed modestly from base case probability inputs. Conclusions: EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. C1 [Trasande, Leonardo] NYU, Sch Med, New York, NY 10016 USA. [Trasande, Leonardo] NYU, Wagner Sch Publ Serv, New York, NY 10012 USA. [Trasande, Leonardo] NYU, Steinhardt Sch Culture Educ & Human Dev, Dept Nutr Food & Publ Hlth, New York, NY 10003 USA. [Trasande, Leonardo] NYU, Global Inst Publ Hlth, New York, NY 10003 USA. [Zoeller, R. Thomas] Univ Massachusetts, Amherst, MA 01003 USA. [Hass, Ulla] Tech Univ Denmark, Natl Food Inst, DK-192860 Soborg, Denmark. [Kortenkamp, Andreas; Hauser, Russ] Brunel Univ, Inst Environm Hlth & Soc, Uxbridge UB8 3PH, Middx, England. [Grandjean, Philippe] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Grandjean, Philippe] Univ Southern Denmark, DK-5000 Odense, Denmark. [Myers, John Peterson] Environm Hlth Sci, Charlottesville, VA 22902 USA. [DiGangi, Joseph] IPEN, SE-40235 Gothenburg, Sweden. [Bellanger, Martine] EHESP Sch Publ Hlth, F-75014 Paris, France. [Legler, Juliette] Vrije Univ Amsterdam, Inst Environm Studies, Dept Biol & Chem, NL-1081 HV Amsterdam, Netherlands. [Skakkebaek, Niels E.] Endocrine Disrupt Male Reprod & Child Hlth EDMaRC, Rigshosp, Dept Growth & Reprod, DK-2100 Copenhagen, Denmark. [Skakkebaek, Niels E.] Univ Copenhagen, DK-2100 Copenhagen, Denmark. [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Trasande, L (reprint author), NYU, Sch Med, Dept Pediat, 227 East 30th St,Room 109, New York, NY 10016 USA. EM leonardo.trasande@nyumc.org OI Legler, Juliette/0000-0001-6321-1567; Grandjean, Philippe/0000-0003-4046-9658 FU Endocrine Society; John Merck Fund; Broad Reach Foundation; Oak Foundation; National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training FX Research reported in this publication was supported by The Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. The contribution of J.J.H. was supported by the National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training. NR 72 TC 51 Z9 52 U1 3 U2 41 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1245 EP 1255 DI 10.1210/jc.2014-4324 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500030 PM 25742516 ER PT J AU Hauser, R Skakkebaek, NE Hass, U Toppari, J Juul, A Andersson, AM Kortenkamp, A Heindel, JJ Trasande, L AF Hauser, Russ Skakkebaek, Niels E. Hass, Ulla Toppari, Jorma Juul, Anders Andersson, Anna Maria Kortenkamp, Andreas Heindel, Jerrold J. Trasande, Leonardo TI Male Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TESTICULAR DYSGENESIS SYNDROME; URINARY PHTHALATE METABOLITES; SERUM TESTOSTERONE LEVELS; CARCINOMA IN-SITU; GERM-CELL TUMORS; UNITED-STATES; SEMEN QUALITY; ADULT MEN; DI(2-ETHYLHEXYL) PHTHALATE; ENVIRONMENTAL ASPECTS AB Introduction: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. Purpose: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). Methods: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. Results: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618 000 additional assisted reproductive technology procedures, costing (sic)4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of (sic)130 million (sensitivity analysis, (sic)117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of (sic)848 million annually (sensitivity analysis, (sic)313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of (sic)7.96 billion. Conclusions: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly (sic)15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs. C1 [Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Skakkebaek, Niels E.; Juul, Anders; Andersson, Anna Maria] EDMaRC, Rigshosp, Dept Growth & Reprod, DK-2100 Copenhagen, Denmark. [Skakkebaek, Niels E.; Juul, Anders; Andersson, Anna Maria] Univ Copenhagen, DK-2100 Copenhagen, Denmark. [Hass, Ulla] Tech Univ Denmark, Natl Food Inst, DK-2800 Soborg, Denmark. [Toppari, Jorma] Univ Turku, Dept Physiol, Turku 20014, Finland. [Toppari, Jorma] Univ Turku, Dept Pediat, Turku 20014, Finland. [Kortenkamp, Andreas] Brunel Univ, Uxbridge UB8 3PH, Middx, England. [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Trasande, Leonardo] NYU, Sch Med, New York, NY 10016 USA. [Trasande, Leonardo] NYU, Wagner Sch Publ Serv, New York, NY 10012 USA. [Trasande, Leonardo] NYU, Steinhardt Sch Culture Educ & Human Dev, Dept Nutr Food & Publ Hlth, New York, NY 10003 USA. [Trasande, Leonardo] NYU, Global Inst Publ Hlth, New York, NY 10003 USA. RP Trasande, L (reprint author), NYU, Sch Med, Dept Pediat, 227 East 30th St,Room 109, New York, NY 10016 USA. EM leonardo.trasande@nyumc.org RI Andersson, Anna-Maria/F-5842-2013; OI Andersson, Anna-Maria/0000-0002-7300-1659; Juul, Anders/0000-0002-0534-4350 FU Endocrine Society; John Merck Fund; Broad Reach Foundation; Oak Foundation FX Research reported in this publication was supported by The Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. The funders and supporters had no role in the writing of the manuscript or the decision to submit it for publication. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institute of Environmental Health Sciences, the National Institutes of Health, or the US Government. NR 89 TC 34 Z9 34 U1 5 U2 27 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1267 EP 1277 DI 10.1210/jc.2014-4325 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500032 PM 25742517 ER PT J AU Legler, J Fletcher, T Govarts, E Porta, M Blumberg, B Heindel, JJ Trasande, L AF Legler, Juliette Fletcher, Tony Govarts, Eva Porta, Miquel Blumberg, Bruce Heindel, Jerrold J. Trasande, Leonardo TI Obesity, Diabetes, and Associated Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PERSISTENT ORGANIC POLLUTANTS; URINARY BISPHENOL-A; RAPID WEIGHT-GAIN; PHTHALATE METABOLITES; CHILDHOOD OBESITY; PRENATAL EXPOSURE; PROSPECTIVE COHORT; INSULIN-RESISTANCE; AMERICAN CHILDREN; ECONOMIC BURDEN AB Context: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. Objective: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. Design: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. Results: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of (sic)24.6 million (sensitivity analysis: (sic)24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of (sic)835million (sensitivity analysis: (sic)835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and (sic)15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with (sic)607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of (sic)1.54 billion. Conclusions: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of (sic)18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures. C1 [Legler, Juliette] Vrije Univ Amsterdam, Inst Environm Studies, Dept Biol & Chem, NL-1081 HV Amsterdam, Netherlands. [Fletcher, Tony] London Sch Trop Hyg, London WC1E 7HT, England. [Govarts, Eva] Flemish Inst Technol Res, Environm Risk & Hlth, B-2400 Mol, Belgium. [Porta, Miquel] Univ Autonoma Barcelona, Sch Med, E-08193 Barcelona, Spain. [Porta, Miquel] Hosp del Mar, Inst Med Res, Barcelona 08003, Spain. [Porta, Miquel] Consorcio Invest Biomed Epidemiol & Salud Publ CI, Madrid 28029, Spain. [Blumberg, Bruce] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Heindel, Jerrold J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Trasande, Leonardo] NYU, Sch Med, New York, NY 10016 USA. [Trasande, Leonardo] NYU, Wagner Sch Publ Serv, New York, NY 10012 USA. [Trasande, Leonardo] NYU, Steinhardt Sch Culture Educ & Human Dev, Dept Nutr Food & Publ Hlth, New York, NY 10003 USA. [Trasande, Leonardo] NYU, Global Inst Publ Hlth, New York, NY 10003 USA. RP Trasande, L (reprint author), NYU, Sch Med, Dept Pediat, 227 East 30th St,Room 109, New York, NY 10016 USA. EM leonardo.trasande@nyumc.org RI Porta, Miquel/B-5787-2008; OI Porta, Miquel/0000-0003-1684-7428; Legler, Juliette/0000-0001-6321-1567 FU Endocrine Society; John Merck Fund; Broad Reach Foundation; Oak Foundation; National Institute of Environmental Health Sciences Division of Extramural Research and Training FX Research reported in this publication was supported by the Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. The contribution of J.J.H. was supported by the National Institute of Environmental Health Sciences Division of Extramural Research and Training. The funders and supporters had no role in the writing of the manuscript or the decision to submit it for publication. NR 78 TC 35 Z9 35 U1 6 U2 26 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1278 EP 1288 DI 10.1210/jc.2014-4326 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500033 PM 25742518 ER PT J AU Tabatabai, LS Cummings, SR Tylavsky, FA Bauer, DC Cauley, JA Kritchevsky, SB Newman, A Simonsick, EM Harris, TB Sebastian, A Sellmeyer, DE AF Tabatabai, L. S. Cummings, S. R. Tylavsky, F. A. Bauer, D. C. Cauley, J. A. Kritchevsky, S. B. Newman, A. Simonsick, E. M. Harris, T. B. Sebastian, A. Sellmeyer, D. E. CA Hlth Aging Body Composition Study TI Arterialized Venous Bicarbonate Is Associated With Lower Bone Mineral Density and an Increased Rate of Bone Loss in Older Men and Women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID URINARY CALCIUM EXCRETION; ACID-BASE-BALANCE; CHRONIC METABOLIC ACIDOSIS; POSTMENOPAUSAL WOMEN; POTASSIUM BICARBONATE; DIETARY-PROTEIN; IN-VITRO; HUMANS; ADULTS; OSTEOPOROSIS AB Context: Higher dietary net acid loads have been associated with increased bone resorption, reduced bone mineral density (BMD), and increased fracture risk. Objective: The objective was to compare bicarbonate (HCO3) measured in arterialized venous blood samples to skeletal outcomes. Design: Arterialized venous samples collected from participants in the Health, Aging and Body Composition (Health ABC) Study were compared to BMD and rate of bone loss. Setting: The setting was a community-based observational cohort. Participants: A total of 2287 men and women age 74 +/- 3 years participated. Intervention: Arterialized venous blood was obtained at the year 3 study visit and analyzed for pH and pCO(2). HCO3 was determined using the Henderson-Hasselbalch equation. Main Outcome Measure: BMD was measured at the hip by dual-energy x-ray absorptiometry at the year 1 (baseline) and year 3 study visits. Results: Plasma HCO3 was positively associated with BMD at both year 1 (P = .001) and year 3 (P = .001) in models adjusted for age, race, sex, clinic site, smoking, weight, and estimated glomerular filtration rate. Plasma HCO3 was inversely associated with rate of bone loss at the total hip over the 2.1 +/- 0.3 (mean +/- SD) years between the two bone density measurements (P < .001). Across quartiles of plasma HCO3, the rate of change in BMD over the 2.1 years ranged from a loss of 0.72%/y in the lowest quartile to a gain of 0.15%/y in the highest quartile of HCO3. Conclusions: Arterialized plasma HCO3 was associated positively with cross-sectional BMD and inversely with the rate of bone loss, implying that systemic acid-base status is an important determinant of skeletal health during aging. Ongoing bone loss was linearly related to arterialized HCO3, even after adjustment for age and renal function. Further research in this area may have major public health implications because reducing dietary net acid load is possible through dietary intervention or through supplementation with alkaline potassium compounds. C1 [Tabatabai, L. S.; Sellmeyer, D. E.] Johns Hopkins Sch Med, Johns Hopkins Hosp, Div Endocrinol, Baltimore, MD 21224 USA. [Cummings, S. R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94118 USA. [Tylavsky, F. A.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Bauer, D. C.; Sebastian, A.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. [Cauley, J. A.; Newman, A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Kritchevsky, S. B.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA. [Simonsick, E. M.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Sellmeyer, DE (reprint author), Johns Hopkins Bayview Med Ctr, 5200 Eastern Ave,MFL Ctr Tower,Suite 4300, Baltimore, MD 21224 USA. EM dsellme1@jhmi.edu RI Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015 OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA Grant [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, and N01-AG-6-2106; NIA Grant R01-AG028050; and National Institute of Nursing Research Grant R01-NR012459. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 49 TC 5 Z9 5 U1 1 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1343 EP 1349 DI 10.1210/jc.2014-4166 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500040 PM 25642590 ER PT J AU Chen, KY Muniyappa, R Abel, BS Mullins, KP Staker, P Brychta, RJ Zhao, XC Ring, M Psota, TL Cone, RD Panaro, BL Gottesdiener, KM Van der Ploeg, LHT Reitman, ML Skarulis, MC AF Chen, Kong Y. Muniyappa, Ranganath Abel, Brent S. Mullins, Katherine P. Staker, Pamela Brychta, Robert J. Zhao, Xiongce Ring, Michael Psota, Tricia L. Cone, Roger D. Panaro, Brandon L. Gottesdiener, Keith M. Van der Ploeg, Lex H. T. Reitman, Marc L. Skarulis, Monica C. TI RM-493, a Melanocortin-4 Receptor (MC4R) Agonist, Increases Resting Energy Expenditure in Obese Individuals SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DOUBLE-BLIND; METABOLIC-RATE; WEIGHT-GAIN; SYSTEM; SAFETY; DIET; FAT; HOMEOSTASIS; HUMANS; RATS AB Context: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date. Objective, Design, and Setting: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting. Study Participants and Methods: Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 +/- 2.9 kg/m(2) (mean +/- SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods. Results: RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 +/- 0.021 vs 0.848 +/- 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed. Conclusions: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals. C1 [Chen, Kong Y.; Muniyappa, Ranganath; Abel, Brent S.; Mullins, Katherine P.; Staker, Pamela; Brychta, Robert J.; Zhao, Xiongce; Ring, Michael; Psota, Tricia L.; Reitman, Marc L.; Skarulis, Monica C.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Cone, Roger D.; Panaro, Brandon L.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Gottesdiener, Keith M.; Van der Ploeg, Lex H. T.] Rhythm Pharmaceut, Boston, MA 02116 USA. RP Skarulis, MC (reprint author), NIDDK, Clin Endocrine Sect, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr MSC 1613,Bldg 10,Room 6-3940, Bethesda, MD 20892 USA. EM monicas@intra.niddk.nih.gov RI Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Rhythm Pharmaceuticals FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and by Rhythm Pharmaceuticals. NR 29 TC 18 Z9 19 U1 4 U2 13 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1639 EP 1645 DI 10.1210/jc.2014-4024 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500075 PM 25675384 ER PT J AU Aroda, VR Christophi, CA Edelstein, SL Zhang, P Herman, WH Barrett-Connor, E Delahanty, LM Montez, MG Ackermann, RT Zhuo, X Knowler, WC Ratner, RE AF Aroda, V. R. Christophi, C. A. Edelstein, S. L. Zhang, P. Herman, W. H. Barrett-Connor, E. Delahanty, L. M. Montez, M. G. Ackermann, R. T. Zhuo, X. Knowler, W. C. Ratner, R. E. CA Diabet Prevention Program Res Grp TI The Effect of Lifestyle Intervention and Metformin on Preventing or Delaying Diabetes Among Women With and Without Gestational Diabetes: The Diabetes Prevention Program Outcomes Study 10-Year Follow-Up SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ORAL GLUCOSE-TOLERANCE; CLINICAL-TRIAL; MELLITUS; MODELS AB Context: Gestational diabetes (GDM) confers a high risk of type 2 diabetes. In the Diabetes Prevention Program (DPP), intensive lifestyle (ILS) and metformin prevented or delayed diabetes in women with a history of GDM. Objective: The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study. Design: This was a randomized controlled clinical trial with an observational follow-up. Setting: The study was conducted at 27 clinical centers. Participants: Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study. The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry. Interventions: Interventions included placebo, ILS, or metformin. Outcomes Measure: Outcomes measure was diabetes mellitus. Results: Over 10 years, women with a history of GDM assigned to placebo had a 48% higher risk of developing diabetes compared with women without a history of GDM. In women with a history of GDM, ILS and metformin reduced progression to diabetes compared with placebo by 35% and 40%, respectively. Among women without a history of GDM, ILS reduced the progression to diabetes by 30%, and metformin did not reduce the progression to diabetes. Conclusions: Women with a history of GDM are at an increased risk of developing diabetes. In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study, both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period. Among women without a history of GDM, lifestyle but not metformin reduced progression to diabetes. C1 [Aroda, V. R.; Ratner, R. E.] MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Christophi, C. A.; Edelstein, S. L.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Zhang, P.; Zhuo, X.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Herman, W. H.] Univ Michigan, Ann Arbor, MI 48109 USA. [Barrett-Connor, E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Delahanty, L. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Delahanty, L. M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Montez, M. G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ackermann, R. T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Knowler, W. C.] NIDDK, Phoenix, AZ 85014 USA. RP Aroda, VR (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 FU National Institutes of Health, NIDDK [U01-DK048489] FX This work was supported by the National Institutes of Health, NIDDK, under U01-DK048489. NR 17 TC 30 Z9 33 U1 2 U2 10 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2015 VL 100 IS 4 BP 1646 EP 1653 DI 10.1210/jc.2014-3761 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5UN UT WOS:000353361500076 PM 25706240 ER PT J AU Peretti, A FitzGerald, PC Bliskovsky, V Buck, CB Pastrana, DV AF Peretti, Alberto FitzGerald, Peter C. Bliskovsky, Valery Buck, Christopher B. Pastrana, Diana V. TI Hamburger polyomaviruses SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MERKEL CELL POLYOMAVIRUS; BOVINE POLYOMAVIRUS; IDENTIFICATION; VIRUS; POLYMERASE; CARCINOMA; GENOMES AB Epidemiological studies have suggested that consumption of beef may correlate with an increased risk of colorectal cancer. One hypothesis to explain this proposed link might be the presence of a carcinogenic infectious agent capable of withstanding cooking. Polyomaviruses are a ubiquitous family of thermostable non-enveloped DNA viruses that are known to be carcinogenic. Using virion enrichment, rolling circle amplification (RCA) and next-generation sequencing, we searched for polyomaviruses in meat samples purchased from several supermarkets. Ground beef samples were found to contain three polyomavirus species. One species, bovine polyomavirus 1 (BoPyV1), was originally discovered as a contaminant in laboratory FCS. A previously unknown species, BoPyV2, occupies the same Glade as human Merkel cell polyomavirus and raccoon polyomavirus, both of which are carcinogenic in their native hosts. A third species, BoPyV3, is related to human polyomaviruses 6 and 7. Examples of additional DNA virus families, including herpesviruses, adenoviruses, circoviruses and gyroviruses were also detected either in ground beef samples or in comparison samples of ground pork and ground chicken. The results suggest that the virion enrichment/RCA approach is suitable for random detection of essentially any DNA virus with a detergent-stable capsid. It will be important for future studies to address the possibility that animal viruses commonly found in food might be associated with disease. C1 [Peretti, Alberto; FitzGerald, Peter C.; Bliskovsky, Valery; Buck, Christopher B.; Pastrana, Diana V.] NIH, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov; pastrand@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU NIH; Italian Foundation for Cancer Research (FIRC); Associazione Italiana per la Ricerca sul Cancro FX This work was funded by the NIH Intramural Research Program, with support from the Italian Foundation for Cancer Research (FIRC). NR 32 TC 6 Z9 6 U1 0 U2 10 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2015 VL 96 BP 833 EP 839 DI 10.1099/vir.0.000033 PN 4 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA CG9CE UT WOS:000353611200012 PM 25568187 ER PT J AU Qiu, LQ Lai, WS Bradbury, A Zeldin, DC Blackshear, PJ AF Qiu, Lian-Qun Lai, Wi S. Bradbury, Alyce Zeldin, Darryl C. Blackshear, Perry J. TI Tristetraprolin (TTP) coordinately regulates primary and secondary cellular responses to proinflammatory stimuli SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; MESSENGER-RNA DEADENYLATION; AU-RICH ELEMENTS; PROTEIN TRISTETRAPROLIN; DEFICIENCY SYNDROME; TNF-ALPHA; INFLAMMATION; MICE; FIBROBLASTS; STABILITY AB TTP is an anti-inflammatory protein that acts by binding to AREs in its target mRNAs, such as Tnf mRNA, and promoting their deadenylation and decay. TNF released from inflammatory cells can then stimulate gene expression in tissue cells, such as fibroblasts. To determine whether TTP could affect the decay of TNF-induced transcripts in fibroblasts, we exposed primary embryonic fibroblasts and stable fibroblast cell lines, derived from WT and TTP KO mice, to TNF. The decay rates of transcripts encoded by several early-response genes, including Cxcl1, Cxcl2, Ier3, Ptgs2, and Lif, were significantly slowed in TTP-deficient fibroblasts after TNF stimulation. These changes were associated with TTP-dependent increases in CXCL1, CXCL2, and IER3 protein levels. The TTP-susceptible transcripts contained multiple, conserved, closely spaced, potential TTP binding sites in their 39-UTRs. WT TTP, but not a nonbinding TTP zinc finger mutant, bound to RNA probes that were based on the mRNA sequences of Cxcl1, Cxcl2, Ptgs2, and Lif. TTP-promoted decay of transcripts encoding chemokines and other proinflammatory mediators is thus a critical post-transcriptional regulatory mechanism in the response of secondary cells, such as fibroblasts, to TNF released from primary immune cells. C1 [Qiu, Lian-Qun; Lai, Wi S.; Blackshear, Perry J.] NIEHS, Labs Signal Transduct, Res Triangle Pk, NC 27709 USA. [Bradbury, Alyce; Zeldin, Darryl C.] NIEHS, Resp Biol, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, U.S. National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, U.S. National Institutes of Health. The authors are grateful to Dr. Deborah J. Stumpo for help with the TTP KO mice and the isolation and culture of primary embryonic fibroblasts. The authors are also grateful to Drs. Donald N. Cook and Michael B. Fessler for constructive comments on the manuscript. NR 44 TC 10 Z9 10 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD APR PY 2015 VL 97 IS 4 BP 723 EP 736 DI 10.1189/jlb.3A0214-106R PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CH3BH UT WOS:000353900100012 PM 25657290 ER PT J AU Choi, H Jung, H Shung, KK AF Choi, Hojong Jung, Hayong Shung, K. Kirk TI Power Amplifier Linearizer for High Frequency Medical Ultrasound Applications SO JOURNAL OF MEDICAL AND BIOLOGICAL ENGINEERING LA English DT Article DE Power amplifier; Linearizer; Ultrasonic transducer ID SYSTEMS AB Power amplifiers (PAs) are used to produce high-voltage excitation signals to drive ultrasonic transducers. A larger dynamic range of linear PAs allows higher contrast resolution, a highly desirable characteristic in ultrasonic imaging. The linearity of PAs can be improved by reducing the nonlinear harmonic distortion components of high-voltage output signals. In this paper, a linearizer circuit is proposed to reduce output signal harmonics when working in conjunction with a PA. The PA performance with and without the linearizer was measured by comparing the output power 1-dB compression point (OP1dB), and the second- and third-order harmonic distortions (HD2 and HD3, respectively). The results show that the PA with the linearizer circuit had higher OP1dB (31.7 dB) and lower HD2 (-61.0 dB) and HD3 (-42.7 dB) compared to those of the PA alone [OP1dB (27.1 dB), HD2 (-38.2 dB), and HD3 (-36.8 dB)] at 140 MHz. A pulse-echo measurement was also performed to further evaluate the capability of the linearizer circuit. The HD2 of the echo signal received by the transducer using a PA with the linearizer (-24.8 dB) was lower than that obtained for the PA alone (-16.6 dB). The linearizer circuit is capable of improving the linearity performance of PA by lowering harmonic distortions. C1 [Choi, Hojong] Kumoh Natl Inst Technol, Dept Med IT Convergence Engn, Gumi 730701, Gyeongbuk, South Korea. [Jung, Hayong; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Jung, Hayong; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Choi, H (reprint author), Kumoh Natl Inst Technol, Dept Med IT Convergence Engn, Daehak Ro 61, Gumi 730701, Gyeongbuk, South Korea. EM hojongch@kumoh.ac.kr FU National Institutes of Health [P41-EB002182] FX The authors would like to thank Mr. Thomas Cummins for his editing contribution. This project was supported by National Institutes of Health Grant #P41-EB002182. NR 19 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1609-0985 EI 2199-4757 J9 J MED BIOL ENG JI J. Med. Biol. Eng. PD APR PY 2015 VL 35 IS 2 BP 226 EP 235 DI 10.1007/s40846-015-0026-7 PG 10 WC Engineering, Biomedical SC Engineering GA CH2BF UT WOS:000353828200009 PM 26622209 ER PT J AU Drummond, MC Barzik, M Bird, JE Zhang, DS Lechene, CP Corey, DP Cunningham, LL Friedman, TB AF Drummond, Meghan C. Barzik, Melanie Bird, Jonathan E. Zhang, Duan-Sun Lechene, Claude P. Corey, David P. Cunningham, Lisa L. Friedman, Thomas B. TI Live-cell imaging of actin dynamics reveals mechanisms of stereocilia length regulation in the inner ear SO NATURE COMMUNICATIONS LA English DT Article ID COCHLEAR HAIR-CELLS; SUPPORTING CELLS; POSTNATAL-DEVELOPMENT; MOLECULAR TREADMILL; HEARING-LOSS; FILAMENTS; MOUSE; POLYMERIZATION; PROTEINS; LOCALIZATION AB The maintenance of sensory hair cell stereocilia is critical for lifelong hearing; however, mechanisms of structural homeostasis remain poorly understood. Conflicting models propose that stereocilia F-actin cores are either continually renewed every 24-48 h via a treadmill or are stable, exceptionally long-lived structures. Here to distinguish between these models, we perform an unbiased survey of stereocilia actin dynamics in more than 500 utricle hair cells. Live-imaging EGFP-beta-actin or dendra2-beta-actin reveal stable F-actin cores with turnover and elongation restricted to stereocilia tips. Fixed-cell microscopy of wild-type and mutant beta-actin demonstrates that incorporation of actin monomers into filaments is required for localization to stereocilia tips. Multi-isotope imaging mass spectrometry and live imaging of single differentiating hair cells capture stereociliogenesis and explain uniform incorporation of N-15-labelled protein and EGFP-beta-actin into nascent stereocilia. Collectively, our analyses support a model in which stereocilia actin cores are stable structures that incorporate new F-actin only at the distal tips. C1 [Drummond, Meghan C.; Barzik, Melanie; Bird, Jonathan E.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, Bethesda, MD 20892 USA. [Zhang, Duan-Sun; Corey, David P.] Harvard Univ, Dept Neurobiol, Sch Med, Boston, MA 02115 USA. [Zhang, Duan-Sun; Corey, David P.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lechene, Claude P.] Brigham & Womens Hosp, Natl Resource Imaging Mass Spectrometry, Cambridge, MA 02139 USA. [Lechene, Claude P.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Lechene, Claude P.] Brigham & Womens Hosp, Dept Med, Div Genet, Cambridge, MA 02139 USA. [Cunningham, Lisa L.] Natl Inst Deafness & Other Commun Disorders, Sect Sensory Cell Biol, NIH, Bethesda, MD 20892 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, Bethesda, MD 20892 USA. EM friedman@nidcd.nih.gov OI Barzik, Melanie/0000-0003-3003-1281; Corey, David/0000-0003-4497-6016; Bird, Jonathan/0000-0001-5531-8794 FU National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) [P41RR14579, P41EB001974]; NIH [R01DC00033, R01DC03463, R01DC04179, R37DK39773, R01EY12963, R01GM47214, R01D K58762]; National Science Foundation Division of Integrative Biology and Neuroscience (NSF/IBN) [IBN-998298]; National Institutes of Health intramural funds from the National Institute on Deafness and Other Communication Disorders [DC000079-02, DC000039-17] FX We acknowledge Dennis Drayna and Benjamin Perrin for critiques of this manuscript. We thank Lindsey May, Elyssa Monzack, Elizabeth Driver and James Hostetter for assistance and advice in live-cell imaging experiments, Inna Belyantseva for gene gun protocols and Liz Wilson and Barb Zwiesler for help with animal procurement. This work was supported by National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) grants P41RR14579 and P41EB001974; NIH grants R01DC00033, R01DC03463, R01DC04179, R37DK39773, R01EY12963, R01GM47214 and R01D K58762; and National Science Foundation Division of Integrative Biology and Neuroscience (NSF/IBN) grant IBN-998298 to C.P.L. D.P.C. is an Investigator of the Howard Hughes Medical Institute. This work was also supported by National Institutes of Health intramural funds from the National Institute on Deafness and Other Communication Disorders DC000079-02 to L.L.C. and DC000039-17 to T.B.F. NR 48 TC 10 Z9 10 U1 1 U2 11 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 APR PY 2015 VL 6 AR 6873 DI 10.1038/ncomms7873 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0IQ UT WOS:000353703400040 PM 25898120 ER PT J AU Fu, HQ Martin, MM Regairaz, M Huang, L You, Y Lin, CM Ryan, M Kim, R Shimura, T Pommier, Y Aladjem, MI AF Fu, Haiqing Martin, Melvenia M. Regairaz, Marie Huang, Liang You, Yang Lin, Chi-Mei Ryan, Michael Kim, RyangGuk Shimura, Tsutomu Pommier, Yves Aladjem, Mirit I. TI The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage SO NATURE COMMUNICATIONS LA English DT Article ID INTRA-S-PHASE; HUMAN-CELLS; SACCHAROMYCES-CEREVISIAE; EUKARYOTIC CELLS; DORMANT ORIGINS; TOPOISOMERASE-I; FRAGILE SITE; FUNCTIONAL INTERACTIONS; GENOMIC INSTABILITY; MAMMALIAN-CELLS AB The Mus81 endonuclease resolves recombination intermediates and mediates cellular responses to exogenous replicative stress. Here, we show that Mus81 also regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events. In the absence of Mus81 endonuclease activity, DNA synthesis is slowed and replication initiation events are more frequent. In addition, Mus81-deficient cells fail to recover from exposure to low doses of replication inhibitors and cell viability is dependent on the XPF endonuclease. Despite an increase in replication initiation frequency, cells lacking Mus81 use the same pool of replication origins as Mus81-expressing cells. Therefore, decelerated DNA replication in Mus81-deficient cells does not initiate from cryptic or latent origins not used during normal growth. These results indicate that Mus81 plays a key role in determining the rate of DNA replication without activating a novel group of replication origins. C1 [Fu, Haiqing; Martin, Melvenia M.; Regairaz, Marie; Huang, Liang; You, Yang; Lin, Chi-Mei; Pommier, Yves; Aladjem, Mirit I.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ryan, Michael; Kim, RyangGuk] InSilico Solut, Fairfax, VA 22033 USA. [Shimura, Tsutomu] Natl Inst Publ Hlth, Dept Environm Hlth, Wako, Saitama 3510197, Japan. RP Aladjem, MI (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov RI Aladjem, Mirit/G-2169-2010; OI Aladjem, Mirit/0000-0002-1875-3110; Huang, Liang/0000-0003-1663-7025 FU CCR, National Cancer Institute, National Institutes of Health FX We thank Drs Paul Meltzer, Chiara Conti, Hong Fang Liu, Elisabeth Leo and Kurt W. Kohn for helpful discussion. We are grateful to Dr James Doroshow and William C. Reinhold for facilitating the bioinformatics pipeline data analysis. The intramural programme of the CCR, National Cancer Institute, National Institutes of Health, funded this work. NR 65 TC 11 Z9 11 U1 0 U2 8 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 APR PY 2015 VL 6 AR 6746 DI 10.1038/ncomms7746 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0IF UT WOS:000353702300003 PM 25879486 ER PT J AU Grontved, L Waterfall, JJ Kim, DW Baek, S Sung, MH Zhao, L Park, JW Nielsen, R Walker, RL Zhu, YLJ Meltzer, PS Hager, GL Cheng, SY AF Grontved, Lars Waterfall, Joshua J. Kim, Dong Wook Baek, Songjoon Sung, Myong-Hee Zhao, Li Park, Jeong Won Nielsen, Ronni Walker, Robert L. Zhu, Yuelin J. Meltzer, Paul S. Hager, Gordon L. Cheng, Sheue-yann TI Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling SO NATURE COMMUNICATIONS LA English DT Article ID ACTION IN-VIVO; NUCLEAR RECEPTOR; GLUCOCORTICOID-RECEPTOR; DIFFERENTIAL EXPRESSION; REGULATORY ELEMENTS; RESPONSE ELEMENTS; GENE-EXPRESSION; FACTOR-BINDING; CO-REPRESSOR; DNASE I AB A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand. C1 [Grontved, Lars; Baek, Songjoon; Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grontved, Lars; Nielsen, Ronni] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. [Waterfall, Joshua J.; Walker, Robert L.; Zhu, Yuelin J.; Meltzer, Paul S.] NCI, Genet Branch, CCR, NIH, Bethesda, MD 20892 USA. [Kim, Dong Wook; Zhao, Li; Park, Jeong Won; Cheng, Sheue-yann] NCI, Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, CCR, NIH, Bldg 37 NIH, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Grontved, Lars/0000-0002-6735-8483 FU National Institutes of Health; National Cancer Institute (NCI); Center for Cancer Research (CCR); Lundbeck Foundation; Danish Research Council; SDU2020 FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute (NCI) and the Center for Cancer Research (CCR). L.G. was supported by a research grant from the Lundbeck Foundation, the Danish Research Council and SDU2020. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. NR 61 TC 15 Z9 16 U1 8 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2015 VL 6 AR 7048 DI 10.1038/ncomms8048 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0KD UT WOS:000353707500001 PM 25916672 ER PT J AU Huang, LZ Li, YJ Xie, XF Zhang, JJ Cheng, CY Yamashiro, K Chen, LJ Ma, XY Cheung, CMG Wang, YS Zhang, CF Bai, YJ Hou, J Chen, XL Qi, Y Li, SS Sun, YY Mei, JP Cheng, Y Yu, WZ Hu, XB Zhuang, FF Fan, L Lu, Y Sun, XH Zhu, XJ Shen, DF Chan, CC Zhao, MW Yoshimura, N Pang, CP Wong, TY Khor, CC Zhang, K Zhou, P Li, XX AF Huang, Lv-Zhen Li, Ying-Jie Xie, Xue-Feng Zhang, Jing-Jing Cheng, Ching-Yu Yamashiro, Kenji Chen, Li-Jia Ma, Xiao-Yun Cheung, Chui Ming G. Wang, Yu-Sheng Zhang, Chun-Fang Bai, Yu-Jing Hou, Jing Chen, Xiao-Li Qi, Yun Li, Shan-Shan Sun, Yao-Yao Mei, Jun-Pu Cheng, Yong Yu, Wen-Zhen Hu, Xiong-Bing Zhuang, Feng-Feng Fan, Lei Lu, Yi Sun, Xing-Huai Zhu, Xiang-Jia Shen, De-Fen Chan, Chi-Chao Zhao, Ming-Wei Yoshimura, Nagahisa Pang, Chi Pui Wong, Tien Yin Khor, Chiea Chuen Zhang, Kang Zhou, Peng Li, Xiao-Xin TI Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; UBIQUITIN-PROTEASOME-SYSTEM; ALZHEIMERS-DISEASE; CONJUGATION; EXPRESSION; GENES; LOCI; EYE AB Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous single-nucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. As a follow-up validation, we evaluate 3,772 neovascular AMD cases and 6,942 controls from five independent cohorts in the East Asian population. Here we show strong evidence of an association at a novel, missense SNV, rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene (P-meta = 1.46 x 10(-9), odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.63-0.88). Furthermore, ablation of the UBE3D protein lead to an abnormal amount of pigment granules deposited in retinal pigment epithelium microvilli area and an abnormal response on electroretinography (ERG) in UBE3D(+/-) heterozygous mice. Our findings indicate that the ubiquitin-proteasome system may play a role in the pathogenesis of neovascular AMD. C1 [Huang, Lv-Zhen; Zhang, Jing-Jing; Bai, Yu-Jing; Hou, Jing; Chen, Xiao-Li; Qi, Yun; Li, Shan-Shan; Sun, Yao-Yao; Cheng, Yong; Yu, Wen-Zhen; Zhao, Ming-Wei; Khor, Chiea Chuen; Li, Xiao-Xin] Minist Educ China, Key Lab Vis Loss & Restorat, Beijing 100044, Peoples R China. [Huang, Lv-Zhen; Zhang, Jing-Jing; Bai, Yu-Jing; Hou, Jing; Chen, Xiao-Li; Qi, Yun; Li, Shan-Shan; Sun, Yao-Yao; Cheng, Yong; Yu, Wen-Zhen; Zhao, Ming-Wei; Li, Xiao-Xin] Peking Univ, Peoples Hosp, Dept Ophthalmol, Beijing 100044, Peoples R China. [Huang, Lv-Zhen; Zhang, Jing-Jing; Bai, Yu-Jing; Hou, Jing; Chen, Xiao-Li; Qi, Yun; Li, Shan-Shan; Sun, Yao-Yao; Yu, Wen-Zhen; Hu, Xiong-Bing; Zhao, Ming-Wei; Li, Xiao-Xin] Beijing Key Lab Diag & Therapy Retinal & Choroid, Beijing 100044, Peoples R China. [Li, Ying-Jie] Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst & Hosp, Dept Abdominal Surg Oncol, Beijing 100021, Peoples R China. [Xie, Xue-Feng] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Cheng, Ching-Yu; Cheung, Chui Ming G.; Mei, Jun-Pu; Wong, Tien Yin] Singapore Eye Res Inst, Singapore 169856, Singapore. [Cheng, Ching-Yu; Wong, Tien Yin] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Zhang, Chun-Fang; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Singapore 119228, Singapore. [Cheng, Ching-Yu; Wong, Tien Yin] Natl Univ Hlth Syst, Singapore 119228, Singapore. [Cheng, Ching-Yu; Cheung, Chui Ming G.; Wang, Yu-Sheng; Wong, Tien Yin] Singapore Natl Eye Ctr, Singapore 168751, Singapore. [Yamashiro, Kenji; Yoshimura, Nagahisa] Kyoto Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Kyoto 6068507, Japan. [Chen, Li-Jia; Pang, Chi Pui] Chinese Univ Hong Kong, Dept Ophthalmol & Visual Sci, Hong Kong 999077, Hong Kong, Peoples R China. [Ma, Xiao-Yun] Guanghua Integrat Med Hosp, Dept Ophthalmol, Shanghai 200052, Peoples R China. [Wang, Yu-Sheng] Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Peoples R China. [Zhang, Chun-Fang] Peking Univ, Peoples Hosp, Dept Clin Epidemiol, Beijing 100044, Peoples R China. [Hu, Xiong-Bing; Zhuang, Feng-Feng] Beijing View Solid Biotechnol, Beijing 100034, Peoples R China. [Fan, Lei; Lu, Yi; Sun, Xing-Huai; Zhu, Xiang-Jia; Zhou, Peng] Fudan Univ, Shanghai Med Coll, Shanghai 200032, Peoples R China. [Lu, Yi; Sun, Xing-Huai; Zhu, Xiang-Jia; Zhou, Peng] Fudan Univ, Eye & ENT Hosp, Dept Ophthalmol, Shanghai 200433, Peoples R China. [Shen, De-Fen; Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. [Khor, Chiea Chuen] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Khor, Chiea Chuen] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117549, Singapore. [Khor, Chiea Chuen] Natl Univ Hlth Syst, Singapore 117549, Singapore. [Zhang, Kang] Inst Genom Med, La Jolla, CA 92093 USA. [Zhang, Kang] Shiley Eye Ctr, La Jolla, CA 92093 USA. [Zhang, Kang] Univ Calif San Diego, La Jolla, CA 92093 USA. [Zhou, Peng] Pkwy Hlth Hongqiao Med Ctr, Shanghai 201101, Peoples R China. RP Li, XX (reprint author), Minist Educ China, Key Lab Vis Loss & Restorat, Beijing 100044, Peoples R China. EM zhaomingwei@medmail.com.cn; drzhoupeng@gmail.com; drlixiaoxin@163.com RI Chen, Li Jia/I-5078-2014; OI Chen, Li Jia/0000-0003-3500-5840; Khor, Chiea Chuen/0000-0002-1128-4729 FU National Basic Research Program of China (973 Program) [2011CB510200]; National Natural Science Foundation of China [81200669, 81100666, 81102003, 81270989, 81100653]; Research Fund for Science and Technology Program of Beijing [Z121100005312006]; Doctoral Program of Higher Education of China [20120071120089]; Zhuo-Xue Project of Fudan University; National Medical Research Council (NMRC) [0796/2003, IRG07nov013, IRG09nov014, NMRC 1176/2008, NIG/1003/2009, STaR/0003/2008, CG/SERI/2010, CSA/033/2012]; Biomedical Research Council in Singapore [BMRC 08/1/35/19/550, 09/1/35/19/616, 10/1/35/19/671]; BrightFocus Foundation, USA [M2011068]; NMRC, Singapore [CSA/033/2012] FX This work was supported by the National Basic Research Program of China (973 Program, no. 2011CB510200), the National Natural Science Foundation of China (nos. 81200669, 81100666, 81102003, 81270989 and 81100653), and the Research Fund for Science and Technology Program of Beijing (no. Z121100005312006), the Doctoral Program of Higher Education of China (no. 20120071120089) and the Zhuo-Xue Project of Fudan University (to P.Z.). This work was also supported by the National Medical Research Council (NMRC grants 0796/2003, IRG07nov013, IRG09nov014, NMRC 1176/2008, NIG/1003/2009, STaR/0003/2008, CG/SERI/2010 and CSA/033/2012), and Biomedical Research Council (BMRC 08/1/35/19/550, 09/1/35/19/616 and 10/1/35/19/671) in Singapore; the BrightFocus Foundation (M2011068), USA. C.-Y.C. is supported by an award from NMRC (CSA/033/2012), Singapore. NR 36 TC 5 Z9 6 U1 1 U2 13 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 APR PY 2015 VL 6 AR 6687 DI 10.1038/ncomms7687 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0GU UT WOS:000353698500001 PM 25872646 ER PT J AU Mikelis, CM Simaan, M Ando, K Fukuhara, S Sakurai, A Amornphimoltham, P Masedunskas, A Weigert, R Chavakis, T Adams, RH Offermanns, S Mochizuki, N Zheng, Y Gutkind, JS AF Mikelis, Constantinos M. Simaan, May Ando, Koji Fukuhara, Shigetomo Sakurai, Atsuko Amornphimoltham, Panomwat Masedunskas, Andrius Weigert, Roberto Chavakis, Triantafyllos Adams, Ralf H. Offermanns, Stefan Mochizuki, Naoki Zheng, Yi Gutkind, J. Silvio TI RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock SO NATURE COMMUNICATIONS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; VE-CADHERIN; ENDOTHELIAL PERMEABILITY; PULMONARY-HYPERTENSION; ADHERENS JUNCTIONS; KINASE INHIBITOR; CELL-JUNCTIONS; SMOOTH-MUSCLE; MYOSIN-II; CANCER AB Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma and anaphylaxis. Yet, how histamine induces the disruption of the endothelial barrier is not well defined. By using genetically modified animal models, pharmacologic inhibitors and a synthetic biology approach, here we show that the small GTPase RhoA mediates histamine-induced vascular leakage. Histamine causes the rapid formation of focal adherens junctions, disrupting the endothelial barrier by acting on H1R G alpha(q)-coupled receptors, which is blunted in endothelial G alpha(q/11) KO mice. Interfering with RhoA and ROCK function abolishes endothelial permeability, while phospholipase C beta plays a limited role. Moreover, endothelial-specific RhoA gene deletion prevents vascular leakage and passive cutaneous anaphylaxis in vivo, and ROCK inhibitors protect from lethal systemic anaphylaxis. This study supports a key role for the RhoA signalling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage. C1 [Mikelis, Constantinos M.; Simaan, May; Sakurai, Atsuko; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Ando, Koji; Fukuhara, Shigetomo; Mochizuki, Naoki] CREST JST, Dept Cell Biol, Natl Cerebral & Cardiovasc Ctr, Res Inst, Suita, Osaka 5658565, Japan. [Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Chavakis, Triantafyllos] Tech Univ Dresden, Dept Clin Pathobiochem, Fac Med, D-01307 Dresden, Germany. [Adams, Ralf H.] Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany. [Adams, Ralf H.] Univ Munster, Fac Med, D-48149 Munster, Germany. [Offermanns, Stefan] Max Planck Inst Heart & Lung Res, Dept Pharmacol, D-61231 Bad Nauheim, Germany. [Zheng, Yi] Univ Cincinnati, Canc & Blood Dis Inst, Cincinnati Childrens Hosp, Coll Med, Cincinnati, OH 45229 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Zheng, Yi/J-7235-2015; OI Zheng, Yi/0000-0001-7089-6074; Adams, Ralf/0000-0003-3031-7677 FU Intramural NIH HHS [Z01 DE000551-17, Z01 DE000558-16] NR 57 TC 19 Z9 19 U1 3 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 APR PY 2015 VL 6 AR 6725 DI 10.1038/ncomms7725 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0HZ UT WOS:000353701700004 PM 25857352 ER PT J AU Papaspyridonos, M Matei, I Huang, YJ Andre, MD Brazier-Mitouart, H Waite, JC Chan, AS Kalter, J Ramos, I Wu, Q Williams, C Wolchok, JD Chapman, PB Peinado, H Anandasabapathy, N Ocean, AJ Kaplan, RN Greenfield, JP Bromberg, J Skokos, D Lyden, D AF Papaspyridonos, Marianna Matei, Irina Huang, Yujie Andre, Maria do Rosario Brazier-Mitouart, Helene Waite, Janelle C. Chan, April S. Kalter, Julie Ramos, Ilyssa Wu, Qi Williams, Caitlin Wolchok, Jedd D. Chapman, Paul B. Peinado, Hector Anandasabapathy, Niroshana Ocean, Allyson J. Kaplan, Rosandra N. Greenfield, Jeffrey P. Bromberg, Jacqueline Skokos, Dimitris Lyden, David TI Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation SO NATURE COMMUNICATIONS LA English DT Article ID SELF-RENEWAL CAPACITY; REGULATORY T-CELLS; TGF-BETA; DENDRITIC CELLS; PERIPHERAL-BLOOD; PROGENITOR CELLS; CANCER-PATIENTS; DIFFERENTIATION; PROTEINS; MELANOMA AB A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGF beta, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFb levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis. C1 [Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; Andre, Maria do Rosario; Brazier-Mitouart, Helene; Chan, April S.; Williams, Caitlin; Peinado, Hector; Lyden, David] Weill Cornell Med Coll, Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA. [Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; Andre, Maria do Rosario; Brazier-Mitouart, Helene; Chan, April S.; Williams, Caitlin; Peinado, Hector; Lyden, David] Weill Cornell Med Coll, Dept Pediat, New York, NY 10021 USA. [Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; Andre, Maria do Rosario; Brazier-Mitouart, Helene; Chan, April S.; Williams, Caitlin; Peinado, Hector; Lyden, David] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10021 USA. Weill Cornell Med Coll, Drukier Inst Childrens Hlth, New York, NY 10021 USA. Weill Cornell Med Coll, Meyer Canc Ctr, New York, NY 10021 USA. [Huang, Yujie; Greenfield, Jeffrey P.] Weill Cornell Med Coll, Dept Neurosurg, New York, NY 10065 USA. [Andre, Maria do Rosario] Univ Nova Lisboa, Fac Ciencias Med, Dept Genet Oncol & Human Toxicol, P-1349008 Lisbon, Portugal. [Waite, Janelle C.; Kalter, Julie; Ramos, Ilyssa; Wu, Qi; Skokos, Dimitris] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, Melanoma & Immunotherapy Serv, New York, NY 10065 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, New York, NY 10065 USA. [Chapman, Paul B.; Bromberg, Jacqueline] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Peinado, Hector] Fdn Ctr Nacl Invest Oncol, Tumor Metastasis Lab, Madrid 28029, Spain. [Anandasabapathy, Niroshana] Harvard Univ, Sch Med, Dept Dermatol, Brigham & Womens Hosp, Boston, MA 02118 USA. [Ocean, Allyson J.] Weill Cornell Med Coll & Med Oncol, Solid Tumor Program, Dept Med, New York, NY 10021 USA. [Kaplan, Rosandra N.] NCI, Ctr Canc Res, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lyden, David] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. RP Skokos, D (reprint author), Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. EM dimitris.skokos@regeneron.com; dcl2001@med.cornell.edu RI Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013 FU UK-US Fulbright Commission; Garrett B. Smith Foundation; 5th District AHEPA Cancer Research Foundation; Children's Cancer and Blood Foundation; Hartwell Foundation; Manning Foundation; Pediatric Oncology Experimental Therapeutics Investigator's Consortium; Stavros S. Niarchos Foundation; Champalimaud Foundation; Nancy C. and Daniel P. Paduano Foundation; Mary Kay Foundation; Malcolm Hewitt Wiener Foundation; National Foundation for Cancer Research; Susan G. Komen for the Cure; Luso-American Development Foundation; American Portuguese Biomedical Research Fund; Fundacao para a Ciencia e a Tecnologia; Beth Tortolani Foundation; Theodore A Rapp Foundation FX We thank the members of our laboratories for their helpful discussions. We thank Dr. Sergei Rudchenko and Mihaela Barbu-Stevanovic at the Hospital for Special Surgery Fannie E. Rippel Foundation Flow Cytometry Core Facility for expert cell sorting. Our work was supported by grants from the UK-US Fulbright Commission (M.P.), the Garrett B. Smith Foundation (M.P.), 5th District AHEPA Cancer Research Foundation (M.P. and D.L.), the Children's Cancer and Blood Foundation (D.L.), The Hartwell Foundation (D.L.), The Manning Foundation (D.L.), Pediatric Oncology Experimental Therapeutics Investigator's Consortium (D.L.), Stavros S. Niarchos Foundation (D.L.), Champalimaud Foundation (D.L.), The Nancy C. and Daniel P. Paduano Foundation (D.L. and H.P.), The Mary Kay Foundation (D.L.), The Malcolm Hewitt Wiener Foundation (D.L.), National Foundation for Cancer Research (D.L.), Susan G. Komen for the Cure (D.L.), Luso-American Development Foundation (M.d.R.A.), American Portuguese Biomedical Research Fund (M.d.R.A.) and D.L. Fundacao para a Ciencia e a Tecnologia (D.L.), Beth Tortolani Foundation (D.L. and J.B.) and Theodore A Rapp Foundation (D.L.). NR 70 TC 8 Z9 9 U1 0 U2 4 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 APR PY 2015 VL 6 AR 6840 DI 10.1038/ncomms7840 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0IQ UT WOS:000353703400007 PM 25924227 ER PT J AU Pathania, R Ramachandran, S Elangovan, S Padia, R Yang, PY Cinghu, S Veeranan-Karmegam, R Arjunan, P Gnana-Prakasam, JP Sadanand, F Pei, LR Chang, CS Choi, JH Shi, HD Manicassamy, S Prasad, PD Sharma, S Ganapathy, V Jothi, R Thangaraju, M AF Pathania, Rajneesh Ramachandran, Sabarish Elangovan, Selvakumar Padia, Ravi Yang, Pengyi Cinghu, Senthilkumar Veeranan-Karmegam, Rajalakshmi Arjunan, Pachiappan Gnana-Prakasam, Jaya P. Sadanand, Fulzele Pei, Lirong Chang, Chang-Sheng Choi, Jeong-Hyeon Shi, Huidong Manicassamy, Santhakumar Prasad, Puttur D. Sharma, Suash Ganapathy, Vadivel Jothi, Raja Thangaraju, Muthusamy TI DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis SO NATURE COMMUNICATIONS LA English DT Article ID CPG-ISLAND METHYLATION; DNA METHYLATION; HEMATOPOIETIC STEM; SELF-RENEWAL; MAMMALIAN DEVELOPMENT; PROGENITOR CELLS; BREAST-CANCER; IN-VITRO; GENOME; GENE AB Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment. C1 [Pathania, Rajneesh; Ramachandran, Sabarish; Elangovan, Selvakumar; Padia, Ravi; Veeranan-Karmegam, Rajalakshmi; Arjunan, Pachiappan; Gnana-Prakasam, Jaya P.; Shi, Huidong; Prasad, Puttur D.; Ganapathy, Vadivel; Thangaraju, Muthusamy] Georgia Regents Univ, Dept Biochem & Mol Biol, Med Coll Georgia, Augusta, GA 30912 USA. [Yang, Pengyi; Cinghu, Senthilkumar; Jothi, Raja] NIEHS, Syst Biol Sect, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sadanand, Fulzele] Georgia Regents Univ, Dept Orthoped Surg, Med Coll Georgia, Augusta, GA 30912 USA. [Pei, Lirong; Chang, Chang-Sheng; Sharma, Suash] Georgia Regents Univ, Dept Pathol, Med Coll Georgia, Augusta, GA 30912 USA. [Choi, Jeong-Hyeon] Georgia Regents Univ, Dept Biostat, Med Coll Georgia, Augusta, GA 30912 USA. [Choi, Jeong-Hyeon; Shi, Huidong; Manicassamy, Santhakumar; Prasad, Puttur D.; Sharma, Suash; Ganapathy, Vadivel; Thangaraju, Muthusamy] Georgia Regents Univ, Canc Res Ctr, Med Coll Georgia, Augusta, GA 30912 USA. RP Thangaraju, M (reprint author), Georgia Regents Univ, Dept Biochem & Mol Biol, Med Coll Georgia, Augusta, GA 30912 USA. EM mthangaraju@gru.edu RI Jothi, Raja/G-3780-2015; Ramachandran, Sabarish/K-8146-2016; PATHANIA, RAJNEESH/H-9985-2016; OI PATHANIA, RAJNEESH/0000-0003-0099-3682; Yang, Pengyi/0000-0003-1098-3138 FU National Institute of Health [CA131402]; Department of Defense [BC074289]; Georgia Regents University (GRU); Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [1ZIAES102625] FX We thank Jeanene Pihkala for Flow sorting and William King for technical assistance. This work was supported by grants from the National Institute of Health (CA131402), Department of Defense (BC074289) and Georgia Regents University (GRU) Intramural Pilot Study grant, Start-up and Bridge funds. P.Y., S.C. and R.J. were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (1ZIAES102625). NR 44 TC 23 Z9 24 U1 1 U2 8 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 APR PY 2015 VL 6 AR 6910 DI 10.1038/ncomms7910 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0IW UT WOS:000353704100018 PM 25908435 ER PT J AU Tapper, W Jones, AV Kralovics, R Harutyunyan, AS Zoi, K Leung, W Godfrey, AL Guglielmelli, P Callaway, A Ward, D Aranaz, P White, HE Waghorn, K Lin, F Chase, A Baxter, EJ Maclean, C Nangalia, J Chen, E Evans, P Short, M Jack, A Wallis, L Oscier, D Duncombe, AS Schuh, A Mead, AJ Griffiths, M Ewing, J Gale, RE Schnittger, S Haferlach, T Stegelmann, F Dohner, K Grallert, H Strauch, K Tanaka, T Bandinelli, S Giannopoulos, A Pieri, L Mannarelli, C Gisslinger, H Barosi, G Cazzola, M Reiter, A Harrison, C Campbell, P Green, AR Vannucchi, A Cross, NCP AF Tapper, William Jones, Amy V. Kralovics, Robert Harutyunyan, Ashot S. Zoi, Katerina Leung, William Godfrey, Anna L. Guglielmelli, Paola Callaway, Alison Ward, Daniel Aranaz, Paula White, Helen E. Waghorn, Katherine Lin, Feng Chase, Andrew Baxter, E. Joanna Maclean, Cathy Nangalia, Jyoti Chen, Edwin Evans, Paul Short, Michael Jack, Andrew Wallis, Louise Oscier, David Duncombe, Andrew S. Schuh, Anna Mead, Adam J. Griffiths, Michael Ewing, Joanne Gale, Rosemary E. Schnittger, Susanne Haferlach, Torsten Stegelmann, Frank Doehner, Konstanze Grallert, Harald Strauch, Konstantin Tanaka, Toshiko Bandinelli, Stefania Giannopoulos, Andreas Pieri, Lisa Mannarelli, Carmela Gisslinger, Heinz Barosi, Giovanni Cazzola, Mario Reiter, Andreas Harrison, Claire Campbell, Peter Green, Anthony R. Vannucchi, Alessandro Cross, Nicholas C. P. TI Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms SO NATURE COMMUNICATIONS LA English DT Article ID POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; GLUCOCORTICOID-RECEPTOR; CONFERS SUSCEPTIBILITY; 6Q23.3 INFLUENCES; C-MYB; GENOME; EXPRESSION; HAPLOTYPE; CELLS AB Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P = 1.27 x 10(-10)) and rs2201862 (MECOM; meta-analysis P = 1.96 x 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P = 4.5 x 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic chi(2) P = 7.3 x 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. C1 [Tapper, William; Jones, Amy V.; Leung, William; White, Helen E.; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Cross, Nicholas C. P.] Univ Southampton, Fac Med, Southampton SO16 6YD, Hants, England. [Tapper, William; Jones, Amy V.; Leung, William; White, Helen E.; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Cross, Nicholas C. P.] Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England. [Kralovics, Robert; Harutyunyan, Ashot S.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria. [Zoi, Katerina; Giannopoulos, Andreas] Acad Athens, Biomed Res Fdn, Haematol Res Lab, Athens 11527, Greece. [Godfrey, Anna L.; Baxter, E. Joanna; Maclean, Cathy; Nangalia, Jyoti; Chen, Edwin; Green, Anthony R.] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 0XY, England. [Godfrey, Anna L.; Baxter, E. Joanna; Maclean, Cathy; Nangalia, Jyoti; Green, Anthony R.] Univ Cambridge, Dept Haematol, Cambridge CB2 0XY, England. [Guglielmelli, Paola; Pieri, Lisa; Mannarelli, Carmela; Vannucchi, Alessandro] Univ Florence, Dept Expt & Clin Med, Lab Congiunto MMPC, I-50134 Florence, Italy. [Evans, Paul; Short, Michael; Jack, Andrew] St James Univ Hosp, St Jamess Inst Oncol, Haematol Malignancy Diagnost Serv, Bexley Wing, Leeds LS9 7TF, W Yorkshire, England. [Wallis, Louise; Oscier, David] Royal Bournemouth Hosp, Dept Haematol, Bournemouth BH7 7DW, Dorset, England. [Duncombe, Andrew S.] Southampton Univ Hosp, Dept Haematol, Southampton SO16 6YD, Hants, England. [Schuh, Anna] Oxford Univ Hosp NHS Trust, Oxford Biomed Res Ctr, Mol Diagnost Lab, Oxford OX3 7LE, England. [Mead, Adam J.] Univ Oxford, Weatherall Inst Mol Med, Haematopoiet Stem Cell Biol Lab, Oxford OX3 9DS, England. [Griffiths, Michael] Univ Birmingham, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England. [Griffiths, Michael] Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Lab, Birmingham B15 2TG, W Midlands, England. [Ewing, Joanne] Birmingham Heartlands Hosp, Birmingham B9 5SS, W Midlands, England. [Gale, Rosemary E.] UCL Canc Inst, Dept Haematol, London WC1E 6BT, England. [Schnittger, Susanne; Haferlach, Torsten] Munich Leukaemia Lab, D-81377 Munich, Germany. [Stegelmann, Frank; Doehner, Konstanze] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Grallert, Harald; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Grallert, Harald] German Ctr Diabet Res, D-85764 Neuherberg, Germany. [Strauch, Konstantin] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-80539 Munich, Germany. [Tanaka, Toshiko] NIA, Longitudinal Study Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50122 Florence, Italy. [Gisslinger, Heinz] Med Univ Vienna, Div Hematol & Blood Coagulat, Dept Internal Med 1, A-1090 Vienna, Austria. [Barosi, Giovanni] IRCCS Policlin San Matteo Fdn, Ctr Study Myelofibrosis, I-27100 Pavia, Italy. [Cazzola, Mario] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy. [Cazzola, Mario] Fdn IRCCS Policlin San Matteo, Dept Hematol Oncol, I-27100 Pavia, Italy. [Reiter, Andreas] Univ Med Mannheim, Med Klin 3, D-68167 Mannheim, Germany. [Harrison, Claire] Guys & St Thomas NHS Fdn Trust, Guys Hosp, Dept Haematol, London SE1 9RT, England. [Campbell, Peter] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. RP Cross, NCP (reprint author), Univ Southampton, Fac Med, Southampton SO16 6YD, Hants, England. EM ncpc@soton.ac.uk RI Grallert, Harald/B-3424-2013; Cross, Nicholas/B-4817-2009; Mead, Adam/A-8796-2012; Guglielmelli, Paola/K-7509-2016; Pieri, Lisa/K-1762-2016; Harutyunyan, Ashot/M-3528-2014; OI Cross, Nicholas/0000-0001-5481-2555; Guglielmelli, Paola/0000-0003-1809-284X; Pieri, Lisa/0000-0003-1812-8072; Giannopoulos, Andreas/0000-0002-1647-9429; Harutyunyan, Ashot/0000-0002-9050-9315; Kralovics, Robert/0000-0002-6997-8539 FU Leukaemia and Lymphoma Research; Kay Kendall Leukaemia Fund; Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano); Wellcome Trust [07611]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovative; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; Cambridge NIHR Biomedical Research Centre; Wellcome Trust-MRC Stem Cell Institute; Cambridge Experimental Cancer Medicine Centre, UK FX W.T., A.C., W.L., K.W. and N.C.P.C. were supported by Leukaemia and Lymphoma Research. A.V.J. was supported by the Kay Kendall Leukaemia Fund. Work in the Italian centers was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) 'Special Program Molecular Clinical Oncology 5 x 1000' to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). A detailed description of the AGIMM project is available at http://www.progettoagimm.it. A full list of the investigators who contributed to the generation of the WTCCC data is available from www.wtccc.org.uk, funding for which was provided by the Wellcome Trust under award 07611. The KORA research platform (KORA, Cooperative Health Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovative. The InCHIANTI study baseline (1998-2000) was supported as a 'targeted project' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust-MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. NR 69 TC 34 Z9 34 U1 1 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 APR PY 2015 VL 6 AR 6691 DI 10.1038/ncomms7691 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0GY UT WOS:000353699000002 PM 25849990 ER PT J AU Wang, T Chai, RJ Kim, GS Pham, N Jansson, L Nguyen, DH Kuo, B May, LA Zuo, J Cunningham, LL Cheng, AG AF Wang, Tian Chai, Renjie Kim, Grace S. Pham, Nicole Jansson, Lina Duc-Huy Nguyen Kuo, Bryan May, Lindsey A. Zuo, Jian Cunningham, Lisa L. Cheng, Alan G. TI Lgr5+cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle SO NATURE COMMUNICATIONS LA English DT Article ID MAMMALIAN INNER-EAR; MATURE GUINEA-PIGS; AVIAN AUDITORY EPITHELIUM; MATH1 GENE-TRANSFER; IN-VITRO EXPANSION; STEM-CELLS; SENSORY EPITHELIA; UTRICULAR MACULA; ACOUSTIC TRAUMA; VESTIBULAR EPITHELIUM AB Recruitment of endogenous progenitors is critical during tissue repair. The inner ear utricle requires mechanosensory hair cells (HCs) to detect linear acceleration. After damage, non-mammalian utricles regenerate HCs via both proliferation and direct transdifferentiation. In adult mammals, limited transdifferentiation from unidentified progenitors occurs to regenerate extrastriolar Type II HCs. Here we show that HC damage in neonatal mouse utricle activates the Wnt target gene Lgr5 in striolar supporting cells. Lineage tracing and time-lapse microscopy reveal that Lgr5+ cells transdifferentiate into HC-like cells in vitro. In contrast to adults, HC ablation in neonatal utricles in vivo recruits Lgr5+ cells to regenerate striolar HCs through mitotic and transdifferentiation pathways. Both Type I and II HCs are regenerated, and regenerated HCs display stereocilia and synapses. Lastly, stabilized beta-catenin in Lgr5+ cells enhances mitotic activity and HC regeneration. Thus Lgr5 marks Wnt-regulated, damage-activated HC progenitors and may help uncover factors driving mammalian HC regeneration. C1 [Wang, Tian; Chai, Renjie; Kim, Grace S.; Pham, Nicole; Jansson, Lina; Duc-Huy Nguyen; Cheng, Alan G.] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Stanford, CA 94305 USA. [Chai, Renjie] Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Minist Educ, Nanjing 210096, Jiangsu, Peoples R China. [Chai, Renjie] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China. [Kuo, Bryan; Zuo, Jian] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38103 USA. [May, Lindsey A.; Cunningham, Lisa L.] NIDCD, NIH, Bethesda, MD 20892 USA. RP Cheng, AG (reprint author), Stanford Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Stanford, CA 94305 USA. EM aglcheng@stanford.edu FU NIH-NCATS-CTSA [UL1 TR001085]; Lucile Packard Foundation for Children's Health; Child Health Research Institute; National Basic Research Program of China [2012CB967904, 2012CB967900, 2015CB965000]; National Natural Science Foundation of China [81470692]; Natural Science Foundation from Jiangsu Province [BK20140620]; Stanford University Medical Scholars Program; Howard Hughes Medical Institute Medical Scholars Fellowship; Swedish Research Council [C0657401, R01DC006471, P30CA21765]; American Lebanese Syrian Associated Charities; Office of Naval Research; NIDCD Division of Intramural Research [1ZIADC000079]; NIDCD/NIH [P30DC010363, K08DC011043, RO1DC013910]; Department of Defense [W81XWH-14-1-0517]; Akiko Yamazaki and Jerry Yang Faculty Scholar Fund; American Hearing Research Foundation; California Initiative in Regenerative Medicine [RN3-06529] FX We thank E. Rubel, D. Wu, S. Heller, M. Drummond, B. Cox for critical reading; R. Nusse, O. Bermingham-McDonogh, J. Corwin, E. Oesterle, J. Stone, A. Ricci and our laboratory members for fruitful discussions; V. Nookala, J. Luo, G. Huang, M. Drummond, L. Tong and Z. Sayyid for excellent technical assistance; M. Taketo for sharing the Catnb-flox(exon3) mouse, E. Rubel for sharing the Pou4f3-DTR mouse, H. Bellen for sharing antibodies; and E. Monzack for figure illustration (5 h). This work was supported by NIH-NCATS-CTSA (UL1 TR001085), the Lucile Packard Foundation for Children's Health, the Child Health Research Institute, the National Basic Research Program of China 2012CB967904, 2012CB967900 (T.W.), the National Basic Research Program of China 2015CB965000, the National Natural Science Foundation of China 81470692, the Natural Science Foundation from Jiangsu Province BK20140620 (R.C.), the Stanford University Medical Scholars Program, the Howard Hughes Medical Institute Medical Scholars Fellowship (G.S.K.), the Swedish Research Council C0657401 (L.J.), R01DC006471, P30CA21765, the American Lebanese Syrian Associated Charities, the Office of Naval Research (J. Z.), NIDCD Division of Intramural Research 1ZIADC000079 (L.L.C.), NIDCD/NIH P30DC010363, K08DC011043, RO1DC013910, Department of Defense W81XWH-14-1-0517 and the Akiko Yamazaki and Jerry Yang Faculty Scholar Fund, the American Hearing Research Foundation and the California Initiative in Regenerative Medicine RN3-06529 (A.G.C.). NR 70 TC 15 Z9 15 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2015 VL 6 AR 6613 DI 10.1038/ncomms7613 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0FS UT WOS:000353695500001 PM 25849379 ER PT J AU Ramos-Alvarez, I Mantey, SA Nakamura, T Nuche-Berenguer, B Moreno, P Moody, TW Maderdrut, JL Coy, DH Jensen, RT AF Ramos-Alvarez, Irene Mantey, Samuel A. Nakamura, Taichi Nuche-Berenguer, Bernardo Moreno, Paola Moody, Terry W. Maderdrut, Jerome L. Coy, David H. Jensen, Robert T. TI A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists SO PEPTIDES LA English DT Article DE PACAP; Vasoactive intestinal peptide; Neuroprotection; Stroke; Traumatic brain injury; Structure-function study ID CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; INTRACELLULAR CYCLIC-AMP; PIG PANCREATIC ACINI; BLOOD-BRAIN-BARRIER; 4 SPLICE VARIANTS; ADENYLATE-CYCLASE; SIGNAL-TRANSDUCTION; GUINEA-PIG; VPAC(1) RECEPTORS AB Pituitary adenylate cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally restricted PACAP-analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1-4, 14-17, 20-22, 28, 34,38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6-78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to 103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases. Published by Elsevier Inc. C1 [Ramos-Alvarez, Irene; Mantey, Samuel A.; Nakamura, Taichi; Nuche-Berenguer, Bernardo; Moreno, Paola; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Moody, Terry W.] NCI, Ctr Canc Res, Off Director, NIH, Bethesda, MD 20892 USA. [Maderdrut, Jerome L.; Coy, David H.] Tulane Univ, Hlth Sci Ctr, Peptide Res Lab, Dept Med, New Orleans, LA 70112 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU NIDDK branch of the National Institutes of Health; National Institute of General Medical Sciences of the National Institutes of Health [1 U54 GM104940] FX This work was supported in part by intramural funds from the NIDDK branch of the National Institutes of Health. This work was also supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 5 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 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD APR PY 2015 VL 66 BP 26 EP 42 DI 10.1016/j.peptides.2015.01.009 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA CH1NE UT WOS:000353787700005 PM 25698233 ER PT J AU Lopez-Contreras, AJ Specks, J Barlow, JH Ambrogio, C Desler, C Vikingsson, S Rodrigo-Perez, S Green, H Rasmussen, LJ Murga, M Nussenzweig, A Fernandez-Capetillo, O AF Lopez-Contreras, Andres J. Specks, Julia Barlow, Jacqueline H. Ambrogio, Chiara Desler, Claus Vikingsson, Svante Rodrigo-Perez, Sara Green, Henrik Juel Rasmussen, Lene Murga, Matilde Nussenzweig, Andre Fernandez-Capetillo, Oscar TI Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice SO GENES & DEVELOPMENT LA English DT Article DE ATR; fragile site; mouse models; RNR; replication stress ID DNA-DAMAGE RESPONSE; EARLY EMBRYONIC LETHALITY; RIBONUCLEOTIDE REDUCTASE; REPLICATION STRESS; GENOME INTEGRITY; NUCLEAR IMPORT; DNTP POOLS; CHECKPOINT; RESISTANT; KINASE AB In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity. Supplemental material is available for this article. C1 [Lopez-Contreras, Andres J.; Specks, Julia; Rodrigo-Perez, Sara; Murga, Matilde; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain. [Barlow, Jacqueline H.; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Ambrogio, Chiara] Spanish Natl Canc Res Ctr CNIO, Expt Oncol Grp, Madrid 28029, Spain. [Desler, Claus; Juel Rasmussen, Lene] Univ Copenhagen, Ctr Hlth Aging, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. [Vikingsson, Svante; Green, Henrik] Linkoping Univ, Div Drug Res Clin Pharmacol, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden. [Green, Henrik] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, SE-58185 Linkoping, Sweden. RP Lopez-Contreras, AJ (reprint author), Univ Copenhagen, Ctr Chromosome Stabil, Dept Cellular & Mol Med, Panum Inst, DK-2200 Copenhagen N, Denmark. EM ajlopez@sund.ku.dk; ofernandez@cnio.es RI Fernandez-Capetillo, Oscar/H-3508-2015; OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885; desler, claus/0000-0002-0125-004X; Ambrogio, Chiara/0000-0003-4122-701X; Lopez-Contreras, Andres Joaquin/0000-0002-5517-7327 FU Spanish Association for Cancer Research (AECC); Spanish government [BES-2012-05 2030]; Swedish Research Council; Swedish Cancer Society; Fundacion Botin; Banco Santander through its Santander Universities Global Division; Ministerio de Economia y Competitividad (MINECO) [SAF2011-23753]; Worldwide Cancer Research [12-0229]; Fundacio La Marato de TV3; Howard Hughes Medical Institute; European Research Council [ERC-617840]; Danish Council for Independent Research (DFF); Danish National Research Foundation FX A.J.L.-C. and C.A. were funded a post-doctoral fellowship from the Spanish Association for Cancer Research (AECC). J.S. is a recipient of a predoctoral fellowship from the Spanish government (BES-2012-05 2030). S.V. and H.G. are funded by the Swedish Research Council and the Swedish Cancer Society. Work in O.F.-C.'s laboratory was supported by Fundacion Botin, Banco Santander through its Santander Universities Global Division, and grants from Ministerio de Economia y Competitividad (MINECO; SAF2011-23753), Worldwide Cancer Research (12-0229), Fundacio La Marato de TV3, Howard Hughes Medical Institute, and the European Research Council (ERC-617840). Work in A.J.L.-C.'s laboratory is funded by the Danish Council for Independent Research (DFF) and the Danish National Research Foundation. NR 40 TC 9 Z9 9 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD APR 1 PY 2015 VL 29 IS 7 BP 690 EP 695 DI 10.1101/gad.256958.114 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CE9KA UT WOS:000352161600002 PM 25838540 ER PT J AU Volkow, ND Koob, G Baler, R AF Volkow, Nora D. Koob, George Baler, Ruben TI Biomarkers in Substance Use Disorders SO ACS CHEMICAL NEUROSCIENCE LA English DT Review DE Addiction; dopamine; MRI; PET; EEG; endophenotype; genetics; epigenetics ID DOPAMINE-D-2 RECEPTORS; COCAINE DEPENDENCE; INHIBITORY CONTROL; COGNITIVE FUNCTION; NEURAL MECHANISMS; ADDICTION; IMPULSIVITY; ABUSE; MEDICATIONS; CORTEX AB The prevention and treatment of substance use disorders (SUDs), including addiction, would benefit from having better biomarkers for the classification of patients into categories that are reproducible and have predictive validity. Direct measurement of drugs or their metabolites in various body fluids constitutes a clinically valuable biomarker but one that can only be used to corroborate acute or relatively recent drug use. Thus, there is an urgent need for biomarkers that reflect chronic drug exposure as well as biomarkers that predict or correlate with disease trajectories and treatment responses. Advances in tools and technologies to investigate genetics, epigenetics and epitranscriptomics, and human brain function and neurochemistry (brain imaging tools including EEG) offer unprecedented opportunities for the development of such biomarkers. Progress in this area will not only enhance our ability to screen and treat patients with SUDs but also accelerate research on the neurobiological processes that underlie SUDs. C1 [Volkow, Nora D.; Baler, Ruben] NIDA, NIH, Bethesda, MD 20892 USA. [Koob, George] NIAAA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. RI koob, george/P-8791-2016 NR 41 TC 17 Z9 17 U1 4 U2 27 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 APR PY 2015 VL 6 IS 4 BP 522 EP 525 DI 10.1021/acschemneuro.5b00067 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CG3MU UT WOS:000353185100003 PM 25734247 ER PT J AU Conroy, JL Free, RB Sibley, DR AF Conroy, Jennie L. Free, R. Benjamin Sibley, David R. TI Identification of G Protein-Biased Agonists That Fail To Recruit beta-Arrestin or Promote Internalization of the D1 Dopamine Receptor SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Dopamine; D1 receptor; functional selectivity; biased agonism; G protein; beta-arrestin; benzazepine ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; FUNCTIONAL SELECTIVITY; RAT-BRAIN; PHOSPHOINOSITIDE HYDROLYSIS; ALLOSTERIC MODULATION; COUPLED RECEPTORS; ADENYLATE-CYCLASE; PHOSPHOLIPASE-C; DRUG DISCOVERY; RHESUS-MONKEYS AB The D1 dopamine receptor (D1R) has been implicated in numerous neuropsychiatric disorders, and D1R-selective ligands have potential as therapeutic agents. Previous studies have identified substituted benzazepines as D1R-selective agonists, but the in vivo effects of these compounds have not correlated well with their in vitro pharmacological activities. A series of substituted benzazepines, and structurally dissimilar D1R-selective agonists, were tested for their functional effects on D1R-mediated cAMP accumulation, D1R-promoted beta-arrestin recruitment, and D1R internalization using live cell functional assays. All compounds tested elicited an increase in the level of cAMP accumulation, albeit with a range of efficacies. However, when the compounds were evaluated for beta-arrestin recruitment, a subset of substituted benzazepines, SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670, failed to activate this pathway, whereas the others showed similar activation efficacies as seen with cAMP accumulation. When tested as antagonists, the five biased compounds all inhibited dopamine-stimulated beta-arrestin recruitment. Further, D1R internalization assays revealed a corroborating pattern of activity in that the G protein-biased compounds failed to promote D1R internalization. Interestingly, the biased signaling was unique for the D1R, as the same compounds were agonists of the related D5 dopamine receptor (D5R), but revealed no signaling bias. We have identified a group of substituted benzazepine ligands that are agonists at D1R-mediated G protein signaling, but antagonists of D1R recruitment of beta-arrestin, and also devoid of agonist-induced receptor endocytosis. These data may be useful for interpreting the contrasting effects of these compounds in vitro versus in vivo, and also for the understanding of pathway-selective signaling of the D1R. C1 [Conroy, Jennie L.; Free, R. Benjamin; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Ln,Room 4S-04, Bethesda, MD 20892 USA. EM sibleyd@helix.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), in the National Institutes of Health (NIH) FX This project was funded by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), in the National Institutes of Health (NIH). NR 66 TC 6 Z9 6 U1 2 U2 9 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 APR PY 2015 VL 6 IS 4 BP 681 EP 692 DI 10.1021/acschemneuro.5b00020 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CG3MU UT WOS:000353185100018 PM 25660762 ER PT J AU Dix, AV Conroy, JL Rosenker, KMG Sibley, DR Appella, DH AF Dix, Andrew V. Conroy, Jennie L. Rosenker, Kara M. George Sibley, David R. Appella, Daniel H. TI PNA-Based Multivalent Scaffolds Activate the Dopamine D-2 Receptor SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Peptide nucleic acid; multivalent display; dopamine D-2 receptor; self-assembly ID PROTEIN-COUPLED RECEPTOR; PEPTIDE NUCLEIC-ACIDS; BETA-ARRESTIN RECRUITMENT; BIVALENT LIGANDS; HOMOBIVALENT LIGANDS; D2 RECEPTORS; BINDING; DNA; DISPLAY; NANOSCAFFOLDS AB Peptide nucleic acid scaffolds represent a promising tool to interrogate the multivalent effects of ligand binding to a membrane receptor. Dopamine D-2 receptors (D2R) are a class of G-protein coupled receptors (GPCRs), and the formation of higher-ordered structures of these receptors has been associated with the progression of several neurological diseases. In this Letter, we describe the synthesis of a library of ligand-modified PNAs bearing a known D2R agonist, (+/-)-PPHT. The D2R activity for each construct was assessed, and the multivalent effects were evaluated. C1 [Dix, Andrew V.; Rosenker, Kara M. George; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Conroy, Jennie L.; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov FU NIDDK at NIH; NINDS at NIH FX This research was supported by the Intramural Research Programs (IRPs) of NIDDK and NINDS at NIH. NR 51 TC 4 Z9 4 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD APR PY 2015 VL 6 IS 4 BP 425 EP 429 DI 10.1021/ml500478m PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CG2IO UT WOS:000353098300011 PM 25893044 ER PT J AU Farmer, C Butter, E Mazurek, MO Cowan, C Lainhart, J Cook, EH DeWitt, MB Aman, M AF Farmer, Cristan Butter, Eric Mazurek, Micah O. Cowan, Charles Lainhart, Janet Cook, Edwin H. DeWitt, Mary Beth Aman, Michael TI Aggression in children with autism spectrum disorders and a clinic-referred comparison group SO AUTISM LA English DT Article DE aggression; autism spectrum disorders; Child Behavior Checklist; Children's Scale for Hostility and Aggression: Reactive/Proactive; proactive aggression; reactive aggression ID PERVASIVE DEVELOPMENTAL DISORDERS; INTELLECTUAL DISABILITY; PHYSICAL AGGRESSION; YOUNG-PEOPLE; CHALLENGING BEHAVIOR; EMOTIONAL-PROBLEMS; EARLY-CHILDHOOD; RISK MARKERS; PREVALENCE; ADOLESCENTS AB A gap exists in the literature regarding aggression in autism spectrum disorders and how this behavior compares to other groups. In this multisite study, the Children's Scale for Hostility and Aggression: Reactive/Proactive and the Aggression subscale of the Child Behavior Checklist were rated for 414 children with autism spectrum disorder (autistic disorder, 69%; pervasive developmental disorder not otherwise specified, 24%; Asperger's disorder, 7%) and 243 clinic-referred children without autism spectrum disorder, aged 1-21 years (mean age about 7 years). Participants were not selected for aggressive behavior. Relative to the comparison group, children with autism spectrum disorder were reported to have less aggression and were more likely to be rated as reactive rather than proactive. Among all subjects, sex was not associated with aggression; higher IQ/adaptive behavior and older age were associated with more sophisticated types of aggression, while lower scores on IQ, adaptive behavior, and communication measures were associated with more physical aggression. The interaction between demographic variables and diagnosis was significant only for age: younger but not older children with autism spectrum disorder showed less aggression than clinic-referred controls. C1 [Farmer, Cristan; Butter, Eric; Aman, Michael] Ohio State Univ, Columbus, OH 43210 USA. [Farmer, Cristan] NIMH, Bethesda, MD 20892 USA. [Butter, Eric] Nationwide Childrens Hosp, Columbus, OH USA. [Mazurek, Micah O.] Univ Missouri, Columbia, MO 65211 USA. [Cowan, Charles] Seattle Childrens Hosp, Seattle, WA USA. [Lainhart, Janet] Univ Utah, Salt Lake City, UT 84112 USA. [Lainhart, Janet] Univ Wisconsin Madison, Madison, WI USA. [Cook, Edwin H.] Univ Illinois, Chicago, IL USA. [DeWitt, Mary Beth] Childrens Med Ctr Dayton, Dayton, OH USA. RP Farmer, C (reprint author), NIMH, 10 Ctr Dr,Room 1C250 MSC 1255, Bethesda, MD 20892 USA. EM farmerca@mail.nih.gov OI Mazurek, Micah/0000-0001-7715-6538 FU Graduate School of the Ohio State University; Organization for Autism Research; [P50 HD055751] FX This work was supported by an Alumni Grant from the Graduate School of the Ohio State University (to Cristan Farmer), a Graduate Student Grant from the Organization for Autism Research (to Cristan Farmer), and P50 HD055751 (to Edwin H Cook). NR 47 TC 9 Z9 9 U1 2 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1362-3613 EI 1461-7005 J9 AUTISM JI Autism PD APR PY 2015 VL 19 IS 3 BP 281 EP 291 DI 10.1177/1362361313518995 PG 11 WC Psychology, Developmental SC Psychology GA CG1IH UT WOS:000353025800004 PM 24497627 ER PT J AU Sharov, A Maran, T Tonnessen, M AF Sharov, Alexei Maran, Timo Tonnessen, Morten TI Towards Synthesis of Biology and Semiotics SO BIOSEMIOTICS LA English DT Editorial Material C1 [Sharov, Alexei] NIA, Baltimore, MD 21224 USA. [Maran, Timo] Univ Tartu, Dept Semiot, EE-50090 Tartu, Estonia. [Tonnessen, Morten] Univ Stavanger, Stavanger, Norway. RP Sharov, A (reprint author), NIA, Baltimore, MD 21224 USA. EM sharoval@mail.nih.gov RI Maran, Timo/G-5504-2016 NR 7 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 EI 1875-1350 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD APR PY 2015 VL 8 IS 1 BP 1 EP 7 DI 10.1007/s12304-015-9239-y PG 7 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA CG4AZ UT WOS:000353223900001 ER PT J AU Sharov, AA Vehkavaara, T AF Sharov, Alexei A. Vehkavaara, Tommi TI Protosemiosis: Agency with Reduced Representation Capacity SO BIOSEMIOTICS LA English DT Article DE Semiotics; Evolution; Molecular signaling; Representation; Categorization; Umwelt ID PHOSPHORYLATION; BIOSEMIOTICS; MACHINES; PARADIGM; LIFE AB Life has semiotic nature; and as life forms differ in their complexity, functionality, and adaptability, we assume that forms of semiosis also vary accordingly. Here we propose a criterion to distinguish between the primitive kind of semiosis, which we call "protosemiosis" (following Prodi) from the advanced kind of semiosis, or "eusemiosis". In protosemiosis, agents associate signs directly with actions without considering objects, whereas in eusemiosis, agents associate signs with objects and only then possibly with actions. Protosemiosis started from the origin of life, and eusemiosis started when evolving agents acquired the ability to track and classify objects. Eusemiosis is qualitatively different from protosemiosis because it can not be reduced to a small number of specific signaling pathways. Proto-signs can be classified into proto-icons that signal via single specific interaction, proto-indexes that combine several functions, and proto-symbols that are processed by a universal subagent equipped with a set of heritable adapters. Prefix "proto" is used here to characterize signs at the protosemiotic level. Although objects are not recognized by protosemiotic agents, they can be reliably reconstructed by human observers. In summary, protosemiosis is a primitive kind of semiosis that supports "know-how" without "know-what". Without studying protosemiosis, the biosemiotics theory would be incomplete. C1 [Sharov, Alexei A.] NIA, Genet Lab, Baltimore, MD 21224 USA. [Vehkavaara, Tommi] Univ Tampere, Sch Social Sci & Humanities, Tampere 33014, Finland. RP Sharov, AA (reprint author), NIA, Genet Lab, Baltimore, MD 21224 USA. EM sharoval@grc.nia.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; School of Social Sciences and Humanities, University of Tampere FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and by the School of Social Sciences and Humanities, University of Tampere. The content of this paper is not endorsed or suggested by the funding agencies. NR 55 TC 4 Z9 4 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 EI 1875-1350 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD APR PY 2015 VL 8 IS 1 BP 103 EP 123 DI 10.1007/s12304-014-9219-7 PG 21 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA CG4AZ UT WOS:000353223900007 PM 25937852 ER PT J AU Mir, MA Kochuparambil, ST Abraham, RS Rodriguez, V Howard, M Hsu, AP Jackson, AE Holland, SM Patnaik, MM AF Mir, Muhammad A. Kochuparambil, Samith T. Abraham, Roshini S. Rodriguez, Vilmarie Howard, Matthew Hsu, Amy P. Jackson, Amie E. Holland, Steven M. Patnaik, Mrinal M. TI Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations SO CANCER MEDICINE LA English DT Article DE GATA2; leukemia; lymphedema; MonoMAC; viral warts ID TRANSCRIPTION FACTOR GATA-2; FAMILIAL MYELODYSPLASTIC SYNDROME; EARLY HEMATOPOIETIC-CELLS; MONOMAC SYNDROME; AUTOSOMAL-DOMINANT; PRIMARY LYMPHEDEMA; STEM-CELLS; MYCOBACTERIAL INFECTION; SPORADIC MONOCYTOPENIA; DENDRITIC CELL AB Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While considerable efforts have been made to identify the mutations that characterize this disorder, pathogenesis remains a work in progress with less than 100 patients described in current literature. Varying clinical presentations offer diagnostic challenges. Allogeneic stem cell transplant remains the treatment of choice. Morbidity, mortality, and social costs due to the familial nature of the disease are considerable. We describe our experience with the disorder in three affected families and a comprehensive review of current literature. C1 [Mir, Muhammad A.] Penn State Milton S Hershey Canc Inst, Hershey, PA USA. [Kochuparambil, Samith T.; Jackson, Amie E.; Patnaik, Mrinal M.] Mayo Clin, Div Hematol Blood & Marrow Transplant, Rochester, MN 55905 USA. [Abraham, Roshini S.; Howard, Matthew] Mayo Clin, Dept Lab Med & Pathol, Div Clin Biochem, Rochester, MN USA. [Abraham, Roshini S.; Howard, Matthew] Mayo Clin, Dept Lab Med & Pathol, Div Immunol, Rochester, MN USA. [Rodriguez, Vilmarie] Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. [Hsu, Amy P.; Holland, Steven M.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Patnaik, MM (reprint author), Mayo Clin, Div Hematol Blood & Marrow Transplant, Rochester, MN 55905 USA. EM patnaik.mrinal@mayo.edu OI Mir, Muhammad/0000-0003-0607-1566 NR 78 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD APR PY 2015 VL 4 IS 4 BP 490 EP 499 DI 10.1002/cam4.384 PG 10 WC Oncology SC Oncology GA CG1MR UT WOS:000353037300002 PM 25619630 ER PT J AU Chai, RC Lambie, D Verma, M Punyadeera, C AF Chai, Ryan C. Lambie, Duncan Verma, Mukesh Punyadeera, Chamindie TI Current trends in the etiology and diagnosis of HPV-related head and neck cancers SO CANCER MEDICINE LA English DT Review DE Biomarkers; epidemiology; HPV; oropharyngeal cancer; saliva diagnostics ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS TYPE-16; IN-SITU HYBRIDIZATION; OROPHARYNGEAL CANCER; SEXUAL-BEHAVIOR; RISK-FACTOR; INTRAEPITHELIAL NEOPLASIA; FAVORABLE PROGNOSIS; INTERNATIONAL HEAD; 16-NEGATIVE HEAD AB Human papilloma virus (HPV) infection is a major risk factor for a distinct subset of head and neck squamous cell carcinoma (HNSCC). The current review summarizes the epidemiology of HNSCC and the disease burden, the infectious cycle of HPV, the roles of viral oncoproteins, E6 and E7, and the downstream cellular events that lead to malignant transformation. Current techniques for the clinical diagnosis of HPV-associated HNSCC will also be discussed, that is, the detection of HPV DNA, RNA, and the HPV surrogate marker, p16 in tumor tissues, as well as HPV-specific antibodies in serum. Such methods do not allow for the early detection of HPV-associated HNSCC and most cases are at an advanced stage upon diagnosis. Novel noninvasive approaches using oral fluid, a clinically relevant biological fluid, allow for the detection of HPV and cellular alterations in infected cells, which may aid in the early detection and HPV-typing of HNSCC tumors. Noninvasive diagnostic methods will enable early detection and intervention, leading to a significant reduction in mortality and morbidity associated with HNSCC. C1 [Chai, Ryan C.; Punyadeera, Chamindie] Univ Queensland, Diamantina Inst, Translat Res Inst, Woolloongabba, Qld 4102, Australia. [Lambie, Duncan] IQ Pathol, West End, Qld 4101, Australia. [Verma, Mukesh] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA. [Punyadeera, Chamindie] Queensland Univ Technol, Inst Hlth & Biomed Sci, Kelvin Grove, Qld 4059, Australia. RP Punyadeera, C (reprint author), Queensland Univ Technol, Inst Hlth & Biomed Sci, Saliva Translat Res Grp, Victoria Pk Rd, Kelvin Grove, Qld 4059, Australia. EM chamindie.punyadeera@qut.edu.au FU Garnett Passe & Rodney Williams Memorial Foundation; Queensland Centre of Excellence for Head and Neck Cancer - Atlantic Philanthropies; Queensland Government; Princess Alexandra Hospital FX This work is supported by Garnett Passe & Rodney Williams Memorial Foundation and the Queensland Centre of Excellence for Head and Neck Cancer funded by Atlantic Philanthropies, the Queensland Government, and the Princess Alexandra Hospital. NR 99 TC 18 Z9 19 U1 5 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD APR PY 2015 VL 4 IS 4 BP 596 EP 607 DI 10.1002/cam4.424 PG 12 WC Oncology SC Oncology GA CG1MR UT WOS:000353037300014 PM 25644715 ER PT J AU Pfeiffer, L Wahl, S Pilling, LC Reischl, E Sandling, JK Kunze, S Holdt, LM Kretschmer, A Schramm, K Adamski, J Klopp, N Illig, T Hedman, AK Roden, M Hernandez, DG Singleton, AB Thasler, WE Grallert, H Gieger, C Herder, C Teupser, D Meisinger, C Spector, TD Kronenberg, F Prokisch, H Melzer, D Peters, A Deloukas, P Ferrucci, L Waldenberger, M AF Pfeiffer, Liliane Wahl, Simone Pilling, Luke C. Reischl, Eva Sandling, Johanna K. Kunze, Sonja Holdt, Lesca M. Kretschmer, Anja Schramm, Katharina Adamski, Jerzy Klopp, Norman Illig, Thomas Hedman, Asa K. Roden, Michael Hernandez, Dena G. Singleton, Andrew B. Thasler, Wolfgang E. Grallert, Harald Gieger, Christian Herder, Christian Teupser, Daniel Meisinger, Christa Spector, Timothy D. Kronenberg, Florian Prokisch, Holger Melzer, David Peters, Annette Deloukas, Panos Ferrucci, Luigi Waldenberger, Melanie TI DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels SO Circulation-Cardiovascular Genetics LA English DT Article DE ABCG1; DNA methylatio; epidemiology; gene expression; myocardial infarction ID BINDING CASSETTE TRANSPORTER; EPIGENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; FOAM-CELL-FORMATION; CHOLESTEROL HOMEOSTASIS; QUANTILE NORMALIZATION; LOWERING DRUGS; HEART-DISEASE; DIET NETWORK; PPAR-ALPHA AB Background-Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. Methods and Results-Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (beta coefficient=-0.049; P=8.26E-17) and triglyceride levels (beta=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). Conclusions-Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases. C1 [Pfeiffer, Liliane; Wahl, Simone; Reischl, Eva; Kunze, Sonja; Kretschmer, Anja; Grallert, Harald; Peters, Annette; Waldenberger, Melanie] Res Unit Mol Epidemiol, Neuherberg, Germany. [Pfeiffer, Liliane; Wahl, Simone; Reischl, Eva; Kunze, Sonja; Kretschmer, Anja; Grallert, Harald; Meisinger, Christa; Peters, Annette; Waldenberger, Melanie] Inst Epidemiol 2, Neuherberg, Germany. [Schramm, Katharina; Prokisch, Holger] Inst Human Genet, Neuherberg, Germany. [Adamski, Jerzy] Inst Expt Genet, Genome Anal Ctr, Neuherberg, Germany. [Gieger, Christian] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Wahl, Simone; Grallert, Harald] German Ctr Diabet Res DZD, Neuherberg, Germany. [Pilling, Luke C.; Melzer, David] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Sandling, Johanna K.; Deloukas, Panos] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Holdt, Lesca M.; Teupser, Daniel] Univ Hosp Munich, Inst Lab Med, Munich, Germany. [Holdt, Lesca M.; Teupser, Daniel] Univ Munich, Munich, Germany. [Kretschmer, Anja] Univ Kiel, Dept Dermatol Venereol & Allergy, Kiel, Germany. [Schramm, Katharina; Prokisch, Holger] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Klopp, Norman; Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Hedman, Asa K.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Roden, Michael; Herder, Christian] German Ctr Diabet Res DZD, Dusseldorf, Germany. [Roden, Michael; Herder, Christian] Univ Dusseldorf, Inst Clin Diabetol, German Diabet Ctr, Leibniz Ctr Diabet Res, Dusseldorf, Germany. [Roden, Michael] Univ Hosp, Dept Endocrinol & Diabetol, Dusseldorf, Germany. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Thasler, Wolfgang E.] Hosp Univ Munich, Biobank Adm HTCR, Dept Gen Visceral Transplantat Vasc & Thorac Surg, Munich, Germany. [Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Kronenberg, Florian] Med Univ Innsbruck, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, A-6020 Innsbruck, Austria. [Peters, Annette] Partner Site Munich, German Res Ctr Cardiovasc Dis DZHK, Munich, Germany. [Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Waldenberger, M (reprint author), Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany. EM waldenberger@helmholtz-muenchen.de RI Grallert, Harald/B-3424-2013; Waldenberger, Melanie/B-5355-2014; Singleton, Andrew/C-3010-2009; Kronenberg, Florian/B-1736-2008; Sandling, Johanna/B-2973-2016; Peters, Annette/A-6117-2011; Deloukas, Panos/B-2922-2013; OI Waldenberger, Melanie/0000-0003-0583-5093; Kronenberg, Florian/0000-0003-2229-1120; Sandling, Johanna/0000-0003-1382-2321; Deloukas, Panos/0000-0001-9251-070X; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Melzer, David/0000-0002-0170-3838 FU Helmholtz Zentrum Munchen-German Research Center for Environmental Health; German Bundesministerium fur Bildung und Forschung; State of Bavaria; European Union [261433, 603288]; German Federal Ministry of Health (Berlin, Germany); Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (Dusseldorf, Germany); Wellcome Trust [081917/Z/07/Z]; European Community's Seventh Framework Programme; National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility; Biomedical Research Centre based at Guy's and St. Thomas' National Health Service Foundation Trust; King's College London; NIHR; [090532] FX The Cooperative Health Research in the Region of Augsburg study was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Bundesministerium fur Bildung und Forschung and by the State of Bavaria. This project has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261433 (Biobank Standardisation and Harmonisation for Research Excellence in the European Union [BioSHaRE-EU]) and under grant agreement: 603288. The German Diabetes Center is funded by the German Federal Ministry of Health (Berlin, Germany) and the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (Dusseldorf, Germany). This study was supported, in part, by a grant from the German Bundesministerium fur Bildung und Forschung to the Deutsches Zentrum fur Diabetesforschung (DZD e.V.). The Multiple Tissue Human Expression Resource Study was funded by the Wellcome Trust (081917/Z/07/Z) and core funding for the Wellcome Trust Centre for Human Genetics (090532). TwinsUK was funded by the Wellcome Trust and European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St. Thomas' National Health Service Foundation Trust in partnership with King's College London. Single-nucleotide polymorphism genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via National Institutes of Health/Center Center for Inherited Disease Research. Dr Deloukas' work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit, supported and funded by the NIHR. NR 55 TC 25 Z9 26 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD APR PY 2015 VL 8 IS 2 BP 334 EP + DI 10.1161/CIRCRESAHA.116.000804 PG 43 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA CG5CV UT WOS:000353309600012 PM 25583993 ER PT J AU Verhaaren, BFJ Debette, S Bis, JC Smith, JA Ikram, MK Adams, HH Beecham, AH Rajan, KB Lopez, LM Barral, S van Buchem, MA van der Grond, J Smith, AV Hegenscheid, K Aggarwal, NT de Andrade, M Atkinson, EJ Beekman, M Beiser, AS Blanton, SH Boerwinkle, E Brickman, AM Bryan, RN Chauhan, G Chen, CPLH Chouraki, V de Craen, AJM Crivello, F Deary, IJ Deelen, J De Jager, PL Dufouil, C Elkind, MSV Evans, DA Freudenberger, P Gottesman, RF Gudnason, V Habes, M Heckbert, SR Heiss, G Hilal, S Hofer, E Hofman, A Ibrahim-Verbaas, CA Knopman, DS Lewis, CE Liao, JM Liewald, DCM Luciano, M van der Lugt, A Martinez, OO Mayeux, R Mazoyer, B Nalls, M Nauck, M Niessen, WJ Oostra, BA Psaty, BM Rice, KM Rotter, JI von Sarnowski, B Schmidt, H Schreiner, PJ Schuur, M Sidney, SS Sigurdsson, S Slagboom, PE Stott, DJM van Swieten, JC Teumer, A Toglhofer, AM Traylor, M Trompet, S Turner, ST Tzourio, C Uh, HW Uitterlinden, AG Vernooij, MW Wang, JJ Wong, TY Wardlaw, JM Windham, BG Wittfeld, K Wolf, C Wright, CB Yang, Q Zhao, W Zijdenbos, A Jukema, JW Sacco, RL Kardia, SLR Amouyel, P Mosley, TH Longstreth, WT DeCarli, CC van Duijn, CM Schmidt, R Launer, LJ Grabe, HJ Seshadri, SS Ikram, MA Fornage, M AF Verhaaren, Benjamin F. J. Debette, Stephanie Bis, Joshua C. Smith, Jennifer A. Ikram, M. Kamran Adams, Hieab H. Beecham, Ashley H. Rajan, Kumar B. Lopez, Lorna M. Barral, Sandra van Buchem, Mark A. van der Grond, Jeroen Smith, Albert V. Hegenscheid, Katrin Aggarwal, Neelum T. de Andrade, Mariza Atkinson, Elizabeth J. Beekman, Marian Beiser, Alexa S. Blanton, Susan H. Boerwinkle, Eric Brickman, Adam M. Bryan, R. Nick Chauhan, Ganesh Chen, Christopher P. L. H. Chouraki, Vincent de Craen, Anton J. M. Crivello, Fabrice Deary, Ian J. Deelen, Joris De Jager, Philip L. Dufouil, Carole Elkind, Mitchell S. V. Evans, Denis A. Freudenberger, Paul Gottesman, Rebecca F. Gudnason, Vilmundur Habes, Mohamad Heckbert, Susan R. Heiss, Gerardo Hilal, Saima Hofer, Edith Hofman, Albert Ibrahim-Verbaas, Carla A. Knopman, David S. Lewis, Cora E. Liao, Jiemin Liewald, David C. M. Luciano, Michelle van der Lugt, Aad Martinez, Oliver O. Mayeux, Richard Mazoyer, Bernard Nalls, Mike Nauck, Matthias Niessen, Wiro J. Oostra, Ben A. Psaty, Bruce M. Rice, Kenneth M. Rotter, Jerome I. von Sarnowski, Bettina Schmidt, Helena Schreiner, Pamela J. Schuur, Maaike Sidney, Stephen S. Sigurdsson, Sigurdur Slagboom, P. Eline Stott, David J. M. van Swieten, John C. Teumer, Alexander Toeglhofer, Anna Maria Traylor, Matthew Trompet, Stella Turner, Stephen T. Tzourio, Christophe Uh, Hae-Won Uitterlinden, Andre G. Vernooij, Meike W. Wang, Jing J. Wong, Tien Y. Wardlaw, Joanna M. Windham, B. Gwen Wittfeld, Katharina Wolf, Christiane Wright, Clinton B. Yang, Qiong Zhao, Wei Zijdenbos, Alex Jukema, J. Wouter Sacco, Ralph L. Kardia, Sharon L. R. Amouyel, Philippe Mosley, Thomas H. Longstreth, W. T., Jr. DeCarli, Charles C. van Duijn, Cornelia M. Schmidt, Reinhold Launer, Lenore J. Grabe, Hans J. Seshadri, Sudha S. Ikram, M. Arfan Fornage, Myriam TI Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI SO Circulation-Cardiovascular Genetics LA English DT Article DE cerebral small vessel diseases; cerebrovascular disorders; genome-wide association study; hypertension; leukoencephalopathies; polymorphisms, single nucleotide ID AUSTRIAN STROKE PREVENTION; SMALL-VESSEL DISEASE; CENTRAL CORNEAL THICKNESS; ONSET ALZHEIMERS-DISEASE; CARDIOVASCULAR HEALTH; ISCHEMIC-STROKE; COGNITIVE IMPAIRMENT; NORTHERN MANHATTAN; KYNURENINE PATHWAY; VASCULAR-DISEASE AB Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7x10(-19)) and identified novel loci on chr10q24 (P=1.6x10(-9)) and chr2p21 (P=4.4x10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0x10(-8)) and chr2p16 (P=1.5x10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms. C1 [Verhaaren, Benjamin F. J.; Adams, Hieab H.; Hofman, Albert; Ibrahim-Verbaas, Carla A.; Oostra, Ben A.; Schuur, Maaike; Uitterlinden, Andre G.; Vernooij, Meike W.; van Duijn, Cornelia M.; Ikram, M. Arfan] Erasmus MC Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands. [Verhaaren, Benjamin F. J.; Adams, Hieab H.; van der Lugt, Aad; Niessen, Wiro J.; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC Univ Med Ctr Rotterdam, Dept Radiol, Rotterdam, Netherlands. [Ibrahim-Verbaas, Carla A.; Schuur, Maaike; van Swieten, John C.; Ikram, M. Arfan] Erasmus MC Univ Med Ctr Rotterdam, Dept Neurol, Rotterdam, Netherlands. [Niessen, Wiro J.] Erasmus MC Univ Med Ctr Rotterdam, Dept Med Informat, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr Rotterdam, Dept Clin Chem, Rotterdam, Netherlands. [Debette, Stephanie; Chauhan, Ganesh; Dufouil, Carole; Tzourio, Christophe; Wolf, Christiane] INSERM, U897, Epidemiol & Biostat, Bordeaux, France. [Crivello, Fabrice; Mazoyer, Bernard] CEA, CNRS, UMR5296, Bordeaux, France. [Debette, Stephanie] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France. [Debette, Stephanie; Chauhan, Ganesh] Univ Bordeaux, Bordeaux, France. [Debette, Stephanie; Beiser, Alexa S.; Chouraki, Vincent; Sidney, Stephen S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Beiser, Alexa S.; Wang, Jing J.; Yang, Qiong] Boston Univ, Sch Med, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Bis, Joshua C.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Heckbert, Susan R.; Psaty, Bruce M.; Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Ikram, M. Kamran; Liao, Jiemin; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Ikram, M. Kamran; Liao, Jiemin; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Natl Univ Hlth Syst, Singapore 117548, Singapore. [Ikram, M. Kamran; Chen, Christopher P. L. H.; Hilal, Saima] Natl Univ Singapore, Memory Aging & Cognit Ctr, Singapore 117548, Singapore. [Beecham, Ashley H.; Blanton, Susan H.] John P Hussman Inst Human Genom, Miami, FL USA. [Blanton, Susan H.] Dr John T Macdonald Fdn, Dept Human Genet, Coral Gables, FL USA. [Blanton, Susan H.; Wright, Clinton B.] Neurosci Program, Coral Gables, FL USA. [Wright, Clinton B.; Sacco, Ralph L.] Dept Epidemiol & Publ Hlth Sci, Coral Gables, FL USA. [Wright, Clinton B.; Sacco, Ralph L.] Dept Neurol, Coral Gables, FL USA. [Wright, Clinton B.; Sacco, Ralph L.] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Coral Gables, FL 33124 USA. [Rajan, Kumar B.; Aggarwal, Neelum T.; Evans, Denis A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Lopez, Lorna M.; Deary, Ian J.; Liewald, David C. M.; Luciano, Michelle; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Psychol, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Scottish Imaging Network, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Barral, Sandra] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Brickman, Adam M.; Mayeux, Richard] Columbia Univ, GH Sergievsky Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Med Ctr, New York, NY USA. [van Buchem, Mark A.; van der Grond, Jeroen] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. [Beekman, Marian; Deelen, Joris; Slagboom, P. Eline] Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands. [de Craen, Anton J. M.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Uh, Hae-Won] Leiden Univ, Dept Med Stat & Bioinformat, Med Ctr, Leiden, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur; Sigurdsson, Sigurdur] Iceland Heart Assoc, Kopavogur, Iceland. [Hegenscheid, Katrin] Univ Med Greifswald, Dept Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Habes, Mohamad] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany. [de Andrade, Mariza; Atkinson, Elizabeth J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Beiser, Alexa S.; Chouraki, Vincent; Sidney, Stephen S.; Wang, Jing J.; Yang, Qiong] NHLBI, Framingham Heart Study, Framingham, MA USA. [Boerwinkle, Eric; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Bryan, R. Nick; Habes, Mohamad] Univ Penn Hlth Syst, Dept Radiol, Perelman Sch Med, Philadelphia, PA USA. [De Jager, Philip L.] Harvard Univ, Dept Neurol, Cambridge, MA 02138 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Elkind, Mitchell S. V.] Columbia Univ, Coll Phys & Surg, Dept Neurol, Mailman Sch Publ Hlth, New York, NY USA. [Elkind, Mitchell S. V.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Freudenberger, Paul; Toeglhofer, Anna Maria] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [Hofer, Edith; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Gottesman, Rebecca F.; Schmidt, Helena] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Heiss, Gerardo] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Martinez, Oliver O.; DeCarli, Charles C.] Univ Calif Davis, Alzheimers Dis Ctr, Imaging Dementia & Aging IdeA Lab, Dept Neurol,Ctr Neurosci, Davis, CA 95616 USA. [Nauck, Matthias] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Div Genom Outcomes, Dept Pediat, Inst Translat Genom & Populat Sci,Los Angeles Bio, Torrance, CA 90509 USA. [Rotter, Jerome I.; von Sarnowski, Bettina] Univ Med Greifswald, Dept Neurol, Greifswald, Germany. [Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Sidney, Stephen S.] Kaiser Permanente, Div Res, Oakland, CA USA. [Stott, David J. M.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Traylor, Matthew] Univ London, Res Ctr Stroke & Dementia, London, England. [Trompet, Stella; Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Windham, B. Gwen] Univ Mississippi, Med Ctr, Div Geriatr Gerontol, Jackson, MS USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA. [Wittfeld, Katharina] German Ctr Neurodegenerat Dis DZNE, Rostock, Germany. [Zijdenbos, Alex] Biospective Inc, Montreal, PQ, Canada. [Amouyel, Philippe] Univ Lille 2, INSERM, U744, Inst Pasteur Lille,Ctr Hosp Reg Univ Lille, Lille, France. RP Fornage, M (reprint author), Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, 1825 Pressler St, Houston, TX 77030 USA. EM myriam.fornage@uth.tmc.edu RI Gudnason, Vilmundur/K-6885-2015; Chen, Christopher/E-7023-2013; hilal, saima/D-6028-2016; Vernooij, Meike/E-4061-2016; Smith, Albert/K-5150-2015; Slagboom, P. Eline/R-4790-2016; Luciano, Michelle/F-7277-2010; Habes, Mohamad/M-2865-2016; Tzourio, christophe/B-4015-2009; OI Seshadri, Sudha/0000-0001-6135-2622; Traylor, Matthew/0000-0001-6624-8621; Ikram, Mohammad Kamran/0000-0003-0173-9571; Beiser, Alexa/0000-0001-8551-7778; Deelen, Joris/0000-0003-4483-3701; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Slagboom, P. Eline/0000-0002-2875-4723; Luciano, Michelle/0000-0003-0935-7682; Habes, Mohamad/0000-0001-9447-5805; Tzourio, christophe/0000-0002-6517-2984; Beekman, Marian/0000-0003-0585-6206; Rajan, Kumar/0000-0003-1268-4617 FU National Institutes of Health (NIH) [N01-AG-1-2100]; National Institute on Aging (NIA) Intramural Research Program; Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HSN268201100006C, HSN26820 1100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN26820-1100011C, HHSN26820 1100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C]; NIH Roadmap for Medical Research; NIH R01 grants [HL084099, NS087541]; Austrian Science Fond (FWF) [P20545-P05, P13180]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN26820 0960009C, N01HC15103, HL080295, HL087652, HL105756, HL103612, HL120393]; NIA [AG023629, AG15928]; National Center for Advancing Translational Sciences; CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]; NIH grant [R01-AG-09966, R01-AG-11101, R01-AG-030146]; 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 (NIA); National Institutes of Health R01 grants [HL084099, NS087541]; National Medical Research Council [0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, CG/SERI/2010]; Biomedical Research Council, Singapore [09/1/35/19/616]; National Medical Research Council, Singapore [R-184-006-184-511]; Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/038/2013]; European Commission FP6 STRP grant [018947, LSHG-CT-2006-01947]; European Community's Seventh Framework Programme [HEALTH-F4-2007-201413]; European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme [QLG2-CT-2002-01254]; Netherlands Organisation for Scientific Research; Russian Foundation for Basic Research [NWO-RFBR 047.017.043]; NHLBI's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; National Institute of Neurological Disorders and Stroke [R01 NS17950]; National Institute of Aging [P30 AG10129, R01s AG033193, AG08122, AG16495]; National Institute of Neurological Disorders and Stroke of the NIH [NS041558]; European Union's Seventh Framework Programme [259679]; Innovation-Oriented Research Program on Genomics [SenterNovem IGE05007]; Centre for Medical Systems Biology; Netherlands Consortium for Healthy Ageing [050-060-810]; Netherlands Genomics Initiative; Netherlands Organization for Scientific Research (NWO); UnileverColworth; BBMRI-NL, a Research Infrastructure - Dutch government (NWO) [184.021.007]; Age UK's Disconnected Mind programme; Research Into Ageing [251, 285]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; Medical Research Council [G1001401, 8200]; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Scottish Funding Council through the SINAPSE Collaboration; NINDS [R37 NS29993, K02 NS 059729]; Evelyn F. McKnight Brain Institute; Bristol-Myers Squibb; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/NWO project [050-060-810]; Netherlands Heart Foundation [2009B102]; Veni-grant [916.13.054]; Erasmus Medical Center; Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw); RIDE; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; German Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Federal Ministry of Education and Research [03ZIK012]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Federal Ministry of Education and Research; German Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Mutuelle Generale de l'Education Nationale; Institut de la Longevite; Conseils Regionaux of Aquitaine and Bourgogne; Fondation de France; Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques; Eisai; National Foundation for Alzheimer Disease and Related Disorders; Institut Pasteur de Lille; Centre National de Genotypage; Washington Heights-Inwood Columbia Aging Project (WHICAP) [P01-AG007232, R01-AG037212, NIH R01-AG034189]; Hjartavernd (the Icelandic Heart Association) FX Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) study has been funded by National Institutes of Health (NIH) contract N01-AG-1-2100, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00 to 063. Atherosclerosis Risk In Communities Study (ARIC) was performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HSN268201100006C, HSN26820 1100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN26820-1100011C, and HHSN26820 1100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant No UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grants HL084099 and NS087541 to MF. Austrian Stroke Prevention Study (ASPS): the research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. Cardiovascular Health Study (CHS) was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN26820 0960009C, N01HC15103; and NHLBI grants HL080295, HL087652, HL105756, HL103612, and HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 and AG15928 from the NIA. A full list of principal CHS investigators and institutions can be found at CHSNHLBI.org/. 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 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. Chicago Health and Aging Project (CHAP) study was funded by NIH grant R01-AG-09966 and R01-AG-11101 for the parent CHAP study. The genetic analysis was supported by NIH grant R01-AG-030146. This study was approved by Rush University Medical Center Internal Review Board. Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and 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 (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This article has been reviewed by CARDIA for scientific content. Genotyping of the CARDIA participants and statistical data analysis was partially supported by National Institutes of Health R01 grants HL084099 and NS087541 to MF. Epidemiology of Dementia in Singapore (EDIS), The Singapore Malay Eye Study (SiMES), and the Singapore Chinese Eye.; Study (SCES) are funded by National Medical Research Council (grants 0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, and CG/SERI/2010) and Biomedical Research Council (grants 09/1/35/19/616), Singapore. The Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services for genotyping. The Epidemiology of Dementia in Singapore study is supported by the National Medical Research Council, Singapore (NMRC/CG/NUHS/2010 [grant no: R-184-006-184-511]). Dr Ikram received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013). Erasmus Rucphen Family (ERF) study as a part of the European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Framingham Heart Study (FHS) was supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (R01 NS17950), the NHLBI (R01 HL093029) and the National Institute of Aging (P30 AG10129, R01s AG033193, AG08122, and AG16495). Genetic Epidemiology Network of Arteriopathy (GENOA) support was provided by the NHLBI (HL054464, HL054457, HL054481, HL071917, and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the NIH. Leiden Longevity Study (LLS) has received funding from the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), UnileverColworth and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). Lothian Birth Cohort 1936 (LBC1936) was funded by the Age UK's Disconnected Mind programme (http://www.disconnectedmind.ed.ac.uk) and also by Research Into Ageing (Refs. 251 and 285). The whole genome association part of the study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; Ref. BB/F019394/1). Analysis of the brain images was funded by the Medical Research Council Grants G1001401 and 8200. The imaging was performed at the Brain Research Imaging Centre, The University of Edinburgh (http://www.bric.ed.ac.uk), a centre in the SINAPSE Collaboration (http://www.sinapse.ac.uk).; The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (http://www.ccace.ed.ac.uk), part of the cross council Lifelong Health and Wellbeing Initiative (Ref. G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Medical Research Council, and Scottish Funding Council through the SINAPSE Collaboration is gratefully acknowledged. Northern Manhattan Study (NOMAS) is supported by the NINDS (grants R37 NS29993 and K02 NS 059729). Genome-wide data were supported by the Evelyn F. McKnight Brain Institute. PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Dr J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). Rotterdam Study (RS I, RS II, RS III): the generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015), the Netherlands Genomics Initiative (NGI)/NWO project nr. 050-060-810. Further funding was received from the Netherlands Heart Foundation (2009B102) and a Veni-grant (916.13.054). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the 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. Study of Health in Pomerania (SHIP and SHIP-TREND) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. SHIP-TREND-0: This cohort is part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg-West Pomerania. CMR encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; see URLs). MRI scans were supported by a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The SHIP-TREND cohort was supported by the Federal Ministry of Education and Research (grant 03ZIK012). Three-City Dijon Study (3C-Dijon Study) conducted under a partnership agreement between the Institut National de la Sante et de la Recherche Medicale (INSERM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study.; The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques. Lille Genopole received an unconditional grant from Eisai. This work was supported by the National Foundation for Alzheimer Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. Washington Heights-Inwood Columbia Aging Project (WHICAP) acknowledge the following grants for supporting this study: P01-AG007232, R01-AG037212, and NIH R01-AG034189. NR 103 TC 18 Z9 21 U1 3 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD APR PY 2015 VL 8 IS 2 BP 398 EP + DI 10.1161/CIRCGENETICS.114.000858 PG 54 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA CG5CV UT WOS:000353309600020 PM 25663218 ER PT J AU Bell, V Sigurdsson, S Westenberg, JJM Gotal, JD Torjesen, AA Aspelund, T Launer, LJ Harris, TB Gudnason, V de Roos, A Mitchell, GF AF Bell, Vanessa Sigurdsson, Sigurdur Westenberg, Jos J. M. Gotal, John D. Torjesen, Alyssa A. Aspelund, Thor Launer, Lenore J. Harris, Tamara B. Gudnason, Vilmundur de Roos, Albert Mitchell, Gary F. TI Relations Between Aortic Stiffness and Left Ventricular Structure and Function in Older Participants in the Age, Gene/Environment Susceptibility-Reykjavik Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE aorta; epidemiology; heart ventricles; pressure; vascular stiffness ID CONGESTIVE-HEART-FAILURE; ELASTIC RECOIL; PRESSURE; HYPERTROPHY; MOTION; ADULTS; FLOW AB Background-Left ventricular (LV) contraction displaces the aortic annulus and produces a force that stretches the ascending aorta. We hypothesized that aortic stiffening increases this previously ignored component of LV load and may contribute to hypertrophy. Conversely, aortic stretch-related work represents stored energy that may facilitate early diastolic filling. Methods and Results-We performed MRI of the aorta and LV in 347 participants (72-91 years old, 189 women) in the Age, Gene/Environment Susceptibility-Reykjavik Study to examine relations of aortic stretch with LV structure and function. Aortic stiffness was evaluated as the product of Young's modulus and aortic wall thickness. Force was computed from Young's modulus and longitudinal aortic strain; work was the integrated product of force and annulus displacement during systole. LV mass and dynamic volume were measured using the area-length method. Filling was assessed from time-resolved LV volume curves. In multivariable models that adjusted for age, sex, height, weight, end-diastolic LV volume, augmentation index, end-systolic pressure, and cardiovascular disease risk factors, higher aortic stiffness was associated with increased LV mass (beta=3.0 +/- 0.8% per SD, P<0.001; sex interaction, P=0.8). Greater stretch-related aortic work was associated with enhanced early filling in men (beta=4.0 +/- 0.8 mL/SD; P<0.001), but not in women (beta=-0.4 +/- 0.7 mL/SD; P=0.6). Conclusions-Higher aortic stiffness was associated with higher LV mass, independently of pressure. Higher stretch-related work was associated with greater early diastolic filling in men only. Impaired diastolic recovery of energy stored by systolic proximal aortic stretch may contribute to increased susceptibility to diastolic dysfunction in women. C1 [Bell, Vanessa; Gotal, John D.; Torjesen, Alyssa A.; Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [Sigurdsson, Sigurdur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Westenberg, Jos J. M.; de Roos, Albert] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Institutes of Health, National Heart, Lung and Blood Institute [HL094898] FX This work was supported by National Institutes of Health (contract N01-AG-12100); the National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); the Althingi (the Icelandic Parliament); and a grant from the National Institutes of Health, National Heart, Lung and Blood Institute (HL094898). NR 28 TC 8 Z9 8 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD APR PY 2015 VL 8 IS 4 AR e003039 DI 10.1161/CIRCIMAGING.114.003039 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CG5CX UT WOS:000353309800013 PM 25795761 ER PT J AU Sousa, FG Matuo, R Tang, SW Rajapakse, VN Luna, A Sander, C Varma, S Simon, PHG Doroshow, JH Reinhold, WC Pommier, Y AF Sousa, Fabricio G. Matuo, Renata Tang, Sai-Wen Rajapakse, Vinodh N. Luna, Augustin Sander, Chris Varma, Sudhir Simon, Paul H. G. Doroshow, James H. Reinhold, William C. Pommier, Yves TI Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity SO DNA REPAIR LA English DT Article DE DNA repair; Cancer; SLX4/FANCP/BTBD12; Cytarabine; Raltitrexed; NCI-60 ID FANCONI-ANEMIA; BREAST-CANCER; ELASTIC-NET; SENSITIVITY; RECOMBINATION; PHARMACOLOGY; REPLICATION; EXPRESSION; SLX4/FANCP; MUTATIONS AB Loss of function of DNA repair (DNAR) genes is associated with genomic instability and cancer predisposition; it also makes cancer cells reliant on a reduced set of DNAR pathways to resist DNA-targeted therapy, which remains the core of the anticancer armamentarium. Because the landscape of DNAR defects across numerous types of cancers and its relation with drug activity have not been systematically examined, we took advantage of the unique drug and genomic databases of the US National Cancer Institute cancer cell lines (the NCI-60) to characterize 260 DNAR genes with respect to deleterious mutations and expression down-regulation; 169 genes exhibited a total of 549 function-affecting alterations, with 39 of them scoring as putative knockouts across 31 cell lines. Those mutations were compared to tumor samples from 12 studies of The Cancer Genome Atlas (TCGA) and The Cancer Cell Line Encyclopedia (CCLE). Based on this compendium of alterations, we determined which DNAR genomic alterations predicted drug response for 20,195 compounds present in the NCI-60 drug database. Among 242 DNA damaging agents, 202 showed associations with at least one DNAR genomic signature. In addition to SLFN11, the Fanconi anemia-scaffolding gene SLX4 (FANCP/BTBD12) stood out among the genes most significantly related with DNA synthesis and topoisomerase inhibitors. Depletion and complementation experiments validated the causal relationship between SLX4 defects and sensitivity to raltitrexed and cytarabine in addition to camptothecin. Therefore, we propose new rational uses for existing anticancer drugs based on a comprehensive analysis of DNAR genomic parameters. Published by Elsevier B.V. C1 [Sousa, Fabricio G.; Matuo, Renata; Tang, Sai-Wen; Rajapakse, Vinodh N.; Luna, Augustin; Varma, Sudhir; Simon, Paul H. G.; Doroshow, James H.; Reinhold, William C.; Pommier, Yves] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Sousa, Fabricio G.; Matuo, Renata; Tang, Sai-Wen; Rajapakse, Vinodh N.; Luna, Augustin; Varma, Sudhir; Simon, Paul H. G.; Doroshow, James H.; Reinhold, William C.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sousa, Fabricio G.; Matuo, Renata] Univ Fed Mato Grosso do Sul, Ctr Estudos Celulas Tronco Terapia Celular & Gene, Posgrad Farm, BR-79070900 Campo Grande, MS, Brazil. [Luna, Augustin; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10021 USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD 20707 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Sousa, Fabricio/O-8878-2015 OI Sousa, Fabricio/0000-0003-0444-754X FU Science Without Borders-CNPq (Brazil); Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z01 BC006150]; Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC006150]; MSKCC Genome Data Analysis Center as part of the National Cancer Institute (NCI)/National Human Genome Research Institute (NHGRI) [U24 CA143840]; FUNDECT/CNPq [DCR 013/2014] FX The authors wish to thank Dr. Agata Smogorzewska for kindly providing the FANCP cell lines, RA3331 and RA3331 complemented with WT SLX4. We thank Kurt W. Kohn, Barry Zeeberg and Salim Khiati for their constructive discussions and suggestions on bioinformatics and methodologies. Fabricio G. Sousa and Renata Matuo were supported by grants from Science Without Borders-CNPq (Brazil) and from the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z01 BC006150). Our studies are supported by the Intramural Program of the National Cancer Institute, Center for Cancer Research (Z01 BC006150). 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) and by FUNDECT/CNPq (DCR 013/2014). NR 54 TC 11 Z9 11 U1 6 U2 12 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 APR PY 2015 VL 28 BP 107 EP 115 DI 10.1016/j.dnarep.2015.01.011 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CG6QJ UT WOS:000353426700012 PM 25758781 ER PT J AU Wilson, SH AF Wilson, Samuel H. TI Uncovering Polymerase-induced Cytotoxicity of an Oxidized Nucleotide SO DNA REPAIR LA English DT Meeting Abstract CT 5th Japan-US DNA Repair Meeting CY OCT 28-31, 2014 CL Naruto, JAPAN C1 [Wilson, Samuel H.] NIEHS, NIH, Morrisville, NC USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2015 VL 28 MA 1.2 BP 139 EP 139 PG 1 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CG6QJ UT WOS:000353426700017 ER PT J AU Bohr, VA Scheybye-Knudsen, M Fang, EF Sykora, P Croteau, D AF Bohr, Vilhelm A. Scheybye-Knudsen, Morten Fang, Evandro Fey Sykora, Peter Croteau, Deborah TI Nuclear-mitochondrial DNA damage and repair signaling SO DNA REPAIR LA English DT Meeting Abstract CT 5th Japan-US DNA Repair Meeting CY OCT 28-31, 2014 CL Naruto, JAPAN C1 [Bohr, Vilhelm A.; Scheybye-Knudsen, Morten; Fang, Evandro Fey; Sykora, Peter; Croteau, Deborah] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2015 VL 28 MA 3.3 BP 141 EP 141 PG 1 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CG6QJ UT WOS:000353426700024 ER PT J AU McIntyre, J McLenigan, MP Frank, E Dai, XX Yang, W Wang, YS Woodgate, R AF McIntyre, Justyna McLenigan, Mary P. Frank, Ekaterina Dai, Xiaoxia Yang, Wei Wang, Yinsheng Woodgate, Roger TI Posttranslational regulation of human DNA polymerase iota SO DNA REPAIR LA English DT Meeting Abstract CT 5th Japan-US DNA Repair Meeting CY OCT 28-31, 2014 CL Naruto, JAPAN C1 [McIntyre, Justyna; McLenigan, Mary P.; Frank, Ekaterina; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Dai, Xiaoxia; Wang, Yinsheng] Univ Calif Riverside, Riverside, CA 92521 USA. [Yang, Wei] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RI McIntyre, Justyna/M-9186-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD APR PY 2015 VL 28 MA 6.4 BP 143 EP 143 PG 1 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CG6QJ UT WOS:000353426700035 ER PT J AU Yang, W Lee, YS Zhao, Y Gregory, M Nakamura, T Biertuempfel, C Hanaoka, F AF Yang, Wei Lee, Young-Sam Zhao, Ye Gregory, Mark Nakamura, Teruya Biertuempfel, Christian Hanaoka, Fumio TI Mechanisms for Translesion DNA Synthesis SO DNA REPAIR LA English DT Meeting Abstract CT 5th Japan-US DNA Repair Meeting CY OCT 28-31, 2014 CL Naruto, JAPAN C1 [Yang, Wei; Lee, Young-Sam; Zhao, Ye; Gregory, Mark; Nakamura, Teruya; Biertuempfel, Christian] NIDDK, LMB, NIH, Bethesda, MD 20892 USA. [Zhao, Ye] Zhejiang Univ, Hangzhou, Zhejiang, Peoples R China. [Nakamura, Teruya] Kumamoto Univ, Kumamoto 860, Japan. [Biertuempfel, Christian] Max Planck Inst Biochem, D-82152 Martinsried, Germany. [Hanaoka, Fumio] Gakushuin Univ, Tokyo 171, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD APR PY 2015 VL 28 MA 6.2 BP 143 EP 143 PG 1 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CG6QJ UT WOS:000353426700033 ER PT J AU Bloom, MS Louis, GMB Sundaram, R Maisog, JM Steuerwald, AJ Parsons, PJ AF Bloom, Michael S. Louis, Germaine M. Buck Sundaram, Rajeshwari Maisog, Jose M. Steuerwald, Amy J. Parsons, Patrick J. TI Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE) SO ENVIRONMENTAL RESEARCH LA English DT Article DE Birth outcomes; Elements; Environment; Metalloids; Metals ID DEVELOPMENTAL TOXICITY; FETAL-GROWTH; ENDOCRINE DISRUPTORS; PROSPECTIVE COHORT; PRENATAL EXPOSURE; MASS-SPECTROMETRY; DEPLETED URANIUM; CADMIUM EXPOSURE; ARSENIC EXPOSURE; GESTATIONAL-AGE AB Evidence suggests that trace exposures to select elements may increase the risk for adverse birth outcomes. To investigate further, we used multiple regression to assess associations between preconception parental exposures to Pb, Cd, and total Hg in blood, and 21 elements in urine, with n=235 singleton birth outcomes, adjusted for confounders and partner's exposure. Earlier gestational age at delivery (GA) was associated with higher tertiles of urine maternal W (-1.22 days) and paternal U (-1.07 days), but GA was later for higher tertiles of maternal (+1.11 days) and paternal (+130 days) blood Hg. Additional analysis indicated shorter GA associated with higher paternal urine Ba, W, and U, and with higher maternal blood Pb for boys, but GA was longer in association with higher maternal urine Cr. Birth weight (BW) was lower for higher tertiles of paternal urine Cs (-237.85 g), U (-18734 g), and Zn (-209.08 g), and for higher continuous Cr (P=0.021). In contrast, BW was higher for higher tertiles of paternal urine As (+194.71 g) and counterintuitively for maternal blood Cd (+178.52 g). Birth length (BL) was shorter for higher tertiles of urine maternal W (-1.22 cm) and paternal U (-1.10 cm). Yet, higher tertiles of maternal (+1.11 cm) and paternal (+1.30) blood Hg were associated with longer BL Head circumference at delivery was lower for higher tertiles of paternal urine U (-0.83 cm), and for higher continuous Mo in boys (-0.57 cm). Overall, associations were most consistently indicated for GA and measures of birth size with urine Wand U, and paternal exposures were more frequently associated than maternal. Though limited by several factors, ours is the largest multi-element investigation of prospective couple-level trace exposures and birth outcomes to date; the novel observations for W and U merit further investigation. (C) 2015 Elsevier Inc. All rights reserved. C1 [Bloom, Michael S.; Steuerwald, Amy J.; Parsons, Patrick J.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Rensselaer, NY USA. [Bloom, Michael S.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Louis, Germaine M. Buck; Sundaram, Rajeshwari; Maisog, Jose M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. [Maisog, Jose M.] Glotech Inc, Rockville, MD USA. [Steuerwald, Amy J.; Parsons, Patrick J.] New York State Dept Hlth, Lab Inorgan & Nucl Chem, Wadsworth Ctr, Albany, NY USA. RP Bloom, MS (reprint author), Sch Publ Hlth, Dept Environm Hlth Sci, Rm 157,One Univ Pl, Rensselaer, NY 12144 USA. EM mbloom@albany.edu OI Parsons, Patrick/0000-0001-9133-875X; Sundaram, Rajeshwari/0000-0002-6918-5002; Bloom, Michael/0000-0002-0028-5494; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development [N01-HD-3-3355, N01-HD-3356, N01-HD-3-3358, HHSN27500001, HHSN27500002] FX This research was supported by the Intramural Research program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3356, N01-HD-3-3358, HHSN27500001, and HHSN27500002). NR 76 TC 7 Z9 7 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD APR PY 2015 VL 138 BP 118 EP 129 DI 10.1016/j.envres.2015.01.008 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CG1CT UT WOS:000353011300015 PM 25707016 ER PT J AU Karami, S Andreotti, G Liao, LM Pfeiffer, RM Weinstein, SJ Purdue, MP Hofmann, JN Albanes, D Mannisto, S Moore, LE AF Karami, Sara Andreotti, Gabriella Liao, Linda M. Pfeiffer, Ruth M. Weinstein, Stephanie J. Purdue, Mark P. Hofmann, Jonathan N. Albanes, Demetrius Mannisto, Satu Moore, Lee E. TI LINE1 methylation levels in pre-diagnostic leukocyte DNA and future renal cell carcinoma risk SO EPIGENETICS LA English DT Article DE ATBC; cohort; global methylation; nested case-contro; PLCO; pre-diagnostic blood DNA; renal cell carcinoma; smoking interaction ID CANCER-RISK; BLADDER-CANCER; BREAST-CANCER; BLOOD DNA; HYPOMETHYLATION; BIOMARKER; PLCO AB Higher levels of LINE1 methylation in blood DNA have been associated with increased kidney cancer risk using post-diagnostically collected samples; however, this association has never been examined using pre-diagnostic samples. We examined the association between LINE1 %5mC and renal cell carcinoma (RCC) risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (215 cases/436 controls), and the Alpha-tocopherol, Beta-carotene Cancer Prevention Study (ATBC) of Finnish male smokers (191 cases/575 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, body mass index, hypertension, dietary alcohol intake, family history of cancer, and sex was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using cohort and sex-specific methylation categories. In PLCO, higher, although non-significant, RCC risk was observed for participants at or above median methylation level (M2) compared to those below the median (M1) (OR: 1.37, 95% CI: 0.96-1.95). The association was stronger in males (M2 vs. M1, OR: 1.54, 95% CI: 1.00-2.39) and statistically significant among male smokers (M2 vs. M1, OR: 2.60, 95% CI: 1.46-4.63). A significant interaction for smoking was also detected (P-interaction: 0.01). No association was found among females or female smokers. Findings for male smokers were replicated in ATBC (M2 vs. M1, OR: 1.31, 95% CI: 1.07-1.60). In a pooled analysis of PLCO and ATBC male smokers (281cases/755controls), the OR among subjects at or above median methylation level (M2) compared to those below the median (M1) was 1.89 (95% CI: 1.34-2.67, P-value: 3 x 10(-4)); a trend was also observed by methylation quartile (P-trend: 0.002). These findings suggest that higher LINE1 methylation levels measured prior to cancer diagnosis may be a biomarker of future RCC risk among male smokers. C1 [Karami, Sara; Andreotti, Gabriella; Liao, Linda M.; Pfeiffer, Ruth M.; Weinstein, Stephanie J.; Purdue, Mark P.; Hofmann, Jonathan N.; Albanes, Demetrius; Moore, Lee E.] US Natl Canc Inst NCI, DCEG, NIH, DHHS, Rockville, MD 20850 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Moore, LE (reprint author), US Natl Canc Inst NCI, DCEG, NIH, DHHS, Rockville, MD 20850 USA. EM moorele@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Liao, Linda/0000-0002-1923-5294 FU Intramural Research Program of the National Cancer Institute, US. National Institutes of Health, Department of Health and Human Services; US. Public Health Service from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute, US. National Institutes of Health, Department of Health and Human Services. Additionally, this research was supported by US. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 22 TC 5 Z9 5 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD APR PY 2015 VL 10 IS 4 BP 282 EP 292 DI 10.1080/15592294.2015.1006505 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CG2ZE UT WOS:000353144300003 PM 25647181 ER PT J AU McHugh, SB Barkus, C Lima, J Glover, LR Sharp, T Bannerman, DM AF McHugh, S. B. Barkus, C. Lima, J. Glover, L. R. Sharp, T. Bannerman, D. M. TI SERT and uncertainty: serotonin transporter expression influences information processing biases for ambiguous aversive cues in mice SO GENES BRAIN AND BEHAVIOR LA English DT Article DE 5-HTT; 5-HTTLPR; ambiguous; animal model; cognitive bias; fear; mice; over-expressing; serotonin transporter; SERT ID HEMODYNAMIC-RESPONSES; PAVLOVIAN FEAR; HUMAN AMYGDALA; ANXIETY; GENE; DEPRESSION; RATS; POLYMORPHISM; HIPPOCAMPUS; OSCILLATIONS AB The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over-expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes. C1 [McHugh, S. B.; Barkus, C.; Lima, J.; Glover, L. R.; Bannerman, D. M.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Glover, L. R.] NIMH, Sect Neuroplast, NIH, Bethesda, MD 20892 USA. [Sharp, T.] Univ Oxford, Dept Pharmacol, Oxford OX1 3UD, England. RP McHugh, SB (reprint author), Univ Oxford, Dept Expt Psychol, 9 South Parks Rd, Oxford OX1 3UD, England. EM stephen.mchugh@psy.ox.ac.uk FU Wellcome Trust [087736]; NIMH FX This study was supported by the Wellcome Trust (Grant No. 087736). L. R. G. was supported by the Intramural Research Program of the NIMH. There are no conflicts of interest associated with this research. NR 43 TC 2 Z9 2 U1 4 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD APR PY 2015 VL 14 IS 4 BP 330 EP 336 DI 10.1111/gbb.12215 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CG6JB UT WOS:000353405000002 PM 25824641 ER PT J AU Saldanha, L Dwyer, J Andrews, K Betz, J Harnly, J Pehrsson, P Rimmer, C Savarala, S AF Saldanha, Leila Dwyer, Johanna Andrews, Karen Betz, Joseph Harnly, James Pehrsson, Pamela Rimmer, Catherine Savarala, Sushma TI Feasibility of Including Green Tea Products for an Analytically Verified Dietary Supplement Database SO JOURNAL OF FOOD SCIENCE LA English DT Article DE analytical methods; botanicals; databases; dietary supplements; green tea; reference materials ID SINGLE-LABORATORY VALIDATION; COCOA-BASED INGREDIENTS; EPICATECHIN ENANTIOMERS; NIH OFFICE; CATECHINS; PROGRESS AB The Dietary Supplement Ingredient Database (DSID) is a federally funded, publicly accessible dietary supplement database that currently contains analytically derived information on micronutrients in selected adult and children's multivitamin and mineral (MVM) supplements. Other constituents in dietary supplement products such as botanicals are also of interest and thus are being considered for inclusion in the DSID. Thirty-eight constituents, mainly botanicals were identified and prioritized by a federal interagency committee. Green tea was selected from this list as the botanical for expansion of the DSID. This article describes the process for prioritizing dietary ingredients in the DSID. It also discusses the criteria for inclusion of these ingredients, and the approach for selecting and testing products for the green tea pilot study. Practical Application This article describes the available reference materials, analytical methods, and the program to qualify laboratories for analyzing the active constituents in green tea dietary supplement products, and how these criteria have been used to expand a dietary supplement composition database for green tea products. This information may be useful for product developers, chemists, and researchers involved in the analysis and formulation of products, and those making public policy decisions. C1 [Saldanha, Leila; Dwyer, Johanna; Betz, Joseph] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Andrews, Karen; Harnly, James; Pehrsson, Pamela; Savarala, Sushma] ARS, USDA, Beltsville, MD USA. [Rimmer, Catherine] NIST, Div Chem Sci, Gaithersburg, MD 20899 USA. RP Saldanha, L (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM Saldanhl@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU Office of Dietary Supplements at the Natl. Inst. of Health FX This study was funded by the Office of Dietary Supplements at the Natl. Inst. of Health. We thank Julia Peterson, PhD, Adjunct Assistant Professor at Tufts Univ.'s Friedman School of Nutrition Science and Policy for her professional review of this article. NR 25 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1147 EI 1750-3841 J9 J FOOD SCI JI J. Food Sci. PD APR PY 2015 VL 80 IS 4 BP H883 EP H888 DI 10.1111/1750-3841.12838 PG 6 WC Food Science & Technology SC Food Science & Technology GA CG1VH UT WOS:000353062800030 PM 25817236 ER PT J AU Naftel, DC Pagani, FD Miller, MA Young, JB Myers, SL Kirklin, JK AF Naftel, D. C. Pagani, F. D. Miller, M. A. Young, J. B. Myers, S. L. Kirklin, J. K. TI Device Implant Strategy and Patient Characteristics Have a Profound Impact on Early, Mid and Late Outcomes After MCSD Implant SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 35th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation CY APR 15-18, 2015 CL Nice, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Naftel, D. C.; Myers, S. L.; Kirklin, J. K.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Pagani, F. D.] Univ Michigan, Cardiac Surg, Ann Arbor, MI 48109 USA. [Miller, M. A.] NHLBI, Bethesda, MD 20892 USA. [Young, J. B.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2015 VL 34 IS 4 SU S MA 202 BP S81 EP S81 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA CG4JN UT WOS:000353251500198 ER PT J AU Pawlotsky, JM Feld, JJ Zeuzem, S Hoofnagle, JH AF Pawlotsky, Jean-Michel Feld, Jordan J. Zeuzem, Stefan Hoofnagle, Jay H. TI From non-A, non-B hepatitis to hepatitis C virus cure SO JOURNAL OF HEPATOLOGY LA English DT Review DE Hepatitis; Discovery; Direct-acting antivirals; Interferon; Ribavirin ID GENOTYPE 1 INFECTION; TREATMENT-EXPERIENCED PATIENTS; TREATMENT-NAIVE PATIENTS; INTERFERON-ALPHA-2B PLUS RIBAVIRIN; SUSTAINED VIROLOGICAL RESPONSE; PLACEBO-CONTROLLED TRIAL; PEGYLATED INTERFERON; DOUBLE-BLIND; CHRONIC HCV; PEGINTERFERON ALPHA-2A AB The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-alpha was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-alpha-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-alpha and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low-to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Pawlotsky, Jean-Michel] Univ Paris Est, Hop Henri Mondor, Natl Reference Ctr Viral Hepatitis B C & D, Dept Virol, Creteil, France. [Pawlotsky, Jean-Michel] INSERM, U955, Creteil, France. [Feld, Jordan J.] Univ Toronto, Sandra Rotman Ctr Global Hlth, Toronto Ctr Liver Dis, Toronto, ON, Canada. [Zeuzem, Stefan] Klinikum Johann Wolfgang Goethe Univ, Med Klin 1, D-60054 Frankfurt, Germany. [Hoofnagle, Jay H.] NIDDK, Div Digest Dis & Nutr, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Pawlotsky, JM (reprint author), Hop Henri Mondor, Dept Virol, 51 Ave Marechal Lattre Tassigny, F-94010 Creteil, France. EM jean-michel.pawlotsky@hmn.aphp.fr FU Gilead Sciences; Abbvie; Boehringer-Ingelheim; Janssen; Merck FX Jean-Michel Pawlotsky has received research grants from Gilead Sciences. He has served as a scientific advisor for Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, and Roche.; Jordan J. Feld has received research grants from Abbvie, Boehringer-Ingelheim, Gilead Sciences, Janssen and Merck. He has served as a scientific advisor to Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Theravance. NR 108 TC 75 Z9 77 U1 7 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD APR PY 2015 VL 62 SU 1 BP S87 EP S99 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CG6JE UT WOS:000353405400017 PM 25920094 ER PT J AU Tycko, R AF Tycko, Robert TI On the problem of resonance assignments in solid state NMR of uniformly N-15, C-13-labeled proteins SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Solid state NMR; Automated resonance assignments; Monte Carlo algorithm ID NUCLEAR-MAGNETIC-RESONANCE; ANGLE-SPINNING NMR; CHEMICAL-SHIFT ASSIGNMENT; BETA-AMYLOID FIBRILS; BACKBONE ASSIGNMENT; CORRELATION SPECTROSCOPY; SECONDARY STRUCTURE; CHAIN ASSIGNMENT; LABELED PROTEINS; PRION PROTEIN AB Determination of accurate resonance assignments from multidimensional chemical shift correlation spectra is one of the major problems in biomolecular solid state NMR, particularly for relative large proteins with less-than-ideal NMR linewidths. This article investigates the difficulty of resonance assignment, using a computational Monte Carlo/simulated annealing (MCSA) algorithm to search for assignments from artificial three-dimensional spectra that are constructed from the reported isotropic N-15 and C-13 chemical shifts of two proteins whose structures have been determined by solution NMR methods. The results demonstrate how assignment simulations can provide new insights into factors that affect the assignment process, which can then help guide the design of experimental strategies. Specifically, simulations are performed for the catalytic domain of SrtC (147 residues, primarily beta-sheet secondary structure) and the N-terminal domain of MLKL (166 residues, primarily alpha-helical secondary structure). Assuming unambiguous residue-type assignments and four ideal three-dimensional data sets (NCACX, NCOCX, CONCA, and CANCA), uncertainties in chemical shifts must be less than 0.4 ppm for assignments for SrtC to be unique, and less than 0.2 ppm for MLKL. Eliminating CANCA data has no significant effect, but additionally eliminating CONCA data leads to more stringent requirements for chemical shift precision. Introducing moderate ambiguities in residue-type assignments does not have a significant effect. Published by Elsevier Inc. C1 [Tycko, Robert] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural AIDS Targeted Antiviral Program of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health. NR 49 TC 1 Z9 1 U1 3 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2015 VL 253 SI SI BP 166 EP 172 DI 10.1016/j.jmr.2015.02.006 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA CG3MM UT WOS:000353184300018 PM 25797013 ER PT J AU Grunseich, C Schindler, AB Chen, KL Bakar, D Mankodi, A Traslavina, R Ray-Chaudhury, A Lehky, TJ Baker, EH Maragakis, NJ Tifft, CJ Fischbeck, KH AF Grunseich, Christopher Schindler, Alice B. Chen, Ke-lian Bakar, Dara Mankodi, Ami Traslavina, Ryan Ray-Chaudhury, Abhik Lehky, Tanya J. Baker, Eva H. Maragakis, Nicholas J. Tifft, Cynthia J. Fischbeck, Kenneth H. TI Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency SO JOURNAL OF NEUROLOGY LA English DT Letter ID HEXOSAMINIDASE-B DEFICIENCY; MUTATION; GENE C1 [Grunseich, Christopher; Schindler, Alice B.; Chen, Ke-lian; Bakar, Dara; Mankodi, Ami; Traslavina, Ryan; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Ray-Chaudhury, Abhik] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lehky, Tanya J.] NINDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Maragakis, Nicholas J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Tifft, Cynthia J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Grunseich, C (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM Christopher.grunseich@nih.gov FU Intramural NIH HHS NR 9 TC 2 Z9 3 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD APR PY 2015 VL 262 IS 4 BP 1066 EP 1068 DI 10.1007/s00415-015-7683-x PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA CG4YL UT WOS:000353295400035 PM 25736553 ER PT J AU Schonberg, MA Breslau, ES Hamel, MB Bellizzi, KM McCarthy, EP AF Schonberg, Mara A. Breslau, Erica S. Hamel, Mary Beth Bellizzi, Keith M. McCarthy, Ellen P. TI Colon Cancer Screening in US Adults Aged 65 and Older According to Life Expectancy and Age SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE colorectal cancer screening; older women; life expectancy ID COLORECTAL-CANCER; MEDICARE BENEFICIARIES; AMERICAN-COLLEGE; TASK-FORCE; COLONOSCOPY; MORTALITY; SURVEILLANCE; IMPACT; SIGMOIDOSCOPY; COMORBIDITY AB ObjectivesTo examine receipt of colorectal cancer (CRC) screening according to age and life expectancy (LE) in adults aged 65 and older. DesignPopulation-based survey. SettingUnited States. ParticipantsCommunity dwelling adults aged 65 and older who participated in the 2008 or 2010 National Health Interview Survey (N=7,747). MeasurementsReceipt of CRC screening (e.g., colonoscopy within 10years) was examined according to age and LE (10 and <10years), adjusting for sociodemographic characteristics and survey year. Frequency of CRC screening was also examined according to age and LE at time of screening (e.g., age at colonoscopy rather than at interview). Participants screened when they were aged 75 and older or had less than a 10-year LE were considered to have received screening inconsistent with guidelines. ResultsOverall, 38.5% of participants had less than a 10-year LE; 40.2% were aged 75 and older, and 56.3% had received recent CRC screening (90.1% by colonoscopy). CRC screening was higher in 2010 (58.9%) than 2008 (53.7%, P<.001) and was associated with longer LE and younger age, although 51.1% of adults aged 75 and older reported receiving CRC screening, as did 50.9% of adults with less than a 10-year LE. Based on age and LE at time of screening (rather than at interview), 28.4% of CRC screening of adults aged 65 and older was targeted to those aged 75 and older and those with less than a 10-year LE. Of adults aged 65 to 75 with a 10-year LE or more (adults recommended for screening by guidelines), 39.2% had not recently been screened. ConclusionOlder adults with little chance of benefit because of limited LE commonly undergo CRC screening, whereas many adults aged 65 to 75 with a 10-year LE or greater are not screened. C1 [Schonberg, Mara A.; Hamel, Mary Beth; McCarthy, Ellen P.] 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. [Bellizzi, Keith M.] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT USA. RP Schonberg, MA (reprint author), Beth Israel Deaconess Med Ctr, 1309 Beacon St,Off 202, Brookline, MA 02446 USA. EM mschonbe@bidmc.harvard.edu FU American Cancer Society [RSGT-10-080-CPHSPS] FX Drs. Schonberg and McCarthy were supported by American Cancer Society Grant RSGT-10-080-CPHSPS. NR 30 TC 4 Z9 4 U1 0 U2 4 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 APR PY 2015 VL 63 IS 4 BP 750 EP 756 DI 10.1111/jgs.13335 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CG4EB UT WOS:000353234900018 PM 25900488 ER PT J AU Francica, JR Sheng, ZZ Zhang, ZH Nishimura, YH Shingai, M Ramesh, A Keele, BF Schmidt, SD Flynn, BJ Darko, S Lynch, RM Yamamoto, T Matus-Nicodemos, R Wolinsky, D Nason, M Valiante, NM Malyala, P De Gregorio, E Barnett, SW Singh, M O'Hagan, DT Koup, RA Mascola, JR Martin, MA Kepler, TB Douek, DC Shapiro, L Seder, RA AF Francica, Joseph R. Sheng, Zizhang Zhang, Zhenhai Nishimura, Yoshiaki Shingai, Masashi Ramesh, Akshaya Keele, Brandon F. Schmidt, Stephen D. Flynn, Barbara J. Darko, Sam Lynch, Rebecca M. Yamamoto, Takuya Matus-Nicodemos, Rodrigo Wolinsky, David Nason, Martha Valiante, Nicholas M. Malyala, Padma De Gregorio, Ennio Barnett, Susan W. Singh, Manmohan O'Hagan, Derek T. Koup, Richard A. Mascola, John R. Martin, Malcolm A. Kepler, Thomas B. Douek, Daniel C. Shapiro, Lawrence Seder, Robert A. CA NISC Comparative Sequencing Progra TI Analysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization SO Nature Communications LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; B-CELL RESPONSES; NEUTRALIZING ANTIBODIES; HIV-1 NEUTRALIZATION; NONHUMAN-PRIMATES; STRUCTURAL BASIS; DENDRITIC CELLS; VACCINE; POTENT AB Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIVAD8 infection and Env protein vaccination with eight different adjuvants. A subset of the SHIVAD8-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies. C1 [Francica, Joseph R.; Schmidt, Stephen D.; Flynn, Barbara J.; Darko, Sam; Lynch, Rebecca M.; Yamamoto, Takuya; Matus-Nicodemos, Rodrigo; Wolinsky, David; Koup, Richard A.; Mascola, John R.; Douek, Daniel C.; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sheng, Zizhang; Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem, New York, NY 10032 USA. [Zhang, Zhenhai] Southern Med Univ, Nanfang Hosp, Ctr Kidney Dis, State Key Lab Organ Failure Res & Natl Clin Res, Guangzhou 510515, Guangdong, Peoples R China. [Nishimura, Yoshiaki; Shingai, Masashi; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Ramesh, Akshaya; Kepler, Thomas B.] Boston Univ, Dept Microbiol & Immunol, Boston, MA 02118 USA. [Keele, Brandon F.] Leidos Biomed Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Nason, Martha] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Valiante, Nicholas M.; Malyala, Padma; De Gregorio, Ennio; Barnett, Susan W.; Singh, Manmohan] Novartis Vaccines & Diagnost, Cambridge, MA 02139 USA. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Schmidt, Stephen/B-5398-2012; OI Yamamoto, Takuya/0000-0003-3753-1211 FU National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX We thank K. McKee, D. Ambrozak, R. Kruthers, R. Plishka, A. Buckler-White, B. Skopets and R. Petros for expert technical help. We also thank N. Longo, B. Hill, N. Doria-Rose, R. Kong, B. Haynes and M. Roederer for helpful discussions. This work was supported in part with federal funds from the National Cancer Institute; National Institutes of Health under contract HHSN261200800001E. NR 70 TC 18 Z9 18 U1 3 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 APR PY 2015 VL 6 AR 6565 DI 10.1038/ncomms7565 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH0FF UT WOS:000353694100001 PM 25858157 ER PT J AU Wan, XL Yeung, C Heske, C Mendoza, A Helman, LJ AF Wan, Xiaolin Yeung, Choh Heske, Christine Mendoza, Arnulfo Helman, Lee J. TI IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma SO NEOPLASIA LA English DT Article ID FACTOR-I RECEPTOR; GROWTH-FACTOR-II; INSULIN; SRC; ANTIBODY; MECHANISMS; FAMILY; DASATINIB; THERAPY; CELLS AB The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody, R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti-IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition-induced activation of YES/SFK and displayed advantageous antitumor activity in vitro and in vivo. Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo. This may be of particular clinical relevance since both Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS. C1 [Wan, Xiaolin; Yeung, Choh; Heske, Christine; Mendoza, Arnulfo; Helman, Lee J.] NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wan, XL (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res,Clin Res Ctr, 1W-3816,10 Ctr Dr, Bethesda, MD 20892 USA. EM xiaolinw@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Disclosure of potential conflicts of interest: none. NR 27 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1476-5586 J9 NEOPLASIA JI Neoplasia PD APR PY 2015 VL 17 IS 4 BP 358 EP 366 DI 10.1016/j.neo.2015.03.001 PG 9 WC Oncology SC Oncology GA CG9HV UT WOS:000353626700004 PM 25925378 ER PT J AU Fufaa, GD Weil, EJ Nelson, RG Hanson, RL Knowler, WC Rovin, BH Wu, HF Klein, JB Mifflin, TE Feldman, HI Vasan, RS Kimmel, PL Kusek, JW Mauer, M AF Fufaa, Gudeta D. Weil, E. Jennifer Nelson, Robert G. Hanson, Robert L. Knowler, William C. Rovin, Brad H. Wu, Haifeng Klein, Jon B. Mifflin, Theodore E. Feldman, Harold I. Vasan, Ramachandran S. Kimmel, Paul L. Kusek, John W. Mauer, Michael CA CKD Biomarkers Consortium RASS Investigators TI Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE biomarkers; diabetic nephropathy; hepcidin; interstitial fibrosis; monocyte chemoattractant protein-1 ID RENIN-ANGIOTENSIN SYSTEM; EARLY NATURAL-HISTORY; KIDNEY-DISEASE; TUBULAR DAMAGE; ASSOCIATION; PREDICTORS; BIOMARKERS; PARAMETERS; DECLINE; MARKERS AB aEuro broken vertical bar the residual risk of renal disease progression in patients with diabetic nephropathy is still extremely high despite current optimal treatment; innate immunity, MCP-1 and macrophage tissue infiltration seem very promising targets for future treatment of diabetic nephropathy on top of the standard of care with RAAS inhibition.Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/aS2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Baseline mean age was 24.6 years, mean duration of T1D 11.2 years, median AER 6.4 A mu g/min and mean iohexol GFR 129 mL/min/1.73 m(2). No associations were found between hepcidin/Cr and morphometric variables. Higher MCP-1/Cr was associated with higher interstitial fractional volume at baseline and after 5 years in women (baseline partial r = 0.244, P = 0.024; 5-year partial r = 0.299, P = 0.005), but not in men (baseline partial r = -0.049, P = 0.678; 5-year partial r = 0.026, P = 0.830). MCP-1 was not associated with glomerular lesions in either sex. Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN. C1 [Fufaa, Gudeta D.; Weil, E. Jennifer; Nelson, Robert G.; Hanson, Robert L.; Knowler, William C.] NIDDK, Phoenix, AZ USA. [Rovin, Brad H.; Wu, Haifeng] Ohio State Univ, Columbus, OH 43210 USA. [Klein, Jon B.] Univ Louisville, Louisville, KY 40292 USA. [Mifflin, Theodore E.; Feldman, Harold I.] Univ Penn, Philadelphia, PA 19104 USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Kimmel, Paul L.; Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Mauer, Michael] Univ Minnesota, Dept Pediat & Med, Minneapolis, MN 55454 USA. RP Mauer, M (reprint author), Univ Minnesota, Dept Pediat & Med, Minneapolis, MN 55454 USA. EM mauer002@umn.edu RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Ramachandran, Vasan/0000-0001-7357-5970 FU Chronic Kidney Disease Biomarker Consortium - NIDDK [U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Chronic Kidney Disease Biomarker Consortium funded by NIDDK U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651 and U01DK085689, and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The RASS Investigators include Bernard Zinman, MD and Sandra Donnelly, MDCM, MSc, University of Toronto, Toronto Canada; Robert Gardiner, MD, Samy Suissa, PhD, Keith Drummond, MD and Paul Goodyer, MD, McGill University, Montreal, Canada; Alan Sinaiko, MD and Trudy Strand, RN, University of Minnesota, Minneapolis, MN; Marie Claire Gubler, MD and Ronald Klein, MD, MPH, University of Wisconsin, Madison, WI. NR 36 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD APR PY 2015 VL 30 IS 4 BP 599 EP 606 DI 10.1093/ndt/gfv012 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA CG8KS UT WOS:000353557000015 PM 25648911 ER PT J AU Burotto, M Manasanch, EE Wilkerson, J Fojo, T AF Burotto, Mauricio Manasanch, Elisabet E. Wilkerson, Julia Fojo, Tito TI Gefitinib and Erlotinib in Metastatic Non-Small Cell Lung Cancer: A Meta-Analysis of Toxicity and Efficacy of Randomized Clinical Trials SO ONCOLOGIST LA English DT Article DE Gefitinib; Erlotinib; Afatinib; Lung cancer; Tyrosine kinase inhibitors ID PHASE-II TRIAL; PLATINUM-BASED CHEMOTHERAPY; COMPREHENSIVE GERIATRIC ASSESSMENT; PREVIOUSLY TREATED PATIENTS; TYROSINE-KINASE INHIBITORS; OPEN-LABEL; 1ST-LINE TREATMENT; 2ND-LINE TREATMENT; ELDERLY-PATIENTS; EGFR MUTATIONS AB Background. Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC. Methods. We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies. Results. We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations. Conclusion. Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC. C1 [Burotto, Mauricio; Wilkerson, Julia; Fojo, Tito] NCI, Med Oncol, NIH, Bethesda, MD 20892 USA. [Burotto, Mauricio; Wilkerson, Julia; Fojo, Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Manasanch, Elisabet E.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. RP Burotto, M (reprint author), NCI, Ctr Canc Res, NIH, Bldg 10,Room 12 N226, Bethesda, MD 20892 USA. EM mauricio.burottopichun@nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 NR 67 TC 19 Z9 22 U1 2 U2 13 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 APR PY 2015 VL 20 IS 4 BP 400 EP 410 DI 10.1634/theoncologist.2014-0154 PG 11 WC Oncology SC Oncology GA CG0ZD UT WOS:000353001900014 PM 25795635 ER PT J AU Korepanov, AP Kostareva, OS Bazhenova, MV Bubunenko, MG Garber, MB Tishchenko, SV AF Korepanov, Alexey P. Kostareva, Olga S. Bazhenova, Maria V. Bubunenko, Mikhail G. Garber, Maria B. Tishchenko, Svetlana V. TI Studying the Properties of Domain I of the Ribosomal Protein L1: Incorporation into Ribosome and Regulation of the L1 Operon Expression SO PROTEIN JOURNAL LA English DT Article DE Translation; Translation regulation; Ribosomal protein L1; Escherichia coli; rplA knockout ID 1ST PEPTIDE-BOND; RNA TARGET SITE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; METHANOCOCCUS-VANNIELII; ANGSTROM RESOLUTION; TRANSLATIONAL REGULATION; THERMUS-THERMOPHILUS; MESSENGER-RNA; MVAL1 OPERON AB L1 is a conserved protein of the large ribosomal subunit. This protein binds strongly to the specific region of the high molecular weight rRNA of the large ribosomal subunit, thus forming a conserved flexible structural element-the L1 stalk. L1 protein also regulates translation of the operon that comprises its own gene. Crystallographic data suggest that L1 interacts with RNA mainly by means of its domain I. We show here for the first time that the isolated domain I of the bacterial protein L1 of Thermus thermophilus and Escherichia coli is able to incorporate in vivo into the E. coli ribosome. Furthermore, domain I of T. thermophilus L1 can regulate expression of the L1 gene operon of Archaea in the coupled transcription-translation system in vitro, as well as the intact protein. We have identified the structural elements of domain I of the L1 protein that may be responsible for its regulatory properties. C1 [Korepanov, Alexey P.; Kostareva, Olga S.; Bazhenova, Maria V.; Garber, Maria B.; Tishchenko, Svetlana V.] Russian Acad Sci, Inst Prot Res, Pushchino 142290, Moscow Region, Russia. [Bubunenko, Mikhail G.] NCI, Mol Control & Genet Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Tishchenko, SV (reprint author), Russian Acad Sci, Inst Prot Res, Pushchino 142290, Moscow Region, Russia. EM korepan@vega.protres.ru; sveta@vega.protres.ru RI Kostareva, Olga/J-7697-2015; Tishchenko, Svetlana/A-7374-2013; Korepanov, Alexey/I-9052-2012 FU Program "Molecular and cellular biology" of the Presidium of the Russian Academy of Sciences; Russian Foundation for Basic Research [14-04-00414, 15-04-05008] FX The authors thank Dr. Alexander Kaliman (Institute of Protein Research) and Dr. Donald L. Court (National Cancer Institute at Frederick) for the plasmids provided. This study was supported by the Program "Molecular and cellular biology" of the Presidium of the Russian Academy of Sciences and the Russian Foundation for Basic Research (Grants No. 14-04-00414 and No. 15-04-05008). SPR experiments were performed at the Human Proteome Shared Facility Center of the Institute of Biomedical Chemistry, Moscow, Russia. NR 38 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1572-3887 EI 1573-4943 J9 PROTEIN J JI Protein J. PD APR PY 2015 VL 34 IS 2 BP 103 EP 110 DI 10.1007/s10930-015-9602-5 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CG3WQ UT WOS:000353210700002 PM 25681234 ER PT J AU Bourne, PE AF Bourne, Philip E. TI DOIs for DICOM Raw Images: Enabling Science Reproducibility SO RADIOLOGY LA English DT Editorial Material C1 NIH, Off Director, Bethesda, MD 20892 USA. RP Bourne, PE (reprint author), NIH, Off Director, 1 Ctr Dr,Bldg 1,Room 228, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2015 VL 275 IS 1 BP 3 EP 4 DI 10.1148/radiol.15150144 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CG4KW UT WOS:000353255000002 PM 25799330 ER PT J AU Meffert, H Brislin, SJ White, SF Blair, JR AF Meffert, Harma Brislin, Sarah J. White, Stuart F. Blair, James R. TI Prediction errors to emotional expressions: the roles of the amygdala in social referencing SO Social Cognitive and Affective Neuroscience LA English DT Article DE social referencing; amygdala; fMRI; emotion; neuroscience; learning ID FUNCTIONAL NEUROANATOMY; FACIAL EXPRESSIONS; ANXIETY DISORDERS; GAZE DIRECTION; HUMAN STRIATUM; REWARD; METAANALYSIS; BRAIN; FMRI; FEAR AB Social referencing paradigms in humans and observational learning paradigms in animals suggest that emotional expressions are important for communicating valence. It has been proposed that these expressions initiate stimulus-reinforcement learning. Relatively little is known about the role of emotional expressions in reinforcement learning, particularly in the context of social referencing. In this study, we examined object valence learning in the context of a social referencing paradigm. Participants viewed objects and faces that turned toward the objects and displayed a fearful, happy or neutral reaction to them, while judging the gender of these faces. Notably, amygdala activation was larger when the expressions following an object were less expected. Moreover, when asked, participants were both more likely to want to approach, and showed stronger amygdala responses to, objects associated with happy relative to objects associated with fearful expressions. This suggests that the amygdala plays two roles in social referencing: (i) initiating learning regarding the valence of an object as a function of prediction errors to expressions displayed toward this object and (ii) orchestrating an emotional response to the object when value judgments are being made regarding this object. C1 [Meffert, Harma; White, Stuart F.; Blair, James R.] NIH, Sect Affect & Cognit Neurosci, Bethesda, MD 20892 USA. [Brislin, Sarah J.] Florida State Univ, Clin Psychol Program, Tallahassee, FL 32306 USA. RP Meffert, H (reprint author), NIMH, NIH, Sect Affect & Cognit Neurosci, 9000 Rockville Pike,Bldg 15k,Room 300-E,MSC 2670, Bethesda, MD 20892 USA. EM harma.meffert@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health under grant number 1-ZIA-MH002860-08. NR 62 TC 2 Z9 2 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD APR PY 2015 VL 10 IS 4 BP 537 EP 544 DI 10.1093/scan/nsu085 PG 8 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CG8HB UT WOS:000353546800010 PM 24939872 ER PT J AU Picut, CA Dixon, D Simons, ML Stump, DG Parker, GA Remick, AK AF Picut, Catherine A. Dixon, Darlene Simons, Michelle L. Stump, Donald G. Parker, George A. Remick, Amera K. TI Postnatal Ovary Development in the Rat: Morphologic Study and Correlation of Morphology to Neuroendocrine Parameters SO TOXICOLOGIC PATHOLOGY LA English DT Article DE endocrine disruptors; female; ovary; postnatal development; pubertal assay; reproduction; Sprague-Dawley rats ID JUVENILE TOXICITY; MOUSE OVARY; FEMALE RATS; PUBERTY; ONSET; FSH; LH AB Histopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic-pituitary-gonadal axis matures. During the neonatal stage (postnatal day [PND] 0-7), ovarian follicle development is independent of pituitary gonadotropins (luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), and follicles remain preantral. Antral development of atypical follicles occurs in the early infantile period (PND 8-14) when the ovary becomes responsive to pituitary gonadotropins. In the late infantile period (PND 15-20), the zona pellucida appears, the hilus forms, and antral follicles mature by losing their atypical appearance. The juvenile stage (PND 21-32) is the stage when atresia of medullary follicles occurs corresponding to a nadir in FSH levels. In the peripubertal period (PND 33-37), atresia subsides as FSH levels rebound, and LH begins its bimodal surge pattern leading to ovulation. This report will provide pathologists with baseline morphologic and endocrinologic information to aid in identification and interpretation of xenobiotic effects in the ovary of the prepubertal rat. C1 [Picut, Catherine A.; Parker, George A.; Remick, Amera K.] WIL Res, Hillsborough, NC 27278 USA. [Dixon, Darlene] NIEHS, Mol Pathogenesis Grp, Natl Toxicol Program, NTP Lab,Div NTP, Res Triangle Pk, NC 27709 USA. [Simons, Michelle L.; Stump, Donald G.] WIL Res, Ashland, OH USA. RP Picut, CA (reprint author), WIL Res, 310 Millstone Dr, Hillsborough, NC 27278 USA. EM catherine.picut@wilresearch.com FU WIL Research; NTP; National Institute of Environmental Health Sciences FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was fully funded by WIL Research and the NTP and National Institute of Environmental Health Sciences. NR 29 TC 11 Z9 11 U1 1 U2 9 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 APR PY 2015 VL 43 IS 3 BP 343 EP 353 DI 10.1177/0192623314544380 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA CG3AN UT WOS:000353148900003 PM 25107574 ER PT J AU Guo, TL Germolec, DR Zheng, JF Kooistra, L Auttachoat, W Smith, MJ White, KL Elmore, SA AF Guo, Tai L. Germolec, Dori R. Zheng, Jian Feng Kooistra, Linda Auttachoat, Wimolnut Smith, Matthew J. White, Kimber L. Elmore, Susan A. TI Genistein Protects Female Nonobese Diabetic Mice from Developing Type 1 Diabetes When Fed a Soy- and Alfalfa-free Diet SO TOXICOLOGIC PATHOLOGY LA English DT Article DE genistein; NOD mouse; type 1 diabetes; islet inflammation ID B6C3F1 MICE; ESTROGEN-RECEPTOR; F-1 GENERATIONS; RODENT DIETS; NOD MOUSE; INSULIN; EXPOSURE; AUTOANTIBODIES; PREVENTION; MELLITUS AB The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6-7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose 250 mg/dl) and severe diabetes (blood glucose 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet. C1 [Guo, Tai L.; Zheng, Jian Feng; Auttachoat, Wimolnut; Smith, Matthew J.; White, Kimber L.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. [Germolec, Dori R.; Elmore, Susan A.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Kooistra, Linda] Charles River Labs, Durham, NC USA. RP Guo, TL (reprint author), Univ Georgia, Coll Vet Med, Dept Vet Biosci & Diagnost Imaging, Athens, GA 30602 USA. EM tlguo1@uga.edu FU NIEHS [N01-ES-55538] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the NIEHS contract N01-ES-55538. NR 58 TC 2 Z9 2 U1 1 U2 7 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 APR PY 2015 VL 43 IS 3 BP 435 EP 448 DI 10.1177/0192623314526318 PG 14 WC Pathology; Toxicology SC Pathology; Toxicology GA CG3AN UT WOS:000353148900011 PM 24713318 ER PT J AU Jones, CP Ferre-D'Amare, AR AF Jones, Christopher P. Ferre-D'Amare, Adrian R. TI RNA quaternary structure and global symmetry SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review DE X-ray crystallography; cooperativity; c-di-AMP riboswitch; glycine riboswitch; FMN riboswitch; bacteriophage phi 29 pRNA ID C-DI-AMP; LARGE RIBOSOMAL-SUBUNIT; DNA PACKAGING MOTOR; X-RAY-SCATTERING; CRYSTAL-STRUCTURE; LIGAND-BINDING; GLYCINE RIBOSWITCHES; ANGSTROM RESOLUTION; BACILLUS-SUBTILIS; GENE-EXPRESSION AB Many proteins associate into symmetric multisubunit complexes. Structural analyses suggested that, by contrast, virtually all RNAs with complex 3D structures function as asymmetric monomers. Recent crystal structures revealed that several biological RNAs exhibit global symmetry at the level of their tertiary and quaternary structures. Here we survey known examples of global RNA symmetry, including the true quaternary symmetry of the bacteriophage phi 29 prohead RNA (pRNA) and the internal pseudosymmetry of the single-chain flavin mononucleotide (FMN), glycine, and cyclic di-AMP (c-di-AMP) riboswitches. For these RNAs, global symmetry stabilizes the RNA fold, coordinates ligand-RNA interactions, and facilitates association with symmetric binding partners. C1 [Jones, Christopher P.; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Biochem & Biophys Ctr, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health (NIH); Lenfant Biomedical Postdoctoral Fellowship FX This work was supported in part by the Intramural Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) and a Lenfant Biomedical Postdoctoral Fellowship awarded to C.P.J. NR 88 TC 6 Z9 6 U1 3 U2 21 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2015 VL 40 IS 4 BP 211 EP 220 DI 10.1016/j.tibs.2015.02.004 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CG8AB UT WOS:000353527900004 PM 25778613 ER PT J AU Volkow, N AF Volkow, Nora TI An interview with Nora Volkow SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material C1 [Volkow, Nora] NIH, NIDA, Rockville, MD 20852 USA. [Volkow, Nora] NYU, New York, NY 10003 USA. [Volkow, Nora] US DOE, Brookhaven Natl Lab, Nucl Med, Upton, NY USA. [Volkow, Nora] US DOE, Brookhaven Natl Lab, Dept Med, Upton, NY USA. [Volkow, Nora] US DOE, Brookhaven Natl Lab, Life Sci, Upton, NY USA. [Volkow, Nora] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY USA. [Volkow, Nora] SUNY Stony Brook, Sch Med, Stony Brook, NY USA. RP Volkow, N (reprint author), NIH, NIDA, Rockville, MD 20852 USA. EM nvoIkow@nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2015 VL 36 IS 4 BP 187 EP 188 DI 10.1016/j.tips.2015.01.006 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG6QA UT WOS:000353425700001 PM 25814055 ER PT J AU Brown, J AF Brown, Jeremy TI The Crisis in the Emergency Medicine Physician Scientist Workforce Reply SO ACADEMIC EMERGENCY MEDICINE LA English DT Letter C1 NIH, Off Emergency Care Res, Bethesda, MD 20892 USA. RP Brown, J (reprint author), NIH, Off Emergency Care Res, Bldg 10, Bethesda, MD 20892 USA. EM jeremy.brown@nih.gov 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 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD APR PY 2015 VL 22 IS 4 SI SI BP 493 EP 493 DI 10.1111/acem.12638 PG 1 WC Emergency Medicine SC Emergency Medicine GA CF5BN UT WOS:000352569900019 PM 25771830 ER PT J AU Liebschner, D Rosenbaum, G Dauter, M Dauter, Z AF Liebschner, Dorothee Rosenbaum, Gerold Dauter, Miroslawa Dauter, Zbigniew TI Radiation decay of thaumatin crystals at three X-ray energies SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE radiation damage; dose limit; energy dependence ID PROTEIN CRYSTALS; MACROMOLECULAR CRYSTALLOGRAPHY; SYNCHROTRON-RADIATION; DAMAGE; CRYOCRYSTALLOGRAPHY; DEPENDENCE; DIFFRACTION AB Radiation damage is an unavoidable obstacle in X-ray crystallographic data collection for macromolecular structure determination, so it is important to know how much radiation a sample can endure before being degraded beyond an acceptable limit. In the literature, the threshold at which the average intensity of all recorded reflections decreases to a certain fraction of the initial value is called the 'dose limit'. The first estimated D-50 dose-limit value, at which the average diffracted intensity was reduced to 50%, was 20 MGy and was derived from observing sample decay in electron-diffraction experiments. A later X-ray study carried out at 100 Kon ferritin protein crystals arrived at a D-50 of 43 MGy, and recommended an intensity reduction of protein reflections to 70%, D-70, corresponding to an absorbed dose of 30 MGy, as a more appropriate limit for macromolecular crystallography. In the macromolecular crystallography community, the rate of intensity decay with dose was then assumed to be similar for all protein crystals. A series of diffraction images of cryocooled (100 K) thaumatin crystals at identical small, 2 degrees rotation intervals were recorded at X-ray energies of 6.33, 12.66 and 19.00 keV. Five crystals were used for each wavelength. The decay in the average diffraction intensity to 70% of the initial value, for data extending to 2.45 angstrom resolution, was determined to be about 7.5 MGy at 6.33 keV and about 11 MGy at the two higher energies. C1 [Liebschner, Dorothee] High Energy Accelerator Res Org, Inst Mat Struct Sci, Photon Factory, Struct Biol Res Ctr, Tsukuba, Ibaraki, Japan. [Rosenbaum, Gerold] Univ Georgia, Dept Biochem, Argonne, IL 60439 USA. [Rosenbaum, Gerold] Argonne Natl Lab, Struct Biol Ctr, Argonne, IL 60439 USA. [Dauter, Miroslawa] Argonne Natl Lab, Basic Sci Program, Leidos Biomed Res Inc, Argonne, IL 60439 USA. [Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, MCL, Natl Canc Inst, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), Argonne Natl Lab, Synchrotron Radiat Res Sect, MCL, Natl Canc Inst, 9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800E]; Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Diffraction data were collected on beamline 19-ID of the Structural Biology Center at the Advanced Photon Source, Argonne National Laboratory operated under contract DE-AC02-06CH11357 of the Department of Energy, Office of Biological and Environmental Research. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 28 TC 4 Z9 4 U1 1 U2 8 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD APR PY 2015 VL 71 BP 772 EP 778 DI 10.1107/S1399004715001030 PN 4 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CF4GQ UT WOS:000352507200004 PM 25849388 ER PT J AU Sliwiak, J Dauter, Z Kowiel, M McCoy, AJ Read, RJ Jaskolski, M AF Sliwiak, Joanna Dauter, Zbigniew Kowiel, Marcin McCoy, Airlie J. Read, Randy J. Jaskolski, Mariusz TI ANS complex of St John's wort PR-10 protein with 28 copies in the asymmetric unit: a fiendish combination of pseudosymmetry with tetartohedral twinning SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE pathogenesis-related class 10 protein; St John's wort; Hypericum perforatum; 8-anilino-1-naphthalene sulfonate ID TRANSLATIONAL NONCRYSTALLOGRAPHIC SYMMETRY; PATHOGENESIS-RELATED PROTEINS; BET V 1; CRYSTAL-STRUCTURES; MACROMOLECULAR CRYSTALLOGRAPHY; INTENSITY STATISTICS; FLUORESCENT-PROBE; X-RAY; BINDING; CYTOKININ AB Hyp-1, a pathogenesis-related class 10 (PR-10) protein from St John's wort (Hypericum perforatum), was crystallized in complex with the fluorescent probe 8-anilino-1-naphthalene sulfonate (ANS). The highly pseudosymmetric crystal has 28 unique protein molecules arranged in columns with sevenfold translational noncrystallographic symmetry (tNCS) along c and modulated X-ray diffraction with intensity crests at l = 7n and l = 7n +/- 3. The translational NCS is combined with pseudotetragonal rotational NCS. The crystal was a perfect tetartohedral twin, although detection of twinning was severely hindered by the pseudosymmetry. The structure determined at 2.4 angstrom resolution reveals that the Hyp-1 molecules (packed as beta-sheet dimers) have three novel ligand-binding sites (two internal and one in a surface pocket), which was confirmed by solution studies. In addition to 60 Hyp-1-docked ligands, there are 29 interstitial ANS molecules distributed in a pattern that violates the arrangement of the protein molecules and is likely to be the generator of the structural modulation. In particular, whenever the stacked Hyp-1 molecules are found closer together there is an ANS molecule bridging them. C1 [Sliwiak, Joanna; Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. [Dauter, Zbigniew] Argonne Natl Lab, Natl Canc Inst, Synchrotron Radiat Res Sect, Argonne, IL 60439 USA. [Kowiel, Marcin] Poznan Univ Med Sci, Dept Organ Chem, Poznan, Poland. [McCoy, Airlie J.; Read, Randy J.] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, PL-60780 Poznan, Poland. RP Jaskolski, M (reprint author), Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. EM mariuszj@amu.edu.pl RI Read, Randy/L-1418-2013 OI Read, Randy/0000-0001-8273-0047 FU European Union within the European Regional Developmental Fund; Polish Ministry of Science and Higher Education [NN 301 003739]; National Science Center [2013/10/M/NZ1/00251]; Principal Research Fellowship from the Wellcome Trust [082961/Z/07/Z]; Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX Financial support for this project was provided by the European Union within the European Regional Developmental Fund and by the Polish Ministry of Science and Higher Education (grant No. NN 301 003739) and National Science Center (2013/10/M/NZ1/00251). RJR was supported by a Principal Research Fellowship from the Wellcome Trust (grant No. 082961/Z/07/Z). ZD was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. The raw images are available from the authors (ZD; zdauter@anl.gov) on request. NR 43 TC 3 Z9 3 U1 0 U2 7 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD APR PY 2015 VL 71 BP 829 EP 843 DI 10.1107/S1399004715001388 PN 4 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CF4GQ UT WOS:000352507200010 PM 25849394 ER PT J AU Fu, ZJ Lofqvist, CA Shao, Z Sun, Y Joyal, JS Hurst, CG Cui, RZ Evans, LP Tian, K SanGiovanni, JP Chen, J Ley, D Pupp, IH Hellstrom, A Smith, LEH AF Fu, Zhongjie Lofqvist, Chatarina A. Shao, Zhuo Sun, Ye Joyal, Jean-Sebastien Hurst, Christian G. Cui, Ricky Z. Evans, Lucy P. Tian, Katherine SanGiovanni, John Paul Chen, Jing Ley, David Pupp, Ingrid Hansen Hellstrom, Ann Smith, Lois E. H. TI Dietary omega-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE omega-3 long-chain polyunsaturated fatty acids; adiponectin; endoplasmic reticulum stress; retinopathy of prematurity; white adipose tissue; neovascularization ID OXYGEN-INDUCED RETINOPATHY; ENDOTHELIAL-CELL APOPTOSIS; MOLECULAR-WEIGHT FORM; PATHOLOGICAL ANGIOGENESIS; PRETERM INFANTS; NITRIC-OXIDE; FISH-OIL; PREMATURITY; MOUSE; SUPPRESSION AB Background: Retinopathy of prematurity (ROP) is a vision-threatening disease in premature infants. Serum adiponectin (APN) concentrations positively correlate with postnatal growth and gestational age, important risk factors for ROP development. Dietary omega-3 (n-3) long-chain polyunsaturated fatty acids (omega-3 LCPUFAs) suppress ROP and oxygen-induced retinopathy (OIR) in a mouse model of human ROP, but the mechanism is not fully understood. Objective: We examined the role of APN in ROP development and whether circulating APN concentrations are increased by dietary omega-3 LCPUFAs to mediate the protective effect in ROP. Design: Serum APN concentrations were correlated with ROP development and serum omega-3 LCPUFA concentrations in preterm infants. Mouse OIR was then used to determine whether omega-3 LCPUFA supplementation increases serum APN concentrations, which then suppress retinopathy. Results: We found that in preterm infants, low serum APN concentrations positively correlate with ROP, and serum APN concentrations positively correlate with serum omega-3 LCPUFA concentrations. In mouse OIR, serum total APN and bioactive high-molecular-weight APN concentrations are increased by omega-3 LCPUFA feed. White adipose tissue, where APN is produced and assembled in the endoplasmic reticulum, is the major source of serum APN. In mouse OIR, adipose endoplasmic reticulum stress is increased, and APN production is suppressed. omega-3 LCPUFA feed in mice increases APN production by reducing adipose endoplasmic reticulum stress markers. Dietary omega-3 LCPUFA suppression of neovascularization is reduced from 70% to 10% with APN deficiency. APN receptors localize in the retina, particularly to pathologic neovessels. Conclusion: Our findings suggest that increasing APN by omega-3 LCPUFA supplementation in total parental nutrition for preterm infants may suppress ROP. C1 [Fu, Zhongjie; Shao, Zhuo; Sun, Ye; Joyal, Jean-Sebastien; Hurst, Christian G.; Cui, Ricky Z.; Evans, Lucy P.; Tian, Katherine; Chen, Jing; Smith, Lois E. H.] Harvard Univ, Childrens Hosp, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. [Lofqvist, Chatarina A.; Hellstrom, Ann] Univ Gothenburg, Sahlgrenska Acad, Dept Ophthalmol, Gothenburg, Sweden. [Ley, David; Pupp, Ingrid Hansen] Lund Univ, Inst Clin Sci, Dept Pediat, Lund, Sweden. [Ley, David; Pupp, Ingrid Hansen] Skane Univ Hosp, Lund, Sweden. [SanGiovanni, John Paul] NEI, Div Epidemiol & Clin Res, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. RP Smith, LEH (reprint author), Childrens Hosp, Dept Ophthalmol, 300 Longwood Ave, Boston, MA 02115 USA. EM lois.smith@childrens.harvard.edu FU NIH/National Eye Institute [EY022275, EY017017, EY024963]; Boston Children's Hospital Mental Retardation and Developmental Disabilities Research Center [P01 HD18655]; project PREVENT-ROP from the Lowy Medical Research Foundation, European Commission FP7 (LEHS) [305485]; project PREVENT-ROP from the European Commission FP7 [305485, VINNOVA 2009-01152]; Swedish Medical Research Council [2011-2432]; Swedish government [ALFGB2770]; Swedish Research Council [14940]; governmental ALF research grants; BrightFocus Foundation Macular Degeneration research grant; career development award from Boston Children's Hospital; Burroughs Wellcome Fund Career Awards for Medical Scientists; Canadian Institutes of Health Research Fellowship; Foundation Fighting Blindness Operational grant FX This work was supported in part by grants EY022275 and EY017017 from the NIH/National Eye Institute, grant P01 HD18655 from the Boston Children's Hospital Mental Retardation and Developmental Disabilities Research Center, and project 305485 PREVENT-ROP from the Lowy Medical Research Foundation, European Commission FP7 (LEHS); project 305485 PREVENT-ROP (VINNOVA 2009-01152) from the European Commission FP7 (CAL); grant 2011-2432 from the Swedish Medical Research Council and grant ALFGB2770 from the Swedish government (AH); grant 14940 from the Swedish Research Council, governmental ALF research grants to Lund University and Skane University Hospital, and project 305485 PREVENT-ROP from the European Commission FP7 (DL); grant EY024963 from the NIH/National Eye Institute, BrightFocus Foundation Macular Degeneration research grant, and a career development award from Boston Children's Hospital (JC); and Burroughs Wellcome Fund Career Awards for Medical Scientists, a Canadian Institutes of Health Research Fellowship, and Foundation Fighting Blindness Operational grant (J-SJ). NR 55 TC 10 Z9 10 U1 0 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR PY 2015 VL 101 IS 4 BP 879 EP 888 DI 10.3945/ajcn.114.099291 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CF1VM UT WOS:000352336000023 PM 25833984 ER PT J AU Greenwood, MP Mecawi, AS Hoe, SZ Mustafa, MR Johnson, KR Al-Mahmoud, GA Elias, LLK Paton, JFR Antunes-Rodrigues, J Gainer, H Murphy, D Hindmarch, CCT AF Greenwood, Michael P. Mecawi, Andre S. Hoe, See Ziau Mustafa, Mohd Rais Johnson, Kory R. Al-Mahmoud, Ghada A. Elias, Lucila L. K. Paton, Julian F. R. Antunes-Rodrigues, Jose Gainer, Harold Murphy, David Hindmarch, Charles C. T. TI A comparison of physiological and transcriptome responses to water deprivation and salt loading in the rat supraoptic nucleus SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE transcriptome; supraoptic nucleus; water restriction; salt load; neuroendocrine ID ACCELERATING FACTOR CD55; CENTRAL-NERVOUS-SYSTEM; IMMEDIATE-EARLY GENES; PROTEIN-C RECEPTOR; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; MESSENGER-RNA; SUBFORNICAL ORGAN; SODIUM APPETITE; PARAVENTRICULAR NUCLEUS; MAGNOCELLULAR NEURONS AB Salt loading (SL) and water deprivation (WD) are experimental challenges that are often used to study the osmotic circuitry of the brain. Central to this circuit is the supraoptic nucleus (SON) of the hypothalamus, which is responsible for the biosynthesis of the hormones, arginine vasopressin (AVP) and oxytocin (OXT), and their transport to terminals that reside in the posterior lobe of the pituitary. On osmotic challenge evoked by a change in blood volume or osmolality, the SON undergoes a function-related plasticity that creates an environment that allows for an appropriate hormone response. Here, we have described the impact of SL and WD compared with euhydrated (EU) controls in terms of drinking and eating behavior, body weight, and recorded physiological data including circulating hormone data and plasma and urine osmolality. We have also used microarrays to profile the transcriptome of the SON following SL and remined data from the SON that describes the transcriptome response to WD. From a list of 2,783 commonly regulated transcripts, we selected 20 genes for validation by qPCR. All of the 9 genes that have already been described as expressed or regulated in the SON by osmotic stimuli were confirmed in our models. Of the 11 novel genes, 5 were successfully validated while 6 were false discoveries. C1 [Greenwood, Michael P.; Murphy, David; Hindmarch, Charles C. T.] Univ Bristol, Sch Clin Sci, Bristol BS8 1TH, Avon, England. [Mecawi, Andre S.; Hoe, See Ziau; Murphy, David; Hindmarch, Charles C. T.] Univ Malaya, Fac Med, Dept Physiol, Kuala Lumpur, Malaysia. [Mecawi, Andre S.] Univ Fed Rural Rio de Janeiro, Inst Biol, Dept Physiol Sci, Seropedica, Brazil. [Mustafa, Mohd Rais] Univ Malaya, Fac Med, Dept Pharmacol, Kuala Lumpur 50603, Malaysia. [Johnson, Kory R.] NINDS, Clin Ctr, NIH, Bethesda, MD 20892 USA. [Al-Mahmoud, Ghada A.] Qatar Univ, Coll Arts & Sci, Dept Biol & Environm Sci, Doha, Qatar. [Elias, Lucila L. K.; Antunes-Rodrigues, Jose] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Physiol, BR-14049 Ribeirao Preto, SP, Brazil. [Paton, Julian F. R.] Univ Walk, Sch Physiol & Pharmacol, Bristol, Avon, England. [Gainer, Harold] NINDS, Lab Neurochem, NIH, Bethesda, MD 20892 USA. RP Hindmarch, CCT (reprint author), Labs Integrat Neurosci & Endocrinol, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM c.hindmarch@bristol.ac.uk RI HOE, SEE ZIAU/B-8637-2010; Mustafa, Mohamed/B-1647-2009; OI Mustafa, Mohamed/0000-0002-7864-5189; Paton, Julian/0000-0001-7410-2913 FU British Heart Foundation [RG/11/28714]; Biotechnology and Biological Sciences Research Council [BB/J005452/1]; University of Malaya [UM.C/625/1/HIR/MOHE/MED/22 H-20001-E000086]; National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This work was supported by funding from the British Heart Foundation (RG/11/28714, to M. Greenwood, J. F. R. Paton, D. Murphy), the Biotechnology and Biological Sciences Research Council (BB/J005452/1, to C. C. T. Hindmarch, J. F. R. Paton, D. Murphy), and a High Impact Research Chancellory Grant (UM.C/625/1/HIR/MOHE/MED/22 H-20001-E000086) from the University of Malaya (to C. C. T. Hindmarch, S. Ziau Hoe, A. S. Mecawi, M. R. Mustafa, D. Murphy). This research was also supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (for H. Gainer and K. R. Johnson). NR 62 TC 8 Z9 8 U1 2 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD APR 1 PY 2015 VL 308 IS 7 BP R559 EP R568 DI 10.1152/ajpregu.00444.2014 PG 10 WC Physiology SC Physiology GA CE9KT UT WOS:000352163600001 PM 25632023 ER PT J AU Wheeler, DC Archer, KJ Burstyn, I Yu, K Stewart, PA Colt, JS Baris, D Karagas, MR Schwenn, M Johnson, A Armenti, K Silverman, DT Friesen, MC AF Wheeler, David C. Archer, Kellie J. Burstyn, Igor Yu, Kai Stewart, Patricia A. Colt, Joanne S. Baris, Dalsu Karagas, Margaret R. Schwenn, Molly Johnson, Alison Armenti, Karla Silverman, Debra T. Friesen, Melissa C. TI Comparison of Ordinal and Nominal Classification Trees to Predict Ordinal Expert-Based Occupational Exposure Estimates in a Case-Control Study SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE classification; diesel exhaust; occupational exposure; ordinal data; statistical learning ID DIESEL EXHAUST EXPOSURE; DECISION RULES; PACKAGE AB Objectives: To evaluate occupational exposures in case-control studies, exposure assessors typically review each job individually to assign exposure estimates. This process lacks transparency and does not provide a mechanism for recreating the decision rules in other studies. In our previous work, nominal (unordered categorical) classification trees (CTs) generally successfully predicted expert-assessed ordinal exposure estimates (i.e. none, low, medium, high) derived from occupational questionnaire responses, but room for improvement remained. Our objective was to determine if using recently developed ordinal CTs would improve the performance of nominal trees in predicting ordinal occupational diesel exhaust exposure estimates in a case-control study. Methods: We used one nominal and four ordinal CT methods to predict expert-assessed probability, intensity, and frequency estimates of occupational diesel exhaust exposure (each categorized as none, low, medium, or high) derived from questionnaire responses for the 14 983 jobs in the New England Bladder Cancer Study. To replicate the common use of a single tree, we applied each method to a single sample of 70% of the jobs, using 15% to test and 15% to validate each method. To characterize variability in performance, we conducted a resampling analysis that repeated the sample draws 100 times. We evaluated agreement between the tree predictions and expert estimates using Somers' d, which measures differences in terms of ordinal association between predicted and observed scores and can be interpreted similarly to a correlation coefficient. Results: From the resampling analysis, compared with the nominal tree, an ordinal CT method that used a quadratic misclassification function and controlled tree size based on total misclassification cost had a slightly better predictive performance that was statistically significant for the frequency metric (Somers' d: nominal tree = 0.61; ordinal tree = 0.63) and similar performance for the probability (nominal = 0.65; ordinal = 0.66) and intensity (nominal = 0.65; ordinal = 0.65) metrics. The best ordinal CT predicted fewer cases of large disagreement with the expert assessments (i.e. no exposure predicted for a job with high exposure and vice versa) compared with the nominal tree across all of the exposure metrics. For example, the percent of jobs with expert-assigned high intensity of exposure that the model predicted as no exposure was 29% for the nominal tree and 22% for the best ordinal tree. Conclusions: The overall agreements were similar across CT models; however, the use of ordinal models reduced the magnitude of the discrepancy when disagreements occurred. As the best performing model can vary by situation, researchers should consider evaluating multiple CT methods to maximize the predictive performance within their data. C1 [Wheeler, David C.; Archer, Kellie J.] Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA 23298 USA. [Burstyn, Igor] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. [Stewart, Patricia A.] LLC, Stewart Exposure Assessments, Arlington, VA 22207 USA. [Colt, Joanne S.; Baris, Dalsu; Silverman, Debra T.; Friesen, Melissa C.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Lebanon, NH 03756 USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME 04333 USA. [Johnson, Alison] Vermont Dept Hlth, Vermont Canc Registry, Burlington, VT 05402 USA. [Armenti, Karla] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. RP Wheeler, DC (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biostat, 830 East Main St, Richmond, VA 23298 USA. EM dcwheels@gmail.com RI Friesen, Melissa/A-5362-2009 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 19 TC 2 Z9 2 U1 1 U2 5 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 APR PY 2015 VL 59 IS 3 BP 324 EP 335 DI 10.1093/annhyg/meu098 PG 12 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA CG1TH UT WOS:000353056600006 PM 25433003 ER PT J AU Schwartz, M Sarusi, A Deitch, RT Tal, M Raz, D Sung, MH Kaplan, T Hakim, O AF Schwartz, Michal Sarusi, Avital Deitch, Rachel T. Tal, Moran Raz, Dana Sung, Myong-Hee Kaplan, Tommy Hakim, Ofir TI Comparative analysis of T4 DNA ligases and DNA polymerases used in chromosome conformation capture assays SO BIOTECHNIQUES LA English DT Article DE chromosome conformation capture; 3C; 4C; nuclear architecture ID HUMAN GENOME; ORGANIZATION; PRINCIPLES AB Three-dimensional (3-D) genome organization in the nuclear space affects various genomic functions. Circular chromosome conformation capture (4C-seq) is a powerful technique that allows researchers to measure long-range chromosomal interactions with a locus of interest across the entire genome. This method relies on enzymatic cleavage of cross-linked chromatin and consecutive ligation to create ligation junctions between physically adjacent loci, followed by PCR amplification of locus-specific associating loci. The enzymes used must meet 4C standards because variations in their efficiency and performance may affect the quality of the obtained data. Here we systematically compare the efficiency and reliability of different T4 DNA ligases and PCR DNA polymerases, assessing the most critical and technically challenging steps in 4C. The results of this analysis enable the use of cost-effective enzymes with superior specificity and efficiency for 4C and save time in screening for appropriate primers. This information provides users with flexibility in their experimental design and guidelines for adapting and testing any enzyme of choice for obtaining standardized results. C1 [Schwartz, Michal; Sarusi, Avital; Deitch, Rachel T.; Tal, Moran; Raz, Dana; Hakim, Ofir] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. [Sung, Myong-Hee] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Kaplan, Tommy] Hebrew Univ Jerusalem, Sch Comp Sci & Engn, Jerusalem, Israel. RP Hakim, O (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. EM ofir.hakim@biu.ac.il FU Israeli Science Foundation (ISF) [41/11]; Marie Curie Integration grant (CIG) [FP7-PEOPLE20013-CIG-618763]; I-CORE Program of the Planning and Budgeting Committee; United States-Israel Bi-national Science Foundation (BSF), Jerusalem, Israel FX The authors thank Tirza Doniger and Hiba Waldman Ben-Asher for computational assistance, and Erez Lavanon for the use of the server cluster. O. H. is funded by the Israeli Science Foundation (ISF), Marie Curie Integration grant (CIG) FP7-PEOPLE20013-CIG-618763 and I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation grant no. 41/11. O. H. and M.- H. S. are supported together by the United States-Israel Bi-national Science Foundation (BSF), Jerusalem, Israel. NR 11 TC 1 Z9 1 U1 0 U2 2 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 EI 1940-9818 J9 BIOTECHNIQUES JI Biotechniques PD APR PY 2015 VL 58 IS 4 BP 195 EP 199 DI 10.2144/000114276 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF8HU UT WOS:000352797800007 PM 25861932 ER PT J AU Rusch, HL Shvil, E Szanton, SL Neria, Y Gill, JM AF Rusch, Heather L. Shvil, Erel Szanton, Sarah L. Neria, Yuval Gill, Jessica M. TI Determinants of psychological resistance and recovery among women exposed to assaultive trauma SO BRAIN AND BEHAVIOR LA English DT Article DE CD-RISC; depression; health; mastery; MDD; optimism; posttraumatic Growth; PTSD; resilience; social support; RRID:rid_000042 ID POSTTRAUMATIC-STRESS-DISORDER; HEALTH SURVEY SF-36; DEPRESSIVE SYMPTOMS; SOCIAL SUPPORT; SEXUAL ASSAULT; PTSD SYMPTOMS; PHYSICAL HEALTH; COMBAT VETERANS; SELF-MASTERY; PRIMARY-CARE AB Introduction: Women exposed to potentially traumatic events (PTEs) are at high risk for developing psychiatric disorders, including posttraumatic stress disorder (PTSD), general anxiety disorder (GAD), major depressive disorder (MDD), and substance-related disorders. However, this risk is not universal. Most women are resistant (i.e., remain asymptomatic), or recover following a brief symptomatic period. This study examined the psychological factors associated with resistant and recovered outcomes in a sample of high-risk women exposed to assault-related PTEs. Method: One hundred and fifty-nine women completed the Life Events Checklist and were administered the Structured Clinical Interview for DSM-IV Axis I Disorders. This resulted in three groups: (1) no diagnosis (no past or current psychiatric disorder diagnosis; n=56), (2) past diagnosis (a past psychiatric disorder diagnosis, but none currently; n=31), and (3) current diagnosis (a current diagnosis of one or more psychiatric disorders; n=72). Groups were compared on sociodemographics, PTE exposure, psychopathology, health-related quality of life (HRQOL), and psychological resilience-related factors. Results: The majority of respondents (79%) did not develop chronic PTSD following assault exposure, and the most common psychiatric outcome was MDD (30%). High endorsement of mastery and social support were associated with the no diagnosis group; and greater reports of mastery and posttraumatic growth were associated with recovery from a past psychiatric disorder. Furthermore, both resilient groups (i.e., no diagnosis and past diagnosis) scored higher on HRQOL measures compared with the current diagnosis group (P<0.001). Conclusion: Psychological resilience has ramifications to health and well-being, and identifying these factors has potential to inform preventive strategies and treatment interventions for assault exposed women. C1 [Rusch, Heather L.; Gill, Jessica M.] NIH, Natl Inst Nursing Res, Bethesda, MD 20892 USA. [Rusch, Heather L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. [Shvil, Erel; Neria, Yuval] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Shvil, Erel; Neria, Yuval] Columbia Univ, Dept Psychiat, Med Ctr, New York, NY 10032 USA. [Szanton, Sarah L.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21205 USA. RP Rusch, HL (reprint author), 1 Cloister Court,Bldg 60 259, Bethesda, MD 20892 USA. EM heather.rusch@nih.gov OI Rusch, Heather/0000-0002-4061-8628 NR 45 TC 0 Z9 0 U1 5 U2 16 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD APR PY 2015 VL 5 IS 4 AR e00322 DI 10.1002/brb3.322 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CF8IF UT WOS:000352799300006 PM 25798336 ER PT J AU Chen, J Hackett, CS Zhang, S Song, YK Bell, RJA Molinaro, AM Quigley, DA Balmain, A Song, JS Costello, JF Gustafson, WC Van Dyke, T Kwok, PY Khan, J Weiss, WA AF Chen, Justin Hackett, Christopher S. Zhang, Shile Song, Young K. Bell, Robert J. A. Molinaro, Annette M. Quigley, David A. Balmain, Allan Song, Jun S. Costello, Joseph F. Gustafson, W. Clay Van Dyke, Terry Kwok, Pui-Yan Khan, Javed Weiss, William A. TI The Genetics of Splicing in Neuroblastoma SO CANCER DISCOVERY LA English DT Article ID RECEPTOR-INTERACTING PROTEIN; FAR UPSTREAM ELEMENT; PROGNOSTIC-SIGNIFICANCE; EXPRESSION; CANCER; GENES; MUTATIONS; DISEASE; GENOME; ISOFORM AB Regulation of mRNA splicing, a critical and tightly regulated cellular function, underlies the majority of proteomic diversity and is frequently disrupted in disease. Using an integrative genomics approach, we combined both genomic data and exon-level transcriptome data in two somatic tissues (cerebella and peripheral ganglia) from a transgenic mouse model of neuroblastoma, a tumor that arises from the peripheral neural crest. Here, we describe splicing quantitative trait loci associated with differential splicing across the genome that we use to identify genes with previously unknown functions within the splicing pathway and to define de novo intronic splicing motifs that influence splicing from hundreds of bases away. Our results show that these splicing motifs represent sites for functional recurrent mutations and highlight novel candidate genes in human cancers, including childhood neuroblastoma. SIGNIFICANCE: Somatic mutations with predictable downstream effects are largely relegated to coding regions, which comprise less than 2% of the human genome. Using an unbiased in vivo analysis of a mouse model of neuroblastoma, we have identified intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers. (C)2015 AACR. C1 [Chen, Justin] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94158 USA. [Chen, Justin; Hackett, Christopher S.; Molinaro, Annette M.; Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Chen, Justin; Hackett, Christopher S.; Molinaro, Annette M.; Weiss, William A.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94158 USA. [Zhang, Shile] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Zhang, Shile; Song, Young K.; Khan, Javed] NCI, Oncogenom Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Bell, Robert J. A.; Molinaro, Annette M.; Quigley, David A.; Balmain, Allan; Costello, Joseph F.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Molinaro, Annette M.; Song, Jun S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA. [Quigley, David A.] Inst Canc Res, Oslo, Norway. [Song, Jun S.] Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. [Song, Jun S.] Univ Illinois, Dept Phys, Urbana, IL 61801 USA. [Gustafson, W. Clay; Weiss, William A.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Van Dyke, Terry] NCI, Mouse Canc Genet Program, Ctr Adv Preclin Res, Frederick, MD 21701 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94158 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. RP Weiss, WA (reprint author), Univ Calif San Francisco, 1450 Third St,HD-220,Room 277,MC 0520, San Francisco, CA 94158 USA. EM waweiss@gmail.com RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Weiss, William/0000-0003-2230-9132 FU NIH [CA176287, CA82103, CA102321, CA148699, CA159859, CA081403, R01CA163336]; Katie Dougherty; Pediatric Brain Tumor; St. Baldricks Foundation; Samuel G. Waxman Foundation; CureSearch Grand Challenge Award; Sontag Foundation Distinguished Scientist Award; NCI [5P30CA082103-15] FX W.A. Weiss was supported by NIH grants CA176287, CA82103, CA102321, CA148699, CA159859, and CA081403; the Katie Dougherty, Pediatric Brain Tumor, St. Baldricks, and Samuel G. Waxman Foundations; and a CureSearch Grand Challenge Award. R.J.A. Bell and J.S. Song were supported by NIH R01CA163336 and the Sontag Foundation Distinguished Scientist Award. Computational analysis was performed using the Helen Diller Family Comprehensive Cancer Center Translational Informatics PowerWulf Compute Cluster, supported by NCI 5P30CA082103-15. NR 56 TC 2 Z9 2 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD APR PY 2015 VL 5 IS 4 BP 380 EP 395 DI 10.1158/2159-8290.CD-14-0892 PG 16 WC Oncology SC Oncology GA CF2JJ UT WOS:000352373300025 PM 25637275 ER PT J AU Palmer, LG Schnermann, J AF Palmer, Lawrence G. Schnermann, Juergen TI Integrated Control of Na Transport along the Nephron SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CORTICAL COLLECTING TUBULE; GLOMERULAR-FILTRATION RATE; RENAL PROXIMAL TUBULE; DISTAL CONVOLUTED TUBULE; SODIUM-CHLORIDE COTRANSPORTER; REGULATE BLOOD-PRESSURE; THICK ASCENDING LIMB; RAT-KIDNEY; FLUID REABSORPTION; ANGIOTENSIN-II AB The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the macula densa) and the distal segments (past the macula densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, allowing the simultaneous regulation of both Na and K excretion. C1 [Palmer, Lawrence G.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Schnermann, Juergen] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Palmer, LG (reprint author), Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, 1300 York Ave, New York, NY 10065 USA. EM lgpalm@med.cornell.edu FU National Institutes of Health [R01-DK27847]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX L.G.P. acknowledges the support of Grant R01-DK27847 from the National Institutes of Health. J.S. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 133 TC 11 Z9 11 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2015 VL 10 IS 4 BP 676 EP 687 DI 10.2215/CJN.12391213 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CF3QK UT WOS:000352463400019 PM 25098598 ER PT J AU Rasooly, RS Akolkar, B Spain, LM Guill, MH Del Vecchio, CT Carroll, LE AF Rasooly, Rebekah S. Akolkar, Beena Spain, Lisa M. Guill, Michael H. Del Vecchio, Corey T. Carroll, Leslie E. TI The National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories: A Valuable Resource for Nephrology Research SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID SUSCEPTIBILITY; COHORT; DESIGN; TYPE-1 AB The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repositories, part of the National Institutes of Health (NIH), are an important resource available to researchers and the general public. The Central Repositories house samples, genetic data, phenotypic data, and study documentation from >100 NIDDK-funded clinical studies, in areas such as diabetes, digestive disease, and liver disease research. The Central Repositories also have an exceptionally rich collection of studies related to kidney disease, including the Modification of Diet in Renal Disease landmark study and recent data from the Chronic Renal Insufficiency Cohort and CKD in Children Cohort studies. The data are carefully curated and linked to the samples from the study. The NIDDK is working to make the materials and data accessible to researchers. The Data Repositories continue to improve flexible online searching tools that help researchers identify the samples or data of interest, and NIDDK has created several different paths to access the data and samples, including some funding initiatives. Over the past several years, the Central Repositories have seen steadily increasing interest and use of the stored materials. NIDDK plans to make more collections available and do more outreach and education about use of the datasets to the nephrology research community in the future to enhance the value of this resource. C1 [Rasooly, Rebekah S.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Akolkar, Beena; Spain, Lisa M.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Guill, Michael H.; Del Vecchio, Corey T.; Carroll, Leslie E.] Informat Management Serv Inc, Calverton, MD USA. RP Rasooly, RS (reprint author), NIDDK, Div Kidney Urol & Hematol Dis, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM rebekah.rasooly@nih.gov OI Rasooly, Rebekah/0000-0002-6357-5528 NR 11 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2015 VL 10 IS 4 BP 710 EP 715 DI 10.2215/CJN.06570714 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA CF3QK UT WOS:000352463400023 PM 25376765 ER PT J AU Wilson, F Ames, N Gori, D Sundaramurthi, T Navaleza, G Johnson, S Frey, M AF Wilson, Florencia Ames, Nancy Gori, Danelle Sundaramurthi, Thiruppavai Navaleza, Glenda Johnson, Susan Frey, Meredith TI Research Study Participation Promotes Leadership and Empowers Nurses to Change Practice Standards SO CRITICAL CARE NURSE LA English DT Meeting Abstract C1 [Wilson, Florencia; Ames, Nancy; Gori, Danelle; Sundaramurthi, Thiruppavai; Navaleza, Glenda; Johnson, Susan; Frey, Meredith] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 0279-5442 EI 1940-8250 J9 CRIT CARE NURSE JI Crit. Care Nurse PD APR PY 2015 VL 35 IS 2 MA EB83 BP E40 EP E41 PG 2 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA CF5VP UT WOS:000352625600047 ER PT J AU Sabino, EC Ribeiro, AL Lee, TH Oliveira, CL Carneiro-Proietti, AB Antunes, AP Menezes, MM Ianni, BM Salemi, VM Nastari, L Fernandes, F Sachdev, V Carrick, DM Deng, X Wright, D Goncalez, TT Murphy, EL Custer, B Busch, MP AF Sabino, E. C. Ribeiro, A. L. Lee, T. H. Oliveira, C. L. Carneiro-Proietti, A. B. Antunes, A. P. Menezes, M. M. Ianni, B. M. Salemi, V. M. Nastari, L. Fernandes, F. Sachdev, V. Carrick, D. M. Deng, X. Wright, D. Goncalez, T. T. Murphy, E. L. Custer, B. Busch, M. P. CA NHLBI REDS-II Int Component TI Detection of Trypanosoma cruzi DNA in blood by PCR is associated with Chagas cardiomyopathy and disease severity SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Trypanosoma cruzi; PCR; cardiomyopathy ID POLYMERASE-CHAIN-REACTION; PARASITE PERSISTENCE; HEART-DISEASE; BENZNIDAZOLE; TRIAL; PROGRESSION; MANAGEMENT; INFECTION; DIAGNOSIS; BENEFIT AB BackgroundThe significance of detection of Trypanosoma cruziDNA in blood of antibody-positive patients for risk of development of Chagas heart disease is not well established. The objective of this study was to compare detection of T. cruziDNA with known clinical and laboratory markers of Chagas cardiomyopathy (CC) severity. MethodsThis is a case-control study nested within a retrospective cohort developed in Brazil to understand the natural history of Chagas disease. The study enrolled 499 T. cruzi seropositive blood donors (SP-BD) and 488 frequency matched seronegative control donors (SN-BD) who had donated between 1996 and 2002, and 101 patients with clinically diagnosed CC. In 2008-2010 all enrolled subjects underwent a health questionnaire, medical examination, electrocardiograms and echocardiograms and polymerase chain reaction (PCR) analyses. A blinded panel of three cardiologists adjudicated the outcome of CC. Trypanosoma cruzi kinetoplast minicircle sequences were amplified by real-time PCR using an assay with a sensitivity of one parasite per 20mL of blood. All testing was performed on coded samples. ResultsRates of PCR detection of T. cruziDNA were significantly (P=0.003) higher in CC patients and SP-BD diagnosed with CC (79/105 [75.2 %]) compared with SP-BD without CC (143/279 [51.3%]). The presence of parasitaemia was significantly associated with known markers of disease progression such as QRS and QT interval duration, lower left ventricular ejection fraction, higher left ventricular index mass, and elevated troponin and NTpro-BNP levels. ConclusionTrypanosoma cruziPCR positivity is associated with presence and severity of cardiomyopathy, suggesting a direct role of parasite persistence in disease pathogenesis. C1 [Sabino, E. C.] Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Sabino, E. C.] Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil. [Sabino, E. C.] Fundacao Pro Sangue Hemoctr Sao Paulo, Sao Paulo, Brazil. [Ribeiro, A. L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ribeiro, A. L.] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Lee, T. H.; Deng, X.; Goncalez, T. T.; Murphy, E. L.; Custer, B.; Busch, M. P.] Blood Syst Res Inst, San Francisco, CA 94118 USA. [Oliveira, C. L.] Univ Fed Sao Joao del Rei, Sao Joao Del Rei, MG, Brazil. [Carneiro-Proietti, A. B.] Hemominas, Belo Horizonte, MG, Brazil. [Carneiro-Proietti, A. B.] Fac Saude & Ecol Humana FASEH, Vespasiano, MG, Brazil. [Antunes, A. P.; Menezes, M. M.] Univ Montes Claros, Ctr Ciencias Biol & Saude, Montes Claros, MG, Brazil. [Ianni, B. M.; Salemi, V. M.; Nastari, L.; Fernandes, F.] Univ Sao Paulo, Cardiomyopathy Unit, Heart Inst InCor, Fac Med, Sao Paulo, Brazil. [Sachdev, V.] NHLBI, Bethesda, MD 20892 USA. [Carrick, D. M.; Wright, D.] Westat Corp, Rockville, MD USA. [Murphy, E. L.; Custer, B.; Busch, M. P.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. RP Busch, MP (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM mbusch@bloodsystems.org RI Ribeiro, Antonio/C-2707-2009; Sabino, Ester/F-7750-2010; Mady, Charles/C-8870-2012; Fernandes, Fabio/D-5994-2012; Nastari, Luciano/C-8528-2012; Salemi, Vera/C-9104-2013; Ianni, Barbara/C-7689-2012 OI Ribeiro, Antonio/0000-0002-2740-0042; Sabino, Ester/0000-0003-2623-5126; Mady, Charles/0000-0002-8838-199X; Nastari, Luciano/0000-0002-7959-3827; Salemi, Vera/0000-0002-7152-1810; Ianni, Barbara/0000-0002-1588-5492 FU NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II), International Component [HHSN268200417175C] FX This study was supported by the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II), International Component, Contract HHSN268200417175C. NR 29 TC 9 Z9 9 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD APR PY 2015 VL 17 IS 4 BP 416 EP 423 DI 10.1002/ejhf.220 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CF1MW UT WOS:000352311100011 PM 25678239 ER PT J AU Choi, JO Daly, RC Lin, G Lahr, BD Wiste, HJ Beaver, TM Iacovoni, A Malinowski, M Friedrich, I Rouleau, JL Favaloro, RR Sopko, G Lang, IM White, HD Milano, CA Jones, RH Lee, KL Velazquez, EJ Oh, JK AF Choi, Jin-Oh Daly, Richard C. Lin, Grace Lahr, Brian D. Wiste, Heather J. Beaver, Thomas M. Iacovoni, Attilio Malinowski, Marcin Friedrich, Ivar Rouleau, Jean L. Favaloro, Roberto R. Sopko, George Lang, Irene M. White, Harvey D. Milano, Carmelo A. Jones, Robert H. Lee, Kerry L. Velazquez, Eric J. Oh, Jae K. TI Impact of surgical ventricular reconstruction on sphericity index in patients with ischaemic cardiomyopathy: follow-up from the STICH trial SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Sphericity index; Surgical ventricular reconstruction and STICH ID ANTERIOR MYOCARDIAL-INFARCTION; HEART-FAILURE; DIASTOLIC FUNCTION; RESTORATION; SURVIVAL; SHAPE; ECHOCARDIOGRAPHY; DETERMINANTS; VOLUME AB AimsWe sought to evaluate associations between baseline sphericity index (SI) and clinical outcome, and changes in SI after coronary artery bypass graft (CABG) surgery with or without surgical ventricular reconstruction (SVR) in ischaemic cardiomyopathy patients enrolled in the SVR study (Hypothesis 2) of the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods and resultsAmong 1000 patients in the STICH SVR study, we evaluated 546 patients (255 randomized to CABG alone and 291 to CABG + SVR) whose baseline SI values were available. SI was not significantly different between treatment groups at baseline. After 4 months, SI had increased in the CABG + SVR group, but was unchanged in the CABG alone group (0.690.10 to 0.77 +/- 0.12 vs. 0.67 +/- 0.07 to 0.66 +/- 0.09, respectively; P < 0.001). SI did not significantly change from 4 months to 2 years in either group. Although LV end-systolic volume and EF improved significantly more in the CABG + SVR group compared with CABG alone, the severity of mitral regurgitation significantly improved only in the CABG alone group, and the estimated LV filling pressure (E/A ratio) increased only in the CABG + SVR group. Higher baseline SI was associated with worse survival after surgery (hazard ratio 1.21, 95% confidence interval 1.02-1.43; P = 0.026). Survival was not significantly different by treatment strategy. Conclusion

Although SVR was designed to improve LV geometry, SI worsened after SVR despite improved LVEF and smaller LV volume. Survival was significantly better in patients with lower SI regardless of treatment strategy. C1 [Choi, Jin-Oh; Lin, Grace; Oh, Jae K.] Mayo Clin, Div Cardiovasc Dis, Echocardiog Core Lab, Rochester, MN 55905 USA. [Choi, Jin-Oh; Oh, Jae K.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Cardiol, Seoul, South Korea. [Daly, Richard C.] Mayo Clin, Div Cardiovasc Surg, Rochester, MN 55905 USA. [Lahr, Brian D.; Wiste, Heather J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Beaver, Thomas M.] Univ Florida, Div Thorac & Cardiovasc Surg, Gainesville, FL USA. [Iacovoni, Attilio] Osped Papa Giovanni XXIII, CardioVasc Dept, Bergamo, Italy. [Malinowski, Marcin] Med Univ Silesia, Dept Cardiac Surg, Katowice, Poland. [Friedrich, Ivar] Krankenhaus Barmherzigen Bruder, Trier, Germany. [Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Favaloro, Roberto R.] Univ Hosp Favaloro Fdn, Buenos Aires, DF, Argentina. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Lang, Irene M.] Med Univ Vienna, Dept Internal Med, Vienna, Austria. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Milano, Carmelo A.; Jones, Robert H.] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Surg Cardiothorac, Durham, NC USA. [Lee, Kerry L.] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Biostat & Bioinformat, Durham, NC USA. [Velazquez, Eric J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Med Cardiol, Durham, NC USA. RP Oh, JK (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 First St SW, Rochester, MN 55905 USA. EM oh.jae@mayo.edu RI choi, jo/O-5940-2014 FU National Heart, Lung, and Blood Institute FX This work was supported by the National Heart, Lung, and Blood Institute. NR 20 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD APR PY 2015 VL 17 IS 4 BP 453 EP 463 DI 10.1002/ejhf.256 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CF1MW UT WOS:000352311100015 PM 25779355 ER PT J AU Scuteri, A Laurent, S Cucca, F Cockcroft, J Cunha, PG Manas, L Raso, FUM Muiesan, ML Ryliskyte, L Rietzschel, E Strait, J Vlachopoulos, C Volzke, H Lakatta, EG Nilsson, PM AF Scuteri, Angelo Laurent, Stephane Cucca, Francesco Cockcroft, John Cunha, Pedro Guimaraes Rodriguez Manas, Leocadio Raso, Francesco U. Mattace Muiesan, Maria Lorenza Ryliskyte, Ligita Rietzschel, Ernst Strait, James Vlachopoulos, Charalambos Volzke, Henry Lakatta, Edward G. Nilsson, Peter M. CA Metabolic Syndrome & Arteries Res TI Metabolic syndrome across Europe: Different clusters of risk factors SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Blood pressure; epidemiology; Europe; glucose; HDL cholesterol; metabolic syndrome; triglycerides; waist circumference ID CARDIOVASCULAR EVENTS; ALL-CAUSE; MEN; METAANALYSIS; POPULATION; PREVALENCE; MORTALITY; SARDINIA; HEALTH; ADULTS AB Background: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. Methods: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose >= 110 mg/dl; low HDL cholesterol, <40mg/dl for men or <50 mg/dl for women; high triglycerides (T), >= 150 mg/dl; elevated blood pressure (B), >= 130/ >= 85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women. Results: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively). Conclusions: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries. C1 [Scuteri, Angelo] San Raffaele Pisana IRCCS, Rome, Italy. [Laurent, Stephane] INSERM, U970, Paris, France. [Laurent, Stephane] Univ Paris 05, Paris, France. [Cucca, Francesco] CNR, Cagliari, Italy. [Cockcroft, John] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. [Cunha, Pedro Guimaraes] Univ Minho, Ctr Hosp Alto Ave, Braga, Portugal. [Rodriguez Manas, Leocadio] Hosp Univ Getafe, Madrid, Spain. [Raso, Francesco U. Mattace] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Muiesan, Maria Lorenza] Univ Brescia, Brescia, Italy. [Muiesan, Maria Lorenza] 2 Med Gen Spedali Civili, Brescia, Italy. [Ryliskyte, Ligita] Vilnius Univ, Hosp Santariskiu Klinik, Vilnius, Lithuania. [Rietzschel, Ernst] Ghent Univ Hosp, Ghent, Belgium. [Rietzschel, Ernst] Univ Ghent, B-9000 Ghent, Belgium. [Strait, James; Lakatta, Edward G.] NIH, Baltimore, MD USA. [Vlachopoulos, Charalambos] Athens Med Sch, Athens, Greece. [Volzke, Henry] Univ Med Greifswald, Greifswald, Germany. [Nilsson, Peter M.] Lund Univ, Malmo, Sweden. RP Scuteri, A (reprint author), San Raffaele Pisana IRCCS, Rome, Italy. EM angeloelefante@interfree.it RI Laurent, Stephane/J-8624-2015; Cunha, Pedro/K-6743-2014 OI Cunha, Pedro/0000-0002-8518-4130 FU Fund for Scientific Research - Flanders (FWO) [G042703, G083810N]; Intramural Research Program of the NIH, National Institute on Aging; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; NIA [NO1-AG-1-2109]; Intramural Research Program of the NIH, National Institute on Aging (USA); Federal Ministry of Education and Research; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Takeda; ISCIII, Ministry of Economics and Competitiveness [RD06/0013, RD12/0043] FX The Asklepios Study is supported by the Fund for Scientific Research - Flanders (FWO research grants G042703 and G083810N).; The Baltimore Longitudinal Study of Aging (BLSA) is supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam.; The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (USA); The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; http://www.medizin.uni-greifswald.de/cm).; The SMART study was originally funded by Takeda.; The Toledo Health Study on Aging (THSA) was funded by Grants RD06/0013 and RD12/0043, ISCIII, Ministry of Economics and Competitiveness. NR 26 TC 22 Z9 22 U1 1 U2 20 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD APR PY 2015 VL 22 IS 4 BP 486 EP 491 DI 10.1177/2047487314525529 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CF8FS UT WOS:000352792100009 PM 24647805 ER PT J AU Chen, JC Desierto, MJ Feng, XM Biancotto, A Young, NS AF Chen, Jichun Desierto, Marie J. Feng, Xingmin Biancotto, Angelique Young, Neal S. TI Immune-mediated bone marrow failure in C57BL/6 mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID ACQUIRED APLASTIC-ANEMIA; RABBIT ANTITHYMOCYTE GLOBULIN; TH1 TRANSCRIPTION FACTOR; ANTI-THYMOCYTE GLOBULIN; REGULATORY T-CELLS; MOUSE MODEL; INTERFERON-GAMMA; STEM-CELLS; EXPRESSION; INFUSION AB We established a model of immune-mediated bone marrow (BM) failure in C57BL16 (B6) mice with 6.5 G total-body irradiation followed by the infusion of 4-10 x 10(6) lymph node (LN) cells/recipient from Friend leukemia virus BIN (FVB) donors. Forty-three percent of animals succumbed, with surviving animals showing marked declines in blood neutrophils, red blood cells, platelets and total BM cells at 8 to 14 days following LN cell infusion. Lowering the total-body irradiation dose to 5 G or altering the LN source from FVB to BALB/cBy donors failed to produce BM destruction. Affected animals showed significant expansion and activation of CD8 T lymphocytes in both the blood and BM; cytotoxic T cells had elevated Fas ligand expression and were oligoclonal, mainly displaying V beta 7 and V beta 17 T cell receptors. There were significant increases in blood plasma interferon gamma and tissue necrosis factor cc in affected animals. Chemokine ligands CCL3, CCL4, CCL5, CCL20, CXCL2, and CXCL5 and hematopoietic growth factors G-CSF, M-CSF, GM-CSF, VEGF were also elevated. In B6 mice carrying a Fas gene mutation, BM failure was attenuated when they were infused with FVB LN cells. Our model establishes a useful platform to define the roles of individual genes and their products in immune-mediated BM failure. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology. C1 [Chen, Jichun; Desierto, Marie J.; Feng, Xingmin; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Biancotto, Angelique; Young, Neal S.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute Intramural Research Program FX This work was supported by funds from National Heart, Lung, and Blood Institute Intramural Research Program. NR 38 TC 2 Z9 3 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD APR PY 2015 VL 43 IS 4 BP 256 EP 267 DI 10.1016/j.exphem.2014.12.006 PG 12 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA CF8QD UT WOS:000352826100001 PM 25555453 ER PT J AU Kattakuzhy, S Levy, R Kottilil, S AF Kattakuzhy, Sarah Levy, Rachel Kottilil, Shyam TI Sofosbuvir for treatment of chronic hepatitis C SO HEPATOLOGY INTERNATIONAL LA English DT Review DE Hepatitis C; Direct-acting antiviral therapy; Interferon free ID TREATMENT-NAIVE PATIENTS; HCV GENOTYPE 1; POLYMERASE INHIBITOR; PHASE-2 TRIAL; PEGYLATED INTERFERON; PLUS SOFOSBUVIR; OPEN-LABEL; INFECTION; RIBAVIRIN; VIRUS AB Chronic hepatitis C is a leading cause of liver-related morbidity and mortality worldwide. If untreated, chronic hepatitis C can progress to advanced liver fibrosis, cirrhosis, liver failure, hepatocellular carcinoma and death. Until recently, treatment of hepatitis C predominantly constituted an immunomodulatory agent, peg-interferon-alfa and ribavirin. In 2011, the first class of directly acting antiviral agents, HCV NS3/4A serine protease inhibitors, was added to peg-interferon-alfa and ribavirin with increased efficacy. In the past year, an NS5B inhibitor, sofosbuvir, has emerged as a potent agent with pangenotypic efficacy, resulting in the first interferon-free regimen for the treatment of hepatitis C. This review summarizes the data that resulted in regulatory approval of sofosbuvir and highlights the future of hepatitis C therapy with sofosbuvir as the backbone of a highly effective antiviral regimen. C1 [Kattakuzhy, Sarah; Kottilil, Shyam] Univ Maryland, Sch Med, Inst Human Virol, Div Infect Dis, Bethesda, MD USA. [Levy, Rachel; Kottilil, Shyam] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Bethesda, MD FX This study has been funded in whole with the federal funds from the intramural program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Bethesda, MD. NR 41 TC 6 Z9 6 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-0533 EI 1936-0541 J9 HEPATOL INT JI Hepatol. Int. PD APR PY 2015 VL 9 IS 2 BP 161 EP 173 DI 10.1007/s12072-014-9606-9 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CF3WQ UT WOS:000352480100003 PM 25788194 ER PT J AU Zhao, XN Usdin, K AF Zhao, Xiao-Nan Usdin, Karen TI The Transcription-Coupled Repair Protein ERCC6/CSB Also Protects Against Repeat Expansion in a Mouse Model of the Fragile X Premutation SO HUMAN MUTATION LA English DT Article DE ERCC6; CSB; fragile X syndrome; FMR1; FX-associated tremor; ataxia syndrome; FX-associated primary ovarian insufficiency ID NUCLEOTIDE EXCISION-REPAIR; FULL MUTATION; CGG REPEATS; DNA INSTABILITY; NORMAL SIZE; HUMAN-CELLS; IN-VITRO; MOSAICISM; ALLELE; MALES AB The fragile X-related disorders (FXDs) are members of the group of diseases known as the repeat expansion diseases. The FXDs result from expansion of an unstable CGG/CCG repeat tract in the 5 UTR of the FMR1 gene. Contractions are also seen, albeit at lower frequency. We have previously shown that ERCC6/CSB plays an auxiliary role in promoting germ line and somatic expansions in a mouse model of the FXDs. However, work in model systems of other repeat expansion diseases has suggested that CSB may protect against expansions by promoting contractions. Since FXD mice normally have such a high expansion frequency, it is possible that such a protective effect would have been masked. We thus examined the effect of the loss of CSB in an Msh2(+/-) background where the germ line expansion frequency is reduced and in an Msh2(-/-) background where expansions do not occur, but contractions do. Our data show that in addition to promoting repeat expansion, CSB does in fact protect the genome from germ line expansions in the FXD mouse model. However, it likely does so not by promoting contractions but by promoting an error-free process that preserves the parental allele. C1 [Zhao, Xiao-Nan; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU NIDDK, NIH [DK057808-07] FX Contract grant sponsor: Intramural program of the NIDDK, NIH (DK057808-07). NR 42 TC 4 Z9 4 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD APR PY 2015 VL 36 IS 4 BP 482 EP 487 DI 10.1002/humu.22777 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA CF1KO UT WOS:000352304200013 PM 25726753 ER PT J AU Coit, P Yalavarthi, S Ognenovski, M Zhao, WP Hasni, S Wren, JD Kaplan, MJ Sawalha, AH AF Coit, Patrick Yalavarthi, Srilakshmi Ognenovski, Mikhail Zhao, Wenpu Hasni, Sarfaraz Wren, Jonathan D. Kaplan, Mariana J. Sawalha, Amr H. TI Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Lupus; Neutrophils; Methylome; LDG; Epigenetics ID NAIVE CD4+T CELLS; RHO-GTPASES; ERYTHEMATOSUS; METHYLATION; PATHOGENESIS; MONOCYTES; DISEASE AB Recent evidence suggests that neutrophils play an important role in the pathogenesis of lupus. The goal of this study was to characterize the epigenetic architecture, by studying the DNA methylome, of neutrophils and low density granulocytes (LDGs) in lupus patients. We studied 15 lupus patients and 15 healthy age, sex, and ethnicity matched controls. Genome-wide DNA methylation was assessed using the Illumina HumanMethylation 450 BeadChip array, which includes over 485,000 methylation sites across the entire genome. Bisulfite DNA sequencing was used to validate the array results. Statistical and bioinformatic analysis was performed to identify and characterize differentially methylated loci and genes. We identified 293 differentially methylated CG sites in neutrophils between lupus patients and controls. The majority (68%) of differentially methylated CG sites were hypomethylated in lupus neutrophils compared to controls, suggesting overall hypomethylation. We found a robust and consistent demethylation of interferon signature genes in lupus neutrophils, and similar demethylation in the same genes in autologous LDGs. Indeed, the DNA methylome in lupus neutrophils and LDGs was almost identical, suggesting similar chromatin architecture in the two granulocyte subsets. A notable exception was the hypomethylation of a CG site in the promoter region of the cytoskeletonre-gulating gene RAC1 in LDGs. Our findings demonstrate a pattern of robust demethylation of interferon signature genes in lupus patients supporting a pathogenic role for neutrophils in lupus. We suggest a model whereby DNA from lupus neutrophils and LDGs externalized by NETosis enhance type-I IFN production via TLR-9 stimulation by hypomethylated DNA. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Coit, Patrick; Yalavarthi, Srilakshmi; Ognenovski, Mikhail; Sawalha, Amr H.] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. [Zhao, Wenpu; Hasni, Sarfaraz; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Wren, Jonathan D.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Program, Oklahoma City, OK 73104 USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. [Sawalha, Amr H.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Sawalha, AH (reprint author), 5520 MSRB 1,SPC 5680,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM asawalha@umich.edu FU Lupus Research Institute; Intramural Research Program, NIAMS, NIH; National Institute of Allergy and Infectious Diseases, NIH [R01AI097134] FX Research reported in this publication was supported by the Lupus Research Institute, the Intramural Research Program, NIAMS, NIH, and the National Institute of Allergy and Infectious Diseases, NIH under award number R01AI097134. NR 28 TC 24 Z9 24 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD APR PY 2015 VL 58 BP 59 EP 66 DI 10.1016/j.jaut.2015.01.004 PG 8 WC Immunology SC Immunology GA CF6KJ UT WOS:000352665300006 PM 25638528 ER PT J AU Roche, J Louis, JM Aniana, A Ghirlando, R Bax, A AF Roche, Julien Louis, John M. Aniana, Annie Ghirlando, Rodolfo Bax, Ad TI Complete dissociation of the HIV-1 gp41 ectodomain and membrane proximal regions upon phospholipid binding SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Backbone dynamics; Chemical shift perturbation; Hemagglutinin; Membrane fusion; MPER; Pre-hairpin intermediate ID INFLUENZA-VIRUS HEMAGGLUTININ; FUSION-ACTIVE CONFORMATION; MODEL-FREE APPROACH; ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE DOMAIN; PROTEIN GP41; CRYOELECTRON MICROSCOPY; ATOMIC-STRUCTURE; MEDIATED FUSION; SPANNING DOMAIN AB The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6HB trimer and the membrane affinity of gp41's ectodomain, including its membrane-proximal regions. Our solution NMR study of the structural and dynamic properties of three constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process. Interactions between the polar termini of the heptad regions, which are not associating with the lipid surface, therefore may constitute the main driving force initiating formation of the final post-fusion states. The absence of significant intermolecular ectodomain interactions in the presence of dodecyl phosphocholine highlights the importance of trimerization of gp41's transmembrane helix to prevent complete dissociation of the trimer during the course of fusion. C1 [Roche, Julien; Louis, John M.; Aniana, Annie; Bax, Ad] NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. EM bax@nih.gov FU NIH Intramural Research Program of the NIDDK; Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX We thank Drs. James Baber and Jinfa Ying for technical support and acknowledge support from the Advanced Mass Spectrometry Core of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This work was funded by the NIH Intramural Research Program of the NIDDK and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 59 TC 5 Z9 5 U1 4 U2 16 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 APR PY 2015 VL 61 IS 3-4 SI SI BP 235 EP 248 DI 10.1007/s10858-015-9900-4 PG 14 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA CF7BU UT WOS:000352711900006 PM 25631354 ER PT J AU Ravichandran, S Luke, BT Collins, JR AF Ravichandran, Sarangan Luke, Brian T. Collins, Jack R. TI Can structural features of kinase receptors provide clues on selectivity and inhibition? A molecular modeling study SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Kinase drugs; Docking; Activity; Mutation; Cross-reactivity; Biological Pathways ID GROWTH-FACTOR-RECEPTOR; ABL TYROSINE KINASE; PROTEIN-LIGAND BINDING; ACQUIRED-RESISTANCE; DRUG DISCOVERY; AUTOMATED DOCKING; LUNG-CANCER; INACTIVE CONFORMATIONS; CRYSTAL-STRUCTURES; FLEXIBLE LIGANDS AB Cancer is a complex disease resulting from the uncontrolled proliferation of cell signaling events. Protein kinases have been identified as central molecules that participate overwhelmingly in oncogenic events, thus becoming key targets for anticancer drugs. A majority of studies converged on the idea that ligand-binding pockets of kinases retain clues to the inhibiting abilities and cross-reacting tendencies of inhibitor drugs. Even though these ideas are critical for drug discovery, validating them using experiments is not only difficult, but also in some cases infeasible. To overcome these limitations and to test these ideas at the molecular level, we present here the results of receptor-focused in-silico docking of nine marketed drugs to 19 different wild-type and mutated kinases chosen from a wide range of families. This investigation highlights the need for using relevant models to explain the correct inhibition trends and the results are used to make predictions that might be able to influence future experiments. Our simulation studies are able to correctly predict the primary targets for each drug studied in majority of cases and our results agree with the existing findings. Our study shows that the conformations a given receptor acquires during kinase activation, and their micro-environment, defines the ligand partners. Type II drugs display high compatibility and selectivity for DFG-out kinase conformations. On the other hand Type I drugs are less selective and show binding preferences for both the open and closed forms of selected kinases. Using this receptor-focused approach, it is possible to capture the observed fold change in binding affinities between the wild-type and disease-centric mutations in ABL kinase for Imatinib and the second-generation ABL drugs. The effects of mutation are also investigated for two other systems, EGFR and B-Raf. Finally, by including pathway information in the design it is possible to model kinase inhibitors with potentially fewer side-effects. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. C1 [Ravichandran, Sarangan; Luke, Brian T.; Collins, Jack R.] Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Ravichandran, S (reprint author), Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, POB B, Frederick, MD 21702 USA. EM ravichandrans@mail.nih.gov OI RAVICHANDRAN, SARANGAN/0000-0001-6349-0172 FU National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX This work was supported in part by funds from the National Cancer Institute/National Institutes of Health contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. There are no financial conflicts. The authors wish to thank the anonymous reviewer for the helpful comments. NR 72 TC 1 Z9 1 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 EI 1873-4243 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD APR PY 2015 VL 57 BP 36 EP 48 DI 10.1016/j.jmgm.2014.12.007 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA CG1AG UT WOS:000353004800005 PM 25635590 ER PT J AU Deac, OM Mills, JL Shane, B Midttun, O Ueland, PM Brosnan, JT Brosnan, ME Laird, E Gibney, ER Fan, RZ Wang, YF Brody, LC Molloy, AM AF Deac, Oana M. Mills, James L. Shane, Barry Midttun, Oivind Ueland, Per M. Brosnan, John T. Brosnan, Margaret E. Laird, Eamon Gibney, Eileen R. Fan, Ruzong Wang, Yifan Brody, Lawrence C. Molloy, Anne M. TI Tryptophan Catabolism and Vitamin B-6 Status Are Affected by Gender and Lifestyle Factors in Healthy Young Adults SO JOURNAL OF NUTRITION LA English DT Article DE tryptophan; kynurenine; 3-hydroxykynurenine; pyridoxal 5 '-phosphate; vitamin B-6; protein ID KYNURENINE PATHWAY METABOLITES; ORAL CONTRACEPTIVE PILL; FOLATE CONCENTRATIONS; PYRIDOXAL-PHOSPHATE; CANCER RISK; INFLAMMATION; PLASMA; ACID; NUTRITION; 3-HYDROXYKYNURENINE AB Background: Abnormalities of tryptophan (Trp) metabolism through the kynurenine (Kyn) pathway have been reported in various diseases; however, nutritional and lifestyle factors that affect this pathway in healthy individuals are not well documented. Objective: Our aim was to examine the effect of vitamin B-6 status and lifestyle factors including the use of vitamin B-6 supplements, alcohol, smoking, and oral contraceptives On Trp and its Kyn metabolites in a cohort of 2436 healthy young adults aged 18-28 y. Methods: Anthropometric and lifestyle data were collected by questionnaire. Participants provided blood samples for analysis of Tip, Kyn, anthranilic acid, kynurenic acid (KA), 3-hydroxykynurenine (HK), 3-hydroxyanthranilic acid (HAA), and xanthurenic acid (XA). Vitamin B-6 species were also measured. Results: Serum Tip metabolites were 10-15% higher among men (n = 993) compared with women (n = 1443; P < 0.0001), except for HK and XA. In all participants, serum Tip was positively associated with plasma pyridoxal 5'-phosphate (PLP; r= 0.28, P< 0.0001), reaching a plateau at PLP concentrations of similar to 83 nmol/L. HK was inversely associated with PLP (r= -0.14, P< 0.01). Users of vitamin 8-6 supplements (n = 671) had 6% lower concentrations of HK than nonusers (n = 1765; P = 0.0006). Oral contraceptive users (n = 385) had lower concentrations of KA (20.7%) but higher XA (24.1%) and HAA (9.0%) than did nonusers (n = 1058; P <,0.0001). After adjustment for gender and other lifestyle variables, XA concentrations were 16% higher in heavy drinkers In = 713) than in never or occasional drinkers In = 975; P = 0.0007). Concentrations of 2 other essential amino acids, methionine and arginine, also were positively associated with serum Trp (r = 0.65 and 0.33, respectively; P < 0.0001). Conclusions: In this population of healthy young adults, gender has the largest influence on serum Kyn metabolite concentrations. The significant covariance of Trp with unrelated amino acids suggests that protein intake may be an important consideration in evaluating Kyn metabolism. C1 [Deac, Oana M.; Molloy, Anne M.] Univ Dublin Trinity Coll, Sch Med, Dublin 2, Ireland. [Laird, Eamon; Molloy, Anne M.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Mills, James L.; Fan, Ruzong; Wang, Yifan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Shane, Barry] Univ Calif Berkeley, Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Midttun, Oivind] Bevital AS, Bergen, Norway. [Ueland, Per M.] Univ Bergen, Inst Med, Sect Pharmacol, Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, N-5021 Bergen, Norway. [Brosnan, John T.; Brosnan, Margaret E.] Mem Univ, Dept Biochem, St John, NF, Canada. [Gibney, Eileen R.] Univ Coll Dublin, Inst Food & Hlth, Dublin 2, Ireland. [Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Molloy, AM (reprint author), Univ Dublin Trinity Coll, Sch Med, Dublin 2, Ireland. EM amolloy@tcd.ie RI Ueland, Per/C-7340-2013; OI Molloy, Anne/0000-0002-1688-9049; Laird, Eamon/0000-0003-4225-5223 FU Health Research Board, Ireland; Intramural Research Program of the Eunice Kennedy Shover National Institute of Child Health and Human Development, NIH, Bethesda, MD [N01HD33348] FX Supported by the Health Research Board, Ireland, and the Intramural Research Program of the Eunice Kennedy Shover National Institute of Child Health and Human Development, NIH, Bethesda, MD (contract N01HD33348) NR 50 TC 7 Z9 7 U1 0 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD APR PY 2015 VL 145 IS 4 BP 701 EP 707 DI 10.3945/jn.114.203091 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CE9RG UT WOS:000352180500005 PM 25833774 ER PT J AU Hansen, JG Tang, WB Hootman, KC Brannon, PM Houston, DK Kritchevsky, SB Harris, TB Garcia, M Lohman, K Liu, YM de Boer, IH Kestenbaum, BR Robinson-Cohen, C Siscovick, DS Cassano, PA AF Hansen, Joyanna G. Tang, Wenbo Hootman, Katie C. Brannon, Patsy M. Houston, Denise K. Kritchevsky, Stephen B. Harris, Tamara B. Garcia, Melissa Lohman, Kurt Liu, Yongmei de Boer, Ian H. Kestenbaum, Bryan R. Robinson-Cohen, Cassianne Siscovick, David S. Cassano, Patricia A. TI Genetic and Environmental Factors Are Associated with Serum 25-Hydroxyvitamin D Concentrations in Older African Americans SO JOURNAL OF NUTRITION LA English DT Article DE vitamin D; 25-hydroxyvitamin D; supplements; GC; GCTA; rs7041 ID D-BINDING PROTEIN; VITAMIN-D INSUFFICIENCY; GENOME-WIDE ASSOCIATION; ELDERLY POPULATION; D DEFICIENCY; SKIN COLOR; DETERMINANTS; ATHEROSCLEROSIS; GC; VARIANTS AB Background: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. Objective: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. Methods: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Results: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-p,g/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P= 0.04). Twenty-three percent (95% Cl: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. Conclusions: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans. C1 [Hansen, Joyanna G.; Tang, Wenbo; Hootman, Katie C.; Brannon, Patsy M.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Lohman, Kurt] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Harris, Tamara B.; Garcia, Melissa] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [de Boer, Ian H.; Kestenbaum, Bryan R.; Robinson-Cohen, Cassianne] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [de Boer, Ian H.; Kestenbaum, Bryan R.; Robinson-Cohen, Cassianne] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Div Biostat & Epidemiol, Dept Healthcare Policy & Res, New York, NY USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM pac6@cornell.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU NIH, National Heart, Lung, and Blood Institute [R03 HL095414]; Ruth L Kirschstein National Research Service Award Institutional Research Training grant [T32-DK-7158-36]; National Institute on Aging [N01AG62101, N01AG62103, N01AG62106, R01AG029364, R01-AG032098-01A1]; NIH [HHSN268200782096C]; NIH, National Institute on Aging; National Heart, Lung, and Blood Institute [R01HL096875, RR-024156, N02-HL-6-4278, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169]; [RC1-AG035835] FX Supported by NIH, National Heart, Lung, and Blood Institute R03 HL095414 (to PAC), by RC1-AG035835 (to SBK, Principal Investigator; to PAC, subcontract Principal Investigator), and by Ruth L Kirschstein National Research Service Award Institutional Research Training grant T32-DK-7158-36 (to JGH). This research was also supported by National Institute on Aging contracts N01AG62101, N01AG62103, N01AG62106, and R01AG029364. The Health, Aging, and Body Composition (Health ABC) Study genome-wide association study was funded by National Institute on Aging grant R01-AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). The CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The Multi-Ethnic Study of Atherosclerosis (MESA) cohort study and MESA SHARe genotyping were supported by grants R01HL096875, RR-024156, N02-HL-6-4278, and N01HC95159 through N01HC95169 from the National Heart, Lung, and Blood Institute. NR 49 TC 6 Z9 6 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD APR PY 2015 VL 145 IS 4 BP 799 EP 805 DI 10.3945/jn.114.202093 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CE9RG UT WOS:000352180500018 PM 25716552 ER PT J AU Kulkarni, A Prochazkova, M Terse, A Hall, B AF Kulkarni, A. Prochazkova, M. Terse, A. Hall, B. TI Cdk5 is an important modulator of mechanical, thermal and chemical pain SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Kulkarni, A.; Prochazkova, M.; Terse, A.; Hall, B.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2015 VL 16 IS 4 SU 1 MA 263 BP S41 EP S41 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CF7PK UT WOS:000352748600165 ER PT J AU Low, L Hyson, L Rauf, I Pitcher, M Bushnell, M AF Low, L. Hyson, L. Rauf, I. Pitcher, M. Bushnell, M. TI Restraint stress training for awake rodent MR imaging causes stress-induced analgesia SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Low, L.; Hyson, L.; Rauf, I.; Pitcher, M.; Bushnell, M.] NCCAM, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2015 VL 16 IS 4 SU 1 MA 306 BP S52 EP S52 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CF7PK UT WOS:000352748600208 ER PT J AU Mannes, A Goswami, S Gross, J Gonnella, G Keller, J Kominsky, H Iadarola, M AF Mannes, A. Goswami, S. Gross, J. Gonnella, G. Keller, J. Kominsky, H. Iadarola, M. TI Systems analyses of RNA-Seq transcriptomic responses in peripheral tissue, DRG and dorsal horn during carrageenan-induced inflammation SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Mannes, A.; Goswami, S.; Gross, J.; Gonnella, G.; Keller, J.; Kominsky, H.; Iadarola, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2015 VL 16 IS 4 SU 1 MA 253 BP S39 EP S39 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CF7PK UT WOS:000352748600155 ER PT J AU Vaughan, K Darbari, D Chadwick, K Seamon, C Diaw, L Quinn, M Waclawiw, M Wallen, G Belfer, I Taylor, J AF Vaughan, K. Darbari, D. Chadwick, K. Seamon, C. Diaw, L. Quinn, M. Waclawiw, M. Wallen, G. Belfer, I. Taylor, J. TI Temporal summation testing provides evidence for increased pain sensitivity and central sensitization in sickle cell anemia SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Vaughan, K.; Darbari, D.; Chadwick, K.; Seamon, C.; Diaw, L.; Quinn, M.; Waclawiw, M.; Wallen, G.; Belfer, I.; Taylor, J.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2015 VL 16 IS 4 SU 1 MA 233 BP S34 EP S34 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CF7PK UT WOS:000352748600135 ER PT J AU Yu, XB Decker, KB Barker, K Neunuebel, MR Saul, J Graves, M Westcott, N Hang, HW LaBaer, J Qiu, J Machner, MP AF Yu, Xiaobo Decker, Kimberly B. Barker, Kristi Neunuebel, M. Ramona Saul, Justin Graves, Morgan Westcott, Nathan Hang, Howard LaBaer, Joshua Qiu, Ji Machner, Matthias P. TI Host-Pathogen Interaction Profiling Using Self-Assembling Human Protein Arrays SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE nucleic acid programmable protein array (NAPPA); interactome; LidA; SidM Rab1; AMPylation ID RAB GTPASE FUNCTION; LEGIONELLA-PNEUMOPHILA; POSTTRANSLATIONAL MODIFICATIONS; GLUCOSYLTRANSFERASE LGT1; NUCLEOTIDE-EXCHANGE; RHO GTPASES; AMPYLATION; MICROARRAYS; VACUOLES; MODULATION AB Host-pathogen protein interactions are fundamental to every microbial infection, yet their identification has remained challenging due to the lack of simple detection tools that avoid abundance biases while providing an open format for experimental modifications. Here, we applied the Nucleic Acid-Programmable Protein Array and a HaloTag-Halo ligand detection system to determine the interaction network of Legionella pneumophila effectors (SidM and LidA) with 10 000 unique human proteins. We identified known targets of these L. pneumophila proteins and potentially novel interaction candidates. In addition, we applied our Click chemistry-based NAPPA platform to identify the substrates for SidM, an effector with an adenylyl transferase domain that catalyzes AMPylation (adenylylation), the covalent addition of adenosine monophosphate (AMP). We confirmed a subset of the novel SidM and LidA targets in independent in vitro pull-down and in vivo cell-based assays, and provided further insight into how these effectors may discriminate between different host Rab GTPases. Our method circumvents the purification of thousands of human and pathogen proteins, and does not require antibodies against or prelabeling of query proteins. This system is amenable to high-throughput analysis of effectors from a wide variety of human pathogens that may bind to and/or post-translationally modify targets within the human proteome. C1 [Yu, Xiaobo; Barker, Kristi; Saul, Justin; Graves, Morgan; LaBaer, Joshua; Qiu, Ji] Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ 85287 USA. [Decker, Kimberly B.; Neunuebel, M. Ramona; Machner, Matthias P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Microbial Pathogenesis Unit, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Westcott, Nathan; Hang, Howard] Rockefeller Univ, Lab Chem Biol & Microbial Pathogenesis, New York, NY 10065 USA. RP LaBaer, J (reprint author), Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ 85287 USA. EM joshua.labaer@asu.edu; ji.qiu@asu.edu; machnerm@mail.nih.gov RI Yu, Xiaobo/F-5997-2015; Machner, Matthias/G-2758-2015 FU NIH; Leukemia & Lymphoma Society [5210-14] FX This work was funded by the Intramural Research Program of NIH (K.B.D., M.R.N., M.P.M.) and the Leukemia & Lymphoma Society (5210-14 to N.W.). We thank Jie Wang and Xiaofang Bian for the fabrication of NAPPA, and Lerys Del Moral for the technical assistance. NR 65 TC 6 Z9 6 U1 3 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 APR PY 2015 VL 14 IS 4 BP 1920 EP 1936 DI 10.1021/pr5013015 PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CF3QJ UT WOS:000352463300025 PM 25739981 ER PT J AU Li, F Yang, XW Krausz, KW Nichols, RG Xu, W Patterson, AD Gonzalez, FJ AF Li, Fei Yang, Xiu-Wei Krausz, Kristopher W. Nichols, Robert G. Xu, Wei Patterson, Andrew D. Gonzalez, Frank J. TI Modulation of Colon Cancer by Nutmeg SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Colon cancer; nutmeg uremic toxin; inflammation; metabolomics; mass spectrometry ID INFLAMMATORY-BOWEL-DISEASE; HUMAN COLORECTAL-CANCER; MYRISTICA-FRAGRANS; HELICOBACTER-PYLORI; MASS-SPECTROMETRY; UREMIC TOXINS; INDOXYL SULFATE; METABOLOMICS; MICE; METABOLISM AB Colon cancer is the most common cancer and the third leading cause of cancer mortality in humans. Using mass spectrometry-based metabolomics, the current study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with an increase in the expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, which exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apc(min/+) mice. Nutmeg-treated Apc(min/+) mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible, in part, for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link among gut microbial metabolism, inflammation, and metabolic disorders and suggest that modulation of gut microbiota and lipid metabolism using dietary intervention or drugs may be effective in colon cancer chemoprevention strategies. C1 [Li, Fei; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Li, Fei] Jiangxi Univ Tradit Chinese Med, Res Ctr Differentiat & Dev Basic Theory Tradit Ch, Nanchang 330004, Peoples R China. [Yang, Xiu-Wei; Xu, Wei] Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs,Dept Nat Med, Beijing 100191, Peoples R China. [Nichols, Robert G.; Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RP Yang, XW (reprint author), Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs,Dept Nat Med, Beijing 100191, Peoples R China. EM xwyang@bjmu.edu.cn; gonzalef@mail.nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 FU U.S.-China Program for Biomedical Collaborative Research; National Cancer Institute Intramural Research Program; National Natural Science Foundation of China [30973863, 81161120429, 81360509] FX The authors thank Drs. Naoki Tanaka and Changtao Jiang for assistance with the culture of primary hepatocytes and Caco-2 cells, respectively. This work was supported by a grant from the U.S.-China Program for Biomedical Collaborative Research and the National Cancer Institute Intramural Research Program to F.J.G., the National Natural Science Foundation of China (30973863 and 81161120429) to X.Y., and the National Natural Science Foundation of China (81360509) to F.L. NR 53 TC 5 Z9 5 U1 3 U2 27 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 APR PY 2015 VL 14 IS 4 BP 1937 EP 1946 DI 10.1021/pr5013152 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CF3QJ UT WOS:000352463300026 PM 25712450 ER PT J AU Chen, M Wu, R Mattson, MP AF Chen, M. Wu, R. Mattson, M. P. TI O-linked N-acetylglucosamine (O-GlcNAc) regulates mitophagy in Neuro2a cells SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Chen, M.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Chen, M.; Wu, R.; Mattson, M. P.] NIA, Intramural Res Program, Baltimore, MD 21224 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2015 VL 63 SU 1 SI SI MA B147 BP S144 EP S144 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900400 ER PT J AU Huisingh-Scheetz, M Wroblewski, K Hue, T Newman, A Satterfield, S Harris, T Schoeller, D AF Huisingh-Scheetz, M. Wroblewski, K. Hue, T. Newman, A. Satterfield, S. Harris, T. Schoeller, D. TI Resting Metabolic Rate and Frailty in the Health, Aging, and Body Composition Study: Variation by Gender SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Huisingh-Scheetz, M.; Wroblewski, K.] Univ Chicago, Chicago, IL 60637 USA. [Hue, T.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, A.] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee, Memphis, TN USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Schoeller, D.] Univ Wisconsin, Madison, WI USA. NR 0 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 APR PY 2015 VL 63 SU 1 SI SI MA B83 BP S120 EP S120 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900336 ER PT J AU Marcum, Z Perera, S Thorpe, J Switzer, G Castle, N Strotmeyer, E Simonsick, E Ayonayon, H Phillips, C Rubin, S Zucker-Levin, A Bauer, D Shorr, RI Hanlon, J AF Marcum, Z. Perera, S. Thorpe, J. Switzer, G. Castle, N. Strotmeyer, E. Simonsick, E. Ayonayon, H. Phillips, C. Rubin, S. Zucker-Levin, A. Bauer, D. Shorr, R. I. Hanlon, J. TI Antidepressant use and recurrent falls in community dwelling older adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Marcum, Z.; Perera, S.; Hanlon, J.] Univ Pittsburgh, Geriatr Med, Pittsburgh, PA USA. [Thorpe, J.; Switzer, G.; Castle, N.; Strotmeyer, E.] Univ Pittsburgh, Pittsburgh, PA USA. [Simonsick, E.; Phillips, C.] NIA, Baltimore, MD 21224 USA. [Ayonayon, H.; Rubin, S.; Bauer, D.] UCSF, San Francisco, CA USA. [Zucker-Levin, A.] UTHSC, Memphis, TN USA. [Shorr, R. I.] GRECC, VAMC, Gainesville, FL 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2015 VL 63 SU 1 SI SI MA B90 BP S123 EP S123 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900343 ER PT J AU Nadkarni, NK Studenski, SA Lopez, O Perera, S Snitz, BE Mathis, C Cohen, AD Nebes, R Klunk, WE AF Nadkarni, N. K. Studenski, S. A. Lopez, O. Perera, S. Snitz, B. E. Mathis, C. Cohen, A. D. Nebes, R. Klunk, W. E. TI The Cognition-Mobility Interface (COMBINE), Amyloid Deposition and Glucose Metabolism in Cognitively Intact Older Adults Without Mobility Problems SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Nadkarni, N. K.; Perera, S.] Univ Pittsburgh, MED GERIATR MED, Pittsburgh, PA USA. [Studenski, S. A.] NIA, Baltimore, MD 21224 USA. [Lopez, O.; Snitz, B. E.] Univ Pittsburgh, Neurol, Pittsburgh, PA USA. [Mathis, C.; Klunk, W. E.] Univ Pittsburgh, Radiol, Pittsburgh, PA USA. [Cohen, A. D.; Nebes, R.; Klunk, W. E.] Univ Pittsburgh, Psychiat, Pittsburgh, PA 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2015 VL 63 SU 1 SI SI MA B150 BP S145 EP S145 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900403 ER PT J AU Naples, JG Marcum, Z Perera, S Gray, SL Newman, AB Shorr, RI Simonsick, EM Yaffe, K Hanlon, J AF Naples, J. G. Marcum, Z. Perera, S. Gray, S. L. Newman, A. B. Shorr, R. I. Simonsick, E. M. Yaffe, K. Hanlon, J. TI Concordance Among Anticholinergic Burden Scales SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Naples, J. G.; Perera, S.; Newman, A. B.; Hanlon, J.] Univ Pittsburgh, Pittsburgh, PA USA. [Marcum, Z.; Gray, S. L.] Univ Washington, Seattle, WA 98195 USA. [Shorr, R. I.] North FL South GA VA GRECC, Gainesville, FL USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. [Hanlon, J.] VA Healthcare Syst, Pittsburgh, PA 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 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2015 VL 63 SU 1 SI SI MA P17 BP S7 EP S7 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900018 ER PT J AU Uechi, M Inaba, M Chen, R Ross, G White, L Abbott, R Petrovich, H Launer, L Bell, C Masaki, K AF Uechi, M. Inaba, M. Chen, R. Ross, G. White, L. Abbott, R. Petrovich, H. Launer, L. Bell, C. Masaki, K. TI Slow Reaction Time Predicts Increased Risk of Incident Dementia: The Honolulu-Asia Aging Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society (AGS) CY MAY 10-17, 2015 CL National Harbor, MD SP Amer Geriatr Soc C1 [Uechi, M.; Inaba, M.; Ross, G.; White, L.; Abbott, R.; Petrovich, H.; Bell, C.; Masaki, K.] Univ Hawaii, Dept Geriatr Med, Honolulu, HI 96822 USA. [Chen, R.; Masaki, K.] Kuakini Med Ctr, Honolulu, HI USA. [Ross, G.] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Abbott, R.] Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan. [Launer, L.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2015 VL 63 SU 1 SI SI MA B149 BP S144 EP S145 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CF5EL UT WOS:000352578900402 ER PT J AU Freitag, DF Butterworth, AS Willeit, P Howson, JMM Burgess, S Kaptoge, S Young, R Ho, WK Wood, AM Sweeting, M Spackman, S Staley, JR Ramond, A Harshfield, E Nielsen, SF Grande, P Lange, LA Bown, MJ Jones, GT Scott, RA Bevan, S Porcu, E Thorleifsson, G Zeng, LY Kessler, T Nikpay, M Do, R Zhang, WH Hopewell, JC Kleber, M Delgado, GE Nelson, CP Goel, A Bis, JC Dehghan, A Ligthart, S Smith, AV Qu, LM van 't Hof, FNG de Bakker, PIW Baas, AF van Rij, A Tromp, G Kuivaniemi, H Ritchie, MD Verma, SS Crawford, DC Malinowski, J de Andrade, M Kullo, IJ Peissig, PL McCarty, CA Bottinger, EP Gottesman, O Crosslin, DR Carrell, DS Rasmussen-Torvik, LJ Pacheco, JA Huang, J Timpson, NJ Kettunen, J Ala-Korpela, M Mitchell, GF Parsa, A Wilkinson, IB Gorski, M Li, Y Franceschini, N Keller, MF Ganesh, SK Langefeld, CD Bruijn, L Brown, MA Evans, DM Baltic, S Ferreira, MA Baurecht, H Weidinger, S Franke, A Lubitz, SA Muller-Nurasyid, M Felix, JF Smith, NL Sudman, M Thompson, SD Zeggini, E Panoutsopoulou, K Nalls, MA Singleton, A Polychronakos, C Bradfield, JP Hakonarson, H Easton, DF Thompson, D Tomlinson, IP Dunlop, M Hemminki, K Morgan, G Eisen, T Goldschmidt, H Allan, JM Henrion, M Whiffin, N Wang, YF Chubb, D Houlston, RS Iles, MM Bishop, DT Law, MH Hayward, NK Luo, Y Nejentsev, S Barbalic, M Crossman, D Sanna, S Soranzo, N Markus, HS Wareham, NJ Rader, DJ Reilly, M Assimes, T Harris, TB Hofman, A Franco, OH Gudnason, V Tracy, R Psaty, BM Farrall, M Watkins, H Hall, AS Samani, NJ Marz, W Clarke, R Collins, R Kooner, JS Chambers, JC Kathiresan, S McPherson, R Erdmann, J Kastrati, A Schunkert, H Stefansson, K Thorsteinsdottir, U Walston, JD Tybjaerg-Hansen, A Alam, DS Majumder, AA Di Angelantonio, E Chowdhury, R Nordestgaard, BG Saleheen, D Thompson, SG Danesh, J AF Freitag, Daniel F. Butterworth, Adam S. Willeit, Peter Howson, Joanna M. M. Burgess, Stephen Kaptoge, Stephen Young, Robin Ho, Weang Kee Wood, Angela M. Sweeting, Michael Spackman, Sarah Staley, James R. Ramond, Anna Harshfield, Eric Nielsen, Sune F. Grande, Peer Lange, Leslie A. Bown, Matthew J. Jones, Gregory T. Scott, Robert A. Bevan, Steve Porcu, Eleonora Thorleifsson, Gudmar Zeng, Lingyao Kessler, Thorsten Nikpay, Majid Do, Ron Zhang, Weihua Hopewell, Jemma C. Kleber, Marcus Delgado, Graciela E. Nelson, Christopher P. Goel, Anuj Bis, Joshua C. Dehghan, Abbas Ligthart, Symen Smith, Albert V. Qu, Liming van 't Hof, Femke N. G. de Bakker, Paul I. W. Baas, Annette F. van Rij, Andre Tromp, Gerard Kuivaniemi, Helena Ritchie, Marylyn D. Verma, Shefali S. Crawford, Dana C. Malinowski, Jennifer de Andrade, Mariza Kullo, Iftikhar J. Peissig, Peggy L. McCarty, Catherine A. Boettinger, Erwin P. Gottesman, Omri Crosslin, David R. Carrell, David S. Rasmussen-Torvik, Laura J. Pacheco, Jennifer A. Huang, Jie Timpson, Nicholas J. Kettunen, Johannes Ala-Korpela, Mika Mitchell, Gary F. Parsa, Afshin Wilkinson, Ian B. Gorski, Mathias Li, Yong Franceschini, Nora Keller, Margaux F. Ganesh, Santhi K. Langefeld, Carl D. Bruijn, Lucie Brown, Matthew A. Evans, David M. Baltic, Svetlana Ferreira, Manuel A. Baurecht, Hansjoerg Weidinger, Stephan Franke, Andre Lubitz, Steven A. Mueller-Nurasyid, Martina Felix, Janine F. Smith, Nicholas L. Sudman, Marc Thompson, Susan D. Zeggini, Eleftheria Panoutsopoulou, Kalliope Nalls, Mike A. Singleton, Andrew Polychronakos, Constantin Bradfield, Jonathan P. Hakonarson, Hakon Easton, Douglas F. Thompson, Deborah Tomlinson, Ian P. Dunlop, Malcolm Hemminki, Kari Morgan, Gareth Eisen, Timothy Goldschmidt, Hartmut Allan, James M. Henrion, Marc Whiffin, Nicola Wang, Yufei Chubb, Daniel Houlston, Richard S. Iles, Mark M. Bishop, D. Timothy Law, Matthew H. Hayward, Nicholas K. Luo, Yang Nejentsev, Sergey Barbalic, Maja Crossman, David Sanna, Serena Soranzo, Nicole Markus, Hugh S. Wareham, Nicholas J. Rader, Daniel J. Reilly, Muredach Assimes, Themistocles Harris, Tamara B. Hofman, Albert Franco, Oscar H. Gudnason, Vilmundur Tracy, Russell Psaty, Bruce M. Farrall, Martin Watkins, Hugh Hall, Alistair S. Samani, Nilesh J. Maerz, Winfried Clarke, Robert Collins, Rory Kooner, Jaspal S. Chambers, John C. Kathiresan, Sekar McPherson, Ruth Erdmann, Jeanette Kastrati, Adnan Schunkert, Heribert Stefansson, Kari Thorsteinsdottir, Unnur Walston, Jeremy D. Tybjaerg-Hansen, Anne Alam, Dewan S. Majumder, Abdullah Al Shafi Di Angelantonio, Emanuele Chowdhury, Rajiv Nordestgaard, Borge G. Saleheen, Danish Thompson, Simon G. Danesh, John CA Interleukin 1 Genetics Consortium European Prospective Invest Canc Aneurysm Consortium Elect Med Records & Genomics Netwo UK 10K Consortium European Prospective Invest Canc METASTROKE Consortium Chronic Kidney Dis Genetics Consor Cohorts Heart & Aging Res Genomic Australo-Anglo-Amer Spondyloarthri Australian Asthma Genetics Consort Atrial Fribrillation Genetics Cons Cohorts Heart & Aging Res Genomic Consortium Juvenile Arthritis Gene Arthritis Res UK Osteoarthritis Ge Int Parkinson's Dis Consortium Breast Canc Assoc Consortium Melanoma Genetics Consortium Cohorts Heart & Aging Res Genomic Myocardial Infarction Genetics Con TI Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID ABDOMINAL AORTIC-ANEURYSM; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; PLACEBO-CONTROLLED TRIAL; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCUS; SEQUENCE VARIANT; COMMON VARIANTS; HEART-DISEASE; DOUBLE-BLIND AB Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND. C1 [Freitag, Daniel F.; Butterworth, Adam S.; Willeit, Peter; Howson, Joanna M. M.; Burgess, Stephen; Kaptoge, Stephen; Young, Robin; Ho, Weang Kee; Wood, Angela M.; Sweeting, Michael; Spackman, Sarah; Staley, James R.; Ramond, Anna; Harshfield, Eric; Bevan, Steve; Wilkinson, Ian B.; Easton, Douglas F.; Thompson, Deborah; Nejentsev, Sergey; Markus, Hugh S.; Di Angelantonio, Emanuele; Chowdhury, Rajiv; Saleheen, Danish; Thompson, Simon G.; Danesh, John] Univ Cambridge, Cambridge CB1 8RN, England. [Nielsen, Sune F.; Grande, Peer; Tybjaerg-Hansen, Anne; Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark. [Lange, Leslie A.; Franceschini, Nora] Univ N Carolina, Chapel Hill, NC USA. [Nelson, Christopher P.; Brown, Matthew A.; Samani, Nilesh J.] Univ Leicester, Leicester, Leics, England. [Nelson, Christopher P.; Brown, Matthew A.; Samani, Nilesh J.] Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England. [Jones, Gregory T.; van Rij, Andre] Univ Otago, Dunedin, New Zealand. [Scott, Robert A.; Wareham, Nicholas J.] MRC, Epidemiol Unit, Cambridge, England. [Porcu, Eleonora; Sanna, Serena] Ist Ric Genet & Biomed, Monserrato, Italy. [Thorleifsson, Gudmar; Stefansson, Kari; Thorsteinsdottir, Unnur] deCODE Genet Amgen, Reykjavik, Iceland. [Zeng, Lingyao; Kessler, Thorsten; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Zeng, Lingyao; Kessler, Thorsten; Mueller-Nurasyid, Martina; Kastrati, Adnan; Schunkert, Heribert] German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada. [Do, Ron; Kathiresan, Sekar] Broad Inst, Cambridge, England. [Do, Ron; Lubitz, Steven A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhang, Weihua; Kooner, Jaspal S.; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Hopewell, Jemma C.; Goel, Anuj; Farrall, Martin; Clarke, Robert; Collins, Rory] Univ Oxford, Oxford, England. [Kleber, Marcus; Delgado, Graciela E.; Goldschmidt, Hartmut] Heidelberg Univ, Heidelberg, Germany. [Bis, Joshua C.; Crosslin, David R.; Smith, Nicholas L.; Psaty, Bruce M.] Univ Washington, Seattle, WA 98195 USA. [Dehghan, Abbas; Ligthart, Symen; Felix, Janine F.; Hofman, Albert; Franco, Oscar H.] Univ Med Ctr Rotterdam, Erasmus Med Ctr, Rotterdam, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Reykjavik, Iceland. [Qu, Liming; Saleheen, Danish] Univ Penn, Philadelphia, PA 19104 USA. [van 't Hof, Femke N. G.; de Bakker, Paul I. W.; Baas, Annette F.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Tromp, Gerard; Kuivaniemi, Helena] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [Ritchie, Marylyn D.; Verma, Shefali S.] Penn State Univ, University Pk, PA 16802 USA. [Crawford, Dana C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Malinowski, Jennifer] Yale Univ, New Haven, CT USA. [de Andrade, Mariza; Kullo, Iftikhar J.] Mayo Clin, Rochester, MN USA. [Peissig, Peggy L.] Marshfield Clin Res Fdn, Marshfield, WI USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Div Res, Duluth, MN USA. [Boettinger, Erwin P.; Gottesman, Omri] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Carrell, David S.] Grp Hlth Res Inst, Seattle, WA USA. [Rasmussen-Torvik, Laura J.; Pacheco, Jennifer A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Huang, Jie; Zeggini, Eleftheria; Panoutsopoulou, Kalliope; Luo, Yang; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge, England. [Timpson, Nicholas J.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Kettunen, Johannes; Ala-Korpela, Mika] Univ Oulu, Oulu, Finland. [Kettunen, Johannes] Natl Inst Hlth & Welf, Helsinki, Finland. [Ala-Korpela, Mika] Univ Bristol, Bristol, Avon, England. [Parsa, Afshin] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Gorski, Mathias] Univ Regensburg, D-93053 Regensburg, Germany. [Li, Yong] Univ Hosp Freiburg, Freiburg, Germany. [Keller, Margaux F.; Nalls, Mike A.; Singleton, Andrew] NIA, NIH, Bethesda, MD 20892 USA. [Ganesh, Santhi K.] Univ Michigan, Ann Arbor, MI 48109 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Winston Salem, NC USA. [Bruijn, Lucie] Amyotroph Lateral Sclerosis Assoc, Washington, DC USA. [Brown, Matthew A.; Evans, David M.] Univ Queensland, Princess Alexandra Hosp, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Baltic, Svetlana] Univ Western Australia, Perth, WA 6009, Australia. [Ferreira, Manuel A.; Law, Matthew H.; Hayward, Nicholas K.] Queensland Inst Med Res, Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Baurecht, Hansjoerg; Weidinger, Stephan] Univ Hosp Schleswig Holstein, Kiel, Germany. [Franke, Andre] Univ Kiel, Kiel, Germany. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] Univ Munich, D-81377 Munich, Germany. [Sudman, Marc; Thompson, Susan D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Polychronakos, Constantin] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Bradfield, Jonathan P.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Tomlinson, Ian P.] Wellcome Trust Ctr Human Genet, Oxford, England. [Dunlop, Malcolm] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Dunlop, Malcolm] MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Hemminki, Kari] German Canc Res Ctr, Heidelberg, Germany. [Hemminki, Kari] Lund Univ, Malmo, Sweden. [Morgan, Gareth] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Eisen, Timothy] Cambridge Univ Hlth Partners, Cambridge, England. [Goldschmidt, Hartmut] Natl Ctr Tumor Dis, Heidelberg, Germany. [Allan, James M.] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Henrion, Marc; Whiffin, Nicola; Wang, Yufei; Chubb, Daniel] Inst Canc Res, Sutton, Surrey, England. [Houlston, Richard S.] Inst Canc Res, London SW3 6JB, England. [Iles, Mark M.; Bishop, D. Timothy] Univ Leeds, Leeds Canc Res UK Ctr, Leeds, W Yorkshire, England. [Barbalic, Maja] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Crossman, David] Univ St Andrews, St Andrews, Fife, Scotland. [Rader, Daniel J.; Reilly, Muredach] Univ Penn, Perleman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA USA. [Rader, Daniel J.; Reilly, Muredach] Univ Penn, Perleman Sch Med, Cardiovasc Inst, Philadelphia, PA USA. [Assimes, Themistocles] Stanford Univ, Stanford, CA 94305 USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Tracy, Russell] Univ Vermont, Coll Med, Burlington, VT USA. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, Mannheim, Germany. [Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Erdmann, Jeanette] German Res Ctr Cardiovasc Res, Lubeck, Germany. [Walston, Jeremy D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Alam, Dewan S.] Int Ctr Diarrhoeal Dis Res, Ctr Control Chron Dis, Dhaka 1000, Bangladesh. [Majumder, Abdullah Al Shafi] Natl Inst Cardiovasc Dis, Dhaka, Bangladesh. RP Freitag, DF (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Interleukin Genet Consortium Coordinating Ctr 1, Cambridge CB1 8RN, England. EM IL1GC@medschl.cam.ac.uk RI de Bakker, Paul/B-8730-2009; Gudnason, Vilmundur/K-6885-2015; Singleton, Andrew/C-3010-2009; Kessler, Thorsten/O-7426-2015; Smith, Albert/K-5150-2015; Bown, Matthew/P-1957-2016; Dunlop, Malcolm/F-1973-2011; Weidinger, Stephan/C-8461-2011; Erdmann, Jeanette/P-7513-2014; OI de Bakker, Paul/0000-0001-7735-7858; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Bown, Matthew/0000-0002-6180-3611; Dunlop, Malcolm/0000-0002-3033-5851; HO, WEANG KEE/0000-0002-8269-7344; Willeit, Peter/0000-0002-1866-7159; Luo, Yang/0000-0001-7385-6166; Felix, Janine/0000-0002-9801-5774; Ramond, Anna/0000-0002-9958-3693; Di Angelantonio, Emanuele/0000-0001-8776-6719; Baltic, Svetlana/0000-0002-3428-940X; Kuivaniemi, Helena/0000-0001-5753-8766; Erdmann, Jeanette/0000-0002-4486-6231; Zeggini, Eleftheria/0000-0003-4238-659X; Bevan, Steve/0000-0003-0490-6830; Bishop, Tim/0000-0002-8752-8785; Jones, Gregory T/0000-0002-6950-4210; Evans, David/0000-0003-0663-4621; Burgess, Stephen/0000-0001-5365-8760; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Houlston, Richard/0000-0002-5268-0242; Li, Yong/0000-0003-2651-8791 FU UK Medical Research Council; British Heart Foundation; UK National Institute for Health Research; National Institute for Health Research Cambridge Biomedical Research Centre; European Research Council; European Commission FX UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7. NR 56 TC 20 Z9 20 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD APR PY 2015 VL 3 IS 4 BP 243 EP 253 DI 10.1016/S2213-8587(15)00034-0 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG1KX UT WOS:000353032600020 ER PT J AU Chaires, JB Hansen, LD Keller, S Brautigam, CA Zhao, HY Schuck, P AF Chaires, Jonathan B. Hansen, Lee D. Keller, Sandro Brautigam, Chad A. Zhao, Huaying Schuck, Peter TI Biocalorimetry SO METHODS LA English DT Editorial Material C1 [Chaires, Jonathan B.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA. [Hansen, Lee D.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Keller, Sandro] Univ Kaiserslautern, Mol Biophys, D-67663 Kaiserslautern, Germany. [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Chaires, JB (reprint author), Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA. EM j.chaires@louisville.edu; schuckp@mail.nih.gov RI Keller, Sandro/G-7202-2016; OI Keller, Sandro/0000-0001-5469-8772; Schuck, Peter/0000-0002-8859-6966 NR 23 TC 1 Z9 1 U1 3 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD APR 1 PY 2015 VL 76 BP 1 EP 2 DI 10.1016/j.ymeth.2015.02.001 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF1TY UT WOS:000352332000001 PM 25817327 ER PT J AU Zhao, HY Piszczek, G Schuck, P AF Zhao, Huaying Piszczek, Grzegorz Schuck, Peter TI SEDPHAT - A platform for global ITC analysis and global multi-method analysis of molecular interactions SO METHODS LA English DT Article DE Isothermal titration calorimetry; Global analysis; Multi-method analysis; Protein interactions; Binding cooperativity; Linked binding ID ISOTHERMAL TITRATION CALORIMETRY; HIGH-AFFINITY BINDING; DIHYDROFOLATE-REDUCTASE; EXPLICIT FORMULATION; PROTEIN INTERACTIONS; SIGNALING COMPLEXES; MULTIPOINT BINDING; SUBSTRATE-BINDING; LIGAND-BINDING; DRUG DESIGN AB Isothermal titration calorimetry experiments can provide significantly more detailed information about molecular interactions when combined in global analysis. For example, global analysis can improve the precision of binding affinity and enthalpy, and of possible linkage parameters, even for simple bimolecular interactions, and greatly facilitate the study of multi-site and multi-component systems with competition or cooperativity. A pre-requisite for global analysis is the departure from the traditional binding model, including an 'n'-value describing unphysical, non-integral numbers of sites. Instead, concentration correction factors can be introduced to account for either errors in the concentration determination or for the presence of inactive fractions of material. SEDPHAT is a computer program that embeds these ideas and provides a graphical user interface for the seamless combination of biophysical experiments to be globally modeled with a large number of different binding models. It offers statistical tools for the rigorous determination of parameter errors, correlations, as well as advanced statistical functions for global ITC (gITC) and global multi-method analysis (GMMA). SEDPHAT will also take full advantage of error bars of individual titration data points determined with the unbiased integration software NITPIC. The present communication reviews principles and strategies of global analysis for ITC and its extension to GMMA in SEDPHAT. We will also introduce a new graphical tool for aiding experimental design by surveying the concentration space and generating simulated data sets, which can be subsequently statistically examined for their information content. This procedure can replace the 'c'-value as an experimental design parameter, which ceases to be helpful for multi-site systems and in the context of gITC. Published by Elsevier Inc. C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), NIH, 13 South Dr,Bldg 13 Rm 3N17, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Heart, Lung, and Blood Institute, National Institutes of Health, United States FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, and the National Heart, Lung, and Blood Institute, National Institutes of Health, United States. NR 81 TC 32 Z9 32 U1 3 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD APR 1 PY 2015 VL 76 BP 137 EP 148 DI 10.1016/j.ymeth.2014.11.012 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF1TY UT WOS:000352332000016 PM 25477226 ER PT J AU Mysliwiec, V Capaldi, VF Gill, J Baxter, T O'Reilly, BM Matsangas, P Roth, BJ AF Mysliwiec, Vincent Capaldi, Vincent F., II Gill, Jessica Baxter, Tristin O'Reilly, Brian M. Matsangas, Panagiotis Roth, Bernard J. TI Adherence to Positive Airway Pressure Therapy in US Military Personnel With Sleep Apnea Improves Sleepiness, Sleep Quality, and Depressive Symptoms SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MOTOR-VEHICLE COLLISIONS; TRAUMATIC BRAIN-INJURY; CPAP ADHERENCE; NASAL CPAP; DAYTIME SLEEPINESS; CONTROLLED-TRIAL; OF-LIFE; ADULTS; AFGHANISTAN AB Objectives: Obstructive sleep apnea (OSA) is frequently diagnosed in U.S. military personnel. OSA is associated with sleepiness, poor sleep quality, and service-related illnesses of insomnia, depression, post-traumatic stress disorder, and traumatic brain injury. Methods: Observational study of active duty military personnel with OSA and adherence to positive airway pressure (PAP) assessed with smart chip technology. Results: 58 men with mean age 36.2 +/- 7.7 years, mean body mass index 31.4 +/- 3.7 with mean apnea-hypopnea index (AHI) 19.1 +/- 19.0 are reported. 23 (39.7%) participants were adherent to PAP, and 35 (60.3%) were nonadherent. No significant differences in baseline demographics, apnea-hypopnea index, service-related illnesses, or clinical instrument scores. Military personnel adherent to PAP had significantly improved sleepiness (p = 0.007), sleep quality (p = 0.013), depressive symptoms (p = 0.01), energy/fatigue (p = 0.027), and emotional well-being (p = 0.024). Participants with moderate-severe OSA were more likely to be in the adherent group when compared with participants diagnosed with mild OSA. Conclusions: Military personnel with OSA have low adherence to PAP. Adherence is associated with improved depressive symptoms, sleepiness, sleep quality, energy/fatigue, emotional well-being, and social functioning. Future research should focus on interventions to improve the management of OSA in military personnel. C1 [Mysliwiec, Vincent; Baxter, Tristin; O'Reilly, Brian M.; Roth, Bernard J.] Madigan Army Med Ctr, Dept Pulm Sleep Med Crit Care, Tacoma, WA 98431 USA. [Capaldi, Vincent F., II] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Gill, Jessica] NIH, Bethesda, MD 20892 USA. [Matsangas, Panagiotis] US Navy, Postgrad Sch, Dept Operat Res, Monterey, CA 93943 USA. RP Mysliwiec, V (reprint author), Madigan Army Med Ctr, Dept Pulm Sleep Med Crit Care, 9040A Fitzsimmons Ave, Tacoma, WA 98431 USA. FU Center for Neuroscience and Regenerative Medicine [60855] FX The authors thank Angela Mysliwiec, MD, Madigan Army Medical Center, for editing assistance and review of the manuscript. Dr. Angela Mysliwiec did not receive compensation for her contributions. This study was supported, in part, by grant no. 60855 from the Center for Neuroscience and Regenerative Medicine. NR 55 TC 2 Z9 2 U1 2 U2 8 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD APR PY 2015 VL 180 IS 4 BP 475 EP 482 DI 10.7205/MILMED-D-14-00197 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CF6UJ UT WOS:000352691600016 PM 25826354 ER PT J AU Perera, T Young, MR Zhang, ZY Murphy, G Colburn, NH Lanza, E Hartman, TJ Cross, AJ Bobe, G AF Perera, Thushanthi Young, Matthew R. Zhang, Zhiying Murphy, Gwen Colburn, Nancy H. Lanza, Elaine Hartman, Terryl J. Cross, Amanda J. Bobe, Gerd TI Identification and monitoring of metabolite markers of dry bean consumption in parallel human and mouse studies SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Biomarkers; Dry bean consumption; Metabolomics; Pipecolic acid; S-methyl cysteine ID POLYP PREVENTION TRIAL; COLORECTAL ADENOMA RECURRENCE; METHYL-L-CYSTEINE; L-PIPECOLIC ACID; S-METHYLCYSTEINE; RAT HEPATOCARCINOGENESIS; DIETARY INTERVENTION; HIGH-FIBER; LOW-FAT; SULFOXIDE AB Scope: Aim of the study was to identify and monitor metabolite markers of dry bean consumption in parallel human and mouse studies that each had shown chemopreventive effects of dry bean consumption on colorectal neoplasia risk. Methods and results: Using LC/mass spectroscopy +/- ESI and GC/mass spectroscopy, serum metabolites of dry beans weremeasured in 46 men before and after a 4-week dry bean enriched diet (250 g/day) and 12 mice that received a standardized diet containing either 0 or 10% navy bean ethanol extract for 6 weeks; we also investigated fecal metabolites in the mice. The serum metabolites identified in these controlled feeding studies were then investigated in 212 polyp-free participants from the Polyp Prevention Trial who self-reported either increased (>= + 31 g/day from baseline), high dry bean intake of >= 42 g/day in year 3 or low, unchanged dry bean consumption of < 8 g/day; serum was analyzed from baseline and year 3. Serum pipecolic acid and S-methyl cysteine were elevated after dry bean consumption in human and mouse studies and reflected dry bean consumption in the Polyp Prevention Trial. Conclusion: Serum levels of pipecolic acid and S-methyl cysteine are useful biomarkers of dry bean consumption. C1 [Perera, Thushanthi; Bobe, Gerd] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA. [Perera, Thushanthi; Bobe, Gerd] Oregon State Univ, Dept Anim & Rangeland Sci, Corvallis, OR 97331 USA. [Young, Matthew R.; Colburn, Nancy H.; Lanza, Elaine] NCI, Lab Canc Prevent, Ctr Canc Res, NIH,DHHS, Frederick, MD 21701 USA. [Zhang, Zhiying] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Murphy, Gwen] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. [Hartman, Terryl J.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Cross, Amanda J.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. RP Bobe, G (reprint author), Oregon State Univ, Linus Pauling Inst, 112 Withycombe Hall, Corvallis, OR 97331 USA. EM gerd.bobe@oregonstate.edu FU Office of Complementary and Alternative Medicine; Office of Dietary Supplements; US Dry Bean Council, Oregon State University; General Research Center at Penn State University (NIH) [M01 RR10732]; Intramural Research Program, National Cancer Institute, NIH, DHHS, Bethesda, MD [Z01 CP10198-08, ZIA BC 010025, 25XS101] FX The authors would like to thank the Polyp Prevention Trial Study Group for their outstanding contribution to this The authors would like to thank the Polyp Prevention Trial Study Group for their outstanding contribution to this project. In addition, the authors thank Edward Karoly, Elizabeth Morin-Kensicki, Robert Mohney, Jeff Pfohl, and Brante Sampey from Metabolon (Research Triangle Park, North Carolina) for metabolomics analysis of the serum samples; Jen Wise and Craig Driver of the Laboratory Animal Sciences Program of SAIC Frederick Inc. for taking care of the mice; and Chris Dextras and Thomas G. McCloud from the Natural Products Support Group of Applied Developmental Research Program of SAIC Frederick Inc. for preparing the dry bean extract. This study was funded by the Office of Complementary and Alternative Medicine, the Office of Dietary Supplements, the US Dry Bean Council, Oregon State University, the General Research Center at Penn State University (NIH grant M01 RR10732), and the Intramural Research Program, National Cancer Institute, NIH, DHHS, Bethesda, MD (Z01 CP10198-08; ZIA BC 010025; subcontract 25XS101). NR 43 TC 3 Z9 3 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD APR PY 2015 VL 59 IS 4 BP 795 EP 806 DI 10.1002/mnfr.201400847 PG 12 WC Food Science & Technology SC Food Science & Technology GA CF8CK UT WOS:000352782800017 PM 25641932 ER PT J AU Defazio, G Hallett, M Jinnah, HA Stebbins, GT Gigante, AF Ferrazzano, G Conte, A Fabbrini, G Berardelli, A AF Defazio, Giovanni Hallett, Mark Jinnah, Hyder A. Stebbins, Glenn T. Gigante, Angelo F. Ferrazzano, Gina Conte, Antonella Fabbrini, Giovanni Berardelli, Alfredo TI Development and Validation of a Clinical Scale for Rating the Severity of Blepharospasm SO MOVEMENT DISORDERS LA English DT Article DE Blepharospasm; Blinking; Dystonia; severity; rating scale ID DYSTONIA AB Existing scales for rating the severity of blepharospasm (BSP) are limited by a number of potential drawbacks. We therefore developed and validated a novel scale for rating the severity of BSP. The development of the scale started with careful examination of the clinical spectrum of the condition by a panel of experts who selected phenomenological aspects thought to be relevant to disease severity. Thereafter, selected items were first checked for reliability, then reliable items were combined to generate the scale, and clinimetric properties of the scale were evaluated. Finally, the confidence with which the scale could be used by people without high levels of movement disorders skill was assessed. The new scale, based on objective criteria, yielded moderate to almost perfect reliability, acceptable internal consistency, satisfactory scaling assumptions, lack of floor and ceiling effects, partial correlations with a prior severity scale and with a quality of life scale, and good sensitivity to change. Despite a few limitations, the foregoing features make the novel scale more suitable than existing scales to assess the severity of BSP in natural history and pathophysiologic studies as well as in clinical trials. (c) 2015 International Parkinson and Movement Disorder Society C1 [Defazio, Giovanni; Gigante, Angelo F.] Aldo Moro Univ Bari, Dept Basic Med Sci Neurosci & Sensory Organs, I-70124 Bari, Italy. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Jinnah, Hyder A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Stebbins, Glenn T.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Ferrazzano, Gina; Conte, Antonella; Fabbrini, Giovanni; Berardelli, Alfredo] Univ Roma La Sapienza, Dept Neurol & Psychiat, I-00185 Rome, Italy. [Conte, Antonella; Fabbrini, Giovanni; Berardelli, Alfredo] IRCCS INM Neuromed, Pozzilli, IS, Italy. RP Defazio, G (reprint author), Aldo Moro Univ Bari, Dept Basic Med Sci Neurosci & Sensory Organs, I-70124 Bari, Italy. EM giovanni.defazio@uniba.it FU Benign Essential Blepharospasm Research Foundation; Dystonia Coalition from the Office of Rare Diseases Research [NS065701]; Dystonia Coalition (National Institute of Neurological Disorders and Stroke) FX This study was funded by the Benign Essential Blepharospasm Research Foundation and a Pilot Project Grant from the Dystonia Coalition (NS065701 from the Office of Rare Diseases Research and the National Institute of Neurological Disorders and Stroke) NR 18 TC 3 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2015 VL 30 IS 4 BP 525 EP 530 DI 10.1002/mds.26156 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA CF5RH UT WOS:000352614200011 PM 25847472 ER PT J AU Huang, XM Alonso, A Guo, XG Umbach, DM Lichtenstein, ML Ballantyne, CM Mailman, RB Mosley, TH Chen, HL AF Huang, Xuemei Alonso, Alvaro Guo, Xuguang Umbach, David M. Lichtenstein, Maya L. Ballantyne, Christie M. Mailman, Richard B. Mosley, Thomas H. Chen, Honglei TI Statins, Plasma Cholesterol, and Risk of Parkinson's Disease: A Prospective Study SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; cholesterol; statin; cohort study ID ATHEROSCLEROSIS RISK; COENZYME Q(10); COMMUNITIES; OXIDATION; MODELS AB Previous findings on the association of statins, plasma lipids, and Parkinson's disease (PD) are confounded by the fact that statins also affect lipid profiles. We prospectively examined plasma lipids and statin use in relation to PD in the Atherosclerosis Risk in Communities (ARIC) Study. Statin use and plasma lipids were assessed at baseline (visit 1, 1987-89) and at three triennial visits thereafter (visits 2-4) until 1998. Potential PD cases were identified from multiple sources and validated where possible. The primary analysis was limited to incident PD cases diagnosed between 1998 and 2008. Odds ratios and 95% confidence intervals were derived from multivariate logistic regression models. Statin use was rare at baseline (0.57%) but increased to 11.2% at visit 4. During this time frame, total-cholesterol levels decreased, particularly among statin users. Fifty-six PD cases were identified after 1998. Statin use before 1998 was associated with significantly higher PD risk after 1998 (odds ratio=2.39, 95% confidence interval 1.11-5.13) after adjusting for total cholesterol and other confounders. Conversely, higher total cholesterol was associated with lower risk for PD after adjustment for statin usage and confounders. Compared with the lowest tertile of average total cholesterol, the odds ratios for PD were 0.56 (0.30-1.04) for the second and 0.43 (0.22-0.87) for the third tertile (P-trend=0.02). Statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk. These data are inconsistent with the hypothesis that statins are protective against PD. (c) 2015 International Parkinson and Movement Disorder Society C1 [Huang, Xuemei; Lichtenstein, Maya L.] Penn State Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Community Hlth, Minneapolis, MN USA. [Guo, Xuguang] Westat Corp, Durham, NC USA. [Umbach, David M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Methodist DeBakey Heart Ctr, Ctr Cardiovasc Dis Prevent, Houston, TX USA. [Mailman, Richard B.] Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA USA. [Mailman, Richard B.] Penn State Univ, Coll Med, Dept Neurol, Hershey, PA USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Huang, XM (reprint author), Penn State Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. EM xuemei@psu.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Mailman, Richard/0000-0003-1353-2738; Chen, Honglei/0000-0003-3446-7779 FU NIH, National Institute of Environmental Health Sciences [Z01-ES-101986]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NIH [R01 NS060722, R01 ES019672, U01 NS082151]; [K23 AG21491] FX This research was in part supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-101986). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. Dr. Xuemei Huang has been currently supported by NIH grants R01 NS060722, R01 ES019672, and U01 NS082151, and a former award (K23 AG21491) provided support at the conception of this research. NR 30 TC 21 Z9 23 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2015 VL 30 IS 4 BP 552 EP 559 DI 10.1002/mds.26152 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CF5RH UT WOS:000352614200015 PM 25639598 ER PT J AU Chen, HM Wang, GD Chuang, YJ Zhen, ZP Chen, XY Biddinger, P Hao, ZL Liu, F Shen, BZ Pan, ZW Xie, J AF Chen, Hongmin Wang, Geoffrey D. Chuang, Yen-Jun Zhen, Zipeng Chen, Xiaoyuan Biddinger, Paul Hao, Zhonglin Liu, Feng Shen, Baozhong Pan, Zhengwei Xie, Jin TI Nanoscintillator-Mediated X-ray Inducible Photodynamic Therapy for In Vivo Cancer Treatment SO NANO LETTERS LA English DT Article DE nanomedicine; X-PDT; nanoscintillator; radioluminescence nanophosphors; singlet oxygen; cancer treatment ID UP-CONVERSION NANOPARTICLES; RETICULOENDOTHELIAL SYSTEM CLEARANCE; MESOPOROUS SILICA; RADIATION; LIGHT; THERAPEUTICS; LUMINESCENCE; NANOSPHERES; IRRADIATION; ENDOCYTOSIS AB Photodynamic therapy is a promising :treatment method, but its applications are limited by the shallow penetration of visible light Here, we report a novel X-ray inducible photodynamic therapy (X-PDT) approach That allows PDT to be regulated by X-rays. Upon X-ray irradiation, the integrated nanosystem, comprised of a Core of a nanoscintillator and a mesoporous silica coating loaded with photosensitizers, converts X-ray photons to visible photons to activate the photosensitizers and cause efficient tumor shrinkage. C1 [Chen, Hongmin; Wang, Geoffrey D.; Zhen, Zipeng; Xie, Jin] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Chen, Hongmin; Zhen, Zipeng; Xie, Jin] Univ Georgia, Bioimaging Res Ctr, Athens, GA 30602 USA. [Chen, Hongmin; Shen, Baozhong] Harbin Med Univ, Hosp 4, Dept Radiol, Harbin 157, Peoples R China. [Chen, Hongmin; Shen, Baozhong] Harbin Med Univ, Mol Imaging Res Ctr, Harbin 157, Peoples R China. [Chuang, Yen-Jun; Liu, Feng; Pan, Zhengwei] Univ Georgia, Coll Engn, Athens, GA 30602 USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Rockville, MD 20852 USA. [Biddinger, Paul] Georgia Regents Univ, Dept Pathol, Augusta, GA 30912 USA. [Hao, Zhonglin] Georgia Regents Univ, Dept Internal Med, Med Coll Georgia, Augusta, GA 30912 USA. RP Xie, J (reprint author), Univ Georgia, Dept Chem, Athens, GA 30602 USA. EM jinxie@uga.edu RI Chen, Hongmin/B-9555-2011; OI Pan, Zhengwei/0000-0002-3854-958X FU NCI/NTH R00 [5R00CA153772]; UGA-GRU seed grant; NSF CAREER grant [CAREER DMR-0955908]; intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); Elsa U. Pardee Foundation Award; National Basic Research Program of China [2015CB931800]; National Natural Science Foundation of China [81130028, 31210103913]; Key Grant Project of Heilongjiang Province [GA12C302]; Ph.D. Programs Foundation of Ministry of Education of China [201123071100203]; Key Laboratory of Molecular Imaging Foundation (College of Heilongjiang Province) FX The authors thank Wei Tang and Trever Todd for their assistance on cell and animal studies and Sullins Benson for his contribution to graph design. The authors also acknowledge Dr. Xufan Li for his help on characterizations of SAO. This research was supported by an NCI/NTH R00 grant (5R00CA153772, J.X.), a UGA-GRU seed grant (J.X.), an NSF CAREER grant (CAREER DMR-0955908, Z.W.P.), and the intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB, X.C.). The research is also supported by an Elsa U. Pardee Foundation Award (J.X.). We also thank the funding support by the National Basic Research Program of China (2015CB931800, B.S.), National Natural Science Foundation of China (81130028,31210103913, B.S.), the Key Grant Project of Heilongjiang Province (GA12C302, B.S.), the Ph.D. Programs Foundation of Ministry of Education of China (201123071100203, B.S.), and the Key Laboratory of Molecular Imaging Foundation (College of Heilongjiang Province, B.S.). NR 47 TC 32 Z9 33 U1 15 U2 94 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD APR PY 2015 VL 15 IS 4 BP 2249 EP 2256 DI 10.1021/nl504044p PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CF7QA UT WOS:000352750200006 PM 25756781 ER PT J AU Ramsden, CE Faurot, KR Zamora, D Palsson, OS MacIntosh, BA Gaylord, S Taha, AY Rapoport, SI Hibbeln, JR Davis, JM Mann, JD AF Ramsden, Christopher E. Faurot, Keturah R. Zamora, Daisy Palsson, Olafur S. MacIntosh, Beth A. Gaylord, Susan Taha, Ameer Y. Rapoport, Stanley I. Hibbeln, Joseph R. Davis, John M. Mann, J. Douglas TI Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial SO PAIN LA English DT Article DE Omega-3; Omega-6; Headache; Anxiety; Somatization; Clinical trial ID MAJOR DEPRESSIVE DISORDER; CORD SYNAPTIC PLASTICITY; INFLAMMATORY PAIN; SPINAL-CORD; EICOSAPENTAENOIC ACID; ANXIETY DISORDERS; UNITED-STATES; MIGRAINE; METABOLITES; PREVALENCE AB Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress. In a randomized trial of 67 subjects with severe headaches, we recently demonstrated that targeted dietary manipulation increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid (the H3-L6 intervention) produced major reductions in headache compared with an omega-6 lowering (L6) intervention. Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life (HRQOL), we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains. Additionally, we examined the effect of the interventions on the-number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory (BSI-18), Medical Outcomes Study Short Forms 12 (SF-12), Headache Impact Test (HIT-6), and the number of headache days per month. In the intention-to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress (BSI-18 mean difference: -6.56; 95% confidence interval.[CI]: -11.43 to -1.69) and improvements in SF-12 mental (mean difference: 6.01; 95% CI: 0.57 to 11.45) and physical (mean difference: 6.65; 95% CI: 2.14 to 11.16) health summary scores. At 12 weeks, the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18, SF-12 physical, HIT-6, and headache days per month was significantly lower in the H3-L6 group. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, was found to also reduce psychological distress and improve HRQOL and function. C1 [Ramsden, Christopher E.; Hibbeln, Joseph R.] NIAAA, Sec Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Ramsden, Christopher E.; Faurot, Keturah R.; Zamora, Daisy; MacIntosh, Beth A.; Gaylord, Susan] Univ N Carolina, Dept Phys Med & Rehabil, Program Integrat Med, Chapel Hill, NC USA. [Palsson, Olafur S.] Univ N Carolina, Ctr Funct GI & Motil Disorders, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [MacIntosh, Beth A.] Univ N Carolina, North Carolina Translat Clin Sci Inst, Nutr Res & Metab Core, Chapel Hill, NC USA. [Taha, Ameer Y.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. [Davis, John M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Mann, J. Douglas] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. RP Ramsden, CE (reprint author), NIAAA, Sec Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, 31 Ctr Dr,Room 1B54, Bethesda, MD 20892 USA. EM chris.ramsden@nih.gov FU Mayday Fund; UNC Research Fellowship in Complementary and Alternative Medicine (NCCAM, NIH) [T32-AT003378]; North Carolina Clinical and Translational Sciences Institute (NCRR, NIH) [UL1RR025747]; UNC Nutrition Obesity Research Center, CHAI Core (NIDDK, NIH) [DK056350]; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This project was supported by the Mayday Fund (primary source); the UNC Research Fellowship in Complementary and Alternative Medicine (grant T32-AT003378, NCCAM, NIH); the North Carolina Clinical and Translational Sciences Institute (grant UL1RR025747, NCRR, NIH); the UNC Nutrition Obesity Research Center, CHAI Core (grant DK056350, NIDDK, NIH); and the Intramural Programs of the National Institute on Aging and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 56 TC 6 Z9 6 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD APR PY 2015 VL 156 IS 4 BP 587 EP 596 DI 10.1097/01.j.pain.0000460348.84965.47 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CF1TN UT WOS:000352330900005 PM 25790451 ER PT J AU Bushnell, MC Case, LK Ceko, M Cotton, VA Gracely, JL Low, LA Pitcher, MH Villemure, C AF Bushnell, M. C. Case, L. K. Ceko, M. Cotton, V. A. Gracely, J. L. Low, L. A. Pitcher, M. H. Villemure, C. TI Effect of environment on the long-term consequences of chronic pain SO PAIN LA English DT Article DE Chronic pain; Environmental enrichment; Yoga; Meditation; Gray matter; Exercise; Anxiety; Depression; Cognition ID CHRONIC INFLAMMATORY PAIN; GRAY-MATTER DENSITY; MINDFULNESS-BASED INTERVENTIONS; EMOTIONAL DECISION-MAKING; PERIPHERAL-NERVE INJURY; COLD-WATER SWIM; NEUROPATHIC PAIN; VOLUNTARY EXERCISE; FIBROMYALGIA PATIENTS; FORCED-EXERCISE AB Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum but has varied comorbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that lifestyle choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by nonpharmacological interventions. C1 [Bushnell, M. C.; Case, L. K.; Ceko, M.; Cotton, V. A.; Gracely, J. L.; Low, L. A.; Pitcher, M. H.; Villemure, C.] NIH, NCCIH, Div Intramural Res, Pain & Integrat Neurosci Branch, Bethesda, MD 20892 USA. RP Bushnell, MC (reprint author), NIH, NCCIH, 35A Convent Dr, Bethesda, MD 20892 USA. EM mary.bushnell@nih.gov OI CEKO, MARTA/0000-0001-8679-8145; Low, Lucie/0000-0001-6082-8625 FU National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA FX All authors are supported by the National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD, USA. NR 160 TC 5 Z9 5 U1 7 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD APR PY 2015 VL 156 IS 4 SU 1 BP S42 EP S49 DI 10.1097/01.j.pain.0000460347.77341.bd PG 8 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CF1TP UT WOS:000352331100008 PM 25789436 ER PT J AU Loo, L Wright, BD Zylka, MJ AF Loo, Lipin Wright, Brittany D. Zylka, Mark J. TI Lipid kinases as therapeutic targets for chronic pain SO PAIN LA English DT Article DE Lipid kinase; PIP2; Phosphatidylinositol-4-phosphate 5-kinase 1C; PIP5K1C; PIP5KI gamma; Phosphoinositide 3-kinase; PI3K; Phosphotidylinositol 4-kinase; PI4K; TRPV1; Pronociceptive receptor; NGF ID PHOSPHATIDYLINOSITOL PHOSPHATE KINASE; DORSAL-ROOT GANGLIA; NEURONAL CALCIUM SENSOR-1; CAPSAICIN RECEPTOR VR1; NERVE GROWTH-FACTOR; PLASMA-MEMBRANE; SPINAL-CORD; SIGNALING PATHWAYS; HEAT HYPERALGESIA; INFLAMMATORY PAIN AB Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal. excitability. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, the focus has shifted toward targeting downstream convergence points of nociceptive signaling. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2); are attractive targets, as these molecules are required for signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. Furthermore, PIP2 regulates the activity of various ion channels. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels, and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons. C1 [Loo, Lipin; Wright, Brittany D.; Zylka, Mark J.] Univ N Carolina, Dept Cell Biol & Physiol, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Wright, Brittany D.] Natl Ctr Advancing Translat Sci, Rockville, MD USA. RP Zylka, MJ (reprint author), 115 Mason Farm Rd,5109D NRB,CB 7545, Chapel Hill, NC 27599 USA. EM zylka@med.unc.edu FU NINDS [R01NS081127, R01NS067688] FX Research in the laboratory of M. J. Zylka is supported by grants from NINDS (R01NS081127 and R01NS067688). L. Loo and B. D. Wright contributed equally. NR 108 TC 1 Z9 1 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD APR PY 2015 VL 156 IS 4 SU 1 BP S2 EP S10 DI 10.1097/01.j.pain.0000460345.92588.4b PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CF1TP UT WOS:000352331100002 PM 25789432 ER PT J AU Yan, L Hicks, M Winslow, K Comella, C Ludlow, C Jinnah, HA Rosen, AR Wright, L Galpern, WR Perlmutter, JS AF Yan, Ling Hicks, Matt Winslow, Korey Comella, Cynthia Ludlow, Christy Jinnah, H. A. Rosen, Ami R. Wright, Laura Galpern, Wendy R. Perlmutter, Joel S. TI Secured web-based video repository for multicenter studies SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Video repository; Clinical trial; Secured access; Dystonia; Video protocol ID DYSTONIA; SCALE AB Background: We developed a novel secured web-based dystonia video repository for the Dystonia Coalition, part of the Rare Disease Clinical Research network funded by the Office of Rare Diseases Research and the National Institute of Neurological Disorders and Stroke. A critical component of phenotypic data collection for all projects of the Dystonia Coalition includes a standardized video of each participant. We now describe our method for collecting, serving and securing these videos that is widely applicable to other studies. Methods: Each recruiting site uploads standardized videos to a centralized secured server for processing to permit website posting. The streaming technology used to view the videos from the website does not allow downloading of video files. With appropriate institutional review board approval and agreement with the hosting institution, users can search and view selected videos on the website using customizable, permissions-based access that maintains security yet facilitates research and quality control. Results: This approach provides a convenient platform for researchers across institutions to evaluate and analyze shared video data. We have applied this methodology for quality control, confirmation of diagnoses, validation of rating scales, and implementation of new research projects. Conclusions: We believe our system can be a model for similar projects that require access to common video resources. (c) 2015 Elsevier Ltd. All rights reserved. C1 [Yan, Ling; Wright, Laura; Perlmutter, Joel S.] Washington Univ, Sch Med, Neurol, St Louis, MO 63110 USA. [Hicks, Matt; Winslow, Korey; Perlmutter, Joel S.] Washington Univ, Sch Med, Radiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Anat & Neurobiol, Phys Therapy, Occupat Therapy, St Louis, MO 63110 USA. [Comella, Cynthia] Neurol Rush Med Sch, Chicago, IL USA. [Ludlow, Christy] James Madison Univ, Dept Commun Sci & Disorders, Harrisonburg, VA USA. [Jinnah, H. A.; Rosen, Ami R.] Emory Univ, Neurol, Atlanta, GA 30322 USA. [Galpern, Wendy R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Perlmutter, JS (reprint author), Washington Univ, Sch Med, Campus Box 8225,660 South Euclid Ave, St Louis, MO 63110 USA. EM yali@ohsu.edu; matt@npg.wustl.edu; koreywinslow@gmail.com; cynthia_comella@rush.edu; ludlowcx@jmu.edu; hjinnah@emory.edu; arosen3@emory.edu; wrightl@npg.wustl.edu; galpernw@ninds.nih.gov; joel@npg.wustl.edu OI Ludlow, Christy/0000-0002-2015-6171 FU NIH from the National Institute of Neurological Disorders and Stroke [NS065701]; Office of Rare Diseases Research at the National Center for Advancing Translational Sciences; NIH [NS41509, NS057105, NS075321, NS040470]; Murphy Fund; American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA; McDonnell Center for Higher Brain Function; Barnes-Jewish Hospital Foundation; Bachmann-Strauss Dystonia & Parkinson Foundation; Benign Essential Blepharospasm Research Foundation; Tyler's Hope for a Cure FX This study received financial support from NIH grant NS065701 from the National Institute of Neurological Disorders and Stroke and the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences as well as NIH grants (NS41509, NS057105, NS075321, NS040470); the Murphy Fund; American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA; McDonnell Center for Higher Brain Function; Barnes-Jewish Hospital Foundation; Bachmann-Strauss Dystonia & Parkinson Foundation, Benign Essential Blepharospasm Research Foundation, and Tyler's Hope for a Cure. The Dystonia Coalition receives additional material or administrative support from industry sponsors (Allergan Inc., Ipsen Biopharm, Medtronics Inc, and Merz Pharmaceuticals) as well as private foundations (The American Dystonia Society, The Bachmann-Strauss Dystonia and Parkinson Foundation, BeatDystonia, The Benign Essential Blepharospasm Foundation, Dystonia Europe, Dystonia Ireland, The Dystonia Medical Research Foundation, The Dystonia Society, The Foundation for Dystonia Research, The National Spasmodic Dysphonia Association, and The National Spasmodic Torticollis Association). NR 6 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD APR PY 2015 VL 21 IS 4 BP 366 EP 371 DI 10.1016/j.parkreldis.2015.01.011 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA CF6MR UT WOS:000352671300004 PM 25630890 ER PT J AU Ni, CP Ma, LH Wang, B Hua, Y Hua, QZ Wallen, GR Gao, B Yan, YP Huang, YQ AF Ni, Chunping Ma, Lihua Wang, Bo Hua, Yan Hua, Qianzhen Wallen, Gwenyth R. Gao, Bo Yan, Yongping Huang, Yueqin TI Screening and Correlates of Neurotic Disorders Among General Medical Outpatients in Xi'an China SO PERSPECTIVES IN PSYCHIATRIC CARE LA English DT Article DE Cross-sectional study; neurotic disorder; outpatient; population distribution; risk factor ID MENTAL-DISORDERS; ANXIETY DISORDERS; PRIMARY-CARE; ASIAN-AMERICANS; PREVALENCE; INSIGHT; SCHIZOPHRENIA; BURDEN AB PurposeLittle is known about the distribution and correlates of neurotic disorders among general medical outpatients. The aim was to identify the population distribution and associated factors of neurotic disorders among general medical outpatients. Design and methodsA cross-sectional design was used. Computer-assisted interviews of 372 general outpatients aged 16 years or older in Xi'an China were conducted using a Chinese version of the World Health Organization Composite International Diagnostic Interview version 3.0 (CIDI-3.0). FindingsThe estimated lifetime prevalence of any ICD-10 neurotic disorder among general medical outpatients was 10.8%. The most prevalent subtype of neurotic disorders was specific phobias (5.7%) followed by obsessive-compulsive disorders (3.8%) and social phobias (1.3%). General outpatients who visited the department of internal medicine (OR = 6.55, 95% CI 1.51-28.38), who were under 40 years old (OR = 4.44, 95% CI 2.05-9.62), had less than high school education (OR = 4.19, 95% CI 1.79-9.79), and were female (OR = 2.25, 95% CI 1.14-4.47) were most likely to report neurotic disorders. Practice implicationsEffective identification of neurotic disorders is crucial for its early detection and targeted intervention among general medical outpatients. Those outpatients who had younger age and lower education level, and were female and had visited internal medicine departments require additional attention. C1 [Ni, Chunping; Hua, Yan; Hua, Qianzhen] Fourth Mil Med Univ, Sch Nursing, Xian 710032, Shaanxi Provinc, Peoples R China. [Ma, Lihua] Lanzhou Univ, Hosp 1, Dept Nursing, Lanzhou 730000, Gansu, Peoples R China. [Wang, Bo; Yan, Yongping] Fourth Mil Med Univ, Dept Epidemiol, Xian 710032, Shaanxi Provinc, Peoples R China. [Wallen, Gwenyth R.] NIH, Nursing Res & Translat Sci, Ctr Clin, Bethesda, MD 20892 USA. [Gao, Bo] Fourth Mil Med Univ, Xijing Hosp, Dept Orthoped Surg, Xian 710032, Shaanxi Provinc, Peoples R China. [Huang, Yueqin] Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. RP Yan, YP (reprint author), Fourth Mil Med Univ, Dept Epidemiol, Xian 710032, Shaanxi Provinc, Peoples R China. EM yanyping@fmmu.edu.cn; huangyq@bjmu.edu.cn FU Ministry of Science and Technology of People's Republic of China [2007BAI17B01]; Department of Science & Technology of Shanxi Province of China [2010K16-02-01]; National Natural Science Foundation of China [71373281]; Chinese Scholarship Council FX The current study was supported in part by the Ministry of Science and Technology of People's Republic of China (grant 2007BAI17B01), the Department of Science & Technology of Shanxi Province of China (grant 2010K16-02-01), the National Natural Science Foundation of China (grant 71373281), and Chinese Scholarship Council. NR 46 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-5990 EI 1744-6163 J9 PERSPECT PSYCHIATR C JI Perspect. Psychiatr. Care PD APR PY 2015 VL 51 IS 2 BP 128 EP 135 DI 10.1111/ppc.12074 PG 8 WC Nursing; Psychiatry SC Nursing; Psychiatry GA CF9DK UT WOS:000352862000008 PM 24957637 ER PT J AU Alves, LMS de Lima, BS dos Santos, CAM da Luz, MS Neumeier, JJ Yu, YK AF Alves, L. M. S. de Lima, B. S. dos Santos, C. A. M. da Luz, M. S. Neumeier, J. J. Yu, Yi-Kuo TI A magnetic field tuned metal-insulator transition in unconventional metallic K-doped MoO2 SO PHYSICA STATUS SOLIDI B-BASIC SOLID STATE PHYSICS LA English DT Article DE metal-insulator transition; molybdenum oxide; unconventional metallic behavior ID TRANSPORT; LIQUID AB This paper reports magnetoresistance measurements in polycrystalline samples of K0.05MoO2-(delta) which demonstrate the occurrence of metal-insulator transition driven by magnetic field. The results are consistent with the Bose metal scenario and the two parameter scaling analysis proposed by Das and Doniach was applied. The results suggest a possible explanation for the unconventional metallic behavior observed in the K0.05MoO2-(delta) compound. (C) 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim C1 [Alves, L. M. S.; de Lima, B. S.; dos Santos, C. A. M.; da Luz, M. S.] Univ Sao Paulo, Escola Engn Lorena, BR-12602810 Lorena, SP, Brazil. [dos Santos, C. A. M.] Univ Fed Triangulo Mineiro, Inst Ciencias Tecnol & Exatas, BR-38064200 Uberaba, MG, Brazil. [Neumeier, J. J.] Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. [Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP da Luz, MS (reprint author), Univ Sao Paulo, Escola Engn Lorena, BR-12602810 Lorena, SP, Brazil. EM daluz.mario@icte.uftm.edu.br RI dos Santos, Carlos/C-1619-2012 FU FAPESP [2009/54001-2, 2010/06637-2]; CNPq [308162/2013-7, 142016/2013-6]; CAPES; FAPEMIG FX This work is based upon work supported by the FAPESP (2009/54001-2 and 2010/06637-2) and CNPq (308162/2013-7 and 142016/2013-6). M. S. da Luz also thanks to CAPES and FAPEMIG for financial support. NR 15 TC 0 Z9 0 U1 3 U2 18 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0370-1972 EI 1521-3951 J9 PHYS STATUS SOLIDI B JI Phys. Status Solidi B-Basic Solid State Phys. PD APR PY 2015 VL 252 IS 4 BP 839 EP 842 DI 10.1002/pssb.201451446 PG 4 WC Physics, Condensed Matter SC Physics GA CF6CI UT WOS:000352643900028 ER PT J AU Colangelo, CM Ivosev, G Chung, L Abbott, T Shifman, M Sakaue, F Cox, D Kitchen, RR Burton, L Tate, SA Gulcicek, E Bonner, R Rinehart, J Nairn, AC Williams, KR AF Colangelo, Christopher M. Ivosev, Gordana Chung, Lisa Abbott, Thomas Shifman, Mark Sakaue, Fumika Cox, David Kitchen, Robert R. Burton, Lyle Tate, Stephen A. Gulcicek, Erol Bonner, Ron Rinehart, Jesse Nairn, Angus C. Williams, Kenneth R. TI Development of a highly automated and multiplexed targeted proteome pipeline and assay for 112 rat brain synaptic proteins SO PROTEOMICS LA English DT Article DE Multiple reaction monitoring; Postsynaptic density; Proteomics database; Targeted proteomics; Technology ID TANDEM MASS-SPECTROMETRY; POSTSYNAPTIC DENSITY; LIQUID-CHROMATOGRAPHY; ABSOLUTE QUANTIFICATION; QUANTITATIVE PROTEOMICS; HUMAN PLASMA; PEPTIDES; ACQUISITION; BIOMARKERS; RETENTION AB We present a comprehensive workflow for large scale (>1000 transitions/run) label-free LC-MRM proteome assays. Innovations include automated MRM transition selection, intelligent retention time scheduling that improves S/N by twofold, and automatic peak modeling. Improvements to data analysis include a novel Q/C metric, normalized group area ratio, MLR normalization, weighted regression analysis, and data dissemination through the Yale protein expression database. As a proof of principle we developed a robust 90 min LC-MRM assay for mouse/rat postsynaptic density fractions which resulted in the routine quantification of 337 peptides from 112 proteins based on 15 observations per protein. Parallel analyses with stable isotope dilution peptide standards (SIS), demonstrate very high correlation in retention time (1.0) and protein fold change (0.94) between the label-free and SIS analyses. Overall, our method achieved a technical CV of 11.4% with >97.5% of the 1697 transitions being quantified without user intervention, resulting in a highly efficient, robust, and single injection LC-MRM assay. C1 [Colangelo, Christopher M.; Chung, Lisa; Abbott, Thomas; Shifman, Mark; Sakaue, Fumika; Kitchen, Robert R.; Gulcicek, Erol; Nairn, Angus C.; Williams, Kenneth R.] Yale NIDA Neuroprote Ctr, New Haven, CT USA. [Colangelo, Christopher M.; Chung, Lisa; Abbott, Thomas; Gulcicek, Erol; Williams, Kenneth R.] Yale Univ, WM Keck Fdn Biotechnol Resource Lab, New Haven, CT 06511 USA. [Colangelo, Christopher M.; Kitchen, Robert R.; Burton, Lyle; Gulcicek, Erol; Williams, Kenneth R.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06511 USA. [Ivosev, Gordana; Cox, David; Tate, Stephen A.; Bonner, Ron] AB Sciex, Concord, ON, Canada. [Sakaue, Fumika; Kitchen, Robert R.; Nairn, Angus C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. [Rinehart, Jesse] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06511 USA. [Rinehart, Jesse] Yale Univ, Sch Med, Syst Biol Inst, New Haven, CT 06511 USA. RP Colangelo, CM (reprint author), Yale Univ, Sch Med, WM Keck Fdn Biotechnol Resource, 300 George St,Room G006, New Haven, CT 06511 USA. EM christopher.colangelo@yale.edu OI Williams, Kenneth/0000-0001-7792-9588; Colangelo, Christopher/0000-0002-0438-1395 FU NIH (NIDA) [P30 DA018343]; NIDA [DA10044]; NIDDK [K01 DK089006]; Yale Center for Clinical Investigation (CTSA/NCRR) [ULRR024139] FX This project was supported by NIH grants to the Yale NIDA Neuroproteomics Center (P30 DA018343, NIDA), NIDA (DA10044), NIDDK (K01 DK089006), and the Yale Center for Clinical Investigation (ULRR024139, CTSA/NCRR). NR 48 TC 4 Z9 4 U1 1 U2 8 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 APR PY 2015 VL 15 IS 7 BP 1202 EP 1214 DI 10.1002/pmic.201400353 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF4IL UT WOS:000352512100004 PM 25476245 ER PT J AU Rinschen, MM Pahmeyer, C Pisitkun, T Schnell, N Wu, XW Maass, M Bartram, MP Lamkemeyer, T Schermer, B Benzing, T Brinkkoetter, PT AF Rinschen, Markus M. Pahmeyer, Caroline Pisitkun, Trairak Schnell, Nicole Wu, Xiongwu Maass, Martina Bartram, Malte P. Lamkemeyer, Tobias Schermer, Bernhard Benzing, Thomas Brinkkoetter, Paul T. TI Comparative phosphoproteomic analysis of mammalian glomeruli reveals conserved podocin C-terminal phosphorylation as a determinant of slit diaphragm complex architecture SO PROTEOMICS LA English DT Article DE Animal proteomics; Glomerulus; Kidney; Phosphoproteomics; Podocin; Slit diaphragm complex ID POSTTRANSLATIONAL MODIFICATIONS; ACTIN CYTOSKELETON; KIDNEY PODOCYTES; PROTEIN PODOCIN; NEPHRIN; COMPONENT; MOUSE AB Glomerular biology is dependent on tightly controlled signal transduction networks that control phosphorylation of signaling proteins such as cytoskeletal regulators or slit diaphragm proteins of kidney podocytes. Cross-species comparison of phosphorylation events is a powerful mean to functionally prioritize and identify physiologically meaningful phosphorylation sites. Here, we present the result of phosphoproteomic analyses of cow and rat glomeruli to allow cross-species comparisons. We discovered several phosphorylation sites with potentially high biological relevance, e.g. tyrosine phosphorylation of the cytoskeletal regulator synaptopodin and the slit diaphragm protein neph-1 (Kirrel). Moreover, cross-species comparisons revealed conserved phosphorylation of the slit diaphragm protein nephrin on an acidic cluster at the intracellular terminus and conserved podocin phosphorylation on the very carboxyl terminus of the protein. We studied a highly conserved podocin phosphorylation site in greater detail and show that phosphorylation regulates affinity of the interaction with nephrin and CD2AP. Taken together, these results suggest that species comparisons of phosphoproteomic data may reveal regulatory principles in glomerular biology. All MS data have been deposited in the ProteomeXchange with identifier PXD001005 (). C1 [Rinschen, Markus M.; Pahmeyer, Caroline; Bartram, Malte P.; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T.] Univ Cologne, Dept Internal Med 2, D-50937 Cologne, Germany. [Rinschen, Markus M.; Pahmeyer, Caroline; Bartram, Malte P.; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T.] Univ Cologne, Ctr Mol Med, D-50937 Cologne, Germany. [Rinschen, Markus M.; Schnell, Nicole; Lamkemeyer, Tobias; Schermer, Bernhard; Benzing, Thomas] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50937 Cologne, Germany. [Rinschen, Markus M.; Schermer, Bernhard; Benzing, Thomas] Univ Cologne, Syst Biol Ageing Cologne Sybacol, D-50937 Cologne, Germany. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. [Wu, Xiongwu] NHLBI, LCB, NIH, Bethesda, MD 20892 USA. [Maass, Martina] Univ Cologne, Dept Cardiol, D-50937 Cologne, Germany. RP Rinschen, MM (reprint author), Univ Cologne, Dept Internal Med 2, Kerpener Str 62, D-50937 Cologne, Germany. EM markus.rinschen@uk-koeln.de; paul.brinkkoetter@uk-koeln.de RI Schermer, Bernhard/E-9972-2014 OI Schermer, Bernhard/0000-0002-5194-9000 FU German Research Foundation [Sonderforschungsbereich 635, SCHE1562-2, BR2955]; German Federal Ministry of Education and Research (GerontoSys2 program Sybacol); Ratchadapiseksomphot Endowment Fund of Chulalongkorn University [RES560530124-HR]; Koln Fortune; German Research Foundation (DFG); Fritz-Scheler-Stipendium of the KFH-Stiftung fur Praventivmedizin FX The MS proteomics data in this paper have been deposited in the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [11]: dataset identifier PXD001005. This work was supported by the German Research Foundation (Sonderforschungsbereich 635 to T.B., SCHE1562-2 to B.S. and BR2955 to P.T.B.]) and the German Federal Ministry of Education and Research (GerontoSys2 program Sybacol to T.B. and B.S.). T.P. was supported by the Ratchadapiseksomphot Endowment Fund of Chulalongkorn University (RES560530124-HR). M.M.R. was supported by Koln Fortune, by German Research Foundation (DFG) in the framework of the German Excellence Initiative (UoC Postdoc Grant) and by the Fritz-Scheler-Stipendium of the KFH-Stiftung fur Praventivmedizin. The authors thank Ruth Herzog, Astrid Wilbrand-Hennes and Rene Grandjean for excellent technical help. The authors thank Andreas Beyer for helpful discussions. The authors thank Fahad Saeed and Boyang Zhao for help with the CPhos software and Jinho Kim and Peter Frommolt for help with the Netphorest software. NR 27 TC 4 Z9 4 U1 1 U2 2 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 APR PY 2015 VL 15 IS 7 BP 1326 EP 1331 DI 10.1002/pmic.201400235 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF4IL UT WOS:000352512100018 PM 25420462 ER PT J AU Marrero, DG Ma, Y de Groot, M Horton, ES Price, DW Barrett-Connor, E Carnethon, MR Knowler, WC AF Marrero, David G. Ma, Yong de Groot, Mary Horton, Edward S. Price, David W. Barrett-Connor, Elizabeth Carnethon, Mercedes R. Knowler, William C. CA Diabet Prevention Program Res Grp TI Depressive Symptoms, Antidepressant Medication Use, and New Onset of Diabetes in Participants of the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE diagnosis of diabetes; depressive symptoms; antidepressant medication; prediabetes; Type 2 diabetes mellitus; prevenion ID GLYCEMIC CONTROL; MEDICINE USE; TYPE-2; METAANALYSIS; ADULTS; RISK; ASSOCIATION; POPULATION; MELLITUS AB Objective To assess in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study whether diagnosis of diabetes predicted elevated depressive symptoms (DS) or use of antidepressant medicine (ADM) following diagnosis; whether diabetes status or duration had significant effect on DS or ADM use; and to determine the associations between A1C, fasting plasma glucose (FPG), normalization of FPG, and DS or ADM use after diagnosis. Methods Diabetes Prevention Program participants in three treatment arms (intensive life style, metformin, placebo) were assessed for diabetes, glucose control, ADM use, and DS, measured using the Beck Depression Inventory (BDI). Among 3234 participants, 1285 developed diabetes. Depression levels were measured before and after diabetes diagnosis. Results Neither DS nor use of ADM increased after diagnosis; higher FPG was associated with greater ADM use in the intensive life style arm; a 10-mg/dl rise in FPG is associated with greater odds of ADM use. Higher FPG and A1C were associated with higher BDI scores in all three arms; A 10-mg/dl rise in FPG had a 0.07 increase in BDI. A 1% higher A1c was associated with a 0.21-point increase in BDI. Normalization of FPG was associated with lower BDI. When FPG had normalized, there was a decrease of 0.30 points in the BDI score compared when FPG had not normalized. Conclusions Contrary to clinical attributions, diabetes diagnosis did not show an immediate impact on BDI scores or ADM use. Higher glucose levels after diagnosis were associated with a small but significantly higher BDI score and more ADM use. Trial Registration: DPPOS: NCT00038727; DPP: NCT00004992 C1 [Marrero, David G.; de Groot, Mary] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Ma, Yong] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Horton, Edward S.] Harvard Univ, Sch Med, Boston, MA USA. [Price, David W.] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family Med, San Diego, CA 92103 USA. [Carnethon, Mercedes R.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. RP Marrero, DG (reprint author), George Washington Univ, Biostat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@bsc.gwu.edu RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 FU DPPOS; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart Lung and Blood Institute; Office of Research on Women's Health; National Institute on Minority Health and Health Disparities; Centers for Disease Control and Prevention; American Diabetes Association; Bristol-Myers Squibb; Parke-Davis FX The Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. During the DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center. The Southwestern American Indian Centers were supported directly by the National Institute of Diabetes and Digestive and Kidney Diseases. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Research on Women's Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication, and LifeScan, Inc donated materials during the DPP and DPPOS. LifeScan Inc; Health O Meter; Hoechst Marion Roussel, Inc; Merck-Medco Managed Care, Inc; Merck and Co; Nike Sports Marketing; Slim Fast Foods Co; and Quaker Oats Co donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp; Matthews Media Group, Inc; and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The authors have no relevant conflicts of interest to disclose. NR 26 TC 1 Z9 2 U1 2 U2 6 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 APR PY 2015 VL 77 IS 3 BP 303 EP 310 DI 10.1097/PSY.0000000000000156 PG 8 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CF9CU UT WOS:000352860000064 PM 25775165 ER PT J AU Guardino, CM Schetter, CD Hobel, CJ Lanzi, RG Schafer, P Shalowitz, MU Thorp, JM AF Guardino, Christine M. Schetter, Christine Dunkel Hobel, Calvin J. Lanzi, Robin Gaines Schafer, Peter Shalowitz, Madeleine U. Thorp, John M. TI Predictors of C-reactive protein in mothers during the first postpartum year SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 73rd Annual Meeting of the American-Psychosomatic-Society CY MAR 18-21, 2015 CL Savannah, GA SP Amer Psychosomat Soc C1 [Guardino, Christine M.; Schetter, Christine Dunkel] Univ Calif Los Angeles, Psychol, Los Angeles, CA USA. [Hobel, Calvin J.] Univ Calif Los Angeles, David Geffen Sch Med, Obstet & Gynecol, Los Angeles, CA 90095 USA. [Lanzi, Robin Gaines] Univ Alabama Birmingham, Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL 35294 USA. [Schafer, Peter] New York Acad Med, Hlth Policy, New York, NY USA. [Shalowitz, Madeleine U.] NorthShore Univ HealthSyst, Pediat, Evanston, IL USA. [Thorp, John M.] Univ N Carolina, Obstet & Gynecol, Chapel Hill, NC USA. [Thorp, John M.] Eunice Kennedy Shriver Natl Inst Child & Hlth Dev, NIH, NICHD, Community Child Hlth Network, Bethesda, MD USA. NR 0 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 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2015 VL 77 IS 3 MA 2812 BP A13 EP A13 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CF9CU UT WOS:000352860000040 ER PT J AU Franasiak, JM Burns, KA Slayden, O Yuan, LW Fritz, MA Korach, KS Lessey, BA Young, SL AF Franasiak, Jason M. Burns, Katherine A. Slayden, Ov Yuan, Lingwen Fritz, Marc A. Korach, Kenneth S. Lessey, Bruce A. Young, Steven L. TI Endometrial CXCL13 Expression Is Cycle Regulated in Humans and Aberrantly Expressed in Humans and Rhesus Macaques With Endometriosis SO REPRODUCTIVE SCIENCES LA English DT Article DE CXCL13; endometriosis; proliferative phase ID GENE-EXPRESSION; CHEMOKINE CXCL13; PROGESTERONE RESISTANCE; IMMUNOLOGICAL ASPECTS; PELVIC ENDOMETRIOSIS; EUTOPIC ENDOMETRIUM; DISEASE-ACTIVITY; CANCER CELLS; WOMEN; RECRUITMENT AB C-X-C ligand 13 (CXCL13), a regulator of mucosal immunity, is secreted by human endometrial epithelium and may be involved in embryo implantation. However, cyclic expression of human endometrial CXCL13 in health and disease is not well studied. This study examines cycle stage-specific endometrial CXCL13 expression in normal humans when compared to those with biopsy-confirmed, stage 1 to 4 endometriosis using real-time reverse transcriptase, real-time polymerase chain reaction and immunohistochemistry. Eutopic endometrial CXCL13 expression was also compared between normal, control Rhesus macaques, and macaques with advanced endometriosis. In healthy women, CXLC13 messenger RNA expression was minimal in the proliferative phase and maximal in the secretory phase. However, in the presence of endometriosis, proliferative-phase endometrial expression markedly increased in both humans and rhesus subjects (P < .05). The cross-species and cross-stage concordance suggests a pathophysiologic role for CXCL13 in endometriosis and its use as a biomarker for disease. C1 [Franasiak, Jason M.] Rutgers State Univ, Obstet Gynecol & Reprod Sci, Robert Wood Johnson Med Sch, Basking Ridge, NJ USA. [Burns, Katherine A.; Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Slayden, Ov] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Yuan, Lingwen; Fritz, Marc A.; Young, Steven L.] UNC Sch Med, Ob Gyn, Chapel Hill, NC USA. [Lessey, Bruce A.] Greenville Hlth Syst, Ob Gyn, Greenville, SC USA. RP Young, SL (reprint author), 4005 Old Clin Bldg,Campus Box 7570, Chapel Hill, NC 27599 USA. EM steven_young@med.unc.edu OI Korach, Kenneth/0000-0002-7765-418X FU University of North Carolina Reproductive Endocrinology and Infertility Division; NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD067721]; Division of Intramural Research of the NIH Health Sciences [Z01 ES70065]; NIH [U51OD011092] 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 by the University of North Carolina Reproductive Endocrinology and Infertility Division (MAF, JMF, and SLY) and the following federal support: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD067721 to BAL & SLY, the Division of Intramural Research of the NIH Health Sciences Z01 ES70065 to KSK and KAB, and NIH U51OD011092 to OS. NR 65 TC 5 Z9 5 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD APR PY 2015 VL 22 IS 4 BP 442 EP 451 DI 10.1177/1933719114542011 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CF8GT UT WOS:000352794900008 PM 25031316 ER PT J AU Morrison, BJ Labo, N Miley, WJ Whitby, D AF Morrison, Brian J. Labo, Nazzarena Miley, Wendell J. Whitby, Denise TI Serodiagnosis for Tumor Viruses SO SEMINARS IN ONCOLOGY LA English DT Review ID EPSTEIN-BARR-VIRUS; HEPATITIS-B-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; MERKEL CELL-CARCINOMA; HUMAN-PAPILLOMAVIRUS TYPE-16; KAPOSIS-SARCOMA; HTLV-II; HUMAN-HERPESVIRUS-8 INFECTION; LAMIVUDINE RESISTANCE; SEROLOGIC ASSAYS AB The known human tumor viruses include the DNA viruses Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV), Merkel cell polyomavirus (MCPyV), human papillomavirus (HPV), and hepatitis B virus (BV). RNA tumor viruses include human T-cell lymphotrophic virus type 1 (HTLV-1) and hepatitis C virus (HCV). The serological identification of antigens/antibodies in serum is a rapidly progressing field with utility for both scientists and clinicians. Serology is useful for conducting seroepidemiology studies and to inform on the pathogenesis and host immune response to a particular viral agent. Clinically, serology is useful for diagnosing current or past infection and for aiding in clinical management decisions. Serology is useful for screening blood donations for infectious agents and for monitoring the outcome of vaccination against these viruses. Serodiagnosis of human tumor viruses has improved in recent years with increased specificity and sensitivity of the assays, as well as reductions in cost and the ability to assess multiple antibody/antigens in single assays. Serodiagnosis of tumor viruses plays an important role in our understanding of the prevalence and transmission of these viruses and ultimately in the ability to develop treatments/preventions for these globally important diseases. C1 [Morrison, Brian J.; Labo, Nazzarena; Miley, Wendell J.; Whitby, Denise] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Viral Oncol Sect, Frederick, MD 21702 USA. [Labo, Nazzarena] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Whitby, D (reprint author), Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Viral Oncol Sect, POB B, Frederick, MD 21702 USA. EM whitbyd@mail.nih.gov FU NCI NIH HHS [HHSN261200800001E] NR 110 TC 5 Z9 6 U1 0 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 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2015 VL 42 IS 2 BP 191 EP 206 DI 10.1053/j.seminoncol.2014.12.024 PG 16 WC Oncology SC Oncology GA CF7SX UT WOS:000352757700002 PM 25843726 ER PT J AU Bhutani, M Polizzotto, MN Uldrick, TS Yarchoan, R AF Bhutani, Manisha Polizzotto, Mark N. Uldrick, Thomas S. Yarchoan, Robert TI Kaposi Sarcoma-Associated Herpesvirus-Associated Malignancies: Epidemiology, Pathogenesis, and Advances in Treatment SO SEMINARS IN ONCOLOGY LA English DT Review ID MULTICENTRIC CASTLEMAN-DISEASE; PRIMARY EFFUSION LYMPHOMA; HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEIN-COUPLED RECEPTOR; PEGYLATED-LIPOSOMAL DOXORUBICIN; NF-KAPPA-B; PHASE-II TRIAL; HUMAN-HERPESVIRUS-8 HHV-8 INFECTION; INFLAMMATORY CYTOKINE SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY AB Kaposi sarcoma associated herpesvirus (KSHV), a gamma 2-herpesvirus, also known as human herpesvirus-8, is the etiologic agent of three virally associated tumors: Kaposi sarcoma, a plasmablastic form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These malignancies are predominantly seen in people with acquired immunodeficiencies, including acquired immunodeficiency syndrome and iatrogenic immunosuppression in the setting of organ transplantation, but can also develop in the elderly. Kaposi sarcoma (KS) is most frequent in regions with high KSHV seroprevalence, such as sub-Saharan Africa and some Mediterranean countries. In the era of combination antiviral therapy, inflammatory. manifestations associated with KSHV-infection, including KSHV-MCD, a recently described KSHV-associated inflammatory cytokine syndrome and KS immune reconstitution syndrome also are increasingly appreciated. Our understanding of viral and immune mechanisms of oncogenesis continues to expand and lead to improved molecular diagnostics, as well as novel therapeutic strategies that employ immune modulatory agents, manipulations of the tumor microenvironment, virus-activated cytotoxic therapy, or agents that target interactions between specific virus-host cell signaling pathways. This review focuses on the epidemiology and advances in molecular and clinical research that reflects the current understanding of viral oncogenesis, clinical manifestations, and therapeutics for KSHV-associated tumors. C1 [Bhutani, Manisha; Polizzotto, Mark N.; Uldrick, Thomas S.; Yarchoan, Robert] NCI, Ctr Canc Res, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, 10 Ctr Dr 6N106, Bethesda, MD 20892 USA. EM Robert.Yarchoan@nih.gov FU Intramural Research Program, National Cancer Institute (NCI), NIH FX This research was supported in part by the Intramural Research Program, National Cancer Institute (NCI), NIH. NR 202 TC 29 Z9 29 U1 2 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2015 VL 42 IS 2 BP 223 EP 246 DI 10.1053/j.seminoncol.2014.12.027 PG 24 WC Oncology SC Oncology GA CF7SX UT WOS:000352757700004 PM 25843728 ER PT J AU Biering-Sorensen, F Alai, S Anderson, K Charlifue, S Chen, Y DeVivo, M Flanders, AE Jones, L Kleitman, N Lans, A Noonan, VK Odenkirchen, J Steeves, J Tansey, K Widerstrom-Noga, E Jakeman, L AF Biering-Sorensen, F. Alai, S. Anderson, K. Charlifue, S. Chen, Y. DeVivo, M. Flanders, A. E. Jones, L. Kleitman, N. Lans, A. Noonan, V. K. Odenkirchen, J. Steeves, J. Tansey, K. Widerstroem-Noga, E. Jakeman, L. TI Common data elements for spinal cord injury clinical research: a National Institute for Neurological Disorders and Stroke project SO SPINAL CORD LA English DT Review ID BASIC DATA SET; ICCP PANEL; INTERNATIONAL CLASSIFICATION; MOTOR RECOVERY; CDE PROJECT; TRIALS; GUIDELINES; CONDUCT; HEALTH; REHABILITATION AB Objectives: To develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in spinal cord injury (SCI) clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. Setting: International Working Groups. Methods: Nine working groups composed of international experts reviewed existing CDEs and instruments, created new elements when needed and provided recommendations for SCI clinical research. The project was carried out in collaboration with and cross-referenced to development of the International Spinal Cord Society (ISCoS) International SCI Data Sets. The recommendations were compiled, subjected to internal review and posted online for external public comment. The final version was reviewed by all working groups and the NINDS CDE team before release. Results: The NINDS SCI CDEs and supporting documents are publically available on the NINDS CDE website and the ISCoS website. The CDEs span the continuum of SCI care and the full range of domains of the International Classification of Functioning, Disability and Health. Conclusion: Widespread use of CDEs can facilitate SCI clinical research and trial design, data sharing and retrospective analyses. Continued international collaboration will enable consistent data collection and reporting, and will help ensure that the data elements are updated, reviewed and broadcast as additional evidence is obtained. C1 [Biering-Sorensen, F.] Univ Copenhagen, Rigshosp, Dept Spinal Cord Injuries, DK-2100 Copenhagen, Denmark. [Alai, S.; Lans, A.] EMMES Corp, Rockville, MD USA. [Anderson, K.; Widerstroem-Noga, E.] Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA. [Charlifue, S.] Craig Hosp, Englewood, CO USA. [Chen, Y.; DeVivo, M.] Univ Alabama Birmingham, Birmingham, AL USA. [Flanders, A. E.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Jones, L.; Kleitman, N.] Craig H Neilsen Fdn, Encino, CA USA. [Noonan, V. K.] Rick Hansen Inst, Vancouver, BC, Canada. [Odenkirchen, J.; Jakeman, L.] NINDS, NIH, Bethesda, MD 20892 USA. [Steeves, J.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Steeves, J.] Vancouver Coastal Hlth, Vancouver, BC, Canada. [Tansey, K.] Emory Univ, Atlanta, GA 30322 USA. [Tansey, K.] Atlanta VA Med Ctr, Atlanta, GA USA. RP Jakeman, L (reprint author), NINDS Repair & Plast, NIH, Ctr Neurosci, MSC 9525,6001 Execut Blvd, Bethesda, MD 20852 USA. EM lyn.jakeman@nih.gov OI Kleitman, Naomi/0000-0003-1089-0257 FU NIH [HHSN271201200034C] FX The views expressed here are those of the authors and do not represent those of the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke (NINDS) or the US Government. Logistics support for this project was provided in part through NIH Contract HHSN271201200034C. The development of the NINDS SCI CDEs was made possible thanks to the great investment of time and effort of all organizing committee and WG members and members of the NINDS CDE Project team, participating from 2007 to 2014. NR 65 TC 8 Z9 8 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 EI 1476-5624 J9 SPINAL CORD JI Spinal Cord PD APR PY 2015 VL 53 IS 4 BP 265 EP 277 DI 10.1038/sc.2014.246 PG 13 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA CF7GX UT WOS:000352725500003 PM 25665542 ER PT J AU Sheliga, BM Quaia, C FitzGibbon, EJ Cumming, BG AF Sheliga, B. M. Quaia, C. FitzGibbon, E. J. Cumming, B. G. TI Anisotropy in spatial summation properties of human Ocular-Following Response (OFR) SO VISION RESEARCH LA English DT Article DE Visual motion; Orientation selectivity; Surround inhibition ID PRIMARY VISUAL-CORTEX; CENTER-SURROUND INTERACTIONS; MACAQUE V1 NEURONS; BEHAVIORAL RECEPTIVE-FIELD; TRACKING EYE-MOVEMENTS; PERCEIVED CONTRAST; MOTION INTEGRATION; TEMPORAL DYNAMICS; CONTEXTUAL MODULATION; APPARENT CONTRAST AB Using sinusoidal gratings we show that an increase in stimulus size confined to the dimension orthogonal to the axis of motion leads to stronger Ocular Following Responses (OFRs) up to a certain optimal size. An increase beyond this optimum produces smaller responses, indicating suppressive interactions. In sharp contrast, when the stimulus growth occurs parallel to the axis of motion OFR magnitudes increase monotonically both for horizontal and vertical directions of motion. Similar results are obtained with 1D white noise patterns. However, the OFR spatial anisotropy is minimal with 2D white noise patterns, revealing a pivotal role of orientation-selective (i.e., cortical) mechanisms in mediating this phenomenon. The lack of anisotropy for 20 patterns suggests that directional signals alone are not sufficient to elicit this suppression. The OFR spatial anisotropy is potentiated if a stationary grating is presented for 600-1000 ms before its motion commences, further emphasizing the importance of static orientation signals. These results suggest that the strength of cortical spatial interactions is asymmetric-i.e., larger in the direction of the ends than the flanks of an orientation-selective receptive field-which corroborates the existing neurophysiological evidence. Published by Elsevier Ltd. C1 [Sheliga, B. M.; Quaia, C.; FitzGibbon, E. J.; Cumming, B. G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sheliga, BM (reprint author), NIH, Sensorimotor Res Lab, Bldg 49 Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural Research Program of the National Eye Institute at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Eye Institute at the National Institutes of Health. NR 55 TC 0 Z9 0 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD APR PY 2015 VL 109 BP 11 EP 19 DI 10.1016/j.visres.2015.02.015 PN A PG 9 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA CF9ZV UT WOS:000352927300002 PM 25743079 ER PT J AU Jaiswal, R Singh, SK Bastia, D Escalante, CR AF Jaiswal, Rahul Singh, Samarendra K. Bastia, Deepak Escalante, Carlos R. TI Crystallization and preliminary X-ray characterization of the eukaryotic replication terminator Reb1-Ter DNA complex SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE protein-DNA complex; Reb1; transcription termination; eukaryotic; RNA Pol I ID SCHIZOSACCHAROMYCES-POMBE; RIBOSOMAL DNA; POLAR ARREST; FORK; CHECKPOINT; YEAST AB The Reb1 protein from Schizosaccharomyces pombe is a member of a family of proteins that control programmed replication termination and/or transcription termination in eukaryotic cells. These events occur at naturally occurring replication fork barriers (RFBs), where Reb1 binds to termination (Ter) DNA sites and coordinates the polar arrest of replication forks and transcription approaching in opposite directions. The Reb1 DNA-binding and replication-termination domain was expressed in Escherichia coli, purified and crystallized in complex with a 26-mer DNA Ter site. Batch crystallization under oil was required to produce crystals of good quality for data collection. Crystals grew in space group P2(1), with unit-cell parameters a = 68.9, b = 162.9, c = 71.1 angstrom beta = 94.7 degrees. The crystals diffracted to a resolution of 3.0 angstrom. The crystals were mosaic and required two or three cycles of annealing. This study is the first to yield structural information about this important family of proteins and will provide insights into the mechanism of replication and transcription termination. C1 [Jaiswal, Rahul; Escalante, Carlos R.] Virginia Commonwealth Univ, Dept Physiol & Biophys, Richmond, VA 23298 USA. [Jaiswal, Rahul] Nanyang Technol Univ, SBS, Singapore 637551, Singapore. [Singh, Samarendra K.; Bastia, Deepak] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Singh, Samarendra K.] NIH, Bethesda, MD 20892 USA. RP Escalante, CR (reprint author), Virginia Commonwealth Univ, Dept Physiol & Biophys, 1220 East Broad St, Richmond, VA 23298 USA. EM cescalante@vcu.edu FU SCTR [1211]; ACS-IRG [11997-IRG-73-001-34-IRG]; [5R01GM098013]; [1R01GM092854] FX This work was supported by grants 5R01GM098013 and SCTR #1211 awarded to DB and 1R01GM092854 and ACS-IRG 11997-IRG-73-001-34-IRG to CRE. We would like to thank members of NSLS beamline X6a, Vivian Stojanoff, Jean Jakoncic and Edwin Lazo, for their valuable help in data collection. NR 17 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD APR PY 2015 VL 71 BP 414 EP 418 DI 10.1107/S2053230X15004112 PN 4 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CF4GY UT WOS:000352508000010 PM 25849502 ER PT J AU Litten, RZ Ryan, ML Falk, DE Reilly, M Fertig, JB Koob, GF AF Litten, Raye Z. Ryan, Megan L. Falk, Daniel E. Reilly, Matthew Fertig, Joanne B. Koob, George F. TI Heterogeneity of Alcohol Use Disorder: Understanding Mechanisms to Advance Personalized Treatment SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material ID DISEASE; CONSUMPTION; DRINKING; PHARMACOTHERAPY; PREVENTION; FOCUS C1 [Litten, Raye Z.; Ryan, Megan L.; Falk, Daniel E.; Fertig, Joanne B.] NIAAA, NCIG, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. [Reilly, Matthew] NIAAA, Div Neurosci & Behav, Bethesda, MD 20892 USA. [Koob, George F.] NIAAA, Off Director, Bethesda, MD 20892 USA. RP Litten, RZ (reprint author), NIAAA, Div Treatment & Recovery Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM rlitten@mail.nih.gov RI koob, george/P-8791-2016 NR 29 TC 24 Z9 24 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2015 VL 39 IS 4 BP 579 EP 584 DI 10.1111/acer.12669 PG 6 WC Substance Abuse SC Substance Abuse GA CF5VR UT WOS:000352625800001 PM 25833016 ER PT J AU Haass-Koffler, CL Leggio, L Davidson, D Swift, RM AF Haass-Koffler, Carolina L. Leggio, Lorenzo Davidson, Dena Swift, Robert M. TI Effects of Idazoxan on Alcohol Pharmacokinetics and Intoxication: A Preliminary Human Laboratory Study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Challenge Study; Idazoxan; Norepinephrine; PK; PD Alcohol Model ID ALPHA-2 ADRENOCEPTOR ANTAGONISTS; PREFERRING P RATS; ETHANOL INTOXICATION; USE DISORDERS; NOREPINEPHRINE; CATECHOLAMINE; CONSUMPTION; CLONIDINE; YOHIMBINE; DRINKING AB BackgroundPreliminary basic and human studies suggest that the (2)-adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects. MethodsThis was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40mg) or placebo, followed by a fixed alcohol dose 60minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition. ResultsThere were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p<0.01) and time to peak (p<0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40mg idazoxan with alcohol decreased alcohol-related stimulation (p<0.05) and increased alcohol-related sedation (p<0.05). ConclusionsThis study supports the safety and tolerability of 40mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients. C1 [Haass-Koffler, Carolina L.; Leggio, Lorenzo] Brown Univ, Dept Behav & Social Sci, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, LCTS, NIH, Bethesda, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Davidson, Dena] Waco VA Med Ctr, Waco, TX USA. [Swift, Robert M.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Swift, Robert M.] Providence VA Med Ctr, Providence, RI USA. RP Haass-Koffler, CL (reprint author), Brown Univ, Sch Publ Hlth, Dept Behav & Social Sci, Ctr Alcohol & Addict Studies, Box G-S121-4, Providence, RI 02912 USA. EM carolina_haass-koffler@brown.edu RI Leggio, Lorenzo/M-2972-2016 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [5T32AA007459-28]; NIAAA Division of Intramural Clinical and Biological Research; National Institute on Drug Abuse (NIDA) Intramural Research Program FX CLH-K's work is supported by the 5T32AA007459-28 training grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). LL's present work is supported by the NIAAA Division of Intramural Clinical and Biological Research and the National Institute on Drug Abuse (NIDA) Intramural Research Program. NR 50 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2015 VL 39 IS 4 BP 594 EP 602 DI 10.1111/acer.12658 PG 9 WC Substance Abuse SC Substance Abuse GA CF5VR UT WOS:000352625800010 PM 25833022 ER PT J AU Blair, EM Nelson, KB AF Blair, Eve M. Nelson, Karin B. TI Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks' gestation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE birth asphyxia; birth defects; pregnancy-induced hypertension; smoking; term and late preterm birth ID INTRAUTERINE GROWTH; NEONATAL ENCEPHALOPATHY; BIRTH-WEIGHT; TERM; ASSOCIATION; AGE; PREECLAMPSIA; HYPERTENSION; POPULATION; PLACENTA AB OBJECTIVE: The objective of the study was to improve the understanding of etiological paths to cerebral palsy (CP) that include fetal growth restriction by examining factors associated with growth restriction that modify CP risk. STUDY DESIGN: In a total population of singletons born at or after 35 weeks, there were 493 children with CP and 508 matched controls for whom appropriateness of fetal growth could be estimated. Fetal growth was considered markedly restricted if birthweight was more than 2 SD below optimal for gender, gestation, maternal height, and parity. We examined maternal blood pressure in pregnancy, smoking, birth asphyxia, and major birth defects recognized by age 6 years as potential modifiers of CP risk in growth-restricted births. RESULTS: More than 80% of term and late preterm markedly growth-restricted singletons were born following a normotensive pregnancy and were at statistically significantly increased risk of CP (odds ratio, 4.81; 95% confidence interval, 2.7-8.5), whereas growth-restricted births following a hypertensive pregnancy were not. Neither a clinical diagnosis of birth asphyxia nor potentially asphyxiating birth events occurred more frequently among growth-restricted than among appropriately grown infants with CP. Major birth defects, particularly cerebral defects, occurred in an increasing proportion of CP with increasing growth deficit. The factor most predictive of CP in growth-restricted singletons was a major birth defect, present in 53% of markedly growth-restricted neonates with later CP. Defects observed in CP were similar whether growth restricted or not, except for an excess of isolated congenital microcephaly in those born growth restricted. The highest observed CP risk was in infants with both growth restriction and a major birth defect (8.9% of total CP in this gestational age group, 0.4% of controls: odds ratio, 30.9; 95% confidence interval, 7.0-136). CONCLUSION: The risk of CP was increased in antenatally growth-restricted singletons born at or near term to normotensive mothers. In growth-restricted singletons, a major birth defect was the dominant predictor, associated with a 30-fold increase in odds of CP. Identification of birth defects in the growth-restricted fetus or neonate may provide significant prognostic information. C1 [Blair, Eve M.] Univ Western Australia, Telethon Kids Inst, Perth, WA 6009, Australia. [Nelson, Karin B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Nelson, Karin B.] NINDS, Bethesda, MD USA. RP Blair, EM (reprint author), Univ Western Australia, Telethon Kids Inst, Perth, WA 6009, Australia. EM Eve.Blair@telethonkids.org.au FU Western Australian State Department of Health FX We thank Linda Watson (Western Australian Register of Developmental Anomaliese-Cerebral Palsy) and Professor Carol Bower (Western Australian Register of Developmental Anomalies) for providing access to the data from their respective registers. This Register is funded by the Western Australian State Department of Health. NR 34 TC 8 Z9 8 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2015 VL 212 IS 4 AR 520.e1 DI 10.1016/j.ajog.2014.10.1103 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CE9EQ UT WOS:000352147100030 PM 25448521 ER PT J AU Facco, FL Parker, CB Reddy, UM Silver, RM Louis, JM Basner, RC Chung, JH Schubert, FP Pien, GW Redline, S Mobley, DR Koch, MA Simhan, HN Nhan-Chang, CL Parry, S Grobman, WA Haas, DM Wing, DA Mercer, BM Saade, GR Zee, PC AF Facco, Francesca L. Parker, Corette B. Reddy, Uma M. Silver, Robert M. Louis, Judette M. Basner, Robert C. Chung, Judith H. Schubert, Frank P. Pien, Grace W. Redline, Susan Mobley, Daniel R. Koch, Matthew A. Simhan, Hyagriv N. Nhan-Chang, Chia-Ling Parry, Samuel Grobman, William A. Haas, David M. Wing, Deborah A. Mercer, Brian M. Saade, George R. Zee, Phyllis C. TI NuMoM2b Sleep-Disordered Breathing study: objectives and methods SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE home sleep test; methods; pregnancy; sleep-disordered breathing; sleep ID INSOMNIA RATING-SCALE; HEART HEALTH; PREGNANT-WOMEN; APNEA SYNDROME; NASAL CPAP; CARDIOVASCULAR-DISEASE; DAYTIME SLEEPINESS; AMERICAN-COLLEGE; CLINICAL-TRIAL; OBESE-PATIENTS AB OBJECTIVE: The objective of the Sleep Disordered Breathing substudy of the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) is to determine whether sleep disordered breathing during pregnancy is a risk factor for adverse pregnancy outcomes. STUDY DESIGN: NuMoM2b is a prospective cohort study of 10,037 nulliparous women with singleton gestations that was conducted across 8 sites with a central Data Coordinating and Analysis Center. The Sleep Disordered Breathing substudy recruited 3702 women from the cohort to undergo objective, overnight in-home assessments of sleep disordered breathing. A standardized level 3 home sleep test was performed between 6(0) - 15(0) weeks' gestation (visit 1) and again between 22(0) - 31(0) weeks' gestation (visit 3). Scoring of tests was conducted by a central Sleep Reading Center. Participants and their health care providers were notified if test results met "urgent referral" criteria that were based on threshold levels of apnea hypopnea indices, oxygen saturation levels, or electrocardiogram abnormalities but were not notified of test results otherwise. The primary pregnancy outcomes to be analyzed in relation to maternal sleep disordered breathing are preeclampsia, gestational hypertension, gestational diabetes mellitus, fetal growth restriction, and preterm birth. RESULTS: Objective data were obtained at visit 1 on 3261 women, which was 88.1% of the studies that were attempted and at visit 3 on 2511 women, which was 87.6% of the studies that were attempted. Basic characteristics of the substudy cohort are reported in this methods article. CONCLUSION: The substudy was designed to address important questions regarding the relationship of sleep- disordered breathing on the risk of preeclampsia and other outcomes of relevance to maternal and child health. C1 [Facco, Francesca L.; Simhan, Hyagriv N.] Univ Pittsburgh, Sch Med, Magee Womens Res Inst & Fdn, Dept Obstet & Gynecol, Pittsburgh, PA 15260 USA. [Parry, Samuel] Univ Penn, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Philadelphia, PA 19104 USA. [Parker, Corette B.; Koch, Matthew A.] RTI Int, Res Triangle Pk, NC USA. [Reddy, Uma M.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. [Pien, Grace W.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Silver, Robert M.] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT USA. [Louis, Judette M.; Mercer, Brian M.] Case Western Reserve Univ, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Cleveland, OH 44106 USA. [Basner, Robert C.] Columbia Univ, Coll Phys & Surg, Dept Clin Med, New York, NY USA. [Nhan-Chang, Chia-Ling] Columbia Univ, Coll Phys & Surg, Div Maternal Fetal Med, Dept Obstet & Gynecol, New York, NY USA. [Chung, Judith H.; Wing, Deborah A.] Univ Calif Irvine, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Irvine, CA 92717 USA. [Schubert, Frank P.; Haas, David M.] Indiana Univ Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Indianapolis, IN 46202 USA. [Redline, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Mobley, Daniel R.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chicago, IL 60611 USA. [Zee, Phyllis C.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Zee, Phyllis C.] Northwestern Univ, Feinberg Sch Med, Ctr Circadian & Sleep Med, Chicago, IL 60611 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX 77555 USA. RP Facco, FL (reprint author), Univ Pittsburgh, Sch Med, Magee Womens Res Inst & Fdn, Dept Obstet & Gynecol, Pittsburgh, PA 15260 USA. EM faccof@upmc.edu RI Louis, Judette/E-5130-2013 OI Louis, Judette/0000-0002-1336-7886 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart Lung and Blood Institute [U10 HD063036, U10 HD063072, U10 HD063047, U10 HD063037, U10 HD063041, U10 HD063020, U10 HD063046, U10 HD063048, U10 HD063053] FX Supported by Supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Heart Lung and Blood Institute: U10 HD063036, Research Triangle Institute; U10 HD063072, Case Western Reserve University; U10 HD063047, Columbia University; U10 HD063037, Indiana University; U10 HD063041, Magee-Women's Hospital; U10 HD063020, Northwestern University; U10 HD063046, University of California Irvine; U10 HD063048, University of Pennsylvania; and U10 HD063053, University of Utah. NR 71 TC 0 Z9 0 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2015 VL 212 IS 4 AR 542.e1 DI 10.1016/j.ajog.2015.01.021 PG 127 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CE9EQ UT WOS:000352147100038 PM 25746730 ER PT J AU Haas, DM Parker, CB Wing, DA Parry, S Grobman, WA Mercer, BM Simhan, HN Hoffman, MK Silver, RM Wadhwa, P Iams, JD Koch, MA Caritis, SN Wapner, RJ Esplin, S Elovitz, MA Foroud, T Peaceman, AM Saade, GR Willinger, M Reddy, UM AF Haas, David M. Parker, Corette B. Wing, Deborah A. Parry, Samuel Grobman, William A. Mercer, Brian M. Simhan, Hyagriv N. Hoffman, Matthew K. Silver, Robert M. Wadhwa, Pathik Iams, Jay D. Koch, Matthew A. Caritis, Steve N. Wapner, Ronald J. Esplin, Sean Elovitz, Michal A. Foroud, Tatiana Peaceman, Alan M. Saade, George R. Willinger, Marian Reddy, Uma M. CA NuMoM2b Study TI A description of the methods of the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE adverse pregnancy outcome; cohort study; methods; nulliparous; prediction; pregnancy; psychosocial ID UTERINE ARTERY DOPPLER; INTRAUTERINE GROWTH RESTRICTION; SPONTANEOUS PRETERM BIRTH; 1ST-TRIMESTER PREDICTION; GESTATIONAL-AGE; BRAIN-DAMAGE; RISK-FACTORS; SHORT-FORM; PREECLAMPSIA; SCALE AB OBJECTIVE: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes. STUDY DESIGN: Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction. RESULTS: We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported. CONCLUSION: The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects. C1 [Haas, David M.] Indiana Univ Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Wing, Deborah A.] Univ Calif Irvine, Sch Med, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Wadhwa, Pathik] Univ Calif Irvine, Sch Med, Dept Psychiat, Irvine, CA 92717 USA. [Parker, Corette B.; Koch, Matthew A.] RTI Int, Res Triangle Pk, NC USA. [Willinger, Marian; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Parry, Samuel; Elovitz, Michal A.] Univ Penn, Sch Med, Dept Obstet, Philadelphia, PA 19104 USA. [Parry, Samuel; Elovitz, Michal A.] Univ Penn, Sch Med, Dept Gynecol, Philadelphia, PA 19104 USA. [Simhan, Hyagriv N.; Caritis, Steve N.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Grobman, William A.; Peaceman, Alan M.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Mercer, Brian M.] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Iams, Jay D.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Hoffman, Matthew K.] Christiana Care Hlth Syst, Newark, DE USA. [Silver, Robert M.; Esplin, Sean] Univ Utah, Sch Med, Salt Lake City, UT USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. RP Haas, DM (reprint author), Indiana Univ Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. EM dahaas@iupui.edu OI Haas, David/0000-0002-8379-0743; Hoffman, Matthew/0000-0002-2927-8693 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD063036, U10 HD063072, U10 HD063047, U10 HD063037, U10 HD063041, U10 HD063020, U10 HD063046, U10 HD063048, U10 HD063053]; Clinical and Translational Science Institutes [UL1TR001108, UL1TR000153] FX Supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10 HD063036, RTI International; U10 HD063072, Case Western Reserve University; U10 HD063047, Columbia University; U10 HD063037, Indiana University; U10 HD063041, University of Pittsburgh; U10 HD063020, Northwestern University; U10 HD063046, University of California Irvine; U10 HD063048, University of Pennsylvania; and U10 HD063053, University of Utah. In addition, support was provided by respective Clinical and Translational Science Institutes to Indiana University (UL1TR001108) and University of California Irvine (UL1TR000153). NR 49 TC 6 Z9 6 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2015 VL 212 IS 4 AR 539.e1 DI 10.1016/j.ajog.2015.01.019 PG 24 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CE9EQ UT WOS:000352147100037 PM 25648779 ER PT J AU Manuck, TA Esplin, S Biggio, J Bukowski, R Parry, S Zhang, H Huang, H Varner, MW Andrews, W Saade, G Sadovsky, Y Reddy, UM Ilekis, J AF Manuck, Tracy A. Esplin, Sean Biggio, Joseph Bukowski, Radek Parry, Samuel Zhang, Heping Huang, Hao Varner, Michael W. Andrews, William Saade, George Sadovsky, Yoel Reddy, Uma M. Ilekis, John CA Eunice Kennedy Shriver Natl Inst C TI The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE phenotype; preterm; racial disparity; spontaneous preterm birth ID RATES; DELIVERY; LABOR AB OBJECTIVE: Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible causes. We hypothesized that a comprehensive classification system appropriately could group women with similar STPB causes and could provide an explanation, at least in part, for the disparities in SPTB that are associated with race and gestational age at delivery. STUDY DESIGN: This was a planned analysis of a multicenter, prospective study of singleton SPTBs. Women with SPTB at <34 weeks' gestation were included. We defined 9 potential SPTB phenotypes based on clinical data: infection/inflammation, maternal stress, decidual hemorrhage, uterine distention, cervical insufficiency, placental dysfunction, premature rupture of the membranes, maternal comorbidities, and familial factors. Each woman's condition was evaluated for each phenotype. Delivery gestational age was compared between those with and without each phenotype. Phenotype profiles were also compared between women with very early (20.0-27.9 weeks' gestation) SPTB vs those with early SPTB (28.0-34.0 weeks' gestation) and between African American and white women. Statistical analysis was by t test and c 2 test, as appropriate. RESULTS: The phenotyping tool was applied to 1025 women with SPTBs who delivered at a mean 30.0 +/- 3.2 (SD) weeks' gestation. Of these, 800 women (78%) had >= 2 phenotypes. Only 43 women (4.2%) had no phenotypes. The 281 women with early SPTBs were more likely to have infection/inflammation, decidual hemorrhage, and cervical insufficiency phenotypes (all P <= .001). African American women had more maternal stress and cervical insufficiency but less decidual hemorrhage and placental dysfunction compared with white women (all P < .05). Gestational age at delivery decreased as the number of phenotypes that were present increased. CONCLUSION: Precise SPTB phenotyping classifies women with SPTBs and identifies specific differences between very early and early SPTB and between African American and white women. C1 [Manuck, Tracy A.; Esplin, Sean; Varner, Michael W.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. [Manuck, Tracy A.; Esplin, Sean; Varner, Michael W.] Intermt Healthcare, Dept Maternal Fetal Med, Salt Lake City, UT USA. [Biggio, Joseph; Andrews, William] Univ Alabama Birmingham, Dept Obstet & Gynecol, Sch Med, Div Maternal Fetal Med, Birmingham, AL USA. [Biggio, Joseph; Andrews, William] Univ Alabama Birmingham, Sch Med, Ctr Womens Reprod Hlth, Birmingham, AL USA. [Bukowski, Radek; Saade, George] Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX 77555 USA. [Parry, Samuel] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Sadovsky, Yoel] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Pittsburgh, PA USA. [Zhang, Heping; Huang, Hao] Yale Univ, Sch Publ Hlth, Collaborat Ctr Stat Sci, New Haven, CT USA. [Reddy, Uma M.; Ilekis, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, Bethesda, MD USA. [Manuck, Tracy A.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chapel Hill, NC USA. [Bukowski, Radek] Yale Univ, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, New Haven, CT 06510 USA. RP Manuck, TA (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. EM tmanuck@med.unc.edu RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomic and Proteomic Network for Preterm Birth Research [U01-HD-050062, U01-HD-050078, U01-HD-050080, U01-HD-050088, U01-HD-050094]; Eunice Kennedy Shriver NICHD [5K23HD067224]; National Institutes of Health; NICHD; National Center for Advancing Translational Sciences FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomic and Proteomic Network for Preterm Birth Research (U01-HD-050062; U01-HD-050078; U01-HD-050080; U01-HD-050088; U01-HD-050094) and by Eunice Kennedy Shriver NICHD grant number 5K23HD067224 (T.A.M.).; The National Institutes of Health, NICHD, and National Center for Advancing Translational Sciences provided grant support for the NICHD Genomics and Proteomics Network for Preterm Birth. Although NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD. NR 19 TC 14 Z9 14 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2015 VL 212 IS 4 AR 487.e1 DI 10.1016/j.ajog.2015.02.010 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CE9EQ UT WOS:000352147100018 PM 25687564 ER PT J AU Steagall, WK Zhang, L Cai, X Pacheco-Rodriguez, G Moss, J AF Steagall, Wendy K. Zhang, Li Cai, Xiong Pacheco-Rodriguez, Gustavo Moss, Joel TI Genetic Heterogeneity of Circulating Cells from Patients with Lymphangioleiomyomatosis with and without Lung Transplantation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID TUMOR-SUPPRESSOR GENE; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; TUBEROUS SCLEROSIS; TSC2; MUTATIONS; LYMPHANGIOMYOMATOSIS; HETEROZYGOSITY C1 [Steagall, Wendy K.; Zhang, Li; Cai, Xiong; Pacheco-Rodriguez, Gustavo; Moss, Joel] NIH, Bethesda, MD 20892 USA. RP Steagall, WK (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 15 TC 3 Z9 3 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD APR 1 PY 2015 VL 191 IS 7 BP 854 EP 856 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CE8UC UT WOS:000352118600020 PM 25830522 ER PT J AU Ismalaj, T Sackett, DL AF Ismalaj, Tony Sackett, Dan L. TI An inexpensive replacement for dry ice in the laboratory SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Dry ice; Lab tip; Freezing samples AB A reusable inexpensive replacement for dry ice in laboratory use is presented. Commercially available small pellets of stone or metal can be stored in a -80 degrees C freezer and used for quickly freezing small samples with a freezing rate that is actually somewhat faster than with dry ice itself. Following use, the material is returned to the freezer to re-chill until the next usage. Published by Elsevier Inc. C1 [Ismalaj, Tony; Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Sackett, DL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM sackettd@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, MD, USA) 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 (Bethesda, MD, USA). NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD APR 1 PY 2015 VL 474 BP 38 EP 39 DI 10.1016/j.ab.2015.01.008 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CE9NN UT WOS:000352170800007 PM 25617823 ER PT J AU Fang, EF Ng, TB AF Fang, Evandro Fei Ng, Tzi Bun TI A Trypsin Inhibitor from Rambutan Seeds with Antitumor, Anti-HIV-1 Reverse Transcriptase, and Nitric Oxide-Inducing Properties SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE Rambutan; Nephelium lappaceum L.; Nitric oxide; Protease inhibitor; Liquid chromatography; Antitumor ID NEPHELIUM-LAPPACEUM L.; BOWMAN-BIRK INHIBITOR; ANTIOXIDANT ACTIVITIES; PHENOLIC-COMPOUNDS; TROPICAL FRUITS; IN-VITRO; PURIFICATION; LECTIN; LIPOPOLYSACCHARIDE; ANAPHYLAXIS AB Nephelium lappaceum L., commonly known as "rambutan," is a typical tropical tree and is well known for its juicy and sweet fruit which has an exotic flavor. Chemical studies on rambutan have led to the identification of various components such as monoterpene lactones and volatile compounds. Here, a 22.5-kDa trypsin inhibitor (N . lappaceum trypsin inhibitor (NLTI)) was isolated from fresh rambutan seeds using liquid chromatographical techniques. NLTI reduced the proteolytic activities of both trypsin and alpha-chymotrypsin. Dithiothreitol reduced the trypsin inhibitory activity of NLTI at a concentration of 1 mM, indicating that an intact disulfide bond is essential to the activity. NLTI inhibited HIV-1 reverse transcriptase with an IC50 of 0.73 mu M. In addition, NLTI manifested a time- and dose-dependent inhibitory effect on growth in many tumor cells. NLTI is one of the few trypsin inhibitors with nitric oxide-inducing activity and may find application in tumor therapy. C1 [Fang, Evandro Fei; Ng, Tzi Bun] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Fang, Evandro Fei] NIA, NIH, Baltimore, MD 21224 USA. RP Ng, TB (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. EM evandro.fang@nih.gov; b021770@mailserv.cuhk.edu.hk NR 39 TC 4 Z9 4 U1 0 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 EI 1559-0291 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD APR PY 2015 VL 175 IS 8 BP 3828 EP 3839 DI 10.1007/s12010-015-1550-1 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA CE8HC UT WOS:000352081500020 PM 25820360 ER PT J AU Chin, LM Keyser, RE Dsurney, J Chan, L AF Chin, Lisa M. Keyser, Randall Eugene Dsurney, John Chan, Leighton TI Improved Cognitive Performance Following Aerobic Exercise Training in People With Traumatic Brain Injury SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Brain injuries; Cognition; Exercise; Neuropsychological tests; Questionnaires; Rehabilitation ID RANDOMIZED CONTROLLED-TRIALS; DEPRESSION FOLLOWING MILD; OLDER-ADULTS; IMPAIRMENT; QUALITY; FITNESS; MUSCULOSKELETAL; INTERVENTIONS; EPIDEMIOLOGY; METAANALYSIS AB Objective: To examine cognitive function in individuals with traumatic brain injury (TBI) prior to and after participation in an aerobic exercise training program. Design: Pre-post intervention study. Setting: Medical research center. Participants: Volunteer sample of individuals (N=7) (age, 33.3 +/- 7.9y) with chronic nonpenetrating TBI (injury severity: 3=mild, 4=moderate; time since most current injury: 4.0 +/- 5.5y) who were ambulatory. Intervention: Twelve weeks of supervised vigorous aerobic exercise training performed 3 times a week for 30 minutes on a treadmill. Main Outcome Measures: Cognitive function was assessed using the Trail Making Test Part A (TMT-A), Trail Making Test Part B (TMT-B), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Sleep quality and depression were measured with the Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory, version 2 (BDI-II). Indices of cardiorespiratory fitness were used to examine the relation between improvements in cognitive function and cardiorespiratory fitness. Results: After training, improvements in cognitive function were observed with greater scores on the TMT-A (10.3 +/- 6.8; P=.007), TMT-B (9.6 +/- 7.0; P=.011), and RBANS total scale (13.3 +/- 9.3; P=.009). No changes were observed in measures of the PSQI and BDI-II. The magnitude of cognitive improvements was also strongly related to the gains in cardiorespiratory fitness. Conclusions: These findings suggest that vigorous aerobic exercise training may improve specific aspects of cognitive function in individuals with TBI and cardiorespiratory fitness gains may be a determinant of these improvements. Archives of Physical Medicine and Rehabilitation 2015;96:754-9 (C) 2015 by the American Congress of Rehabilitation Medicine C1 [Chin, Lisa M.; Keyser, Randall Eugene] George Mason Univ, Dept Rehabil Sci, Fairfax, VA 22030 USA. [Chin, Lisa M.; Keyser, Randall Eugene; Dsurney, John; Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Dsurney, John; Chan, Leighton] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. RP Chin, LM (reprint author), George Mason Univ, Dept Rehabil Sci, 4400 Univ Dr, Fairfax, VA 22030 USA. EM lchin2@gmu.edu RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU Center for Neuroscience and Regenerative Medicine [G192HI-H]; National Institutes of Health Clinical Center FX Supported by the Center for Neuroscience and Regenerative Medicine (grant no. G192HI-H) and the National Institutes of Health Clinical Center (rehabilitation medicine department intramural funds). NR 42 TC 8 Z9 9 U1 2 U2 34 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD APR PY 2015 VL 96 IS 4 BP 754 EP 759 DI 10.1016/j.apmr.2014.11.009 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CE9RC UT WOS:000352180100025 PM 25433219 ER PT J AU Harris-Love, MO Joe, G Davenport, TE Koziol, D Rose, KA Shrader, JA Vasconcelos, OM McElroy, B Dalakas, MC AF Harris-Love, Michael O. Joe, Galen Davenport, Todd E. Koziol, Deloris Rose, Kristen Abbett Shrader, Joseph A. Vasconcelos, Olavo M. McElroy, Beverly Dalakas, Marinos C. TI Reliability of the Adult Myopathy Assessment Tool in Individuals With Myositis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; INCLUSION-BODY MYOSITIS; ASSESSMENT SCALE CMAS; NEUROMUSCULAR DISEASES; FUNCTIONAL INDEX-2; PHYSICAL-ACTIVITY; MUSCLE FUNCTION; SAMPLE-SIZE; DERMATOMYOSITIS; POLYMYOSITIS AB ObjectiveThe Adult Myopathy Assessment Tool (AMAT) is a 13-item performance-based battery developed to assess functional status and muscle endurance. The purpose of this study was to determine the intrarater and interrater reliability of the AMAT in adults with myositis. MethodsNineteen raters (13 physical therapists and 6 physicians) scored videotaped recordings of patients with myositis performing the AMAT for a total of 114 tests and 1,482 item observations per session. Raters rescored the AMAT test and item observations during a followup session (mean SD 19 6 days between scoring sessions). All raters completed a single, self-directed, electronic training module prior to the initial scoring session. ResultsIntrarater and interrater reliability correlation coefficients were 0.94 for the AMAT functional subscale, endurance subscale, and total score (all P < 0.02 for H-o, 0.75). All AMAT items had satisfactory intrarater agreement (kappa statistics with Fleiss-Cohen weights, with values (w) = 0.57-1.00). Interrater agreement was acceptable for each AMAT item ( = 0.56-0.89) except the sit up ( = 0.16). The standard error of measurement and 95% confidence interval range for the AMAT total scores did not exceed 2 points across all observations (AMAT total score range 0-45). ConclusionThe AMAT is a reliable, domain-specific assessment of functional status and muscle endurance for adult subjects with myositis. Results of this study suggest that physicians and physical therapists may reliably score the AMAT following a single training session. The AMAT functional subscale, endurance subscale, and total score exhibit interrater and intrarater reliability suitable for clinical and research use. C1 [Harris-Love, Michael O.] George Washington Univ, Vet Affairs Med Ctr, Washington, DC USA. [Harris-Love, Michael O.] George Washington Univ, Sch Publ Hlth, Milken Inst, Washington, DC USA. [Joe, Galen; Koziol, Deloris; Rose, Kristen Abbett; Shrader, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Davenport, Todd E.] Univ Pacific, Thomas J Long Sch Pharm & Hlth Sci, Stockton, CA 95211 USA. [Vasconcelos, Olavo M.] Hunter Holmes McGuire Vet Affairs Med Ctr, Richmond, VA USA. [Vasconcelos, Olavo M.; McElroy, Beverly; Dalakas, Marinos C.] NINDS, Bethesda, MD 20892 USA. [Dalakas, Marinos C.] Thomas Jefferson Univ, Philadelphia, PA USA. [Dalakas, Marinos C.] Univ Athens, Sch Med, GR-11527 Athens, Greece. RP Harris-Love, MO (reprint author), Washington DC Vet Affairs Med Ctr, Res Serv Geriatr & Extended Care Serv, Dept Vet Affairs, 11G,50 Irving St NW, Washington, DC 20422 USA. EM Michael.Harris-Love@va.gov RI Harris-Love, Michael/J-1359-2014 OI Harris-Love, Michael/0000-0002-1842-3269 FU Intramural Research Program of the NIH; National Institute of Neurological Disorders and Stroke [02-N-0121]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [02-AR-0156]; Rehabilitation Medicine Department of the NIH Clinical Center FX Supported by the Intramural Research Program of the NIH, the National Institute of Neurological Disorders and Stroke (protocol 02-N-0121), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (protocol 02-AR-0156), and the Rehabilitation Medicine Department of the NIH Clinical Center. NR 42 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD APR PY 2015 VL 67 IS 4 BP 563 EP 570 DI 10.1002/acr.22473 PG 8 WC Rheumatology SC Rheumatology GA CE8RM UT WOS:000352111800014 PM 25201624 ER PT J AU Figueroa, JD Yang, H Garcia-Closas, M Davis, S Meltzer, P Lissowska, J Horne, HN Sherman, ME Lee, M AF Figueroa, Jonine D. Yang, Howard Garcia-Closas, Montserrat Davis, Sean Meltzer, Paul Lissowska, Jolanta Horne, Hisani N. Sherman, Mark E. Lee, Maxwell TI Integrated analysis of DNA methylation, immunohistochemistry and mRNA expression, data identifies a methylation expression index (MEI) robustly associated with survival of ER-positive breast cancer patients SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Methylation; Breast cancer; Survival ID MOLECULAR SUBTYPES; BASAL-LIKE; HORMONE-RECEPTOR; RISK-FACTORS; ESTROGEN; HYPERMETHYLATION; TUMORS; OVEREXPRESSION; DYSREGULATION; PROGRESSION AB Identification of prognostic gene expression signatures may enable improved decisions about management of breast cancer. To identify a prognostic signature for breast cancer, we performed DNA methylation profiling and identified methylation markers that were associated with expression of ER, PR, HER2, CK5/6, and EGFR proteins. Methylation markers that were correlated with corresponding mRNA expression levels were identified using 208 invasive tumors from a population-based case-control study conducted in Poland. Using this approach, we defined the methylation expression index (MEI) signature that was based on a weighted sum of mRNA levels of 57 genes. Classification of cases as low or high MEI scores was related to survival using Cox regression models. In the Polish study, women with ER-positive low MEI cancers had reduced survival at a median of 5.20 years of follow-up, HR = 2.85 95 % CI = 1.25-6.47. Low MEI was also related to decreased survival in four independent datasets totaling over 2500 ER-positive breast cancers. These results suggest that integrated analysis of tumor expression markers, DNA methylation, and mRNA data may be an important approach for identifying breast cancer prognostic signatures. Prospective assessment of MEI along with other prognostic signatures should be evaluated in future studies. C1 [Figueroa, Jonine D.; Yang, Howard; Davis, Sean; Meltzer, Paul; Horne, Hisani N.; Sherman, Mark E.; Lee, Maxwell] NCI, NIH, HHS, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, London SW3 6JB, England. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. RP Figueroa, JD (reprint author), Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 9609 Med Ctr Dr RM 7E122 MSC 9774, Bethesda, MD 20892 USA. EM figueroaj@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Davis, Sean/0000-0002-8991-6458 FU Intramural NIH HHS [ZIA CP010126-16] NR 44 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD APR PY 2015 VL 150 IS 2 BP 457 EP 466 DI 10.1007/s10549-015-3314-6 PG 10 WC Oncology SC Oncology GA CE9ZL UT WOS:000352202200022 PM 25773928 ER PT J AU Lubet, RA Scheiman, JM Bode, A White, J Minasian, L Juliana, MM Boring, DL Steele, VE Grubbs, CJ AF Lubet, Ronald A. Scheiman, James M. Bode, Ann White, Jonathan Minasian, Lori Juliana, M. Margaret Boring, Daniel L. Steele, Vernon E. Grubbs, Clinton J. TI Prevention of Chemically Induced Urinary Bladder Cancers by Naproxen: Protocols to Reduce Gastric Toxicity in Humans Do Not Alter Preventive Efficacy SO CANCER PREVENTION RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SPORADIC COLORECTAL ADENOMAS; TRANSITIONAL-CELL CARCINOMA; CYCLOOXYGENASE-2 INHIBITOR; CONTROLLED-TRIAL; POOLED ANALYSIS; DOUBLE-BLIND; CELECOXIB; RISK; CHEMOPREVENTION AB The COX inhibitors (NSAID/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2-specific inhibitors have progressed to clinical trials and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular effects. Certain NSAIDs (e.g., naproxen) have a good cardiac profile, but can cause gastric toxicity. The present study examined protocols to reduce this toxicity of naproxen. Female Fischer-344 rats were treated weekly with the urinary bladder-specific carcinogen hydroxybutyl(butyl) nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/kg body weight/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/kg body weight/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN-treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), naproxen alone or combined with omeprazole-prevented cancers, yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN-treated rats were administered naproxen: (A) daily, (B) 1 week daily naproxen/1week vehicle, (C) 3 weeks daily naproxen/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C, and Dresulted in palpable cancers in 27%, 22%, 19%, and96% of rats (P < 0.01). Short-term naproxen treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols that should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g., naproxen) in clinical prevention trials. (C)2015 AACR. C1 [Lubet, Ronald A.; Minasian, Lori; Boring, Daniel L.; Steele, Vernon E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Scheiman, James M.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Bode, Ann] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [White, Jonathan] Midwest Res Inst, Kansas City, MO 64110 USA. [Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. RP Grubbs, CJ (reprint author), Univ Alabama Birmingham, 1720 2nd Ave South,VH-G78D, Birmingham, AL 35294 USA. EM clintongrubbs@uabmc.edu FU NCI [HHSN261200433001C (NO1-CN-43301)] FX The funding for the studies was provided in part by NCI Contract Number HHSN261200433001C (NO1-CN-43301) awarded to C.J. Grubbs at the University of Alabama at Birmingham (Birmingham, AL). NR 39 TC 2 Z9 2 U1 2 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2015 VL 8 IS 4 BP 296 EP 302 DI 10.1158/1940-6207.CAPR-14-0347 PG 7 WC Oncology SC Oncology GA CE8FP UT WOS:000352077400007 PM 25762530 ER PT J AU Zhang, Q Pan, J Lubet, RA Komas, SM Kalyanaraman, B Wang, Y You, M AF Zhang, Qi Pan, Jing Lubet, Ronald A. Komas, Steven M. Kalyanaraman, Balaraman Wang, Yian You, Ming TI Enhanced Antitumor Activity of 3-Bromopyruvate in Combination with Rapamycin In Vivo and In Vitro SO CANCER PREVENTION RESEARCH LA English DT Article ID CELL LUNG-CANCER; POLYPHENON-E; MAMMALIAN TARGET; DRUG-DELIVERY; A/J MICE; TUMORIGENESIS; MTOR; INHIBITION; GLYCOLYSIS; CHEMOPREVENTION AB 3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention. (C)2015 AACR. C1 [Zhang, Qi; Pan, Jing; Wang, Yian; You, Ming] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Zhang, Qi; Pan, Jing; Wang, Yian; You, Ming] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. [Lubet, Ronald A.] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. [Komas, Steven M.; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. RP You, M (reprint author), Med Coll Wisconsin, Ctr Canc, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM myou@mcw.edu FU NIH [R01CA139959, R01CA134433, R01CA175360, N01CN201200013(7), N01CN201200015(1), R01 CA152810]; MCW Cancer Center Bioenergetics shared resource and Advancing Healthier Wisconsin FX This work was supported in part by NIH grants: R01CA139959, R01CA134433, R01CA175360, N01CN201200013(7), N01CN201200015(1) (to Y.W. and M.Y.) and R01 CA152810 (to B.K.), this work was also supported by the MCW Cancer Center Bioenergetics shared resource and Advancing Healthier Wisconsin. NR 29 TC 1 Z9 1 U1 3 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2015 VL 8 IS 4 BP 318 EP 326 DI 10.1158/1940-6207.CAPR-14-0142 PG 9 WC Oncology SC Oncology GA CE8FP UT WOS:000352077400010 PM 25644152 ER PT J AU Janakiram, NB Mohammed, A Bryant, T Lightfoot, S Collin, PD Steele, VE Rao, CV AF Janakiram, Naveena B. Mohammed, Altaf Bryant, Taylor Lightfoot, Stan Collin, Peter D. Steele, Vernon E. Rao, Chinthalapally V. TI Improved Innate Immune Responses by Frondanol A5, a Sea Cucumber Extract, Prevent Intestinal Tumorigenesis SO CANCER PREVENTION RESEARCH LA English DT Article ID COLON-CANCER; CUCUMARIA-FRONDOSA; SCAVENGER RECEPTOR; COLORECTAL-CANCER; CELLS; INHIBITION; MICE; INFLAMMATION; GROWTH; CD163 AB Sea cucumbers are a source of antibacterial, anti-inflammatory, and anticancer compounds. We show that sea cucumber extract Frondanol A5 is capable of enhancing innate immune responses and inhibiting intestinal tumors in APC(Min/+) mice. APC(Min/+) mice were fed semi-purified diets containing 0, 250, or 500 ppm FrondanolA5 for 14 weeks before we assessed intestinal tumor inhibition. Dietary Frondanol A5 suppressed small intestinal polyp sizes and formation up to 30% (P < 0.02) in males and up to 50% (P < 0.01) in females. Importantly, 250 and 500 ppm Frondanol A5 diet suppressed colon tumor multiplicities by 65% (P < 0.007) and 75% (P < 0.0001), compared with untreated male APC(Min/+) mice. In female APC(Min/+) mice, both dose levels of Frondanol A5 suppressed colon tumor multiplicities up to 80% (P < 0.0001). Isolated peritoneal macrophages from treated mice showed increased phagocytosis efficiency (control 24% vs. treated 50%; P < 0.01) and an increase in GILT mRNA expression, indicating increased innate immune responses by these cells in treated animals. Similarly, we observed an increase in GILT expression in treated tumors, compared with untreated tumors. Furthermore, an increase in G-CSF cytokine, a decrease in inflammatory cytokines and marker 5-LOX, its regulator FLAP, proliferation (PCNA), and angiogenesis (VEGF) markers were observed in treatment groups. These data suggest that Frondanol A5 decreased inflammatory angiogenic molecules and increased GILT expression and macrophage phagocytosis. These decreases may have improved the innate immune systems of the treated mice, thus aiding in inhibition of intestinal tumor formation. These results suggest that Frondanol A5 exhibits significant chemopreventive potential against intestinal tumorigenesis. (C)2015 AACR. C1 [Janakiram, Naveena B.; Mohammed, Altaf; Bryant, Taylor; Lightfoot, Stan; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Dept Med,Hem Onc Sect, Oklahoma City, OK 73104 USA. [Collin, Peter D.] Coastside Bio Resources, Deer Isle, ME USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM naveena-janakiram@ouhsc.edu; cv-rao@ouhsc.edu FU [N01-CN-53300]; [R01CA094962] FX This study was supported by grants N01-CN-53300 and R01CA094962 (to C.V. Rao). NR 47 TC 3 Z9 3 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2015 VL 8 IS 4 BP 327 EP 337 DI 10.1158/1940-6207.CAPR-14-0380 PG 11 WC Oncology SC Oncology GA CE8FP UT WOS:000352077400011 PM 25657017 ER PT J AU O'Reilly, LA Hughes, P Lin, A Waring, P Siebenlist, U Jain, R Gray, DHD Gerondakis, S Strasser, A AF O'Reilly, L. A. Hughes, P. Lin, A. Waring, P. Siebenlist, U. Jain, R. Gray, D. H. D. Gerondakis, S. Strasser, A. TI Loss of c-REL but not NF-kappa B2 prevents autoimmune disease driven by FasL mutation SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID NF-KAPPA-B; ATOPIC-DERMATITIS; IMMUNE-SYSTEM; TRANSCRIPTION FACTORS; EXHIBIT DEFECTS; SELF-TOLERANCE; MICE LACKING; CELLS; EXPRESSION; APOPTOSIS AB FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL(Delta m/Delta m)), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL(Delta m/Delta m) mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-kappa B-regulated cytokine levels, indicating that NF-kappa B-dependent inflammation may be a key pathological driver in this multifaceted autoimmune disease. We tested this hypothesis by genetically impairing canonical or non-canonical NF-kappa B signaling in FasL(Delta m/Delta m) mice by deleting the c-Rel or NF-kappa B2 genes, respectively. Although the loss of NF-kappa B2 reduced the levels of inflammatory cytokines and autoantibodies, the impact on animal survival was minor due to substantially accelerated and exacerbated lymphoproliferative disease. In contrast, a marked increase in lifespan resulting from the loss of c-REL coincided with a striking reduction in classical parameters of autoimmune pathology, including the levels of cytokines and antinuclear autoantibodies. Notably, the decrease in regulatory T-cell numbers associated with loss of c-REL did not exacerbate autoimmunity in FasL(Delta m/Delta m)c-rel(-/-) mice. These findings indicate that selective inhibition of c-REL may be an attractive strategy for the treatment of autoimmune pathologies driven by defects in FASL/FAS signaling that would be expected to circumvent many of the complications caused by pan-NF-kappa B inhibition. C1 [O'Reilly, L. A.; Hughes, P.; Lin, A.; Jain, R.; Gray, D. H. D.; Strasser, A.] Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3052, Australia. [O'Reilly, L. A.; Jain, R.; Gray, D. H. D.; Strasser, A.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. [Hughes, P.] Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic 3052, Australia. [Waring, P.] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Siebenlist, U.] NIAID, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Gerondakis, S.] Monash Univ, Cent Clin Sch, Australian Ctr Blood Dis, Melbourne, Vic 3004, Australia. [Gerondakis, S.] Monash Univ, Cent Clin Sch, Dept Clin Hematol, Melbourne, Vic 3004, Australia. RP O'Reilly, LA (reprint author), Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, 1G Royal Parade, Parkville, Vic 3052, Australia. EM oreilly@wehi.edu.au; strasser@wehi.edu.au RI Gray, Daniel/A-3293-2013; Strasser, Andreas/C-7581-2013; OI Gray, Daniel/0000-0002-8457-8242; Strasser, Andreas/0000-0002-5020-4891 FU NHMRC (Canberra) [461221, 1016701, 637353, 1009145, 637332]; NHMRC infrastructure grant; Independent Research Institutes Infrastructure Support Scheme Grant [361646]; Victorian State Government (OIS grant); Leukemia and Lymphoma Society (SCOR grant) [7413, 7001-13]; JDRF/NHMRC [466658]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US) FX We thank G Siciliano, K Hughes, J Coughlin, K McKenzie and F Dabrowski, for animal care; J Corbin for automated blood analysis; B Helbert and C Young for genotyping; and E Tsui, V Babo, K Weston and all histology staff for preparation of histological sections. This work was supported by fellowships and grants from the NHMRC (Canberra; programs #461221 and #1016701, fellowship; (DG) #637353 and project grants #1009145 (LOR), #637332 (DG) and an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme Grant #361646, the Victorian State Government (OIS grant), the Leukemia and Lymphoma Society (SCOR grant #7413 and #7001-13) and the JDRF/NHMRC #466658 (AS). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US). NR 55 TC 4 Z9 4 U1 0 U2 4 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 APR PY 2015 VL 22 IS 5 BP 767 EP 778 DI 10.1038/cdd.2014.168 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CF3XQ UT WOS:000352482800006 PM 25361085 ER PT J AU Herbst, RS Gandara, DR Hirsch, FR Redman, MW LeBlanc, M Mack, PC Schwartz, LH Vokes, E Ramalingam, SS Bradley, JD Sparks, D Zhou, Y Miwa, C Miller, VA Yelensky, R Li, YL Allen, JD Sigal, EV Wholley, D Sigman, CC Blumenthal, GM Malik, S Kelloff, GJ Abrams, JS Blanke, CD Papadimitrakopoulou, VA AF Herbst, Roy S. Gandara, David R. Hirsch, Fred R. Redman, Mary W. LeBlanc, Michael Mack, Philip C. Schwartz, Lawrence H. Vokes, Everett Ramalingam, Suresh S. Bradley, Jeffrey D. Sparks, Dana Zhou, Yang Miwa, Crystal Miller, Vincent A. Yelensky, Roman Li, Yali Allen, Jeff D. Sigal, Ellen V. Wholley, David Sigman, Caroline C. Blumenthal, Gideon M. Malik, Shakun Kelloff, Gary J. Abrams, Jeffrey S. Blanke, Charles D. Papadimitrakopoulou, Vassiliki A. TI Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400 SO CLINICAL CANCER RESEARCH LA English DT Article ID CLINICAL-TRIALS; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; BREAST-CANCER; IN-VIVO; ONCOLOGY; GENOMICS; ALECTINIB; AZD4547; DESIGN AB The Lung Master Protocol (Lung-MAP, S1400) is a ground-breaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform(next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care. (C) 2015 AACR. C1 [Herbst, Roy S.; Zhou, Yang] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. [Gandara, David R.; Mack, Philip C.] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. [Hirsch, Fred R.] Univ Colorado, Dept Med Oncol, Hlth Sci Ctr, Aurora, CO USA. [Redman, Mary W.; LeBlanc, Michael] SWOG Stat Ctr, Seattle, WA USA. [Redman, Mary W.; LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schwartz, Lawrence H.] Columbia Univ, Dept Radiol, Coll Med, New York, NY USA. [Vokes, Everett] Univ Chicago Med & Biol Sci, Dept Med, Chicago, IL USA. [Ramalingam, Suresh S.] Emory Univ, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Bradley, Jeffrey D.] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. [Sparks, Dana; Miwa, Crystal] SWOG Operat Off, San Antonio, TX USA. [Miller, Vincent A.; Yelensky, Roman; Li, Yali] Fdn Med, Cambridge, MA USA. [Allen, Jeff D.; Sigal, Ellen V.] Friends Canc Res, Washington, DC USA. [Wholley, David] Fdn Natl Inst Hlth, Bethesda, MD USA. [Sigman, Caroline C.] CCS Associates, Mountain View, CA USA. [Blumenthal, Gideon M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Malik, Shakun] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Kelloff, Gary J.] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Blanke, Charles D.] SWOG Grp Chairs Office, Portland, OR USA. [Blanke, Charles D.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Papadimitrakopoulou, Vassiliki A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Herbst, RS (reprint author), Yale Univ, Sch Med, Yale Canc Ctr, POB 208028, New Haven, CT 06520 USA. EM roy.herbst@yale.edu FU NCI of the NIH [U10CA180888, U10CA180819, R01CA155196]; Amgen; AstraZeneca; Genentech; Pfizer, through the Foundation for the National Institutes of Health FX This work was supported in part by the NCI of the NIH under award numbers U10CA180888 (to SWOG), U10CA180819 (to SWOG), and R01CA155196 (to R.S. Herbst) and by Amgen, AstraZeneca, Genentech, and Pfizer, through the Foundation for the National Institutes of Health and in partnership with Friends of Cancer Research. NR 42 TC 41 Z9 42 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2015 VL 21 IS 7 BP 1514 EP 1524 DI 10.1158/1078-0432.CCR-13-3473 PG 11 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700004 PM 25680375 ER PT J AU Fouladi, M Perentesis, JP Wagner, LM Vinks, AA Reid, JM Ahern, C Thomas, G Mercer, CA Krueger, DA Houghton, PJ Doyle, LA Chen, H Weigel, B Blaney, SM AF Fouladi, Maryam Perentesis, John P. Wagner, Lars M. Vinks, Alexander A. Reid, Joel M. Ahern, Charlotte Thomas, George Mercer, Carol A. Krueger, Darcy A. Houghton, Peter J. Doyle, L. Austin Chen, Helen Weigel, Brenda Blaney, Susan M. TI A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: AChildren's Oncology Group Phase I Consortium Report SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; IGF-1R ANTIBODY CIXUTUMUMAB; PRECLINICAL TESTING PROGRAM; METASTATIC BREAST-CANCER; PEDIATRIC-PATIENTS; MAMMALIAN TARGET; FACTOR-RECEPTOR; RAPAMYCIN; MTOR; ACTIVATION AB Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. Results: Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m(2), the median temsirolimus AUC was 2,946 ng * h/mL (range, 937-5,536) with a median sirolimus AUC of 767 ng * h/mL (range, 245-3,675). Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. (C) 2014 AACR. C1 [Fouladi, Maryam; Perentesis, John P.; Wagner, Lars M.; Vinks, Alexander A.; Krueger, Darcy A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Reid, Joel M.] Mayo Clin, Coll Med, Rochester, MN USA. [Ahern, Charlotte] Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. [Thomas, George; Mercer, Carol A.] Univ Cincinnati, Cincinnati, OH USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Doyle, L. Austin; Chen, Helen] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. [Weigel, Brenda] Univ Minnesota, Minneapolis, MN USA. [Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. RP Fouladi, M (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM maryam.fouladi@cchmc.org FU NCI [U01 CA97452, UM1 CA097452-11] FX This work was supported by NCI grant nos. U01 CA97452 and UM1 CA097452-11. NR 48 TC 4 Z9 4 U1 0 U2 2 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 APR 1 PY 2015 VL 21 IS 7 BP 1558 EP 1565 DI 10.1158/1078-0432.CCR-14-0595 PG 8 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700010 PM 25467181 ER PT J AU Kummar, S Oza, AM Fleming, GF Sullivan, DM Gandara, DR Naughton, MJ Villalona-Calero, MA Morgan, RJ Szabo, PM Youn, A Chen, AP Ji, JP Allen, DE Lih, CJ Mehaffey, MG Walsh, WD McGregor, PM Steinberg, SM Williams, PM Kinders, RJ Conley, BA Simon, RM Doroshow, JH AF Kummar, Shivaani Oza, Amit M. Fleming, Gini F. Sullivan, Daniel M. Gandara, David R. Naughton, Michael J. Villalona-Calero, Miguel A. Morgan, Robert J., Jr. Szabo, Peter M. Youn, Ahrim Chen, Alice P. Ji, Jiuping Allen, Deborah E. Lih, Chih-Jian Mehaffey, Michele G. Walsh, William D. McGregor, Paul M., III Steinberg, Seth M. Williams, P. Mickey Kinders, Robert J. Conley, Barbara A. Simon, Richard M. Doroshow, James H. TI Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID REFRACTORY SOLID TUMORS; POLY(ADP-RIBOSE) POLYMERASE; PARP INHIBITORS; CLINICAL-TRIAL; SOMATIC MUTATIONS; BREAST-CANCER; PHASE-I; COMBINATION; RESISTANCE; DNA AB Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression. Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival. (C)2015 AACR. C1 [Kummar, Shivaani; Szabo, Peter M.; Youn, Ahrim; Chen, Alice P.; Allen, Deborah E.; Steinberg, Seth M.; Conley, Barbara A.; Simon, Richard M.; Doroshow, James H.] NCI, NIH, Bethesda, MD 20814 USA. [Oza, Amit M.] Univ Toronto, Princess Margaret Hosp, Toronto, ON M5S 1A1, Canada. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Sullivan, Daniel M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Gandara, David R.] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Naughton, Michael J.] Washington Univ, Sch Med, St Louis, MO USA. [Villalona-Calero, Miguel A.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Villalona-Calero, Miguel A.] Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. [Morgan, Robert J., Jr.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Ji, Jiuping; Lih, Chih-Jian; Mehaffey, Michele G.; Walsh, William D.; McGregor, Paul M., III; Williams, P. Mickey; Kinders, Robert J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Doroshow, JH (reprint author), NCI, NIH, Bldg 31,Room 3444,31 Ctr Dr, Bethesda, MD 20814 USA. EM doroshoj@mail.nih.gov FU NCI, NIH [HHSN261200800001E, N01-CM-2011-00032, N01-CM-2011-00038, N01-CM-2011-00071, N01-CM-2011-00099, N01-CM-2011-00100]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in part with federal funds from the NCI, NIH, under contract numbers HHSN261200800001E and N01-CM-2011-00032, N01-CM-2011-00038, N01-CM-2011-00071, N01-CM-2011-00099, and N01-CM-2011-00100, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 27 Z9 29 U1 0 U2 12 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 APR 1 PY 2015 VL 21 IS 7 BP 1574 EP 1582 DI 10.1158/1078-0432.CCR-14-2565 PG 9 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700012 PM 25589624 ER PT J AU O'Leary, BR Fath, MA Bellizzi, AM Hrabe, JE Button, AM Allen, BG Case, AJ Altekruses, S Wagner, BA Buettner, GR Lynch, CF Hernandez, BY Cozen, W Beardsley, RA Keene, J Henry, MD Domann, FE Spitz, DR Mezhir, JJ AF O'Leary, Brianne R. Fath, Melissa A. Bellizzi, Andrew M. Hrabe, Jennifer E. Button, Anna M. Allen, Bryan G. Case, Adam J. Altekruses, Sean Wagner, Brett A. Buettner, Garry R. Lynch, Charles F. Hernandez, Brenda Y. Cozen, Wendy Beardsley, Robert A. Keene, Jeffery Henry, Michael D. Domann, Frederick E. Spitz, Douglas R. Mezhir, James J. TI Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human pancreatic Ductal Adenocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID EXTRACELLULAR-SUPEROXIDE-DISMUTASE; NITRIC-OXIDE BIOAVAILABILITY; CANCER CELL INVASION; ANTIOXIDANT ENZYMES; REDOX IMBALANCE; LUNG-CANCER; GROWTH; MICE; OVEREXPRESSION; TRANSFORMATION AB Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. (C) 2015 AACR. C1 [O'Leary, Brianne R.; Hrabe, Jennifer E.; Mezhir, James J.] Univ Iowa, Dept Surg, Iowa City, IA 52242 USA. [Fath, Melissa A.; Allen, Bryan G.; Case, Adam J.; Wagner, Brett A.; Buettner, Garry R.; Domann, Frederick E.; Spitz, Douglas R.; Mezhir, James J.] Univ Iowa, Dept Radiat Oncol, Iowa City, IA USA. [Bellizzi, Andrew M.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Button, Anna M.] Univ Iowa, Dept Biostat, Iowa City, IA 52242 USA. [Altekruses, Sean] NCI, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Hernandez, Brenda Y.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Cozen, Wendy] Univ So Calif, Los Angeles, CA USA. [Beardsley, Robert A.; Keene, Jeffery] Galcra Therapeut, Malvern, PA USA. [Henry, Michael D.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. RP Mezhir, JJ (reprint author), Univ Iowa Hosp & Clin, Div Surg Oncol & Endocrine Surg, 200 Hawkins Dr,4642 JCP, Iowa City, IA 52242 USA. EM james-mezhir@uiowa.edu OI Case, Adam/0000-0003-3404-1428; Domann, Frederick/0000-0002-0489-2179; Buettner, Garry/0000-0002-5594-1903 FU American Surgical Association Foundation Fellowship; American Cancer Society [IRG-77-004-31]; NIH [T32CA148062, P30 CA086862]; University of Iowa Carver College of medicine Collaborative Pilot Grant; NCI [N01-PC-35143, N01-PC-35137, N01-PC-35139]; [R01 CA182804]; [R01CA133114]; [R21 CA161182]; [R01 CA169046]; [R01 CA115438]; [R01 CA130916] FX This work was supported by the American Surgical Association Foundation Fellowship (toll. Menhir); This work was supported by Grant IRG-77-004-31 from the American Cancer Society, administered through The Holden Comprehensive Cancer Center at The University of Iowa (to J.J. Mezhir); NIH grant T32CA148062 (to J.J. Menhir); University of Iowa Carver College of medicine Collaborative Pilot Grant (J.J. Menhir); generous gifts from the families of John Van Sickel and lack Kloet and grateful patient donations to the Holden Comprehensive Cancer Center for pancreatic cancer research. Radiation and Free Radical Research Core in the Holden Comprehensive Cancer Center as The University of Iowa core laboratory support through NIH P30 CA086862. D.R. Spitz and M.A. Fath were supported by R01 CA182804, R01CA133114, and R21 CA161182; G.R. Buettner and B.A. Wagner were supported by R01 CA169046; F. E. Domann was supported by R01 CA115438; and M.D. Henry was supported by R01 CA130916. Constmaion of the pancreatic TMA was supported by NCI contract numbers N01-PC-35143 (Iowa), N01-PC-35137 (Hawaii), and N01-PC-35139 (Los Angeles). NR 41 TC 9 Z9 10 U1 1 U2 6 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 APR 1 PY 2015 VL 21 IS 7 BP 1741 EP 1751 DI 10.1158/1078-0432.CCR-14-1959 PG 11 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700028 PM 25634994 ER PT J AU Zhu, XX Cimino, JJ AF Zhu, Xinxin Cimino, James J. TI Clinicians' evaluation of computer-assisted medication summarization of electronic medical records SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Electronic health record; Medication error; Medication summarization; Timeline; Performance efficiency; Performance inaccuracy AB Each year thousands of patients die of avoidable medication errors. When a patient is admitted to, transferred within, or discharged from a clinical facility, clinicians should review previous medication orders, current orders and future plans for care, and reconcile differences if there are any. If medication reconciliation is not accurate and systematic, medication errors such as omissions, duplications, dosing errors, or drug interactions may occur and cause harm. Computer-assisted medication applications showed promise as an intervention to reduce medication summarization inaccuracies and thus avoidable medication errors. In this study, a computer-assisted medication summarization application, designed to abstract and represent multi-source time-oriented medication data, was introduced to assist clinicians with their medication reconciliation processes. An evaluation study was carried out to assess clinical usefulness and analyze potential impact of such application. Both quantitative and qualitative methods were applied to measure clinicians' performance efficiency and inaccuracy in medication summarization process with and without the intervention of computer-assisted medication application. Clinicians' feedback indicated the feasibility of integrating such a medication summarization tool into clinical practice workflow as a complementary addition to existing electronic health record systems. The result of the study showed potential to improve efficiency and reduce inaccuracy in clinician performance of medication summarization, which could in turn improve care efficiency, quality of care, and patient safety. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Zhu, Xinxin] IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA. [Cimino, James J.] NIH, Bethesda, MD USA. RP Zhu, XX (reprint author), IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA. EM zhux@us.ibm.com OI Cimino, James/0000-0003-4101-1622 FU National Library of Medicine [RO1 LM06910, T15 LM07079] FX This study was supported by National Library of Medicine RO1 LM06910 and T15 LM07079. The authors thank Dr. David Kaufman and all study participants for their valuable comments and insights. NR 8 TC 0 Z9 0 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD APR 1 PY 2015 VL 59 BP 221 EP 231 DI 10.1016/j.compbiomed.2013.12.006 PG 11 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA CE9OF UT WOS:000352172600026 PM 24393492 ER PT J AU Lahiri, S Toulmay, A Prinz, WA AF Lahiri, Sujoy Toulmay, Alexandre Prinz, William A. TI Membrane contact sites, gateways for lipid homeostasis SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article AB Maintaining the proper lipid composition of cellular membranes is critical for numerous cellular processes but mechanisms of membrane lipid homeostasis are not well understood. There is growing evidence that membrane contact sites (MCSs), regions where two organelles come in close proximity to one another, play major roles in the regulation of intracellular lipid composition and distribution. MCSs are thought to mediate the exchange of lipids and signals between organelles. In this review, we discuss how lipid exchange occurs at MCSs and evidence for roles of MCSs in regulating lipid synthesis and degradation. We also discuss how networks of organelles connected by MCSs may modulate cellular lipid homeostasis and help determine organelle lipid composition. C1 [Lahiri, Sujoy; Toulmay, Alexandre; Prinz, William A.] NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. We thank Orna Cohen-Fix and Amit Joshi for critically reading the manuscript. NR 45 TC 35 Z9 35 U1 1 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD APR PY 2015 VL 33 BP 82 EP 87 DI 10.1016/j.ceb.2014.12.004 PG 6 WC Cell Biology SC Cell Biology GA CF0IM UT WOS:000352226700013 PM 25569848 ER PT J AU Hedman, AC Smith, JM Sacks, DB AF Hedman, Andrew C. Smith, Jessica M. Sacks, David B. TI The biology of IQGAP proteins: beyond the cytoskeleton SO EMBO REPORTS LA English DT Review DE biology; IQGAP1; IQGAP2; IQGAP3; therapeutics ID FOCAL ADHESION KINASE; CELL-CELL ADHESION; GTPASE-ACTIVATING PROTEIN-1; SMOOTH-MUSCLE CONTRACTION; RAC-BOUND BETA-1-INTEGRIN; FISSION YEAST CYTOKINESIS; BREAST-CANCER CELLS; GROWTH-FACTOR; ACTIN-BINDING; IN-VIVO AB IQGAP scaffold proteins are evolutionarily conserved in eukaryotes and facilitate the formation of complexes that regulate cytoskeletal dynamics, intracellular signaling, and intercellular interactions. Fungal and mammalian IQGAPs are implicated in cytokinesis. IQGAP1, IQGAP2, and IQGAP3 have diverse roles in vertebrate physiology, operating in the kidney, nervous system, cardiovascular system, pancreas, and lung. The functions of IQGAPs can be corrupted during oncogenesis and are usurped by microbial pathogens. Therefore, IQGAPs represent intriguing candidates for novel therapeutic agents. While modulation of the cytoskeletal architecture was initially thought to be the primary function of IQGAPs, it is now clear that they have roles beyond the cytoskeleton. This review describes contributions of IQGAPs to physiology at the organism level. C1 [Hedman, Andrew C.; Smith, Jessica M.; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 FU Intramural Research Program of the National Institutes of Health FX We apologize to those authors whose primary work was omitted due to space restrictions. This work was supported by the Intramural Research Program of the National Institutes of Health. NR 220 TC 14 Z9 15 U1 4 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD APR PY 2015 VL 16 IS 4 BP 427 EP 446 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CE9MG UT WOS:000352167500007 PM 25722290 ER PT J AU Zhang, F Qi, Y Zhou, K Zhang, GF Linask, K Xu, H AF Zhang, Fan Qi, Yun Zhou, Kiet Zhang, Guofeng Linask, Kaari Xu, Hong TI The cAMP phosphodiesterase Prune localizes to the mitochondrial matrix and promotes mtDNA replication by stabilizing TFAM SO EMBO REPORTS LA English DT Article DE cyclic adenosine 3 ',5 '-monophosphate; cyclic nucleotide phosphodiesterase; mitochondrial DNA; mitochondrial transcription factor A; neurodegeneration ID DEPENDENT PROTEIN-KINASE; DNA COPY NUMBER; TRANSCRIPTION FACTOR; DROSOPHILA-MELANOGASTER; SIGNAL-TRANSDUCTION; HUMAN-DISEASE; LON PROTEASE; DYNAMICS; CELLS; PHOSPHORYLATION AB Compartmentalized cAMP signaling regulates mitochondrial dynamics, morphology, and oxidative phosphorylation. However, regulators of the mitochondrial cAMP pathway, and its broad impact on organelle function, remain to be explored. Here, we report that Drosophila Prune is a cyclic nucleotide phosphodiesterase that localizes to the mitochondrial matrix. Knocking down prune in cultured cells reduces mitochondrial transcription factor A (TFAM) and mitochondrial DNA (mtDNA) levels. Our data suggest that Prune stabilizes TFAM and promotes mitochondrial DNA (mtDNA) replication through downregulation of mitochondrial cAMP signaling. In addition, our work demonstrates the prevalence of mitochondrial cAMP signaling in metazoan and its new role in mitochondrial biogenesis. C1 [Zhang, Fan; Qi, Yun; Zhou, Kiet; Linask, Kaari; Xu, Hong] NHLBI, Mol Genet Lab, Bethesda, MD 20892 USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Xu, H (reprint author), NHLBI, Mol Genet Lab, Bldg 10, Bethesda, MD 20892 USA. EM hong.xu@nih.gov RI Xu, Hong/H-9997-2016 OI Xu, Hong/0000-0003-1049-1184 FU NHLBI Intramural Research Program FX We thank R. Balaban and T. Finkel for their comments on the work; C. Clark for manuscript editing assistance; NHLBI FACS core for the technical assistance; H. Richardson, E. Matsuura, and Developmental Studies Hybridoma Bank for various antibodies; J. Zhang for ICUE3 plasmids; Bloomington stock center for Drosophila stocks; and Best Gene Inc. for embryonic injection service. This work is supported by the NHLBI Intramural Research Program. NR 35 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD APR PY 2015 VL 16 IS 4 BP 520 EP 527 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CE9MG UT WOS:000352167500015 PM 25648146 ER PT J AU Arbuckle, TE Marro, L Davis, K Fisher, M Ayotte, P Belanger, P Dumas, P LeBlanc, A Berube, R Gaudreau, E Provencher, G Faustman, EM Vigoren, E Ettinger, AS Dellarco, M MacPherson, S Fraser, WD AF Arbuckle, Tye E. Marro, Leonora Davis, Karelyn Fisher, Mandy Ayotte, Pierre Belanger, Patrick Dumas, Pierre LeBlanc, Alain Berube, Rene Gaudreau, Eric Provencher, Gilles Faustman, Elaine M. Vigoren, Eric Ettinger, Adrienne S. Dellarco, Michael MacPherson, Susan Fraser, William D. TI Exposure to Free and Conjugated Forms of Bisphenol A and Triclosan among Pregnant Women in the MIREC Cohort SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TANDEM MASS-SPECTROMETRY; PERSONAL CARE PRODUCTS; URINARY CONCENTRATIONS; PRENATAL EXPOSURE; BIRTH OUTCOMES; BIOMONITORING EQUIVALENTS; ENVIRONMENTAL CHEMICALS; US POPULATION; PHENOLS; CHILDREN AB Background: Bisphenol A (BPA) and triclosan (TCS) are two non-persistent chemicals that have been frequently measured in spot urine samples from the general population but less so in pregnant women; however, data are limited on the free (bioactive) and conjugated forms of these phenols. Objectives: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study addressed these data gaps by utilizing stored maternal urine samples from a large multi-center cohort study of Canadian pregnant women. Methods: Concentrations of free and conjugated forms of BPA and TCS were measured in about 1,890 first-trimester urine samples by ultra performance liquid chromatograpy-tandem mass spectrometry using isotope dilution. Results: The glucuronides of BPA and TCS were the predominant forms of these chemicals measured (detected in 95% and 99% of samples, respectively), whereas the free forms were detected in 43% and 80% of samples, respectively. The geometric mean urinary concentrations for glucuronides of BPA and TCS were 0.80 mu g/L (95% CI: 0.75, 0.85) and 12.30 mu g/L (95% CI: 11.08, 13.65), respectively. Significant predictors of BPA included maternal age < 25 vs. >= 35 years, current smoking, low vs. high household income, and low vs. high education. For TCS, urinary concentrations were significantly higher in women >= 25 years of age, never vs. current smokers, and women with high household income and high education. Conclusions: The results from this study represent the largest national-level data on urinary concentrations of free and conjugated forms of BPA and TCS in pregnant women and suggest that maternal characteristics predicting elevated urinary concentrations of these phenols largely act in opposite directions. C1 [Arbuckle, Tye E.; Marro, Leonora; Davis, Karelyn; Fisher, Mandy; MacPherson, Susan] Hlth Canada, Healthy Environm & Consumer Safety Branch, Populat Studies Div, Ottawa, ON K1A 0K9, Canada. [Ayotte, Pierre; Belanger, Patrick; Dumas, Pierre; LeBlanc, Alain; Berube, Rene; Gaudreau, Eric; Provencher, Gilles] Inst Natl Sante Publ Quebec, Toxicol Lab, Quebec City, PQ, Canada. [Ayotte, Pierre] Ctr Hosp Univ, Quebec Res Ctr, Populat Hlth & Optimal Hlth Practices Res Unit, Quebec City, PQ, Canada. [Faustman, Elaine M.; Vigoren, Eric] Univ Washington, Inst Risk Anal & Risk Commun, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Ettinger, Adrienne S.] Yale Univ, Sch Publ Hlth, Ctr Perinatal Pediat & Environm Epidemiol, New Haven, CT USA. [Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Fraser, William D.] CHU St Justine, Res Ctr, Mother & Child Univ Hosp Ctr, Montreal, PQ, Canada. RP Arbuckle, TE (reprint author), Hlth Canada, Healthy Environm & Consumer Safety Branch, Populat Studies Div, AL 0801A,50 Colombine Dr, Ottawa, ON K1A 0K9, Canada. EM Tye.Arbuckle@hc-sc.gc.ca OI Faustman, Elaine/0000-0002-3085-6403 FU Health Canada's Chemicals Management Plan; Canadian Institute of Health Research [MOP-81285]; Ontario Ministry of the Environment; University of Washington; Ste. Justine's Hospital in Montreal; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [HHSN267200700023C] FX The MIREC Study was funded by Health Canada's Chemicals Management Plan, the Canadian Institute of Health Research (grant MOP-81285), and the Ontario Ministry of the Environment. The triclosan and bisphenol A laboratory analysis was funded by a contract between the University of Washington and Ste. Justine's Hospital in Montreal as part of formative research for the U.S. National Children's Study with federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under contract HHSN267200700023C. NR 59 TC 15 Z9 16 U1 4 U2 36 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 APR PY 2015 VL 123 IS 4 BP 277 EP 284 DI 10.1289/ehp.1408187 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9ML UT WOS:000352168000011 PM 25494523 ER PT J AU Qiu, LQ Abey, S Harris, S Shah, R Gerrish, KE Blackshear, PJ AF Qiu, Lian-Qun Abey, Sarah Harris, Shawn Shah, Ruchir Gerrish, Kevin E. Blackshear, Perry J. TI Global Analysis of Posttranscriptional Gene Expression in Response to Sodium Arsenite SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID 5-AMINOLEVULINIC ACID SYNTHASE; HUMAN FIBROBLASTS; MESSENGER-RNA; ACTINOMYCIN-D; CELLS; PATHWAYS; EXPOSURE; HEME; MICE; STRESS AB Background: Inorganic arsenic species are potent environmental toxins and causes of numerous health problems. Most studies have assumed that arsenic-induced changes in mRNA levels result from effects on gene transcription. Objectives: We evaluated the prevalence of changes in mRNA stability in response to sodium arsenite in human fibroblasts. Methods: We used microarray analyses to determine changes in steady-state mRNA levels and mRNA decay rates following 24-hr exposure to non-cytotoxic concentrations of sodium arsenite, and we confirmed some of these changes using real-time reverse-transcription polymerase chain reaction (RT-PCR). Results: In arsenite-exposed cells, 186 probe set-identified transcripts were significantly increased and 167 were significantly decreased. When decay rates were analyzed after actinomycin D treatment, only 4,992 (9.1%) of probe set-identified transcripts decayed by > 25% after 4 hr. Of these, 70 were among the 353 whose steady-state levels were altered by arsenite, and of these, only 4 exhibited significantly different decay rates between arsenite and control treatment. Real-time RT-PCR confirmed a major, significant arsenite-induced stabilization of the mRNA encoding delta aminolevulinate synthase 1 (ALAS1), the rate-limiting enzyme in heme biosynthesis. This change presumably accounted for at least part of the 2.7-fold increase in steady-state ALAS1 mRNA levels seen after arsenite treatment. This could reflect decreases in cellular heme caused by the massive induction by arsenite of heme oxygenase mRNA (HMOX1; 68-fold increase), the rate-limiting enzyme in heme catabolism. Conclusions: We conclude that arsenite modification of mRNA stability is relatively uncommon, but in some instances can result in significant changes in gene expression. C1 [Qiu, Lian-Qun; Abey, Sarah; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Harris, Shawn; Shah, Ruchir] Social & Sci Syst Inc, Res Triangle Pk, NC USA. [Gerrish, Kevin E.] NIEHS, Mol Genom Core Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, F1-13 Bldg 101,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Black009@niehs.nih.gov FU Intramural Research Program of the NIEHS, NIH FX This work was supported by the Intramural Research Program of the NIEHS, NIH. NR 47 TC 1 Z9 1 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 APR PY 2015 VL 123 IS 4 BP 324 EP 330 DI 10.1289/ehp.1408626 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9ML UT WOS:000352168000017 PM 25493608 ER PT J AU Gao, XH Yu, LD Moore, AB Kissling, GE Waalkes, MP Dixon, D AF Gao, Xiaohua Yu, Linda Moore, Alicia B. Kissling, Grace E. Waalkes, Michael P. Dixon, Darlene TI Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BREAST-CANCER CELLS; SIGNALING PATHWAYS; TYROSINE KINASES; IN-VIVO; PREMENOPAUSAL WOMEN; PROSPECTIVE COHORT; EPITHELIAL-CELLS; TRACE-ELEMENTS; EXPRESSION; EGFR AB Background: It has been proposed that cadmium (Cd) is an environmental "metalloestrogen" and that its action is mediated via the estrogen receptor (ER). Cd mimics the effects of estrogen in the rat uterus, and blood Cd concentrations positively correlate with ER levels in uteri of women with fibroids. Objectives: In the present study we explored whether Cd could stimulate proliferation of estrogen-responsive human uterine leiomyoma (ht-UtLM) cells and uterine smooth muscle cells (ht-UtSMCs) through classical interactions with ER alpha and ER beta, or by nongenomic mechanisms. Methods: We used estrogen response element (ERE) reporters, phosphorylated receptor tyrosine kinase arrays, Western blot analysis, estrogen binding, and cell proliferation assays to evaluate the effects of Cd on ht-UtLM cells and ht-UtSMCs. Results: Cd stimulated growth of both cell types at lower concentrations and inhibited growth at higher concentrations (>= 50 mu M). Cd did not significantly bind to ER alpha or ER beta, nor did it show transactivation in both cell types transiently transfected with ERE reporter genes. However, in both cells types, Cd (0.1 mu M and 10 mu M) activated p44/42 MAPK (ERK1/2), and a MAPK inhibitor (PD98059) abrogated Cd-induced cell proliferation. Cd in ht-UtLM cells, but not in ht-UtSMCs, activated the growth factor receptors EGFR, HGFR, and VEGF-R1 upstream of MAPK. Additional studies in ht-UtLM cells showed that AG1478, an EGFR inhibitor, abolished Cd-induced phosphorylation of EGFR and MAPK. Conclusions: Our results show that low concentrations of Cd stimulated cell proliferation in estrogen-responsive uterine cells by nongenomic activation of MAPK, but not through classical ER-mediated pathways. C1 [Gao, Xiaohua; Yu, Linda; Moore, Alicia B.; Dixon, Darlene] Natl Inst Environm Hlth Sci, Mol Pathogenesis Grp, NTP Lab, DNTP,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, Biostat Branch, DIR, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, DNTP, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Waalkes, Michael P.] Natl Inst Environm Hlth Sci, Inorgan Toxicol Grp, DNTP, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), Natl Inst Environm Hlth Sci, Natl Toxicol Program, POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural Research Program of the NIH, NIEHS; DNTP FX This research was supported by the Intramural Research Program of the NIH, NIEHS, and DNTP. NR 50 TC 6 Z9 6 U1 5 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2015 VL 123 IS 4 BP 331 EP 336 DI 10.1289/ehp.1408234 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9ML UT WOS:000352168000018 PM 25343777 ER PT J AU Hewitt, SC Winuthayanon, W Pockette, B Kerns, RT Foley, JF Flagler, N Ney, E Suksamrarn, A Piyachaturawat, P Bushel, PR Korach, KS AF Hewitt, Sylvia C. Winuthayanon, Wipawee Pockette, Brianna Kerns, Robnet T. Foley, Julie F. Flagler, Norris Ney, Elizabeth Suksamrarn, Apichart Piyachaturawat, Pawinee Bushel, Pierre R. Korach, Kenneth S. TI Development of Phenotypic and Transcriptional Biomarkers to Evaluate Relative Activity of Potentially Estrogenic Chemicals in Ovariectomized Mice SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID RECEPTOR-ALPHA; IN-VIVO; ENVIRONMENTAL ESTROGENS; BISPHENOL-A; GENE; RESPONSES; PROLIFERATION; MODULATION; ACTIVATION; ESTRADIOL AB Background: Concerns regarding potential endocrine-disrupting chemicals (EDCs) have led to a need for methods to evaluate candidate estrogenic chemicals. Our previous evaluations of two such EDCs revealed a response similar to that of estradiol (E-2) at 2 hr, but a less robust response at 24 hr, similar to the short-acting estrogen estriol (E-3). Objectives: Microarray analysis using tools to recognize patterns of response have been utilized in the cancer field to develop biomarker panels of transcripts for diagnosis and selection of treatments most likely to be effective. Biological effects elicited by long-versus short-acting estrogens greatly affect the risks associated with exposures; therefore, we sought to develop tools to predict the ability of chemicals to maintain estrogenic responses. Methods: We used biological end points in uterine tissue and a signature pattern-recognizing tool that identified coexpressed transcripts to develop and test a panel of transcripts in order to classify potentially estrogenic compounds using an in vivo system. The end points used are relevant to uterine tissue, but the resulting classification of the compounds is important for other sensitive tissues and species. Results: We evaluated biological and transcriptional end points with proven short-and long-acting estrogens and verified the use of our approach using a phytoestrogen. With our model, we were able to classify the diarylheptanoid D3 as a short-acting estrogen. Conclusions: We have developed a panel of transcripts as biomarkers which, together with biological end points, might be used to screen and evaluate potentially estrogenic chemicals and infer mode of activity. C1 [Hewitt, Sylvia C.; Winuthayanon, Wipawee; Pockette, Brianna; Korach, Kenneth S.] NIEHS, Receptor Biol Reprod & Dev Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Hewitt, Sylvia C.; Winuthayanon, Wipawee; Pockette, Brianna; Korach, Kenneth S.] NIEHS, Microarray & Genome Informat Grp, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kerns, Robnet T.] Kelly Govt Solut Inc, Morrisville, NC USA. [Foley, Julie F.; Flagler, Norris; Ney, Elizabeth] NIEHS, Cellular & Mol Pathol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Suksamrarn, Apichart] Ramkhamhang Univ, Fac Sci, Dept Chem, Bangkok, Thailand. [Piyachaturawat, Pawinee] Mahidol Univ, Fac Sci, Dept Physiol, Bangkok 10400, Thailand. [Bushel, Pierre R.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sylvia.hewitt@nih.gov FU NIEHS Microarray Core; Histology and Immunohistology Core; Comparative Medicine Branch; Intramural Research Program of the NIH, NIEHS [NIH IRP Z0170065] FX We appreciate the support and expertise offered by the NIEHS Microarray Core, Histology and Immunohistology Core, and Comparative Medicine Branch.; This research was supported, in part, by the Intramural Research Program of the NIH, NIEHS (NIH IRP Z0170065). NR 28 TC 2 Z9 2 U1 1 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2015 VL 123 IS 4 BP 344 EP 352 DI 10.1289/ehp.1307935 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9ML UT WOS:000352168000020 PM 25575267 ER PT J AU Schroeder, JC Booker, SM AF Schroeder, Jane C. Booker, Susan M. TI New Developments at EHP SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Schroeder, Jane C.; Booker, Susan M.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Schroeder, JC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM schroederjc@niehs.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 2 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 APR PY 2015 VL 123 IS 4 BP A78 EP A78 DI 10.1289/ehp.1509968 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE9ML UT WOS:000352168000001 PM 25830487 ER PT J AU Reinders, I Murphy, RA Song, X Visser, M Cotch, MF Lang, TF Garcia, ME Launer, LJ Siggeirsdottir, K Eiriksdottir, G Jonsson, PV Gudnason, V Harris, TB Brouwer, IA AF Reinders, I. Murphy, R. A. Song, X. Visser, M. Cotch, M. F. Lang, T. F. Garcia, M. E. Launer, L. J. Siggeirsdottir, K. Eiriksdottir, G. Jonsson, P. V. Gudnason, V. Harris, T. B. Brouwer, I. A. TI Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID OLDER-ADULTS; PHYSICAL PERFORMANCE; CARDIOVASCULAR HEALTH; MUSCLE STRENGTH; SKELETAL-MUSCLE; DIETARY-INTAKE; OMEGA-3-FATTY-ACIDS; POPULATION; DEPRESSION; COHORT AB BACKGROUND/OBJECTIVES: Low intake of long chain polyunsaturated fatty acids (PUFAs) are associated with physical disability; however, prospective studies of circulating PUFAs are scarce. We examined associations between plasma phospholipid n -3 and n -6 PUFAs with risk of incident mobility disability and gait speed decline. SUBJECTS/METHODS: Data are from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik Study, a population-based study of risk factors for disease and disability in old age. In this subgroup (n = 556, mean age 75.1 +/- 5.0 years, 47.5% men), plasma phospholipid PUFAs were assessed at baseline using gas chromatography. Mobility disability and usual gait speed were assessed at baseline and after 5.2 +/- 0.2 years. Mobility disability was defined as the following: having much difficulty, or being unable to walk 500m or climb up 10 steps; decline in gait speed was defined as change >= 0.10 m/s. Logistic regression analyses were performed to determine associations between sex-specific s. d. increments in PUFAs with risk of incident mobility disability and gait speed decline. Odds ratios (95% confidence intervals) adjusted for demographics, follow-up time, risk factors and serum vitamin D were reported. RESULTS: In women, but not men, every s. d. increment increase of total n -3 PUFAs and docosahexaenoic acid (DHA) was associated with lower mobility disability risk, odds ratio 0.48 (0.25; 0.93) and odds ratio 0.45 (0.24; 0.83), respectively. There was no association between n -6 PUFAs and the risk of incident mobility disability or gait speed decline. CONCLUSIONS: Higher concentrations of n -3 PUFAs and, particularly, DHA may protect women from impaired mobility but does not appear to have such an effect in men. C1 [Reinders, I.; Murphy, R. A.; Garcia, M. E.; Launer, L. J.; Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20814 USA. [Reinders, I.; Visser, M.; Brouwer, I. A.] VU UnivAmsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Reinders, I.; Visser, M.; Brouwer, I. A.] VU UnivAmsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Song, X.] Fred Hutchinson Canc Res Ctr, Biomarker Lab, Seattle, WA 98104 USA. [Visser, M.] Vrije Univ Amsterdam Med Ctr, Internal Med, Dept Nutr & Dietet, Amsterdam, Netherlands. [Cotch, M. F.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Lang, T. F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Siggeirsdottir, K.; Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Jonsson, P. V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Jonsson, P. V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Gudnason, V.] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Reinders, I (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, 7201 Wisconsin Ave,3C-309 Gateway Bldg, Bethesda, MD 20814 USA. EM ilse.reinders@nih.gov RI Lang, Thomas/B-2685-2012; Gudnason, Vilmundur/K-6885-2015; OI Lang, Thomas/0000-0002-3720-8038; Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350 FU National Institutes of Health Office of Dietary Supplements, NIH [N01-AG012100]; National Institute on Aging Intramural Research Program; National Eye Institute [ZIAEY00401]; Banting Postdoctoral Fellowship FX The authors thank the study participants and the Icelandic Heart Association clinic staff for their contribution. This Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by the National Institutes of Health Office of Dietary Supplements, NIH contract N01-AG012100, the National Institute on Aging Intramural Research Program and the National Eye Institute (ZIAEY00401), with contributions from National Institute on Deafness and Other Communication Disorders and National Heart, Lung and Blood Institute, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). We also acknowledge Pho Diep for technical assistance with the fatty acid analyses. RAM holds a Banting Postdoctoral Fellowship. NR 39 TC 2 Z9 2 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD APR PY 2015 VL 69 IS 4 BP 489 EP 493 DI 10.1038/ejcn.2014.277 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CF0ET UT WOS:000352216300013 PM 25585599 ER PT J AU Luque-Fernandez, MA Ananth, CV Jaddoe, VWV Gaillard, R Albert, PS Schomaker, M McElduff, P Enquobahrie, DA Gelaye, B Williams, MA AF Luque-Fernandez, Miguel Angel Ananth, Cande V. Jaddoe, Vincent W. V. Gaillard, Romy Albert, Paul S. Schomaker, Michael McElduff, Patrick Enquobahrie, Daniel A. Gelaye, Bizu Williams, Michelle A. TI Is the fetoplacental ratio a differential marker of fetal growth restriction in small for gestational age infants? SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Placenta; Fetal growth retardation; Birth weight; Siblings; Epidemiology; Regression analysis ID BIRTH-WEIGHT; PLACENTAL WEIGHT; INTRAUTERINE GROWTH; LAMINAR NECROSIS; MULTIPLE IMPUTATION; SIZE; RETARDATION; PREGNANCY; MEMBRANES; COHORT AB Higher placental weight relative to birthweight has been described as an adaptive mechanism to fetal hypoxia in small for gestational age (SGA) infants. However, placental weight alone may not be a good marker reflecting intrauterine growth restriction. We hypothesized that fetoplacental ratio (FPR)-the ratio between birthweight and placental weight-may serve as a good marker of SGA after adjustment for surrogates of fetal hypoxemia (maternal iron deficiency anemia, smoking and choriodecidual necrosis). We conducted a within-sibling analysis using data from the US National Collaborative Perinatal Project (1959-1966) of 1,803 women who delivered their first two (or more) consecutive infants at term (n = 3,494). We used variance-component fixed-effect linear regression models to explore the effect of observed time-varying factors on placental weight and conditional logistic regression to estimate the effects of the tertiles of FPRs (1st small, 2nd normal and 3rd large) on the odds of SGA infants. We found placental weights to be 15 g [95 % confidence interval (CI) 8, 23] higher and -7 g (95 % CI -13, -2) lower among women that had anemia and choriodecidual necrosis, respectively. After multivariable adjustment, newborns with a small FPR (1st-tertile a parts per thousand currency sign7) had twofold higher odds of being SGA (OR 2.0, 95 % CI 1.2, 3.5) than their siblings with a large FPR (3nd-tertile a parts per thousand yen9). A small FPR was associated with higher odds of SGA, suggesting that small FPR may serve as an indicator suggestive of adverse intrauterine environment. This observation may help to distinguish pathological from constitutional SGA. C1 [Luque-Fernandez, Miguel Angel; Gelaye, Bizu; Williams, Michelle A.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth Boston, Boston, MA 02215 USA. [Ananth, Cande V.] Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY USA. [Ananth, Cande V.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Jaddoe, Vincent W. V.; Gaillard, Romy] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD USA. [Schomaker, Michael] Univ Cape Town, CIDER, Fac Hlth Sci, Sch Publ Hlth, ZA-7925 Cape Town, South Africa. [McElduff, Patrick] Univ Newcastle, Sch Publ Hlth, Fac Hlth Sci, Callaghan, NSW 2308, Australia. [Enquobahrie, Daniel A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Luque-Fernandez, MA (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth Boston, 677 Huntington Ave, Boston, MA 02215 USA. EM mluquefe@hsph.harvard.edu RI LUQUE FERNANDEZ, MIGUEL ANGEL/L-4053-2015; OI LUQUE FERNANDEZ, MIGUEL ANGEL/0000-0001-6683-5164; Gelaye, Bizu/0000-0001-7934-548X NR 62 TC 3 Z9 4 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD APR PY 2015 VL 30 IS 4 BP 331 EP 341 DI 10.1007/s10654-015-9993-9 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CF1CG UT WOS:000352280600006 PM 25630563 ER PT J AU Chen, WJ Konkel, JE AF Chen, WanJun Konkel, Joanne E. TI Development of thymic Foxp3(+) regulatory T cells: TGF-beta matters SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Review DE Apoptosis; Foxp3; IL-2; Thymic Treg cells; TGF- beta ID NEGATIVE SELECTION; TRANSCRIPTION FACTOR; EPITHELIAL-CELLS; APOPTOTIC CELLS; SELF-PEPTIDE; ANTIGEN; THYMOCYTES; RECEPTOR; DIFFERENTIATION; MECHANISMS AB CD4(+) regulatory T cells expressing the transcription factor Foxp3 can be generated in the thymus (tTreg cells), but the cellular and molecular pathways driving their development remain incompletely understood. TGF- is essential for the generation of Foxp3(+) Treg cells converted from peripheral naive CD4(+) T cells (pTreg cells), yet a role for TGF- in tTreg-cell development was initially refuted. Nevertheless, recent studies have unmasked a requirement for TGF- in the generation of tTreg cells. Experimental evidence reveals that TGF-in the context of TCR stimulation induces Foxp3 gene transcription in thymic Treg precursors, CD4(+)CD8(-)CD25(-) semimature and mature single-positive thymocytes. Intriguingly, thymic apoptosis was found to be intrinsically linked to the generation of tTreg cells, as apoptosis induced expression of TGF- intrathymically. In this short review, we will highlight key data, discuss the experimental evidence and propose a modified model of tTreg-cell development involving TGF-. We will also outline the remaining unresolved questions concerning generation of thymic Foxp3(+) Treg cells and provide our personal perspectives on the mechanisms controlling tTreg-cell development. C1 [Chen, WanJun] NIDCR, Mucosal Immunol Sect, OPCB, Bethesda, MD 20892 USA. [Konkel, Joanne E.] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Konkel, Joanne E.] Univ Manchester, Manchester Collaborat Ctr Inflammat Res, Manchester, Lancs, England. RP Chen, WJ (reprint author), NIDCR, Mucosal Immunol Sect, OPCB, NIH, Bldg 30,Room 304,30 Convent Dr, Bethesda, MD 20892 USA. EM wchen@mail.nih.gov FU National Institutes of Health, NIDCR; Wellcome Trust ISSF award FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR (WC) and by a Wellcome Trust ISSF award (JEK). We would like to apologize for those important primary articles omitted due to the space limitations. NR 54 TC 11 Z9 14 U1 2 U2 9 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 APR PY 2015 VL 45 IS 4 BP 958 EP 965 DI 10.1002/eji.201444999 PG 8 WC Immunology SC Immunology GA CF4SZ UT WOS:000352543300002 PM 25684698 ER PT J AU Tassi, I Rikhi, N Claudio, E Wang, H Tang, WH Ha, HL Saret, S Kaplan, DH Siebenlist, U AF Tassi, Ilaria Rikhi, Nimisha Claudio, Estefania Wang, Hongshan Tang, Wanhu Ha, Hye-lin Saret, Sun Kaplan, Daniel H. Siebenlist, Ulrich TI The NF-kappa B regulator Bcl-3 modulates inflammation during contact hypersensitivity reactions in radioresistant cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Bcl-3; Chemokines; Contact hypersensitivity; Keratinocytes; NF-B ID LANGERHANS CELLS; IMMUNE EVENTS; T-CELLS; CHEMOKINES; MICE; DERMATITIS; EXPRESSION; KERATINOCYTES; ELICITATION; RECRUITMENT AB Bcl-3 is an atypical member of the IB family. Bcl-3 functions as a cofactor of p50/NF-B1 or p52/NF-B2 homodimers in nuclei, where it modulates NF-B-regulated transcription in a context-dependent way. Bcl-3 has tumorigenic potential, is critical in host defense of pathogens, and has been reported to ameliorate or exacerbate inflammation, depending on disease model. However, cell-specific functions of Bcl-3 remain largely unknown. Here, we explored the role of Bcl-3 in a contact hypersensitivity (CHS) mouse model, which depends on the interplay between keratinocytes and immune cells. Bcl-3-deficient mice exhibited an exacerbated and prolonged CHS response to oxazolone. Increased inflammation correlated with higher production of chemokines CXCL2, CXCL9, and CXCL10, and consequently increased recruitment of neutrophils and CD8(+) T cells. BM chimera experiments indicated that the ability of Bcl-3 to reduce the CHS response depended on Bcl-3 activity in radioresistant cells. Specific ablation of Bcl-3 in keratinocytes resulted in increased production of CXCL9 and CXCL10 and sustained recruitment of specifically CD8(+) T cells. These findings identify Bcl-3 as a critical player during the later stage of the CHS reaction to limit inflammation via actions in radioresistant cells, including keratinocytes. C1 [Tassi, Ilaria; Rikhi, Nimisha; Claudio, Estefania; Wang, Hongshan; Tang, Wanhu; Ha, Hye-lin; Saret, Sun; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kaplan, Daniel H.] Univ Minnesota, Dept Dermatol, Minneapolis, MN 55455 USA. RP Siebenlist, U (reprint author), NIAID, NIH, LMI, Bldg 10,Rm 11B15A, Bethesda, MD 20892 USA. EM us3n@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIH [5R01AR056632-05] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and NIH grant 5R01AR056632-05 (DHK). Author contributions: IT, NR, and US designed the study and interpreted results; IT and US wrote the manuscript; EC, HW, WT, HH, and SP assisted in experiments and contributed to design and discussion of experiments; DHK provided Langerin-Cre mice and advice. NR 36 TC 2 Z9 2 U1 1 U2 5 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 APR PY 2015 VL 45 IS 4 BP 1059 EP 1068 DI 10.1002/eji.201444994 PG 10 WC Immunology SC Immunology GA CF4SZ UT WOS:000352543300012 PM 25616060 ER PT J AU Kapanadze, T Medina-Echeverz, J Gamrekelashvili, J Weiss, JM Wiltrout, RH Kapoor, V Hawk, N Terabe, M Berzofsky, JA Manns, MP Wang, E Marincola, FM Korangy, F Greten, TF AF Kapanadze, Tamar Medina-Echeverz, Jose Gamrekelashvili, Jaba Weiss, Jonathan M. Wiltrout, Robert H. Kapoor, Veena Hawk, Nga Terabe, Masaki Berzofsky, Jay A. Manns, Michael P. Wang, Ena Marincola, Francesco M. Korangy, Firouzeh Greten, Tim F. TI Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD40; Concanavalin A; -Galactosylceramide; Immune-mediated hepatitis; Myeloid-derived suppressor cells; Reactive oxygen species ID HEPATOCELLULAR-CARCINOMA PATIENTS; INDUCED LIVER-INJURY; CONCANAVALIN-A; BEARING MICE; NKT CELLS; T-CELLS; ALPHA-GALACTOSYLCERAMIDE; OXIDATIVE STRESS; NECROSIS-FACTOR; KUPFFER CELLS AB Immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or -galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naive mice exacerbated Con A induced liver damage. Hepatic CD11b(+)Gr-1(+) cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN--dependent upregulation of CD40 on hepatic CD11b(+)Gr-1(+) cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+)Gr-1(+) MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. C1 [Kapanadze, Tamar; Medina-Echeverz, Jose; Gamrekelashvili, Jaba; Korangy, Firouzeh; Greten, Tim F.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kapanadze, Tamar; Gamrekelashvili, Jaba; Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Weiss, Jonathan M.; Wiltrout, Robert H.] NCI, Expt Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kapoor, Veena; Hawk, Nga] NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Greten, TF (reprint author), NCI, NIH, CCR Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov FU Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer; Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health FX We would like to thank to Alpa Shah (Department of Laboratory Medicine, NIH/Clinical Research Center) for determining liver aminotransferases; and Dr. Noriko Sato (Molecular Imaging Program, NIH/NCI) for providing Rag-1-/- mice. This work was supported by the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health. NR 59 TC 2 Z9 2 U1 1 U2 5 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 APR PY 2015 VL 45 IS 4 BP 1148 EP 1158 DI 10.1002/eji.201445093 PG 11 WC Immunology SC Immunology GA CF4SZ UT WOS:000352543300020 PM 25616156 ER PT J AU Winthrop, KL Ku, JH Marras, TK Griffith, DE Daley, CL Olivier, KN Aksamit, TR Varley, CD Mackey, K Prevots, DR AF Winthrop, Kevin L. Ku, Jennifer H. Marras, Theodore K. Griffith, David E. Daley, Charles L. Olivier, Kenneth N. Aksamit, Timothy R. Varley, Cara D. Mackey, Katherine Prevots, D. Rebecca TI The tolerability of linezolid in the treatment of nontuberculous mycobacterial disease SO EUROPEAN RESPIRATORY JOURNAL LA English DT Letter ID DRUG-RESISTANT TUBERCULOSIS; MULTIDRUG-RESISTANT; SAFETY; METAANALYSIS; EFFICACY; TB C1 [Winthrop, Kevin L.; Ku, Jennifer H.; Varley, Cara D.; Mackey, Katherine] Oregon Hlth & Sci Univ, Div Infect Dis, Portland, OR 97239 USA. [Winthrop, Kevin L.; Ku, Jennifer H.; Varley, Cara D.; Mackey, Katherine] Oregon Hlth & Sci Univ, Div Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Marras, Theodore K.] Univ Toronto, Toronto, ON, Canada. [Griffith, David E.] Univ Texas Tyler, Tyler, TX 75799 USA. [Daley, Charles L.] Natl Jewish Hlth, Denver, CO USA. [Olivier, Kenneth N.] NIAID, Bethesda, MD 20892 USA. [Aksamit, Timothy R.] Mayo Clin, Rochester, MN USA. RP Winthrop, KL (reprint author), Oregon Hlth & Sci Univ, Div Infect Dis, 3375 Terwilliger Blvd, Portland, OR 97239 USA. EM Winthrop@ohsu.edu FU Intramural NIH HHS NR 14 TC 3 Z9 3 U1 4 U2 7 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 APR PY 2015 VL 45 IS 4 BP 1177 EP 1179 DI 10.1183/09031936.00169114 PG 3 WC Respiratory System SC Respiratory System GA CE7MB UT WOS:000352023800032 PM 25614169 ER PT J AU Connell, MT Szatkowski, JM Terry, N DeCherney, AH Propst, AM Hill, MJ AF Connell, Matthew T. Szatkowski, Jennifer M. Terry, Nancy DeCherney, Alan H. Propst, Anthony M. Hill, Micah J. TI Timing luteal support in assisted reproductive technology: a systematic review SO FERTILITY AND STERILITY LA English DT Review DE Progesterone; luteal support; in vitro fertilization ID IN-VITRO FERTILIZATION; GONADOTROPIN-RELEASING-HORMONE; RECOMBINANT LUTEINIZING-HORMONE; CIRCULATING PROGESTERONE LEVELS; FOLLICLE-STIMULATING-HORMONE; HUMAN CHORIONIC-GONADOTROPIN; FINAL OOCYTE MATURATION; CRINONE 8-PERCENT GEL; LIVE BIRTH-RATES; PHASE SUPPORT AB Objective: To summarize the available published randomized controlled trial data regarding timing of P supplementation during the luteal phase of patients undergoing assisted reproductive technology (ART). Design: A systematic review. Setting: Not applicable. Patient(s): Undergoing IVF. Intervention(s): Different starting times of P for luteal support. Main Outcome Measure(s): Clinical pregnancy (PR) and live birth rates. Result(s): Five randomized controlled trials were identified that met inclusion criteria with a total of 872 patients. A planned meta-analysis was not performed because of a high degree of clinical heterogeneity with regard to the timing, dose, and route of P. Two studies compared P initiated before oocyte retrieval versus the day of oocyte retrieval and PRs were 5%-12% higher when starting P on the day of oocyte retrieval. One study compared starting P on day 6 after retrieval versus day 3, reporting a 16% decrease in pregnancy in the day 6 group. Trials comparing P start times on the day of oocyte retrieval versus 2 or 3 days after retrieval showed no significant differences in pregnancy. Conclusion(s): There appears to be a window for P start time between the evening of oocyte retrieval and day 3 after oocyte retrieval. Although some studies have suggested a potential benefit in delaying vaginal P start time to 2 days after oocyte retrieval, this review could not find randomized controlled trials to adequately assess this. Further randomized clinical trials are needed to better define P start time for luteal support after ART. (C) 2015 by American Society for Reproductive Medicine. C1 [Connell, Matthew T.; Szatkowski, Jennifer M.; DeCherney, Alan H.; Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Terry, Nancy] Natl Inst Hlth Lib, Bethesda, MD USA. [Propst, Anthony M.] Texas Fertil Ctr, Austin, TX USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov OI Hill, Micah/0000-0002-3104-7763 FU Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 54 TC 5 Z9 5 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2015 VL 103 IS 4 BP 939 EP U112 DI 10.1016/j.fertnstert.2014.12.125 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CE8QZ UT WOS:000352110400021 PM 25638420 ER PT J AU Diamond, MP Legro, RS Coutifaris, C Alvero, R Robinson, RD Casson, P Christman, GM Ager, J Huang, H Hansen, KR Baker, V Usadi, R Seungdamrong, A Bates, GW Rosen, RM Haisonleder, D Krawetz, SA Barnhart, K Trussell, JC Jin, Y Santoro, N Eisenberg, E Zhang, H AF Diamond, Michael P. Legro, Richard S. Coutifaris, Christos Alvero, Ruben Robinson, Randal D. Casson, Peter Christman, Gregory M. Ager, Joel Huang, Hao Hansen, Karl R. Baker, Valerie Usadi, Rebecca Seungdamrong, Aimee Bates, G. Wright Rosen, R. Mitchell Haisonleder, Daniel Krawetz, Stephen A. Barnhart, Kurt Trussell, J. C. Jin, Yufeng Santoro, Nanette Eisenberg, Esther Zhang, Heping TI Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics SO FERTILITY AND STERILITY LA English DT Article DE Unexplained infertility; aromatase inhibitors; letrozole; gonadotropins; clomiphene citrate; multiple gestations ID GENERAL PSYCHOMETRIC PROPERTIES; RANDOMIZED CLINICAL-TRIAL; FERTIQOL TOOL DEVELOPMENT; IN-VITRO FERTILIZATION; CLOMIPHENE CITRATE; PRIME-MD; SUPEROVULATION; PREGNANCIES; INFERTILITY; LETROZOLE AB Objective: To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. Design: Randomized, prospective clinical trial. Setting: Multicenter university-based clinical practices. Patient(s): A total of 900 couples with unexplained infertility. Intervention(s): Collection of baseline demographics, blood samples, and ultrasonographic assessments. Main Outcome Measure(s): Demographic, laboratory, imaging, and survey characteristics. Result(s): Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 +/- 4.4 years and infertility duration was 34.7 +/- 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimullerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. Conclusion(s): The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimullerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. (C) 2015 by American Society for Reproductive Medicine. C1 [Diamond, Michael P.; Ager, Joel; Krawetz, Stephen A.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA 30912 USA. [Diamond, Michael P.; Ager, Joel; Krawetz, Stephen A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Legro, Richard S.] Penn State Univ, Dept Obstet & Gynecol, Hershey, PA USA. [Coutifaris, Christos; Barnhart, Kurt] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Alvero, Ruben; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Robinson, Randal D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Christman, Gregory M.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI USA. [Huang, Hao; Jin, Yufeng; Zhang, Heping] Yale Univ, Sch Publ Hlth, Dept Biostatist, New Haven, CT USA. [Hansen, Karl R.] Univ Oklahoma, Coll Med, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Baker, Valerie] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Usadi, Rebecca] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Seungdamrong, Aimee] Univ Med & Dent New Jersey, New Jersey Med Sch, Rutgers, NJ USA. [Bates, G. Wright] Univ Alabama Birmingham, Birmingham, AL USA. [Rosen, R. Mitchell] Univ Calif San Francisco, Dept Reprod Endocrinol & Infertil, San Francisco, CA 94143 USA. [Haisonleder, Daniel] Univ Virginia, Ctr Res Reprod, Ligand Core Lab, Charlottesville, VA USA. [Trussell, J. C.] Upstate Univ Hosp, Syracuse, NY USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Rockville, MD USA. RP Diamond, MP (reprint author), Georgia Regents Univ, Dept Obstet & Gynecol, 1120 15th St BA 7300, Augusta, GA 30912 USA. EM Michael.Diamond@gru.edu OI Seungdamrong, Aimee/0000-0002-0065-1845; Diamond, Michael/0000-0001-6353-4489 FU National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, U10HD055925, U10 U54-HD29834]; American Recovery and Reinvestment Act [U10HD03005-0851, U10HD055925-02W1]; EMD Serono; AbbVie; BioSante; Ferring; Novartis; Merck; American Society for Reproductive Medicine; Yale University/Reproductive Medicine Network/NICHD; Roche Diagnostics; Ferring International Pharmascience US; Bayer, Inc. FX Supported by the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants U10 HD39005 (to M.P.D.), U10 HD38992 (to R.S.L.), U10 HD27049 (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.M.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act (U10HD03005-0851 to M.P.D., U10HD055925-02W1 to H.Z.).; M.P.D. reports grants from EMD Serono, AbbVie, BioSante, Ferring, and Novartis; is a consultant for Auxogyn, Actamax, Teijan Pharmaceuticals, and ZSX Medical; and is a stockholder and on the Board of Directors of Advanced Reproductive Care. R.S.L. has nothing to disclose. C.C. has nothing to disclose. R.A. has nothing to disclose. R.D.R. reports a grant from AbbVie; payment for lectures from Merck; and payment for development of educational material from American Society for Reproductive Medicine. P.C. has nothing to disclose. G.M.C. has nothing to disclose. J.A. has nothing to disclose. H.H. has nothing to disclose. K.R.H. reports grants from Yale University/Reproductive Medicine Network/NICHD, Roche Diagnostics, and Ferring International Pharmascience US. V.B. has nothing to disclose. R.U. has nothing to disclose. A.S. has nothing to disclose. G.W.B. has nothing to disclose. R.M.R. has nothing to disclose. D.H. has nothing to disclose. S.A.K. has nothing to disclose. K.B. has nothing to disclose. J.C.T. has nothing to disclose. Y.J. has nothing to disclose. N.S. reports a grant from Bayer, Inc., and has stock options in Menogenix. E.E. has nothing to disclose. H.Z. has nothing to disclose. NR 31 TC 8 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2015 VL 103 IS 4 BP 962 EP U143 DI 10.1016/j.fertnstert.2014.12.130 PG 16 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CE8QZ UT WOS:000352110400024 PM 25707331 ER PT J AU Kadiiska, MB Peddada, S Herbert, RA Basu, S Hensley, K Jones, DP Hatch, GE Mason, RP AF Kadiiska, Maria B. Peddada, Shyamal Herbert, Ronald A. Basu, Samar Hensley, Kenneth Jones, Dean P. Hatch, Gary E. Mason, Ronald P. TI Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE LPS; Oxidative stress; Biomarkers; Plasma antioxidants; Mini-pig model; Free radicals ID EXPERIMENTAL SEPTIC SHOCK; NITRIC-OXIDE SYNTHASE; TOLL-LIKE RECEPTORS; HUMAN-BLOOD PLASMA; VITAMIN-E; URIC-ACID; LIPID-PEROXIDATION; INNATE IMMUNITY; ASCORBIC-ACID; REDOX STATE AB This is the newest report in a series of publications aiming to identify a blood-based antioxidant biomarker that could serve as an in vivo indicator of oxidative stress. The goal of the study was to test whether acutely exposing Gottingen mini pigs to the endotoxin lipopolysaccharide (LPS) results in a loss of antioxidants from plasma. We set as a criterion that a significant effect should be measured in plasma and seen at both doses and at more than one time point Animals were injected with two doses of LPS at 2.5 and 514/kg iv. Control plasma was collected from each animal before the LPS injection. After the LPS injection, plasma samples were collected at 2, 16, 48, and 72 h. Compared with the controls at the same time point, statistically significant losses were not found for either dose at multiple time points in any of the following potential markers: ascorbic acid, tocopherols (alpha, delta, gamma), ratios of GSH/GSSG and cysteine/cystine, mixed disulfides, and total antioxidant capacity. However, uric acid, total GSH, and total Cys were significantly increased, probably because LPS had a harmful effect on the liver. The leakage of substances from damaged cells into the plasma may have increased plasma antioxidant concentrations, making changes difficult to interpret Although this study used a mini-pig animal model of LPS-induced oxidative stress, it confirmed our previous findings in different rat models that measurement of antioxidants in plasma is not useful for the assessment of oxidative damage in vivo. Published by Elsevier Inc. C1 [Kadiiska, Maria B.; Peddada, Shyamal; Herbert, Ronald A.; Mason, Ronald P.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Basu, Samar] Uppsala Univ, Fac Med, Dept Publ Hlth & Caring Sci, Oxidat Stress & Inflammat, Uppsala, Sweden. [Hensley, Kenneth] Univ Toledo, Med Ctr, Dept Pathol, Toledo, OH 43614 USA. [Jones, Dean P.] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Hatch, Gary E.] US EPA, Res Triangle Pk, NC 27711 USA. RP Kadiiska, MB (reprint author), NIEHS, 111 TW Alexander Dr,MD F0-02, Res Triangle Pk, NC 27709 USA. EM Kadiiska@niehs.nih.gov FU National Institute of Environmental Health Sciences Intramural Research Program, National Institutes of Health FX The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This research was supported by the National Institute of Environmental Health Sciences Intramural Research Program, National Institutes of Health. The authors thank Jean Corbett Ralph Wilson, Ralph Slade, Kay Crissman, and Judy Richards, for excellent technical support The authors also thank Dr. Ann Motten and Ms. Mary J. Mason for editorial assistance. NR 53 TC 9 Z9 11 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD APR PY 2015 VL 81 BP 100 EP 106 DI 10.1016/j.freeradbiomed.2015.01.006 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CE9PL UT WOS:000352175800011 PM 25614459 ER PT J AU Yang, S Yang, Y Yu, P Yang, J Jiang, X Villar, VAM Sibley, DR Jose, PA Zeng, C AF Yang, S. Yang, Y. Yu, P. Yang, J. Jiang, X. Villar, V. A. M. Sibley, D. R. Jose, P. A. Zeng, C. TI Dopamine D-1 and D-5 receptors differentially regulate oxidative stress through paraoxonase 2 in kidney cells SO FREE RADICAL RESEARCH LA English DT Article DE dopamine receptors; paraoxonase 2; reactive oxygen species; NADPH oxidase; lipid rafts ID OXYGEN SPECIES PRODUCTION; LIPID RAFT MICRODOMAINS; PROXIMAL TUBULE CELLS; NADPH OXIDASE; BLOOD-PRESSURE; RESPIRATORY BURST; ANGIOTENSIN-II; DEFICIENT MICE; HYPERTENSION; PROTEIN AB Background. The renal dopaminergic system plays an important role in the pathogenesis of hypertension. Dopamine D-1-like receptors (D1R and D5R) decrease reactive oxygen species (ROS) production via inhibition of pro-oxidant enzymes such as NADPH oxidase. Paraoxonase 2 (PON2) is also involved in the inhibition of NADPH oxidase activity. Therefore, we tested the hypothesis that D1R and D5R inhibit ROS production by increasing the expression of PON2, including those in membrane microdomains. Methods and results. PON2 colocalized with D1R and D5R in mouse renal proximal tubules (RPTs), human RPT (hRPT) cells, and HEK293 cells heterologously expressing human D1R (HEK-hD(1)R ) or D5R (HEK-hD(5)R). Fenoldopam, an agonist for both D1R and D5R, increased PON2 co-immunoprecipitation with D1R and D5R in HEK-hD(1)R and HEK-hD(5)R cells, respectively. Silencing PON2 increased ROS production and NADPH oxidase activity, and impaired the inhibitory effect of fenoldopam. Fenoldopam increased PON2 protein in both lipid rafts (LRs) and non-LRs in HEK-hD(1)R cells, but only in non-LRs in HEK-hD(5)R and hRPT cells. Long-term (hrs) fenoldopam stimulation increased PON2 protein in a time-dependent manner in HEK-hD(5)R, but not in HEK-hD(1)R cells. Because the effects of fenoldopam on non-LR and total PON2 expressions were similar in HEK-hD(5)R and hRPT cells, additional studies were performed to determine the relationship between D5R and PON2. Renal PON2 protein was decreased in D-5(- /-) mice. In hRPT cells, silencing D5R decreased PON2 expression and increased ROS production. Conclusions. We conclude that D-1-like receptors inhibit ROS production by altering PON2 distribution in membrane microdomains in the short-term, and by increasing PON2 expression in the long-term. C1 [Yang, S.; Zeng, C.] Third Mil Med Univ, Daping Hosp, Dept Cardiol, Chongqing, Peoples R China. [Yang, S.; Zeng, C.] Chongqing Inst Cardiol, Chongqing, Peoples R China. [Yang, S.; Yang, Y.; Yu, P.; Yang, J.; Jiang, X.; Villar, V. A. M.; Jose, P. A.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Sibley, D. R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Jose, P. A.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. RP Zeng, C (reprint author), Univ Maryland, Sch Med, Dept Med, Div Nephrol, 20 Penn St,Suite S003C, Baltimore, MD 21201 USA. EM pjose@medicine.umaryland.edu; chunyuzeng01@163.com FU National Natural Science Foundation of China [31130029, 81100500]; US National Institutes of Health [5P01HL074940] FX These studies were supported in part by grants from the National Natural Science Foundation of China (31130029, 81100500), and grant from the US National Institutes of Health, 5P01HL074940. NR 61 TC 2 Z9 2 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 EI 1029-2470 J9 FREE RADICAL RES JI Free Radic. Res. PD APR PY 2015 VL 49 IS 4 BP 397 EP 410 DI 10.3109/10715762.2015.1006215 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF6YT UT WOS:000352703600004 PM 25740199 ER PT J AU Finigan-Carr, NM Cheng, TL Gielen, A Haynie, DL Simons-Morton, B AF Finigan-Carr, Nadine M. Cheng, Tina L. Gielen, Andrea Haynie, Denise L. Simons-Morton, Bruce TI Using the Theory of Planned Behavior to Predict Aggression and Weapons Carrying in Urban African American Early Adolescent Youth SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE adolescence; aggression; perceived behavioral control; self-control; theory of planned behavior; youth violence ID PHYSICAL AGGRESSION; COMMUNITY VIOLENCE; YOUNG ADOLESCENTS; SOCIAL SUPPORT; MIDDLE SCHOOL; RISK-FACTORS; CHILDREN; ATTITUDES; STUDENTS; EXPOSURE AB Aggressive and weapons carrying behaviors are indicative of youth violence. The theory of planned behavior is used in the current analysis to improve our understanding of violence-related behaviors. We examine the influence of perceived behavioral control (self-control and decision making) as a part of the overall framework for understanding the risk and protective factors for aggressive behaviors and weapons carrying. As the baseline assessment of an intervention trial, survey data were collected on 452 sixth-grade students (50% girls; 96.6% African American; mean age 12.0 years) from urban middle schools. A total of 18.4% carried a weapon in the prior 12 months, with boys more likely to carry a weapon than girls (22.5% vs. 14.2%, p = .02). Of the youth, 78.4% reported aggressive behaviors with no significant differences found between girls (81.3%) and boys (75.5%). In logistic regression models, having peers who engage in problem behaviors was found to be a significant risk factor. Youth with peers who engaged in numerous problem behaviors were five times more likely to be aggressive than those who reported little or no peer problem behaviors. Teens who reported that their parents opposed aggression (odds ratio [OR] = 0.76; confidence interval [CI] = 0.66, 0.88) and who used self-control strategies (OR = 0.59; CI = 0.39, 0.87) were found to report less aggressive behaviors. For weapons carrying, being a girl (OR = 0.56; CI = 0.32, 0.97) and self-control (OR = 0.52; CI = 0.29, 0.92) were protective factors. This study demonstrated that the theory of planned behavior may provide a useful framework for the development of violence prevention programs. Practitioners should consider integrating strategies for developing healthy relationships and improving self-control. C1 [Finigan-Carr, Nadine M.] Univ Maryland, Baltimore, MD 21210 USA. [Cheng, Tina L.; Gielen, Andrea] Johns Hopkins Univ, Baltimore, MD USA. [Haynie, Denise L.; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Finigan-Carr, NM (reprint author), Univ Maryland, Ruth H Young Ctr Families & Children, 550 West Baltimore St, Baltimore, MD 21210 USA. EM nfinigan@ssw.umaryland.edu OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-2-3344]; NICHD [1K24HD052559-01]; NICHD Intramural Research Program; Centers for Disease Control and Prevention [U49CE000728] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Contract Number N01-HD-2-3344 and NICHD Grant Number 1K24HD052559-01 (Cheng), the NICHD Intramural Research Program (Haynie and Simons-Morton), and Centers for Disease Control and Prevention (U49CE000728). NR 47 TC 1 Z9 1 U1 3 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD APR PY 2015 VL 42 IS 2 BP 220 EP 230 DI 10.1177/1090198114548479 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CF0IX UT WOS:000352228000010 PM 25228369 ER PT J AU Gao, B AF Gao, Bin TI Interplay of Interleukin-22 and Its Binding Protein in Controlling Liver Scarring SO HEPATOLOGY LA English DT Editorial Material ID HEPATITIS-B-VIRUS; STELLATE CELLS; IL-22; INFLAMMATION; INFECTION; FIBROSIS; MICE C1 NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov FU Intramural NIH HHS NR 19 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2015 VL 61 IS 4 BP 1121 EP 1123 DI 10.1002/hep.27688 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE8NM UT WOS:000352099700007 PM 25580805 ER PT J AU Maricic, I Sheng, HM Marrero, I Seki, E Kisseleva, T Chaturvedi, S Molle, N Mathews, SA Gao, B Kumar, V AF Maricic, Igor Sheng, Huiming Marrero, Idania Seki, Ekihiro Kisseleva, Tatiana Chaturvedi, Som Molle, Natasha Mathews, Stephanie A. Gao, Bin Kumar, Vipin TI Inhibition of Type I Natural Killer T Cells by Retinoids or Following Sulfatide-Mediated Activation of Type II Natural Killer T Cells Attenuates Alcoholic Liver Disease in Mice SO HEPATOLOGY LA English DT Article ID NKT CELLS; NEUTROPHIL INFILTRATION; CARBON-TETRACHLORIDE; IMMUNE REGULATION; SELF-ANTIGENS; INNATE-LIKE; ACID; PATHOGENESIS; OSTEOPONTIN; FIBROSIS AB Innate immune mechanisms leading to liver injury subsequent to chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that after chronic plus binge feeding of Lieber-DeCarli liquid diet in male C57BL/6 mice, type I, but not type II, NKT cells are activated, leading to recruitment of inflammatory Gr-1(high)CD11b(+) cells into the liver. A central finding is that liver injury after alcohol feeding is dependent upon type I NKT cells. Thus, liver injury is significantly inhibited in J18(-/-) mice deficient in type I NKT cells as well as after their inactivation by sulfatide-mediated activation of type II NKT cells. Furthermore, we have identified a novel pathway involving all-trans retinoic acid (ATRA) and its receptor (RAR) signaling that inhibits type I NKT cells and, consequently, ALD. A semiquantitative polymerase chain reaction analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their up-regulation in ALD is dependent upon type I NKT cells. Conclusions: Type I, but not type II, NKT cells become activated after alcohol feeding. Type I NKT cell-induced inflammation and neutrophil recruitment results in liver tissue damage whereas type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Given that the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD. (Hepatology 2015;61:1357-1369) C1 [Maricic, Igor; Sheng, Huiming; Marrero, Idania; Chaturvedi, Som; Molle, Natasha; Kumar, Vipin] Torrey Pines Inst Mol Studies, Lab Autoimmun, San Diego, CA 92121 USA. [Seki, Ekihiro; Kisseleva, Tatiana] Univ Calif San Diego, Dept Med, Div Gastroenterol, La Jolla, CA 92093 USA. [Mathews, Stephanie A.; Gao, Bin] NIH, Bethesda, MD 20892 USA. RP Kumar, V (reprint author), Torrey Pines Inst Mol Studies, Lab Autoimmun, 3550 Gen Atom Court, San Diego, CA 92121 USA. EM vkumar@tpims.org RI Seki, Ekihiro/K-2481-2016 FU National Institutes of Health [R01 CA100660, R01 AA020864] FX This work was supported by grants from the National Institutes of Health (R01 CA100660 and R01 AA020864; to V.K.). NR 43 TC 17 Z9 18 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2015 VL 61 IS 4 BP 1357 EP 1369 DI 10.1002/hep.27632 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE8NM UT WOS:000352099700030 PM 25477000 ER PT J AU Kuniholm, MH Engle, RE Purcell, RH Nelson, KE AF Kuniholm, Mark H. Engle, Ronald E. Purcell, Robert H. Nelson, Kenrad E. TI Hepatitis E Virus Seroprevalence in the United States: No Easy Answers SO HEPATOLOGY LA English DT Letter ID NATIONAL-HEALTH; EPIDEMIOLOGY C1 [Kuniholm, Mark H.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Nelson, Kenrad E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Kuniholm, MH (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. FU NCATS NIH HHS [UL1 TR001073]; NCRR NIH HHS [UL1RR025750, KL2 RR025749, UL1 RR025750, KL2RR025749]; NHLBI NIH HHS [R21 HL121740, R21HL121740] NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2015 VL 61 IS 4 BP 1441 EP 1442 DI 10.1002/hep.27286 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE8NM UT WOS:000352099700048 PM 24995930 ER PT J AU Engle, RE Kuniholm, MH Nelson, KE Purcell, RH AF Engle, Ronald E. Kuniholm, Mark H. Nelson, Kenrad E. Purcell, Robert H. TI Hepatitis E Virus Seroprevalence in the National Health and Nutrition Examination Survey: Facts Trump Opinion SO HEPATOLOGY LA English DT Letter C1 [Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Kuniholm, Mark H.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Nelson, Kenrad E.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Engle, RE (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2015 VL 61 IS 4 BP 1442 EP 1443 DI 10.1002/hep.27292 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE8NM UT WOS:000352099700049 PM 24995541 ER PT J AU Israeli, M Roelen, DL Carrington, M Petersdorf, EW Claas, FHJ Haasnoot, GW Oudshoorn, M AF Israeli, Moshe Roelen, Dave L. Carrington, Mary Petersdorf, Effie W. Claas, Frans H. J. Haasnoot, Geert W. Oudshoorn, Machteld TI ASSOCIATION BETWEEN CTL PRECURSOR FREQUENCY TO HLA-C MISMATCHES AND HLA-C ANTIGEN CELL SURFACE EXPRESSION SO HUMAN IMMUNOLOGY LA English DT Meeting Abstract CT 40th Annual Meeting of the American-Society-for-Histocompatibility-and-Immunogenetics (ASHI) CY OCT 20-24, 2014 CL Denver, CO SP Amer Soc Histocompatibil & Immunogenet C1 [Israeli, Moshe; Roelen, Dave L.; Claas, Frans H. J.; Haasnoot, Geert W.; Oudshoorn, Machteld] Leiden Univ, Med Ctr, Leiden, Netherlands. [Carrington, Mary] Frederick Natl Lab Canc Res, Frederick, MD USA. [Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD APR PY 2015 VL 76 IS 4 MA LBOR03 BP 212 EP 212 PG 1 WC Immunology SC Immunology GA CF7PS UT WOS:000352749400004 ER PT J AU Li, YW Hofstetter, CR Wahlgren, D Irvin, V Chhay, D Hovell, MF AF Li, Yawen Hofstetter, C. Richard Wahlgren, Dennis Irvin, Veronica Chhay, Doug Hovell, Melbourne F. TI Social networks and immigration stress among first-generation Mandarin-speaking Chinese immigrants in Los Angeles SO INTERNATIONAL JOURNAL OF SOCIAL WELFARE LA English DT Article DE social networks; immigration stress; Chinese immigrants in the USA ID IDENTITY ACCULTURATION SCALE; KOREAN IMMIGRANTS; FAMILY-SIZE; SUPPORT; HEALTH; DEPRESSION; PARTICIPATION; MEMBERSHIP; DEMANDS; FUTURE AB This study examined relationships between social networks and immigration stress among first-generation Chinese immigrants. Using data from a larger study of health behavior among first-generation Mandarin/English-speaking immigrants residing in the Los Angeles metropolitan area (N = 1,183), this study found that Chinese immigrants living closer to immediate family and maintaining larger social networks experienced lower immigration stress. Unexpectedly, immigrants with larger family sizes and who participated in voluntary associations (e.g., religious, alumni, and nationality associations) reported increased immigration stress. The findings suggest that practitioners need to be cautious of a possible downside in designing interventions to expand social networks among immigrant clients. The study is especially important in the context of a rapidly increasing immigrant population from Mainland China to the USA. Key Practitioner Message: . Working with immigration families should incorporate assessment of their social network; . Interventions designed to facilitate supportive social networks should differentiate different social network ties; . Different social network ties may affect the stress level of immigrants differently. C1 [Li, Yawen] San Diego State Univ, Sch Social Work, San Diego, CA 92182 USA. [Hofstetter, C. Richard] San Diego State Univ, Dept Polit Sci, San Diego, CA 92182 USA. [Wahlgren, Dennis; Chhay, Doug] San Diego State Univ, Ctr Behav Epidemiol & Community Hlth, San Diego, CA 92182 USA. [Irvin, Veronica] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Irvin, Veronica] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Hovell, Melbourne F.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. RP Li, YW (reprint author), San Diego State Univ, Sch Social Work, 5500 Campanile Dr,HH103, San Diego, CA 92182 USA. EM yli@mail.sdsu.edu NR 60 TC 2 Z9 2 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1369-6866 EI 1468-2397 J9 INT J SOC WELF JI Int. J. Soc. Welf. PD APR PY 2015 VL 24 IS 2 BP 170 EP 181 DI 10.1111/ijsw.12103 PG 12 WC Social Work SC Social Work GA CE8LO UT WOS:000352094000007 ER PT J AU Mathias, TJ Natarajan, K Shukla, S Doshi, KA Singh, ZN Ambudkar, SV Baer, MR AF Mathias, Trevor J. Natarajan, Karthika Shukla, Suneet Doshi, Kshama A. Singh, Zeba N. Ambudkar, Suresh V. Baer, Maria R. TI The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Crenolanib; ABCB1; FLT3; Platelet-derived growth factor receptor; Acutemyeloid leukemia; Glioma ID ACUTE MYELOID-LEUKEMIA; GASTROINTESTINAL STROMAL TUMORS; INTERNAL TANDEM DUPLICATION; TYROSINE KINASE INHIBITORS; MEDIATED DRUG-RESISTANCE; P-GLYCOPROTEIN; CELL-LINE; HEMATOPOIETIC-CELLS; POTENT INHIBITOR; MUTATIONS AB Background Crenolanib (crenolanib besylate, 4-piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate) is a potent and specific type I inhibitor of fms-like tyrosine kinase 3 (FLT3) that targets the active kinase conformation and is effective against FLT3 with internal tandem duplication (ITD) with point mutations induced by, and conferring resistance to, type II FLT3 inhibitors in acute myeloid leukemia (AML) cells. Crenolanib is also an inhibitor of platelet-derived growth factor receptor alpha and beta and is in clinical trials in both gastrointestinal stromal tumors and gliomas. Methods We tested crenolanib interactions with the multidrug resistance-associated ATP-binding cassette proteins ABCB1 (P-glycoprotein), ABCG2 (breast cancer resistance protein) and ABCC1 (multidrug resistance-associated protein 1), which are expressed on AML cells and other cancer cells and are important components of the blood-brain barrier. Results We found that crenolanib is a substrate of ABCB1, as evidenced by approximate five-fold resistance of ABCB1-overexpressing cells to crenolanib, reversal of this resistance by the ABCB1-specific inhibitor PSC-833 and stimulation of ABCB1 ATPase activity by crenolanib. In contrast, crenolanib was not a substrate of ABCG2 or ABCC1. Additionally, it did not inhibit substrate transport by ABCB1, ABCG2 or ABCC1, at pharmacologically relevant concentrations. Finally, incubation of the FLT3-ITD AML cell lines MV4-11 and MOLM-14 with crenolanib at a pharmacologically relevant concentration of 500 nM did not induce upregulation of ABCB1 cell surface expression. Conclusions Thus ABCB1 expression confers resistance to crenolanib and likely limits crenolanib penetration of the central nervous system, but crenolanib at therapeutic concentrations should not alter cellular exposure to ABC protein substrate chemotherapy drugs. C1 [Mathias, Trevor J.; Natarajan, Karthika; Doshi, Kshama A.; Baer, Maria R.] Univ Maryland Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Natarajan, Karthika; Baer, Maria R.] Univ Maryland Sch Med, Dept Med, Baltimore, MD USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Singh, Zeba N.] Univ Maryland Sch Med, Dept Pathol, Baltimore, MD USA. RP Baer, MR (reprint author), Univ Maryland Greenebaum Canc Ctr, 22 South Greene St, Baltimore, MD 21201 USA. EM mbaer@umm.edu FU Leukemia and Lymphoma Society Translational Research Award; University of Maryland, Baltimore UMMG Cancer Research Grant [CH 649 CRF]; State of Maryland Department of Health and Mental Hygiene (DHMH) under Cigarette Restitution Fund Program; NCI Cancer Center Support Grant [P30 CA134274]; NIH, National Cancer Institute, Center for Cancer Research FX This work was funded by a Leukemia and Lymphoma Society Translational Research Award (M.R. Baer), University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF, State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program (M.R. Baer), and NCI Cancer Center Support Grant P30 CA134274 (UMGCC). Drs. S. Shukla and S.V. Ambudkar were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 64 TC 1 Z9 1 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2015 VL 33 IS 2 BP 300 EP 309 DI 10.1007/s10637-015-0205-y PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CF3JK UT WOS:000352444600004 PM 25597754 ER PT J AU Esposito, G Nakazawa, J Venuti, P Bornstein, MH AF Esposito, Gianluca Nakazawa, Jun Venuti, Paola Bornstein, Marc H. TI Judgment of infant cry: The roles of acoustic characteristics and sociodemographic characteristics SO JAPANESE PSYCHOLOGICAL RESEARCH LA English DT Article DE infant cry; perception of cry; tree-based models ID AUTISM SPECTRUM DISORDER; TREE-BASED MODELS; DISTRESS VOCALIZATIONS; TYPICAL DEVELOPMENT; YOUNG-CHILDREN; PERCEPTIONS; RESPONSES; INTERVENTION; EXPRESSION; CRIES AB Adult judgments of infant cry are determined by both acoustic properties of the cry and listener sociodemographic characteristics. The main purpose of this research was to investigate how these two sources shape adult judgments of infant cry. We systematically manipulated both the acoustic properties of infant cries and contrasted listener sociodemographic characteristics. Then, we asked participants to listen to several acoustic manipulations of infant cries and to judge the level of distress the infant was expressing and the level of distress participants felt when listening. Finally, as a contrasting condition, participants estimated the age of the crying infant. Using tree-based models, we found that judgments of the level of distress the infant was expressing as well as the level of distress listeners felt are mainly accounted for by select acoustic properties of infant cry (proportion of sound/pause, fundamental frequency, and number of utterances), whereas age estimates of a crying infant are determined mainly by listener sociodemographic characteristics (gender and parental status). Implications for understanding infant cry and its effects as well as early caregiver-infant interactions are discussed. C1 [Esposito, Gianluca; Venuti, Paola] Univ Trento, I-38068 Rovereto, TN, Italy. [Nakazawa, Jun] Chiba Univ, Chiba, Japan. [Bornstein, Marc H.] NICHHD, Rockville, MD USA. RP Esposito, G (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Corso Bettini 31, I-38068 Rovereto, TN, Italy. EM gianluca.esposito@unitn.it FU Japan Society for the Promotion of Science [22530694, 24730563, 26285149]; FPR Programme (RIKEN Brain Science Institute); NIH, NICHD (USA) FX This research was supported by the Grant-in-aid for Scientific Research from Japan Society for the Promotion of Science (Projects #22530694, #24730563 and #26285149), the FPR Programme (RIKEN Brain Science Institute), and the Intramural Research Programme of the NIH, NICHD (USA). NR 31 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-5368 EI 1468-5884 J9 JPN PSYCHOL RES JI Jpn. Psychol. Res. PD APR PY 2015 VL 57 IS 2 BP 126 EP 134 DI 10.1111/jpr.12072 PG 9 WC Psychology, Multidisciplinary SC Psychology GA CF1DH UT WOS:000352283300004 ER PT J AU Nugent, AC Martinez, A D'Alfonso, A Zarate, CA Theodore, WH AF Nugent, Allison C. Martinez, Ashley D'Alfonso, Alana Zarate, Carlos A. Theodore, William H. TI The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABA(A)-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE functional connectivity; GABA; glucose metabolism; glutamate; resting state; temporal lobe epilepsy ID QUALITY-OF-LIFE; BENZODIAZEPINE-RECEPTORS; FUNCTIONAL CONNECTIVITY; HUMAN BRAIN; PET; BINDING; HYPOMETABOLISM; TOPOGRAPHY; DISCHARGES; ASTROCYTES AB Glucose metabolism has been associated with magnitude of blood oxygen level-dependent (BOLD) signal and connectivity across subjects within the default mode and dorsal attention networks. Similar correlations within subjects across the entire brain remain unexplored. [F-18]-fluorodeoxyglucose positron emission tomography ([F-18]-FDG PET), [C-11]-flumazenil PET, and resting-state functional magnetic resonance imaging (fMRI) scans were acquired in eight healthy individuals and nine with temporal lobe epilepsy (TLE). Regional metabolic rate of glucose (rMRGlu) was correlated with amplitude of low frequency fluctuations (ALFFs) in the fMRI signal, global fMRI connectivity (GC), regional homogeneity (ReHo), and gamma-aminobutyric acid A-binding potential (GABA(A) BPND) across the brain. Partial correlations for ALFFs, GC, and ReHo with GABA(A) BPND were calculated, controlling for rMRGlu. In healthy subjects, significant positive correlations were observed across the brain between rMRGlu and ALFF, ReHo and GABA(A) BPND, and between ALFFs and GABA(A) BPND, controlling for rMRGlu. Brain-wide correlations between rMRGlu and ALFFs were significantly lower in TLE patients, and correlations between rMRGlu and GC were significantly greater in TLE than healthy subjects. These results indicate that the glutamatergic and GABAergic systems are coupled across the healthy human brain, and that ALFF is related to glutamate use throughout the healthy human brain. TLE may be a disorder of altered long-range connectivity in association with glutamate function. C1 [Nugent, Allison C.; Zarate, Carlos A.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Martinez, Ashley; D'Alfonso, Alana; Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Nugent, AC (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 9000 Rockville Pike,MSC 1282, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Programs at the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke, National Institutes of Health (IRP-NIMH-NIH, IRP-NINDS-NIH) [09-N-0182, NCT00931619]; National Alliance for Research on Schizophrenia and Depression Award FX Funding for this work was received by the Intramural Research Programs at the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke, National Institutes of Health (IRP-NIMH-NIH, IRP-NINDS-NIH; grant number 09-N-0182, NCT00931619), and by a National Alliance for Research on Schizophrenia and Depression Award to CAZ. A patent application for the use of ketamine in depression has been submitted listing CAZ among the inventors; he has assigned his rights on the patent to the US government, but will share a percentage of any royalties that may be received by the government. All other authors have no conflicts of interest to disclose, financial or otherwise. NR 45 TC 11 Z9 12 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD APR PY 2015 VL 35 IS 4 BP 583 EP 591 DI 10.1038/jcbfm.2014.228 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA CE7NF UT WOS:000352027900008 PM 25564232 ER PT J AU Proia, RL Hla, T AF Proia, Richard L. Hla, Timothy TI Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; INFLUENZA-VIRUS INFECTION; PERSISTENT STAT3 ACTIVATION; PROTEIN-COUPLED RECEPTOR; IMMUNE-SYSTEM FUNCTION; MULTIPLE-SCLEROSIS; LYMPHOCYTE EGRESS; TRANSPORTER SPNS2; ENDOTHELIAL-CELLS; VASCULAR LEAK AB Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound SW is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, SW signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones. C1 [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Hla, Timothy] Cornell Univ, Ctr Vasc Biol, Dept Pathol & Lab Med, Weill Cornell Med Coll, New York, NY 10065 USA. RP Hla, T (reprint author), Cornell Univ, Ctr Vasc Biol, Dept Pathol & Lab Med, Weill Cornell Med Coll, 1300 York Ave, New York, NY 10065 USA. EM tih2002@med.cornell.edu RI Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH [HL67330, HL89934, CA77839, HL117798]; Fondation LeDucq grant-SphingoNet FX R.L. Proia was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. T. Hla was supported by NIH grants HL67330, HL89934, CA77839, and HL117798. We also acknowledge the support of the Fondation LeDucq grant-SphingoNet. NR 122 TC 59 Z9 61 U1 2 U2 22 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 APR PY 2015 VL 125 IS 4 BP 1379 EP 1387 DI 10.1172/JCI76369 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CF0QF UT WOS:000352248600004 PM 25831442 ER PT J AU Kouiavskaia, D Chen, ZC Dragunsky, E Mirochnitchenko, O Purcell, R Chumakov, K AF Kouiavskaia, Diana Chen, Zhaochun Dragunsky, Eugenia Mirochnitchenko, Olga Purcell, Robert Chumakov, Konstantin TI A single chimpanzee-human neutralizing monoclonal antibody provides post-exposure protection against type 1 and type 2 polioviruses SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Polio eradication; Antiviral therapy; Drug-resistance; Chronic virus excretors; Emergency prophylaxis ID RESISTANCE; VACCINE; VARIANTS; ERADICATION; V-073; POLIO; MICE AB Background: Development of anti-poliovirus therapies to complement vaccination is an urgent priority. A number of antiviral drugs are in development. Recently we have developed human monoclonal antibodies that could be used for treatment of chronically infected individuals and emergency response to potential reappearance of polioviruses after eradication. Objective: The aim of this study was to characterize neutralizing activity of anti-poliovirus monoclonal antibody A12 against wild type, vaccine-derived, and drug-resistant poliovirus strains, evaluate in vivo pre- and post-exposure protective properties of the antibody against polioviruses of serotypes 1 and 2, and to determine whether it interferes with response to immunization with poliovirus vaccine. Study design: Immunogenicity studies were performed in CD1 mice. Poliovirus neutralizing titers were determined in poliovirus microneutralization assay. Poliovirus immunization-challenge experiments were performed in poliovirus-susceptible TgPVR21 mice. Results: We show that monoclonal antibody A12 effectively neutralizes in vitro a broad range of type 1 and type 2 wild and vaccine-derived polioviruses, provides effective pre- and post-exposure protection of TgPVR21 mice from challenge with a lethal dose of poliovirus. Treatment of animals with the antibody concurrent with IPV immunization does not prevent immune response to the vaccine. Conclusions: Anti-poliovirus antibody A12 effectively neutralizes a range of wild and VDPV strains and protectstransgenic mice susceptible to poliovirus against lethal challenge upon pre- and post-exposure administration. This suggests that the antibodies could be used in combination with drugs and/or vaccine to improve their efficacy and prevent emergence of resistant variants, and provides a justification for initiating their clinical evaluation. Published by Elsevier B.V. C1 [Kouiavskaia, Diana; Dragunsky, Eugenia; Mirochnitchenko, Olga; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Chen, Zhaochun; Purcell, Robert] NIAID, NIH, Bethesda, MD 20892 USA. RP Chumakov, K (reprint author), CBER FDA, 10903 New Hampshire Ave,Bldg 52,Room 1128, Silver Spring, MD 20993 USA. EM konstantin.chumakov@fda.hhs.gov FU intramural research programs at the Food and Drug Administration; National Institute of Allergy and Infectious Diseases FX This study was supported by the intramural research programs at the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases. NR 24 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD APR PY 2015 VL 65 BP 32 EP 37 DI 10.1016/j.jcv.2015.01.023 PG 6 WC Virology SC Virology GA CF6XZ UT WOS:000352701500007 PM 25766984 ER PT J AU Haugen, AC Schug, TT Collman, G Heindel, JJ AF Haugen, A. C. Schug, T. T. Collman, G. Heindel, J. J. TI Evolution of DOHaD: the impact of environmental health sciences SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Review DE development; DOHaD; environmental health; exposures; portfolio analysis ID ISCHEMIC-HEART-DISEASE; LEVEL LEAD-EXPOSURE; EPIGENETIC TRANSGENERATIONAL ACTIONS; BENCHMARK DOSE CALCULATIONS; GENE-EXPRESSION; DEVELOPMENTAL ORIGINS; ENDOCRINE DISRUPTORS; COGNITIVE FUNCTION; BISPHENOL-A; METHYLMERCURY EXPOSURE AB Environmental exposures have a significant influence on the chronic health conditions plaguing children and adults. Although the Developmental Origins of Health and Disease (DOHaD) paradigm historically has focused on nutrition, an expanding body of research specifically communicates the effects of chemical exposures on early-life development and the propagation of non-communicable disease across the lifespan. This paper provides an overview of 20 years of research efforts aimed at identifying critical windows of susceptibility to environmental exposures and the signaling changes and epigenetic influences associated with disease progression. DOHaD grants funded by the National Institute of Environmental Health Sciences (NIEHS) in 1991, 2001 and 2011 are identified by grant-analysis software, and each portfolio is analyzed for exposures, disease endpoints, windows of exposure, study design and impact on the field based on publication data. Results show that the 1991 and 2001 portfolios comprised metals, PCBs and air pollutants; however, by 2011, the portfolio has evolved to include or expand the variety of endocrine disruptors, pesticides/persistent organic pollutants and metals. An assortment of brain-health endpoints is most targeted across the portfolios, whereas reproduction and cancer increase steadily over the same time period, and new endpoints like obesity are introduced by 2011. With mounting evidence connecting early-life exposures to later-life disease, we conclude that it is critical to expand the original DOHaD concept to include environmental chemical exposures, and to continue a research agenda that emphasizes defining sensitive windows of exposure and the mechanisms that cause disease. C1 [Haugen, A. C.; Schug, T. T.; Collman, G.; Heindel, J. J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, 530 Davis Dr, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 64 TC 20 Z9 20 U1 2 U2 15 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD APR PY 2015 VL 6 IS 2 BP 55 EP 64 DI 10.1017/S2040174414000580 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CF7LR UT WOS:000352738400001 PM 25471238 ER PT J AU Horwitz, BN Marceau, K Narusyte, J Ganiban, J Spotts, EL Reiss, D Lichtenstein, P Neiderhiser, JM AF Horwitz, Briana N. Marceau, Kristine Narusyte, Jurgita Ganiban, Jody Spotts, Erica L. Reiss, David Lichtenstein, Paul Neiderhiser, Jenae M. TI Parental Criticism Is an Environmental Influence on Adolescent Somatic Symptoms SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE extended children of twins; gene-environment correlation; parental criticism; somatic symptoms ID CHILDREN-OF-TWINS; EXPRESSED EMOTION; DEVELOPMENTAL PSYCHOPATHOLOGY; PHYSICAL HEALTH; ADJUSTMENT; DEPRESSION; FAMILIES; SWEDISH; RELAPSE; PAIN AB Previous studies have suggested that parental criticism leads to more somatic symptoms in adolescent children. However, this research has not assessed the direction of causation or whether genetic and/or environmental influences explain the association between parental criticism and adolescent somatic symptoms. As such, it is impossible to understand the mechanisms that underlie this association. The current study uses the Extended Children of Twins design to examine whether parents' genes, adolescents' genes, and/or environmental factors explain the relationship between parental criticism and adolescent somatic symptoms. Participants came from 2 twin samples, including the Twin and Offspring Study in Sweden (N = 868 pairs of adult twins and each twin's adolescent child) and from the Twin Study of Child and Adolescent Development (N = 690 pairs of twin children and their parents). Findings showed that environmental influences account for the association between parental criticism and adolescent somatic symptoms. This suggests that parents' critical behaviors exert a direct environmental effect on somatic symptoms in adolescent children. Results support the use of intervention programs focused on parental criticism to help reduce adolescents' somatic symptoms. C1 [Horwitz, Briana N.] Calif State Univ Fullerton, Dept Psychol, Fullerton, CA 92831 USA. [Marceau, Kristine] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Narusyte, Jurgita] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Ganiban, Jody] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Spotts, Erica L.] NIA, Off Behav & Social Sci Res, NIH, Bethesda, MD 20892 USA. [Reiss, David] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Lichtenstein, Paul] Karolinska Inst, Dept Epidemiol & Biostat, Stockholm, Sweden. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. RP Horwitz, BN (reprint author), Calif State Univ Fullerton, H-710I Humanities Bldg, Fullerton, CA 92831 USA. EM bhorwitz@fullerton.edu OI Marceau, Kristine/0000-0002-8924-6597 FU National Institute of Mental Health [R01MH54601]; Swedish Council for Working Life and Social Research [2004-0383]; Swedish Research Council [2004-1415]; National Institute on Aging [F32 AG039165]; National Institute on Drug Abuse [F31 DA033737] FX The authors thank the principle investigators and families of the TOSS and TCHAD studies. Funding for TOSS was provided by the National Institute of Mental Health Grant R01MH54601; funding for TCHAD was provided by the Swedish Council for Working Life and Social Research (project 2004-0383) and the Swedish Research Council (2004-1415). Additional funding was provided by the National Institute on Aging (F32 AG039165) and the National Institute on Drug Abuse (F31 DA033737). NR 32 TC 0 Z9 0 U1 1 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 EI 1939-1293 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD APR PY 2015 VL 29 IS 2 BP 283 EP 289 DI 10.1037/fam0000065 PG 7 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA CF1PV UT WOS:000352320700015 PM 25844495 ER PT J AU Underhill, SM Wheeler, DS Amara, SG AF Underhill, Suzanne M. Wheeler, David S. Amara, Susan G. TI Differential Regulation of Two Isoforms of the Glial Glutamate Transporter EAAT2 by DLG1 and CaMKII SO JOURNAL OF NEUROSCIENCE LA English DT Article DE CaMKII; DLG1; EAAT2; glutamate transporter; PDZ ID SYNAPSE-ASSOCIATED PROTEIN-97; SPLICE VARIANTS; HIPPOCAMPAL-NEURONS; RAT-BRAIN; KINASE-II; LOCALIZATION; PSD-95; CELLS; GLT1; FORM AB The gene for EAAT2, the major astrocytic glutamate transporter, generates two carrier isoforms (EAAT2a and EAAT2b) that vary at their C termini as a consequence of alternative RNA splicing. The EAAT2b cytoplasmic C terminus contains a postsynaptic density-95/Discs large/zona occludens-1 (PDZ) ligand, which is absent in EAAT2a. To understand how the distinct C termini might affect transporter trafficking and surface localization, we generated Madin-Darby canine kidney (MDCK) cells that stably express EGFP-EAAT2a or EGFP-EAAT2b and found robust basolateral membrane expression of the EAAT2b isoform. In contrast, EAAT2a displayed a predominant distribution within intracellular vesicle compartments, constitutively cycling to and from the membrane. Addition of the PDZ ligand to EAAT2a as well as its deletion from EAAT2b confirmed the importance of the motif for cell-surface localization. Using EAAT2 constructs with an extracellular biotin acceptor tag to directly assess surface proteins, we observed significant PDZ ligand-dependent EAAT2b surface expression in cultured astrocytes, consistent with observations in cell lines. Discs large homolog 1 (DLG1; SAP97), a PDZ protein prominent in both astrocytes and MDCK cells, colocalized and coimmunoprecipitated with EAAT2b. shRNA knockdown of DLG1 expression decreased surface EAAT2b in both MDCK cells and cultured astrocytes, suggesting that the DLG scaffolding protein stabilizes EAAT2b at the surface. DLG1 can be phosphorylated by Ca2+/calmodulin-dependent protein kinase (CaMKII), resulting in disruption of its PDZ-mediated interaction. In murine astrocytes and acute brain slices, activation of CaMKII decreases EAAT2b surface expression but does not alter the distribution of EAAT2a. These data indicate that the surface expression and function of EAAT2b can be rapidly modulated through the disruption of its interaction with DLG1 by CaMKII activation. C1 [Underhill, Suzanne M.; Amara, Susan G.] NIMH, Lab Mol & Cellular Neurosci, NIH, Bethesda, MD 20892 USA. [Wheeler, David S.] Univ Pittsburgh, Sch Med, Dept Cellular Biol, Pittsburgh, PA 15260 USA. RP Underhill, SM (reprint author), NIMH, Lab Mol & Cellular Neurosci, 35 Convent Dr,Room 3A-207 MSC3742, Bethesda, MD 20892 USA. EM suzanne.underhill@nih.gov FU NIH [DA07595, MH080726]; American Heart Association [0525616U]; Intramural Research Program of the NIMH FX This work was funded by NIH Grants DA07595 and MH080726, American Heart Association Grant 0525616U, and the Intramural Research Program of the NIMH. We thank Geoff Murdoch, Mads Larsen, Bozena Kutyba-Brooks, and Megan Miller for their technical assistance. The NIH Fellows Editorial Board assisted in editing this manuscript. NR 45 TC 9 Z9 9 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 1 PY 2015 VL 35 IS 13 BP 5260 EP 5270 DI 10.1523/JNEUROSCI.4365-14.2015 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CF0BT UT WOS:000352208200017 PM 25834051 ER PT J AU Joshi, DC Zhang, CL Lin, TM Gusain, A Harris, MG Tree, E Yin, YW Wu, C Sheng, ZH Dempsey, RJ Fabry, Z Chiu, SY AF Joshi, Dinesh C. Zhang, Chuan-Li Lin, Tien-Min Gusain, Anchal Harris, Melissa G. Tree, Esther Yin, Yewin Wu, Connie Sheng, Zu-Hang Dempsey, Robert J. Fabry, Zsuzsanna Chiu, Shing Yan TI Deletion of Mitochondrial Anchoring Protects Dysmyelinating Shiverer: Implications for Progressive MS SO JOURNAL OF NEUROSCIENCE LA English DT Article DE axonal degeneration; mitochondria; multiple sclerosis; oxidative stress; syntaphilin ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; MULTIPLE-SCLEROSIS; OXIDATIVE DAMAGE; MUTANT MICE; MOUSE MODEL; AXONS; SYNTAPHILIN; NEURONS; INACTIVATION AB The demyelinating disease multiple sclerosis (MS) has an early inflammatory phase followed by an incurable progressive phase with subdued inflammation and poorly understood neurodegenerative mechanism. In this study, we identified various parallelisms between progressive MS and the dysmyelinating mouse model Shiverer and then genetically deleted a major neuron-specific mitochondrial anchoring protein Syntaphilin (SNPH) from the mouse. Prevailing evidence suggests that deletion of SNPH is harmful in demyelination. Surprisingly, SNPH deletion produces striking benefits in the Shiverer by prolonging survival, reducing cerebellar damage, suppressing oxidative stress, and improving mitochondrial health. In contrast, SNPH deletion does not benefit clinical symptoms in experimental autoimmune encephalomyelitis (EAE), a model for early-phase MS. We propose that deleting mitochondrial anchoring is a novel, specific treatment for progressive MS. C1 [Joshi, Dinesh C.; Zhang, Chuan-Li; Lin, Tien-Min; Tree, Esther; Yin, Yewin; Wu, Connie; Chiu, Shing Yan] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurosci, Madison, WI 53705 USA. [Gusain, Anchal; Dempsey, Robert J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurol Surg, Madison, WI 53705 USA. [Harris, Melissa G.; Fabry, Zsuzsanna] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Chiu, SY (reprint author), Univ Wisconsin, Sch Med, Dept Neurosci, Madison, WI 53705 USA. EM schiu1@wisc.edu FU National Institutes of Health [RO1NS073743, R21NS082725]; Intramural Research Program of NINDS, NIH FX This work was supported by the National Institutes of Health (Grants RO1NS073743 and R21NS082725 to S.Y.C.) and by the Intramural Research Program of NINDS, NIH (Z.-H.S). We thank Phil Smith, Lance Rodenkirch (UW Keck imaging facility), and Randall Massey(UW medical school electron microscopy facility) for help in data collection and Timothy Gomez and Miles Epstein for helpful discussion during this work. NR 37 TC 4 Z9 4 U1 2 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 1 PY 2015 VL 35 IS 13 BP 5293 EP 5306 DI 10.1523/JNEUROSCI.3859-14.2015 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CF0BT UT WOS:000352208200020 PM 25834054 ER PT J AU Lai, JY Luo, J O'Connor, C Jing, X Nair, V Ju, W Randolph, A Ben-Dov, IZ Matar, RN Briskin, D Zavadil, J Nelson, RG Tuschl, T Brosius, FC Kretzler, M Bitzer, M AF Lai, Jennifer Y. Luo, Jihghui O'Connor, Christopher Jing, Xiaohong Nair, Viji Ju, Wenjun Randolph, Ann Ben-Dov, Iddo Z. Matar, Regina N. Briskin, Daniel Zavadil, Jiri Nelson, Robert G. Tuschl, Thomas Brosius, Frank C., III Kretzler, Matthias Bitzer, Markus TI MicroRNA-21 in Glomerular Injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GROWTH-FACTOR-BETA; PROMOTES RENAL FIBROSIS; DIABETIC-NEPHROPATHY; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; GENE-EXPRESSION; TRANSGENIC MICE; PODOCYTE DEPLETION; HUMAN-DISEASE; UP-REGULATION AB TGF-beta(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-beta(1), and miR-21 inhibits apoptosis in cancer cells. TGF-beta(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-beta(1) and is higher in kidneys of TGF-beta(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-beta(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-beta(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-beta/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with nniR-21 expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-beta 1 and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-beta signaling and functions. C1 [Lai, Jennifer Y.; Luo, Jihghui; O'Connor, Christopher; Nair, Viji; Ju, Wenjun; Randolph, Ann; Matar, Regina N.; Brosius, Frank C., III; Kretzler, Matthias; Bitzer, Markus] Univ Michigan, Internal Med, Ann Arbor, MI 48109 USA. [Luo, Jihghui] Southern Med Univ, Nanfang Hosp, Dept Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China. [Jing, Xiaohong] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Ben-Dov, Iddo Z.; Briskin, Daniel; Tuschl, Thomas] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Zavadil, Jiri] NYU, Sch Med, Dept Pathol, New York, NY USA. [Zavadil, Jiri] NYU, Sch Med, NYU Ctr Hlth Informat & Bioinformat, New York, NY USA. [Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. RP Bitzer, M (reprint author), 1150 West Med Ctr Dr,1570C MSRB2, Ann Arbor, MI 48105 USA. EM markusbi@umich.edu OI Zavadil, Jiri/0000-0003-0640-5562 FU NephCure Young Investigator Award; American Society of Nephrology Gottschalk Young Investigator Award; Amgen Young Investigator Award; National Institutes of Health Pilot and Feasibility Grant from the Michigan Diabetes Research and Training Center [5P60-DK020572]; Barbour Fellowship; National Research Service Award Institutional Research Training Grant [T32-DK007378] FX This research was supported by a NephCure Young Investigator Award, the American Society of Nephrology Gottschalk Young Investigator Award, the Amgen Young Investigator Award, and National Institutes of Health Pilot and Feasibility Grant 5P60-DK020572 from the Michigan Diabetes Research and Training Center (to M.B.). LY.L was supported by the Barbour Fellowship and postdoctoral National Research Service Award Institutional Research Training Grant T32-DK007378. NR 67 TC 26 Z9 28 U1 2 U2 10 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2015 VL 26 IS 4 BP 805 EP 816 DI 10.1681/ASN.2013121274 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CE7UZ UT WOS:000352048700009 PM 25145934 ER PT J AU Kallakuri, S Yu, JXA Li, JD Li, YY Weinstein, BM Nicoli, S Sun, ZX AF Kallakuri, Sowjanya Yu, Jianxin A. Li, Jade Li, Yuanyuan Weinstein, Brant M. Nicoli, Stefania Sun, Zhaoxia TI Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HEDGEHOG SIGNAL-TRANSDUCTION; POLYCYSTIC KIDNEY-DISEASE; PROTEIN-KINASE-A; INTRAFLAGELLAR TRANSPORT PROTEINS; SMOOTH-MUSCLE-CELLS; ZINC-FINGER PROTEIN; VESSEL FUSION; VE-CADHERIN; BASAL BODY; I-SCEI AB The cilium is a signaling platform of the vertebrate cell. It has a critical role in polycystic kidney disease and nephronophthisis. Cilia have been detected on endothelial cells, but the function of these organelles in the vasculature remains incompletely defined. In this study, using genetic and chemical genetic tools in the model organism zebrafish, we reveal an essential role of cilia in developmental vascular integrity. Embryos expressing mutant intraflagellar transport genes, which are essential and specific for cilia biogenesis, displayed increased risk of developmental intracranial hemorrhage, whereas the morphology of the vasculature remained normal. Moreover, cilia were present on endothelial cells in the developing zebrafish vasculature. We further show that the involvement of cilia in vascular integrity is endothelial autonomous, because endothelial-specific re-expression of intraflagellar transport genes in respective mutants rescued the intracranial hemorrhage phenotype. Finally, whereas inhibition of Hedgehog signaling increased the risk of intracranial hemorrhage in ciliary mutants, activation of the pathway rescued this phenotype. In contrast, embryos expressing an inactivating mutation in pkd2, one of two autosomal dominant cystic kidney disease genes, did not show increased risk of developmental intracranial hemorrhage. These results suggest that Hedgehog signaling is a major mechanism for this novel role of endothelial cilia in establishing vascular integrity. C1 [Kallakuri, Sowjanya; Li, Jade; Li, Yuanyuan; Sun, Zhaoxia] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Nicoli, Stefania] Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, New Haven, CT 06520 USA. [Yu, Jianxin A.; Weinstein, Brant M.] NICHD, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Sun, ZX (reprint author), Yale Univ, SHM I 329A, POB 208005,333 Cedar St, New Haven, CT 06520 USA. EM zhaoxia.sun@yale.edu FU National Institutes of Health [R01-DK092808, 1P30-DK090744]; National Institute of Child Health and Development Intramural Program [ZO1-001011]; National Heart, Lung, and Blood Institute [ROO-HL105791-04]; American Cancer Society [RSG-10-247-01-DDC] FX This work was supported by National Institutes of Health Grant R01-DK092808 (to Z.S.), National Institutes of Health Grant 1P30-DK090744 Animal Core, National Institute of Child Health and Development Intramural Program Grant ZO1-001011 (to B.M.W.), National Heart, Lung, and Blood Institute Grant ROO-HL105791-04 (to S.N.), and American Cancer Society Research Grant RSG-10-247-01-DDC (to Z.S.). NR 71 TC 7 Z9 7 U1 1 U2 10 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2015 VL 26 IS 4 BP 864 EP 875 DI 10.1681/ASN.2013121314 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CE7UZ UT WOS:000352048700014 PM 25214579 ER PT J AU Bansal, N Anderson, AH Yang, W Christenson, RH Defilippi, CR Deo, R Dries, DL Go, AS He, J Kusek, JW Lash, JP Raj, D Rosas, S Wolf, M Zhang, XM Shlipak, MG Feldman, HI AF Bansal, Nisha Anderson, Amanda Hyre Yang, Wei Christenson, Robert H. deFilippi, Christopher R. Deo, Rajat Dries, Daniel L. Go, Alan S. He, Jiang Kusek, John W. Lash, James P. Raj, Dominic Rosas, Sylvia Wolf, Myles Zhang, Xiaoming Shlipak, Michael G. Feldman, Harold I. TI High-Sensitivity Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and Risk of Incident Heart Failure in Patients with CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; GLOMERULAR-FILTRATION-RATE; ALL-CAUSE MORTALITY; CREATINE-KINASE-MB; C-REACTIVE PROTEIN; CARDIAC TROPONIN; PROGNOSTIC VALUE; CARDIOVASCULAR EVENTS; REFERENCE LIMITS AB High-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predict heart failure (HF) in the general population. However, the interpretation of levels of these biomarkers as predictors of HF is uncertain among patients with CKD. Here, we investigated whether hsTnT and NT-proBNP are associated with incident HF among patients with CKD. In a prospective cohort analysis, we studied 3483 people with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study recruited from June of 2003 to August of 2008 who were free of HF at baseline. We used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident HF after adjustment for demographic factors, traditional cardiovascular risk factors, markers of kidney. disease, pertinent medication use, and mineral metabolism markers. At baseline, hsTnT levels ranged from <= 5.0 to 378.7 pg/ml, and NT-proBNP levels ranged from <= 5 to 35,000 pg/ml. Compared with those who had undetectable hsTnT, participants in the highest quartile (>26.5 ng/ml) had a significantly higher rate of HF (hazard ratio, 4.77; 95% confidence interval, 2.49 to 9.14). Similarly, compared with those in the lowest NT-proBNP quintile (<47.6 ng/ml), participants in the highest quintile (>433.0 ng/ml) experienced a substantially higher rate of HF (hazard ratio, 9.57; 95% confidence interval, 4.40 to 20.83). In conclusion, hsTnT and NT-proBNP were strongly associated with incident HF among a diverse cohort of individuals with mild to severe CKD. Elevations in these biomarkers may indicate subclinical changes in volume and myocardial stress that subsequently contribute to clinical HF. C1 [Bansal, Nisha] Univ Washington, Seattle, WA 98104 USA. [Anderson, Amanda Hyre; Yang, Wei; Deo, Rajat; Rosas, Sylvia; Zhang, Xiaoming; Feldman, Harold I.] Univ Penn, Philadelphia, PA 19104 USA. [Christenson, Robert H.; deFilippi, Christopher R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Dries, Daniel L.] Yale Univ, New Haven, CT USA. [Go, Alan S.] Kaiser Permanente No Calif, Oakland, CA USA. [He, Jiang] Tulane Univ, New Orleans, LA 70118 USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Lash, James P.] Univ Illinois, Chicago, IL USA. [Raj, Dominic] George Washington Univ, Washington, DC USA. [Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Bansal, N (reprint author), Univ Washington, Kidney Res Inst, 908 Jefferson St,3rd Floor, Seattle, WA 98104 USA. EM nbansal@nephrology.washington.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K23-DK088865, K01-DK092353, 1DK066488, K24-DK02651]; NIDDK [U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, U01-DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NTH)/National Center for Advancing Translational Sciences (NCATS) [UL1-TR000003]; Johns Hopkins University [UL1-TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland Grant from the NCATS component of the NIH [UL1-TR000439]; NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research [UL1-TR000433]; University of Illinois at Chicago Grant [CTSA ULI-RR029879]; Tulane University Translational Research in Hypertension and Renal Biology Grant [P30-GM103337]; Kaiser Permanente NIH/National Center for Research Resources [UCSF-CTSI UL1 RR-024131] FX This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K23-DK088865 to N.B., K01-DK092353 to A.H.A., 1DK066488 to M.G.S., and K24-DK02651 to H.I.F.). Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement from the NIDDK (Grants U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, and U01-DK060902). In addition, this work was supported, in part, by Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NTH)/National Center for Advancing Translational Sciences (NCATS) Grant UL1-TR000003, Johns Hopkins University Grant UL1-TR-000424, University of Maryland Grant GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland Grant UL1-TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research Grant UL1-TR000433, University of Illinois at Chicago Grant CTSA ULI-RR029879, Tulane University Translational Research in Hypertension and Renal Biology Grant P30-GM103337, and Kaiser Permanente NIH/National Center for Research Resources Grant UCSF-CTSI UL1 RR-024131. This work was not supported by any industry funds. NR 51 TC 14 Z9 16 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2015 VL 26 IS 4 BP 946 EP 956 DI 10.1681/ASN.2014010108 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA CE7UZ UT WOS:000352048700021 PM 25278510 ER PT J AU Geetha, D Specks, U Stone, JH Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Fessler, BJ Ding, L Tchao, NK Ikle, D Jepson, B Brunetta, P Fervenza, FC AF Geetha, Duvuru Specks, Ulrich Stone, John H. Merkel, Peter A. Seo, Philip Spiera, Robert Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. St Clair, E. William Fessler, Barri J. Ding, Linna Tchao, Nadia K. Ikle, David Jepson, Brett Brunetta, Paul Fervenza, Fernando C. CA Rituximab ANCA-Associated TI Rituximab Versus Cyclophosphamide for ANCA-Associated Vasculitis with Renal Involvement SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ANTIBODY-ASSOCIATED VASCULITIS; WEGENERS-GRANULOMATOSIS; REMISSION-INDUCTION; SERUM CREATININE; POLYANGIITIS; MAINTENANCE; PREDICTION; EXPERIENCE; RELAPSE; INDEX AB Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) x 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids. C1 [Geetha, Duvuru; Seo, Philip] Johns Hopkins Univ, Div Nephrol, Baltimore, MD USA. [Geetha, Duvuru; Seo, Philip] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [Specks, Ulrich; Fervenza, Fernando C.] Mayo Clin, Coll Med, Div Pulm & Crit Care Med, Rochester, MN 55901 USA. [Specks, Ulrich; Fervenza, Fernando C.] Mayo Clin, Coll Med, Div Nephrol & Hypertens, Rochester, MN 55901 USA. [Stone, John H.] Massachusetts Gen Hosp, Rheumatol Unit, Boston, MA 02114 USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Spiera, Robert] Hosp Special Surg, Div Rheumatol, New York, NY 10021 USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin Fdn, Ctr Vasculitis Care & Res, Cleveland, OH 44195 USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 AV Groningen, Netherlands. [St Clair, E. William] Duke Univ, Div Rheumatol & Immunol, Durham, NC USA. [Fessler, Barri J.] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA. [Ikle, David; Jepson, Brett] Rho Inc, Chapel Hill, NC USA. [Brunetta, Paul] Genentech Inc, San Francisco, CA 94080 USA. RP Fervenza, FC (reprint author), Mayo Clin, Coll Med, Div Nephrol & Hypertens, 200 First St SW, Rochester, MN 55901 USA. EM fervenza.fernando@mayo.edu OI Carey, John/0000-0001-7292-2328 FU NIH [N01-AI-15416]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec.; Clinical and Translational Science Award (CTSA) from the National Center for Research Resources (NCRR) [UL1-RR024150-01]; CTSA from the NCRR [UL1-RR025005, UL1-RR025771, NIH M01-RR00533]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [K24-AR049185, K23-AR052820]; NIAMS [K24-AR02224]; Arthritis Foundation Investigator Award FX This research was performed as a project of the Immune Tolerance Network (NIH contract N01-AI-15416; protocol number ITN021AI), an international clinical research consortium headquartered at the University of California, San Francisco.; Supported by the National Institute of Allergy and Infectious Diseases, the Juvenile Diabetes Research Foundation, Genentech, and Biogen Idec. At the Mayo Clinic, the trial was supported by a Clinical and Translational Science Award (CTSA) grant (UL1-RR024150-01) from the National Center for Research Resources (NCRR). At Johns Hopkins, the trial was supported by a CTSA grant (UL1-RR025005) from the NCRR and by grants (K24-AR049185, to J.H.S. and K23-AR052820, to P.S.) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). At Boston University, the trial was supported by CTSA grants (UL1-RR025771 and NIH M01-RR00533) from the NCRR and a grant (K24-AR02224) from the NIAMS (all to P.A.M.) and an Arthritis Foundation Investigator Award (to P.M.). NR 20 TC 19 Z9 20 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 APR PY 2015 VL 26 IS 4 BP 976 EP 985 DI 10.1681/ASN.2014010046 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CE7UZ UT WOS:000352048700024 PM 25381429 ER PT J AU Lundgren, IS Heltshe, SL Smith, AL Chibwana, J Fried, MW Duffy, PE AF Lundgren, Ingrid S. Heltshe, Sonya L. Smith, Arnold L. Chibwana, Jerome Fried, Michal W. Duffy, Patrick E. TI Bacteremia and Malaria in Tanzanian Children Hospitalized for Acute Febrile Illness SO JOURNAL OF TROPICAL PEDIATRICS LA English DT Article DE Bacteremia; Malaria; Acute febrile illness ID HAEMOPHILUS-INFLUENZAE; INFECTIONS; RISK AB We recorded the reason for presentation to a rural hospital in an area endemic for malaria in 909 children between January 2006 and March 2009. Blood smears were examined for Plasmodium falciparum parasites, and blood spots dried on filter paper were prepared for 464 children. A PCR assay utilizing the stored blood spots was developed for Streptococcus pneumoniae (lytA) and Haemophilus influenzae (pal). Malaria was present in 299 children whose blood was tested by polymerase chain reaction (PCR); 19 had lytA and 15 had pal. The overall prevalence of lytA was 25 of the 464 children, while that of pal was 18 children. Fever was present in 369 children of whom 19 had lytA DNA while 11 had pal DNA detected. Of the 95 afebrile children, six had lytA and seven pal. We conclude that there are no clinical features that distinguish malaria alone from bacteremia alone or the presence of both infections. C1 [Lundgren, Ingrid S.; Heltshe, Sonya L.; Smith, Arnold L.] Univ Washington, Seattle Childrens Hosp, Dept Global Hlth, Seattle, WA 98195 USA. [Heltshe, Sonya L.; Smith, Arnold L.] Seattle Childrens Res Inst, Washington, DC USA. [Chibwana, Jerome] MOMS Project Morogoro Reg Hosp, Morogoro, Tanzania. [Chibwana, Jerome] Seattle Biomed Res Inst, Morogoro, Tanzania. [Fried, Michal W.; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, Bethesda, MD 20892 USA. RP Smith, AL (reprint author), Seattle Childrens Researh Inst, C9S-8,1900 Ninth Ave, Seattle, WA 98101 USA. EM arnold.smith@seattlechildrens.org; duffype@niaid.nih.gov FU National Institute of Child Health and Human Development: The Seattle Children's Research Institute Seed Fund [T32 HD07233]; Foundation for NIH, The Gates Foundation Grand Challenges in Global Health [1364]; Intramural Research Program, NIAID, NIH FX This work was supported by T32 HD07233 from the National Institute of Child Health and Human Development: The Seattle Children's Research Institute Seed Fund; the Foundation for NIH, The Gates Foundation Grand Challenges in Global Health (grant 1364) to PED and the Intramural Research Program, NIAID, NIH (PED). NR 15 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0142-6338 EI 1465-3664 J9 J TROP PEDIATRICS JI J. Trop. Pediatr. PD APR PY 2015 VL 61 IS 2 BP 81 EP 85 DI 10.1093/tropej/fmu069 PG 5 WC Pediatrics; Tropical Medicine SC Pediatrics; Tropical Medicine GA CF4DH UT WOS:000352498300002 PM 25505140 ER PT J AU Gonzalez, MW DeVico, AL Lewis, GK Spouge, JL AF Gonzalez, Mileidy W. DeVico, Anthony L. Lewis, George K. Spouge, John L. TI Conserved Molecular Signatures in gp120 Are Associated with the Genetic Bottleneck during Simian Immunodeficiency Virus (SIV), SIV-Human Immunodeficiency Virus (SHIV), and HIV Type 1 (HIV-1) Transmission SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-MEDIATED CYTOTOXICITY; EFFECTOR FUNCTION; ENVELOPE GLYCOPROTEIN; CD4 BINDING; INFECTION; ANTIBODY; VACCINE; TRIAL; SEQUENCES; TRIMER AB Human immunodeficiency virus (HIV) transmission typically results from infection by a single transmitted/founder (T/F) variant. Are T/F variants chosen uniformly at random from the donor pool, or are they selected based on advantageous traits facilitating transmission? Finding evidence for selection during transmission is of particular interest, because it would indicate that phenotypic and/or genetic properties of the viruses might be harnessed as potential vaccine targets or immunotherapies. Here, we systematically evaluated the differences between the Env proteins of simian immunodeficiency virus/simian HIV (SIV/SHIV) stock and T/F variants in search of "signature" sites of transmission. We also surveyed residue preferences in HIV at the SIV/SHIV signature sites. Four sites of gp120 showed significant selection, and an additional two sites showed a similar trend. Therefore, the six sites clearly differentiate T/F viruses from the majority of circulating variants in the stocks. The selection of SIV/SHIV could be inferred reasonably across both vaccinated and unvaccinated subjects, with infections resulting from vaginal, rectal, and intravenous routes of transmission and regardless of viral dosage. The evidence for selection in SIV and SHIV T/F variants is strong and plentiful, and in HIV the evidence is suggestive though commensurate with the availability of suitable data for analysis. Two of the signature residues are completely conserved across the SIV, SHIV, and HIV variants we examined. Five of the signature residues map to the C1 region of gp120 and one to the signal peptide. Our data raise the possibility that C1, while governing the association between gp120 and gp41, modulates transmission efficiency, replicative fitness, and/or host cell tropism at the level of virus-cell attachment and entry. IMPORTANCE The present study finds significant evidence of selection on gp120 molecules of SIV/SHIV T/F viruses. The data provide ancillary evidence suggesting the same sites are under selection in HIV. Our findings suggest that the signature residues are involved in increasing the transmissibility of infecting viruses; therefore, they are potential targets for developing a vaccine or other protective measures. A recent study identified the same T/F signature motif but interpreted it as an effect of neutralization resistance. Here, we show that the T/F motif has broader functional significance beyond neutralization sensitivity, because it is present in nonimmune subjects. Also, a vaccine regimen popular in animal trials might have increased the transmission of variants with otherwise low transmission fitness. Our observations might explain why many animal vaccine trials have not faithfully predicted outcomes in human vaccine trials and suggest that current practices in vaccine design need to be reexamined accordingly. C1 [Gonzalez, Mileidy W.; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [DeVico, Anthony L.; Lewis, George K.] Univ Maryland, Sch Med, Div Basic Sci & Vaccine Res, Inst Human Virol, Baltimore, MD 21201 USA. RP Gonzalez, MW (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM gonzale3@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine; Bill and Melinda Gates Foundation; NIAID, NIH FX M.W.G. and J.L.S. were supported by the Intramural Research Program of the NIH, National Library of Medicine. A.L.D. and G.K.L. were funded by grants from The Bill and Melinda Gates Foundation and NIAID, NIH. NR 44 TC 11 Z9 11 U1 1 U2 11 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 APR PY 2015 VL 89 IS 7 BP 3619 EP 3629 DI 10.1128/JVI.03235-14 PG 11 WC Virology SC Virology GA CF0ER UT WOS:000352216100015 PM 25589663 ER PT J AU Strauss, M Filman, DJ Belnap, DM Cheng, NQ Noel, RT Hogle, JM AF Strauss, Mike Filman, David J. Belnap, David M. Cheng, Naiqian Noel, Roane T. Hogle, James M. TI Nectin-Like Interactions between Poliovirus and Its Receptor Trigger Conformational Changes Associated with Cell Entry SO JOURNAL OF VIROLOGY LA English DT Article ID CRYOELECTRON MICROSCOPY RECONSTRUCTION; HUMAN RHINOVIRUS; 3-DIMENSIONAL STRUCTURE; STRUCTURAL-ANALYSIS; ELECTRON-MICROSCOPY; COXSACKIEVIRUS B3; TYPE-3 POLIOVIRUS; CRYSTAL-STRUCTURE; MEMBRANE COMPLEX; ANTIVIRAL AGENTS AB Poliovirus infection is initiated by attachment to a receptor on the cell surface called Pvr or CD155. At physiological temperatures, the receptor catalyzes an irreversible expansion of the virus to form an expanded form of the capsid called the 135S particle. This expansion results in the externalization of the myristoylated capsid protein VP4 and the N-terminal extension of the capsid protein VP1, both of which become inserted into the cell membrane. Structures of the expanded forms of poliovirus and of several related viruses have recently been reported. However, until now, it has been unclear how receptor binding triggers viral expansion at physiological temperature. Here, we report poliovirus in complex with an enzymatically partially deglycosylated form of the 3-domain ectodomain of Pvr at a 4-angstrom resolution, as determined by cryo-electron microscopy. The interaction of the receptor with the virus in this structure is reminiscent of the interactions of Pvr with its natural ligands. At a low temperature, the receptor induces very few changes in the structure of the virus, with the largest changes occurring within the footprint of the receptor, and in a loop of the internal protein VP4. Changes in the vicinity of the receptor include the displacement of a natural lipid ligand (called "pocket factor"), demonstrating that the loss of this ligand, alone, is not sufficient to induce particle expansion. Finally, analogies with naturally occurring ligand binding in the nectin family suggest which specific structural rearrangements in the virus-receptor complex could help to trigger the irreversible expansion of the capsid. IMPORTANCE The cell-surface receptor (Pvr) catalyzes a large structural change in the virus that exposes membrane-binding protein chains. We fitted known atomic models of the virus and Pvr into three-dimensional experimental maps of the receptor-virus complex. The molecular interactions we see between poliovirus and its receptor are reminiscent of the nectin family, by involving the burying of otherwise-exposed hydrophobic groups. Importantly, poliovirus expansion is regulated by the binding of a lipid molecule within the viral capsid. We show that receptor binding either causes this molecule to be expelled or requires it, but that its loss is not sufficient to trigger irreversible expansion. Based on our model, we propose testable hypotheses to explain how the viral shell becomes destabilized, leading to RNA uncoating. These findings give us a better understanding of how poliovirus has evolved to exploit a natural process of its host to penetrate the membrane barrier. C1 [Strauss, Mike; Filman, David J.; Hogle, James M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Belnap, David M.; Cheng, Naiqian] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Belnap, David M.; Noel, Roane T.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Belnap, David M.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Belnap, David M.] Univ Utah, Dept Biochem, Salt Lake City, UT USA. RP Hogle, JM (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM james_hogle@hms.harvard.edu FU Alexander von Humboldt Foundation; National Institutes of Health [NIH-AI020566, R15AI084085]; University of Utah; BYU; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX M.S. was sponsored by the Alexander von Humboldt Foundation. This study was supported in part by the grant NIH-AI020566 to J.M.H. and R15AI084085 from the National Institutes of Health to D.M.B. This study was also supported by University of Utah and BYU institutional funds (to D.M.B.) and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (D.M.B. and N.C.). NR 82 TC 17 Z9 17 U1 2 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 APR PY 2015 VL 89 IS 8 BP 4143 EP 4157 DI 10.1128/JVI.03101-14 PG 15 WC Virology SC Virology GA CF0FL UT WOS:000352218400011 PM 25631086 ER PT J AU Lynch, RM Wong, P Tran, L O'Dell, S Nason, MC Li, YX Wu, XL Mascola, JR AF Lynch, Rebecca M. Wong, Patrick Tran, Lillian O'Dell, Sijy Nason, Martha C. Li, Yuxing Wu, Xueling Mascola, John R. TI HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; B-CELL RECEPTORS; TYPE-1 INFECTION; CD4-BINDING SITE; POTENT NEUTRALIZATION; STRUCTURAL BASIS; RATIONAL DESIGN; HUMANIZED MICE; VIRAL FITNESS AB Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or beta 23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway in vivo using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection. IMPORTANCE Some antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally. C1 [Lynch, Rebecca M.; Wong, Patrick; Tran, Lillian; O'Dell, Sijy; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD USA. [Wu, Xueling] Aaron Diamond AIDS Res Ctr, New York, NY USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.mascola@nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, NIH FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. NR 67 TC 23 Z9 24 U1 0 U2 3 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 APR PY 2015 VL 89 IS 8 BP 4201 EP 4213 DI 10.1128/JVI.03608-14 PG 13 WC Virology SC Virology GA CF0FL UT WOS:000352218400016 PM 25631091 ER PT J AU Ramalingam, D Happel, C Ziegelbauer, JM AF Ramalingam, Dhivya Happel, Christine Ziegelbauer, Joseph M. TI Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID INFLAMMATORY-CYTOKINE EXPRESSION; VIRUS-ENCODED MICRORNAS; HUMAN ENDOTHELIAL-CELLS; MEDIATED TRANSACTIVATION; LYTIC REACTIVATION; GENE-EXPRESSION; DNA-SEQUENCES; KAPPA-B; BCR; TARGET AB MicroRNAs (miRNAs) are small, similar to 22-nucleotide-long RNAs that regulate gene expression posttranscriptionally. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-miRNAs during latency, and the functional significance of these microRNAs during KSHV infection and their cellular targets have been emerging recently. Using a previously reported microarray profiling analysis, we identified breakpoint cluster region mRNA (Bcr) as a cellular target of the KSHV miRNA miR-K12-6-5p (miR-K6-5). Bcr protein levels were repressed in human umbilical vein endothelial cells (HUVECs) upon transfection with miR-K6-5 and during KSHV infection. Luciferase assays wherein the Bcr 3' untranslated region (UTR) was cloned downstream of a luciferase reporter showed repression in the presence of miR-K6-5, and mutation of one of the two predicted miR-K6-5 binding sites relieved this repression. Furthermore, inhibition or deletion of miR-K6-5 in KSHV-infected cells showed increased Bcr protein levels. Together, these results show that Bcr is a direct target of the KSHV miRNA miR-K6-5. To understand the functional significance of Bcr knockdown in the context of KSHV-associated disease, we hypothesized that the knockdown of Bcr, a negative regulator of Rac1, might enhance Rac1-mediated angiogenesis. We found that HUVECs transfected with miR-K6-5 had increased Rac1-GTP levels and tube formation compared to HUVECs transfected with control miRNAs. Knockdown of Bcr in latently KSHV-infected BCBL-1 cells increased the levels of viral RTA, suggesting that Bcr repression by KSHV might aid lytic reactivation. Together, our results reveal a new function for both KSHV miRNAs and Bcr in KSHV infection and suggest that KSHV miRNAs, in part, promote angiogenesis and lytic reactivation. IMPORTANCE Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) infection is linked to multiple human cancers and lymphomas. KSHV encodes small nucleic acids (microRNAs) that can repress the expression of specific human genes, the biological functions of which are still emerging. This report uses a variety of approaches to show that a KSHV microRNA represses the expression of the human gene called breakpoint cluster region (Bcr). Repression of Bcr correlated with the activation of a protein previously shown to cause KS-like lesions in mice (Rac1), an increase in KS-associated phenotypes (tube formation in endothelial cells and vascular endothelial growth factor [VEGF] synthesis), and modification of the life cycle of the virus (lytic replication). Our results suggest that KSHV microRNAs suppress host proteins and contribute to KS-associated pathogenesis. C1 [Ramalingam, Dhivya; Happel, Christine; Ziegelbauer, Joseph M.] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ziegelbauer, JM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 NR 61 TC 8 Z9 8 U1 0 U2 2 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 APR PY 2015 VL 89 IS 8 BP 4249 EP 4261 DI 10.1128/JVI.03687-14 PG 13 WC Virology SC Virology GA CF0FL UT WOS:000352218400020 PM 25631082 ER PT J AU Jain, S Trivett, MT Ayala, VI Ohlen, C Ott, DE AF Jain, Sumiti Trivett, Matthew T. Ayala, Victor I. Ohlen, Claes Ott, David E. TI African Green Monkey TRIM5 alpha Restriction in Simian Immunodeficiency Virus-Specific Rhesus Macaque Effector CD4 T Cells Enhances Their Survival and Antiviral Function SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; REVERSE TRANSCRIPTION; HIV-1 INFECTION; RETROVIRAL RESTRICTION; TYPE-1 INFECTION; TRIM5 PROTEINS; OLD-WORLD; IN-VIVO; GENE; REPLICATION AB The expression of xenogeneic TRIM5 alpha proteins can restrict infection in various retrovirus/host cell pairings. Previously, we have shown that African green monkey TRIM5 alpha (AgmTRIM5 alpha) potently restricts both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus mac239 (SIVmac239) replication in a transformed human T-cell line (L. V. Coren, et al., Retrovirology 12:11, 2015, http://dx.doi.org/10.1186/s12977-015-0137-9). To assess AgmTRIM5 alpha restriction in primary cells, we transduced AgmTRIM5 alpha into primary rhesus macaque CD4 T cells and infected them with SIVmac239. Experiments with T-cell clones revealed that AgmTRIM5 alpha could reproducibly restrict SIVmac239 replication, and that this restriction synergizes with an intrinsic resistance to infection present in some CD4 T-cell clones. AgmTRIM5 alpha transduction of virus-specific CD4 T-cell clones increased and prolonged their ability to suppress SIV spread in CD4 target cells. This increased antiviral function was strongly linked to decreased viral replication in the AgmTRIM5 alpha-expressing effectors, consistent with restriction preventing the virus-induced cytopathogenicity that disables effector function. Taken together, our data show that AgmTRIM5 alpha restriction, although not absolute, reduces SIV replication in primary rhesus CD4 T cells which, in turn, increases their antiviral function. These results support prior in vivo data indicating that the contribution of virus-specific CD4 T-cell effectors to viral control is limited due to infection. IMPORTANCE The potential of effector CD4 T cells to immunologically modulate SIV/HIV infection likely is limited by their susceptibility to infection and subsequent inactivation or elimination. Here, we show that AgmTRIM5 alpha expression inhibits SIV spread in primary effector CD4 T cells in vitro. Importantly, protection of effector CD4 T cells by AgmTRIM5 alpha markedly enhanced their antiviral function by delaying SIV infection, thereby extending their viability despite the presence of virus. Our in vitro data support prior in vivo HIV-1 studies suggesting that the antiviral CD4 effector response is impaired due to infection and subsequent cytopathogenicity. The ability of AgmTRIM5 alpha expression to restrict SIV infection in primary rhesus effector CD4 T cells now opens an opportunity to use the SIV/rhesus macaque model to further elucidate the potential and scope of anti-AIDS virus effector CD4 T-cell function. C1 [Jain, Sumiti; Trivett, Matthew T.; Ayala, Victor I.; Ohlen, Claes; Ott, David E.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Ott, DE (reprint author), Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM ottde@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. NR 61 TC 1 Z9 1 U1 0 U2 4 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 APR PY 2015 VL 89 IS 8 BP 4449 EP 4456 DI 10.1128/JVI.03598-14 PG 8 WC Virology SC Virology GA CF0FL UT WOS:000352218400034 PM 25653448 ER PT J AU Kwa, S Sadagopal, S Shen, X Hong, JJ Gangadhara, S Basu, R Victor, B Iyer, SS LaBranche, CC Montefiori, DC Tomaras, GD Villinger, F Moss, B Kozlowski, PA Amara, RR AF Kwa, Suefen Sadagopal, Shanmugalakshmi Shen, Xiaoying Hong, Jung Joo Gangadhara, Sailaja Basu, Rahul Victor, Blandine Iyer, Smita S. LaBranche, Celia C. Montefiori, David C. Tomaras, Georgia D. Villinger, Francois Moss, Bernard Kozlowski, Pamela A. Amara, Rama Rao TI CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus ( SIV) Vaccine Enhances Protection against Neutralization-Resistant Mucosal SIV Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CELLULAR-IMMUNITY; DNA/MVA VACCINE; CHALLENGE AB Here, we show that a CD40L-adjuvanted DNA/modified vaccinia virus Ankara (MVA) simian immunodeficiency virus (SIV) vaccine enhances protection against a pathogenic neutralization-resistant mucosal SIV infection, improves long-term viral control, and prevents AIDS. Analyses of serum IgG antibodies to linear peptides of SIV Env revealed a strong response to V2, with targeting of fewer epitopes in the immunodominant region of gp41 (gp41-ID) and the V1 region as a correlate for enhanced protection. Greater expansion of antiviral CD8 T cells in the gut correlated with long-term viral control. C1 [Kwa, Suefen; Sadagopal, Shanmugalakshmi; Gangadhara, Sailaja; Basu, Rahul; Victor, Blandine; Iyer, Smita S.; Amara, Rama Rao] Emory Univ, Dept Microbiol & Immunol, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Kwa, Suefen; Sadagopal, Shanmugalakshmi; Gangadhara, Sailaja; Basu, Rahul; Victor, Blandine; Iyer, Smita S.; Amara, Rama Rao] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Hong, Jung Joo; Villinger, Francois] Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Hong, Jung Joo; Villinger, Francois] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [LaBranche, Celia C.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. RP Amara, RR (reprint author), Emory Univ, Dept Microbiol & Immunol, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM ramara@emory.edu RI Tomaras, Georgia/J-5041-2016 FU National Institutes of Health [P01 AI088575]; Yerkes National Primate Research Center [P51 RR00165]; Emory CFAR grant [P30 AI050409]; NIAID, NIH [HHSN27201100016C]; Division of Intramural Research, NIAID, NIH FX This work was supported by National Institutes of Health grant P01 AI088575 to R.R.A., Yerkes National Primate Research Center base grant P51 RR00165, and Emory CFAR grant P30 AI050409. Funding for the neutralization assays was provided by NIAID, NIH, contract no. HHSN27201100016C to D.C.M. Partial support for MVA construction was provided by the Division of Intramural Research, NIAID, NIH. NR 9 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2015 VL 89 IS 8 BP 4690 EP 4695 PG 6 WC Virology SC Virology GA CF0FL UT WOS:000352218400057 PM 25653428 ER PT J AU Allen, A McRae-Clark, A Saladin, ME Gray, KM Wetherington, CL McKee, SA Allen, SS AF Allen, Alicia McRae-Clark, Aimee Saladin, Michael E. Gray, Kevin M. Wetherington, Cora Lee McKee, Sherry A. Allen, Sharon S. TI Determining Menstrual Phase in Clinical Research: A Review with Recommendations SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Allen, Alicia; Allen, Sharon S.] Univ Minnesota, Minneapolis, MN USA. [McRae-Clark, Aimee; Saladin, Michael E.; Gray, Kevin M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Wetherington, Cora Lee] NIDA, Bethesda, MD 20892 USA. [McKee, Sherry A.] Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR 1 PY 2015 VL 24 IS 4 MA P2 BP 2 EP 2 PG 1 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 CF5YE UT WOS:000352632500003 ER PT J AU Paykov, ME Nelson, RG Knowler, WC Cheng, YL Krolewski, AS Niewczas, MA AF Paykov, Meda E. Nelson, Robert G. Knowler, William C. Cheng, Yiling Krolewski, Andrzej S. Niewczas, Monika A. TI Elevation of circulating TNF receptors 1 and 2 increases the risk of end-stage renal disease in American Indians with type 2 diabetes SO KIDNEY INTERNATIONAL LA English DT Article DE diabetic nephropathy; ESRD; TNF ID TUMOR-NECROSIS-FACTOR; APOPTOSIS-INDUCING LIGAND; INSULIN-RESISTANCE; KIDNEY-FUNCTION; ADIPOSE-TISSUE; HUMAN OBESITY; PIMA-INDIANS; FACTOR-ALPHA; NEPHROPATHY; EXPRESSION AB In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (INFR2) predict end-stage renal disease (ESRD). Here we examined this relationship in a longitudinal cohort study of American Indians with type 2 diabetes with measured glomerular filtration rate (mGFR, iothalamate) and urinary albumin-to-creatinine ratio (ACR). ESRD was defined as dialysis, kidney transplant, or death attributed to diabetic kidney disease. Age-gender-adjusted incidence rates and incidence rate ratios of ESRD were computed by Mantel-Haenszel stratification. The hazard ratio of ESRD was assessed per interquartile range increase in the distribution of each TNFR after adjusting for baseline age, gender, mean blood pressure, HbA1c, ACR, and mGFR. Among the 193 participants, 62 developed ESRD and 25 died without E5RD during a median follow-up of 9.5 years. The age-gender-adjusted incidence rate ratio of ESRD was higher among participants in the highest versus lowest quartile for TNFR1 (6.6, 95% confidence interval (Cl) 3.3-13.3) or TNFR2 (8.8, 95% Cl 4.3-18.0). In the fully adjusted model, the risk of ESRD per interquartile range increase was 1.6 times (95% Cl 1.1-2.2) as high for TNFR1 and 1.7 times (95% CI 1.2-2.3) as high for TNFR2. Thus, elevated serum concentrations of TNFR1 or TNFR2 are associated with increased risk of ESRD in American Indians with type 2 diabetes after accounting for traditional risk factors including ACR and mGFR. C1 [Paykov, Meda E.; Cheng, Yiling] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Nelson, Robert G.; Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. [Krolewski, Andrzej S.; Niewczas, Monika A.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Krolewski, Andrzej S.; Niewczas, Monika A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Nelson, RG (reprint author), NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, 1550 East Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health (NIH) [DRC P30DK036836, DK41526, DK67638] FX This study was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by grants from the National Institutes of Health (NIH): DRC P30DK036836 to MAN; DK41526 and DK67638 to ASK. NR 48 TC 0 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD APR PY 2015 VL 87 IS 4 BP 812 EP 819 DI 10.1038/ki.2014.330 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CE9QZ UT WOS:000352179800020 ER PT J AU Burotto, M Prasad, V Fojo, T AF Burotto, Mauricio Prasad, Vinay Fojo, Tito TI Non-inferiority trials: why oncologists must remain wary SO LANCET ONCOLOGY LA English DT Editorial Material ID BREAST-CANCER; CAPECITABINE C1 [Burotto, Mauricio; Prasad, Vinay; Fojo, Tito] NCI, Ctr Canc Res, Natl Inst Hlth, Med Oncol, Bethesda, MD 20892 USA. RP Burotto, M (reprint author), NCI, Ctr Canc Res, Natl Inst Hlth, Med Oncol, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 11 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2015 VL 16 IS 4 BP 364 EP 366 PG 4 WC Oncology SC Oncology GA CE7LA UT WOS:000352020000037 PM 25846084 ER PT J AU Arakelyan, A Ivanova, O Vasilieva, E Grivel, JC Margolis, L AF Arakelyan, Anush Ivanova, Oxana Vasilieva, Elena Grivel, Jean-Charles Margolis, Leonid TI Antigenic composition of single nano-sized extracellular blood vesicles SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Extracellular vesicles; Microvesicles; Exosomes; Flow cytometry; Antigenic make-up ID CIRCULATING MICROPARTICLES; FLOW-CYTOMETRY; CELLS; PARTICLES; EXOSOMES; CANCER; VIRUS; MICROVESICLES; COAGULATION; ACTIVATION AB Extracellular vesicles (EVs) are important in normal physiology and are altered in various pathologies. EVs produced by different cells are antigenically different. Since the majority of EVs are too small for routine flow cytometry, EV composition is studied predominantly in bulk, thus not addressing their antigenic heterogeneity. Here, we describe a nanoparticle-based technique for analyzing antigens on single nano-sized EVs. The technique consists of immuno-capturing of EVs with 15-nm magnetic nanoparticles, staining captured EVs with antibodies against their antigens, and separating them from unbound EVs and free antibodies in a magnetic field, followed by flow analysis. This technique allows us to characterize EVs populations according to their antigenic distribution, including minor EV fractions. We demonstrated that the individual blood EVs carry different sets of antigens, none being ubiquitous, and quantified their distribution. The physiological significance of antigenically different EVs and their correlation with different pathologies can now be directly addressed. Published by Elsevier Inc. C1 [Arakelyan, Anush; Grivel, Jean-Charles; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Ivanova, Oxana; Vasilieva, Elena] Moscow State Univ Med & Dent, Atherothrombosis Dept, Moscow, Russia. RP Grivel, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM grivelj@mail.nih.gov; margolis@helix.nih.gov RI Vasilieva, Elena/B-2137-2016; Ivanova, Oxana/L-8578-2016 OI Ivanova, Oxana/0000-0002-8477-9706 FU Intramural NICHD Program; Russian Federation Government grant "Immunovirology of atherosclerosis" [14.B25.31.0016] FX The work of A.A., J.-C.G., and L.M. was supported by the Intramural NICHD Program. The work of E.V. and O.I. was supported by Russian Federation Government grant "Immunovirology of atherosclerosis" #14.B25.31.0016. NR 45 TC 8 Z9 9 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD APR PY 2015 VL 11 IS 3 BP 489 EP 498 DI 10.1016/j.nano.2014.09.020 PG 10 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA CE8GY UT WOS:000352081100001 PM 25481806 ER PT J AU Izumi, K Nakato, R Zhang, Z Edmondson, AC Noon, S Dulik, MC Rajagopalan, R Venditti, CP Gripp, K Samanich, J Zackai, EH Deardorff, MA Clark, D Allen, JL Dorsett, D Misulovin, Z Komata, M Bando, M Kaur, M Katou, Y Shirahige, K Krantz, ID AF Izumi, Kosuke Nakato, Ryuichiro Zhang, Zhe Edmondson, Andrew C. Noon, Sarah Dulik, Matthew C. Rajagopalan, Ramakrishnan Venditti, Charles P. Gripp, Karen Samanich, Joy Zackai, Elaine H. Deardorff, Matthew A. Clark, Dinah Allen, Julian L. Dorsett, Dale Misulovin, Ziva Komata, Makiko Bando, Masashige Kaur, Maninder Katou, Yuki Shirahige, Katsuhiko Krantz, Ian D. TI Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin SO NATURE GENETICS LA English DT Article ID DE-LANGE-SYNDROME; BROMODOMAIN PROTEIN BRD4; TRANSCRIPTION ELONGATION; NOVO MUTATIONS; P-TEFB; GENE; LEUKEMIA; CELLS; AF4; ACETYLATION AB Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin. C1 [Izumi, Kosuke; Edmondson, Andrew C.; Noon, Sarah; Zackai, Elaine H.; Deardorff, Matthew A.; Clark, Dinah; Kaur, Maninder; Krantz, Ian D.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Izumi, Kosuke; Nakato, Ryuichiro; Komata, Makiko; Bando, Masashige; Katou, Yuki; Shirahige, Katsuhiko] Univ Tokyo, Inst Mol & Cellular Biosci, Res Ctr Epigenet Dis, Tokyo, Japan. [Zhang, Zhe] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Dulik, Matthew C.; Rajagopalan, Ramakrishnan] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Venditti, Charles P.] NHGRI, US NIH, Bethesda, MD 20892 USA. [Gripp, Karen] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA. [Samanich, Joy] Montefiore Med Ctr, Dept Pediat, Div Genet, Bronx, NY 10467 USA. [Zackai, Elaine H.; Deardorff, Matthew A.; Allen, Julian L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Allen, Julian L.] Childrens Hosp Philadelphia, Div Pulm Med, Philadelphia, PA 19104 USA. [Dorsett, Dale; Misulovin, Ziva] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. [Shirahige, Katsuhiko] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Kawaguchi, Saitama, Japan. RP Krantz, ID (reprint author), Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. EM kshirahi@iam.u-tokyo.ac.jp; ian2@mail.med.upenn.edu OI Dorsett, Dale/0000-0002-0507-2762 FU MEXT (Ministry of Education, Culture, Sports, Science and Technology); CdLS Foundation; Children's Hospital of Philadelphia; US National Institutes of Health (NIH)/National Institute of Child Health and Development (NICHD) [PO1 HD052860] FX We thank K. Nakagawa, S. Watanabe and E. Rappaport for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research (S) and for innovative science from MEXT (Ministry of Education, Culture, Sports, Science and Technology) (K.S.) and by research grants from the CdLS Foundation, development funds from the Children's Hospital of Philadelphia and grant PO1 HD052860 from the US National Institutes of Health (NIH)/National Institute of Child Health and Development (NICHD) (I.D.K.). NR 42 TC 18 Z9 19 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2015 VL 47 IS 4 BP 338 EP U82 DI 10.1038/ng.3229 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CE6CH UT WOS:000351922900008 PM 25730767 ER PT J AU Zhang, XL Joehanes, R Chen, BH Huan, TX Ying, SX Munson, PJ Johnson, AD Levy, D O'Donnell, CJ AF Zhang, Xiaoling Joehanes, Roby Chen, Brian H. Huan, Tianxiao Ying, Saixia Munson, Peter J. Johnson, Andrew D. Levy, Daniel O'Donnell, Christopher J. TI Identification of common genetic variants controlling transcript isoform variation in human whole blood SO NATURE GENETICS LA English DT Article ID SYNONYMOUS SNPS; EXPRESSION QTL; DISEASE; FRAMINGHAM; GENOME; ASSOCIATIONS; POPULATION; TISSUES; TRAITS; DESIGN AB An understanding of the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of common disease. The available evidence from splicing quantitative trait locus (sQTL) studies has been limited to small samples. We performed genome-wide screening to identify SNPs that might control mRNA splicing in whole blood collected from 5,257 Framingham Heart Study participants. We identified 572,333 cis sQTLs involving 2,650 unique genes. Many sQTL-associated genes (40%) undergo alternative splicing. Using the National Human Genome Research Institute (NHGRI) genome-wide association study (GWAS) catalog, we determined that 528 unique sQTLs were significantly enriched for 8,845 SNPs associated with traits in previous GWAS. In particular, we found 395 (4.5%) GWAS SNPs with evidence of cis sQTLs but not gene-level cis expression quantitative trait loci (eQTLs), suggesting that sQTL analysis could provide additional insights into the functional mechanism underlying GWAS results. Our findings provide an informative sQTL resource for further characterizing the potential functional roles of SNPs that control transcript isoforms relevant to common diseases. C1 [Zhang, Xiaoling; Joehanes, Roby; Chen, Brian H.; Huan, Tianxiao; Johnson, Andrew D.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Zhang, Xiaoling; Joehanes, Roby; Chen, Brian H.; Huan, Tianxiao; Johnson, Andrew D.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Joehanes, Roby; Ying, Saixia; Munson, Peter J.] US NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP O'Donnell, CJ (reprint author), NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. EM odonnellc@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013; OI Chen, Brian/0000-0001-9065-3301 FU US NIH [N01-HC-25195]; NHLBI, Division of Intramural Research FX The FHS is funded by US NIH contract N01-HC-25195; this work was also supported by the NHLBI, Division of Intramural Research. NR 45 TC 19 Z9 19 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2015 VL 47 IS 4 BP 345 EP U92 DI 10.1038/ng.3220 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CE6CH UT WOS:000351922900009 PM 25685889 ER PT J AU Michailidou, K Beesley, J Lindstrom, S Canisius, S Dennis, J Lush, MJ Maranian, MJ Bolla, MK Wang, Q Shah, M Perkins, BJ Czene, K Eriksson, M Darabi, H Brand, JS Bojesen, SE Nordestgaard, BG Flyger, H Nielsen, SF Rahman, N Turnbull, C Fletcher, O Peto, J Gibson, L dos-Santos-Silva, I Chang-Claude, J Flesch-Janys, D Rudolph, A Eilber, U Behrens, S Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Khan, S Aaltonen, K Ahsan, H Kibriya, MG Whittemore, AS John, EM Malone, KE Gammon, MD Santella, RM Ursin, G Makalic, E Schmidt, DF Casey, G Hunter, DJ Gapstur, SM Gaudet, MM Diver, WR Haiman, CA Schumacher, F Henderson, BE Le Marchand, L Berg, CD Chanock, SJ Figueroa, J Hoover, RN Lambrechts, D Neven, P Wildiers, H van Limbergen, E Schmidt, MK Broeks, A Verhoef, S Cornelissen, S Couch, FJ Olson, JE Hallberg, E Vachon, C Waisfisz, Q Meijers-Heijboer, H Adank, MA van der Luijt, RB Li, JM Liu, JJ Humphreys, K Kang, D Choi, JY Park, SK Yoo, KY Matsuo, K Ito, H Iwata, H Tajima, K Guenel, P Truong, T Mulot, C Sanchez, M Burwinkel, B Marme, F Surowy, H Sohn, C Wu, AH Tseng, CC Van den Berg, D Stram, DO Gonzalez-Neira, A Benitez, J Zamora, MP Perez, JIA Shu, XO Lu, W Gao, YT Cai, H Cox, A Cross, SS Reed, MWR Andrulis, IL Knight, JA Glendon, G Mulligan, AM Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Lindblom, A Margolin, S Teo, SH Yip, CH Taib, NAM Tan, GH Hooning, MJ Hollestelle, A Martens, JWM Collee, JM Blot, W Signorello, LB Cai, QY Hopper, JL Southey, MC Tsimiklis, H Apicella, C Shen, CY Hsiung, CN Wu, PE Hou, MF Kristensen, VN Nord, S Alnaes, GIG Giles, GG Milne, RL McLean, C Canzian, F Trichopoulos, D Peeters, P Lund, E Sund, M Khaw, KT Gunter, MJ Palli, D Mortensen, LM Dossus, L Huerta, JM Meindl, A Schmutzler, RK Sutter, C Yang, R Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Hartman, M Miao, H Chia, KS Chan, CW Fasching, PA Hein, A Beckmann, MW Haeberle, L Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Ashworth, A Orr, N Schoemaker, MJ Swerdlow, AJ Brinton, L Garcia-Closas, M Zheng, W Halverson, SL Shrubsole, M Long, J Goldberg, MS Labreche, F Dumont, M Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Brauch, H Hamann, U Bruning, T Radice, P Peterlongo, P Manoukian, S Bernard, L Bogdanova, NV Dork, T Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Devilee, P Tollenaar, RAEM Seynaeve, C Van Asperen, CJ Jakubowska, A Lubinski, J Jaworska, K Huzarski, T Sangrajrang, S Gaborieau, V Brennan, P Mckay, J Slager, S Toland, AE Ambrosone, CB Yannoukakos, D Kabisch, M Torres, D Neuhausen, SL Anton-Culver, H Luccarini, C Baynes, C Ahmed, S Healey, CS Tessier, DC Vincent, D Bacot, F Pita, G Alonso, MR Alvarez, N Herrero, D Simard, J Pharoah, PPDP Kraft, P Dunning, AM Chenevix-Trench, G Hall, P Easton, DF AF Michailidou, Kyriaki Beesley, Jonathan Lindstrom, Sara Canisius, Sander Dennis, Joe Lush, Michael J. Maranian, Mel J. Bolla, Manjeet K. Wang, Qin Shah, Mitul Perkins, Barbara J. Czene, Kamila Eriksson, Mikael Darabi, Hatef Brand, Judith S. Bojesen, Stig E. Nordestgaard, Borge G. Flyger, Henrik Nielsen, Sune F. Rahman, Nazneen Turnbull, Clare Fletcher, Olivia Peto, Julian Gibson, Lorna dos-Santos-Silva, Isabel Chang-Claude, Jenny Flesch-Janys, Dieter Rudolph, Anja Eilber, Ursula Behrens, Sabine Nevanlinna, Heli Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Khan, Sofia Aaltonen, Kirsimari Ahsan, Habibul Kibriya, Muhammad G. Whittemore, Alice S. John, Esther M. Malone, Kathleen E. Gammon, Marilie D. Santella, Regina M. Ursin, Giske Makalic, Enes Schmidt, Daniel F. Casey, Graham Hunter, David J. Gapstur, Susan M. Gaudet, Mia M. Diver, W. Ryan Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Le Marchand, Loic Berg, Christine D. Chanock, Stephen J. Figueroa, Jonine Hoover, Robert N. Lambrechts, Diether Neven, Patrick Wildiers, Hans van Limbergen, Erik Schmidt, Marjanka K. Broeks, Annegien Verhoef, Senno Cornelissen, Sten Couch, Fergus J. Olson, Janet E. Hallberg, Emily Vachon, Celine Waisfisz, Quinten Meijers-Heijboer, Hanne Adank, Muriel A. van der Luijt, Rob B. Li, Jingmei Liu, Jianjun Humphreys, Keith Kang, Daehee Choi, Ji-Yeob Park, Sue K. Yoo, Keun-Young Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Guenel, Pascal Truong, Therese Mulot, Claire Sanchez, Marie Burwinkel, Barbara Marme, Frederik Surowy, Harald Sohn, Christof Wu, Anna H. Tseng, Chiu-chen Van den Berg, David Stram, Daniel O. Gonzalez-Neira, Anna Benitez, Javier Zamora, M. Pilar Arias Perez, Jose Ignacio Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Lindblom, Annika Margolin, Sara Teo, Soo Hwang Yip, Cheng Har Taib, Nur Aishah Mohd Tan, Gie-Hooi Hooning, Maartje J. Hollestelle, Antoinette Martens, John W. M. Collee, J. Margriet Blot, William Signorello, Lisa B. Cai, Qiuyin Hopper, John L. Southey, Melissa C. Tsimiklis, Helen Apicella, Carmel Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Hou, Ming-Feng Kristensen, Vessela N. Nord, Silje Alnaes, Grethe I. Grenaker Giles, Graham G. Milne, Roger L. McLean, Catriona Canzian, Federico Trichopoulos, Dimitrios Peeters, Petra Lund, Eiliv Sund, Malin Khaw, Kay-Tee Gunter, Marc J. Palli, Domenico Mortensen, Lotte Maxild Dossus, Laure Huerta, Jose-Maria Meindl, Alfons Schmutzler, Rita K. Sutter, Christian Yang, Rongxi Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Hartman, Mikael Miao, Hui Chia, Kee Seng Chan, Ching Wan Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Haeberle, Lothar Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Ashworth, Alan Orr, Nick Schoemaker, Minouk J. Swerdlow, Anthony J. Brinton, Louise Garcia-Closas, Montserrat Zheng, Wei Halverson, Sandra L. Shrubsole, Martha Long, Jirong Goldberg, Mark S. Labreche, France Dumont, Martine Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Brauch, Hiltrud Hamann, Ute Bruening, Thomas Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Bernard, Loris Bogdanova, Natalia V. Doerk, Thilo Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Van Asperen, Christi J. Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Huzarski, Tomasz Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Slager, Susan Toland, Amanda E. Ambrosone, Christine B. Yannoukakos, Drakoulis Kabisch, Maria Torres, Diana Neuhausen, Susan L. Anton-Culver, Hoda Luccarini, Craig Baynes, Caroline Ahmed, Shahana Healey, Catherine S. Tessier, Daniel C. Vincent, Daniel Bacot, Francois Pita, Guillermo Rosario Alonso, M. Alvarez, Nuria Herrero, Daniel Simard, Jacques Pharoah, Paul P. D. P. Kraft, Peter Dunning, Alison M. Chenevix-Trench, Georgia Hall, Per Easton, Douglas F. CA BOCS KConFab Investigators AOCS Grp NBCS GENICA Network TI Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer SO NATURE GENETICS LA English DT Article ID CONFER SUSCEPTIBILITY; GENOTYPE IMPUTATION; COMMON VARIANTS; OVARIAN-CANCER; RISK; ESTROGEN; CHEK2-ASTERISK-1100DELC; METAANALYSIS; ALLELES; BRCA1 AB Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. C1 [Michailidou, Kyriaki; Dennis, Joe; Lush, Michael J.; Bolla, Manjeet K.; Wang, Qin; Pharoah, Paul P. D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Beesley, Jonathan; Chenevix-Trench, Georgia] Queensland Inst Med Res, Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4006, Australia. [Lindstrom, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Canisius, Sander] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands. [Maranian, Mel J.; Shah, Mitul; Perkins, Barbara J.; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Pharoah, Paul P. D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S.; Li, Jingmei; Humphreys, Keith; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Rahman, Nazneen; Turnbull, Clare; Schoemaker, Minouk J.; Swerdlow, Anthony J.; Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Fletcher, Olivia; Ashworth, Alan; Orr, Nick; Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel] London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, London WC1, England. [Chang-Claude, Jenny; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Nevanlinna, Heli; Muranen, Taru A.; Khan, Sofia; Aaltonen, Kirsimari] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Ahsan, Habibul; Kibriya, Muhammad G.] Univ Chicago, Ctr Canc Epidemiol & Prevent, Chicago, IL 60637 USA. [Ahsan, Habibul; Kibriya, Muhammad G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Whittemore, Alice S.; John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Whittemore, Alice S.; John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Santella, Regina M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Ursin, Giske] Canc Registry Norway, Oslo, Norway. [Makalic, Enes; Schmidt, Daniel F.] Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Casey, Graham; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Wu, Anna H.; Tseng, Chiu-chen; Van den Berg, David; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Gapstur, Susan M.; Gaudet, Mia M.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Berg, Christine D.] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Chanock, Stephen J.; Figueroa, Jonine; Hoover, Robert N.; Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Neven, Patrick; Wildiers, Hans; van Limbergen, Erik] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Leuven, Belgium. [Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Oncogenet, Amsterdam, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Div Biomed Genet, Utrecht, Netherlands. [Liu, Jianjun] Genome Inst Singapore, Human Genet Div, Singapore, Singapore. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Surowy, Harald] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 812, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 464, Japan. [Tajima, Kazuo] Mie Univ Hosp, Epidemiol Ctr Dis Control & Prevent, Tsu, Mie, Japan. [Guenel, Pascal; Truong, Therese; Sanchez, Marie] INSERM, Environm Epidemiol Canc, CESP, Ctr Res Epidemiol & Populat Hlth,U1018, Villejuif, France. [Guenel, Pascal; Truong, Therese; Sanchez, Marie] Univ Paris Sud, UMRS 1018, Villejuif, France. [Mulot, Claire] Univ Paris Sorbonne Cite, INSERM, UMRS 775, Paris, France. [Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Yang, Rongxi] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara; Yang, Rongxi] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Gonzalez-Neira, Anna; Benitez, Javier; Pita, Guillermo; Rosario Alonso, M.; Alvarez, Nuria; Herrero, Daniel] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain. [Zamora, M. Pilar] Hosp Univ La Paz, Med Oncol Serv, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Shu, Xiao-Ou; Cai, Hui; Blot, William; Cai, Qiuyin; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Shu, Xiao-Ou; Cai, Hui; Blot, William; Cai, Qiuyin; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. 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[Sund, Malin] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Sch Clin Med, Cambridge, England. [Palli, Domenico] Ist Studio Prevenz Oncol, Canc Res & Prevent Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Mortensen, Lotte Maxild] Aarhus Univ, Sect Epidemiol, Aarhus, Denmark. [Dossus, Laure] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, Villejuif, France. [Dossus, Laure] Univ Paris 11, Villejuif, France. [Huerta, Jose-Maria] CIBER Epidemiol & Salud Publ, Consejeria Sanidad & Polit Social, Dept Epidemiol, Murcia, Spain. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Schmutzler, Rita K.; Radice, Paolo] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Fac Med, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Sutter, Christian] Univ Heidelberg Hosp, Inst Human Genet, Heidelberg, Germany. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Nonthaburi, Thailand. [Hartman, Mikael] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Hartman, Mikael; Miao, Hui; Chia, Kee Seng] Natl Univ Hlth Syst, Singapore, Singapore. [Hartman, Mikael; Miao, Hui; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Chan, Ching Wan] Natl Univ Hlth Syst, Div Gen Surg, Singapore, Singapore. [Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Haeberle, Lothar] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, Univ Hosp Erlangen, Dept Gynecol & Obstet,Univ Breast,Ctr Franconia, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina; Brauch, Hiltrud] German Canc Consortium DKTK, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Swerdlow, Anthony J.] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. [Labreche, France] Univ Montreal, Ecole Sante Publ, Dept Sante Environnementale & Sante Travail, Montreal, PQ, Canada. [Labreche, France] Univ Montreal, Ecole Sante Publ, Dept Social & Prevent Med, Montreal, PQ, Canada. [Dumont, Martine; Simard, Jacques] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Dept Mol Med, Quebec City, PQ, Canada. [Winqvist, Robert] Univ Oulu, Dept Clin Chem & Bioctr Oulu, Lab Canc Genet & Tumor Biol, NordLab Oulu,Oulu Univ Hosp, Oulu, Finland. [Pylkas, Katri; Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu Univ Hosp, Oulu, Finland. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud] German Canc Res Ctr, Heidelberg, Germany. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Radice, Paolo] Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Fdn IRCCS, I-20133 Milan, Italy. [Peterlongo, Paolo] Italian Fdn Canc Res Oncol Mol IFOM, Fdn Ist FIRC, Milan, Italy. [Manoukian, Siranoush] Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Fdn IRCCS, I-20133 Milan, Italy. [Bernard, Loris] Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Bernard, Loris] Cogentech Canc Genet Test Lab, Milan, Italy. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, Cent Finland Hosp Dist, Jyvaskyla, Finland. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst Thailand, Bangkok, Thailand. [Gaborieau, Valerie; Brennan, Paul; Mckay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Toland, Amanda E.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Radioisotopes & Radiodiagnost Prod, Athens, Greece. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Easton, DF (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM dfe20@medschl.cam.ac.uk RI Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Hein, Alexander/F-6999-2010; Li, Jingmei/I-2904-2012; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Helland, Aslaug/H-3910-2015; Knight, Julia/A-6843-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Hartman, Mikael/B-4324-2011; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Nord, Silje/R-5212-2016; Saunders, Christobel/H-5779-2014; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Rahman, Nazneen/D-2802-2013; OI Bowtell, David/0000-0001-9089-7525; Hein, Alexander/0000-0003-2601-3398; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Helland, Aslaug/0000-0002-5520-0275; Shrubsole, Martha/0000-0002-5591-7575; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Muranen, Taru/0000-0002-5895-1808; Arndt, Volker/0000-0001-9320-8684; Evans, Gareth/0000-0002-8482-5784; Bruning, Thomas/0000-0001-9560-5464; Nord, Silje/0000-0002-3271-5356; Saunders, Christobel/0000-0003-2281-9829; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Rahman, Nazneen/0000-0003-4376-0440; Schoemaker, Minouk/0000-0001-8403-2234; Cross, Simon/0000-0003-2044-1754; PALLI, Domenico/0000-0002-5558-2437; Khan, Sofia/0000-0003-4185-8882 FU Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A10710, C8197/A16565]; European Community's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175) (COGS)]; European Union COST programme [BM0606]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative [1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative)] FX BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the the Supplementary Note. NR 38 TC 88 Z9 92 U1 6 U2 43 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2015 VL 47 IS 4 BP 373 EP U127 DI 10.1038/ng.3242 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CE6CH UT WOS:000351922900013 PM 25751625 ER PT J AU Dahlin, JL Inglese, J Walters, MA AF Dahlin, Jayme L. Inglese, James Walters, Michael A. TI Mitigating risk in academic preclinical drug discovery SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID PROTEIN-PROTEIN INTERFACES; THERMAL SHIFT ASSAY; CHEMICAL LIBRARIES; STRUCTURAL BIOLOGY; FALSE POSITIVES; IN-VITRO; TARGET; INHIBITORS; THERAPEUTICS; PROBES AB The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. C1 [Dahlin, Jayme L.] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [Inglese, James] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Inglese, James] NHGRI, Bethesda, MD 20892 USA. [Walters, Michael A.] Univ Minnesota Twin Cities, Inst Therapeut Discovery & Dev, Minneapolis, MN 55414 USA. RP Walters, MA (reprint author), Univ Minnesota Twin Cities, Inst Therapeut Discovery & Dev, 717 Delaware St SE,Room 609, Minneapolis, MN 55414 USA. EM mwalters@umn.edu FU NIH predoctoral fellowship [F30 DK092026-01]; Pharmaceutical Research and Manufacturers of America Foundation predoctoral pharmacology/toxicology fellowship; Mayo Foundation; intramural programme in the National Center for Advancing Translational Sciences (NCATS), at the NIH; NIH; Minnesota Partnership for Biotechnology and Medical Genomics FX J.L.D. was supported by the following funding bodies: an NIH predoctoral fellowship (F30 DK092026-01); a Pharmaceutical Research and Manufacturers of America Foundation predoctoral pharmacology/toxicology fellowship; and the Mayo Foundation. J.I. is supported by the intramural programme in the National Center for Advancing Translational Sciences (NCATS), at the NIH. M.A.W. acknowledges research funding from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. The authors specifically acknowledge the helpful comments and corrections suggested by the referees. The authors also acknowledge K. Nelson for critical reading of the manuscript and the many other important contributions in the drug discovery community that, regrettably, could not be cited owing to space constraints. NR 102 TC 25 Z9 25 U1 3 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD APR PY 2015 VL 14 IS 4 BP 279 EP 294 DI 10.1038/nrd4578 PG 16 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CE9WW UT WOS:000352195200018 PM 25829283 ER PT J AU Beard, WA Wilson, SH AF Beard, William A. Wilson, Samuel H. TI Structures of human DNA polymerases nu and theta expose their end game SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID BASE EXCISION-REPAIR; FIDELITY; RECOMBINATION; EFFICIENCY; DAMAGE AB Although the two B-family human DNA polymerases, pol delta and pol epsilon, are responsible for the bulk of nuclear genome replication, at least 14 additional polymerases have roles in nuclear DNA repair and replication. In this issue, newly reported crystal structures of two specialized A-family polymerases, pol nu and pol theta, expose these enzymes' strategies for handling aberrant DNA ends. C1 [Beard, William A.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 19 TC 0 Z9 0 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2015 VL 22 IS 4 BP 273 EP 275 DI 10.1038/nsmb.3006 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CF1OU UT WOS:000352317000001 PM 25837870 ER PT J AU Williams, JS Clausen, AR Lujan, SA Marjavaara, L Clark, AB Burgers, PM Chabes, A Kunkel, TA AF Williams, Jessica S. Clausen, Anders R. Lujan, Scott A. Marjavaara, Lisette Clark, Alan B. Burgers, Peter M. Chabes, Andrei Kunkel, Thomas A. TI Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID EUKARYOTIC REPLICATION FORK; POLYMERASE-EPSILON; MISMATCH REPAIR; SACCHAROMYCES-CEREVISIAE; GENOME INTEGRITY; EXCISION-REPAIR; RNASE H2; IN-VIVO; YEAST; MUTATIONS AB Ribonucleotides incorporated during DNA replication are removed by RNase H2-dependent ribonucleotide excision repair (RER). In RER-defective yeast, topoisomerase 1 (Top1) incises DNA at unrepaired ribonucleotides, initiating their removal, but this is accompanied by RNA-DNA-damage phenotypes. Here we show that these phenotypes are incurred by a high level of ribonucleotides incorporated by a leading strand-replicase variant, DNA polymerase (Pol) epsilon, but not by orthologous variants of the lagging-strand replicases, Pols alpha or delta. Moreover, loss of both RNases H1 and H2 is lethal in combination with increased ribonucleotide incorporation by Pol epsilon but not by Pols alpha or delta. Several explanations for this asymmetry are considered, including the idea that Top1 incision at ribonucleotides relieves torsional stress in the nascent leading strand but not in the nascent lagging strand, in which preexisting nicks prevent the accumulation of superhelical tension. C1 [Williams, Jessica S.; Clausen, Anders R.; Lujan, Scott A.; Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Marjavaara, Lisette; Chabes, Andrei] Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Chabes, Andrei] Umea Univ, Lab Mol Infect Med Sweden MIMS, Umea, Sweden. RP Kunkel, TA (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Clausen, Anders Ranegaard/0000-0002-5069-0930; Chabes, Andrei/0000-0003-1708-8259 FU Division of Intramural Research of the US National Institutes of Health (NIH), NIEHS [Z01 ES065070]; Swedish Cancer Society; US NIH [GM032431] FX We thank K. Bebenek, C. Orebaugh and S. Williams for helpful comments on the manuscript and all members of the Kunkel laboratory for thoughtful discussions. We acknowledge the US National Institute of Environmental Health Sciences (NIEHS) Molecular Genetics Core Facility for sequence analysis of 5-FOA-resistant mutants and the NIEHS Flow Cytometry Center for fluorescence-activated cell-sorting analysis. This work was supported by project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the US National Institutes of Health (NIH), NIEHS, by the Swedish Cancer Society to A.C. and by US NIH grant GM032431 to P.M.B. NR 48 TC 11 Z9 11 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2015 VL 22 IS 4 BP 291 EP U35 DI 10.1038/nsmb.2989 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CF1OU UT WOS:000352317000006 PM 25751426 ER PT J AU Lee, YS Gao, Y Yang, W AF Lee, Young-Sam Gao, Yang Yang, Wei TI How a homolog of high-fidelity replicases conducts mutagenic DNA synthesis SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID UNIQUE ERROR SIGNATURE; POLYMERASE-THETA POLQ; STRUCTURAL BASIS; GENOME STABILITY; BYPASS ACTIVITY; MECHANISM; INSTABILITY; DAMAGE; CELLS; ZETA AB All DNA replicases achieve high fidelity by a conserved mechanism, but each translesion polymerase carries out mutagenic DNA synthesis in its own way. Here we report crystal structures of human DNA polymerase. (Pol nu), which is homologous to high-fidelity replicases yet is error prone. Instead of a simple open-to-closed movement of the O helix upon binding of a correct incoming nucleotide, Pol nu has a different open state and requires the finger domain to swing sideways and undergo both opening and closing motions to accommodate the nascent base pair. A single-amino acid substitution in the O helix of the finger domain improves the fidelity of Pol nu nearly ten-fold. A unique cavity and the flexibility of the thumb domain allow Pol nu to generate and accommodate a looped-out primer strand. Primer loop-out may be a mechanism for DNA trinucloetide-repeat expansion. C1 [Lee, Young-Sam; Gao, Yang; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Gao, Yang/O-3445-2016 FU US National Institutes of Health [DK036146-08] FX We thank D. Leahy and R. Craigie for editing the manuscript. The research was supported by the intramural research program of the US National Institutes of Health (DK036146-08, W.Y.). NR 49 TC 7 Z9 7 U1 3 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2015 VL 22 IS 4 BP 298 EP U42 DI 10.1038/nsmb.2985 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CF1OU UT WOS:000352317000007 PM 25775266 ER PT J AU Contoreggi, C AF Contoreggi, Carlo TI Corticotropin releasing hormone and imaging, rethinking the stress axis SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE CRH; Stress; MRI; MRS; PET; Dopamine; GABA; Depression; Anxiety; PTSD ID POSITRON-EMISSION-TOMOGRAPHY; OPIOID RECEPTOR-BINDING; TILAPIA OREOCHROMIS-MOSSAMBICUS; NALOXONE-INDUCED CORTISOL; POLYCYSTIC-OVARY-SYNDROME; EARLY-LIFE STRESS; PREFRONTAL CORTEX; MAJOR DEPRESSION; IN-VIVO; DOPAMINE RELEASE AB The stress system provides integration of both neurochemical and somatic physiologic functions within organisms as an adaptive mechanism to changing environmental conditions throughout evolution. In mammals and primates the complexity and sophistication of these systems have surpassed other species in triaging neurochemical and physiologic signaling to maximize chances of survival. Corticotropin releasing hormone (CRH) and its related peptides and receptors have been identified over the last three decades and are fundamental molecular initiators of the stress response. They are crucial in the top down regulatory cascade over a myriad of neurochemical, neuroendocrine and sympathetic nervous system events. From neuroscience, we've seen that stress activation impacts behavior, endocrine and somatic physiology and influences neurochemical events that one can capture in real time with current imaging technologies. To delineate these effects one can demonstrate how the CRH neuronal networks infiltrate critical cognitive, emotive and autonomic regions of the central nervous system (CNS) with somatic effects. Abundant predinical and clinical studies show inter-regulatory actions of CRH with multiple neurotransmitters/peptides. Stress, both acute and chronic has epigenetic effects which magnify genetic susceptibilities to alter neurochemistry; stress system activation can add critical variables in design and interpretation of basic and clinical neuroscience and related research. This review will attempt to provide an overview of the spectrum of known functions and speculative actions of CRH and stress responses in light of imaging technology and its interpretation. Metabolic and neuroreceptor positron emission/single photon tomography (PET/SPECT), fiinctional magnetic resonance imaging (fMRI), anatomic MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (pMRS) are technologies that can delineate basic mechanisms of neurophysiology and pharmacology. Stress modulates the myriad of neurochemical and networks within and controlled through the central and peripheral nervous system and the effects of stress activation on imaging will be highlighted. Published by Elsevier Inc. C1 [Contoreggi, Carlo] NIDA, IRP, NIH, Baltimore, MD 21224 USA. RP Contoreggi, C (reprint author), Johns Hopkins Bayview Med Ctr, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM ccontore@intra.nida.nih.gov FU Intramural NIH HHS [ZID DA000535-02, Z99 DA999999] NR 134 TC 1 Z9 1 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD APR PY 2015 VL 42 IS 4 BP 323 EP 339 DI 10.1016/j.nucmedbio.2014.11.008 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CE9RY UT WOS:000352182300001 PM 25573209 ER PT J AU Zimmermann, E Angquist, LH Mirza, SS Zhao, JH Chasman, DI Fischer, K Qi, Q Smith, AV Thinggaard, M Jarczok, MN Nalls, MA Trompet, S Timpson, NJ Schmidt, B Jackson, AU Lyytikainen, LP Verweij, N Mueller-Nurasyid, M Vikstrom, M Marques-Vidal, P Wong, A Meidtner, K Middelberg, RP Strawbridge, RJ Christiansen, L Kyvik, KO Hamsten, A Jaaskelainen, T Tjonneland, A Eriksson, JG Whitfield, JB Boeing, H Hardy, R Vollenweider, P Leander, K Peters, A van der Harst, P Kumari, M Lehtimaki, T Meirhaeghe, A Tuomilehto, J Jockel, KH Ben-Shlomo, Y Sattar, N Baumeister, SE Smith, GD Casas, JP Houston, DK Marz, W Christensen, K Gudnason, V Hu, FB Metspalu, A Ridker, PM Wareham, NJ Loos, RJF Tiemeier, H Sonestedt, E Sorensen, TIA AF Zimmermann, E. Angquist, L. H. Mirza, S. S. Zhao, J. H. Chasman, D. I. Fischer, K. Qi, Q. Smith, A. V. Thinggaard, M. Jarczok, M. N. Nalls, M. A. Trompet, S. Timpson, N. J. Schmidt, B. Jackson, A. U. Lyytikainen, L. P. Verweij, N. Mueller-Nurasyid, M. Vikstrom, M. Marques-Vidal, P. Wong, A. Meidtner, K. Middelberg, R. P. Strawbridge, R. J. Christiansen, L. Kyvik, K. O. Hamsten, A. Jaaskelainen, T. Tjonneland, A. Eriksson, J. G. Whitfield, J. B. Boeing, H. Hardy, R. Vollenweider, P. Leander, K. Peters, A. van der Harst, P. Kumari, M. Lehtimaki, T. Meirhaeghe, A. Tuomilehto, J. Joeckel, K. -H. Ben-Shlomo, Y. Sattar, N. Baumeister, S. E. Smith, G. Davey Casas, J. P. Houston, D. K. Maerz, W. Christensen, K. Gudnason, V. Hu, F. B. Metspalu, A. Ridker, P. M. Wareham, N. J. Loos, R. J. F. Tiemeier, H. Sonestedt, E. Sorensen, T. I. A. CA The FTO-Mortality Collaborating TI Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults SO OBESITY REVIEWS LA English DT Article DE FTO; meta-analysis; mortality; obesity ID GENOME-WIDE ASSOCIATION; MAJOR RISK-FACTORS; MIDDLE-AGED MEN; BODY-MASS INDEX; MENDELIAN RANDOMIZATION; WAIST CIRCUMFERENCE; COHORT PROFILE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; METABOLIC SYNDROME AB Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n=169,551; 0.32kgm(-2); 95% CI 0.28-0.32, P<1x10(-32)), WC (n=152,631; 0.76cm; 0.68-0.84, P<1x10(-32)) and FMI (n=48,192; 0.17kgm(-2); 0.13-0.22, P=1.0x10(-13)). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P=0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P=0.662) and for FMI (HR: 1.00; 0.96-1.04, P=0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes. C1 [Zimmermann, E.; Angquist, L. H.; Sorensen, T. I. A.] Bispebjerg Hosp, Inst Prevent Med, DK-2400 Copenhagen, Denmark. [Zimmermann, E.; Angquist, L. H.; Sorensen, T. I. A.] Frederiksberg Univ Hosp, Inst Prevent Med, Copenhagen, Denmark. [Mirza, S. S.; Tiemeier, H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Zhao, J. H.; Wareham, N. J.; Loos, R. J. F.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 2QQ, England. [Chasman, D. I.; Ridker, P. M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, D. I.; Ridker, P. M.] Harvard Univ, Sch Med, Boston, MA USA. [Fischer, K.; Metspalu, A.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Qi, Q.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Smith, A. V.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, A. V.; Gudnason, V.] Univ Iceland, IS-101 Reykjavik, Iceland. [Thinggaard, M.; Christiansen, L.; Christensen, K.] Univ So Denmark, Danish Aging Res Ctr, Odense, Denmark. [Thinggaard, M.; Christiansen, L.; Christensen, K.] Univ So Denmark, Inst Publ Hlth, Danish Twin Registry Epidemiol Biostat & Biodemog, Odense, Denmark. [Jarczok, M. N.] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Nalls, M. A.] NIA, Lab Neurogenet, Intramural Res Program, Bethesda, MD 20892 USA. [Trompet, S.] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, S.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Timpson, N. J.; Smith, G. Davey; Sorensen, T. I. A.] Univ Bristol, MRC, IEU, Bristol, Avon, England. [Schmidt, B.; Joeckel, K. -H.] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Jackson, A. U.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, A. U.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Lyytikainen, L. P.; Lehtimaki, T.] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, L. P.; Lehtimaki, T.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Verweij, N.; van der Harst, P.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Mueller-Nurasyid, M.] Univ Munich, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, M.] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller-Nurasyid, M.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, M.; Peters, A.] Deutsch Forsch Zentrum Herz Kreislauferkrankungen, Partner Site Munich Heart Alliance, Munich, Germany. [Vikstrom, M.; Leander, K.] Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [Marques-Vidal, P.; Vollenweider, P.] Lausanne Univ Hosp CHUV, Internal Med, Dept Internal Med, Lausanne, Switzerland. [Wong, A.; Hardy, R.] UCL, MRC Unit Lifelong Hlth & Ageing, London, England. [Meidtner, K.] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, Nuthetal, Germany. [Meidtner, K.; Boeing, H.] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Middelberg, R. P.; Whitfield, J. B.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Strawbridge, R. J.; Hamsten, A.] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden. [Kyvik, K. O.] Odense Univ Hosp, Inst Reg Hlth Serv Res, DK-5000 Odense, Denmark. [Kyvik, K. O.] Odense Univ Hosp, Odense Patient Data Explorat Network, DK-5000 Odense, Denmark. [Jaaskelainen, T.] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Tjonneland, A.] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Eriksson, J. G.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Inst Clin Med, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Peters, A.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [van der Harst, P.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [van der Harst, P.] ICIN Neterlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Kumari, M.] UCL, Dept Epidemiol & Publ Hlth, London, England. [Kumari, M.] Univ Essex, ISER, Colchester CO4 3SQ, Essex, England. [Meirhaeghe, A.] Univ Lille Nord France, Inst Pasteur Lille, INSERM, U744, Lille, France. [Tuomilehto, J.] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, J.] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, J.] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanit, Madrid, Spain. [Tuomilehto, J.] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia. [Ben-Shlomo, Y.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Sattar, N.] BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland. [Baumeister, S. E.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Casas, J. P.] London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, London WC1, England. [Casas, J. P.] UCL, Inst Cardiovasc Sci, London, England. [Houston, D. K.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC USA. [Maerz, W.] Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Endocrinol Diabet R, Mannheim, Germany. [Maerz, W.] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, W.] Synlab Serv GmbH, Synlab Acad, Mannheim, Germany. [Christensen, K.] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Christensen, K.] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense, Denmark. [Hu, F. B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, F. B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Loos, R. J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY USA. [Tiemeier, H.] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Tiemeier, H.] Erasmus MC, Dept Psychiat, Rotterdam, Netherlands. [Sonestedt, E.] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Sorensen, T. I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Frederiksberg, Denmark. RP Zimmermann, E (reprint author), Frederiksberg Univ Hosp, Inst Prevent Med, Nordre Fasanvej 57,Indgang 5, DK-2000 Frederiksberg, Denmark. EM esther.zimmermann@regionh.dk RI Davey Smith, George/A-7407-2013; Leander, Karin/C-7261-2017; Marques-Vidal, Pedro/C-9449-2009; Meirhaeghe, Aline/E-4663-2015; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Sonestedt, Emily/I-3814-2016; Smith, Albert/K-5150-2015; Veglia, Fabrizio/K-1958-2016; Kyvik, Kirsten /K-5680-2016; kinnunen, leena/B-7059-2012; Jarczok, Marc/A-2383-2014; Verweij, Niek/A-4499-2017; Colaus, PsyColaus/K-6607-2013; Gudnason, Vilmundur/K-6885-2015 OI Kumari, Meena/0000-0001-9716-1035; Jaaskelainen, Tiina/0000-0002-1202-0936; Verweij, Niek/0000-0002-4303-7685; Nothen, Markus/0000-0002-8770-2464; Eriksson, Johan/0000-0002-2516-2060; Kleber, Marcus/0000-0003-0663-7275; Peters, Annette/0000-0001-6645-0985; Davey Smith, George/0000-0002-1407-8314; Leander, Karin/0000-0002-1404-9222; Humphries, Stephen E/0000-0002-8221-6547; Meidtner, Karina/0000-0001-5810-4062; Strawbridge, Rona/0000-0001-8506-3585; Magi, Reedik/0000-0002-2964-6011; Tiemeier, Henning/0000-0002-4395-1397; Marques-Vidal, Pedro/0000-0002-4548-8500; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Sonestedt, Emily/0000-0002-0747-4562; Smith, Albert/0000-0003-1942-5845; Veglia, Fabrizio/0000-0002-9378-8874; Kyvik, Kirsten /0000-0003-2981-0245; kinnunen, leena/0000-0001-8739-4812; Jarczok, Marc/0000-0002-6055-385X; Gudnason, Vilmundur/0000-0001-5696-0084 FU Danish Strategic Research Council (GENDINOB) [09-067111]; Region Skane; City of Malmo; Pahlsson Foundation; Swedish Heart and Lung Foundation; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810]; Erasmus Medical Center, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Medical Research Council UK; Cancer Research UK; European Union; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; Wellcome Trust; National Heart, Lung, and Blood Institute (NHLBI) [HL043851, HL080467]; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Amgen; FP7 [278913, 306031, 313010]; Center of Excellence in Genomics (EXCEGEN); University of Tartu [SP1GVARENG]; Estonian Research Council [IUT20-60]; Estonian Research Roadmap through the Estonian Ministry of Education and Research; Estonian Science Foundation [ETF9353]; National Institutes of Health (NIH) [DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, P30DK46200, U01CA137088, U54CA155626, DK58845, DK098311, U01HG004728, EY015473, CA134958, DK70756, DK46200]; NIH [N01-AG-1-2100, R01-DK062370, LM010098]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Danish National Research Foundation; National Institute on Aging; Velux Foundation; 6th Framework Program (integrated project Bloodomics) of the European Union [LSHM-CT-2004-503485]; 7th Framework Program (integrated project AtheroRemo) of the European Union [201668]; 7th Framework Program (RiskyCAD) of the European Union [305739]; INTERREG IV Oberrhein Program [A28]; European Regional Development Fund (ERDF); Wissenschaftsoffensive TMO; Intramural Research Program of the NIH, National Institute on Aging; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C]; British Heart Foundation [PG/13/66/30442, RG2008/08, RG2008/014]; Department of Health Policy Research Programme [0090049]; National Institute of Health Research University College London Hospitals Biomedical Research Centre; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032, NHS2010B280]; European Commission [223004, QLG1-CT-2002-00896]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; MRC (UK); German Federal Ministry of Research and Education (NGFN programme) [01GS0820]; Heinz Nixdorf Foundation (Germany); German Research Council [SI 236/8-1, SI 236/9-1]; Conseil Regional du Nord-Pas de Calais; Caisse Primaire d'Assurance Maladie de Selestat; Association Regionale de Cardiologie d'Alsace, ONIVINS; Parke-Davis Laboratory; Mutuelle Generale de l'Education Nationale (MGEN); Groupe Fournier; Reseau National de Sante Publique; Direction Generale de la Sante; Institut National de la Sante Et de la Recherche Medicale (INSERM); Institut Pasteur de Lille; Unite d'Evaluation du Centre Hospitalier et Universitaire de Lille; Competitive Research Funding of the Tampere University Hospital [9M048, 9N035]; Finnish Cultural Foundation; Finnish Foundation for Cardiovascular Research; Emil Aaltonen Foundation, Finland; Tampere Tuberculosis Foundation; Medical Research Council; Health and Safety Executive; NHLBI [HL036310]; National Institute on Aging, USA, NIH [AG13196]; Agency for Health Care Policy Research [HS06516]; John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; Dutch Kidney Foundation [E033]; Netherlands Organization for Scientific Research (NWO-Groot) [175.010.2007.006]; Netherlands Organization for Scientific Research (NWO VENI) [916.761.70]; Netherlands Organization for Scientific Research (NWO VIDI) [917.13.350]; Netherlands Organization for Scientific Research (ZonMW) [90.700.441]; Dutch Inter University Cardiology Institute Netherlands; Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; Swedish Council for Social Research; Swedish Council for Work Life Research; Stockholm County Council; Swedish Research Council; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne, Switzerland; Swiss National Science Foundation [3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468]; Medical Research Council [MC_UU_12019/1]; Federal Ministry of Science, Germany [01 EA 9401]; European Union [SOC 95201408 05 F02, IMI/115006, QLG2-CT-2002-01254]; German Cancer Aid [70-2488-Ha I]; European Community [SOC 98200769 05 F02]; Australian National Health and Medical Research Council (NHMRC) [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485]; US NIH (NIH) [AA07535, AA10248, AA014041]; Australian Research Council (ARC) [DP0770096]; NHMRC Career Development Award; Academy of Finland [120386, 125876, 110413]; Finnish Diabetes Research Society; Novo Nordisk Foundation; Finska Lakaresallskapet; Liv och Halsa; Samfundet Folkhalsan; Signe and Ane Gyllenberg foundation; Danish Cancer Society; Academy of Finland; Nord Forsk; Nordic Centre of Excellent Sysdiet; US NIH [DK62370]; Swedish Heart-Lung Foundation; Swedish Research Council [8691, 0593]; Knut and Alice Wallenberg Foundation; Foundation for Strategic Research; Stockholm County Council [592229]; Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet; Magnus Bergwall Foundation; Italian Ministry of Health (Ricerca Corrente); Tore Nilsson foundation; Gamla Tjanarinnor and Fredrik foundation; Ingrid Thurings foundation; Danish Medical Research Council; Danish Diabetes Association; NOVO Foundation; Danish Heart Foundation; Apotekerfonden; Foundation of A. and J. Louis-Hansen; Foundation of Direktor E. Danielsen and wife; Foundation of Direktor K. Bonnelycke and wife Grethe; Foundation of Laegevidenskabens Fremme; Foundation of A. F. Bolding; Foundation of O. William and E. B. Olesen; Faculty of Health at University of Southern Denmark; Danish National Science Foundation; T. Steenbeck's Foundation; Gangsted Foundation; King Christian the Tenth's Foundation; National Danish Science Foundation FX L. H. Angquist was supported by a grant from the Danish Strategic Research Council (GENDINOB; grant number: 09-067111).; The Malmo Diet & Cancer Study was initiated and planned in collaboration with the International Agency for Research on Cancer, the Swedish Cancer Society and Swedish Medical Research Council and the Faculty of Medicine Lund University, Sweden. The study is also funded by Region Skane, City of Malmo, Pahlsson Foundation and the Swedish Heart and Lung Foundation.; This work of Dr. S. SMirza and Dr. H. Tiemeier is supported by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Ageing (NCHA) project No. 050-060-810.; The Rotterdam Study is funded by Erasmus Medical Center, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science and the Ministry for Health, Welfare and Sports.; The EPIC Norfolk Study is funded by programme grants from the Medical Research Council UK and Cancer Research UK and by additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency and the Wellcome Trust.; The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute (NHLBI) and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation, with collaborative scientific support and funding for genotyping provided by Amgen.; EGCUT received financing by FP7 grants (278913, 306031, 313010), Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG), Estonian Research Council Grant IUT20-60, the Estonian Research Roadmap through the Estonian Ministry of Education and Research and the Estonian Science Foundation (ETF9353).; The NHS and HPFS were supported by grants DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, P30DK46200, U01CA137088, U54CA155626, DK58845, DK098311, U01HG004728, EY015473, CA134958, DK70756 and DK46200 from the National Institutes of Health (NIH), with additional support for genotyping from Merck Research Laboratories, North Wales, PA.; The Age, Gene/Environment Susceptibility (AGES) study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.; The 1905-cohort is supported by a grant from the Danish National Research Foundation and the National Institute on Aging. The Danish Aging Research Center is supported by the Velux Foundation.; LURIC received funding by the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485), by the 7th Framework Program (integrated project AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union, by the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. The Health, Aging, and Body Composition (HealthABC) Study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.; The British Women Heart and Health Study is supported by British Heart Foundation programme grant no. PG/13/66/30442 and Department of Health Policy Research Programme (0090049). Professor J. P. Casas is supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre.; The SHIP study is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' programme of the Siemens AG and the Cache Campus program of the InterSystems GmbH.; The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Professor Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework programme of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810).; The Caerphilly prospective study was set up by Professor Peter Elwood (MRC Unit South Wales). The DNA archive was established by a MRC (UK) grant. The Health and Social Care Information Centre (formerly the Office of National Statistics) provided the linked mortality data. The CaPS data archive is maintained by the SSCM, University of Bristol.; The Heinz Nixdorf Recall Study thank the Heinz Nixdorf Foundation (Germany), the German Federal Ministry of Research and Education (NGFN programme project #01GS0820) and projects SI 236/8-1 and SI 236/9-1 from the German Research Council for the generous support of this study. We acknowledge the support of the Sarstedt AG & Co. (Numbrecht, Germany) for laboratory equipment. We are indebted to all study participants and to the dedicated personnel of the study centre of the Heinz Nixdorf Recall study. Advisory Board: Meinertz T, Hamburg, Germany (Chair); Bode C, Freiburg, Germany; de Feyter PJ, Rotterdam, Netherlands; Guntert B, Hall i.T., Austria; Gutzwiller F, Bern, Switzerland; Heinen H, Bonn, Germany; Hess O, Bern, Switzerland; Klein B, Essen, Germany; Lowel H, Neuherberg, Germany; Reiser M, Munich, Germany; Schwaiger M, Munich, Germany; Steinmuller C, Bonn, Germany; Theorell T, Stockholm, Sweden; Willich SN, Berlin, Germany.; Support for FUSION was provided by NIH grants R01-DK062370 (to M. Boehnke).; The MONICA population surveys were supported by unrestricted grants from the Conseil Regional du Nord-Pas de Calais, the Caisse Primaire d'Assurance Maladie de Selestat, the Association Regionale de Cardiologie d'Alsace, ONIVINS, the Parke-Davis Laboratory, the Mutuelle Generale de l'Education Nationale (MGEN), the Groupe Fournier, the Reseau National de Sante Publique, the Direction Generale de la Sante, the Institut National de la Sante Et de la Recherche Medicale (INSERM), the Institut Pasteur de Lille, and the Unite d'Evaluation du Centre Hospitalier et Universitaire de Lille.; The FINCAVAS work was supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data.; The WHII study has been supported by grants from the Medical Research Council, British Heart Foundation; Health and Safety Executive; Department of Health; NHLBI (HL036310) and National Institute on Aging (AG13196), USA, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. Professor MK's time on this manuscript was partially supported by the (HL36310).; PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the NIH (grant LM010098), The Netherlands Organization for Scientific Research (NWO-Groot 175.010.2007.006, NWO VENI grant 916.761.70 and NWO VIDI grant 917.13.350, ZonMW grant 90.700.441) and the Dutch Inter University Cardiology Institute Netherlands. N. Verweij is supported by the Netherlands Heart Foundation (grant NHS2010B280).; The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ.; The SHEEP study was supported by the Swedish Council for Social Research, the Swedish Council for Work Life Research, the Stockholm County Council, the Swedish Heart and Lung Foundation and the Swedish Research Council.; The CoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, Switzerland and four grants of the Swiss National Science Foundation (grants #3200B0-105993, #3200B0-118308, #33CSCO-122661 and 33CS30-139468) and thankfully acknowledges Diana Marek's contributions to this study.; The MRC NSHD study was funded by the Medical Research Council (MC_UU_12019/1).; We thank all EPIC-Potsdam participants for their invaluable contribution to the study. Furthermore, we thank Ellen Kohlsdorf for data management as well as the follow-up team headed by Dr. Manuala Bergmann. 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).; The Australian Twin-Family Study (AUSTWIN) acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739 and 552485), US NIH (NIH grants AA07535, AA10248 and AA014041) and the Australian Research Council (ARC grant DP0770096). P. M. Ridker was supported by an NHMRC Career Development Award.; Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (Grant No. 120386 and 125876 to J. G. Eriksson), the Finnish Diabetes Research Society, Novo Nordisk Foundation, Finska Lakaresallskapet, Liv och Halsa, Samfundet Folkhalsan, Finska Lakaresallskapet and the Signe and Ane Gyllenberg foundation.; The Danish Diet, Cancer and Health (DCH) cohort is supported by the Danish Cancer Society.; The Finnish Diabetes Prevention Study was funded by the Academy of Finland, Nord Forsk and Nordic Centre of Excellent Sysdiet; furthermore, contributions from the Finnish Diabetes Prevention Study group and especially Markku Peltonen and Professor Matti Uusitupa are gratefully acknowledged.; The SAVITAIPALE study received grant support from the US NIH (DK62370); The IMPROVE study was supported by the European Commission (Contract number: QLG1-CT-2002-00896), Swedish Heart-Lung Foundation, Swedish Research Council (projects 8691 and 0593), Knut and Alice Wallenberg Foundation, Foundation for Strategic Research, Stockholm County Council (project 592229), Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council, European Union Framework Programme 7 (FP7/2007-2013) for Innovative Medicine Initiative (no IMI/115006 [the SUMMIT consortium]), Magnus Bergwall Foundation, Academy of Finland (Grant #110413), British Heart Foundation (RG2008/08, RG2008/014) and Italian Ministry of Health (Ricerca Corrente). R. J. Strawbridge is supported by the Swedish Heart-Lung Foundation, the Tore Nilsson, Gamla Tjanarinnor and Fredrik and Ingrid Thurings foundations.; The GEMINAKAR project was supported by grants from the Danish Medical Research Council, the Danish Diabetes Association, the NOVO Foundation, the Danish Heart Foundation, Apotekerfonden, the Foundation of A. and J. Louis-Hansen, the Foundation of Direktor E. Danielsen and wife, the Foundation of Direktor K. Bonnelycke and wife Grethe, the Foundation of Laegevidenskabens Fremme, the Foundation of A. F. Bolding, the Foundation of O. William and E. B. Olesen, the Faculty of Health at University of Southern Denmark, the Danish National Science Foundation, T. Steenbeck's Foundation, the Gangsted Foundation and King Christian the Tenth's Foundation. K. O. Kyvik received funding from the European Union Contract No. QLG2-CT-2002-01254 (the GenomEUtwin project). The Danish Epidemiology Science Centre is supported by the National Danish Science Foundation. Finally, we would like to thank all twins participating in the GEMINAKAR Study. NR 60 TC 0 Z9 0 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7881 EI 1467-789X J9 OBES REV JI Obes. Rev. PD APR PY 2015 VL 16 IS 4 BP 327 EP 340 DI 10.1111/obr.12263 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CE1ZS UT WOS:000351612400006 PM 25752329 ER PT J AU Thanos, PK Robison, LS Steier, J Hwang, YF Cooper, T Swanson, JM Komatsu, DE Hadjiargyrou, M Volkow, ND AF Thanos, Panayotis K. Robison, Lisa S. Steier, Jessica Hwang, Yu Fen Cooper, Thomas Swanson, James M. Komatsu, David E. Hadjiargyrou, Michael Volkow, Nora D. TI A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Methylphenidate; Ritalin; Attention deficit hyperactivity disorder; Psychostimulant; Dopamine transporter ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; OF-THE-LITERATURE; ADOLESCENT RATS; PRESCRIPTION STIMULANTS; EXPLORATORY-BEHAVIOR; CROSS-SENSITIZATION; PERIADOLESCENT RATS; LOCOMOTOR-ACTIVITY; CHIRALITY MATTER AB Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60 mg/kg/day; as well as dual-dosages of 4 and 10 mg/kg/day, 20 and 30 mg/kg/day, or 30 and 60 mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60 mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at similar to 30 ng/mL), while the 4/10 mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at similar to 8 ng/mL). Treatment with the higher dual-dosage (HD: 30/60 mg/kg) resulted in hyperactivity, while the lower (LD: 4/10 mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Thanos, Panayotis K.; Robison, Lisa S.; Steier, Jessica; Hwang, Yu Fen] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Cooper, Thomas] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Swanson, James M.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Komatsu, David E.] SUNY Stony Brook, Dept Orthopaed, Stony Brook, NY 11794 USA. [Hadjiargyrou, Michael] New York Inst Technol, Dept Life Sci, Old Westbury, NY 11568 USA. [Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. RP Thanos, PK (reprint author), SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. EM peter.thanos@stonybrook.edu FU NICHD [1R01HD070888-01A1]; Research Foundation of NY [1115107] FX This work was supported by NICHD (1R01HD070888-01A1) and The Research Foundation of NY (1115107). NR 75 TC 4 Z9 4 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2015 VL 131 BP 143 EP 153 DI 10.1016/j.pbb.2015.01.005 PG 11 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA CE9OL UT WOS:000352173200022 PM 25641666 ER PT J AU Blanco, I Kuchenbaecker, K Cuadras, D Wang, XS Barrowdale, D Garibay, GR Librado, P Sanchez-Gracia, A Rozas, J Bonifaci, N McGuffog, L Pankratz, VS Islam, A Mateo, F Berenguer, A Petit, A Catala, I Brunet, J Feliubadalo, L Tornero, E Benitez, J Osorio, A Cajal, TRY Nevanlinna, H Aittomaki, K Arun, BK Toland, AE Karlan, BY Walsh, C Lester, J Greene, MH Mai, PL Nussbaum, RL Andrulis, IL Domchek, SM Nathanson, KL Rebbeck, TR Barkardottir, RB Jakubowska, A Lubinski, J Durda, K Jaworska-Bieniek, K Claes, K Van Maerken, T Diez, O Hansen, TV Jonson, L Gerdes, AM Ejlertsen, B de la Hoya, M Caldees, T Dunning, AM Oliver, C Fineberg, E Cook, M Peock, S McCann, E Murray, A Jacobs, C Pichert, G Lalloo, F Chu, C Dorkins, H Paterson, J Ong, KR Teixeira, MR Teixeira Hogervorst, FBL van der Hout, AH Seynaeve, C van der Luijt, RB Ligtenberg, MJL Devilee, P Wijnen, JT Rookus, MA Meijers-Heijboer, HEJ Blok, MJ van den Ouweland, AMW Aalfs, CM Rodriguez, GC Phillips, KAA Piedmonte, M Nerenstone, SR Bae-Jump, VL O'Malley, DM Ratner, ES Schmutzler, RK Wappenschmidt, B Rhiem, K Engel, C Meindl, A Ditsch, N Arnold, N Plendl, HJ Niederacher, D Sutter, C Wang-Gohrke, S Steinemann, D Preisler-Adams, S Kast, K Varon-Mateeva, R Gehrig, A Bojesen, A Pedersen, IS Sunde, L Jensen, UB Thomassen, M Kruse, TA Foretova, L Peterlongo, P Bernard, L Peissel, B Scuvera, G Manoukian, S Radice, P Ottini, L Montagna, M Agata, S Maugard, C Simard, J Soucy, P Berger, A Fink-Retter, A Singer, CF Rappaport, C Geschwantler-Kaulich, D Tea, MK Pfeiler, G John, EM Miron, A Neuhausen, SL Terry, MB Chung, WK Daly, MB Goldgar, DE Janavicius, R Dorfling, CM van Rensburg, EJ Fostira, F Konstantopoulou, I Garber, J Godwin, AK Olah, E Narod, SA Rennert, G Paluch, SS Laitman, Y Friedman, E Liljegren, A Rantala, J Stenmark-Askmalm, M Loman, N Imyanitov, EN Hamann, U Spurdle, AB Healey, S Weitzel, JN Herzog, J Margileth, D Gorrini, C Esteller, M Gomez, A Sayols, S Vidal, E Heyn, H Stoppa-Lyonnet, Leone, M Barjhoux, L Fassy-Colcombet, M de Pauw, A Lasset, C Ferrer, SF Castera, L Berthet, P Cornelis, F Bignon, YJ Damiola, F Mazoyer, S Sinilnikova, OM Maxwell, CA Vijai, J Robson, M Kauff, N Corines, MJ Villano, D Cunningham, J Lee, A Lindor, N Lazaro, C Easton, DF Offit, K Chenevix-Trench, G Couch, FJ Antoniou, AC Pujana, MA AF Blanco, Ignacio Kuchenbaecker, Karoline Cuadras, Daniel Wang, Xianshu Barrowdale, Daniel Ruiz de Garibay, Gorka Librado, Pablo Sanchez-Gracia, Alejandro Rozas, Julio Bonifaci, Nuria McGuffog, Lesley Pankratz, Vernon S. Islam, Abul Mateo, Francesca Berenguer, Antoni Petit, Anna Catala, Isabel Brunet, Joan Feliubadalo, Lidia Tornero, Eva Benitez, Javier Osorio, Ana Cajal, Teresa Ramon Y. Nevanlinna, Heli Aittomaki, Kristiina Arun, Banu K. Toland, Amanda E. Karlan, Beth Y. Walsh, Christine Lester, Jenny Greene, Mark H. Mai, Phuong L. Nussbaum, Robert L. Andrulis, Irene L. Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Timothy R. Barkardottir, Rosa B. Jakubowska, Anna Lubinski, Jan Durda, Katarzyna Jaworska-Bieniek, Katarzyna Claes, Kathleen Van Maerken, Tom Diez, Orland Hansen, Thomas V. Jonson, Lars Gerdes, Anne-Marie Ejlertsen, Bent de la Hoya, Miguel Caldes, Trinidad Dunning, Alison M. Oliver, Clare Fineberg, Elena Cook, Margaret Peock, Susan McCann, Emma Murray, Alex Jacobs, Chris Pichert, Gabriella Lalloo, Fiona Chu, Carol Dorkins, Huw Paterson, Joan Ong, Kai-Ren Teixeira, Manuel R. Teixeira Hogervorst, Frans B. L. van der Hout, Annemarie H. Seynaeve, Caroline van der Luijt, Rob B. Ligtenberg, Marjolijn J. L. Devilee, Peter Wijnen, Juul T. Rookus, Matti A. Meijers-Heijboer, Hanne E. J. Blok, Marinus J. van den Ouweland, Ans M. W. Aalfs, Cora M. Rodriguez, Gustavo C. Phillips, Kelly-Anne A. Piedmonte, Marion Nerenstone, Stacy R. Bae-Jump, Victoria L. O'Malley, David M. Ratner, Elena S. Schmutzler, Rita K. Wappenschmidt, Barbara Rhiem, Kerstin Engel, Christoph Meindl, Alfons Ditsch, Nina Arnold, Norbert Plendl, Hansjoerg J. Niederacher, Dieter Sutter, Christian Wang-Gohrke, Shan Steinemann, Doris Preisler-Adams, Sabine Kast, Karin Varon-Mateeva, Raymonda Gehrig, Andrea Bojesen, Anders Pedersen, Inge Sokilde Sunde, Lone Jensen, Uffe Birk Thomassen, Mads Kruse, Torben A. Foretova, Lenka Peterlongo, Paolo Bernard, Loris Peissel, Bernard Scuvera, Giulietta Manoukian, Siranoush Radice, Paolo Ottini, Laura Montagna, Marco Agata, Simona Maugard, Christine Simard, Jacques Soucy, Penny Berger, Andreas Fink-Retter, Anneliese Singer, Christian F. Rappaport, Christine Geschwantler-Kaulich, Daphne Tea, Muy-Kheng Pfeiler, Georg John, Esther M. Miron, Alex Neuhausen, Susan L. Terry, Mary Beth Chung, Wendy K. Daly, Mary B. Goldgar, David E. Janavicius, Ramunas Dorfling, Cecilia M. van Rensburg, Elisabeth J. Fostira, Florentia Konstantopoulou, Irene Garber, Judy Godwin, Andrew K. Olah, Edith Narod, Steven A. Rennert, Gad Paluch, Shani Shimon Laitman, Yael Friedman, Eitan Liljegren, Annelie Rantala, Johanna Stenmark-Askmalm, Marie Loman, Niklas Imyanitov, Evgeny N. Hamann, Ute Spurdle, Amanda B. Healey, Sue Weitzel, Jeffrey N. Herzog, Josef Margileth, David Gorrini, Chiara Esteller, Manel Gomez, Antonio Sayols, Sergi Vidal, Enrique Heyn, Holger Stoppa-Lyonnet, Dominique Leone, Melanie Barjhoux, Laure Fassy-Colcombet, Marion de Pauw, Antoine Lasset, Christine Ferrer, Sandra Fert Castera, Laurent Berthet, Pascaline Cornelis, Francois Bignon, Yves-Jean Damiola, Francesca Mazoyer, Sylvie Sinilnikova, Olga M. Maxwell, Christopher A. Vijai, Joseph Robson, Mark Kauff, Noah Corines, Marina J. Villano, Danylko Cunningham, Julie Lee, Adam Lindor, Noralane Lazaro, Conxi Easton, Douglas F. Offit, Kenneth Chenevix-Trench, Georgia Couch, Fergus J. Antoniou, Antonis C. Angel Pujana, Miguel CA BCFR SWE-BRCA KConFab Investigators GEMO TI Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers SO PLOS ONE LA English DT Article ID GENETIC INTERACTION NETWORKS; GENOME-WIDE ASSOCIATION; EXPRESSION SIGNATURE; SUSCEPTIBILITY LOCI; CHIP-SEQ; CELL; POLYMORPHISM; MODIFIERS; SURVIVAL; ELEMENTS AB While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. C1 [Blanco, Ignacio; Feliubadalo, Lidia; Tornero, Eva; Lazaro, Conxi] Bellvitge Inst Biomed Res IDIBELL, Hereditary Canc Program, Catalan Inst Oncol ICO, Lhospitalet Del Llobrega, Catalonia, Spain. [Kuchenbaecker, Karoline; Barrowdale, Daniel; McGuffog, Lesley; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Epidemiol Study Familial Breast Canc,Ctr Canc Gen, Cambridge, England. [Cuadras, Daniel; Berenguer, Antoni] Bellvitge Inst Biomed Res IDIBELL, Stat Unit, Lhospitalet Del Llobrega, Catalonia, Spain. [Wang, Xianshu; Cunningham, Julie; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Ruiz de Garibay, Gorka; Bonifaci, Nuria; Mateo, Francesca; Angel Pujana, Miguel] Bellvitge Inst Biomed Res IDIBELL, Breast Canc & Syst Biol Unit, Catalan Inst Oncol ICO, Lhospitalet Del Llobrega, Catalonia, Spain. [Librado, Pablo; Sanchez-Gracia, Alejandro; Rozas, Julio] Univ Barcelona, Dept Genet & Biodivers Res Inst IRBio, Barcelona, Catalonia, Spain. [Pankratz, Vernon S.; Cunningham, Julie; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Islam, Abul] Univ Dhaka, Dept Genet Engn & Biotechnol, Dhaka 1000, Bangladesh. [Petit, Anna; Catala, Isabel] Bellvitge Inst Biomed Res IDIBELL, Univ Hosp Bellvitge, Dept Pathol, Lhospitalet Del Llobrega, Catalonia, Spain. [Brunet, Joan] Hosp Josep Trueta, Girona Biomed Res Inst IDIBGI, Hereditary Canc Program, Catalan Inst Oncol ICO, Girona, Catalonia, Spain. [Benitez, Javier; Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier; Osorio, Ana] Biomed Network Rare Dis, Madrid, Spain. [Cajal, Teresa Ramon Y.] Hosp Santa Creu & Sant Pau, Oncol Serv, Barcelona, Catalonia, Spain. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med & Mol Virol Immunol & Med Genet, Div Human Canc Genet, Columbus, OH 43210 USA. [Karlan, Beth Y.; Walsh, Christine; Lester, Jenny] Cedars Sinai Med Ctr, Ctr Comprehens Canc, Womens Canc Program Samuel Oschin, Los Angeles, CA 90048 USA. [Greene, Mark H.; Mai, Phuong L.] Natl Canc Inst, Div Canc Epidemiol & Genet, Clin Genet Branch, Rockville, MD USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA. [Andrulis, Irene L.] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. 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[Dorfling, Cecilia M.; van Rensburg, Elisabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Arcadia, South Africa. [Fostira, Florentia; Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, Inst Radioisotopes & Radiodiagnost Prod, Mol Diagnost Lab, Athens, Greece. [Garber, Judy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Commun Med & Epidemiol, Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [Paluch, Shani Shimon] Chaim Sheba Med Ctr, Inst Oncol, Ramat Gan, Israel. [Laitman, Yael; Friedman, Eitan] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, Ramat Gan, Israel. 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[Leone, Melanie; Sinilnikova, Olga M.] Hosp Civils Lyon, Ctr Leon Berard, Unit Mixte Genet Constitut Canc Frequents, Lyon, France. [Barjhoux, Laure; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.] Univ Lyon 1, CNRS, INSERM, Ctr Rech Cancerol Lyon,U1052,UMR5286, F-69365 Lyon, France. [Lasset, Christine] Univ Lyon 1, CNRS, UMR5558, F-69365 Lyon, France. [Lasset, Christine] Ctr Leon Berard, Unit Prevent & Epidemiol Genet, F-69373 Lyon, France. [Ferrer, Sandra Fert] Hop Hotel Dieu, Ctr Hosp, Lab Genet Chromosom, Chambery, France. [Berthet, Pascaline] Ctr Francois Baclesse, F-14021 Caen, France. [Cornelis, Francois] Avicenne Hosp, AP HP, Genet Unit, Paris, France. [Cornelis, Francois] Sud Francilien Hosp, Evry, France. [Cornelis, Francois] Univ Hosp, Clermont Ferrand, France. [Bignon, Yves-Jean] Univ Clermont Ferrand, Ctr Jean Perrin, Dept Oncogenet, Clermont Ferrand, France. [Maxwell, Christopher A.] Univ British Columbia, Dept Pediat, Child & Family Res Inst, Vancouver, BC V6T 1W5, Canada. [Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, New York, NY 10021 USA. [Lee, Adam] Mayo Clin, Dept Oncol, Rochester, MN USA. [Lindor, Noralane] Mayo Clin Scottsdale, Ctr Individualized Med, Scottsdale, AZ USA. RP Antoniou, AC (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Epidemiol Study Familial Breast Canc,Ctr Canc Gen, Cambridge, England. EM aca20@medschl.cam.ac.uk; mapujana@iconcologia.net RI Spurdle, Amanda/A-4978-2011; Feliubadalo, Lidia/G-4577-2016; Rozas, Julio/A-1733-2009; Sanchez-Gracia, Alejandro/F-4686-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Ehrencrona, Hans/M-5619-2014; Gomez Moruno, Antonio/H-7574-2015; montagna, marco/E-2225-2012; Vidal, Enrique/A-9455-2014; Maxwell, Christopher/B-3044-2011; Esteller, Manel/L-5956-2014; Ligtenberg, Marjolijn/N-9666-2013; Vidal, Enrique/J-7118-2015; Osorio, Ana/I-4324-2014; Teixeira, Manuel/E-4885-2011; Andrulis, Irene/E-7267-2013; OMalley, David/E-3789-2011; Mateo, Francesca/K-7746-2015; Saunders, Christobel/H-5779-2014; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; OI Blanco, Ignacio/0000-0002-7414-7481; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Phillips, Kelly-Anne/0000-0002-0475-1771; Feliubadalo, Lidia/0000-0002-1736-0112; Sunde, Lone/0000-0002-8479-165X; Dunning, Alison Margaret/0000-0001-6651-7166; Brunet, Joan/0000-0003-1945-3512; Kauff, Noah/0000-0001-7242-6156; Sayols, Sergi/0000-0002-3877-4170; Joseph, Vijai/0000-0002-7933-151X; Heyn, Holger/0000-0002-3276-1889; Rozas, Julio/0000-0002-6839-9148; Sanchez-Gracia, Alejandro/0000-0003-4543-4577; Ehrencrona, Hans/0000-0002-5589-3622; Gomez Moruno, Antonio/0000-0001-5308-981X; montagna, marco/0000-0002-4929-2150; Vidal, Enrique/0000-0002-4217-1807; Maxwell, Christopher/0000-0002-0860-4031; Esteller, Manel/0000-0003-4490-6093; Ligtenberg, Marjolijn/0000-0003-1290-1474; Vidal, Enrique/0000-0002-4217-1807; Osorio, Ana/0000-0001-8124-3984; Teixeira, Manuel/0000-0002-4896-5982; Mateo, Francesca/0000-0002-2342-7010; Saunders, Christobel/0000-0003-2281-9829; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Robson, Mark/0000-0002-3109-1692; Berenguer-LLergo, Antoni/0000-0002-3742-8161; Cuadras, Daniel/0000-0001-8780-1764 FU National Cancer Institute [UM1 CA164920]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [LIG-07/2012]; Hereditary Cancer Association (Paveldimo vezio asociacija); LSC grant [10.0010.08]; ESF [2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016]; Liepaja's municipal council; Cancer Association of South Africa (CANSA); Morris and Horowitz Familes Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); COH-CCGCRN: City of Hope Clinical Cancer Genetics Community Network from the National Cancer Institute and the Office of the Director, National Institutes of Health; Hereditary Cancer Research Registry from the National Cancer Institute and the Office of the Director, National Institutes of Health [RC4CA153828]; Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research-United Kingdom grant [C12292/A11174, C1287/ A10118]; NHMRC Program Grant; DKFZ; 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: ARISTEIA; European Social Fund; Cancer Research United Kingdom Grants [C1287/A10118, C1287/A11990]; National Institute of Health Research (NIHR) grant; NIHR grant; Royal Marsden NHS Foundation Trust; Cancer Research United Kingdom Grant [C5047/A8385]; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; AKG [5U01CA113916, R01CA140323]; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlonsen!" Award; Canadian Institutes of Health Research; Fund for Scientific Research Flanders (FWO); National Cancer Institute grant [CA 27469]; GOG Statistical and Data Center [CA 37517]; GOG's Cancer Prevention and Control Committee [CA 101165]; Intramural Research Program, NCI; ISCIII (Spain) [RD12/00369/0006, 12/00539]; European Regional Development FEDER funds; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society grant [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hungarian Research Grant [KTIA-OTKA CK-80745]; Norwegian EEA Financial Mechanism [HU0115/NA/2008-3/OP-9]; Spanish Ministry of Health ISCIII FIS [PI10/01422, PI12/01528, PI13/00285]; RTICC [RD12/0036/0008]; Ramon Areces (XV) Foundation; Eugenio Rodriguez Pascual Foundation; Roses Contra el Cancer Foundation; Spanish Association Against Cancer (AECC); AGAUR Generalitat de Catalunya [2009-SGR290, 2009-SGR293]; Polish Foundation of Science; Icelandic Association "Walking for Breast Cancer Research"; Nordic Cancer Union; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade-grant [PSR-SIIRI-701]; Ministero dell'Istruzione, dell'Universita e della Ricerca and Ministero della Salute; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Foundation of Western Australia; Cancer Councils of Tasmania; National Institutes of Health grant [CA128978]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; United States Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Jewish General Hospital Weekend; Quebec Ministry of Economic Development, Innovation and Export Trade; Cancer Councils of South Australia; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; MH CZ-DRO (MMCI) [00209805]; Niehaus Family Genetics Research Fund; STARR Cancer Consortium Grant; NAROD [1R01 CA149429-01]; NCI Intramural Research Program, National Institutes of Health [NO2-CP-11019-50, N02-CP-65504]; Westat, Inc, Rockville, Maryland; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), New York; Russian Federation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]; Federal Agency for Science and Innovations, Russia [02.740.11.0780]; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and grant from the National Cancer Institute [UM1 CA164920]; Breast Cancer Family Registry (BCFR); United States Government or the BCFR; Ohio State University Comprehensive Cancer Center; Isreal cancer association; Israeli Inherited breast cancer consortium; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Rooney Family Foundation; Susan G. Komen Foundation for the cure, Basser Research Center; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; SAF2010-20493; [PBZ_KBN_122/P05/2004]; Associazione Italiana per la Ricerca sul Cancro FX BCFR-all. This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government or the BCFR. BFBOCC: BFBOCC is supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant LIG-07/2012 and Hereditary Cancer Association (Paveldimo vezio asociacija); Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr. 2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 and Liepaja's municipal council. BMBSA: BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to EJR. BRICOH: SLN was partially supported by the Morris and Horowitz Familes Endowed Professorship. CBCS: This work was supported by the NEYE Foundation. CNIO: This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493. COH-CCGCRN: City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: JW) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5x1000') to SM. Italian Association for Cancer Research (AIRC) to LO. CORE: The CIMBA data management and data analysis were supported by Cancer Research-United Kingdom grants C12292/A11174 and C1287/A10118. SH is supported by an NHMRC Program Grant to GCT. ACA is a Cancer Research -United Kingdom Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. DKFZ: The DKFZ study was supported by the DKFZ. DEMOKRITOS: 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 of the General Secretariat for Research & Technology: ARISTEIA. Investing in knowledge society through the European Social Fund. EMBRACE: EMBRACE is supported by Cancer Research United Kingdom Grants C1287/A10118 and C1287/A11990. DGE and FL are supported by an National Institute of Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. RE and EB are supported by Cancer Research United Kingdom Grant C5047/A8385. FCCC: The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship.; GC-HBOC: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, RKS) and by the Center for Molecular Medicine Cologne (CMMC). GEMO: The study was supported by the Ligue National Contre le Cancer; the Association "Le cancer du sein, parlonsen!" Award; and the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program. G-FAST: TVM is a postdoctoral researcher funded by the Fund for Scientific Research Flanders (FWO). GOG: This study was supported 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 GOG's Cancer Prevention and Control Committee (CA 101165). MHG, PLM and Dr. Savage were supported by funding from the Intramural Research Program, NCI. HCSC: Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: The HEBON study is 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. HUNBOCS: Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. ICO: The ICO-IDIBELL study was supported by grants from the Spanish Ministry of Health ISCIII FIS (PI10/01422, PI12/01528, and PI13/00285) and RTICC (RD12/0036/0008); the Ramon Areces (XV), Eugenio Rodriguez Pascual (2012), and Roses Contra el Cancer (2012) Foundations; the Spanish Association Against Cancer (AECC 2010); and the AGAUR Generalitat de Catalunya (2009-SGR290 and 2009-SGR293). IHCC: The IHCC was supported by Grant PBZ_KBN_122/P05/2004; Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. ILUH: The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research", by the Nordic Cancer Union and by the Landspitali University Hospital Research Fund. INHERIT: This work was supported 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. IOVHBOCS: The study was supported by Ministero dell'Istruzione, dell'Universita e della Ricerca and Ministero della Salute. IPOBCS: This study was in part supported by Liga Portuguesa Contra o Cancro. KCONFAB: kConFab is 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. GCT and ABS are NHMRC Senior Research Fellows.; MAYO: MAYO is supported by National Institutes of Health grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a United States Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD: The work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) and MH CZ-DRO (MMCI, 00209805). MSKCC: MSKCC is supported by Breast Cancer Research Foundation, the Niehaus Family Genetics Research Fund, and the STARR Cancer Consortium Grants. NAROD: 1R01 CA149429-01. NCI: The research of MHG and PLM was supported by the NCI Intramural Research Program, National Institutes of Health, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, Maryland. This study was supported 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 GOG's Cancer Prevention and Control Committee (CA 101165). NICCC: NICCC is supported by Clalit Health Services in Israel. Some of it's activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), New York. NNPIO: This work has been supported by the Russian Federation for Basic Research (grants 11-04-00227, 12-04-00928 and 12-04-01490) and the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780). OCGN: This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government or the BCFR. OSUCCG: OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. SMC: This project was partially funded through a grant by the Isreal cancer association and the funding for the Israeli Inherited breast cancer consortium. SWE-BRCA: SWE-BRCA collaborators are supported by the Swedish Cancer Society. UCHICAGO: UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Rooney Family Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. WCP: The Women's Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 2 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 1 PY 2015 VL 10 IS 4 AR UNSP e0120020 DI 10.1371/journal.pone.0120020 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE9AM UT WOS:000352135600019 PM 25830658 ER PT J AU Panlilio, LV Hogarth, L Shoaib, M AF Panlilio, Leigh V. Hogarth, Lee Shoaib, Mohammed TI Concurrent access to nicotine and sucrose in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; Choice; Individual differences; Concurrent schedule; Self-administration; Varenicline ID CONDITIONED TASTE-AVERSION; ALTERNATIVE REINFORCER; ENVIRONMENTAL MANIPULATIONS; CONTINGENCY MANAGEMENT; CHOICE PROCEDURE; PARTIAL AGONIST; DRUG-SEEKING; COCAINE; FOOD; EXPOSURE AB Animal models that allow concurrent access to drug and nondrug reinforcers provide unique insight into the etiology, maintenance, and treatment of drug use. We sought to develop and utilize a concurrent access procedure with nicotine and sucrose in rats. Pressing one lever delivered intravenous nicotine, and pressing another lever delivered sucrose pellets, with both reinforcers freely available throughout daily sessions. Rats that had been pretrained with nicotine on some days and sucrose on other days responded on both levers when subsequently given concurrent access, but almost all responded at substantially higher rates on the sucrose lever. In contrast, rats pretrained exclusively with nicotine before being given concurrent access showed individual differences, with about half responding more on the nicotine lever. Treatment with the nicotinic receptor partial agonist varenicline selectively decreased nicotine self-administration. Food restriction and removal of the sucrose lever both increased nicotine self-administration. The finding that rats continue to take nicotine when sucrose is concurrently available-and in many cases take it more frequently than sucrose-demonstrates that nicotine self-administration does not only occur in the absence of alternative reinforcement options. As a model of human nicotine use, concurrent access is more naturalistic and has higher face validity than procedures in which only one reinforcer is available or choosing one reinforcer precludes access to other reinforcers. As such, this procedure could be useful for evaluating therapeutic agents and improving our understanding of environmental conditions that promote or discourage nicotine use. C1 [Shoaib, Mohammed] Newcastle Univ, Sch Med, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Panlilio, Leigh V.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Hogarth, Lee] Univ Exeter, Sch Psychol, Exeter EX4 4QG, Devon, England. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM lpanlili@mail.nih.gov OI Hogarth, Lee/0000-0002-0299-5748 FU Newcastle University; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; [MRC G0701456] FX All experiments were conducted at Newcastle University and supported by internal funds from Newcastle University and funds donated by Dr. L. Hogarth (MRC G0701456). Preparation of the manuscript was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services (LVP). NR 55 TC 5 Z9 5 U1 0 U2 4 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 APR PY 2015 VL 232 IS 8 BP 1451 EP 1460 DI 10.1007/s00213-014-3787-8 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CF1HB UT WOS:000352294200010 PM 25366874 ER PT J AU Moriya, Y Kasahara, Y Hall, FS Sakakibara, Y Uhl, GR Tomita, H Sora, I AF Moriya, Yuki Kasahara, Yoshiyuki Hall, F. Scott Sakakibara, Yasufumi Uhl, George R. Tomita, Hiroaki Sora, Ichiro TI Sex differences in the effects of adolescent social deprivation on alcohol consumption in mu-opioid receptor knockout mice SO PSYCHOPHARMACOLOGY LA English DT Article DE mu-Opioid receptor (MOP); Knockout (KO) mice; Social isolation; Stress; Sex-dependent manner; Abuse; Alcoholism ID POPULATION-BASED SAMPLE; GENDER-DIFFERENCES; C57BL/6J MICE; WISTAR RATS; ETHANOL-CONSUMPTION; NUCLEUS-ACCUMBENS; VENTRAL STRIATUM; LABORATORY RATS; FORCED SWIM; FEMALE RATS AB Evidence based on clinical and experimental animal studies indicates that adolescent social deprivation influences alcohol consumption in a sex-dependent manner, perhaps by influencing stress responses. However, the mechanisms underlying the interaction between these phenomena remain to be elucidated. Since the mu-opioid receptor (MOP) has been reported to have key roles in social stress responses as well as the reinforcing/addictive effects of ethanol, MOP is a candidate molecule that may link adolescent social deprivation and subsequent alterations in alcohol consumption. To evaluate the involvement of MOP and social isolation-induced changes in alcohol consumption, as well as the effect of sex differences on responses to social isolation, alcohol consumption was assessed using a two-bottle home-cage consumption procedure (8 % ethanol vs. water) in MOP knockout (MOP-KO) and wild type (WT) mice of both sexes exposed to adolescent social deprivation or reared socially. Isolation rearing had no effects upon alcohol consumption of WT mice, whereas it significantly altered alcohol consumption in both male and female MOP-KO mice. Interestingly, social isolation affected ethanol consumption differently in male and female mice. Ethanol consumption was increased in male MOP-KO mice, but decreased in female MOP-KO mice, by isolation rearing. These results indicate that disturbances of MOP function influence the effects of isolation rearing on ethanol consumption in a sex-dependent manner. Consequently, this suggests the possibility that genetic variation that influences MOP function may have differential roles in alcoholism in men and women, and alcoholism treatments that target MOP function may be differentially effective in males and females. C1 [Moriya, Yuki; Kasahara, Yoshiyuki; Sakakibara, Yasufumi; Tomita, Hiroaki; Sora, Ichiro] Tohoku Univ, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. [Moriya, Yuki; Kasahara, Yoshiyuki; Sakakibara, Yasufumi; Tomita, Hiroaki] Tohoku Univ, Grad Sch Med, Dept Disaster Psychiat, Sendai, Miyagi 980, Japan. [Moriya, Yuki; Kasahara, Yoshiyuki; Sakakibara, Yasufumi; Tomita, Hiroaki] Tohoku Univ, Int Res Inst Disaster Sci IRIDeS, Sendai, Miyagi 980, Japan. [Tomita, Hiroaki] Tohoku Univ, Tohoku Med Megabank Org ToMMo, Sendai, Miyagi 980, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Sora, Ichiro] Kobe Univ, Grad Sch Med, Dept Psychiat, Chuo Ku, Kobe, Hyogo 6570017, Japan. RP Sora, I (reprint author), Kobe Univ, Grad Sch Med, Dept Psychiat, Chuo Ku, 7-5-1 Kusunoki Cho, Kobe, Hyogo 6570017, Japan. EM sora@med.kobe-u.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Japan Society for the Promotion Science (JSPS) KAKENHI [254961]; Intramural Research Grant for Collaboration on Special Project Research from IRIDeS, Tohoku University, JSPS [24116007]; MHLW of Japan; Ministry of Health, Labour and Welfare of Japan; Global COE Program (Basic & Translational Research Center for Global Brain Science) from MEXT of Japan; Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA FX This work was supported by a Japan Society for the Promotion Science (JSPS) KAKENHI Grant-in-Aid for JSPS Fellows (254961); by an Intramural Research Grant for Collaboration on Special Project Research from IRIDeS, Tohoku University, JSPS Grant-in-Aid for scientific research on innovative areas (24116007); by a Grant-in-Aid for Health and Labour Science Research (Research on Pharmaceutical and Medical Safety) from MHLW of Japan; by a Grant from the Ministry of Health, Labour and Welfare of Japan; by the Global COE Program (Basic & Translational Research Center for Global Brain Science) from MEXT of Japan; and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH). NR 89 TC 1 Z9 1 U1 3 U2 8 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 APR PY 2015 VL 232 IS 8 BP 1471 EP 1482 DI 10.1007/s00213-014-3784-y PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CF1HB UT WOS:000352294200012 PM 25363463 ER PT J AU Sparks, R Salskov, AH Chang, AS Wentworth, KL Gupta, PP Staiger, TO Anawalt, BD AF Sparks, Rachel Salskov, Alex H. Chang, Anita S. Wentworth, Kelly L. Gupta, Pritha P. Staiger, Thomas O. Anawalt, Bradley D. TI Pocket Change: A Simple Educational Intervention Increases Hospitalist Documentation of Comorbidities and Improves Hospital Quality Performance Measures SO QUALITY MANAGEMENT IN HEALTH CARE LA English DT Article DE hospitalist; medical documentation; pocket card; quality improvement ID DIAGNOSIS AB Background: Complete documentation of patient comorbidities in the medical record is important for clinical care, hospital reimbursement, and quality performance measures. We designed a pocket card reminder and brief educational intervention aimed at hospitalists with the goal of improving documentation of 6 common comorbidities present on admission: coagulation abnormalities, metastatic cancer, anemia, fluid and electrolyte abnormalities, malnutrition, and obesity. Methods: Two internal medicine inpatient teams led by 10 hospitalist physicians at an academic medical center received the educational intervention and pocket card reminder (n = 520 admissions). Two internal medicine teams led by nonhospitalist physicians served as a control group (n = 590 admissions). Levels of documentation of 6 common comorbidities, expected length of stay, and expected mortality were measured at baseline and during the 9-month study period. Results: The intervention was associated with increased documentation of anemia, fluid and electrolyte abnormalities, malnutrition, and obesity in the intervention group, both compared to baseline and compared to the control group during the study period. The expected length of stay increased in the intervention group during the study period. Conclusions: A simple educational intervention and pocket card reminder were associated with improved documentation and hospital quality measures at an academic medical center. C1 [Sparks, Rachel; Salskov, Alex H.; Chang, Anita S.; Gupta, Pritha P.; Staiger, Thomas O.; Anawalt, Bradley D.] Univ Washington, Dept Med, Seattle, WA USA. [Wentworth, Kelly L.] Univ Calif San Francisco, Div Endocrinol, San Francisco, CA 94143 USA. RP Sparks, R (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 12C103,MSC 1899, Bethesda, MD 20892 USA. EM rachel.sparks@nih.gov FU National Institutes of Health (NIH-NICHD) [U554 HD042454-06] FX Dr Anawalt is currently receiving grant support from the National Institutes of Health (NIH-NICHD U554 HD042454-06); he is also a consultant for the United States Anti-Doping Agency and has provided expert testimony for the Federal Trade Commission. The study itself received no NIH or other funding. For the remaining authors, no conflicts of interest were declared. The authors thank Elaine Giusti for her excellent data support. NR 14 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 1063-8628 EI 1550-5154 J9 QUAL MANAG HEALTH CA JI Qual. Manag. Health Care PD APR-JUN PY 2015 VL 24 IS 2 BP 74 EP 78 DI 10.1097/QMH.0000000000000052 PG 5 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE9WC UT WOS:000352193100004 PM 25830615 ER PT J AU Floridi, C Radaelli, A Abi-Jaoudeh, N Grass, M Lin, MD Chiaradia, M Geschwind, JF Kobeiter, H Squillaci, E Maleux, G Giovagnoni, A Brunese, L Wood, B Carrafiello, G Rotondo, A AF Floridi, Chiara Radaelli, Alessandro Abi-Jaoudeh, Nadine Grass, Michael Lin, MingDe Chiaradia, Melanie Geschwind, Jean-Francois Kobeiter, Hicham Squillaci, Ettore Maleux, Geert Giovagnoni, Andrea Brunese, Luca Wood, Bradford Carrafiello, Gianpaolo Rotondo, Antonio TI C-arm cone-beam computed tomography in interventional oncology: technical aspects and clinical applications (vol 119, pg 521, 2014) SO RADIOLOGIA MEDICA LA English DT Correction C1 [Floridi, Chiara; Carrafiello, Gianpaolo] Insubria Univ, Dept Radiol, I-21100 Varese, Italy. [Radaelli, Alessandro] Philips Healthcare, Best, Netherlands. [Abi-Jaoudeh, Nadine; Wood, Bradford] NIH, Ctr Intervent Oncol, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Grass, Michael] Philips Res, Hamburg, Germany. [Lin, MingDe] Philips Res North Amer, Briarcliff Manor, NY USA. [Chiaradia, Melanie; Kobeiter, Hicham] Henri Mondor Hosp, Dept Radiol & Med Imaging, Creteil, France. [Geschwind, Jean-Francois] Johns Hopkins Univ Hosp, Div Vasc & Intervent Radiol, Baltimore, MD 21287 USA. [Squillaci, Ettore] Univ Tor Vergata, Dept Diagnost & Mol Imaging Intervent Radiol & Ra, Rome, Italy. [Maleux, Geert] Katholieke Univ Leuven Hosp, Dept Radiol, B-3000 Louvain, Belgium. [Giovagnoni, Andrea] Univ Ancona, Dept Radiol, Ancona, Italy. [Brunese, Luca] Univ Molise, Dept Radiol, Campobasso, Italy. [Rotondo, Antonio] Univ Naples 2, Dept Radiol, Naples, Italy. RP Floridi, C (reprint author), Insubria Univ, Dept Radiol, Viale Borri 57, I-21100 Varese, Italy. EM chiara.floridi@gmail.com FU NCI NIH HHS [R01 CA160771] NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0033-8362 EI 1826-6983 J9 RADIOL MED JI Radiol. Med. PD APR PY 2015 VL 120 IS 4 BP 406 EP 406 DI 10.1007/s11547-014-0450-8 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CE8IQ UT WOS:000352086000011 PM 25100305 ER PT J AU Keyser, RE Christensen, EJ Chin, LMK Woolstenhulme, JG Drinkard, B Quinn, A Connors, G Weir, NA Nathan, SD Chan, LE AF Keyser, Randall E. Christensen, Eric J. Chin, Lisa M. K. Woolstenhulme, Joshua G. Drinkard, Bart Quinn, Anne Connors, Gerilynn Weir, Nargues A. Nathan, Steven D. Chan, Leighton E. TI Changes in fatigability following intense aerobic exercise training in patients with interstitial lung disease SO RESPIRATORY MEDICINE LA English DT Article DE Interstitial lung disease; Fatigability; Pulmonary rehabilitation; Aerobic exercise physical activity; Fatigue severity ID OBSTRUCTIVE PULMONARY-DISEASE; 6-MINUTE WALK TEST; QUALITY-OF-LIFE; ANAEROBIC THRESHOLD; CARDIORESPIRATORY FUNCTION; TRANSPLANT CANDIDATES; OXYGEN-CONSUMPTION; GAS-EXCHANGE; REHABILITATION; FIBROSIS AB Objective: To determine if, in patients with interstitial lung disease (ILD), fatigue might be lessened after vigorous aerobic exercise. Methods: 13 physically inactive patients (5 men and 8 women; age 57.2 +/- 9.1 years, BMI 28.2 +/- 4.6 kgm(-2)) with ILD of heterogeneous etiology and able to walk on a motor driven treadmill without physical limitation were enrolled. Subjects underwent cardiopulmonary exercise (CPET) and 6-min walk (6MWT) tests and completed Fatigue Severity Scale and Human Activity Profile questionnaires before and after an aerobic exercise-training regimen. The training regimen required participation in at least 24 of 30 prescribed aerobic exercise training sessions at a target heart rate of 70-80% of the heart rate reserve, 30 min per session, 3 times perweek for 10 weeks. Results: After training, a 55% (p < 0.001) increase in time to anaerobic threshold on the CPET, and an 11% (p = 0.045) reduction in performance fatigability index (PFI), calculated from the performance on the 6MWT were observed. Distance walked on the 6MWT (6MWD) increased by 49.7 +/- 46.9 m (p = 0.002). Significant improvements in scores on the Fatigue Severity Scale (p = 0.046) and Human Activity Profile (AAS p = 0.024; MAS p = 0.029) were also observed. No adverse events related to the training regimen were noted. Conclusion: After training, the decrease in fatigability appeared to result in increased 6MWD and was associated with physical activity. Since significant declines in 6MWD may be a marker for impending mortality in ILD, a better understanding of the etiological state of fatigue in patients with ILD and its reversal might provide fundamental insight into disease progression and even survival. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Keyser, Randall E.; Chin, Lisa M. K.; Woolstenhulme, Joshua G.] George Mason Univ, Coll Hlth & Human Serv, Dept Rehabil Sci, Fairfax, VA 22030 USA. [Keyser, Randall E.; Christensen, Eric J.; Chin, Lisa M. K.; Woolstenhulme, Joshua G.; Drinkard, Bart; Quinn, Anne; Chan, Leighton E.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Weir, Nargues A.; Nathan, Steven D.] Inova Fairfax Hosp, Adv Lung Dis & Transplant Program, Falls Church, VA 22046 USA. [Connors, Gerilynn] Inova Farifax Hosp, Pulm Rehabil Ctr, Falls Church, VA 22046 USA. RP Keyser, RE (reprint author), George Mason Univ, Coll Hlth & Human Serv, Dept Rehabil Sci, 4400 Univ Dr,MS 2G7, Fairfax, VA 22030 USA. EM rkeyser@gmu.edu RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU National Institutes of Health Intramural Research Program [1 Z01 CL060068-02 CC] FX This study was supported by the National Institutes of Health Intramural Research Program [1 Z01 CL060068-02 CC]. NR 47 TC 1 Z9 1 U1 1 U2 9 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD APR PY 2015 VL 109 IS 4 BP 517 EP 525 DI 10.1016/j.rmed.2015.01.021 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA CE9PW UT WOS:000352176900011 PM 25698651 ER PT J AU Roschewski, M AF Roschewski, Mark TI Cracking the Diverse Biologic Code of Diffuse Large B-Cell Lymphoma SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NCI, Ctr Canc Res, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Ctr Canc Res, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2015 VL 52 IS 2 BP 55 EP 56 DI 10.1053/j.seminhematol.2015.01.010 PG 2 WC Hematology SC Hematology GA CE9RK UT WOS:000352180900001 PM 25805584 ER PT J AU Xie, Y Pittaluga, S Jaffe, ES AF Xie, Yi Pittaluga, Stefania Jaffe, Elaine S. TI The Histological Classification of Diffuse Large B-cell Lymphomas SO SEMINARS IN HEMATOLOGY LA English DT Article ID GRAY-ZONE LYMPHOMA; PYOTHORAX-ASSOCIATED LYMPHOMA; PRIMARY EFFUSION LYMPHOMA; HIV-SERONEGATIVE PATIENT; NERVOUS-SYSTEM LYMPHOMA; GENE-EXPRESSION; HODGKIN LYMPHOMA; CLINICOPATHOLOGICAL ENTITY; PLASMABLASTIC LYMPHOMAS; CHRONIC INFLAMMATION AB Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic, and pathologic diversity, in part reflecting the functional diversity of the B-cell system and multiple pathways of transformation. In recent years, the advent of new high-throughput genomic technologies has provided new insights into the biology of DLBCL, leading to the identification of distinct molecular identities and novel pathogenetic pathways. This increasing complexity had led to an expanding number of entities in the World Health Organization classification. Using a multi-modality approach, the updated 2008 classification delineated some new subgroups, including DLBCLs associated with particular age groups or specific anatomic sites, as well as two borderline categories (tumors at the interface between classical Hodgkin lymphoma and DLBCL as well as between Burkitt lymphoma and DLBCL). This article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes included in the 2008 classification, with emphasis on some of the new entities as well as areas of diagnostic challenge. Published by Elsevier Inc. C1 [Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Ctr Canc Res, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NIH, Bldg 10 Room 2B42,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov FU Intramural NIH HHS [Z01 BC011070-01] NR 91 TC 5 Z9 5 U1 0 U2 4 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 APR PY 2015 VL 52 IS 2 BP 57 EP 66 DI 10.1053/j.seminhematol.2015.01.006 PG 10 WC Hematology SC Hematology GA CE9RK UT WOS:000352180900002 PM 25805585 ER PT J AU Young, RM Shaffer, AL Phelan, JD Staudt, LM AF Young, Ryan M. Shaffer, Arthur L., III Phelan, James D. Staudt, Louis M. TI B-Cell Receptor Signaling in Diffuse Large B-Cell lymphoma SO SEMINARS IN HEMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; BRUTONS TYROSINE KINASE; ANTIGEN RECEPTOR; MOLECULAR SUBTYPES; SURVIVAL; IMMUNOGLOBULIN; ACTIVATION; MATURE; BCR AB The importance of understanding the genetic and biochemical basis of B-cell receptor (BCR) survival signaling in diffuse large B-cell lymphoma (DLBCL) is underscored by the recent clinical success of agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular subtypes with divergent clinical outcomes. The activated B-cell like (ABC) subtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-kappa B activity. The origins of this NF-kappa B activity remained obscure until RNA interference screens established that the majority of ABC DLBCL cell lines rely on expression of BCR components and downstream signaling effectors for NF-kappa B activation. Pharmacological inhibition with ibrutinib of Bruton's tyrosine kinase, a kinase that is required for BCR signaling to engage NF-kappa B, is selectively toxic for ABC DLBCL tumors; a finding that has now been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, but also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways. Published by Elsevier Inc. C1 [Young, Ryan M.; Shaffer, Arthur L., III; Phelan, James D.; Staudt, Louis M.] NCI, Ctr Canc Res, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), 9000 Rockville Pike Bldg 10,Room 6N105, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural NIH HHS [ZIA BC011008-07] NR 68 TC 28 Z9 29 U1 0 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2015 VL 52 IS 2 BP 77 EP 85 DI 10.1053/j.seminhematol.2015.01.008 PG 9 WC Hematology SC Hematology GA CE9RK UT WOS:000352180900004 PM 25805587 ER PT J AU Dunleavy, K Steidl, C AF Dunleavy, Kieron Steidl, Christian TI Emerging Biological Insights and Novel Treatment Strategies in Primary Mediastinal Large B-Cell Lymphoma SO SEMINARS IN HEMATOLOGY LA English DT Article ID CLASSICAL HODGKIN LYMPHOMA; GRAY ZONE LYMPHOMA; BRENTUXIMAB VEDOTIN; STAT6; JAK2; CHEMOTHERAPY; ACTIVATION; EXPRESSION; MUTATIONS; RITUXIMAB AB While primary mediastinal large B-cell lymphoma (PMBCL) is considered to be a subtype of diffuse large B-cell lymphoma, it is a distinct clinicopathologic entity, with clinical and biological features closely resembling nodular sclerosing Hodgkin lymphoma. Recent studies have highlighted the shared biology of these two entities and identified novel critical pathways of lymphomagenesis, including the presence of distinct mutations. Mediastinal grey zone lymphomas with features in between PMBCL and nodular sclerosing Hodgkin lymphoma have been described as the missing link between the two parent entities. While the standard therapeutic approach to PMBCL has been immunochemotherapy followed by mediastinal radiation, strategies that obviate the need for radiation and thus eliminate its long-term toxicities have recently been developed. The identification of novel targets in PMBCL and mediastinal grey zone lymphomas have paved the way for testing of agents such as small molecule inhibitors of Janus kinase pathways and immune checkpoint inhibitors. Future directions in these diseases should focus on combining effective novel agents with immunochemotherapy platforms. Published by Elsevier Inc. C1 [Dunleavy, Kieron] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steidl, Christian] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. RP Dunleavy, K (reprint author), NCI, Bldg 10,Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU Intramural Program of the National Cancer Institute; Canadian Institutes of Health Research (OFR); Michael Smith Foundation for Health Research FX The authors have no relevant conflicts of interest to report. Dr Dunleavy receives funding from the Intramural Program of the National Cancer Institute. Dr Steidl is supported by a New Investigator Award from the Canadian Institutes of Health Research (OFR) and a Career Investigator Award from the Michael Smith Foundation for Health Research. NR 48 TC 3 Z9 3 U1 2 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2015 VL 52 IS 2 BP 119 EP 125 DI 10.1053/j.seminhematol.2015.01.002 PG 7 WC Hematology SC Hematology GA CE9RK UT WOS:000352180900008 PM 25805591 ER PT J AU Park, IK Olivier, KN AF Park, In Kwon Olivier, Kenneth N. TI Nontuberculous Mycobacteria in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE nontuberculous mycobacteria; mycobacterium avium complex; mycobacterium abscessus; Cystic fibrosis; bronchiectasis ID COMPLEX LUNG-DISEASE; AVIUM COMPLEX; CLINICAL-SIGNIFICANCE; MACROLIDE RESISTANCE; RESPIRATORY MUCOSA; ABSCESSUS; MASSILIENSE; PREVALENCE; IDENTIFICATION; INFECTIONS AB Increasing numbers of cystic fibrosis (CF) and non-CF bronchiectasis :patients are affected by pulmonary nontuberculous mycobacteria (NTM) infection worldwide. Two species of NTM account for up to 95% of the pulmonary NTM infections: Mycobacteriurri avium complex -(MAC)- and Mycobacterium abscesus:us complex,(MABSC). Diagnosis of pulmonary :NTM infection is based on criteria specified in the 2007 American Thoracic Society/infectious Disease Society of America (ATS/IDSA) guidelines. While many initial positive cultures do not progress to active NTM disease, even a single positive NTM sputum culture Obtained-from higher risk groups such as classic CF or older women with bronchiectasis and very low body mass index should be closely monitored for progressive disease. Macrolides remain the most effective agents available against MAC and MABSC. Infection with MABSC may be associated with worse clinical outcomes,, as more than half of MABSC isolates have inducible macrolide resistance. conferred by an active erm(41) gene. Of growing concern in CF -is that MABSC is becoming more common than MAC, seems to target younger patients with classic CF, and is more difficult to manage, often requiring prolonged courses of intravenous antibiotics. Recurrence rates-of NTM after initial successful treatment remain high, likely due to nonmodifiable risk factor-raising the question of whether secondary prophylaxis is feasible. More rapid and readily available methods for-detecting inducible macrolide resistance and better in vitro Susceptibility testing methods for other drugs that correlate with clinical responses are needed. This is crucial to identify more effective regimens Of existing drugs and for development of novel drugs for NTM infection. C1 [Park, In Kwon] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, 10 Ctr Dr,CRC 6-3130, Bethesda, MD 20892 USA. EM kenneth.olivier@nih.gov FU Intramural Research Programs of the National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases, NIH FX This work was supported in part by the Intramural Research Programs of the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases, NIH. NR 60 TC 9 Z9 9 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD APR PY 2015 VL 36 IS 2 BP 217 EP 224 DI 10.1055/s-0035-1546751 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CE6SU UT WOS:000351969300006 PM 25826589 ER PT J AU Whellan, DJ Kraus, WE Kitzman, DW Rooney, B Keteyian, SJ Pina, IL Ellis, SJ Ghali, JK Lee, KL Cooper, LS O'Connor, CM AF Whellan, David J. Kraus, William E. Kitzman, Dalane W. Rooney, Bridget Keteyian, Steven J. Pina, Ileana L. Ellis, Stephen J. Ghali, Jalal K. Lee, Kerry L. Cooper, Lawton S. O'Connor, Christopher M. TI Authorship in a multicenter clinical trial: The Heart Failure -A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) Authorship and Publication (HAP) Scoring System Results SO AMERICAN HEART JOURNAL LA English DT Article AB Background Few guidelines exist regarding authorship on manuscripts resulting from large multicenter trials. The HF-ACTION investigators devised a system to address assignment of authorship on trial publications and tested the outcomes in the course of conducting the large, multicenter, National Heart, Lung, and Blood Institute-funded trial (n = 2,331; 82 clinical sites; 3 countries). The HF-ACTION Authorship and Publication (HAP) scoring system was designed to enhance rate of dissemination, recognize investigator contributions to the successful conduct of the trial, and harness individual expertise in manuscript generation. Methods The HAP score was generated by assigning points based on investigators' participation in trial enrollment, follow-up, and adherence, as well as participation in committees and other trial activity. Overall publication rates, publication rates by author, publication rates by site, and correlation between site publication and HAP score using a Poisson regression model were examined. Results Fifty peer-reviewed, original manuscripts were published within 6.5 years after conclusion of study enrollment. In total, 137 different authors were named in at least 1 publication. Forty-five (55%) of the 82 sites had an author named to at least 1 article. A Poisson regression model examining incident rate ratios revealed that a higher HAP score resulted in a higher incidence of a manuscript, with a 100-point increase in site score corresponding to an approximately 32% increase in the incidence of a published article. Conclusions Given the success in publishing a large number of manuscripts and widely distributing authorship, regular use of a transparent, objective authorship assignment system for publishing results from multicenter trials may be recommended to optimize fairness and dissemination of trial results. C1 [Whellan, David J.; Rooney, Bridget] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Kraus, William E.; Ellis, Stephen J.; Lee, Kerry L.; O'Connor, Christopher M.] Duke Univ, Sch Med, Durham, NC USA. [Kitzman, Dalane W.] Wake Forest Sch Med, Winston Salem, NC USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Ghali, Jalal K.] Mercer Univ, Sch Med, Macon, GA 31207 USA. [Cooper, Lawton S.] NHLBI, Bethesda, MD 20892 USA. RP Whellan, DJ (reprint author), Sidney Kimmel Med Coll, Dept Cardiol, 1015 Chestnut St,Suite 317, Philadelphia, PA 19107 USA. EM David.Whellan@jefferson.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health (HF-ACTION Main Trial) [U01HL063747] FX The main study discussed in this article was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health (HF-ACTION Main Trial, U01HL063747). NR 6 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD APR PY 2015 VL 169 IS 4 BP 457 EP + DI 10.1016/j.ahj.2014.11.022 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE6MC UT WOS:000351949500007 PM 25819851 ER PT J AU Januzzi, JL Sharma, U Zakroysky, P Truong, QA Woodard, PK Pope, JH Hauser, T Mayrhofer, T Nagurney, JT Schoenfeld, D Peacock, WF Fleg, JL Wiviott, S Pang, PS Udelson, J Hoffmann, U AF Januzzi, James L. Sharma, Umesh Zakroysky, Pearl Truong, Quynh A. Woodard, Pamela K. Pope, J. Hector Hauser, Thomas Mayrhofer, Thomas Nagurney, J. Toby Schoenfeld, David Peacock, W. Frank Fleg, Jerome L. Wiviott, Stephen Pang, Peter S. Udelson, James Hoffmann, Udo TI Sensitive troponin assays in patients with suspected acute coronary syndrome: Results from the multicenter rule out myocardial infarction using computer assisted tomography II trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CHEST-PAIN; 3RD UNIVERSAL DEFINITION; EARLY-DIAGNOSIS; EMERGENCY-DEPARTMENT; TASK-FORCE; ANGIOGRAPHY AB Background Sensitive troponin (Tn) assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially available sensitive Tn I (sTnI) and precommercial highly sTnI (hsTnI) method to conventional Tn (cTn) assays. Methods Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, 2 and 4 hours after presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization as well as their associations with coronary artery disease in patients randomized to coronary computed tomographic angiography (CTA) was assessed. Results Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with unstable angina pectoris (UAP). Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared with cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute myocardial infarction with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CTA. Conclusions In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one-third of UAP to myocardial infarction. Very low values for hsTnI excluded underlying coronary artery disease. C1 [Januzzi, James L.; Truong, Quynh A.; Hoffmann, Udo] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Sharma, Umesh; Mayrhofer, Thomas; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zakroysky, Pearl; Schoenfeld, David] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Woodard, Pamela K.] Washington Univ, Mallinckrodt Inst Radiol, St Louis, MO USA. [Pope, J. Hector] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Hauser, Thomas] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. [Nagurney, J. Toby] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Boston, MA USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Wiviott, Stephen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Pang, Peter S.] Indiana Univ, Dept Emergency Med, Indianapolis, IN 46204 USA. [Udelson, James] Tufts Med Ctr, Dept Med, Boston, MA USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Yawkey 5984, Boston, MA 02114 USA. EM JJanuzzi@partners.org FU NHLBI NIH HHS [UO1HL092022, K23 HL098370, K23HL098370, K24 HL113128, L30 HL093806, L30HL093896, U01 HL092040, U01HL092040] NR 21 TC 3 Z9 3 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD APR PY 2015 VL 169 IS 4 BP 572 EP + DI 10.1016/j.ahj.2014.12.023 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE6MC UT WOS:000351949500021 PM 25819865 ER PT J AU Savage, WJ Buchanan, GR Yawn, BP Afenyi-Annan, AN Ballas, SK Goldsmith, JC Hassell, KL James, AH John-Sowah, J Jordan, L Lottenberg, R Murad, MH Ortiz, E Tanabe, PJ Ware, RE Lanzkron, SM AF Savage, William J. Buchanan, George R. Yawn, Barbara P. Afenyi-Annan, Araba N. Ballas, Samir K. Goldsmith, Jonathan C. Hassell, Kathryn L. James, Andra H. John-Sowah, Joylene Jordan, Lanetta Lottenberg, Richard Murad, M. Hassan Ortiz, Eduardo Tanabe, Paula J. Ware, Russell E. Lanzkron, Sophie M. TI Evidence gaps in the management of sickle cell disease: A summary of needed research SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID HYDROXYUREA; ANEMIA C1 [Savage, William J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Buchanan, George R.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Yawn, Barbara P.] Olmsted Med Ctr, Rochester, MN USA. [Afenyi-Annan, Araba N.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Ballas, Samir K.] Thomas Jefferson Univ, Cardeza Fdn, Dept Med Hematol, Philadelphia, PA 19107 USA. [Goldsmith, Jonathan C.] US FDA, Rare Dis Program, Off New Drugs, Silver Spring, MD USA. [Hassell, Kathryn L.] Univ Colorado, Dept Med, Denver, CO USA. [James, Andra H.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [John-Sowah, Joylene] NHLBI, Bethesda, MD 20892 USA. [Jordan, Lanetta] Univ Miami, Miller Sch Med, Fdn Sickle Cell Dis Res, Miami, FL 33136 USA. [Lottenberg, Richard] Univ Florida, Dept Med, Gainesville, FL USA. [Murad, M. Hassan] Mayo Clin, Coll Med, Dept Preventat Occupat & Aerosp Med, Rochester, MN USA. [Ortiz, Eduardo] Atlas Res, Washington, DC USA. [Tanabe, Paula J.] Duke Univ, Sch Nursing, Durham, NC USA. [Tanabe, Paula J.] Duke Univ, Sch Med, Durham, NC USA. [Ware, Russell E.] Cincinnati Childrens Hosp Med Ctr, Dept Hematol, Cincinnati, OH 45229 USA. [Lanzkron, Sophie M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Savage, WJ (reprint author), 75 Francis St,Amory 260, Boston, MA 02115 USA. EM wjsavage@partners.org NR 5 TC 8 Z9 8 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2015 VL 90 IS 4 BP 273 EP 275 DI 10.1002/ajh.23945 PG 3 WC Hematology SC Hematology GA CE2WE UT WOS:000351680800009 PM 25639238 ER PT J AU Yiu, G Chiu, SJ Petrou, PA Stinnett, S Sarin, N Farsiu, S Chew, EY Wong, WT Toth, CA AF Yiu, Glenn Chiu, Stephanie J. Petrou, Philip A. Stinnett, Sandra Sarin, Neeru Farsiu, Sina Chew, Emily Y. Wong, Wai T. Toth, Cynthia A. TI Relationship of Central Choroidal Thickness With Age-Related Macular Degeneration Status SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; CENTRAL SEROUS CHORIORETINOPATHY; GROWTH-FACTOR THERAPY; HEALTHY-SUBJECTS; AUTOMATIC SEGMENTATION; GEOGRAPHIC ATROPHY; BLOOD-FLOW; EYES; CHORIOCAPILLARIS; DRUSEN AB PURPOSE: To compare choroidal thickness in patients with intermediate or advanced age-related macular degeneration (AMD) and control subjects using enhanced-depth imaging optical coherence tomography (EDI-OCT). DESIGN: Retrospective cross-sectional study of 325 eyes from 164 subjects who underwent EDI-OCT for the Age-Related Eye Disease Study (AREDS) 2 Ancillary Spectral Domain OCT study. METHODS: Choroidal thickness was measured by semiautomated segmentation of EDI-OCT images from 1.5 mm nasal to 1.5 mm temporal to the fovea. Multivariate linear regression was used to evaluate the association of subfoveal choroidal thickness or average choroidal thickness across the central 3-mm segment with systemic and ocular variables. Choroidal thickness measurements were compared between eyes with no AMD (n = 154) (ie, controls), intermediate A/vfD (n = 109), and advanced AMD (n = 62). " RESULTS: Both subfoveal and average chorciidal thicknesses were associated with age (P < .001) and refractive error (P < .001), but not other variables tested. Mean average choroidal thickness was significantly reduced in advanced AMD as compared with control eyes (P =.008), with no significant difference between advanced and intermediate AMD eyes (P = .152) or between intermediate AMD and control eyes (P = .098). Choroidal thinning was also noted from 1.5 mm nasal to 1.5 mm temporal to the fovea when comparing advanced AIYID with control eyes (P < .05 at all 0.5 mm interval locations). After adjustment for age and refractive error, however, there was no significant difference in subfoveal (P = .675) or average choroidal thickness (P = .746) across all 3 groups. " CONCLUSIONS: When adjusted for age and refractive error, central choroidal thickness may not be significantly influenced by AMD status based on AREDS categorization. (C) 2015 by Elsevier Inc. All rights reserved. C1 [Yiu, Glenn; Stinnett, Sandra; Sarin, Neeru; Farsiu, Sina; Toth, Cynthia A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Chiu, Stephanie J.; Farsiu, Sina] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. [Petrou, Philip A.; Chew, Emily Y.; Wong, Wai T.] NEI, NIH, Bethesda, MD 20892 USA. [Yiu, Glenn] Univ Calif Davis, Dept Ophthalmol, Sacramento, CA 95817 USA. RP Toth, CA (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, 2351 Erwin Rd,Box 3802, Durham, NC 27710 USA. EM cynthia.toth@duke.edu RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU AREDS2 Ancillary (A2A) SDOCT Study (Clinical-Trials.gov identifier [NCT00734487]; American Health Assistance Foundation; Research to Prevent Blindness; Genentech (San Francisco, California) [IST-4400S]; Alcon Laboratories (unrestricted grant; Fort Worth, Texas); National Eye Institute (Bethesda, Maryland) [HHS-N-260-2005-00007-C]; ADB [N01-EY-5-0007]; Heed Ophthalmic Foundation; Ronald G. Michels Fellowship Foundation FX This research was supported by the AREDS2 Ancillary (A2A) SDOCT Study (Clinical-Trials.gov identifier: NCT00734487), the American Health Assistance Foundation (S.F.), and Research to Prevent Blindness (S.F.). The A2A SDOCT study is supported predominantly by Genentech (IST-4400S grant; San Francisco, California), and in part by Bioptigen (equipment; 'Morrisville, North Carolina) and Alcon Laboratories (unrestricted grant; Fort Worth, Texas). The AREDS2 Trial is sponsored by the National Eye Institute (Bethesda, Maryland; contract #HHS-N-260-2005-00007-C and ADB Contract #N01-EY-5-0007). Dr Yiu is funded in part by the Heed Ophthalmic Foundation and the Ronald G. Michels Fellowship Foundation. The sponsor or funding organizations had no role in the design or conduct of this research. NR 47 TC 17 Z9 17 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2015 VL 159 IS 4 BP 617 EP 626 DI 10.1016/j.ajo.2014.12.010 PG 10 WC Ophthalmology SC Ophthalmology GA CE4FV UT WOS:000351787400001 PM 25526948 ER PT J AU Chew, EY Clemons, TE Peto, T Sallo, FB Ingerman, A Tao, W Singerman, L Schwartz, SD Peachey, NS Bird, AC AF Chew, Emily Y. Clemons, Traci E. Peto, Tunde Sallo, Ferenc B. Ingerman, Avner Tao, Weng Singerman, Lawrence Schwartz, Steven D. Peachey, Neal S. Bird, Alan C. CA Mactel-Cntf Res Grp TI Ciliary Neurotrophic Factor for Macular Telangiectasia Type 2: Results From a Phase 1 Safety Trial SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID JUXTAFOVEOLAR RETINAL TELANGIECTASIS; CELL INTRAOCULAR IMPLANTS; INTRAVITREAL TRIAMCINOLONE; PARAFOVEAL TELANGIECTASIS; DEGENERATION; MICROPERIMETRY; CNTF; NEOVASCULARIZATION; RANIBIZUMAB; MOUSE AB PURPOSE: To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. DESIGN: An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. METHODS: The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. RESULTS: The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. CONCLUSIONS: The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. Published by Elsevier Inc. C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Peto, Tunde] Moorfields Eye Hosp, Natl Hlth Serv Fdn Trust, Biomed Res Ctr, Natl Inst Hlth Res, London, England. [Peto, Tunde] UCL Inst Ophthalmol, London, England. [Sallo, Ferenc B.] Moorfields Eye Hosp, Dept Res & Dev, London, England. [Bird, Alan C.] Moorfields Eye Hosp, Dept Inherited Eye Dis, London, England. [Sallo, Ferenc B.] UCL, Inst Ophthalmol, London, England. [Ingerman, Avner] ATIS Consultants, Scarsdale, NY USA. [Tao, Weng] Neurotech Pharmaceut, Cumberland, RI USA. [Singerman, Lawrence] Retina Associates Cleveland, Cleveland, OH USA. [Schwartz, Steven D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Peachey, Neal S.] Cleveland Clin, Dept Ophthalmol, Cleveland, OH 44106 USA. [Peachey, Neal S.] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. RP Chew, EY (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Alcon; Allergan; Genentech; Lowy Medical Research Institute; Novartis; Roche; National Eye Institute; Lowy Medical Research Institute, Sydney, Australia; NIHR BMRC at Moorfields Eye Hospital; UCL Institute of Ophthalmology FX Weng Tao was an employee of Neurotech; Lawrence Singerman receives grant support from Alcon, Allergan, Genentech, Lowy Medical Research Institute, and Novartis; Lawrence Singerman is a consultant and equity owner of Artic Dx, Inc, Ohr Pharmaceuticals, and Ophthotech, and is an advisor for Valeant; Steven Schwartz receives grant support from Alcon, Allergan, Genentech Roche, Lowy Medical Research Institute, National Eye Institute, and Novartis. The study was supported by the Lowy Medical Research Institute, Sydney, Australia. Tunde Peto is funded by the NIHR BMRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The sponsor had no role in the study design, collection, analyses and interpretation of the data, or the writing of the manuscript. NR 39 TC 10 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2015 VL 159 IS 4 BP 659 EP 666 DI 10.1016/j.ajo.2014.12.013 PG 8 WC Ophthalmology SC Ophthalmology GA CE4FV UT WOS:000351787400006 PM 25528956 ER PT J AU Rosenkrantz, AB Verma, S Turkbey, B AF Rosenkrantz, Andrew B. Verma, Sadhna Turkbey, Baris TI Prostate Cancer: Top Places Where Tumors Hide on Multiparametric MRI SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE biopsy; MRI; peripheral zone; prostate cancer; transition zone ID POSITIVE SURGICAL MARGINS; NORMAL CENTRAL ZONE; RADICAL PROSTATECTOMY; DIAGNOSTIC-ACCURACY; ANTERIOR PROSTATE; B-VALUE; ULTRASOUND FUSION; TRANSITION ZONE; 12-CORE BIOPSY; RESONANCE AB OBJECTIVE. Prostate tumors occasionally have unusual manifestations on multiparametric MR images that can present a diagnostic dilemma and result in a false-negative interpretation. This article presents examples of such "hiding places" of prostate tumors, four in the peripheral zone and four in the central gland. CONCLUSION. The provided pointers in multiparametric MRI assessment can aid the radiologist in achieving an accurate diagnosis of tumor in the eight scenarios described. C1 [Rosenkrantz, Andrew B.] NYU, Langone Med Ctr, Ctr Biomed Imaging, Dept Radiol, New York, NY 10016 USA. [Verma, Sadhna] Univ Cincinnati, Med Ctr, Dept Radiol, Cincinnati, OH 45267 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Rosenkrantz, AB (reprint author), NYU, Langone Med Ctr, Ctr Biomed Imaging, Dept Radiol, 660 First Ave,3rd Fl, New York, NY 10016 USA. EM Andrew.Rosenkrantz@nyumc.org NR 47 TC 5 Z9 5 U1 3 U2 7 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 APR PY 2015 VL 204 IS 4 BP W449 EP W456 DI 10.2214/AJR.14.13280 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CE2AN UT WOS:000351614700009 PM 25794094 ER PT J AU van der Marel, J Berkhof, J Ordi, J Torne, A Del Pino, M van Baars, R Schiffman, M Wentzensen, N Jenkins, D Quint, WGV AF van der Marel, Jacolien Berkhof, Johannes Ordi, Jaume Torne, Aureli Del Pino, Marta van Baars, Romy Schiffman, Mark Wentzensen, Nicolas Jenkins, David Quint, Wim G. V. TI Attributing Oncogenic Human Papillomavirus Genotypes to High-grade Cervical Neoplasia Which Type Causes the Lesion? SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE laser-capture microdissection; biopsy; HPV genotype; multiple HPV infections; cytology; colposcopy ID SQUAMOUS INTRAEPITHELIAL LESIONS; LINE PROBE ASSAY; SCREENING POPULATION; MULTIPLE TYPES; VIRUS TYPES; PCR ASSAY; HPV TYPES; CANCER; INFECTIONS; RISK AB Human papillomavirus (HPV) is found in most women with high-grade cervical intraepithelial neoplasia (CIN) 2/3 in cervical cytology and biopsies. Multiple high-risk HPV (hrHPV) genotypes are present in 15% to 50% of cytology samples. We have shown by laser-capture microscopy (LCM)-polymerase chain reaction (PCR) that each lesion is associated with a single hrHPV type. Attribution of hrHPV types to CIN2/3 is important to understand the oncogenic role of different types and the limitations of cytologic typing. We studied hrHPV genotypes in 257 women with histologic CIN2/3 referred on the basis of abnormal cytology. HPV typing was done on cytology and CIN2/3 biopsies. If the whole-tissue section of the biopsy was positive for multiple hrHPV types, LCM-PCR was performed. We found 181 (70%) single and 71 (28%) multiple hrHPV infections in cytology, with 5 (2%) cases HPV-positive only on whole-tissue section PCR. Of cases with multiple cytologic hrHPV infections, 47/71 (66%) showed a single type in CIN2/3 lesions. In total, in 232 of 257 (90%) women with CIN2/3, a single hrHPV type caused CIN2/3. One was nonattributable on the LCM level. The remaining 24 women had 2 or more contiguous or separated lesions, each associated with a single hrHPV infection. The probability of HPV16 being present in CIN2/3, if detected in cytology, was 0.96 (95% confidence interval = 0.90-0.98). LCM-PCR confirms that only 9% of histologic CIN2/3 is associated with multiple hrHPV types, much less than cytology would indicate, and each lesion was associated with a single hrHPV infection. C1 [van der Marel, Jacolien; van Baars, Romy; Jenkins, David; Quint, Wim G. V.] DDL Diagnost Lab, NL-2288 ER Rijswijk, Netherlands. [Berkhof, Johannes] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Berkhof, Johannes; Ordi, Jaume] CRESIB Ctr Recerca Salut Int Barcelona, Dept Pathol, Barcelona, Spain. [Torne, Aureli; Del Pino, Marta] Hosp Clin Barcelona, Inst Clin Gynecol Obstet & Neonatol, Barcelona, Spain. [Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP van der Marel, J (reprint author), DDL Diagnost Lab, Visseringlaan 25, NL-2288 ER Rijswijk, Netherlands. EM jacolien.van.der.marel@ddl.nl FU Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands; Fondo de Investigaciones Sanitarias, Barcelona, Spain [PI12/01231, PI12/01165] FX Funded by the Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands. This work was also supported in part by the grants PI12/01231 and PI12/01165 from the Fondo de Investigaciones Sanitarias, Barcelona, Spain. The sponsors had no involvement in study design, data interpretation, writing of the manuscript, and decision to submit the manuscript for publication. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 38 TC 8 Z9 8 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD APR PY 2015 VL 39 IS 4 BP 496 EP 504 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA CE2XE UT WOS:000351684200008 PM 25353286 ER PT J AU Randhawa, P Pastrana, DV Zeng, G Huang, Y Shapiro, R Sood, P Puttarajappa, C Berger, M Hariharan, S Buck, CB AF Randhawa, P. Pastrana, D. V. Zeng, G. Huang, Y. Shapiro, R. Sood, P. Puttarajappa, C. Berger, M. Hariharan, S. Buck, C. B. TI Commercially Available Immunoglobulins Contain Virus Neutralizing Antibodies Against All Major Genotypes of Polyomavirus BK SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID RENAL-TRANSPLANT RECIPIENTS; INTRAVENOUS IMMUNOGLOBULIN; NEPHROPATHY; INFECTION; REPLICATION; HEPATITIS; GLOBULIN; PROTEINS; REGISTRY; THERAPY AB Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed. C1 [Randhawa, P.; Zeng, G.; Huang, Y.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Pastrana, D. V.; Buck, C. B.] NCI, Bethesda, MD 20892 USA. [Shapiro, R.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Sood, P.; Puttarajappa, C.; Hariharan, S.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Berger, M.] CSL Behring, Immunol R&D, King Of Prussia, PA USA. RP Randhawa, P (reprint author), Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. EM randhawapa@upmc.edu OI Buck, Christopher/0000-0003-3165-8094 FU CSL Behring, Inc. FX This work was supported by CSL Behring, Inc. NR 33 TC 12 Z9 12 U1 0 U2 2 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 APR PY 2015 VL 15 IS 4 BP 1014 EP 1020 DI 10.1111/ajt.13083 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA CE2US UT WOS:000351675600021 PM 25736704 ER PT J AU Escott-Price, V Nalls, MA Morris, HR Lubbe, S Brice, A Gasser, T Heutink, P Wood, NW Hardy, J Singleton, AB Williams, NM AF Escott-Price, Valentina Nalls, Mike A. Morris, Huw R. Lubbe, Steven Brice, Alexis Gasser, Thomas Heutink, Peter Wood, Nicholas W. Hardy, John Singleton, Andrew B. Williams, Nigel M. CA Int Parkinson's Dis Genomics Conso IPDGC Consortium TI Polygenic Risk of Parkinson Disease Is Correlated with Disease Age at Onset SO ANNALS OF NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; SEGREGATION ANALYSIS; GENETIC RISK; MUTATIONS; VARIANTS; SUSCEPTIBILITY; REGION; LOCI; SNCA AB ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset. MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset. ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p=3.76 x 10(-6)). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p=0.00014). InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582-591 C1 [Escott-Price, Valentina; Williams, Nigel M.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Ctr Neuropsychiat Genet & Genom, Med Res Council,Dept Psychol Med & Neurol,Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Morris, Huw R.; Lubbe, Steven; Wood, Nicholas W.; Hardy, John] UCL, Dept Clin Neurosci, Inst Neurol, London, England. [Brice, Alexis] Dept Genet, Paris, France. [Brice, Alexis] CNRS, UMR 7225, F-75013 Paris, France. [Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Gasser, Thomas; Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Wood, Nicholas W.] UCL, Genet Inst, London, England. RP Williams, NM (reprint author), Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff CF14 4XN, S Glam, Wales. EM williamsnm@cf.ac.uk RI Hardy, John/C-2451-2009; Lubbe, Steven/L-8261-2013; Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Wood, Nicholas/C-2505-2009; OI Morris, Huw/0000-0002-5473-3774; Wood, Nicholas/0000-0002-9500-3348; Escott-Price, Valentina/0000-0003-1784-5483 FU Parkinson's UK [K0906, 8047, J-0804]; Department of Health National Institute for Health Research Biomedical Research Centre; Medical Research Council [G0700943]; German National Genome Network (German Ministry for Education and Research) [01GS08134]; German Center for Neurodegenerative Diseases; NIH Intramural Research Program of the National Institute on Aging, Department of Health and Human Services [Z01 AG000949-06, Z01 AG000950-10]; French National Agency of Research [ANR-08-MNP-012]; National Research Funding Agency [ANR-08-NEUR-004-01]; Hersenstichting Nederland; Neuroscience Campus Amsterdam; Section of Medical Genomics, Prinses Beatrix Fonds FX This work was supported by Parkinson's UK (reference number K0906). Additionally, part of the study was undertaken at University College London Hospitals/University College London using funding through a Department of Health National Institute for Health Research Biomedical Research Centre. This work was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council (grant G0700943). The German work was also supported by the German National Genome Network (NGFNplus #01GS08134, German Ministry for Education and Research). Institutional funding was received from the German Center for Neurodegenerative Diseases. This work was supported by the NIH Intramural Research Program of the National Institute on Aging, Department of Health and Human Services (project numbers Z01 AG000949-06 and Z01 AG000950-10). The French GWA scan work was supported by the French National Agency of Research (http://www.agence-nationale-recherche.fr, ANR-08-MNP-012) and by the National Research Funding Agency (ANR-08-NEUR-004-01) in the ERA-NET NEURON framework (http://www.neuron-eranet.eu). The Hersenstichting Nederland (http://www.hersenstichting.nl), Neuroscience Campus Amsterdam, and Section of Medical Genomics, Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) sponsored this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. NR 32 TC 20 Z9 20 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2015 VL 77 IS 4 BP 582 EP 591 DI 10.1002/ana.24335 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CE8OK UT WOS:000352102500005 PM 25773351 ER PT J AU Giancane, G Ter Haar, NM Wulffraat, N Vastert, SJ Barron, K Hentgen, V Kallinich, T Ozdogan, H Anton, J Brogan, P Cantarini, L Frenkel, J Galeotti, C Gattorno, M Grateau, G Hofer, M Kone-Paut, I Kuemmerle-Deschner, J Lachmann, HJ Simon, A Demirkaya, E Feldman, B Uziel, Y Ozen, S AF Giancane, Gabriella Ter Haar, Nienke M. Wulffraat, Nico Vastert, Sebastiaan J. Barron, Karyl Hentgen, Veronique Kallinich, Tilmann Ozdogan, Huri Anton, Jordi Brogan, Paul Cantarini, Luca Frenkel, Joost Galeotti, Caroline Gattorno, Marco Grateau, Gilles Hofer, Michael Kone-Paut, Isabelle Kuemmerle-Deschner, Jasmin Lachmann, Helen J. Simon, Anna Demirkaya, Erkan Feldman, Brian Uziel, Yosef Ozen, Seza TI Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID PHENOTYPE-GENOTYPE CORRELATION; MEFV-GENE; INFLAMMATORY DISORDERS; MOLECULAR DIAGNOSIS; RECURRENT FEVERS; RISK-FACTOR; MUTATIONS; CHILDREN; FMF; POPULATION AB Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype-phenotype correlation, genotype-age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe. C1 [Giancane, Gabriella; Wulffraat, Nico; Vastert, Sebastiaan J.] UMC, Dept Pediat Immunol, NL-3508 AB Utrecht, Netherlands. [Ter Haar, Nienke M.] UMC, Lab Translat Immunol, NL-3508 AB Utrecht, Netherlands. [Barron, Karyl] NIH, Bethesda, MD 20892 USA. [Hentgen, Veronique] Ctr Hosp Versailles, Reference Ctr Autoinflammatory Disorders CEREMAI, Le Chesnay, France. [Kallinich, Tilmann] Charite, D-13353 Berlin, Germany. [Ozdogan, Huri] Cerrahpasa Ic Hastaliklari Klin, Istanbul, Turkey. [Anton, Jordi] Univ Barcelona, Hosp St Joan de Deu, Barcelona, Spain. [Brogan, Paul] UCL Inst Child Hlth, Infect Inflammat & Rheumatol Sect, London, England. [Cantarini, Luca] Univ Siena, Policlin Le Scotte, I-53100 Siena, Italy. [Frenkel, Joost] UMC, Dept Pediat, NL-3508 AB Utrecht, Netherlands. [Galeotti, Caroline] Univ Paris Sud, Bicetre Hosp, Reference Ctr Autoinflammatory Disorders CEREMAI, F-94275 Le Kremlin Bicetre, France. [Gattorno, Marco] G Gaslini Inst Children, UO Pediat 2, Genoa, Italy. [Grateau, Gilles] Univ Paris 06, Hop Tenon, AP HP, Ctr Natl Reference Amyloses Origine Inflammatoire, Paris, France. [Hofer, Michael] Univ Lausanne, Dept Pediat, Pediat Rheumatol, Lausanne, Switzerland. [Hofer, Michael] Univ Geneva, Geneva, Switzerland. [Kone-Paut, Isabelle] Univ Paris Sud, Bicetre Hosp, Reference Ctr Autoinflammatory Disorders CEREMAI, Div Paediat Rheumatol, Paris, France. [Kuemmerle-Deschner, Jasmin] Univ Klinikum Tubingen, Autoinflammat Reference Ctr Tubingen, Abt Padiatr Rheumatol, Klin Kinder & Jugendmed, Tubingen, Germany. [Lachmann, Helen J.] UCL, Sch Med, Natl Amyloidosis Ctr, London W1N 8AA, England. [Simon, Anna] Radboud Univ Nijmegen, Med Ctr, Div Gen Internal Med, Dept Med, NL-6525 ED Nijmegen, Netherlands. [Demirkaya, Erkan] Gulhane Mil Med Fac, Inst Hlth Sci, R&D Ctr, Ankara, Turkey. [Feldman, Brian] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Uziel, Yosef] Tel Aviv Univ, Sackler Sch Med, Meir Med Ctr, Dept Pediat, IL-69978 Tel Aviv, Israel. [Ozen, Seza] Hacettepe Univ, Fac Med, Dept Pediat, TR-06100 Ankara, Turkey. RP Giancane, G (reprint author), UMC, Dept Pediat Immunol, NL-3508 AB Utrecht, Netherlands. EM ggiancan@umcutrecht.nl RI Simon, Anna/D-3757-2009; Anton, Jordi/A-9848-2017; OI Simon, Anna/0000-0002-6141-7921; Anton, Jordi/0000-0002-8792-4219; ter Haar, Nienke/0000-0001-6127-2438; Cantarini, Luca/0000-0002-7352-1275 FU European Agency for Health and Consumers (EAHC) [2011 1202] FX This project is supported by a grant from European Agency for Health and Consumers (EAHC), grant number 2011 1202. The initial findings of the project were presented at 2014 ACR/ARHP Annual Meeting. We thank Faye Schreiber for medical editing. NR 44 TC 18 Z9 18 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2015 VL 74 IS 4 BP 635 EP 641 DI 10.1136/annrheumdis-2014-206844 PG 7 WC Rheumatology SC Rheumatology GA CE2AV UT WOS:000351615700004 PM 25628446 ER PT J AU Chen, WZ Li, W Ying, TL Wang, YP Feng, Y Dimitrov, DS AF Chen, Weizao Li, Wei Ying, Tianlei Wang, Yanping Feng, Yang Dimitrov, Dimiter S. TI Germlining of the HIV-1 broadly neutralizing antibody domain m36 SO ANTIVIRAL RESEARCH LA English DT Article DE HIV-1; Antibody domain; Mutation; Germ lining; Neutralization ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXCEPTIONALLY POTENT; GP120; CD4; INHIBITORS; FRAMEWORK; GLYCOPROTEIN; REGIONS; COMPLEX AB Engineered antibody domains (eAds) have emerged as a novel class of HIV-1 inhibitors and are currently under preclinical testing as promising drug candidates for prevention and therapy of HIV-1 infection. Reverse mutation of antibodies to germline sequences (germlining) could not only identify less mutated variants with lower probability of immunogenicity and other improved properties but also help elucidate their mechanisms of action. In this study, we sequentially reverted the framework (FRs) and complementary determining regions (CDRs) of m36, a human antibody heavy chain variable domain-based eAd targeting the coreceptor binding site of the viral envelope glycoprotein gp120, back to germline sequences. Two types of amino acid mutations and one region in the antibody V segment were identified that are critical for HIV-1 neutralization. These include four mutations to acidic acid residues distributed in the CDR1 and CDR2, two mutations to hydrophobic residues in the FR3 and CDR3, and partial FR2 and FR3 sequences flanking the CDR2 that are derived from a different gene family. An m36 variant with all five mutations in the FRs reverted back to germline showed slightly increased neutralizing activity against two HIV-1 isolates tested. Another variant with seven of twelve mutations in the V segment reverted retained potency within threefold of that of the mature antibody. These results, together with an analysis of m36-gp120-CD4 docking structures, could have implications for the further development of m36 and elucidation of its mechanism of potent and broad HIV-1 neutralization. Published by Elsevier B.V. C1 [Chen, Weizao; Li, Wei; Ying, Tianlei; Wang, Yanping; Feng, Yang; Dimitrov, Dimiter S.] Ctr Canc Res, Natl Canc Inst, Natl Inst Hlth, Prot Interact Sect,Expt Immunol Lab, Frederick, MD 21702 USA. [Wang, Yanping] Geneva Fdn, Tacoma, WA 98402 USA. RP Chen, WZ (reprint author), 1050 Boyles St,Bldg 567,Room 180, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov FU Intramural AIDS Targeted Antiviral Program (IATAP) of the National Institutes of Health (NIH); Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research; U.S.-China Program for Biomedical Research Cooperation FX We thank Tim Fouts for providing reagents. This project was supported by the Intramural AIDS Targeted Antiviral Program (IATAP) of the National Institutes of Health (NIH), the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research, and the U.S.-China Program for Biomedical Research Cooperation. NR 20 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD APR PY 2015 VL 116 BP 62 EP 66 DI 10.1016/j.antiviral.2015.02.001 PG 5 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA CE4LU UT WOS:000351802900011 PM 25676867 ER PT J AU Zhan, YL Liu, H Wu, YS Wei, PY Chen, ZC Williamson, JS AF Zhan, Yulian Liu, Hua Wu, Yunshan Wei, Pingying Chen, Zhencheng Williamson, John S. TI Biotransformation of artemisinin by Aspergillus niger SO APPLIED MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE Biotransformation; Artemisinin; Antimalarial drugs; Aspergillus niger ID TRANSFORMATION; ANTIMALARIAL; QINGHAOSU; ANNUA AB Biotransformation of artemisinin (1) by Aspergillus niger was investigated. During 12 days at 28 A degrees C and pH 6.0, A. niger transformed artemisinin into four products. They were identified as 3 beta-hydroxy-4,12-epoxy-1-deoxyartemisinin (2), artemisinin G (3), 3,13-epoxyartemisinin (4), and 4 alpha-hydroxy-1-deoxyartemisinin (5). Products 2 and 4 are new compounds and are being reported here for the first time. The product 4 contains a 3,13-epoxy structure. This is the first report of epoxidation of artemisinin using microbial strains. The product 4 still has an intact peroxide bridge and therefore can be used as a scaffold for further structural modification using chemical and biological methods in the search for new antimalarial drugs. C1 [Zhan, Yulian; Wei, Pingying; Chen, Zhencheng] Guilin Univ Elect Technol, Sch Life & Environm Sci, Guilin 541004, Peoples R China. [Zhan, Yulian; Liu, Hua; Wu, Yunshan; Williamson, John S.] Univ Mississippi, Dept Med Chem, University, MS 38677 USA. [Williamson, John S.] NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Zhan, YL (reprint author), Univ Mississippi, Dept Med Chem, University, MS 38677 USA. EM zhanyulian@hotmail.com; williamsonjs@mail.nih.gov FU CDC [U01 CI000211]; NIH National Center for Research Resources [C06RR14503] FX This work was supported by the CDC Cooperative (agreement number U01 CI000211), and the content is solely the responsibility of the authors. This investigation was conducted in a facility constructed with support from research facilities improvement program C06RR14503 from the NIH National Center for Research Resources. NR 15 TC 0 Z9 2 U1 3 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7598 EI 1432-0614 J9 APPL MICROBIOL BIOT JI Appl. Microbiol. Biotechnol. PD APR PY 2015 VL 99 IS 8 BP 3443 EP 3446 DI 10.1007/s00253-015-6464-x PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CE3QP UT WOS:000351743600010 PM 25712678 ER PT J AU Yin, Y Li, XY Sha, XJ Xi, H Li, YF Shao, Y Mai, JT Virtue, A Lopez-Pastrana, J Meng, S Tilley, DG Monroy, MA Choi, ET Thomas, CJ Jiang, XH Wang, H Yang, XF AF Yin, Ying Li, Xinyuan Sha, Xiaojin Xi, Hang Li, Ya-Feng Shao, Ying Mai, Jietang Virtue, Anthony Lopez-Pastrana, Jahaira Meng, Shu Tilley, Douglas G. Monroy, M. Alexandra Choi, Eric T. Thomas, Craig J. Jiang, Xiaohua Wang, Hong Yang, Xiao-Feng TI Early Hyperlipidemia Promotes Endothelial Activation via a Caspase-1-Sirtuin 1 Pathway SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; caspase-1; inflammation ID SMOOTH-MUSCLE-CELLS; APOE-DEFICIENT MICE; E-KNOCKOUT MICE; VASCULAR INFLAMMATION; DECREASES ATHEROSCLEROSIS; CHOLESTEROL CRYSTALS; SIRT1; INFLAMMASOMES; EXPRESSION; RECRUITMENT AB Objective-The role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation. Approach and Results-Using biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase-1(-/-) /ApoE-/mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE(-/-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway. Conclusions-Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations. C1 [Yin, Ying; Li, Xinyuan; Sha, Xiaojin; Xi, Hang; Li, Ya-Feng; Shao, Ying; Mai, Jietang; Virtue, Anthony; Lopez-Pastrana, Jahaira; Meng, Shu; Monroy, M. Alexandra; Choi, Eric T.; Jiang, Xiaohua; Wang, Hong; Yang, Xiao-Feng] Temple Univ, Sch Med, Ctr Metab Dis Res, Cardiovasc Res,Thrombosis Res, Philadelphia, PA 19140 USA. [Tilley, Douglas G.] Temple Univ, Ctr Translat Med, Sch Med, Philadelphia, PA 19140 USA. [Yin, Ying; Li, Xinyuan; Sha, Xiaojin; Xi, Hang; Li, Ya-Feng; Shao, Ying; Mai, Jietang; Virtue, Anthony; Lopez-Pastrana, Jahaira; Meng, Shu; Tilley, Douglas G.; Jiang, Xiaohua; Wang, Hong; Yang, Xiao-Feng] Temple Univ, Dept Pharmacol, Sch Med, Philadelphia, PA 19140 USA. [Monroy, M. Alexandra; Choi, Eric T.] Temple Univ, Dept Surg, Sch Med, Philadelphia, PA 19140 USA. [Thomas, Craig J.] NIH, Chem Genom Ctr, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD USA. RP Yang, XF (reprint author), Temple Univ, Sch Med, Ctr Metab Dis Res, MERB 1059,3500 N Broad St, Philadelphia, PA 19140 USA. EM xfyang@temple.edu RI Li, Xinyuan/B-1139-2015 FU National Institutes of Health FX This work was partially supported by the National Institutes of Health Grants to X.F. Yang and H. Wang. NR 45 TC 18 Z9 18 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2015 VL 35 IS 4 BP 804 EP 816 DI 10.1161/ATVBAHA.115.305282 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CE3EQ UT WOS:000351709200013 PM 25705917 ER PT J AU McEvoy, JW Nasir, K DeFilippis, AP Lima, JAC Bluemke, DA Hundley, WG Barr, RG Budoff, MJ Szklo, M Navas-Acien, A Polak, JF Blumenthal, RS Post, WS Blaha, MJ AF McEvoy, John W. Nasir, Khurram DeFilippis, Andrew P. Lima, Joao A. C. Bluemke, David A. Hundley, W. Gregory Barr, R. Graham Budoff, Matthew J. Szklo, Moyses Navas-Acien, Ana Polak, Joseph F. Blumenthal, Roger S. Post, Wendy S. Blaha, Michael J. TI Relationship of Cigarette Smoking With Inflammation and Subclinical Vascular Disease The Multi-Ethnic Study of Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; coronary artery disease; inflammation; smoking ID CORONARY-HEART-DISEASE; INDIVIDUAL PARTICIPANT METAANALYSIS; CARDIOVASCULAR RISK-FACTORS; LEFT-VENTRICULAR MASS; C-REACTIVE PROTEIN; ARTERY CALCIFICATION; CESSATION; ASSOCIATION; INTERLEUKIN-6; MARKERS AB Objective-We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former smokers only) on 3 important domains of cardiovascular disease: inflammation, vascular dynamics and function, and subclinical atherosclerosis. Approach and Results-The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior cardiovascular disease. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and (1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, and fibrinogen); (2) vascular dynamics and function (brachial flow-mediated dilation and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and (3) subclinical atherosclerosis (coronary artery calcification, carotid intima-media thickness, and ankle-brachial index). We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or flow-mediated dilation outcomes. However, compared with never smokers, the adjusted association between current smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former smoking (eg, odds ratio for hsCRP>2 mg/L of 1.7 [95% confidence interval, 1.5-2.1] versus 1.2 [1.1-1.4], odds ratio for coronary artery calcification> 0 of 1.8 [1.5-2.1] versus 1.4 [1.2-1.6], respectively). Similar associations were seen for interleukin-6, fibrinogen, carotid intima-media thickness, and ankle-brachial index. A monotonic association was also found between higher pack-year quartiles and increasing inflammatory markers. Furthermore, current smokers with hsCRP> 2 mg/L were more likely to have increased carotid intima-media thickness, abnormal ankle-brachial index, and coronary artery calcification> 75th percentile for age, sex, and race (relative to smokers with hsCRP<2 mg/L, interaction P<0.05 for all 3 outcomes). In contrast, time since quitting in former smokers was independently associated with lower inflammation and atherosclerosis (eg, odds ratio for hsCRP> 2 mg/L of 0.91 [0.88-0.95] and odds ratio for coronary artery calcification> 0 of 0.94 [0.90-0.97] for every 5-year cessation interval). Conclusions-These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation. C1 [McEvoy, John W.; Nasir, Khurram; DeFilippis, Andrew P.; Blumenthal, Roger S.; Blaha, Michael J.] Johns Hopkins Univ, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. [Lima, Joao A. C.; Post, Wendy S.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21287 USA. [Nasir, Khurram] Baptist Hlth South Florida, Ctr Wellness & Prevent, Miami Beach, FL USA. [DeFilippis, Andrew P.] Univ Louisville, Rudd Heart & Lung Ctr, Div Cardiol, Louisville, KY 40292 USA. [Bluemke, David A.] NIH, Radiol & Imagine Sci, Bethesda, MD 20892 USA. [Hundley, W. Gregory] Wake Forest Univ, Div Cardiol, Hlth Ctr, Winston Salem, NC 27109 USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Div Gen Med, Div Pulm,Allergy & Crit Care,Dept Med, New York, NY USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Dept Epidemiol, New York, NY USA. [Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Szklo, Moyses; Navas-Acien, Ana; Post, Wendy S.; Blaha, Michael J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. RP Blaha, MJ (reprint author), Johns Hopkins Univ, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. EM mblaha1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086; McEvoy, John/0000-0001-6530-5479 FU American Heart Association Tobacco Regulation and Addiction Center (A-TRAC) [NIH 1 P50 HL120163-01]; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; Pollin Cardiovascular Prevention Fellowship; [R01-HL077612] FX This analysis was supported by funding from the American Heart Association Tobacco Regulation and Addiction Center (A-TRAC, NIH 1 P50 HL120163-01), a member of the Food and Drug Administration (FDA) Tobacco Centers of Regulatory Science for Research Relevant to the Family Smoking Prevention and Tobacco Control Act (P50). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the FDA. The MESA study which supplied the data for this analysis was supported by contracts N01-HC-95159 through N01-HC-95167 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. The cotinine measurement was supported by contract R01-HL077612. Dr McEvoy is supported by the Pollin Cardiovascular Prevention Fellowship. NR 30 TC 21 Z9 23 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2015 VL 35 IS 4 BP 1002 EP 1010 DI 10.1161/ATVBAHA.114.304960 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CE3EQ UT WOS:000351709200033 PM 25745060 ER PT J AU Huan, TX Rong, J Tanriverdi, K Meng, QY Bhattacharya, A McManus, DD Joehanes, R Assimes, TL McPherson, R Samani, NJ Erdmann, J Schunkert, H Courchesne, P Munson, PJ Johnson, AD O'Donnell, CJ Zhang, B Larson, MG Freedman, JE Levy, D Yang, X AF Huan, Tianxiao Rong, Jian Tanriverdi, Kahraman Meng, Qingying Bhattacharya, Anindya McManus, David D. Joehanes, Roby Assimes, Themistocles L. McPherson, Ruth Samani, Nilesh J. Erdmann, Jeanette Schunkert, Heribert Courchesne, Paul Munson, Peter J. Johnson, Andrew D. O'Donnell, Christopher J. Zhang, Bin Larson, Martin G. Freedman, Jane E. Levy, Daniel Yang, Xia CA Coronary ARteryDIs Genome Wide Rep TI Dissecting the Roles of MicroRNAs in Coronary Heart Disease via Integrative Genomic Analyses SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary disease; genetics; systems biology ID DAVID BIOINFORMATICS RESOURCES; LARGE GENE LISTS; B-CELLS; ARTERY-DISEASE; EXPRESSION SIGNATURES; WIDE ASSOCIATION; ATHEROSCLEROSIS; TARGETS; BIOLOGY; FAILURE AB Objective-The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. Approach and Results-At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases versus controls (80% versus 30%; P<1x10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function. Conclusions-Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs. C1 [Huan, Tianxiao; Joehanes, Roby; Courchesne, Paul; Johnson, Andrew D.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Huan, Tianxiao; Joehanes, Roby; Courchesne, Paul; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20892 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, Bethesda, MD 20892 USA. [Rong, Jian; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Tanriverdi, Kahraman; McManus, David D.; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Meng, Qingying; Bhattacharya, Anindya; Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Joehanes, Roby; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Joehanes, Roby] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [McPherson, Ruth] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [McPherson, Ruth] Univ Ottawa, Dept Biochem, Ottawa, ON, Canada. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Freedman, Jane E.] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Schunkert, Heribert; Freedman, Jane E.] DZHK German Res Ctr Cardiovasc Res Partner Site H, Munich, Germany. [Schunkert, Heribert] Tech Univ Munich, Herzzentrum Munchen, D-80290 Munich, Germany. [Zhang, Bin] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Freedman, JE (reprint author), Univ Massachusetts, Sch Med, AS7-1051,368 Plantat St, Worcester, MA 01605 USA. EM jane.freedman@umassmed.edu; Levyd@nih.gov; xyang123@ucla.edu RI Erdmann, Jeanette/P-7513-2014; Bhattacharya, Anindya/K-3740-2016; Johnson, Andrew/G-6520-2013; OI Erdmann, Jeanette/0000-0002-4486-6231; Assimes, Themistocles/0000-0003-2349-0009 FU National Institutes of Health (NIH) [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute; NIH [N01-HC-25195]; Division of Intramural Research; National Heart, Lung, and Blood Institute, and the Center for Information Technology, NIH, Bethesda, MD [KL2RR031981]; American Heart Association; Leducq Foundation FX The Framingham Heart Study was funded by National Institutes of Health (NIH) contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and NIH contract N01-HC-25195. The analytic component of this project was funded by the Division of Intramural Research and KL2RR031981 (D.D. McManus), National Heart, Lung, and Blood Institute, and the Center for Information Technology, NIH, Bethesda, MD. X. Yang was funded by the American Heart Association Scientist Development Grant and the Leducq Foundation. NR 52 TC 14 Z9 14 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2015 VL 35 IS 4 BP 1011 EP 1021 DI 10.1161/ATVBAHA.114.305176 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CE3EQ UT WOS:000351709200034 PM 25657313 ER PT J AU Andrade, D Kim, M Blanco, LP Karumanchi, SA Koo, GC Redecha, P Kirou, K Alvarez, AM Mulla, MJ Crow, MK Abrahams, VM Kaplan, MJ Salmon, JE AF Andrade, Danieli Kim, Mimi Blanco, Luz P. Karumanchi, S. Ananth Koo, Gloria C. Redecha, Patricia Kirou, Kyriakos Alvarez, Angela M. Mulla, Melissa J. Crow, Mary K. Abrahams, Vikki M. Kaplan, Mariana J. Salmon, Jane E. TI Interferon-alpha and Angiogenic Dysregulation in Pregnant Lupus Patients Who Develop Preeclampsia SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ENDOMETRIAL ENDOTHELIAL-CELLS; RETROSPECTIVE CASE-CONTROL; FETAL-GROWTH RESTRICTION; SOLUBLE ENDOGLIN; UNITED-STATES; I INTERFERON; IFN-ALPHA; ERYTHEMATOSUS; PATHOGENESIS; RECEPTORS AB Objective. To investigate whether an elevated interferon-alpha (IFN) level early in pregnancy is associated with poor pregnancy outcomes and to examine the relationship of an elevated IFN level to angiogenic imbalance. Methods. Women were enrolled in a longitudinal case-control study of pregnant patients with lupus. Serum samples obtained monthly throughout pregnancy were assayed for IFN alpha and for the antiangiogenic factor soluble Flt-1 and the proangiogenic factor placenta growth factor (PlGF). Each of 28 patients with systemic lupus erythematosus (SLE) with a poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFN alpha and/or soluble Flt-1 on human endothelial cells and endothelial cell-trophoblast interactions were assessed. Results. Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFN alpha levels before clinical symptoms. Patients without autoimmune disease who developed preeclampsia did not have increased IFN alpha levels. In SLE patients with low IFN alpha levels, marked angiogenic imbalance (higher soluble Flt-1, lower PlGF, and higher soluble Flt-1:PlGF ratios) preceded maternal manifestations of preeclampsia, whereas in SLE patients with high IFN alpha levels, preeclampsia occurred without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with soluble Flt-1 induced expression of sFLT1 messenger RNA, and IFN alpha dramatically amplified responses to soluble Flt-1. In a model of spiral artery transformation, only the combination of IFN alpha and soluble Flt-1 disrupted the ability of trophoblast cells to remodel endothelial tube structures. Conclusion. Our findings identify a new mechanism by which IFN alpha induces an antiangiogenic milieu and increases the sensitivity of endothelial cells to soluble Flt-1, and suggest that elevated IFN alpha levels may contribute to the pathogenesis of preeclampsia in some pregnant patients with SLE. C1 [Andrade, Danieli; Koo, Gloria C.; Redecha, Patricia; Kirou, Kyriakos; Crow, Mary K.; Salmon, Jane E.] Hosp Special Surg, New York, NY 10021 USA. [Andrade, Danieli; Koo, Gloria C.; Redecha, Patricia; Kirou, Kyriakos; Crow, Mary K.; Salmon, Jane E.] Weill Cornell Med Coll, New York, NY USA. [Kim, Mimi] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY USA. [Blanco, Luz P.; Kaplan, Mariana J.] NIAMS, NIH, Bethesda, MD USA. [Karumanchi, S. Ananth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02115 USA. [Alvarez, Angela M.] Univ Antioquia, Sch Med, Medellin, Colombia. [Alvarez, Angela M.; Mulla, Melissa J.; Abrahams, Vikki M.] Yale Univ, Sch Med, New Haven, CT USA. RP Salmon, JE (reprint author), Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. EM salmonj@hss.edu FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] [R01-AR-49772, R01-AR-49772-07S2]; National Council of Technological and Scientific Development of Brazil (CNPq) [200591/2008]; NIH (NIAMS Intramural Research Program); Administrative Department of Science, Technology, and Innovation, Government of Colombia (Colciencias grant) [1115-49326157]; March of Dimes; Siemens Diagnostics; Eisai; Lilly; Takeda; Bristol-Myers Squibb; GlaxoSmithKline; Regeneron; Alexion FX Dr. Andrade, Dr. Kim, Ms Redecha, and Dr. Salmon's work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grants R01-AR-49772 and R01-AR-49772-07S2). Dr. Andrade's work was also supported by the National Council of Technological and Scientific Development of Brazil (CNPq grant 200591/2008). Drs. Blanco and Kaplan's work was supported by the NIH (NIAMS Intramural Research Program). Dr. Karumanchi is a Howard Hughes Medical Institute investigator. Ms Alvarez' work was supported by the Administrative Department of Science, Technology, and Innovation, Government of Colombia (Colciencias grant 1115-49326157); Ms Alvarez is a Colciencias fellow. Dr. Abrahams' work was supported by the March of Dimes.; Dr. Karumanchi has received consulting fees from Siemens Diagnostics (less than $10,000) and owns stock or stock options in Aggamin Therapeutics, which is developing therapies for vascular disorders. Dr. Karumanchi is a coinventor on and receives royalties from patents related to angiogenic biomarkers for use in preeclampsia diagnosis and prediction; the patents are held by Beth Israel Deaconess Medical Center. Dr. Crow has received consulting fees, speaking fees, and/or honoraria from Eisai, Lilly, Takeda, Bristol-Myers Squibb, and GlaxoSmithKline (less than $10,000 each). Dr. Salmon has received consulting fees, speaking fees, and/or honoraria from Regeneron and Alexion (less than $10,000 each). NR 51 TC 9 Z9 10 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD APR PY 2015 VL 67 IS 4 BP 977 EP 987 DI 10.1002/art.39029 PG 11 WC Rheumatology SC Rheumatology GA CE5AJ UT WOS:000351841800017 PM 25603823 ER PT J AU Esber, GR Torres-Tristani, K Holland, PC AF Esber, Guillem R. Torres-Tristani, Karina Holland, Peter C. TI Amygdalo-Striatal Interaction in the Enhancement of Stimulus Salience in Associative Learning SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE amygdala central nucleus; associative learning; attention; dorsal striatum; salience ID POSTERIOR PARIETAL CORTEX; SURPRISE-INDUCED ENHANCEMENT; LESIONS DISRUPT INCREMENTS; CENTRAL NUCLEUS FUNCTION; SUBSTANTIA-NIGRA; CONDITIONED-STIMULUS; DORSOCENTRAL STRIATUM; RATS; ATTENTION; EXPRESSION AB Function of the central nucleus of the amygdala (CeA) is critical to 2 aspects of attention in associative learning: the conditioning of orienting responses (ORs) to cues paired with food, and the enhancement of cue salience by the surprising omission of expected events. Such salience enhancements have been found to depend on interactions within a circuit that includes CeA, the substantia nigra pars compacta (SNc), the substantia innominata (SI), and the posterior parietal cortex (PPC). The acquisition and expression of conditioned ORs requires interactions among CeA, SNc, and the dorsal lateral striatum (DLS), but not SI or PPC. Here, we considered whether CeA-DLS interactions are also important in surprise-induced salience enhancements in a serial prediction task. Rats received unilateral lesions of CeA and DLS, either contralaterally, which disrupted interactions between those structures, or ipsilaterally, which produced comparable damage to each structure but permitted interactions between them in 1 hemisphere. Rats with ipsilateral lesions of CeA and DLS showed the salience enhancements normally observed in this task, but rats with contralateral lesions of those structures did not. Thus, convergence of information processing by CeA and DLS is essential for surprise-induced salience enhancements, as well as for conditioned ORs. C1 [Esber, Guillem R.] NIDA, Intramural Res Program, Bethesda, MD 20892 USA. [Torres-Tristani, Karina] Univ Puerto Rico, Rio Piedras, PR 00931 USA. [Holland, Peter C.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. RP Holland, PC (reprint author), 232 Ames Hall,3400 North Charles St, Baltimore, MD 21218 USA. EM pch@jhu.edu FU NIH [MH-53667] FX We thank Weidong Hu for assistance with surgery and histology. This work was performed at Johns Hopkins University, and supported in part by NIH Grant MH-53667. NR 42 TC 4 Z9 4 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2015 VL 129 IS 2 BP 87 EP 95 DI 10.1037/bne0000041 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CE1XX UT WOS:000351607300001 PM 25730120 ER PT J AU Thompson, SM Josey, M Holmes, A Brigman, JL AF Thompson, Shannon M. Josey, Megan Holmes, Andrew Brigman, Jonathan L. TI Conditional Loss of GluN2B in Cortex and Hippocampus Impairs Attentional Set SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE executive function; prefrontal cortex; conditional knock-out; behavioral flexibility ID LONG-TERM-POTENTIATION; MEDIAL PREFRONTAL CORTEX; NMDA RECEPTORS; FRONTAL-CORTEX; BEHAVIORAL FLEXIBILITY; SYNAPTIC PLASTICITY; DOUBLE DISSOCIATION; RAT; MICE; LESIONS AB The ability to attend to appropriate stimuli, to plan actions and then alter those actions when environmental conditions change, is essential for an organism to thrive. There is increasing evidence that these executive control processes are mediated in part by N-methyl-D-aspartate receptors ( NMDAR). NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules and are differentially expressed during development. Recent findings have suggested that the GluN2B subunit may play a unique role in both the acquisition of adaptive choice and the behavioral flexibility required to shift between choices. Here we investigated the role of GluN2B containing NMDARs in the ability to learn, reverse and shift between stimulus dimensions. Mutant mice (floxed-GluN2B x CaMKII-Cre) lacking GluN2B in the dorsal CA1 of the hippocampus and throughout the cortex were tested on an attentional set-shifting task. To explore the role that alterations in motor behavior may have on these behaviors, gross and fine motor behaviors were analyzed in mutant and floxed-control mice. Results show that corticohippocampal loss of GluN2B selectively impaired an initial reversal in a stimulus specific manner and impaired the ability of mutant mice to form an attentional set. Further, GluN2B mice showed normal motor behavior in both overall movement and individual limb behaviors. Together, these results further support the role of NMDAR, and GluN2B in particular, in aspects of executive control including behavioral flexibility and attentional processes. C1 [Thompson, Shannon M.; Josey, Megan; Brigman, Jonathan L.] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. [Holmes, Andrew] NIH, Lab Behav & Genom Neurosci, Rockville, MD USA. RP Brigman, JL (reprint author), Univ New Mexico, Sch Med, Dept Neurosci, MSC08 4740,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM jbrigman@salud.unm.edu RI Brigman, Jonathan/O-4978-2016 FU National Institutes of Health [1K22AA020303-01]; National Institute on Alcohol Abuse and Alcoholism FX Research supported by National Institutes of Health Grant 1K22AA020303-01 and the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 43 TC 3 Z9 3 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2015 VL 129 IS 2 BP 105 EP 112 DI 10.1037/bne0000045 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CE1XX UT WOS:000351607300003 PM 25798630 ER PT J AU Kose, S Steinberg, JL Moeller, FG Gowin, JL Zuniga, E Kamdar, ZN Schmitz, JM Lane, SD AF Kose, Samet Steinberg, Joel L. Moeller, F. Gerard Gowin, Joshua L. Zuniga, Edward Kamdar, Zahra N. Schmitz, Joy M. Lane, Scott D. TI Neural Correlates of Impulsive Aggressive Behavior in Subjects With a History of Alcohol Dependence SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE aggression; alcohol dependence; impulsivity; fMRI ID ANTISOCIAL PERSONALITY-DISORDER; HUMAN ORBITOFRONTAL CORTEX; INTIMATE PARTNER VIOLENCE; DECISION-MAKING; RESPONSE-INHIBITION; INDUCED IMPAIRMENT; DOMESTIC VIOLENCE; DRUG-DEPENDENCE; BRAIN ACTIVITY; FMRI AB Alcohol-related aggression is a complex and problematic phenomenon with profound public health consequences. We examined neural correlates potentially moderating the relationship between human aggressive behavior and chronic alcohol use. Thirteen subjects meeting DSM-IV criteria for past alcohol-dependence in remission (AD) and 13 matched healthy controls (CONT) participated in an fMRI study adapted from a laboratory model of human aggressive behavior (Point Subtraction Aggression Paradigm, or PSAP). Blood oxygen level dependent (BOLD) activation was measured during bouts of operationally defined aggressive behavior, during postprovocation periods, and during monetary-reinforced behavior. Whole brain voxelwise random-effects analyses found group differences in brain regions relevant to chronic alcohol use and aggressive behavior (e.g., emotional and behavioral control). Behaviorally, AD subjects responded on both the aggressive response and monetary response options at significantly higher rates than CONT. Whole brain voxelwise random-effects analyses revealed significant group differences in response to provocation (monetary subtractions), with CONT subjects showing greater activation in frontal and prefrontal cortex, thalamus, and hippocampus. Collapsing data across all subjects, regression analyses of postprovocation brain activation on aggressive response rate revealed significant positive regression slopes in precentral gyrus and parietal cortex; and significant negative regression slopes in orbitofrontal cortex, prefrontal cortex, caudate, thalamus, and middle temporal gyrus. In these collapsed analyses, response to provocation and aggressive behavior were associated with activation in brain regions subserving inhibitory and emotional control, sensorimotor integration, and goal directed motor activity. C1 [Kose, Samet; Schmitz, Joy M.; Lane, Scott D.] UT Med Sch, Dept Psychiat, Houston, TX 77054 USA. [Kose, Samet; Kamdar, Zahra N.; Schmitz, Joy M.; Lane, Scott D.] CNRA, Houston, TX USA. [Steinberg, Joel L.; Moeller, F. Gerard; Zuniga, Edward] Virginia Commonwealth Univ, Sch Med, Inst Drug & Alcohol Studies, Richmond, VA 23284 USA. [Gowin, Joshua L.] NIAAA, Intramural Res Program, Bethesda, MD USA. RP Lane, SD (reprint author), UT Med Sch, Dept Psychiat & Behav Sci, Ctr Neurobehav Res Addict, 1941 East Rd, Houston, TX 77054 USA. EM scott.d.lane@uth.tmc.edu FU National Institutes of Health [R01 AA016965] FX This work was supported by National Institutes of Health Grant R01 AA016965 (SDL). The authors would like to acknowledge the technical assistance and contributions of Vips Patel, Nuvan Rathnayaka, and Tara Watts, and the guidance and legacy of Dr. Don Cherek. NR 98 TC 3 Z9 3 U1 6 U2 22 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2015 VL 129 IS 2 BP 183 EP 196 DI 10.1037/bne0000038 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CE1XX UT WOS:000351607300010 PM 25664566 ER PT J AU Degese, MS Tanos, T Naipauer, J Gingerich, T Chiappe, D Echeverria, P LaMarre, J Gutkind, JS Coso, OA AF Degese, Maria Sol Tanos, Tamara Naipauer, Julian Gingerich, Tim Chiappe, Diego Echeverria, Pablo LaMarre, Jonathan Gutkind, J. Silvio Coso, Omar A. TI An interplay between the p38 MAPK pathway and AUBPs regulates c-fos mRNA stability during mitogenic stimulation SO BIOCHEMICAL JOURNAL LA English DT Article DE stability of mRNAs; c-fos; p38 MAPKs; AUBPs ID ACTIVATED PROTEIN-KINASE; AU-RICH ELEMENTS; BINDING PROTEIN; POSTTRANSLATIONAL MODIFICATION; CELLULAR-TRANSFORMATION; COUPLED RECEPTORS; GENE-EXPRESSION; GROWTH-FACTOR; IN-VIVO; HUR AB Mitogen-activated protein kinase (MAPK) pathways constitute key regulatory elements linking extracellular stimuli to nuclear gene expression. Immediate-early responsive genes (IEGs) of the activator protein 1 (AP-1) family, such as fos, achieve peak expression levels shortly after cells are stimulated with growth factors and sharply decrease thereafter. Several AU-rich binding proteins (AUBPs), including HuR (Hu-antigen R, Elav-like protein 1, ELAVL1) and KSRP (far upstream element-binding protein 2, KHSRP) bind to a fos AU-rich element (ARE) present in the 3'-UTR (untranslated region) of fos mRNA regulating its stability by a still poorly defined mechanism. We show in the present study that, whereas HuR binds and stabilizes transcribed reporter mRNAs bearing the fos 3'-UTR, KSRP counteracts this effect. Furthermore, we found that fos mRNA stability and HuR phosphorylation status are dependent on the activity of p38 MAPK in both epithelial cells and fibroblasts upon proliferative stimulation. Analysing PPI (protein-protein interaction) networks, we performed a thorough query of interacting proteins for p38 MAPKs, HuR and other AUBPs upon growth factor stimulation. This revealed novel HuR interactors including inhibitors of protein phosphatase 2 (PP2A) activity. Over-expression of two of these interactors, pp32 and APRIL (acidic leucine-rich nuclear phosphoprotein 32 family member B, ANP32B) and pharmacological inhibition of PP2A stabilized a fos reporter mRNA. Our results indicate that p38 MAPK regulates fos mRNA decay by affecting the state of phosphorylation of HuR while controlling yet to be fully elucidated PP regulatory networks. C1 [Degese, Maria Sol; Tanos, Tamara; Naipauer, Julian; Coso, Omar A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol, LFBM DFBMC, Buenos Aires, DF, Argentina. [Degese, Maria Sol; Tanos, Tamara; Naipauer, Julian; Coso, Omar A.] IFIBYNE CONICET, Buenos Aires, DF, Argentina. [Gingerich, Tim; LaMarre, Jonathan] Univ Guelph, Ontario Vet Coll, DBMS, Guelph, ON N1G 2W1, Canada. [Chiappe, Diego] Ecole Polytech Fed Lausanne, Prote Core Facil, CH-1015 Lausanne, Switzerland. [Echeverria, Pablo] Univ Geneva, Dept Biol Cellulaire, CH-1211 Geneva 4, Switzerland. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Coso, OA (reprint author), Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol, LFBM DFBMC, C1428EHA, Buenos Aires, DF, Argentina. EM ocoso@fbmc.fcen.uba.ar OI Echeverria, Pablo/0000-0003-1367-9692 FU University of Buenos Aires [20020100100949]; Consejo Nacional de Ciencia y Tecnica [PIP 11220110100573CO]; Agencia Nacional de Promocion Cientifica y Tecnologica [1637]; Union for International Cancer [ICR-08-120, ICR-11-008]; Miami CFAR/Sylvester Cancer Center-Argentine Network for Translational Research in AIDS Malignancies - NCI/OHAM Supplements [P30AI073961] FX This work was supported by the University of Buenos Aires [grant number 20020100100949]; the Consejo Nacional de Ciencia y Tecnica [grant number PIP 11220110100573CO]; and the Agencia Nacional de Promocion Cientifica y Tecnologica [grant number PICT 2011 # 1637]; the Union for International Cancer [grant numbers ICR-08-120 and ICR-11-008]; and the Miami CFAR/Sylvester Cancer Center-Argentine Network for Translational Research in AIDS Malignancies which is supported by NCI/OHAM Supplements to Miami CFAR [grant P30AI073961]. NR 45 TC 4 Z9 4 U1 2 U2 6 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD APR 1 PY 2015 VL 467 BP 77 EP 90 DI 10.1042/BJ20141100 PN 1 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2YF UT WOS:000351687500006 PM 25588078 ER PT J AU Shulman, HM Cardona, DM Greenson, JK Hingorani, S Horn, T Huber, E Kreft, A Longerich, T Morton, T Myerson, D Prieto, VG Rosenberg, A Treister, N Washington, K Ziemer, M Pavletic, SZ Lee, SJ Flowers, MED Schultz, KR Jagasia, M Martin, PJ Vogelsang, GB Kleiner, DE AF Shulman, Howard M. Cardona, Diana M. Greenson, Joel K. Hingorani, Sangeeta Horn, Thomas Huber, Elisabeth Kreft, Andreas Longerich, Thomas Morton, Thomas Myerson, David Prieto, Victor G. Rosenberg, Avi Treister, Nathaniel Washington, Kay Ziemer, Mirjana Pavletic, Steven Z. Lee, Stephanie J. Flowers, Mary E. D. Schultz, Kirk R. Jagasia, Madan Martin, Paul J. Vogelsang, Georgia B. Kleiner, David E. TI NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. The 2014 Pathology Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Consensus; Diagnosis; Pathology; Histology ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; DONOR LYMPHOCYTE INFUSION; BRONCHIOLITIS OBLITERANS SYNDROME; FIBROSING CHOLESTATIC HEPATITIS; MOFETIL-RELATED COLITIS; MINOR SALIVARY-GLANDS; MYCOPHENOLATE-MOFETIL; NEPHROTIC SYNDROME; HISTOLOGIC FEATURES AB The 2005 National Institute of Health (NIH) Consensus Conference outlined histopathological diagnostic criteria for the major organ systems affected by both acute and chronic graft-versus-host disease (GVHD). The 2014 Consensus Conference led to this updated document with new information from histopathological studies of GVHD in the gut, liver, skin, and oral mucosa and an expanded discussion of GVHD in the lungs and kidneys. The recommendations for final histological diagnostic categories have been simplified from 4 categories to 3: no GVHD, possible GVHD, and likely GVHD, based on better reproducibility achieved by combining the previous categories of "consistent with GVHD" and "definite GVHD" into the single category of "likely GVHD." Issues remain in the histopathological characterization of GVHD, particularly with respect to the threshold of histological changes required for diagnostic certainty. Guidance is provided for the incorporation of biopsy information into prospective clinical studies of GVHD, particularly with respect to biomarker validation. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Shulman, Howard M.; Hingorani, Sangeeta; Myerson, David; Lee, Stephanie J.; Flowers, Mary E. D.; Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Cardona, Diana M.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC USA. [Greenson, Joel K.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Hingorani, Sangeeta; Morton, Thomas] Univ Washington, Dept Pediat Gastroenterol & Pathol, Seattle, WA 98195 USA. [Hingorani, Sangeeta] Seattle Childrens Hosp, Seattle, WA USA. [Horn, Thomas] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Huber, Elisabeth] Univ Regensburg, Inst Pathol, D-93053 Regensburg, Germany. [Kreft, Andreas] Univ Med Ctr Mainz, Inst Pathol, Mainz, Germany. [Longerich, Thomas] Univ Hosp RWTH Aachen, Inst Pathol, Aachen, Germany. [Myerson, David] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Prieto, Victor G.; Kleiner, David E.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Rosenberg, Avi] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Treister, Nathaniel] Dana Farber Brigham & Womens Canc Ctr, Div Oral Med & Dent, Boston, MA USA. [Washington, Kay] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN 37235 USA. [Ziemer, Mirjana] Univ Hosp Leipzig, Dept Dermatol, Leipzig, Germany. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Schultz, Kirk R.] Univ British Columbia, BC Childrens Hosp, Dept Pediat, Vancouver, BC V5Z 1M9, Canada. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [Vogelsang, Georgia B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD USA. RP Kleiner, DE (reprint author), NCI, Lab Oratory Pathol, Bldg 10,Room 2B50,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov OI Rosenberg, Avi/0000-0003-2356-950X FU National Institutes of Health's National Cancer Institute; Center for Cancer Research; Intramural Research Program and Division of Cancer Treatment and Diagnosis; Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; National Cancer Institute [CA18029, CA118953]; National Institutes of Health; American Society for Blood and Marrow Transplantation; Center for International Bone and Marrow Transplant Research; ORDR/NCATS; NCI; German-Austrian-Swiss chronic GVHD Consortium; National Marrow Donor Program; Health Resources and Services Administration; Division of Transplantation; US Department of Human Health and Services; Canadian Blood and Marrow Transplant Group; European Group for Blood and Marrow Transplantation; Pediatric Blood and Marrow Transplant Consortium; Brazilian Chronic GVHD consortium; Deutsche Jose Carreras Leukamie-Stiftung FX This project was supported by the National Institutes of Health's National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. This work was also supported in part by grants CA18029 and CA118953 from the National Cancer Institute and the National Institutes of Health. The authors want to acknowledge the following individuals and organizations that, by their participation, made this project possible: American Society for Blood and Marrow Transplantation, Center for International Bone and Marrow Transplant Research, US Chronic GVHD Consortium (supported by ORDR/NCATS and NCI), German-Austrian-Swiss chronic GVHD Consortium, National Marrow Donor Program, the Health Resources and Services Administration, Division of Transplantation, US Department of Human Health and Services, Canadian Blood and Marrow Transplant Group, European Group for Blood and Marrow Transplantation, Pediatric Blood and Marrow Transplant Consortium, and the representatives of the Brazilian Chronic GVHD consortium (Drs. Maria Claudia Moreira, Marcia de Matos Silva and Vaneuza Funke) and Deutsche Jose Carreras Leukamie-Stiftung. The organizers are indebted to patients and patient and research advocacy groups, who made this process much more meaningful by their engagement. Acknowledgement goes to the Meredith Cowden GVHD foundation for facilitating the initial planning meeting in Cleveland in November of 2013 in conjunction with the National GVHD Symposium. The project group also recognizes the contributions of numerous colleagues in the field of blood and marrow transplantation in the United States and internationally, medical specialists and consultants, the pharmaceutical industry, and the National Institutes of Health and US Food and Drug Administration professional staff for their intellectual input, dedication, and enthusiasm on the road to completion of these documents. The opinions expressed are those of the authors and do not represent the position of the National Cancer Institute, the National Heart, Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the Food and Drug Administration, or the United States Government. NR 148 TC 19 Z9 20 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2015 VL 21 IS 4 BP 589 EP 603 DI 10.1016/j.bbmt.2014.12.031 PG 15 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CE4GY UT WOS:000351790300004 PM 25639770 ER PT J AU Arora, M Hemmer, MT Ahn, KW Klein, JP Cutler, CS Urbano-Ispizua, A Courie, DR Alousi, AM Gale, RP Inamoto, Y Weisdorf, DJ Li, P Antin, JH Bolwell, BJ Boyiadzis, M Cahn, JY Cairo, MS Isola, LM Jacobsohn, DA Jagasia, M Klumpp, TR Petersdorf, EW Santarone, S Schouten, HC Wingard, JR Spellman, SR Pavletic, SZ Lee, SJ Horowitz, MM Flowers, MED AF Arora, Mukta Hemmer, Michael T. Ahn, Kwang Woo Klein, John P. Cutler, Corey S. Urbano-Ispizua, Alvaro Courie, Daniel R. Alousi, Amin M. Gale, Robert Peter Inamoto, Yoshihiro Weisdorf, Daniel J. Li, Peigang Antin, Joseph H. Bolwell, Brian J. Boyiadzis, Michael Cahn, Jean-Yves Cairo, Mitchell S. Isola, Luis M. Jacobsohn, David A. Jagasia, Madan Klumpp, Thomas R. Petersdorf, Effie W. Santarone, Stella Schouten, Harry C. Wingard, John R. Spellman, Stephen R. Pavletic, Steven Z. Lee, Stephanie J. Horowitz, Mary M. Flowers, Mary E. D. TI Center for International Blood and Marrow Transplant Research Chronic Graft-versus-Host Disease Risk Score Predicts Mortality in an Independent Validation Cohort SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease (CGVHD); Risk score; Nonrelapse mortality ID CHRONIC GVHD; IMMUNOSUPPRESSIVE TREATMENT; CELL TRANSPLANTATION; CONSENSUS CRITERIA; SURVIVAL; OUTCOMES; CLASSIFICATION; PREDNISONE; CONSORTIUM; DURATION AB We previously reported a risk score that predicted mortality in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (HCT) between 1995 and 2004 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We sought to validate this risk score in an independent CIBMTR cohort of 1128 patients with CGVHD who underwent transplantation between 2005 and 2007 using the same inclusion criteria and risk score calculations. According to the sum of the overall risk score (range, 1 to 12), patients were assigned to 4 risk groups (RGs): RG1 (0 to 2), RG2 (3 to 6), RG3 (7 to 8), and RG4 (9 to 10). RG3 and RG4 were combined, as RG4 accounted for only 1% of the total cohort. Cumulative incidences of nonrelapse mortality (NRM) and probability of overall survival were significantly different between each RG (all P < .01). NRM and overall survival at 5 years after CGVHD for each RG were 17% and 72% in RG1, 26% and 53% in RG2, and 44% and 25% in RG3, respectively (all P < .01). Our study validates the prognostic value of the CIBMTR CGVHD RGs for overall survival and NRM in a contemporary transplantation population. The CIBMTR CGVHD RGs can be used to predict major outcomes, tailor treatment planning, and enroll patients in clinical trials. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Div Hematol Oncol & Transplantat, Dept Med, Minneapolis, MN 55455 USA. [Hemmer, Michael T.; Ahn, Kwang Woo; Klein, John P.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplantat Res, Dept Med, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo; Klein, John P.] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Urbano-Ispizua, Alvaro] Univ Barcelona, Dept Hematol, Hosp Clin, IDIBAPS, Barcelona, Spain. [Urbano-Ispizua, Alvaro] Inst Res Josep Carreras, Barcelona, Spain. [Courie, Daniel R.] Univ Michigan, Dept Internal Med, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Alousi, Amin M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplant & Cellular Therapy, Houston, TX 77030 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Hematol Res Ctr, Div Expt Med, Dept Med, London, England. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Bolwell, Brian J.] Cleveland Clin, Leukemia Program, Hematol Oncol & Blood Disorders, Taussig Canc Inst, Cleveland, OH 44106 USA. [Boyiadzis, Michael] Univ Pittsburgh, Dept Med, Ctr Canc, Med Ctr, Pittsburgh, PA USA. [Cahn, Jean-Yves] Univ Hosp, Dept Hematol, Grenoble, France. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat Hematol Oncol, Valhalla, NY 10595 USA. [Isola, Luis M.] Mt Sinai Med Ctr, Div Blood & Marrow Transplantat, New York, NY 10029 USA. [Jacobsohn, David A.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Jagasia, Madan] Vanderbilt Univ, Div Hematol Oncol, Med Ctr, Nashville, TN 37235 USA. [Klumpp, Thomas R.] Temple Univ, Sch Med, Dept Med, Bone Marrow Transplant Program, Philadelphia, PA 19122 USA. [Petersdorf, Effie W.; Lee, Stephanie J.; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Santarone, Stella] Osped Civile, Dept Hematol, BMT Ctr, Pescara, Italy. [Schouten, Harry C.] Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands. [Wingard, John R.] Shands Canc Ctr, Div Hematol & Oncol, Dept Med, Gainesville, FL USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Spellman, Stephen R.] Ctr Int Blood & Marrow Transplantat Res, Natl Marrow Donor Program, Minneapolis, MN USA. [Pavletic, Steven Z.] NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Flowers, MED (reprint author), Fred Hutchinson Canc Res Ctr, D5-290,POB 19024, Seattle, WA 98109 USA. EM mflowers@fhcrc.org FU National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah; Wellpoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. NR 30 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2015 VL 21 IS 4 BP 640 EP 645 DI 10.1016/j.bbmt.2014.10.022 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CE4GY UT WOS:000351790300010 PM 25528390 ER PT J AU Salami, SS Ben-Levi, E Yaskiv, O Ryniker, L Turkbey, B Kavoussi, LR Villani, R Rastinehad, AR AF Salami, Simpa S. Ben-Levi, Eran Yaskiv, Oksana Ryniker, Laura Turkbey, Baris Kavoussi, Louis R. Villani, Robert Rastinehad, Ardeshir R. TI In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12-core biopsy still necessary in addition to a targeted biopsy? SO BJU INTERNATIONAL LA English DT Article DE prostate imaging; prostate fusion biopsy; prostate cancer screening; negative prostate biopsy; false-negative prostate biopsy ID CANCER-DETECTION; REPEAT BIOPSY; URINE ASSAY; MEN; PCA3; TRIAL; RISK; COMPLICATIONS; DUTASTERIDE; PREDICTORS AB Objectives To evaluate the performance of multiparametric magnetic resonance imaging (mpMRI) in predicting prostate cancer on repeat biopsy; and to compare the cancer detection rates (CDRs) of MRI/transrectal ultrasonography (TRUS) fusion-guided biopsy with standard 12-core biopsy in men with at least one previous negative biopsy. Patients and Methods We prospectively enrolled men with elevated or rising PSA levels and/or abnormal digital rectal examination into our MRI/TRUS fusion-guided prostate biopsy trial. Participants underwent a 3 T mpMRI with an endorectal coil. Three radiologists graded all suspicious lesions on a 5-point Likert scale. MRI/TRUS fusion-guided biopsies of suspicious prostate lesions and standard TRUS-guided 12-core biopsies were performed. Analysis of 140 eligible men with at least one previous negative biopsy was performed. We calculated CDRs and estimated area under the receiver operating characteristic curves (AUCs) of mpMRI in predicting any cancer and clinically significant prostate cancer. Results The overall CDR was 65.0% (91/140). Higher level of suspicion on mpMRI was significantly associated with prostate cancer detection (P < 0.001) with an AUC of 0.744 compared with 0.653 and 0.680 for PSA level and PSA density, respectively. The CDRs of MRI/TRUS fusion-guided and standard 12-core biopsy were 52.1% (73/140) and 48.6% (68/140), respectively (P = 0.435). However, fusion biopsy was more likely to detect clinically significant prostate cancer when compared with the 12-core biopsy (47.9% vs 30.7%; P < 0.001). Of the cancers missed by 12-core biopsy, 20.9% (19/91) were clinically significant. Most cancers missed by 12-core biopsy (69.6%) were located in the anterior fibromuscular stroma and transition zone. Using a fusion-biopsy-only approach in men with an MRI suspicion score of >= 4 would have missed only 3.5% of clinically significant prostate cancers. Conclusions Using mpMRI and subsequent MRI/TRUS fusion-guided biopsy platform may improve detection of clinically significant prostate cancer in men with previous negative biopsies. Addition of a 12-core biopsy may be needed to avoid missing some clinically significant prostate cancers. C1 [Salami, Simpa S.; Ryniker, Laura; Kavoussi, Louis R.; Rastinehad, Ardeshir R.] Hofstra North Shore LIJ Sch Med, Arthur Smith Inst Urol, New Hyde Pk, NY 11040 USA. [Ben-Levi, Eran; Villani, Robert; Rastinehad, Ardeshir R.] Hofstra North Shore LIJ Sch Med, Dept Diagnost & Intervent Radiol, New Hyde Pk, NY 11040 USA. [Yaskiv, Oksana] Hofstra North Shore LIJ Sch Med, Dept Pathol, New Hyde Pk, NY 11040 USA. [Turkbey, Baris] Natl Inst Hlth, Mol Imaging Program, Bethesda, MD USA. RP Rastinehad, AR (reprint author), Hofstra North Shore LIJ Sch Med, Arthur Smith Inst Urol, 450 Lakeville Rd,Suite M-41, New Hyde Pk, NY 11040 USA. EM arastine@nshs.edu NR 32 TC 41 Z9 41 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD APR PY 2015 VL 115 IS 4 BP 562 EP 570 DI 10.1111/bju.12938 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CE6LZ UT WOS:000351949200014 PM 25252133 ER PT J AU Nilubol, N Kebebew, E AF Nilubol, Naris Kebebew, Electron TI Should Small Papillary Thyroid Cancer Be Observed? A Population-Based Study SO CANCER LA English DT Article DE thyroid cancer; mortality; Surveillance; Epidemiology; and End Results Program; prognostic factor; cancer-specific survival ID LYMPH-NODE METASTASES; RETROSPECTIVE ANALYSIS; UNITED-STATES; 2 CM; MICROCARCINOMA; CARCINOMA; STATISTICS; AGE AB BACKGROUNDSome centers have advocated selecting patients with small papillary thyroid cancer (PTC) to undergo active surveillance without surgical treatment. The objectives of the current study were to analyze thyroid cancer (TC)-related mortality in a population-based cohort and to determine the impact of small PTCs (defined as tumors 2 cm in greatest dimension) on TC-related mortality. METHODSData on patients with TC of follicular cell origin from the National Cancer Institute's Surveillance, Epidemiology, and End Results 17 Registries database (1988-2007) were used to analyze the characteristics of PTCs 2 cm in patients who died from TC-related causes. The effects of clinical features on disease-specific survival were analyzed. RESULTSOver the 20-year study period, the rate of TC-related mortality was 2.8% (n=1753 of 61,523 patients). Of the patients who died from TC-related causes, 38% had PTC, 10% had follicular TC, and 31.3% had anaplastic TC. PTCs 2 cm accounted for 12.3% of TC-related mortalities. Compared with patients who did not experience TC-related mortality from PTCs 2 cm, there were significantly higher rates of men (30% vs 17%; P<.01), patients aged 45 years (92% vs 52%; P<.01), tumors measuring >1 cm (59% vs 46%; P<.01), extrathyroid extension (41% vs 11%; P<.01), lymph node metastases (77% vs 28%; P<.01), and distant metastases (31% vs 1%; P<.01) among the patients who died from PTCs 2 cm. Independent risk factors for death from PTCs 2 cm included age 45 years, lymph node and distant metastases, extrathyroid extension, and undergoing less than thyroid lobectomy. CONCLUSIONSBecause 12.3% of patients who experienced TC-related deaths had PTCs 2 cm despite undergoing thyroidectomy, the current results indicate that nonoperative management for patients who have PTCs 2 cm should be used with caution. Patients aged 45 years with PTCs 2 cm should undergo thyroidectomy. Cancer 2015;121:1017-1024. (c) 2014 American Cancer Society. Nonoperative management should be used with caution for patients who have papillary thyroid cancers that measure 2 cm in greatest dimension. Patients aged 45 years with papillary thyroid cancers 2 cm should undergo thyroidectomy. C1 [Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, Clin Res Ctr, 10 Ctr Dr,Room 3-5840, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The research activities described in this article were supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 27 TC 11 Z9 14 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2015 VL 121 IS 7 BP 1017 EP 1024 DI 10.1002/cncr.29123 PG 8 WC Oncology SC Oncology GA CE2AW UT WOS:000351615800009 PM 25425528 ER PT J AU Hobbs, GS Landrum, MB Arora, NK Ganz, PA van Ryn, M Weeks, JC Mack, JW Keating, NL AF Hobbs, Gabriela S. Landrum, Mary Beth Arora, Neeraj K. Ganz, Patricia A. van Ryn, Michelle Weeks, Jane C. Mack, Jennifer W. Keating, Nancy L. TI The Role of Families in Decisions Regarding Cancer Treatments SO CANCER LA English DT Article DE cohort study; colorectal neoplasms; lung neoplasms; decision-making; shared; professional-family relations ID CARE OUTCOMES RESEARCH; BREAST-CANCER; SOCIAL SUPPORT; OF-LIFE; QUALITY; PATIENT; PARTICIPATION; COMMUNICATION; COMPANIONS; CAREGIVERS AB BACKGROUNDShared decision-making is an important component of patient-centered care and is associated with improved outcomes. To the authors' knowledge, little is known concerning the extent and predictors of the involvement of a patient's family in decisions regarding cancer treatments. METHODSThe Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium is a large, multiregional, prospective cohort study of the cancer care and outcomes of patients with lung and colorectal cancer. Participants reported the roles of their families in decision-making regarding treatment. Multinomial logistic regression was used to assess patient factors associated with family roles in decisions. RESULTSAmong 5284 patients, 80 (1.5%) reported family-controlled decisions, with the highest adjusted rates (12.8%) noted among non-English-speaking Asians. Among the 5204 remaining patients, 49.4% reported equally sharing decisions with family, 22.1% reported some family input, and 28.5% reported little family input. In adjusted analyses, patients who were married, female, older, and insured more often reported equally shared decisions with family (all P <.001). Adjusted family involvement varied by race/ethnicity and language, with Chinese-speaking Asian (59.8%) and Spanish-speaking Hispanic (54.8%) patients equally sharing decisions with family more often than white individuals (47.6%). Veterans Affairs patients were least likely to report sharing decisions with family, even after adjustment for marital status and social support (P <.001). CONCLUSIONSThe majority of patients with newly diagnosed lung or colorectal cancer involve family members in treatment decisions. Non-English-speaking Asians and Hispanics rely significantly on family. Further studies are needed to determine the impact of family involvement in treatment decisions on outcomes; until then, physicians should consider eliciting patients' preferences for family involvement. Cancer 2015;121:1079-1087. (c) 2015 American Cancer Society. In this large study of patients with newly diagnosed lung or colorectal cancer, the majority of patients reported involving family members in treatment decisions. Non-English-speaking Asian and Hispanic patients were particularly likely to rely on family for decision-making. C1 [Hobbs, Gabriela S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med Oncol, Boston, MA USA. [Landrum, Mary Beth; Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [van Ryn, Michelle] Mayo Clin, Hlth Serv Res, Rochester, MN USA. [Weeks, Jane C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Populat Sci,Dept Med Oncol, Boston, MA 02115 USA. [Mack, Jennifer W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu OI Hobbs, Gabriela/0000-0002-0199-9333 FU National Cancer Institute (NCI) [U01CA093344]; NCI [U01CA093332]; Harvard Medical School/Northern California Cancer Center [U01CA093324]; RAND/University of California at Los Angeles [U01CA093348]; University of Alabama at Birmingham [U01CA093329]; University of Iowa [U01 CA093339]; University of North Carolina [U01CA093326]; Department of Veterans Affairs [CRS02-164] FX This work of the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01CA093344) and the NCI-supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network [U01CA093332], Harvard Medical School/Northern California Cancer Center [U01CA093324], RAND/University of California at Los Angeles [U01CA093348], University of Alabama at Birmingham [U01CA093329], University of Iowa [U01 CA093339], and University of North Carolina [U01CA093326]) and by a Department of Veterans Affairs grant to the Durham VA Medical Center (CRS02-164). NR 33 TC 11 Z9 11 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2015 VL 121 IS 7 BP 1079 EP 1087 DI 10.1002/cncr.29064 PG 9 WC Oncology SC Oncology GA CE2AW UT WOS:000351615800017 PM 25708952 ER PT J AU Lewis, DR Travis, WD Devesa, SS AF Lewis, Denise Riedel Travis, William D. Devesa, Susan S. TI Reply to US Lung Cancer Trends by Histologic Type SO CANCER LA English DT Letter C1 [Lewis, Denise Riedel] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Devesa, Susan S.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lewis, DR (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2015 VL 121 IS 7 BP 1152 EP 1153 DI 10.1002/cncr.29179 PG 2 WC Oncology SC Oncology GA CE2AW UT WOS:000351615800030 PM 25470011 ER PT J AU Phillips, SM Padgett, LS Leisenring, WM Stratton, KK Bishop, K Krull, KR Alfano, CM Gibson, TM de Moor, JS Hartigan, DB Armstrong, GT Robison, LL Rowland, JH Oeffinger, KC Mariotto, AB AF Phillips, Siobhan M. Padgett, Lynne S. Leisenring, Wendy M. Stratton, Kayla K. Bishop, Ken Krull, Kevin R. Alfano, Catherine M. Gibson, Todd M. de Moor, Janet S. Hartigan, Danielle Blanch Armstrong, Gregory T. Robison, Leslie L. Rowland, Julia H. Oeffinger, Kevin C. Mariotto, Angela B. TI Survivors of Childhood Cancer in the United States: Prevalence and Burden of Morbidity SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LONG-TERM SURVIVORS; HEALTH SURVEY SF-36; YOUNG-ADULT CANCER; PEDIATRIC CANCER; FOLLOW-UP; ADOLESCENT; COHORT; RISK; HOSPITALIZATION; INTERVENTION AB Background: No studies have estimated the population-level burden of morbidity in individuals diagnosed with cancer as children (ages 0-19 years). We updated prevalence estimates of childhood cancer survivors as of 2011 and burden of morbidity in this population reflected by chronic conditions, neurocognitive dysfunction, compromised health-related quality of life, and health status (general health, mental health, functional impairment, functional limitations, pain, and fear/anxiety). Methods: Surveillance, Epidemiology, and End Results (SEER) Program data from 1975 to 2011 were used to update the prevalence of survivors of childhood cancers in the United States. Childhood Cancer Survivor Study data were used to obtain estimates of morbidity burden indicators, which were then extrapolated to SEER data to obtain population-level estimates. Results: There were an estimated 388,501 survivors of childhood cancer in the United States as of January 1, 2011, of whom 83.5% are >= 5 years after diagnosis. The prevalence of any chronic condition among >5-year survivors ranged from 66% (ages 5-19) to 88% (ages 40-49). Estimates for specific morbidities ranged from 12% (pain) to 35% (neurocognitive dysfunction). Generally, morbidities increased by age. However, mental health and anxiety remained fairly stable, and neurocognitive dysfunction exhibited initial decline and then remained stable by time since diagnosis. Conclusions: The estimated prevalence of survivors of childhood cancer is increasing, as is the estimated prevalence of morbidity in those >= 5 years after diagnosis. Impact: Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.(C) 2015 AACR. C1 [Phillips, Siobhan M.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Padgett, Lynne S.; Bishop, Ken; Alfano, Catherine M.; de Moor, Janet S.; Rowland, Julia H.; Mariotto, Angela B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Leisenring, Wendy M.; Stratton, Kayla K.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Leisenring, Wendy M.; Stratton, Kayla K.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Krull, Kevin R.; Gibson, Todd M.; Armstrong, Gregory T.; Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Hartigan, Danielle Blanch] Bentley Univ, Waltham, MA USA. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. RP Phillips, SM (reprint author), Northwestern Univ, 680 N Lakeshore Dr,Suite 1400, Chicago, IL 60611 USA. EM smphillips@northwestern.edu FU NCI [U24-CA-55727] FX The CCSS is supported by a grant (U24-CA-55727; to G.T. Armstrong, Principal Investigator) from the NCI. NR 43 TC 33 Z9 33 U1 1 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 APR PY 2015 VL 24 IS 4 BP 653 EP 663 DI 10.1158/1055-9965.EPI-14-1418 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NV UT WOS:000351955900002 PM 25834148 ER PT J AU Kuhs, KAL Anantharaman, D Waterboer, T Johansson, M Brennan, P Michel, A Willhauck-Fleckenstein, M Purdue, MP Holcatova, I Ahrens, W Lagiou, P Polesel, J Simonato, L Merletti, F Healy, CM Kjaerheim, K Conway, DI Macfarlane, TV Thomson, P Castellsague, X Znaor, A Black, A Huang, WY Krogh, V Trichopoulou, A Bueno-De-Mesquita, HB Clavel-Chapelon, F Weiderpass, E Ekstrom, J Riboli, E Tjonneland, A Sanchez, MJ Travis, RC Hildesheim, A Pawlita, M Kreimer, AR AF Kuhs, Krystle A. Lang Anantharaman, Devasena Waterboer, Tim Johansson, Mattias Brennan, Paul Michel, Angelika Willhauck-Fleckenstein, Martina Purdue, Mark P. Holcatova, Ivana Ahrens, Wolfgang Lagiou, Pagona Polesel, Jerry Simonato, Lorenzo Merletti, Franco Healy, Claire M. Kjaerheim, Kristina Conway, David I. Macfarlane, Tatiana V. Thomson, Peter Castellsague, Xavier Znaor, Ariana Black, Amanda Huang, Wen-Yi Krogh, Vittorio Trichopoulou, Antonia Bueno-de-Mesquita, H. B. Clavel-Chapelon, Francoise Weiderpass, Elisabete Ekstroem, Johanna Riboli, Elio Tjonneland, Anne Sanchez, Maria-Jose Travis, Ruth C. Hildesheim, Allan Pawlita, Michael Kreimer, Aimee R. TI Human Papillomavirus 16 E6 Antibodies in Individuals without Diagnosed Cancer: A Pooled Analysis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; INVASIVE CERVICAL-CANCER; NECK-CANCER; OROPHARYNGEAL CANCERS; TONSILLAR CARCINOMA; INCIDENCE RATES; DATA-COLLECTION; UNITED-STATES; ORAL-CANCER; HEAD AB Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) >= 484 and <1,000] or (ii) high seroreactivity (MFI >= 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated. Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity againstHPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observedwithmoderateHPV16 E6 seroreactivity. Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. Impact: Some HPV16 E6 seropositive individuals without diagnosedHPV- drivencancer, especiallythosewithseropositivityagainst other HPV16 proteins, may harbor a biologically relevant HPV16 infection. (C) 2015 AACR. C1 [Kuhs, Krystle A. Lang; Purdue, Mark P.; Black, Amanda; Huang, Wen-Yi; Hildesheim, Allan; Kreimer, Aimee R.] NCI, NIH, Bethesda, MD 20892 USA. [Anantharaman, Devasena; Johansson, Mattias; Brennan, Paul] IARC, Lyon, France. [Waterboer, Tim; Michel, Angelika; Willhauck-Fleckenstein, Martina; Pawlita, Michael] German Canc Res Ctr, Heidelberg, Germany. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. [Holcatova, Ivana] Charles Univ Prague, Fac Med 1, Prague, Czech Republic. [Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Lagiou, Pagona; Trichopoulou, Antonia] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Polesel, Jerry] CRO Aviano Natl Canc Inst, Aviano, Italy. [Simonato, Lorenzo] Univ Padua, Dept Mol Med, Lab Publ Hlth & Populat Studies, Padua, Italy. [Merletti, Franco] Univ Turin, Dept Med Sci, Turin, Italy. [Healy, Claire M.] Trinity Coll Sch Dent Sci, Dublin, Ireland. [Kjaerheim, Kristina; Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Conway, David I.] Univ Glasgow, Glasgow, Lanark, Scotland. [Macfarlane, Tatiana V.] Univ Aberdeen, Aberdeen, Scotland. [Thomson, Peter] Univ Newcastle, Newcastle, NSW 2300, Australia. [Castellsague, Xavier] Hosp Llobregat, CIBERESP, IDIBELL, ICO,Unit Infect & Canc, Catalonia, Spain. [Znaor, Ariana] Croatian Natl Inst Publ Hlth, Zagreb, Croatia. [Krogh, Vittorio] Ist Nazl Tumori, Fdn IRCCS, I-20133 Milan, Italy. [Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Trichopoulou, Antonia] Acad Athens, Athens, Greece. [Bueno-de-Mesquita, H. B.] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B.] Univ Med Ctr, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Bueno-de-Mesquita, H. B.] Univ Malaya, Kuala Lumpur, Malaysia. [Clavel-Chapelon, Francoise] Ctr Res Epidemiol & Populat Hlth CESP, Villejuif, France. [Clavel-Chapelon, Francoise] Univ Paris Sud, Villejuif, France. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, Villejuif, France. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Ekstroem, Johanna] Lund Univ, Dept Clin Sci, Lund, Sweden. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, London, England. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Sanchez, Maria-Jose] Univ Granada, Hosp Univ Granada, Inst Invest Biosanit Ibs GRANADA, Escuela Andaluza Salud Publ, Granada, Spain. [Sanchez, Maria-Jose] CIBERESP, Madrid, Spain. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. RP Kuhs, KAL (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, 9609 Med Ctr Dr,RM 6-E210, Bethesda, MD 20892 USA. EM Krystle.Kuhs@nih.gov RI SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015; Thomson, Peter/L-7719-2016; Castellsague Pique, Xavier/N-5795-2014; Purdue, Mark/C-9228-2016; Krogh, Vittorio/K-2628-2016; Weiderpass, Elisabete/M-4029-2016; Waterboer, Tim/G-1252-2010; OI SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Hildesheim, Allan/0000-0003-0257-2363; Thomson, Peter/0000-0002-2007-7975; Macfarlane, Tatiana/0000-0002-9392-0812; Castellsague Pique, Xavier/0000-0002-0802-3595; Purdue, Mark/0000-0003-1177-3108; Krogh, Vittorio/0000-0003-0122-8624; Weiderpass, Elisabete/0000-0003-2237-0128; Kjaerheim, Kristina/0000-0003-0691-3735; Healy, Claire M/0000-0001-7940-4611; Pawlita, Michael/0000-0002-4720-8306; Ahrens, Wolfgang/0000-0003-3777-570X FU Intramural Research Program of the National Cancer Institute; Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health; Spanish Regional Government of Andalucia; Spanish Regional Government of Asturias; Spanish Regional Government of Basque Country; Spanish Regional Government of Murcia; Spanish Regional Government of Navarra; Catalan Institute of Oncology, Spain; ISCIII of the Spanish Ministry of Health (RETICC) [DR06/0020]; Cancer Research UK; Medical Research Council, United Kingdom; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC-Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare, and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; General Councils of France; European Commission's 5th Framework Program [QLK1-2001-00182]; Health General Directorate of the French Social Affairs and Health Ministry; European Commission's 7th Framework Program [FP7-HEALTH-2011-282562]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX This work was supported by the Intramural Research Program of the National Cancer Institute (to A.R. Kreimer).; The EPIC study has been supported by the Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra; Catalan Institute of Oncology, Spain; the ISCIII of the Spanish Ministry of Health (RETICC DR06/0020); Cancer Research UK; Medical Research Council, United Kingdom; Greek Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Associazione Italiana per la Ricerca sul Cancro-AIRC-Milan; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare, and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; NordForsk (Centre of excellence programme HELGA), Norway; French League against Cancer (LNCC), France; National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; and General Councils of France (to P. Brennan).; The ARCAGE study was supported by the grant from European Commission's 5th Framework Program (contract QLK1-2001-00182). This project was partly funded by the Health General Directorate of the French Social Affairs and Health Ministry. The serology testing was supported in part by a grant from the European Commission's 7th Framework Program (contract FP7-HEALTH-2011-282562; to P. Brennan).; PLCO was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. NR 35 TC 8 Z9 8 U1 1 U2 8 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 APR PY 2015 VL 24 IS 4 BP 683 EP 689 DI 10.1158/1055-9965.EPI-14-1217 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CE6NV UT WOS:000351955900006 ER PT J AU Alamino, VA Mascanfroni, ID Montesinos, MM Gigena, N Donadio, AC Blidner, AG Milotich, SI Cheng, SY Masini-Repiso, AM Rabinovich, GA Pellizas, CG AF Alamino, Vanina A. Mascanfroni, Ivan D. Montesinos, Maria M. Gigena, Nicolas Donadio, Ana C. Blidner, Ada G. Milotich, Sonia I. Cheng, Sheue-yann Masini-Repiso, Ana M. Rabinovich, Gabriel A. Pellizas, Claudia G. TI Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor beta SO CANCER RESEARCH LA English DT Article ID TRANSGENIC MICE; PROTECTIVE IMMUNITY; CROSS-PRESENTATION; EXPRESSION; CANCER; IMMUNOTHERAPY; APOPTOSIS; MELANOMA; RESISTANCE; MATURATION AB Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) beta mutant mouse (TR beta PV) to establish the relevance of the T3-TR beta system in vivo. In this model, TR beta signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TR beta increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFN gamma-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TR beta signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy. (C)2015 AACR. C1 [Alamino, Vanina A.; Mascanfroni, Ivan D.; Montesinos, Maria M.; Gigena, Nicolas; Donadio, Ana C.; Masini-Repiso, Ana M.; Pellizas, Claudia G.] Univ Nacl Cordoba, Fac Cicncias Quim, Dpto Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol CIBICI CONICET, RA-5000 Cordoba, Argentina. [Blidner, Ada G.; Rabinovich, Gabriel A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Lab Inmunopatol, Inst Biol & Med Expt IBYME CONICET, Buenos Aires, DF, Argentina. [Blidner, Ada G.; Rabinovich, Gabriel A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Buenos Aires, DF, Argentina. [Milotich, Sonia I.] Sanatorio Allende, Hosp Materno Neonatal Ramon Carrillo, Cordoba, Argentina. [Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pellizas, CG (reprint author), Ctr Invest Bioquim Clin & Inmunol CIBICI CONICET, Haya Torre & Medina Allende, RA-5000 Cordoba, Argentina. EM claudia@fcq.unc.edu.ar FU Agenda Nacional de Promocion Cientifica y Tecnologica (ANPCyT); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba (SeCyT); Agencia Cordoba Ciencia; Fundacion Sales FX This study was supported by grants from Agenda Nacional de Promocion Cientifica y Tecnologica (ANPCyT), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba (SeCyT), Agencia Cordoba Ciencia, and Fundacion Sales. NR 49 TC 6 Z9 7 U1 1 U2 7 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 APR 1 PY 2015 VL 75 IS 7 BP 1265 EP 1274 DI 10.1158/0008-5472.CAN-14-1875 PG 10 WC Oncology SC Oncology GA CE6LW UT WOS:000351948900014 PM 25672979 ER PT J AU Scortegagna, M Lau, E Zhang, TW Feng, YM Sereduk, C Yin, HW De, SK Meeth, K Platt, JT Langdon, CG Halaban, R Pellecchia, M Davies, MA Brown, K Stern, DF Bosenberg, M Ronai, ZA AF Scortegagna, Marzia Lau, Eric Zhang, Tongwu Feng, Yongmei Sereduk, Chris Yin, Hongwei De, Surya K. Meeth, Katrina Platt, James T. Langdon, Casey G. Halaban, Ruth Pellecchia, Maurizio Davies, Michael A. Brown, Kevin Stern, David F. Bosenberg, Marcus Ronai, Ze'ev A. TI PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets SO CANCER RESEARCH LA English DT Article ID 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1; SIGNAL-TRANSDUCTION; BREAST-CANCER; RESISTANCE; AKT; MUTATIONS; PTEN; PATHWAY; CELLS; INHIBITION AB Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutantmelanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. (C) 2015 AACR. C1 [Scortegagna, Marzia; Lau, Eric; Feng, Yongmei; De, Surya K.; Pellecchia, Maurizio; Ronai, Ze'ev A.] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. [Zhang, Tongwu; Brown, Kevin] NCI, Div Canc Epidemiol & Genet, Lab Translat Genom, Bethesda, MD 20892 USA. [Sereduk, Chris; Yin, Hongwei] Translat Gcnom Res Inst TGen, Canc & Cell Biol Div, Phoenix, AZ USA. [Meeth, Katrina; Platt, James T.; Langdon, Casey G.; Halaban, Ruth; Bosenberg, Marcus] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Meeth, Katrina; Platt, James T.; Langdon, Casey G.; Stern, David F.; Bosenberg, Marcus] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Melanoma Med Oncol, Houston, TX 77030 USA. RP Ronai, ZA (reprint author), Sanford Burnham Med Res Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM ronai@sbmri.org RI Zhang, Tongwu/M-4975-2015 FU NCI [CA179170, CA128814]; Hervey Family Non-endowment Fund at The San Diego Foundation; Melanoma Research Foundation FX Z.A. Ronai gratefully acknowledges support from the NCI (CA179170 and CA128814), the Hervey Family Non-endowment Fund at The San Diego Foundation, and the Melanoma Research Foundation. NR 34 TC 10 Z9 11 U1 1 U2 4 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 APR 1 PY 2015 VL 75 IS 7 BP 1399 EP 1412 DI 10.1158/0008-5472.CAN-14-2785 PG 14 WC Oncology SC Oncology GA CE6LW UT WOS:000351948900026 PM 25712345 ER PT J AU Korn, EL Freidlin, B AF Korn, Edward L. Freidlin, Boris TI Are outcome-adaptive allocation trials ethical? Commentary SO CLINICAL TRIALS LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIALS; ACUTE MYELOID-LEUKEMIA; CYTARABINE; THERAPY; DESIGN; OLDER C1 [Korn, Edward L.; Freidlin, Boris] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, 9609 Med Ctr Dr,5W112, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 18 TC 4 Z9 4 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2015 VL 12 IS 2 BP 28 EP 30 DI 10.1177/174077451556961 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CE9OQ UT WOS:000352173700008 ER PT J AU Berger, VW AF Berger, Vance W. TI A note on masking in the SOX trial SO CLINICAL TRIALS LA English DT Letter C1 [Berger, Vance W.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Berger, Vance W.] NCI, Biometry Res Grp, Rockville, MD 20850 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vb78c@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2015 VL 12 IS 2 BP 83 EP 83 DI 10.1177/1740774515569854 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CE9OQ UT WOS:000352173700016 ER PT J AU Poirier, MC Gibbons, AT Rugeles, MT Andre-Schmutz, I Blanche, S AF Poirier, Miriam C. Gibbons, Alexander T. Rugeles, Maria T. Andre-Schmutz, Isabelle Blanche, Stephane TI Fetal consequences of maternal antiretroviral nucleoside reverse transcriptase inhibitor use in human and nonhuman primate pregnancy SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE aneuploidy; electron microscopy; genotoxicity; mitochondrial DNA; zidovudine ID EXPOSED-UNINFECTED CHILDREN; MITOCHONDRIAL TOXICITY; IN-UTERO; PATAS MONKEYS; INFANTS BORN; CORD BLOOD; HIV; GENOTOXICITY; THERAPY; MOTHERS AB Purpose of review Here we present fetal genotoxicity and mitochondrial toxicity, induced by nucleoside reverse transcriptase inhibitors (NRTIs), in HIV-1-infected pregnant women treated to prevent mother-to-child HIV-1 transmission, and in virus-free pregnant patas monkeys. Recent findings In the offspring of pregnant patas monkeys given human-equivalent NRTI protocols, aneuploidy was found in cultured bone marrow cells taken at birth, 1, and 3 years of age. In some newborn human infants, the offspring of HIV-1-infected mothers given zidovudine (AZT) therapy, aneuploidy, mitochondrial DNA (mtDNA) depletion, morphologically damaged mitochondria, and reduction in cardiac left ventricular muscle were observed. NRTI-exposed human and patas umbilical cords had similar levels of mtDNA depletion and mitochondrial morphological damage. NRTI-exposed patas offspring showed a compensatory increase in heart mtDNA, and a 50% loss of brain mtDNA at 1 year of age. Mitochondrial morphological damage and mtDNA loss were persistent in blood cells of NRTI-exposed infants up to 2 years of age, and in heart and brain from NRTI-exposed patas up to 3 years of age (human equivalent of 15 years). Summary Whereas use of NRTIs in human pregnancy protects many thousands of children worldwide, some HIV-1-uninfected infants born to HIV-1-infected mothers receiving antiretroviral drug therapy sustain toxicities that may have adverse consequences later in life. C1 [Poirier, Miriam C.; Gibbons, Alexander T.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Bethesda, MD 20892 USA. [Rugeles, Maria T.] Univ Antioquia, Sch Med, Grp Imunovirol, Medellin, Colombia. [Andre-Schmutz, Isabelle] Univ Paris 05, Sorbonne Paris Cite, Inst Natl Sante & Rech Med, Paris, France. [Blanche, Stephane] Hop Necker Enfants Malad, Unite Immunol Hematol Pediat, Paris, France. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Bldg 37 Room 4032 NIH,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov RI Andre-Schmutz, Isabelle/M-1279-2016 FU Center for Cancer Research, National Cancer Institute, NIH; French Agence Nationale de Recherche sur le SIDA; Sustainability Program, Immunovirology Group, Universidad de Antioquia FX The study was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, NIH; the French Agence Nationale de Recherche sur le SIDA; and, the Sustainability Program 2014-2015, Immunovirology Group, Universidad de Antioquia. NR 31 TC 5 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2015 VL 27 IS 2 BP 233 EP 239 DI 10.1097/MOP.0000000000000193 PG 7 WC Pediatrics SC Pediatrics GA CE2VI UT WOS:000351677800014 PM 25635584 ER PT J AU Heindel, JJ Vandenberg, LN AF Heindel, Jerrold J. Vandenberg, Laura N. TI Developmental origins of health and disease: a paradigm for understanding disease cause and prevention SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE developmental origins of health and disease; environmental chemicals; epigenetic program; nutrition; transgenerational inheritance ID EPIGENETIC TRANSGENERATIONAL INHERITANCE; ENDOCRINE-DISRUPTING CHEMICALS; EARLY-LIFE NUTRITION; ADULT-ONSET DISEASE; DNA METHYLATION; SPERM EPIMUTATIONS; PRENATAL EXPOSURE; GENE-EXPRESSION; PUBLIC-HEALTH; OBESITY AB Purpose of review Although diseases may appear clinically throughout the lifespan, it is clear that many diseases have origins during development. Altered nutrition, as well as exposure to environmental chemicals, drugs, infections, or stress during specific times of development, can lead to functional changes in tissues, predisposing those tissues to diseases that manifest later in life. This review will focus on the role of altered nutrition and exposures to environmental chemicals during development in the role of disease and dysfunction. Recent findings The effects of altered nutrition or exposure to environmental chemicals during development are likely because of altered programming of epigenetic marks, which persist across the lifespan. Indeed some changes can be transmitted to future generations. Summary The evidence in support of the developmental origins of the health and disease paradigm is sufficiently robust and repeatable across species, including humans, to suggest a need for greater emphasis in the clinical area. As a result of these data, obesity, diabetes, cardiovascular morbidity, and neuropsychiatric diseases can all be considered pediatric diseases. Disease prevention must start with improved nutrition and reduced exposure to environmental chemicals during development. C1 [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Vandenberg, Laura N.] Univ Massachusetts, Sch Publ Hlth, Div Environm Hlth Sci, Amherst, MA 01003 USA. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 52 TC 14 Z9 14 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2015 VL 27 IS 2 BP 248 EP 253 DI 10.1097/MOP.0000000000000191 PG 6 WC Pediatrics SC Pediatrics GA CE2VI UT WOS:000351677800016 PM 25635586 ER PT J AU Kumar, A Lualdi, M Lyozin, GT Sharma, P Loncarek, J Fu, XY Kuehn, MR AF Kumar, Amit Lualdi, Margaret Lyozin, George T. Sharma, Prashant Loncarek, Jadranka Fu, Xin-Yuan Kuehn, Michael R. TI Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Nodal signaling; DVE/AVE; Visceral endoderm; Epiblast; Ttr-Cre ID ANTERIOR-POSTERIOR AXIS; EARLY MOUSE EMBRYO; RIGHT ASYMMETRIC EXPRESSION; CELL FATE DECISIONS; REGULATORY ELEMENTS; PRIMITIVE ENDODERM; PLURIPOTENT CELLS; ESTABLISHMENT; GASTRULATION; ENHANCER AB In the early mouse embryo, a specialized population of extraembryonic visceral endoderm (VE) cells called the distal VE (DVE) arises at the tip of the egg cylinder stage embryo and then asymmetrically migrates to the prospective anterior, recruiting additional distal cells. Upon migration these cells, called the anterior VE (AVE), establish the anterior posterior (AP) axis by restricting gastrulation-inducing signals to the opposite pole. The Nodal-signaling pathway has been shown to have a critical role in the generation and migration of the DVE/AVE. The Nodal gene is expressed in both the VE and in the pluripotent epiblast, which gives rise to the germ layers. Previous findings have provided conflicting evidence as to the relative importance of Nodal signaling from the epiblast vs. VE for AP patterning. Here we show that conditional mutagenesis of the Nodal gene specifically within the VE leads to reduced Nodal expression levels in the epiblast and incomplete or failed DVE/AVE migration. These results support a required role for VE Nodal to maintain normal levels of expression in the epiblast, and suggest signaling from both VE and epiblast is important for DVE/AVE migration. Published by Elsevier Inc. C1 [Kumar, Amit; Sharma, Prashant; Loncarek, Jadranka; Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Lualdi, Margaret] SAIC Frederick, Lab Anim Sci Program, Frederick, MD 21702 USA. [Lyozin, George T.] Univ Utah, Dept Pediat Neonatol, Salt Lake City, UT 84112 USA. [Fu, Xin-Yuan] Canc Sci Inst Singapore, Singapore 117599, Singapore. RP Kuehn, MR (reprint author), NCI, Lab Prot Dynam & Signaling, Bldg 560 Rm 12-90, Frederick, MD 21702 USA. EM mkuehn@mail.nih.gov RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 FU National Cancer Institute, National Institutes of Health FX We thank the Transgenic Mouse Model Laboratory for generation of Nodal EYFP transgenic mice; and Dr. Terry Yamaguchi for comments on the manuscript This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services and nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 44 TC 2 Z9 2 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD APR 1 PY 2015 VL 400 IS 1 BP 1 EP 9 DI 10.1016/j.ydbio.2014.12.016 PG 9 WC Developmental Biology SC Developmental Biology GA CE9RQ UT WOS:000352181500001 PM 25536399 ER PT J AU Pruett, JR Kandala, S Hoertel, S Snyder, AZ Elison, JT Nishino, T Feczko, E Dosenbach, NUF Nardos, B Power, JD Adeyemo, B Botteron, KN McKinstry, RC Evans, AC Hazlett, HC Dager, SR Paterson, S Schultz, RT Collins, DL Fonov, VS Styner, M Gerig, G Das, S Kostopoulos, P Constantino, JN Estes, AM Petersen, SE Schlaggar, BL Piven, J AF Pruett, John R., Jr. Kandala, Sridhar Hoertel, Sarah Snyder, Abraham Z. Elison, Jed T. Nishino, Tomoyuki Feczko, Eric Dosenbach, Nico U. F. Nardos, Binyam Power, Jonathan D. Adeyemo, Babatunde Botteron, Kelly N. McKinstry, Robert C. Evans, Alan C. Hazlett, Heather C. Dager, Stephen R. Paterson, Sarah Schultz, Robert T. Collins, D. Louis Fonov, Vladimir S. Styner, Martin Gerig, Guido Das, Samir Kostopoulos, Penelope Constantino, John N. Estes, Annette M. Petersen, Steven E. Schlaggar, Bradley L. Piven, Joseph CA IBIS Network TI Accurate age classification of 6 and 12 month-old infants based on resting-state functional connectivity magnetic resonance imaging data SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Functional connectivity magnetic; resonance imaging (fcMRI); Infant; Development; Multivariate pattern analysis (MVPA); Support vector machine (SVM); Functional brain networks ID AUTISM SPECTRUM DISORDERS; DIAGNOSTIC OBSERVATION SCHEDULE; HUMAN BRAIN; STRUCTURAL CONNECTIVITY; FMRI; NETWORKS; MOTION; MRI; ATTENTION; ORGANIZATION AB Human scale functional brain networks are hypothesized to undergo significant changes over development. Little is known about these functional architectural changes, particularly during the second half of the first year of life. We used multivariate pattern classification of resting-state functional connectivity magnetic resonance imaging (fcMRI) data obtained in an on-going, multi-site, longitudinal study of brain and behavioral development to explore whether fcMRI data contained information sufficient to classify infant age. Analyses carefully account for the effects of fcMRI motion artifact. Support vector machines (SVMs) classified 6 versus 12 month-old infants (128 datasets) above chance based on fcMRI data alone. Results demonstrate significant changes in measures of brain functional organization that coincide with a special period of dramatic change in infant motor, cognitive, and social development. Explorations of the most different correlations used for SVM lead to two different interpretations about functional connections that support 6 versus 12-month age categorization. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Pruett, John R., Jr.; Kandala, Sridhar; Hoertel, Sarah; Snyder, Abraham Z.; Nishino, Tomoyuki; Dosenbach, Nico U. F.; Nardos, Binyam; Adeyemo, Babatunde; Botteron, Kelly N.; McKinstry, Robert C.; Constantino, John N.; Petersen, Steven E.; Schlaggar, Bradley L.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Elison, Jed T.] Univ Minnesota, Minneapolis, MN 55455 USA. [Feczko, Eric] Emory Univ, Atlanta, GA 30322 USA. [Power, Jonathan D.] NIMH, NIH, Bethesda, MD 20814 USA. [Evans, Alan C.; Collins, D. Louis; Fonov, Vladimir S.; Das, Samir; Kostopoulos, Penelope] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ H3A 2B4, Canada. [Hazlett, Heather C.; Styner, Martin; Piven, Joseph] Univ N Carolina, Chapel Hill, NC 27514 USA. [Dager, Stephen R.; Estes, Annette M.] Univ Washington, Seattle, WA 98195 USA. [Paterson, Sarah; Schultz, Robert T.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Paterson, Sarah; Schultz, Robert T.] Univ Penn, Philadelphia, PA 19104 USA. [Gerig, Guido] Univ Utah, Salt Lake City, UT 84112 USA. RP Pruett, JR (reprint author), Washington Univ, Sch Med, 660 South Euclid Ave,Campus Box 8134, St Louis, MO 63110 USA. EM pruettj@psychiatry.wustl.edu; kandalas@psychiatry.wustl.edu; sarah.hoertel@gmail.com; avi@npg.wustl.edu; jtelison@umn.edu; nishinot@mir.wustl.edu; eric.j.feczko@emory.edu; nico@npg.wustl.edu; binyamn@npg.wustl.edu; jonathan.power@nih.gov; adeyemob@cabernet.wustl.edu; botteronk@mir.wustl.edu; mckinstryb@mir.wustl.edu; alan.acehigh@gmail.com; Heather_Cody@med.unc.edu; srd@u.washington.edu; patersons@email.chop.edu; schultzrt@email.chop.edu; louis.collins@mcgill.ca; vladimir.fonov@mcgill.ca; styner@cs.unc.edu; gerig@sci.utah.edu; samir@bic.mni.mcgill.ca; penelope.kostopoulos@mcgill.ca; constanj@psychiatry.wustl.edu; estesa@u.washington.edu; sep@npg.wustl.edu; schlaggarb@neuro.wustl.edu; joe_piven@med.unc.edu RI Pike, Bruce/K-5562-2014; OI Pike, Bruce/0000-0001-8924-683X; Network, IBIS/0000-0002-4932-4693; Gerig, Guido/0000-0002-9547-6233 FU McDonnell Center for Systems Neuroscience; [R01 MH093510]; [R01 HD055741]; [P30 NS048056]; [K12 EY016336] FX We thank Jeffrey Neil, Terrie Inder, and Chris Smyser for contribution of an infant brain atlas and comparison scan sequence. We thank Weili Lin for technical and administrative support. We thank James Harper and Siyang Yang for assistance with selection of the ROIs. We would also like to thank Britt Gott and Teddi Gray for help with manuscript preparation. This work was supported by: R01 MH093510 (Pruett), R01 HD055741 (Piven), P30 NS048056 (Snyder), K12 EY016336 (Pruett, completed), and the McDonnell Center for Systems Neuroscience. NR 57 TC 10 Z9 10 U1 2 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD APR PY 2015 VL 12 BP 123 EP 133 DI 10.1016/j.dcn.2015.01.003 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CE6MJ UT WOS:000351950500012 PM 25704288 ER PT J AU Dettmer, AM Murphy, AM Suomi, SJ AF Dettmer, Amanda M. Murphy, Ashley M. Suomi, Stephen J. TI Development of a Cognitive Testing Apparatus for Socially Housed Mother-Peer-Reared Infant Rhesus Monkeys SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE cognition; development; mother-reared; normative; rhesus macaque ID MACAQUES MACACA-MULATTA; GENERAL TEST APPARATUS; INHIBITORY CONTROL; HAIR CORTISOL; PERFORMANCE; STRESS; BEHAVIOR AB Though cognitive testing of infant monkeys has been practiced for the past 40 years, these assessments have been limited primarily to nursery-reared infants due to the confounds of separating mother-reared infants for assessments. Here, we describe a pilot study in which we developed a cognitive testing apparatus for socially housed, mother-peer-reared rhesus macaques under 1 year of age (Macaca mulatta) that allowed the infants to freely return to their mothers for contact comfort. Infants aged 151.2 +/- 18.3 days (mean +/- SEM; n=5) were trained and tested on an object detour reach task. Infants completed training in 5.0 +/- 0.2 days, and completed testing in 6.2 +/- 0.9 days. Across 4 days of testing, infants improved to nearly errorless performance (Friedman test: (2)=13.27, df=3, p=0.004) and learned to do the task more quickly (Friedman test: (2)=11.69, df=3, p=0.009). These are the first cognitive data in group-housed, mother-peer-reared rhesus monkeys under 1 year of age, and they underscore the utility of this apparatus for studying cognitive development in a normative population of infant monkeys. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Dev Psychobiol :349-355, 2015. C1 [Dettmer, Amanda M.; Murphy, Ashley M.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. [Murphy, Ashley M.] Hood Coll, Dept Biol, Frederick, MD 21701 USA. RP Dettmer, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, POB 529, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov FU NICHD Division of Intramural Research at NIH FX Contract grant sponsor: NICHD Division of Intramural Research at NIH NR 30 TC 1 Z9 1 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 EI 1098-2302 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD APR PY 2015 VL 57 IS 3 BP 349 EP 355 DI 10.1002/dev.21285 PG 7 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA CE4BL UT WOS:000351775700007 PM 25782609 ER PT J AU Arwady, MA Bawo, L Hunter, JC Massaquoi, M Matanock, A Dahn, B Ayscue, P Nyenswah, T Forrester, JD Hensley, LE Monroe, B Schoepp, RJ Chen, TH Schaecher, KE George, T Rouse, E Schafer, IJ Pillai, SK De Cock, KM AF Arwady, M. Allison Bawo, Luke Hunter, Jennifer C. Massaquoi, Moses Matanock, Almea Dahn, Bernice Ayscue, Patrick Nyenswah, Tolbert Forrester, Joseph D. Hensley, Lisa E. Monroe, Benjamin Schoepp, Randal J. Chen, Tai-Ho Schaecher, Kurt E. George, Thomas Rouse, Edward Schafer, Ilana J. Pillai, Satish K. De Cock, Kevin M. TI Evolution of Ebola Virus Disease from Exotic Infection to Global Health Priority, Liberia, Mid-2014 SO EMERGING INFECTIOUS DISEASES LA English DT Article AB Over the span of a few weeks during July and August 2014, events in West Africa changed perceptions of Ebola virus disease (EVD) from an exotic tropical disease to a priority for global health security. We describe observations during that time of a field team from the Centers for Disease Control and Prevention and personnel of the Liberian Ministry of Health and Social Welfare. We outline the early epidemiology of EVD within Liberia, including the practical limitations on surveillance and the effect on the country's health care system, such as infections among health care workers. During this time, priorities included strengthening EVD surveillance; establishing safe settings for EVD patient care (and considering alternative isolation and care models when Ebola Treatment Units were overwhelmed); improving infection control practices; establishing an incident management system; and working with Liberian airport authorities to implement EVD screening of departing passengers. C1 [Arwady, M. Allison; Hunter, Jennifer C.; Matanock, Almea; Ayscue, Patrick; Forrester, Joseph D.; Monroe, Benjamin; Chen, Tai-Ho; George, Thomas; Rouse, Edward; Schafer, Ilana J.; Pillai, Satish K.; De Cock, Kevin M.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Bawo, Luke; Massaquoi, Moses; Dahn, Bernice; Nyenswah, Tolbert] Minist Hlth & Social Welf, Monrovia, Liberia. [Hensley, Lisa E.] Natl Inst Hlth, Bethesda, MD USA. [Schoepp, Randal J.; Schaecher, Kurt E.] US Army Med Res Inst Infect Dis, Frederick, MD USA. RP Arwady, MA (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop E92, Atlanta, GA 30329 USA. EM xdr3@cdc.gov NR 5 TC 13 Z9 14 U1 3 U2 52 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 APR PY 2015 VL 21 IS 4 BP 578 EP 584 DI 10.3201/eid2104.141940 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CE2NK UT WOS:000351652100004 PM 25811176 ER PT J AU Tempia, S Walaza, S Viboud, C Cohen, AL Madhi, SA Venter, M von Mollendorf, C Moyes, J McAnerney, JM Cohen, C AF Tempia, Stefano Walaza, Sibongile Viboud, Cecile Cohen, Adam L. Madhi, Shabir A. Venter, Marietjie von Mollendorf, Claire Moyes, Jocelyn McAnerney, Johanna M. Cohen, Cheryl TI Deaths Associated with Respiratory Syncytial and Influenza Viruses among Persons >= 5 Years of Age in HIV-Prevalent Area, South Africa, 1998-2009 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; TRACT INFECTION; PANDEMIC INFLUENZA; MORTALITY BURDEN; HOSPITALIZATIONS; CHILDREN; ADULTS; EPIDEMIOLOGY; SURVEILLANCE; SEVERITY AB We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >= 5 years of age in South Africa during 1998-2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza associated deaths was 9,093 (rate 21.6). Persons >= 65 years of age and HIV-positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1) pdm09-associated deaths. The mean of annual RSV-associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >= 45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa. C1 [Tempia, Stefano; Walaza, Sibongile; Madhi, Shabir A.; von Mollendorf, Claire; Moyes, Jocelyn; McAnerney, Johanna M.; Cohen, Cheryl] Natl Hlth Lab Serv, Johannesburg, South Africa. [Tempia, Stefano; Cohen, Adam L.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Tempia, Stefano; Cohen, Adam L.; Venter, Marietjie] Ctr Dis Control & Prevent, Pretoria, South Africa. [Viboud, Cecile] NIH, Bethesda, MD 20892 USA. [Madhi, Shabir A.; Moyes, Jocelyn; Cohen, Cheryl] Univ Witwatersrand, Johannesburg, South Africa. RP Tempia, S (reprint author), Natl Inst Communicable Dis, US Ctr Dis Control & Prevent, Private Bag X4, ZA-2131 Johannesburg, Gauteng, South Africa. EM wlu4@cdc.gov RI Venter, Marietjie/P-9604-2016 OI Venter, Marietjie/0000-0003-2696-824X FU GlaxoSmithKline; Novartis; Pfizer FX Stefano Tempia, DVM, MSc, PhD; Sibongile Walaza, MB BCh; Cede Viboud, PhD; Adam L. Cohen, MD, MPH; Marietjie Venter, PhD; Claire von Mollendorf, MB BCh, MSc; Jocelyn Moyes, MB BCh, MSc (Med); Johanna M. McAnerney; and Cheryl Cohen, PhD, have disclosed no relevant financial relationships. Shabir A. Madhi, MD, PhD, has disclosed the following relevant financial relationships: served as an advisor or consultant for GlaxoSmithKline, Pfizer; served as a speaker or a member of a speakers bureau for GlaxoSmithKline, Pfizer, Sanofi Pasteur; received grants for clinical research from GlaxoSmithKline, Novartis, Pfizer. NR 39 TC 4 Z9 4 U1 0 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD APR PY 2015 VL 21 IS 4 BP 600 EP 608 DI 10.3201/eid2104.141033 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CE2NK UT WOS:000351652100007 PM 25811455 ER PT J AU de Wit, E Marzi, A Bushmaker, T Brining, D Scott, D Richt, JA Geisbert, TW Feldmann, H AF de Wit, Emmie Marzi, Andrea Bushmaker, Trenton Brining, Doug Scott, Dana Richt, Juergen A. Geisbert, Thomas W. Feldmann, Heinz TI Safety of Recombinant VSV-Ebola Virus Vaccine Vector in Pigs SO EMERGING INFECTIOUS DISEASES LA English DT Article ID VESICULAR STOMATITIS-VIRUS; NONHUMAN-PRIMATES; GLYCOPROTEINS AB The ongoing Ebola outbreak in West Africa has resulted in fast-track development of vaccine candidates. We tested a vesicular stomatitis virus vector expressing Ebola virus glycoprotein for safety in pigs. Inoculation did not cause disease and vaccine virus shedding was minimal, which indicated that the vaccine virus does not pose a risk of dissemination in pigs. C1 [de Wit, Emmie; Marzi, Andrea; Bushmaker, Trenton; Brining, Doug; Scott, Dana; Feldmann, Heinz] NIAID, Hamilton, MT 59840 USA. [Richt, Juergen A.] Kansas State Univ, Coll Vet Med, Manhattan, KS 66506 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Feldmann, Heinz] Univ Manitoba, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 11 TC 3 Z9 3 U1 1 U2 27 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 APR PY 2015 VL 21 IS 4 BP 702 EP 704 DI 10.3201/eid2104.142012 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CE2NK UT WOS:000351652100026 PM 25811738 ER PT J AU Lorber, M Schecter, A Paepke, O Shropshire, W Christensen, K Birnbaum, L AF Lorber, Matthew Schecter, Arnold Paepke, Olaf Shropshire, William Christensen, Krista Birnbaum, Linda TI Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Bisphenol A; EPA NHANES Dietary exposure ID UNITED-STATES; CHEMICALS; MARKET; MILK AB Bisphenol A (BPA) is a high-volume, synthetic compound found in epoxy resins and plastics used in food packaging. Food is believed to be a major source of BPA intake. In this study, we measured the concentration of BPA in convenience samplings of foodstuffs purchased in Dallas, Texas. Sampling entailed collection of 204 samples of fresh, frozen, and canned foods in two rounds in 2010. BPA was positive in 73% of the canned food samples, while it was found in only 7% of non-canned foods at low concentrations. The results of this food sampling program were used to calculate adult dietary intakes of BPA. A pathway approach combined food intakes, a "canned fraction" parameter which described what portion of total intake of that food came from canned products, and measured food concentrations. Dietary intakes were calculated as 12.6 ng/kg-day, of which 12.4 ng/kg-day was from canned foods. Canned vegetable intakes alone were 11.9 ng/kg-day. This dietary intake was compared to total intakes of BPA estimated from urine measurements of the National Health and Nutrition Examination Survey (NHANFS). Total adult central tendency intakes ranged from 30 to 70 ng/kg-day for NHANES cycles between 2005 and 2010. Three possibilities were explored to explain the difference between these two approaches for intake estimation. Not all foods which may have been canned, particularly canned beverages such as soft drinks, were sampled in our food sampling program. Second, non-food pathways of exposure may be important for adults, including thermal paper exposures, and dust and air exposures. Finally, our canned food concentrations may not be adequately representative of canned foods in the United States; they were found to be generally lower compared to canned food concentrations measured in six other worldwide food surveys including three in North America. Our finding that canned food concentrations greatly exceeded non-canned concentrations was consistent with other studies, and underscores the importance of canned foods in the overall exposure of adults of BPA. Published by Elsevier Ltd. C1 [Lorber, Matthew] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Schecter, Arnold] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Paepke, Olaf] Eurofins GfA Lab Serv, Hamburg, Germany. [Shropshire, William] Univ Texas Dallas, Sch Publ Hlth, Environm & Occupat Hlth Sci Program, Dallas, TX 75230 USA. [Christensen, Krista] Bur Environm & Occupat Hlth, Wisconsin Div Publ Hlth, Madison, WI USA. [Birnbaum, Linda] NCI, NIH, Res Triangle Pk, NC USA. RP Lorber, M (reprint author), US EPA, Natl Ctr Environm Assessment, 8623D,1200 Penn Ave,NW, Washington, DC 20460 USA. EM lorber.matthew@epa.gov FU Intramural NIH HHS [Z99 ES999999] NR 41 TC 13 Z9 13 U1 7 U2 52 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD APR PY 2015 VL 77 BP 55 EP 62 DI 10.1016/j.envint.2015.01.008 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA CE4FP UT WOS:000351786800008 PM 25645382 ER PT J AU Zeiger, E Gollapudi, B Aardema, MJ Auerbach, S Boverhof, D Custer, L Dedon, P Honma, M Ishida, S Kasinski, AL Kim, JH Manjanatha, MG Marlowe, J Pfuhler, S Pogribny, I Slikker, W Stankowski, LF Tanir, JY Tice, R van Benthem, J White, P Witt, KL Thybaud, V AF Zeiger, Errol Gollapudi, Bhaskar Aardema, Marilyn J. Auerbach, Scott Boverhof, Darrell Custer, Laura Dedon, Peter Honma, Masamitsu Ishida, Seiichi Kasinski, Andrea L. Kim, James H. Manjanatha, Mugimane G. Marlowe, Jennifer Pfuhler, Stefan Pogribny, Igor Slikker, William Stankowski, Leon F., Jr. Tanir, Jennifer Y. Tice, Raymond van Benthem, Jan White, Paul Witt, Kristine L. Thybaud, Veronique TI Opportunities to Integrate New Approaches in Genetic Toxicology: An ILSI-HESI Workshop Report SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE genetic toxicity; mutation; epigenetics; genomics AB Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided. Environ. Mol. Mutagen. 56:277-285, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Zeiger, Errol] Errol Zeiger Consulting, Chapel Hill, NC 27514 USA. [Gollapudi, Bhaskar; Boverhof, Darrell] Dow Chem Co USA, Midland, MI 48674 USA. [Aardema, Marilyn J.] BioReliance Corp, Marilyn Aardema Consulting LLC, Rockville, MD USA. [Auerbach, Scott; Tice, Raymond; Witt, Kristine L.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Custer, Laura] Bristol Myers Squibb Co, Dept Genet Toxicol, New York, NY 10154 USA. [Dedon, Peter] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Honma, Masamitsu] Natl Inst Hlth Sci, Div Genet & Mutagenesis, Tokyo, Japan. [Ishida, Seiichi] Natl Inst Hlth Sci, Div Pharmacol, Tokyo, Japan. [Kasinski, Andrea L.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Kim, James H.; Tanir, Jennifer Y.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Manjanatha, Mugimane G.; Pogribny, Igor; Slikker, William] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Marlowe, Jennifer] Novartis, Cambridge, MA USA. [Pfuhler, Stefan] Procter & Gamble Co, Cincinnati, OH USA. [Stankowski, Leon F., Jr.] BioReliance Corp, Rockville, MD USA. [van Benthem, Jan] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [White, Paul] Hlth Canada, Environm Hlth Sci & Res Div, Ottawa, ON K1A 0L2, Canada. [Thybaud, Veronique] Sanofi, Vitry Alfortville Res Ctr, Vitry Sur Seine, France. RP Zeiger, E (reprint author), Errol Zeiger Consulting, Chapel Hill, NC 27514 USA. EM zeiger@nc.rr.com RI Kasinski, Andrea/E-7951-2014; OI Dedon, Peter/0000-0003-0011-3067; white, paul/0000-0001-5853-4759 FU ILSI/HESI IVGT committee FX The organizing committee is grateful to the researchers who agreed to participate in this Workshop. In addition, the support of the ILSI/HESI staff, particularly Eric Moore, was invaluable for the organization, logistics, and day-to-day running of the Workshop. The authors also thank the ILSI/HESI IVGT committee for its financial and intellectual support. NR 3 TC 1 Z9 1 U1 0 U2 15 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 APR PY 2015 VL 56 IS 3 BP 277 EP 285 DI 10.1002/em.21923 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CE4BZ UT WOS:000351777100001 PM 25482136 ER PT J AU Salz, T Baxi, SS Raghunathan, N Onstad, EE Freedman, AN Moskowitz, CS Dalton, SO Goodman, KA Johansen, C Matasar, MJ Brown, PD Oeffinger, KC Vickers, AJ AF Salz, Talya Baxi, Shrujal S. Raghunathan, Nirupa Onstad, Erin E. Freedman, Andrew N. Moskowitz, Chaya S. Dalton, Susanne Oksbjerg Goodman, Karyn A. Johansen, Christoffer Matasar, Matthew J. Brown, Peter de Nully Oeffinger, Kevin C. Vickers, Andrew J. TI Are we ready to predict late effects? A systematic review of clinically useful prediction models SO EUROPEAN JOURNAL OF CANCER LA English DT Review DE Neoplasms; Survivors; Risk; Decision support techniques; Secondary prevention ID CHILDHOOD-CANC