FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Fleischhacker, S Roberts, E Camplain, R Evenson, KR Gittelsohn, J AF Fleischhacker, Sheila Roberts, Erica Camplain, Ricky Evenson, Kelly R. Gittelsohn, Joel TI Promoting Physical Activity Among Native American Youth: a Systematic Review of the Methodology and Current Evidence of Physical Activity Interventions and Community-wide Initiatives SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE American Indians; Alaskan Natives; Active living; Physical activity; Exercise; Obesity ID OBESITY-PREVENTION PROGRAM; RANDOMIZED CONTROLLED-TRIAL; LIFE-STYLE INTERVENTION; INDIAN CHILDREN; PARTICIPATORY RESEARCH; UNITED-STATES; FORMATIVE ASSESSMENT; BODY-COMPOSITION; SCHOOL MEALS; CARDIOVASCULAR CURRICULUM AB Promoting physical activity using environmental, policy, and systems approaches could potentially address persistent health disparities faced by American Indian and Alaska Native children and adolescents. To address research gaps and help inform tribally led community changes that promote physical activity, this review examined the methodology and current evidence of physical activity interventions and community-wide initiatives among Native youth. A keyword-guided search was conducted in multiple databases to identify peer-reviewed research articles that reported on physical activity among Native youth. Ultimately, 20 unique interventions (described in 76 articles) and 13 unique community-wide initiatives (described in 16 articles) met the study criteria. Four interventions noted positive changes in knowledge and attitude relating to physical activity but none of the interventions examined reported statistically significant improvements on weight-related outcomes. Only six interventions reported implementing environmental, policy, and system approaches relating to promoting physical activity and generally only shared anecdotal information about the approaches tried. Using community-based participatory research or tribally driven research models strengthened the tribal-research partnerships and improved the cultural and contextual sensitivity of the intervention or community-wide initiative. Few interventions or community-wide initiatives examined multi-level, multi-sector interventions to promote physical activity among Native youth, families, and communities. More research is needed to measure and monitor physical activity within this understudied, high risk group. Future research could also focus on the unique authority and opportunity of tribal leaders and other key stakeholders to use environmental, policy, and systems approaches to raise a healthier generation of Native youth. C1 [Fleischhacker, Sheila] NIDDKD, Off Nutr Res, NIH, US Dept HHS, Two Democracy Plaza,Room 635, Bethesda, MD 20892 USA. [Roberts, Erica] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, 2242 Valley Dr, College Pk, MD 20742 USA. [Camplain, Ricky] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, 137 East Franklin St,Suite 303A, Chapel Hill, NC 27514 USA. [Evenson, Kelly R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. [Gittelsohn, Joel] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, 615 N Wolfe St,Rm W2041, Baltimore, MD 21205 USA. RP Fleischhacker, S (reprint author), NIDDKD, Off Nutr Res, NIH, US Dept HHS, Two Democracy Plaza,Room 635, Bethesda, MD 20892 USA. EM sheila.fleischhacker@nih.gov; eblue@umd.edu; camplain@email.unc.edu; kelly_evenson@unc.edu; jgittels@jhsph.edu FU Intramural NIH HHS [Z99 DK999999]; NIMH NIH HHS [T32 MH075854] NR 127 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD DEC PY 2016 VL 3 IS 4 BP 608 EP 624 DI 10.1007/s40615-015-0180-1 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC5TN UT WOS:000388199400007 PM 27294756 ER PT J AU Allen, AJ Kuczmarski, MF Evans, MK Zonderman, AB Waldstein, SR AF Allen, Allyssa J. Kuczmarski, Marie Fanelli Evans, Michele K. Zonderman, Alan B. Waldstein, Shari R. TI Race Differences in Diet Quality of Urban Food-Insecure Blacks and Whites Reveals Resiliency in Blacks SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE Food insecurity; Diet quality; Health disparities; SNAP; Food stamps; Race; Urban ID UNITED-STATES; ADULTS; POVERTY; CONSUMPTION; AMERICANS AB Introduction Evidence from epidemiological studies shows a link between food insecurity and diet intake or quality. However, the moderating effect of race in this relation has not yet been studied. Methods Food insecurity (USDA Food Security Module) and diet quality (Healthy Eating Index-2010; HEI) were measured in 1741 participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Data were collected from 2004 to 2009 and analyzed in 2014. Multivariable regression assessed the interaction of race and food insecurity on HEI scores, adjusting for age, sex, poverty status, single parent status, drug, alcohol and cigarette use, and comorbid diseases. Results The interaction of food insecurity and race was significantly associated with diet quality (p = 0.001). In the absence of food insecurity, HEI scores were similar across race. However, with each food insecurity item endorsed, HEI scores were substantially lower for Whites compared to Blacks. An ad hoc analysis revealed that Blacks were more likely than Whites to participate in SNAP (p < 0.05). Further, race stratified analyses revealed that Blacks participating in SNAP showed diminished associations of food insecurity with diet quality. Conclusions Study findings provide the first evidence that the influence of food insecurity on diet quality may be potentiated for Whites, but not Blacks. Additionally, results show that Blacks are more likely to participate in SNAP and show attendant buffering of the effects of food insecurity on diet quality. These findings may have important implications for understanding how food insecurity affects diet quality differentially by race. C1 [Allen, Allyssa J.; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. [Kuczmarski, Marie Fanelli; Evans, Michele K.; Zonderman, Alan B.] NIA, Baltimore, MD 21224 USA. [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. RP Allen, AJ (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM allyssaallen@gmail.com FU NIA NIH HHS [R01 AG034161] NR 24 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD DEC PY 2016 VL 3 IS 4 BP 706 EP 712 DI 10.1007/s40615-015-0189-5 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC5TN UT WOS:000388199400016 PM 27294760 ER PT J AU Moore, JC Mulligan, TS Yordan, NT Castranova, D Pham, VN Tang, Q Lobbardi, R Anselmo, A Liwski, RS Berman, JN Sadreyev, RI Weinstein, BM Langenau, DM AF Moore, John C. Mulligan, Timothy S. Yordan, Nora Torres Castranova, Daniel Pham, Van N. Tang, Qin Lobbardi, Riadh Anselmo, Anthony Liwski, Robert S. Berman, Jason N. Sadreyev, Ruslan I. Weinstein, Brant M. Langenau, David M. TI T Cell Immune Deficiency in zap70 Mutant Zebrafish SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; TRANSGENIC ZEBRAFISH; VASCULAR DEVELOPMENT; TYROSINE KINASE; EMBRYONAL RHABDOMYOSARCOMA; SYK; ZAP-70; TRANSPLANTATION; EXPRESSION; MICE AB ZAP70 [zeta-chain (TCR)-associated protein kinase, 70-kDa], is required for T cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immune deficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70(y442)) that was created using transcription activator-like effector nucleases (TALENs). In contrast to what has been reported for morphant zebrafish, zap70(y442) homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae. However, mutant fish had reduced lck: GFP(+) thymic T cells by 5 days postfertilization that persisted into adult stages. Morphological analysis, RNA sequencing, and single-cell gene expression profiling of whole kidney marrow cells of adult fish revealed complete loss of mature T cells in zap70(y442) mutant animals. T cell immune deficiency was confirmed through transplantation of unmatched normal and malignant donor cells into zap70(y442) mutant zebrafish, with T cell loss being sufficient for robust allogeneic cell engraftment. zap70 mutant zebrafish show remarkable conservation of immune cell dysfunction as found in mice and humans and will serve as a valuable model to study zap70 immune deficiency. C1 [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA. [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Moore, John C.; Yordan, Nora Torres; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Mulligan, Timothy S.; Castranova, Daniel; Pham, Van N.; Weinstein, Brant M.] NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Yordan, Nora Torres] Harvard Univ, Cambridge, MA 02138 USA. [Anselmo, Anthony; Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Anselmo, Anthony] Harvard Med Sch, Dept Genet, Boston, MA USA. [Liwski, Robert S.; Berman, Jason N.] Dalhousie Univ, Izaak Walton Killam Hlth Ctr, Halifax, NS, Canada. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Boston, MA USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov; dlangenau@mgh.harvard.edu FU HHS \ National Institutes of Health (NIH) [R01CA154923, U54CA168512]; HHS \ NIH \ NIH Office of the Director (OD) [R24OD016761]; HHS \ NIH \ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [ZIA-HD008808] FX This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar National Institutes of Health (NIH) (R01CA154923). This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar National Institutes of Health (NIH) (U54CA168512). This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar NIH vertical bar NIH Office of the Director (OD) (R24OD016761). This work, including the efforts of Timothy Mulligan, Daniel Castranova, Van Pham, and Brant Weinstein, was funded by HHS vertical bar NIH vertical bar Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (ZIA-HD008808). NR 41 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2016 VL 36 IS 23 BP 2868 EP 2876 DI 10.1128/MCB.00281-16 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EC9MU UT WOS:000388469500001 ER PT J AU Roy, A Kundu, M Jana, M Mishra, RK Yung, YN Luan, CH Gonzalez, FJ Pahan, K AF Roy, Avik Kundu, Madhuchhanda Jana, Malabendu Mishra, Rama K. Yung, Yeni Luan, Chi-Hao Gonzalez, Frank J. Pahan, Kalipada TI Identification and characterization of PPAR alpha ligands in the hippocampus SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED-RECEPTOR; RAT HIPPOCAMPUS; UP-REGULATION; BODY-WEIGHT; MOUSE MODEL; BRAIN; OLEOYLETHANOLAMIDE; EXPRESSION; NEURONS; DISEASE AB Peroxisome proliferator-activated receptor-alpha (PPAR alpha) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPAR alpha is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPAR alpha ligands3- hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide-in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay results clearly indicated that these three compounds served as ligands of PPAR alpha. Site-directed mutagenesis studies further revealed that PPAR alpha Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPAR alpha and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPAR alpha capable of modulating synaptic functions. C1 [Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Pahan, Kalipada] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Mishra, Rama K.] Northwestern Univ, Med & Synthet Chem Core, Ctr Mol Innovat & Drug Discovery, Evanston, IL USA. [Yung, Yeni] Univ Illinois, Res Resources Ctr, Chicago, IL USA. [Luan, Chi-Hao] Northwestern Univ, High Throughput Anal Lab, Evanston, IL USA. [Luan, Chi-Hao] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pahan, Kalipada] Jesse Brown Vet Affairs Med Ctr, Div Res & Dev, Chicago, IL 60612 USA. RP Pahan, K (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA.; Pahan, K (reprint author), Jesse Brown Vet Affairs Med Ctr, Div Res & Dev, Chicago, IL 60612 USA. EM kalipada_pahan@rush.edu FU Chicago Biomedical Consortium; US National Institutes of Health [AG050431, NS83054]; Veterans Affairs [1I01BX003033-01] FX The authors thank ChemCore at the Northwestern University Center for Molecular Innovation and Drug Discovery, which is funded by the Chicago Biomedical Consortium. This study was supported by grants from the US National Institutes of Health (AG050431 and NS83054) and a merit award (1I01BX003033-01) from Veterans Affairs to K.P. NR 38 TC 1 Z9 1 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2016 VL 12 IS 12 BP 1075 EP + DI 10.1038/NCHEMBIO.2204 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED1CZ UT WOS:000388582900017 PM 27748752 ER PT J AU Cressey, TR Hazra, R Wiznia, A Foca, M Jean-Philippe, P Graham, B King, JR Britto, P Carey, VJ Acosta, EP Yogev, R AF Cressey, Tim R. Hazra, Rohan Wiznia, Andrew Foca, Marc Jean-Philippe, Patrick Graham, Bobbie King, Jennifer R. Britto, Paula Carey, Vincent J. Acosta, Edward P. Yogev, Ram CA IMPAACT P1058A Team TI Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pharmacokinetics; antiretrovirals; atazanavir; pediatrics ID EFFICACY; INFANTS AB HIV protease inhibitor use in pediatrics is challenging due to the poor palatability and/or toxicity of concomitant low-dose ritonavir. Atazanavir without ritonavir (unboosted) is not recommended for patients with prior virologic failure, a common problem for perinatally-infected adolescents. Atazanavir 400 mg once-daily provided suboptimal exposure. Higher unboosted doses or splitting the daily dose to twice-daily warrants investigation in this treatment-experienced population. C1 [Cressey, Tim R.] Chiang Mai Univ, Dept Med Technol, Fac Associated Med Sci, Program HIV Prevent & Treatment IRD UMI 174, Chiang Mai, Thailand. [Cressey, Tim R.; Britto, Paula; Carey, Vincent J.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Wiznia, Andrew] Jacobi Med Ctr, Bronx, NY USA. [Foca, Marc] Columbia Univ, Med Ctr, New York, NY USA. [Jean-Philippe, Patrick] HJF DAIDS, Bethesda, MD USA. [Graham, Bobbie] Frontier Sci & Technol, Amherst, NY USA. [King, Jennifer R.; Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Yogev, Ram] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Chicago, IL 60614 USA. RP Cressey, TR (reprint author), Fac Associated Med Sci, Dept Med Technol, PHPT IRD UMI 174, 6th Floor,110 Inthawaroros Rd, Mueang Chiang Mai 50200, Thailand. EM tim.cressey@phpt.org FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); NIAID, NIH, Department of Health and Human Services [HHSN272200800014C] FX The authors would like to thank the patients, families, investigators, and trial site personnel for their contributions to the study. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). This project has been funded in whole or in part with federal funds from the NIAID, NIH, Department of Health and Human Services, under Contract No. HHSN272200800014C. NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2016 VL 35 IS 12 BP 1333 EP 1335 DI 10.1097/INF.0000000000001320 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA EC6AH UT WOS:000388217900017 PM 27583590 ER PT J AU Liu, S Comandur, R Jones, CP Tsang, P Musier-Forsyth, K AF Liu, Sheng Comandur, Roopa Jones, Christopher P. Tsang, Pearl Musier-Forsyth, Karin TI Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase SO RNA LA English DT Article DE anticodon-binding domain; human lysyl-tRNA synthetase; tRNA-like element; HIV-1 genome; NMR; chemical shift perturbation ID N-15 RESONANCE ASSIGNMENT; N-TERMINAL DOMAIN; TRNA(LYS); AMINOACYLATION; RECOGNITION; COMPLEX; MIMICRY; C-13; H-1 AB A critical step in the HIV-1 lifecycle involves reverse transcription of the viral genomic RNA (gRNA). Human tRNA(LYs3) serves as a primer for transcription initiation and is selectively enriched in virus particles. Human lysyl-tRNA synthetase (hLysRS) is also packaged into virions. Recently, a tRNA-like element (TLE) within the HIV-1 gRNA was shown to mimic the global tRNA fold and bind competitively to hLysRS, suggesting a mechanism of tRNA targeting to the primer binding site (PBS) and release from the synthetase. Here, we use NMR to investigate hLysRS anticodon-binding domain (ACB) binding to six RNA oligonucleotides, including a hairpin derived from the HIV-1 gRNA TLE. We show that ACB interacts with submicromolar affinity to U-rich RNA oligonucleotides the tRNALYs3 anticodon stem loop (ACSL), the WT TLE, and a nonanucleotide, U9. In contrast, the ACB bound only weakly to two TLE loop mutants and a C9 nonanucleotide. NMR chemical shift perturbations induced by each RNA indicate that the ACSL and the WT TLE both interact with the ACB in a strikingly similar manner. Taken together, these findings support the conclusion that tRNA mimicry by the HIV-1 genome leads to a highly specific protein RNA interaction that facilitates efficient primer release from hLysRS prior to reverse transcription. C1 [Liu, Sheng; Tsang, Pearl] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. [Comandur, Roopa; Jones, Christopher P.; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Dept Chem & Biochem, Columbus, OH 43210 USA. [Comandur, Roopa; Jones, Christopher P.; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Jones, Christopher P.] NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tsang, P (reprint author), Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA.; Musier-Forsyth, K (reprint author), Ohio State Univ, Ctr Retrovirus Res, Dept Chem & Biochem, Columbus, OH 43210 USA.; Musier-Forsyth, K (reprint author), Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. EM pearl.tsang@uc.edu; musier@chemistry.ohio-state.edu FU National Institutes of Health [RO1 GM113887]; University of Cincinnati LEAF FX We thank Dr. William Cantara for critical reading of the manuscript. This work was funded by National Institutes of Health RO1 GM113887 (to K.M.-F.) and University of Cincinnati LEAF funding (to P.T.). NR 21 TC 0 Z9 0 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD DEC PY 2016 VL 22 IS 12 BP 1828 EP 1835 DI 10.1261/rna.058081.116 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC6MV UT WOS:000388251300004 PM 27852925 ER PT J AU Valentine, HA AF Valentine, Hannah A. TI Science Has a Gender Problem Women face discrimination of many kinds. We need a culture change SO SCIENTIFIC AMERICAN LA English DT Editorial Material C1 [Valentine, Hannah A.] NIH, Sci Workforce Divers, Bldg 10, Bethesda, MD 20892 USA. RP Valentine, HA (reprint author), NIH, Sci Workforce Divers, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD DEC PY 2016 VL 315 IS 6 BP 12 EP 12 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC5GM UT WOS:000388161400013 ER PT J AU Long, Y Xu, M Li, R Dai, S Beers, J Chen, GK Soheilian, F Baxa, U Wang, MQ Marugan, JJ Muro, S Li, ZY Brady, R Zheng, W AF Long, Yan Xu, Miao Li, Rong Dai, Sheng Beers, Jeanette Chen, Guokai Soheilian, Ferri Baxa, Ulrich Wang, Mengqiao Marugan, Juan J. Muro, Silvia Li, Zhiyuan Brady, Roscoe Zheng, Wei TI Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Niemann-Pick disease type A; Induced pluripotent stem cells; Differentiated neural stem cells; Cyclodextrin; delta-Tocopherol; alpha-Tocopherol; Acid sphingomyelinase ID LYSOSOMAL STORAGE DISORDERS; ENZYME REPLACEMENT; C-DISEASE; IDENTIFICATION; MICE; CYCLODEXTRIN; PATHOGENESIS; GENE; CHOLESTEROL; DEFICIENCY AB Niemann-Pick disease type A (NPA) is a lysosomal storage disease caused by mutations in the SMPD1 gene that encodes acid sphingomyelinase (ASM). Deficiency in ASM function results in lysosomal accumulation of sphingomyelin and neurodegeneration. Currently, there is no effective treatment for NPA. To accelerate drug discovery for treatment of NPA, we generated induced pluripotent stem cells from two patient dermal fibroblast lines and differentiated them into neural stem cells. The NPA neural stem cells exhibit a disease phenotype of lysosomal sphingomyelin accumulation and enlarged lysosomes. By using this disease model, we also evaluated three compounds that reportedly reduced lysosomal lipid accumulation in Niemann-Pick disease type C as well as enzyme replacement therapy with ASM. We found that a-tocopherol, d-tocopherol, hydroxypropyl-beta-cyclodextrin, and ASM reduced sphingomyelin accumulation and enlarged lysosomes in NPA neural stem cells. Therefore, the NPA neural stem cells possess the characteristic NPA disease phenotype that can be ameliorated by tocopherols, cyclodextrin, and ASM. Our results demonstrate the efficacies of cyclodextrin and tocopherols in the NPA cell-based model. Our data also indicate that the NPA neural stem cells can be used as a new cell-based disease model for further study of disease pathophysiology and for high-throughput screening to identify new lead compounds for drug development. C1 [Long, Yan; Xu, Miao; Li, Rong; Dai, Sheng; Wang, Mengqiao; Marugan, Juan J.; Zheng, Wei] NIH, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA. [Beers, Jeanette; Chen, Guokai] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Brady, Roscoe] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Long, Yan; Li, Zhiyuan] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou, Guangdong, Peoples R China. [Xu, Miao; Dai, Sheng] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China. [Chen, Guokai] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. [Soheilian, Ferri; Baxa, Ulrich] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Electron Microscopy Lab, Frederick, MD USA. [Muro, Silvia] Univ Maryland, Inst Biosci & Biotechnol Res, College Pk, MD 20742 USA. [Muro, Silvia] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Zheng, W (reprint author), NIH, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Programs of the National Center for Advancing Translational Sciences; China Scholarship Council; National Natural Science Foundation of China [81503170]; Guangdong Natural Science Foundation [2016A030313170]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN26120080001E]; Natural Science Foundation of Zhejiang Province for Distinguished Young Scholars [LR14H090001]; National Institutes of Health [R01-HL098416]; University of Macau [MYRG2015-00228-FHS] FX This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences. This work was also supported by grants from the China Scholarship Council and grants from the National Natural Science Foundation of China (81503170 to Y.L.) and Guangdong Natural Science Foundation (2016A030313170 to Y.L.), from federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (under contract HHSN26120080001E to U.B. and F.S.), from the Natural Science Foundation of Zhejiang Province for Distinguished Young Scholars (LR14H090001 to M.X.), from the National Institutes of Health (R01-HL098416 to S.M.), and from the University of Macau (MYRG2015-00228-FHS to G.C.). NR 39 TC 0 Z9 0 U1 4 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD DEC PY 2016 VL 5 IS 12 BP 1644 EP 1655 DI 10.5966/sctm.2015-0373 PG 12 WC Cell & Tissue Engineering SC Cell Biology GA EC5TD UT WOS:000388198200005 PM 27484861 ER PT J AU Zhang, WH Jerneren, F Lehne, BC Chen, MH Luben, RN Johnston, C Elshorbagy, A Eppinga, RN Scott, WR Adeyeye, E Scott, J Boger, RH Khaw, KT van der Harst, P Wareham, NJ Vasan, RS Chambers, JC Refsum, H Kooner, JS AF Zhang, Weihua Jerneren, Fredrik Lehne, Benjamin C. Chen, Ming-Huei Luben, Robert N. Johnston, Carole Elshorbagy, Amany Eppinga, Ruben N. Scott, William R. Adeyeye, Elizabeth Scott, James Boeger, Rainer H. Khaw, Kay-Tee van der Harst, Pim Wareham, Nicholas J. Vasan, Ramachandran S. Chambers, John C. Refsum, Helga Kooner, Jaspal S. TI Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Serum L-arginine concentration; genome-wide association; coagulation; kallikrein-kinin system ID ANGIOTENSIN-CONVERTING ENZYME; CORONARY-ARTERY-DISEASE; GENOTYPE IMPUTATION; METABOLITE LEVELS; PLASMA-LEVELS; NITRIC-OXIDE; BRADYKININ; BLOOD; METAANALYSIS; EXPRESSION AB L-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of single nucleotide polymorphism (SNP) rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 mu mol/l per allele copy, p=1x10(-24)), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 mu mol/l per allele copy, p=7x10(-12)). Together these two loci explain 7 % of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements ( p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5'-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk. C1 [Zhang, Weihua; Lehne, Benjamin C.; Chambers, John C.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Jerneren, Fredrik; Adeyeye, Elizabeth; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Dept Cardiol, Uxbridge Rd, Southall, Middx, England. [Johnston, Carole; Elshorbagy, Amany; Refsum, Helga] Univ Oxford, Dept Pharmacol, Oxford, England. [Chen, Ming-Huei] NHLBI, Populat Sci Branch, NIH, Framingham, MA USA. [Luben, Robert N.; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Elshorbagy, Amany] Univ Alexandria, Dept Physiol, Fac Med, Alexandria, Egypt. [Eppinga, Ruben N.; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Eppinga, Ruben N.; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Scott, William R.; Scott, James; Kooner, Jaspal S.] Imperial Coll London, Hammersmith Hosp Campus, Natl Heart & Lung Inst, London, England. [Adeyeye, Elizabeth] Imperial Coll London, Fac Med, South Kensington Campus, London, England. [Boeger, Rainer H.] Univ Med Ctr Hamburg Eppendorf, Dept Clin Pharmacol & Toxicol, Hamburg, Germany. [Wareham, Nicholas J.] Univ Cambridge, MRC, Epidemiol Unit, Cambridge, England. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol & Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Refsum, Helga] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Fac Med, Oslo, Norway. RP Zhang, WH (reprint author), Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Epidemiol & Biostat, Norfolk Pl, London W2 1PG, England. EM weihua.zhang@imperial.ac.uk FU British Heart Foundation [SP/04/002]; Medical Research Council [G0601966, G0700931, G0401527, G1000143]; Wellcome Trust [084723/Z/08/Z]; NIHR [RP-PG-0407-10371]; European Union FP7 (EpiMigrant) [279143]; Action on Hearing Loss [G51]; Cancer Research UK [C864/A8257]; Norwegian research Council; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix Inc. [N02-HL-6-4278] FX The British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931, G0401527, G1000143), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143), Action on Hearing Loss (G51), Cancer Research UK (C864/A8257), the Norwegian research Council, and the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix Inc. for genotyping services (Contract No. N02-HL-6-4278). NR 49 TC 1 Z9 1 U1 1 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD DEC PY 2016 VL 116 IS 6 BP 1041 EP 1049 DI 10.1160/TH16-02-0151 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA ED6MC UT WOS:000388968700006 PM 27656708 ER PT J AU Yakovlev, S Belkin, AM Chen, L Cao, CZ Zhang, L Strickland, DK Medved, L AF Yakovlev, Sergiy Belkin, Alexey M. Chen, Ling Cao, Chunzhang Zhang, Li Strickland, Dudley K. Medved, Leonid TI Anti-VLDL receptor monoclonal antibodies inhibit fibrin-VLDL receptor interaction and reduce fibrin-dependent leukocyte transmigration SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Fibrinogen/fibrin; VLDL receptor; leukocyte transmigration; monoclonal antibodies ID DENSITY-LIPOPROTEIN RECEPTOR; ENDOTHELIAL-CELL RECEPTOR; VE-CADHERIN; BINDING SITE; ALPHA-2-MACROGLOBULIN RECEPTOR; LDL RECEPTOR; MIGRATION; PROTEIN; IDENTIFICATION; LOCALIZATION AB Our previous studies revealed that the interaction of fibrin with the very low density lipoprotein receptor (VLDLR) promotes transendothelial migration of leukocytes and thereby inflammation, and localised the fibrin-binding site to CR-domains 2-4 of this receptor. In the present study, we tested interaction of three anti-VLDLR monoclonal antibodies, mAb 1H10, 1H5, and 5F3, with recombinant fragments of VLDLR containing various combinations of its CR-domains and found that the epitopes for mAb 1H10 and mAb 1H5 overlap with the fibrinbinding site of VLDLR. Based on these findings, we hypothesised that mAb 1H10 and mAb 1H5 should inhibit fibrin-VLDLR interaction and modulate leukocyte transmigration. To test this hypothesis, we first demonstrated that these monoclonal antibodies both have high affinity to the fibrin-binding fragments of the VLDL receptor and efficiently inhibit interaction between the VLDLR-binding fragment of fibrin and the fibrin-binding fragments of VLDLR. Next, in the in vitro experiments using leukocyte transendothelial migration assay we found that both monoclonal antibodies efficiently inhibit leukocyte transmigration induced by fibrin mimetic NDSK-II. Finally, in vivo experiments using mouse model of peritonitis revealed that mAb 1H10 and mAb 1H5 both significantly reduce infiltration of leukocytes into the peritoneum. Furthermore, our experiments using mouse model of myocardial ischemia-reperfusion injury revealed that both monoclonal antibodies significantly reduce myocardial injury induced by ischaemia- reperfusion. Thus, the results obtained indicate that monoclonal antibodies 1H10 and 1H5 are novel specific inhibitors of fibrin-VLDLR-dependent leukocyte transmigration pathway. They may represent potential therapeutics for treatment of fibrin-dependent inflammation including myocardial ischaemia-reperfusion injury. C1 [Yakovlev, Sergiy; Belkin, Alexey M.; Cao, Chunzhang; Zhang, Li; Strickland, Dudley K.; Medved, Leonid] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, 800 West Baltimore St, Baltimore, MD 21201 USA. [Yakovlev, Sergiy; Belkin, Alexey M.; Medved, Leonid] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Chen, Ling] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Chen, Ling; Cao, Chunzhang; Zhang, Li; Strickland, Dudley K.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Strickland, Dudley K.] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA. [Belkin, Alexey M.] NIH, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA. RP Medved, L (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, 800 West Baltimore St, Baltimore, MD 21201 USA. EM Lmedved@som.umaryland.edu FU National Institutes of Health R01 Grants [HL056051, HL114379, HL120388, NS082607] FX This work was supported by National Institutes of Health R01 Grants HL056051 to L.M., HL114379 and HL120388 to D.K.S, and NS082607 to L.Z. NR 26 TC 0 Z9 0 U1 1 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD DEC PY 2016 VL 116 IS 6 BP 1122 EP 1130 DI 10.1160/TH16-04-0333 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA ED6MC UT WOS:000388968700014 PM 27580629 ER PT J AU Socias, ME Volkow, N Wood, E AF Socias, M. Eugenia Volkow, Nora Wood, Evan TI Adopting the "cascade of care' framework: an opportunity to close the implementation gap in addiction care? SO ADDICTION LA English DT Editorial Material DE Addiction medicine; cascade of care; evidence-based; performance measures; quality measurement; substance use disorders ID SUBSTANCE USE DISORDERS; HIV CARE; MEDICINE; ACT AB Despite a growing number of evidenced-based addiction treatments, a substantial implementation gap in addiction medicine remains. The 'cascade of care' framework can serve as a tool to identify gaps along the continuum of care and tailor interventions to improve the quality of addiction care and outcomes. C1 [Socias, M. Eugenia; Wood, Evan] Univ British Columbia, St Pauls Hosp, Dept Med, Vancouver, BC, Canada. [Socias, M. Eugenia; Wood, Evan] St Pauls Hosp, British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Volkow, Nora] NIDA, NIH, Rockville, MD USA. RP Wood, E (reprint author), Univ British Columbia, St Pauls Hosp, Dept Med, Vancouver, BC, Canada.; Wood, E (reprint author), St Pauls Hosp, British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. EM uhri-ew@cfenet.ubc.ca FU US National Institute on Drug Abuse [R25-DA037756]; British Columbia Node of the Canadian Research Initiative on Substance Misuse; Tier 1 Canada Research Chair; Michael Smith Foundation for Health Research Post-Doctoral fellowship award; Canada Addiction Medicine Research Fellowship (US National Institute on Drug Abuse) [R25-DA037756] FX The study was supported by the US National Institute on Drug Abuse (R25-DA037756) and the British Columbia Node of the Canadian Research Initiative on Substance Misuse. E.W. is supported by a Tier 1 Canada Research Chair. M.E.S. is supported by a Michael Smith Foundation for Health Research Post-Doctoral fellowship award and a Canada Addiction Medicine Research Fellowship (US National Institute on Drug Abuse, R25-DA037756). NR 16 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD DEC PY 2016 VL 111 IS 12 BP 2079 EP 2081 DI 10.1111/add.13479 PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EB5KO UT WOS:000387413400001 PM 27412876 ER PT J AU Harada, Y Tanaka, N Ichikawa, M Kamijo, Y Sugiyama, E Gonzalez, FJ Aoyama, T AF Harada, Yukiko Tanaka, Naoki Ichikawa, Motoki Kamijo, Yuji Sugiyama, Eiko Gonzalez, Frank J. Aoyama, Toshifumi TI PPAR alpha-dependent cholesterol/testosterone disruption in Leydig cells mediates 2,4-dichlorophenoxyacetic acid-induced testicular toxicity in mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE 2,4-dichlorophenoxyacetic acid; PPAR alpha; Cholesterol; Leydig cell; Testosterone; Testicular toxicity ID ACTIVATED RECEPTOR-ALPHA; PEROXISOME PROLIFERATORS; 2,4,5-TRICHLOROPHENOXYACETIC ACID; ADULT-RAT; CHOLESTEROL; EXPRESSION; LIVER; 2,4-D; GENE; STEROIDOGENESIS AB It was reported that 2,4-dichlorophenoxyacetic acid (2,4-D), a commonly used herbicide and a possible endocrine disruptor, can disturb spermatogenesis, but the precise mechanism is not understood. Since 2,4-D is a weak peroxisome proliferator in hepatocytes and peroxisome proliferator-activated receptor alpha (PPAR alpha) is also expressed in Leydig cells, this study aimed to investigate the link between PPAR alpha and 2,4-D-mediated testicular dysfunction. 2,4-D (130 mg/kg/day) was administered to wild-type and Ppara-null mice for 2 weeks, and the alterations in testis and testosterone/cholesterol metabolism in Leydig cells were examined. Treatment with 2,4-D markedly decreased testicular testosterone in wild-type mice, leading to degeneration of spermatocytes and Sertoli cells. The 2,4-D decreased cholesterol levels in Leydig cells of wild-type mice through down-regulating the expression of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 and reductase, involved in de novo cholesterogenesis. However, the mRNAs encoding the important proteins involved in testosterone synthesis were unchanged by 2,4-D except for CYP17A1, indicating that exhausted cholesterol levels in the cells is a main reason for reduced testicular testosterone. Additionally, pregnancy rate and the number of pups between 2,4-D-treated wild-type male mice and untreated female mice were significantly lower compared with those between untreated couples. These phenomena were not observed in 2,4-D-treated Ppara-null males. Collectively, these results suggest a critical role for PPAR alpha in 2,4-D-induced testicular toxicity due to disruption of cholesterol/testosterone homeostasis in Leydig cells. This study yields novel insights into the possible mechanism of testicular dysfunction and male infertility caused by 2,4-D. C1 [Harada, Yukiko; Tanaka, Naoki; Aoyama, Toshifumi] Shinshu Univ, Dept Metab Regulat, Grad Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. [Harada, Yukiko] Shinshu Univ, Dept Pediat, Sch Med, Matsumoto, Nagano, Japan. [Tanaka, Naoki; Kamijo, Yuji] Shinshu Univ, Dept Internal Med, Sch Med, Matsumoto, Nagano, Japan. [Ichikawa, Motoki] Shinshu Univ, Dept Family & Child Nursing, Sch Hlth Sci, Matsumoto, Nagano, Japan. [Sugiyama, Eiko] Nagano Prefectural Coll, Dept Nutr Sci, Nagano, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Dept Metab Regulat, Grad Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan.; Tanaka, N (reprint author), Shinshu Univ, Dept Internal Med, Sch Med, Matsumoto, Nagano, Japan. EM naopi@shinshu-u.ac.jp NR 33 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD DEC PY 2016 VL 90 IS 12 BP 3061 EP 3071 DI 10.1007/s00204-016-1669-z PG 11 WC Toxicology SC Toxicology GA EB9FH UT WOS:000387697600012 PM 26838045 ER PT J AU Ismaili, E Walsh, S O'Brien, PMS Backstrom, T Brown, C Dennerstein, L Eriksson, E Freeman, EW Ismail, KMK Panay, N Pearlstein, T Rapkin, A Steiner, M Studd, J Sundstrom-Paromma, I Endicott, J Epperson, CN Halbreich, U Reid, R Rubinow, D Schmidt, P Yonkers, K AF Ismaili, Elgerta Walsh, Sally O'Brien, Patrick Michael Shaughn Backstrom, Torbjorn Brown, Candace Dennerstein, Lorraine Eriksson, Elias Freeman, Ellen W. Ismail, Khaled M. K. Panay, Nicholas Pearlstein, Teri Rapkin, Andrea Steiner, Meir Studd, John Sundstrom-Paromma, Inger Endicott, Jean Epperson, C. Neill Halbreich, Uriel Reid, Robert Rubinow, David Schmidt, Peter Yonkers, Kimberley CA Int Soc Premenstrual Disorders TI Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE PMS (premenstrual syndrome); PMD (premenstrual disorder); PMDD (premenstrual disorder/premenstrual dysphoric disorder) ID SEROTONIN-REUPTAKE INHIBITORS; DYSPHORIC DISORDER; EFFICACY AB Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care. C1 [Ismaili, Elgerta] Univ Hosp North Staffordshire NHS Trust, City Gen Hosp, Dept Obstet & Gynaecol, Newcastle Rd, Stoke On Trent ST4 6QG, Staffs, England. [Ismaili, Elgerta; Walsh, Sally] Univ Hosp North Midlands, Stoke On Trent, Staffs, England. [O'Brien, Patrick Michael Shaughn] Keele Univ, Sch Med, Univ Hosp North Staffordshire, Stoke On Trent, Staffs, England. [Backstrom, Torbjorn] Norrland Univ Hosp, Dept Clin Sci, Umea Neurosteroid Res Ctr, Umea, Sweden. [Brown, Candace] Univ Tennessee, Dept Psychiat, Memphis, TN USA. [Brown, Candace] Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. [Dennerstein, Lorraine] Univ Melbourne, Dept Psychiat, Melbourne, Vic, Australia. [Dennerstein, Lorraine] Natl Ageing Res Inst, Melbourne, Vic, Australia. [Eriksson, Elias] Gothenburg Univ, Inst Neurosci & Physiol, Gothenburg, Sweden. [Freeman, Ellen W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Ismail, Khaled M. K.] Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Panay, Nicholas] Chelsea & Westminster Hosp, Dept Obstet & Gynaecol, London, England. [Pearlstein, Teri] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. [Rapkin, Andrea] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Steiner, Meir] McMaster Univ, Dept Psychiat, 100 West 5th St, Hamilton, ON L8N 3K7, Canada. [Steiner, Meir] McMaster Univ, Dept Behav Neurosci, 100 West 5th St, Hamilton, ON L8N 3K7, Canada. [Steiner, Meir] McMaster Univ, Dept Obstet & Gynecol, 100 West 5th St, Hamilton, ON L8N 3K7, Canada. [Studd, John] Chelsea & Westminster Hosp, Dept Gynaecol, London, England. [Sundstrom-Paromma, Inger] Uppsala Univ, Dept Womens & Childrens Hlth, Obstet & Gynaecol, S-75185 Uppsala, Sweden. [Endicott, Jean] Columbia Univ, Dept Psychiat, New York, NY USA. [Epperson, C. Neill; Yonkers, Kimberley] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Epperson, C. Neill; Yonkers, Kimberley] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Halbreich, Uriel] SUNY Buffalo, New York, NY USA. [Halbreich, Uriel] WPA, New York, NY USA. [Reid, Robert] Queens Univ, Kingston, ON, Canada. [Rubinow, David] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Schmidt, Peter] NIH, Sect Behav Endocrinol, Bldg 10, Bethesda, MD 20892 USA. RP Ismaili, E (reprint author), Univ Hosp North Staffordshire NHS Trust, City Gen Hosp, Dept Obstet & Gynaecol, Newcastle Rd, Stoke On Trent ST4 6QG, Staffs, England.; Ismaili, E (reprint author), Univ Hosp North Midlands, Stoke On Trent, Staffs, England. EM elgertaismaili@virginmedia.com NR 17 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2016 VL 19 IS 6 BP 953 EP 958 DI 10.1007/s00737-016-0631-7 PG 6 WC Psychiatry SC Psychiatry GA EB8QT UT WOS:000387656600002 PM 27378473 ER PT J AU Lee, MR Weerts, EM AF Lee, Mary R. Weerts, Elise M. TI Oxytocin for the treatment of drug and alcohol use disorders SO BEHAVIOURAL PHARMACOLOGY LA English DT Review DE addiction; alcoholism; dependence; oxytocin; substance-use disorder; treatment ID CONDITIONED PLACE PREFERENCE; METHAMPHETAMINE-SEEKING BEHAVIOR; CHRONIC MORPHINE TREATMENT; MEDIAL PREFRONTAL CORTEX; SOCIAL ANXIETY DISORDER; PITUITARY-ADRENAL AXIS; NUCLEUS-ACCUMBENS CORE; LONG-TERM ABSTINENCE; BLOOD-BRAIN-BARRIER; PROLYL-D-LEUCINE AB There is growing interest in the use of oxytocin (OT) as a potential treatment for alcohol and other substance-use disorders. OT is a neuropeptide that modulates adaptive processes associated with addiction including reward, tolerance, associative learning, memory, and stress responses. OT exerts its effects through interactions with the hypothalamic-pituitary-adrenal axis and multiple neurotransmitter systems including the dopamine mesolimbic reward and corticotrophin-releasing factor stress systems. The effects of OT on stress systems are of high interest, given the strong link between stress, drug use and relapse, and known dysregulation of hypothalamic-pituitary-adrenal-axis activity associated with substance-use disorders. At the same time, the OT system is itself altered by acute or chronic drug exposure. This review summarizes the preclinical and clinical literature on the OT system and its relevance to drug and alcohol addiction. In addition, findings from recent clinical trials conducted in participants with cocaine, cannabis, or alcohol use disorder are included and evidence that OT may help to normalize blunted stress responses, and attenuate withdrawal-associated hypercortisolism, negative mood, and withdrawal symptoms is summarized. (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Lee, Mary R.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD USA. [Lee, Mary R.] NIDA, Bethesda, MD 20892 USA. [Weerts, Elise M.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. RP Weerts, EM (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. EM eweerts@jhmi.edu FU Bench-to-Bedside (B2B) grant - NIH Office of Behavioral and Social Sciences Research (OBSSR); National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R21 AA022679] FX This work was supported by a Bench-to-Bedside (B2B) grant (PI: Mary R. Lee) funded by the NIH Office of Behavioral and Social Sciences Research (OBSSR) and by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) R21 AA022679 (PI: Elise M. Weerts). NR 122 TC 0 Z9 0 U1 24 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD DEC PY 2016 VL 27 IS 8 BP 640 EP 648 DI 10.1097/FBP.0000000000000258 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EB9KD UT WOS:000387711900002 PM 27603752 ER PT J AU Papadakis, GZ Millo, C Sadowski, SM Bagci, U Patronas, NJ AF Papadakis, Georgios Z. Millo, Corina Sadowski, Samira M. Bagci, Ulas Patronas, Nicholas J. TI Kidney Tumor in a von Hippel-Lindau (VHL) Patient With Intensely Increased Activity on Ga-68-DOTA-TATE PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE von Hippel-Lindau (VHL) disease; Ga-68-DOTA-TATE PET/CT; Kidney tumor; CT; MRI ID IMAGING FEATURES; DISEASE AB Renal and pancreatic cysts and tumors are the most common visceral manifestations of von Hippel-Lindau (VHL) disease, a heritable multisystem cancer syndrome characterized by development of a variety of malignant and benign tumors. We report a case of a VHL patient with multiple renal cystic and complex cystic/solid lesions. The patient underwent Ga-68-DOTA-TATE-PET/CT showing intensely increased activity by a solid lesion which demonstrated enhancement on both CT and MRI scans, raising high suspicion for malignancy. The presented case indicates application of SSTR-imaging using Ga-68-DOTA-conjugated peptides in VHL-patients and emphasizes the need for cautious interpretation of renal parenchyma Ga-68-DOTATATE activity. C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] NIH, Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr CC, Bldg 10, Bethesda, MD 20892 USA. [Millo, Corina] NIH, Div Nucl Med, RAD & IS, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Millo, Corina] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Endocrine & Thorac Surg, Geneva, Switzerland. [Bagci, Ulas] Univ Cent Florida, CRCV, Elect & Comp Sci Dept, Orlando, FL 32816 USA. RP Patronas, NJ (reprint author), NIH, Neuroradiol Branch, Warren Grant Magnuson Clin Ctr CC, Bldg 10,Room 1C361X 10 CTR DR,Mail Stop 1182, Bethesda, MD 20814 USA. EM NPatronas@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 11 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD DEC PY 2016 VL 41 IS 12 BP 970 EP 971 DI 10.1097/RLU.0000000000001393 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC3BI UT WOS:000387999000029 PM 27749408 ER PT J AU Hinkle, SN Louis, GMB Rawal, S Zhu, YY Albert, PS Zhang, CL AF Hinkle, Stefanie N. Louis, Germaine M. Buck Rawal, Shristi Zhu, Yeyi Albert, Paul S. Zhang, Cuilin TI A longitudinal study of depression and gestational diabetes in pregnancy and the postpartum period SO DIABETOLOGIA LA English DT Article DE Depression; Gestational diabetes; Postpartum; Pregnancy ID BIDIRECTIONAL ASSOCIATION; PERINATAL DEPRESSION; PREDICTORS; SYMPTOMS; MELLITUS; OBESITY; COHORT; TYPE-2; HYPERGLYCEMIA; OUTCOMES AB Depression and glucose intolerance commonly co-occur among non-pregnant individuals; however, the temporal relationship between gestational diabetes (GDM) and depression during pregnancy and the postpartum period is less understood. Our objective was to assess longitudinal associations between depression early in pregnancy and GDM risk, as well as GDM and subsequent risk of postpartum depression. Data came from the prospective National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort (2009-2013), and had been collected at 12 US clinical centres. Pregnant women without psychiatric disorders, diabetes or other chronic conditions before pregnancy were followed throughout pregnancy (n = 2477). Only women with GDM and matched controls were followed up at 6 weeks postpartum (n = 162). GDM was ascertained by a review of the medical records. Depression was assessed in the first (8-13 gestational weeks) and second (16-22 weeks) trimesters and at 6 weeks postpartum using the Edinburgh Postnatal Depression Scale. Postpartum depression was defined as a depressive symptom score aeyen10 or antidepressant medicine use after delivery. RR and 95% CI were adjusted for pre-pregnancy BMI and other risk factors. GDM was considered to be the outcome for the first set of analyses, with depression in the first and second trimesters as the exposures. Postpartum depression was considered as the outcome for the second set of analyses, with GDM as the exposure. Overall, comparing the highest and lowest quartiles of first-trimester depression scores, the scores from the highest quartile were associated with a significant twofold (95% CI 1.06, 3.78) increased risk of GDM, but this was attenuated to 1.72-fold (95% CI 0.92, 3.23) after adjustment; the second-trimester results were similar. The risk was stronger and significant in both trimesters among non-obese women (p for trend 0.02 and 0.01, respectively), but null for obese women. Women with persistently high depression scores in both trimesters had the greatest risk of GDM (highest vs lowest quartile in both trimesters: adjusted RR 3.21, 95% CI 1.00, 10.28). GDM was associated with an adjusted 4.62-fold (95% CI 1.26, 16.98) increased risk of subsequent postpartum depression. This prospective study demonstrates a modest association between depressive symptoms early in pregnancy and an increased risk of incident GDM, as well as between GDM and subsequent postpartum depression risk, highlighting pregnancy and the postpartum period as an important susceptible time window during the life course for the interplay between depression and glucose intolerance phenotypes. GDM risk associated with elevated depressive symptoms was particularly high among non-obese women and women with symptoms persisting across the first two trimesters of pregnancy. C1 [Hinkle, Stefanie N.; Rawal, Shristi; Zhu, Yeyi; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Epidemiol Branch, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20817 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Off Director, Bethesda, MD 20817 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Bethesda, MD 20817 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Epidemiol Branch, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20817 USA. EM zhangcu@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver NICHD; National Institutes of Health; ARRA [HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver NICHD, National Institutes of Health and through ARRA funding (contracts: HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C). NR 38 TC 0 Z9 0 U1 9 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD DEC PY 2016 VL 59 IS 12 BP 2594 EP 2602 DI 10.1007/s00125-016-4086-1 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EB7UN UT WOS:000387596300016 PM 27640810 ER PT J AU Sallard, E Tallet, J Thut, G Deiber, MP Barral, J AF Sallard, Etienne Tallet, Jessica Thut, Gregor Deiber, Marie-Pierre Barral, Jerome TI Age-related changes in post-movement beta synchronization during a selective inhibition task SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Inhibitory control; Electroencephalography; Time-frequency; Oscillations; Source localization ID OSCILLATORY CORTICAL ACTIVITY; OLDER-ADULTS; FUNCTIONAL NEUROANATOMY; BIMANUAL COORDINATION; RESPONSE-INHIBITION; FINGER MOVEMENT; IMAGERY CONTENT; MOTOR TASK; MEMORY; BRAIN AB Post-movement beta synchronization (PMBS) modulations have been related to sensory reafferences after movement initiation and inhibitory processes after movement interruption. Although these processes have been separately studied in young and old adults, little is known about the age-related changes in PMBS during selective inhibitory control (i.e. stop a part of an action). The present study examines the age-related modulations of PMBS associated with sensory reafferences and inhibitory processes in selective inhibitory control. Young (n = 17) and old (n = 13) participants performed a switching task first engaging bimanual finger tapping then requiring to stop the left while maintaining the right unimanual tapping (i.e. selective inhibition) at an imperative stimulus. Age groups were compared on behavioral (mean, variability and percentage of errors of inter-tap interval during and after the switching) and electrophysiological (time-frequency and source estimations in the 14-30 Hz beta frequency range) data time-locked on the imperative stimulus. Behaviorally, old adults showed larger variability and percentage of errors during the switching but performed as well as young adults after the switching. Electrophysiologically, PMBS significantly increased after the switching in the old compared to the young group within bilateral frontal and parietal areas. Our results show that the effort to maintain selective inhibition involves increased brain activation in old compared to young adults. The larger PMBS within frontal and parietal regions in old adults may reflect an age-related brain compensation enabling to efficiently maintain post-switching inhibition. C1 [Sallard, Etienne; Barral, Jerome] Univ Lausanne, Res Grp Inst Sport Sci, Lausanne, Switzerland. [Tallet, Jessica] INSERM UPS CHU PURPAN, Toulouse Neuroimaging Ctr UMR1214, Pavillon BAUDOT, F-31024 Toulouse, France. [Thut, Gregor] Univ Glasgow, Inst Neurosci & Psychol, Glasgow, Lanark, Scotland. [Deiber, Marie-Pierre] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Biomarkers Vulnerabil Unit, Geneva, Switzerland. [Deiber, Marie-Pierre] Fac Med, INSERM U1039, La Tronche, France. [Sallard, Etienne] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 10,Room 7D50-52, Bethesda, MD 20892 USA. RP Sallard, E (reprint author), Univ Lausanne, Res Grp Inst Sport Sci, Lausanne, Switzerland.; Sallard, E (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 10,Room 7D50-52, Bethesda, MD 20892 USA. EM etienne.sallard@gmail.com RI Centre d'imagerie Biomedicale, CIBM/B-5740-2012; Deiber, Marie-Pierre/M-5949-2014 FU Center for Biomedical Imaging (CIBM) of Geneva and Lausanne FX Cartool software has been programmed by Denis Brunet, from the Functional Brain Mapping Laboratory, Geneva, Switzerland, and supported by the Center for Biomedical Imaging (CIBM) of Geneva and Lausanne. NR 64 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD DEC PY 2016 VL 234 IS 12 BP 3543 EP 3553 DI 10.1007/s00221-016-4753-y PG 11 WC Neurosciences SC Neurosciences & Neurology GA EB6LV UT WOS:000387495900014 PM 27531152 ER PT J AU Gallea, C Horovitz, SG Najee-Ullah, M'A Hallett, M AF Gallea, Cecile Horovitz, Silvina G. Najee-Ullah, Muslimah 'Ali Hallett, Mark TI Impairment of a parieto-premotor network specialized for handwriting in writer's cramp SO HUMAN BRAIN MAPPING LA English DT Article DE human; dystonia; motor program; task specificity; neuroimaging ID FOCAL HAND DYSTONIA; VOXEL-BASED MORPHOMETRY; CORTICAL MOTOR SYSTEM; FUNCTIONAL CONNECTIVITY; BASAL GANGLIA; CORTEX; BRAIN; PLASTICITY; STIMULATION; MOVEMENT AB Handwriting with the dominant hand is a highly skilled task singularly acquired in humans. This skill is the isolated deficit in patients with writer's cramp (WC), a form of dystonia with maladaptive plasticity, acquired through intensive and repetitive motor practice. When a skill is highly trained, a motor program is created in the brain to execute the same movement kinematics regardless of the effector used for the task. The task- and effector-specific symptoms in WC suggest that a problem particularly occurs in the brain when the writing motor program is carried out by the dominant hand. In this MRI study involving 12 WC patients (with symptoms only affecting the right dominant hand during writing) and 15 age matched unaffected controls we showed that: (1) the writing program recruited the same network regardless of the effector used to write in both groups; (2) dominant handwriting recruited a segregated parieto-premotor network only in the control group; (3) local structural alteration of the premotor area, the motor component of this network, predicted functional connectivity deficits during dominant handwriting and symptom duration in the patient group. Dysfunctions and structural abnormalities of a segregated parieto-premotor network in WC patients suggest that network specialization in focal brain areas is crucial for well-learned motor skill. Hum Brain Mapp 37:4363-4375, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Gallea, Cecile; Horovitz, Silvina G.; Najee-Ullah, Muslimah 'Ali; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, 10 Ctr Dr,Bldg 10-7D37, Bethesda, MD 20892 USA. [Gallea, Cecile] UPMC Univ Paris 06, Ctr Neuroimagerie Rech CENIR, Sorbonne Univ, INSERM,U1127 CNRS,UMR 7225,UMR S 1127,ICM, F-75013 Paris, France. RP Gallea, C (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, 10 Ctr Dr,Bldg 10-7D37, Bethesda, MD 20892 USA. EM cecile.gallea.icm@gmail.com FU NINDS intramural program; Fondation pour la Recherche Medicale (FRM, "Programme Espoir de la Recherche, Posdoctorat a l'etranger"); NINDS Competitive Fellowship (intramural program) FX Contract grant sponsor: NINDS intramural program; Contract grant sponsor: Fondation pour la Recherche Medicale (FRM, "Programme Espoir de la Recherche, Posdoctorat a l'etranger") and an NINDS Competitive Fellowship (intramural program) (to C.G.). NR 82 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD DEC PY 2016 VL 37 IS 12 BP 4363 EP 4375 DI 10.1002/hbm.23315 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB5FL UT WOS:000387399200011 PM 27466043 ER PT J AU Taylor, PA Alhamud, A van der Kouwe, A Saleh, MG Laughton, B Meintjes, E AF Taylor, Paul A. Alhamud, A. van der Kouwe, Andre Saleh, Muhammad G. Laughton, Barbara Meintjes, Ernesta TI Assessing the performance of different DTI motion correction strategies in the presence of EPI distortion correction SO HUMAN BRAIN MAPPING LA English DT Article DE diffusion tensor imaging; motion correction; echo planar imaging volumetric navigator; fractional anisotropy; tractography ID IN-DIFFUSION MRI; SUBJECT-MOTION; WHITE-MATTER; HEAD MOTION; SPIN-ECHO; TRACTOGRAPHY; REPRODUCIBILITY; ARTIFACTS; IMAGES; BRAIN AB Diffusion tensor imaging (DTI) is susceptible to several artifacts due to eddy currents, echo planar imaging (EPI) distortion and subject motion. While several techniques correct for individual distortion effects, no optimal combination of DTI acquisition and processing has been determined. Here, the effects of several motion correction techniques are investigated while also correcting for EPI distortion: prospective correction, using navigation; retrospective correction, using two different popular packages (FSL and TORTOISE); and the combination of both methods. Data from a pediatric group that exhibited incidental motion in varying degrees are analyzed. Comparisons are carried while implementing eddy current and EPI distortion correction. DTI parameter distributions, white matter (WM) maps and probabilistic tractography are examined. The importance of prospective correction during data acquisition is demonstrated. In contrast to some previous studies, results also show that the inclusion of retrospective processing also improved ellipsoid fits and both the sensitivity and specificity of group tractographic results, even for navigated data. Matches with anatomical WM maps are highest throughout the brain for data that have been both navigated and processed using TORTOISE. The inclusion of both prospective and retrospective motion correction with EPI distortion correction is important for DTI analysis, particularly when studying subject populations that are prone to motion. Hum Brain Mapp 37:4405-4424, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Taylor, Paul A.; Alhamud, A.; Saleh, Muhammad G.; Meintjes, Ernesta] Univ Cape Town, Dept Human Biol, Fac Hlth Sci, MRC UCT Med Imaging Res Unit, Cape Town, South Africa. [Taylor, Paul A.] African Inst Math Sci, Muizenberg, Western Cape, South Africa. [Taylor, Paul A.] NIH, Sci & Stat Comp Core, Bldg 10, Bethesda, MD 20892 USA. [van der Kouwe, Andre] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Laughton, Barbara] Univ Stellenbosch, Dept Paediat & Child Hlth, Childrens Infect Dis Clin Res Unit, Stellenbosch, South Africa. RP Taylor, PA (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Human Biol, ZA-7925 Cape Town, South Africa. EM neon.taylor@gmail.com FU NRF/DST South African Research Chairs Initiative; NIH [R01HD071664, R21MH096559]; NRF [CPR20110614000019421]; Medical Research Council (MRC); NIMH; NINDS Intramural Research Programs of the NIH FX Contract grant sponsor: NRF/DST South African Research Chairs Initiative; Contract grant sponsor: NIH; Contract grant number: R01HD071664 and R21MH096559; Contract grant sponsor: NRF; Contract grant number: CPR20110614000019421; Contract grant sponsor: The Medical Research Council (MRC); Contract grant sponsor: NIMH and NINDS Intramural Research Programs of the NIH NR 44 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD DEC PY 2016 VL 37 IS 12 BP 4405 EP 4424 DI 10.1002/hbm.23318 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB5FL UT WOS:000387399200014 PM 27436169 ER PT J AU Eleftherianos, I Castillo, JC Patrnogic, J AF Eleftherianos, Ioannis Castillo, Julio Cesar Patrnogic, Jelena TI TGF-beta signaling regulates resistance to parasitic nematode infection in Drosophila melanogaster SO IMMUNOBIOLOGY LA English DT Article DE Immunity; Infection; TGF-beta ID PHOTORHABDUS-ASYMBIOTICA; ENTOMOPATHOGENIC NEMATODES; IMMUNE-RESPONSES; ADULT FLIES; BACTERIA; INSECT; HOST; MODEL; RECOGNITION; PATHWAY AB Over the past decade important advances have been made in the field of innate immunity; however, our appreciation of the signaling pathways and molecules that participate in host immune responses to parasitic nematode infections lags behind that of responses to microbial challenges. Here we have examined the regulation and immune activity of Transforming Growth Factor-beta (TGF-beta) signaling in the model host Drosophila melanogaster upon infection with the nematode parasites Heterorhabditis gerrardi and H. bacteriophora containing their mutualistic bacteria Photorhabdus. We have found that the genes encoding the Activin and Bone Morphogenic Protein (BMP) ligands Dawdle (Daw) and Decapentaplegic (Dpp) are transcriptionally induced in flies responding to infection with the nematode parasites, containing or lacking their associated bacteria. We also show that deficient Daw or Dpp regulates the survival of D. melanogaster adults to the pathogens, whereas inactivation of Daw reduces the persistence of the nematodes in the mutant flies. These findings demonstrate a novel role for the TGF-beta signaling pathways in the host anti-nematode immune response. Understanding the molecular mechanisms of host anti-nematode processes will potentially lead to the development of novel means for the efficient control of parasitic nematodes. (C) 2016 Elsevier GmbH. All rights reserved. C1 [Eleftherianos, Ioannis; Castillo, Julio Cesar; Patrnogic, Jelena] George Washington Univ, Dept Biol Sci, 800 22nd St NW, Washington, DC 20052 USA. [Castillo, Julio Cesar] NIH, Lab Malaria & Vector Res, Bldg 10, Bethesda, MD 20892 USA. RP Eleftherianos, I (reprint author), George Washington Univ, Dept Biol Sci, 800 22nd St NW, Washington, DC 20052 USA. EM ioannise@gwu.edu FU NIH [1R01AI110675-01, 1R56AI110675-01] FX We thank members of the Department of Biological Sciences at GWU for critical reading of the manuscript. The research herein was supported by NIH grants 1R01AI110675-01 and 1R56AI110675-01. NR 47 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD DEC PY 2016 VL 221 IS 12 BP 1362 EP 1368 DI 10.1016/j.imbio.2016.07.011 PG 7 WC Immunology SC Immunology GA EC1AF UT WOS:000387835200005 PM 27473342 ER PT J AU Karami, S Han, Y Pande, M Cheng, I Rudd, J Pierce, BL Nutter, EL Schumacher, FR Kote-Jarai, Z Lindstrom, S Witte, JS Fang, S Han, J Kraft, P Hunter, DJ Song, F Hung, RJ McKay, J Gruber, SB Chanock, SJ Risch, A Shen, H Haiman, CA Boardman, L Ulrich, CM Casey, G Peters, U Al Olama, AA Berchuck, A Berndt, SI Bezieau, S Brennan, P Brenner, H Brinton, L Caporaso, N Chan, AT Chang-Claude, J Christiani, DC Cunningham, JM Easton, D Eeles, RA Eisen, T Gala, M Gallinger, SJ Gayther, SA Goode, EL Gronberg, H Henderson, BE Houlston, R Joshi, AD Kury, S Landi, MT Le Marchand, L Muir, K Newcomb, PA Permuth-Wey, J Pharoah, P Phelan, C Potter, JD Ramus, SJ Risch, H Schildkraut, J Slattery, ML Song, H Wentzensen, N White, E Wiklund, F Zanke, BW Sellers, TA Zheng, W Chatterjee, N Amos, CI Doherty, JA AF Karami, Sara Han, Younghun Pande, Mala Cheng, Iona Rudd, James Pierce, Brandon L. Nutter, Ellen L. Schumacher, Fredrick R. Kote-Jarai, Zsofia Lindstrom, Sara Witte, John S. Fang, Shenying Han, Jiali Kraft, Peter Hunter, David J. Song, Fengju Hung, Rayjean J. McKay, James Gruber, Stephen B. Chanock, Stephen J. Risch, Angela Shen, Hongbing Haiman, Christopher A. Boardman, Lisa Ulrich, Cornelia M. Casey, Graham Peters, Ulrike Al Olama, Ali Amin Berchuck, Andrew Berndt, Sonja I. Bezieau, Stephane Brennan, Paul Brenner, Hermann Brinton, Louise Caporaso, Neil Chan, Andrew T. Chang-Claude, Jenny Christiani, David C. Cunningham, Julie M. Easton, Douglas Eeles, Rosalind A. Eisen, Timothy Gala, Manish Gallinger, Steven J. Gayther, Simon A. Goode, Ellen L. Gronberg, Henrik Henderson, Brian E. Houlston, Richard Joshi, Amit D. Kury, Sebastien Landi, Mari T. Le Marchand, Loic Muir, Kenneth Newcomb, Polly A. Permuth-Wey, Jenny Pharoah, Paul Phelan, Catherine Potter, John D. Ramus, Susan J. Risch, Harvey Schildkraut, Joellen Slattery, Martha L. Song, Honglin Wentzensen, Nicolas White, Emily Wiklund, Fredrik Zanke, Brent W. Sellers, Thomas A. Zheng, Wei Chatterjee, Nilanjan Amos, Christopher I. Doherty, Jennifer A. CA GECCO GAME-ON Network CORECT CORECT DRIVE ELLIPSE FOCI TRICL TI Telomere structure and maintenance gene variants and risk of five cancer types SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE telomere structure; telomere maintenance; cancer risk; GWAS; meta-analysis; lung cancer; breast cancer; ovarian cancer; prostate cancer; colorectal cancer ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; OVARIAN-CANCER; IDENTIFIES 3; METAANALYSIS; LENGTH; IMPUTATION; BREAST; REGIONS AB Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs <= 3.08 X 10(-5)). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. C1 [Karami, Sara; Rudd, James; Nutter, Ellen L.; Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH USA. [Han, Younghun; Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Pande, Mala] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Cheng, Iona] Stanford Canc Inst, Stanford, CA USA. [Pierce, Brandon L.] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Pierce, Brandon L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Pierce, Brandon L.] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Schumacher, Fredrick R.; Gruber, Stephen B.; Haiman, Christopher A.; Casey, Graham; Gayther, Simon A.; Henderson, Brian E.; Ramus, Susan J.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA USA. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, Oncogenet Team, London, England. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London, England. [Lindstrom, Sara; Christiani, David C.] Harvard TH Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Genet & Canc Epidemiol, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Fang, Shenying] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Han, Jiali] Indiana Univ, Dept Epidemiol, Fairbanks Sch Publ Hlth, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Kraft, Peter; Hunter, David J.; Joshi, Amit D.] Harvard Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. [Song, Fengju] Tianjin Med Univ, Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Epidemiol & Biostat,Key Lab Canc Prevent & T, Tianjin, Peoples R China. [Hung, Rayjean J.; Gallinger, Steven J.] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McKay, James; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Genet Canc Susceptibil Grp, Lyon, France. [Chanock, Stephen J.; Berndt, Sonja I.; Brinton, Louise; Caporaso, Neil; Landi, Mari T.; Wentzensen, Nicolas; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, TLRC H, Heidelberg, Germany. [Shen, Hongbing] Nanjing Med Univ, Dept Epidemiol & Biostat, Collaborat Innovat Ctr Canc Med,Sch Publ Hlth, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Jiangsu, Peoples R China. [Boardman, Lisa; Cunningham, Julie M.; Goode, Ellen L.] Mayo Clin, Rochester, MN USA. [Ulrich, Cornelia M.; Slattery, Martha L.] Huntsman Canc Inst, Salt Lake City, UT USA. [Ulrich, Cornelia M.; Peters, Ulrike; Newcomb, Polly A.; Potter, John D.; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Al Olama, Ali Amin; Easton, Douglas] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Berchuck, Andrew] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Bezieau, Stephane; Kury, Sebastien] CHU Nantes, Serv Genet Med, Nantes, France. [Brenner, Hermann] Deutsch Krebsforschungszentrum, Klin Epidemiol & Alternsforsch, Heidelberg, Germany. [Chan, Andrew T.; Gala, Manish] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Easton, Douglas; Pharoah, Paul; Song, Honglin] Univ Cambridge, Dept Oncol, Cambridge, England. [Eisen, Timothy] Addenbrookes Hosp, Cambridge Biomed Campus, Cambridge, England. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Houlston, Richard] Inst Canc Res, London, England. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Div Epidemiol, Honolulu, HI 96822 USA. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Permuth-Wey, Jenny; Phelan, Catherine; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Risch, Harvey] Yale Sch Publ Hlth, New Haven, CT USA. [Schildkraut, Joellen] Univ Virginia, Charlottesville, VA USA. [Zanke, Brent W.] Univ Ottawa, Ottawa Hosp, Res Inst, Div Hematol, Ottawa, ON, Canada. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. RP Doherty, JA (reprint author), Geisel Sch Med Dartmouth, Dept Community & Family Med, Dept Epidemiol, One Med Ctr Dr,7927 Rubin Bldg,Room 853, Lebanon, NH 03756 USA. EM Jennifer.A.Doherty@Dartmouth.edu RI Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; Risch, Angela/H-2669-2013; OI Brenner, Hermann/0000-0002-6129-1572; Risch, Angela/0000-0002-8026-5505; Pierce, Brandon/0000-0002-7829-952X; Houlston, Richard/0000-0002-5268-0242 FU National Institutes of Health (NIH), National Cancer Institute (NCI) [R01 CA151989]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; (COGS), Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; US NCI GAME-ON Post-GWAS Initiative [U19-CA148112]; TRICL (Transdisciplinary Research for Cancer of Lung): NIH [U19 CA148127-01]; Canadian Cancer Society Research Institute [020214]; DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): NIH [U19 CA148065]; CORECT (ColoRectal Transdisciplinary Study): NIH [U19 CA148107, R01 CA81488, P30 CA014089]; ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility); GAMEON U19 initiative for prostate cancer (ELLIPSE) [U19 CA148537]; FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies) [NIH U19 CA148112-01, R01-CA122443, P50-CA136393, P30-CA15083]; Cancer Research UK [C490/A8339, C490/A16561, C490/A10119, C490/A10124]; GECCO: NCI, NIH, U.S. Department of Health and Human Services (DHHS) [U01 CA137088, R01 CA059045]; ASTERISK: a Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); COLO23: NIH [R01 CA60987]; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NIH [R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003, UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA042182]; MEC: NIH [R37 CA54281, P01 CA033619, R01 CA63464]; Ontario Registry for Studies of Familial Colorectal Cancer (OFCCR: NIH) [U01 CA074783]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research (OFCCR); Ontario Ministry of Research and Innovation; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, NCI, NIH, DHHS; Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS; Nat Genet; Colon CGEMS pancreatic cancer scan (PanScan); NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200, NIH U01 HG004446, NIH GEI U01 HG 004438]; GENEVA Coordinating Center; Johns Hopkins University Center for Inherited Disease Research; PMH: NIH [R01 CA076366]; VITAL: NIH [K05 CA154337]; WHI: National Heart, Lung, and Blood Institute, NIH, DHHS (The WHI program) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; MD Anderson: NCI [NIH K07CA160753] FX Grant sponsor: The National Institutes of Health (NIH), National Cancer Institute (NCI); Grant number: R01 CA151989; Grant sponsor: European Community's Seventh Framework Programme under grant agreement no 223175; Grant number: HEALTH-F2-2009-223175; Grant sponsor: (COGS), Cancer Research UK; Grant numbers: C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/ A8384, C5047/A15007, C5047/A10692, C8197/A16565; Grant sponsor: National Institutes of Health; Grant number: CA128978; Grant sponsor: Post-Cancer GWAS initiative; Grant numbers: 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 -the GAME-ON initiative; Grant sponsor: Department of Defense; Grant number: W81XWH-10-1-0341; Grant sponsors: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund; Grant sponsor: US NCI GAME-ON Post-GWAS Initiative; Grant number: U19-CA148112; Grant sponsor: TRICL (Transdisciplinary Research for Cancer of Lung): NIH U19 CA148127-01 (PI: Amos); Grant sponsors: Canadian Cancer Society Research Institute (no. 020214, PI: Hung); DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): NIH U19 CA148065; CORECT (ColoRectal Transdisciplinary Study): NIH U19 CA148107; R01 CA81488, P30 CA014089; ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility); Grant sponsors: GAMEON U19 initiative for prostate cancer (ELLIPSE); Grant number: U19 CA148537; Grant sponsor: FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies); Grant numbers: NIH U19 CA148112-01 (PI: Sellers), R01-CA122443, P50-CA136393, P30-CA15083 (PI: Goode); Grant sponsor: Cancer Research UK; Grant numbers: C490/A8339, C490/A16561, C490/A10119, C490/A10124 (PI: Pharoah); Grant sponsor: GECCO: NCI, NIH, U.S. Department of Health and Human Services (DHHS); Grant numbers: U01 CA137088, R01 CA059045; Grant sponsors: ASTERISK: a Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC); COLO2&3: NIH (R01 CA60987); Grant sponsor: DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: NIH (R01 CA48998 to M. L. Slattery); Grant sponsor: NIH (HPFS); Grant numbers: P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003; Grant sponsor: NIH (NHS); Grant numbers: UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003; Grant sponsors: NIH (PHS); Grant number: R01 CA042182; Grant sponsor: MEC: NIH; Grant numbers: R37 CA54281, P01 CA033619 and R01 CA63464; Grant sponsor: Ontario Registry for Studies of Familial Colorectal Cancer (OFCCR: NIH); Grant number: U01 CA074783; Grant sponsors: Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research (OFCCR), Ontario Ministry of Research and Innovation; Grant sponsors: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and Division of Cancer Prevention, NCI, NIH, DHHS; Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al.; Genome-wide association study of prostate cancer identifies a second risk locus at 8q24; Grant sponsors: Nat Genet 2007 May; 39(5): 645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep; 41(9): 986-90, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar; 42(3): 224-8), and the Lung Cancer and Smoking study (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov; 85(5): 679-91); the prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems. cancer. gov/data/) accession numbers phs000207. v1. p1 and phs000206. v3. p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www. ncbi. nlm. nih. gov/gap) through accession number phs000093.v2.p2; Grant sponsor: NIH, Genes, Environment and Health Initiative (GEI) (Lung Cancer and Smoking study); Grant numbers: Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438; Grant sponsors: GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping; Grant sponsor: PMH: NIH; Grant number: R01 CA076366 to P. A. Newcomb; Grant sponsors: VITAL: NIH; Grant numbers: K05 CA154337; Grant sponsors: WHI: National Heart, Lung, and Blood Institute, NIH, DHHS (The WHI program); Grant numbers: HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C; Grant sponsor: MD Anderson: NCI; Grant number: NIH K07CA160753 (PI: Pande) NR 47 TC 0 Z9 0 U1 21 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC PY 2016 VL 139 IS 12 BP 2655 EP 2670 DI 10.1002/ijc.30288 PG 16 WC Oncology SC Oncology GA EB8CU UT WOS:000387619400003 PM 27459707 ER PT J AU Hussain, S Kodavanti, PP Marshburn, JD Janoshazi, A Marinakos, SM George, M Rice, A Wiesner, MR Garantziotis, S AF Hussain, Salik Kodavanti, Preeti P. Marshburn, Jamie D. Janoshazi, Agnes Marinakos, Stella M. George, Margaret Rice, Annette Wiesner, Mark R. Garantziotis, Stavros TI Decreased Uptake and Enhanced Mitochondrial Protection Underlie Reduced Toxicity of Nanoceria in Human Monocyte-Derived Macrophages SO JOURNAL OF BIOMEDICAL NANOTECHNOLOGY LA English DT Article DE Nanoceria; Nanotoxicity; Monocyte-Derived Macrophages; Mitochondrial Damage ID CERIUM OXIDE NANOPARTICLES; DIOXIDE NANOPARTICLES; OXIDATIVE STRESS; CARBON-BLACK; CEO2 NANOPARTICLES; EPITHELIAL-CELLS; CELLULAR UPTAKE; SURFACE-AREA; IN-VITRO; LUNG AB Cerium dioxide nanoparticles (nanoceria), currently used as catalysts including additives to diesel fuel, also present potential as a novel therapeutic agent for disorders involving oxidative stress. However, little is known about the effects of nanoceria on primary human cells involved in the innate immune response. Here, we evaluate nanoceria effects on monocyte derived macrophages (MDMs) from healthy human subjects. Peripheral blood monocytes were isolated from healthy human volunteers. MDMs were obtained by maturing monocytes over a five-day period. MDMs were exposed to well-characterized nanoceria suspensions (0, 5, 10, 20 mu g/mL) for 24 or 48 hours. We evaluated particle uptake, ultrastructural changes, cytotoxicity, and mitochondrial damage in MDMs through transmission electron microscopy (TEM), confocal imaging, flow cytometry, spectrometry, western blots, and immunofluorescence techniques. The role that intracellular concentration of nanoceria plays in the toxicity of MDMs was evaluated by 3D image analysis and compared to monocytes as a nanoceria sensitive cell model. Nanoceria failed to induce cytotoxicity in MDMs at the tested doses. Nanoceria-exposed MDMs showed no mitochondrial damage and displayed significant accumulation of anti-apoptotic proteins (Mcl-1 and Bcl-2) during the maturation process. TEM and confocal analyses revealed efficient uptake of nanoceria by MDMs, however 3D image analyses revealed lower nanoceria accumulation per unit cell volume in MDMs compared to monocytes. Taken together, our results suggest that mitochondrial protection and reduced volume-corrected intracellular nanoparticle concentration account for the lower sensitivity of human MDMs to nanoceria. C1 [Hussain, Salik; Kodavanti, Preeti P.; Marshburn, Jamie D.; George, Margaret; Rice, Annette; Garantziotis, Stavros] NIEHS, Clin Res Unit, POB 12233, Res Triangle Pk, NC 27709 USA. [Janoshazi, Agnes] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Marinakos, Stella M.; Wiesner, Mark R.] Duke Univ, Ctr Environm Implicat NanoTechnol, Durham, NC 27708 USA. RP Hussain, S (reprint author), NIEHS, Clin Res Unit, POB 12233, Res Triangle Pk, NC 27709 USA. EM salik.hussain@nih.gov RI Garantziotis, Stavros/A-6903-2009; Hussain, Salik/O-1687-2016 OI Garantziotis, Stavros/0000-0003-4007-375X; FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS); National Science Foundation (NSF); Environmental Protection Agency (EPA) under NSF [EF-0830093, DBI-1266252]; Center for the Environmental Implications of NanoTechnology (CEINT) FX This work was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS). A portion of this work was supported by the National Science Foundation (NSF) and the Environmental Protection Agency (EPA) under NSF Cooperative Agreement EF-0830093 and DBI-1266252, Center for the Environmental Implications of NanoTechnology (CEINT). We wish to gratefully acknowledge Carl Bortner, Maria Sifre, Kevin Katen, Connie Cummings and Deloris Sutton for technical assistance and the contribution of the Clinical Research Unit staff in the recruitment of human subjects for this study. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the NSF or the EPA. This work has not been subjected to EPA review and no official endorsement should be inferred. NR 48 TC 0 Z9 0 U1 13 U2 13 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1550-7033 EI 1550-7041 J9 J BIOMED NANOTECHNOL JI J. Biomed. Nanotechnol. PD DEC PY 2016 VL 12 IS 12 BP 2139 EP 2150 DI 10.1166/jbn.2016.2320 PG 12 WC Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Science & Technology - Other Topics; Materials Science GA EC0JH UT WOS:000387786100005 PM 28286432 ER PT J AU Auld, DS Jimenez, M Yue, K Busby, S Chen, YC Bowes, S Wendel, G Smith, T Zhang, JH AF Auld, Douglas S. Jimenez, Marta Yue, Kimberley Busby, Scott Chen, Yu-Chi Bowes, Scott Wendel, Greg Smith, Thomas Zhang, Ji-Hu TI Matrix-Based Activity Pattern Classification as a Novel Method for the Characterization of Enzyme Inhibitors Derived from High-Throughput Screening SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE mode of inhibition; enzyme inhibitors; inhibitor classification; enzyme assays ID FIREFLY LUCIFERASE; RNA-POLYMERASE; IDENTIFICATION; DISCOVERY; REPORTER; ORIGINS; BINDING; DRUGS; MODE AB One of the central questions in the characterization of enzyme inhibitors is determining the mode of inhibition (MOI). Classically, this is done with a number of low-throughput methods in which inhibition models are fitted to the data. The ability to rapidly characterize the MOI for inhibitors arising from high-throughput screening in which hundreds to thousands of primary inhibitors may need to be characterized would greatly help in lead selection efforts. Here we describe a novel method for determining the MOI of a compound without the need for curve fitting of the enzyme inhibition data. We provide experimental data to demonstrate the utility of this new high-throughput MOI classification method based on nonparametric analysis of the activity derived from a small matrix of substrate and inhibitor concentrations (e.g., from a 4(S) x 4(I) matrix). Lists of inhibitors from four different enzyme assays are studied, and the results are compared with the previously described IC50-shift method for MOI classification. The MOI results from this method are in good agreement with the known MOI and compare favorably with those from the IC50-shift method. In addition, we discuss some advantages and limitations of the method and provide recommendations for utilization of this MOI classification method. C1 [Auld, Douglas S.; Jimenez, Marta; Yue, Kimberley; Busby, Scott; Chen, Yu-Chi; Bowes, Scott; Wendel, Greg; Smith, Thomas; Zhang, Ji-Hu] Novartis Inst Biomed Res, Ctr Prote Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA. [Chen, Yu-Chi] Natl Ctr Adv Translat Sci, Bethesda, MD USA. RP Zhang, JH (reprint author), Novartis Inst Biomed Res, Ctr Prote Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA. EM ji-hu.zhang@novartis.com NR 24 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD DEC PY 2016 VL 21 IS 10 BP 1075 EP 1089 DI 10.1177/1087057116667255 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA EB9MW UT WOS:000387720200007 PM 27601436 ER PT J AU Dai, S Li, R Long, Y Titus, S Zhao, JH Huang, RL Xia, MH Zheng, W AF Dai, Sheng Li, Rong Long, Yan Titus, Steve Zhao, Jinghua Huang, Ruili Xia, Menghang Zheng, Wei TI One-Step Seeding of Neural Stem Cells with Vitronectin-Supplemented Medium for High-Throughput Screening Assays SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE high-content screening; high-throughput screening; HTS; induced pluripotent stem cells; iPSC; neuronal cells; neural stem cells; plate coating; vitronectin ID PATIENT; NEURONS; DISEASE; CULTURE; PROGENITORS; EVOLUTION AB Human neuronal cells differentiated from induced pluripotent cells have emerged as a new model system for the study of disease pathophysiology and evaluation of drug efficacy. Differentiated neuronal cells are more similar in genetics and biological content to human brain cells than other animal disease models. However, culture of neuronal cells in assay plates requires a labor-intensive procedure of plate precoating, hampering its applications in high-throughput screening (HTS). We developed a simplified method with one-step seeding of neural stem cells in assay plates by supplementing the medium with a recombinant human vitronectin (VTN), thus avoiding plate precoating. Robust results were obtained from cell viability, calcium response, and neurite outgrowth assays using this new method. Our data demonstrate that this approach greatly simplifies high-throughput assays using neuronal cells differentiated from human stem cells for translational research. C1 [Dai, Sheng; Li, Rong; Long, Yan; Titus, Steve; Zhao, Jinghua; Huang, Ruili; Xia, Menghang; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. [Dai, Sheng] Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Hangzhou, Zhejiang, Peoples R China. [Long, Yan] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou, Guangdong, Peoples R China. RP Zheng, W (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health FX This work was funded by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. NR 30 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD DEC PY 2016 VL 21 IS 10 BP 1112 EP 1124 DI 10.1177/1087057116670068 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA EB9MW UT WOS:000387720200010 PM 27647668 ER PT J AU Foley, TL Dorjsuren, D Dexheimer, TS Burkart, MD Wight, WC Simeonov, A AF Foley, Timothy L. Dorjsuren, Dorjbal Dexheimer, Thomas S. Burkart, Michael D. Wight, William C. Simeonov, Anton TI A Platform to Enable the Pharmacological Profiling of Small Molecules in Gel-Based Electrophoretic Mobility Shift Assays SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE high-throughput screening (HTS); small-molecule testing; electrophoretic techniques; enzymatic assays and analyses; electrophoretic mobility shift assay (EMSA); polyacrylamide gel electrophoresis (PAGE) ID INHIBITORS; IDENTIFICATION AB We describe a polyacrylamide gel casting cassette that overcomes limitations of commercially available gel electrophoresis equipment. This apparatus molds a single polyacrylamide gel that can evaluate more than 200 samples in parallel, is loaded with a multichannel pipettor, and is flexible with respect to composition of the separating matrix. We demonstrate its use to characterize inhibitors of enzymes that modify protein and nucleic acid substrates. Throughputs of greater than 1000 samples per day were achieved when this system was paired with a quantitative laser-based imaging system, yielding data of remarkable quality. C1 [Foley, Timothy L.; Dorjsuren, Dorjbal; Dexheimer, Thomas S.; Simeonov, Anton] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. [Burkart, Michael D.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Wight, William C.] Luxon Engn LLC, San Diego, CA USA. [Foley, Timothy L.] Pfizer, Primary Pharmacol Grp, Pharmacokinet Dynam & Metabolism New Chem EntE, Groton, CT USA. [Dexheimer, Thomas S.] Michigan State Univ, Dept Pharmacol & Toxicol, Assay Dev & Drug Repurposing Core Facil, E Lansing, MI 48824 USA. RP Simeonov, A (reprint author), NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM asimeono@mail.nih.gov FU intramural research program of the National Center for Advancing Translational Sciences; NIH [1R03MH083266, R21AI090213] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the intramural research program of the National Center for Advancing Translational Sciences, as well as NIH award numbers 1R03MH083266 and R21AI090213 (M.D.B.). NR 12 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD DEC PY 2016 VL 21 IS 10 BP 1125 EP 1131 DI 10.1177/1087057116652895 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA EB9MW UT WOS:000387720200011 PM 27269812 ER PT J AU Schmidt, KT Chau, CH Price, DK Figg, WD AF Schmidt, Keith T. Chau, Cindy H. Price, Douglas K. Figg, William D. TI Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE precision medicine; oncology; molecular targeted therapy; next-generation sequencing ID CELL LUNG-CANCER; METASTATIC BREAST-CANCER; IMPLEMENTATION CONSORTIUM GUIDELINES; THIOPURINE METHYLTRANSFERASE GENOTYPE; 1ST GLOBAL APPROVAL; BRAF V600 MUTATIONS; GROUP 1-98 TRIAL; PHASE-II TRIAL; OPEN-LABEL; TRASTUZUMAB EMTANSINE AB Precision medicine in oncology is the result of an increasing awareness of patient-specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (eg, HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to an FDA-approved targeted therapy (eg, trastuzumab, erlotinib). Clinically relevant germline mutations in drug-metabolizing enzymes and transporters (eg, TPMT, DPYD) have been shown to impact drug response, providing a rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers has been shown to help direct treatment decisions, especially in breast cancer (eg, Oncotype DX). More recently, the use of next-generation sequencing to detect many potential actionable cancer molecular alterations is further shifting the 1 gene-1 drug paradigm toward a more comprehensive, multigene approach. Currently, many clinical trials (eg, NCI-MATCH, NCI-MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials such as the NCI-MATCH will help determine the clinical utility and future development of the precision-medicine approach. C1 [Schmidt, Keith T.; Figg, William D.] NIH, Clin Pharmacol Program, Off Clin Director, Bldg 10, Bethesda, MD 20892 USA. [Chau, Cindy H.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10 Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. NR 124 TC 3 Z9 3 U1 19 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD DEC PY 2016 VL 56 IS 12 BP 1484 EP 1499 DI 10.1002/jcph.765 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB8SP UT WOS:000387661500004 PM 27197880 ER PT J AU Alves, MC Galeano, DC Santos, WS Lee, C Bolch, WE Hunt, JG da Silva, AX Carvalho, AB AF Alves, M. C. Galeano, D. C. Santos, W. S. Lee, Choonsik Bolch, Wesley E. Hunt, John G. da Silva, A. X. Carvalho, A. B., Jr. TI Comparison of the effective dose rate to aircrew members using hybrid computational phantoms in standing and sitting postures SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article DE aircrew dosimetry; effective dose conversion coefficients; Monte Carlo simulation; effective dose rate; sitting phantom ID COSMIC-RADIATION EXPOSURE; CONVERSION COEFFICIENTS; CREW; ATMOSPHERE; DOSIMETRY; ORGAN; NURBS AB Aircraft crew members are occupationally exposed to considerable levels of cosmic radiation at flight altitudes. Since aircrew (pilots and passengers) are in the sitting posture for most of the time during flight, and up to now there has been no data on the effective dose rate calculated for aircrew dosimetry in flight altitude using a sitting phantom, we therefore calculated the effective dose rate using a phantom in the sitting and standing postures in order to compare the influence of the posture on the radiation protection of aircrew members. We found that although the better description of the posture in which the aircrews are exposed, the results of the effective dose rate calculated with the phantom in the sitting posture were very similar to the results of the phantom in the standing posture. In fact we observed only a 1% difference. These findings indicate the adequacy of the use of dose conversion coefficients for the phantom in the standing posture in aircrew dosimetry. We also validated our results comparing the effective dose rate obtained using the standing phantom with values reported in the literature. It was observed that the results presented in this study are in good agreement with other authors (the differences are below 30%) who have measured and calculated effective dose rates using different phantoms. C1 [Alves, M. C.; Galeano, D. C.; Carvalho, A. B., Jr.] Univ Fed Sergipe, Dept Fis, Campus Prof Jose Aloisio de Campos, BR-100000 Sao Cristovao, SE, Brazil. [Santos, W. S.] Univ Fed Uberlandia, Inst Fis, INFIS UFU, Caixa Postal 593, BR-38400902 Uberlandia, MG, Brazil. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Bolch, Wesley E.] Univ Florida, Dept Nucl & Radiol Engn, Gainesville, FL 32611 USA. [Hunt, John G.] Inst Radioprotecao & Dosimetria, Dosimetry Div, BR-22783127 Rio De Janeiro, RJ, Brazil. [Hunt, John G.] Univ Fed Rio de Janeiro, Dept Nucl Engn, Escola Politecn, BR-21941972 Rio De Janeiro, Brazil. [Galeano, D. C.] Univ Fed Rondonia, Dept Fis, Porto Velho, RO, Brazil. RP Alves, MC (reprint author), Univ Fed Sergipe, Dept Fis, Campus Prof Jose Aloisio de Campos, BR-100000 Sao Cristovao, SE, Brazil. EM alves.materia@gmail.com FU UFS; CNPq; INCT; CAPES FX The authors thank UFS, CNPq, INCT and CAPES for the partial financial support. NR 31 TC 0 Z9 0 U1 6 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD DEC PY 2016 VL 36 IS 4 BP 885 EP 901 DI 10.1088/0952-4746/36/4/885 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA EB8YY UT WOS:000387679200001 PM 27798410 ER PT J AU Lack, JB Lange, JD Tang, AD Corbett-Detig, RB Pool, JE AF Lack, Justin B. Lange, Jeremy D. Tang, Alison D. Corbett-Detig, Russell B. Pool, John E. TI A Thousand Fly Genomes: An Expanded Drosophila Genome Nexus SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE Drosophila melanogaster; genomic variation; reference alignment; data resource ID GENETIC REFERENCE PANEL; MELANOGASTER; POPULATION; PATTERNS; RESOURCE; LINES AB The Drosophila Genome Nexus is a population genomic resource that provides D. melanogaster genomes from multiple sources. To facilitate comparisons across data sets, genomes are aligned using a common reference alignment pipeline which involves two rounds of mapping. Regions of residual heterozygosity, identity-by-descent, and recent population admixture are annotated to enable data filtering based on the user's needs. Here, we present a significant expansion of the Drosophila Genome Nexus, which brings the current data object to a total of 1,121 wild-derived genomes. New additions include 305 previously unpublished genomes from inbred lines representing six population samples in Egypt, Ethiopia, France, and South Africa, along with another 193 genomes added from recently-published data sets. We also provide an aligned D. simulans genome to facilitate divergence comparisons. This improved resource will broaden the range of population genomic questions that can addressed from multi-population allele frequencies and haplotypes in this model species. The larger set of genomes will also enhance the discovery of functionally relevant natural variation that exists within and between populations. C1 [Lack, Justin B.; Lange, Jeremy D.; Pool, John E.] Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. [Tang, Alison D.; Corbett-Detig, Russell B.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Lack, Justin B.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Corbett-Detig, Russell B.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. RP Pool, JE (reprint author), Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. EM jpool@wisc.edu FU NIH [R01 GM111797, F32 GM106594]; USDA Hatch grant [WIS01900] FX The UW-Madison Center for High Throughput Computing provided computational assistance and resources for this work. This research was funded by NIH grants R01 GM111797 to JEP and F32 GM106594 to JBL, and by USDA Hatch grant WIS01900 to JEP. NR 23 TC 1 Z9 1 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD DEC PY 2016 VL 33 IS 12 BP 3308 EP 3313 DI 10.1093/molbev/msw195 PG 6 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA EC2FO UT WOS:000387925300024 PM 27687565 ER PT J AU Kelsey, JS Cataisson, C Chen, JQ Herrmann, MA Petersen, ME Baumann, DO McGowan, KM Yuspa, SH Keck, GE Blumberg, PM AF Kelsey, Jessica S. Cataisson, Christophe Chen, Jinqiu Herrmann, Michelle A. Petersen, Mark E. Baumann, David O. McGowan, Kevin M. Yuspa, Stuart H. Keck, Gary E. Blumberg, Peter M. TI Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin SO MOLECULAR CARCINOGENESIS LA English DT Article DE PMA; tumor promotion; bryostatin; Merle 23; mouse epidermal cells; skin cancer ID PROTEIN-KINASE-C; ESTER TUMOR PROMOTERS; PHORBOL ESTER; CLINICAL DEVELOPMENT; DOWN-REGULATION; PKC INHIBITORS; IN-VITRO; CANCER; LNCAP; DELTA AB Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12-myristate 13-acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity. (c) 2016 Wiley Periodicals, Inc. C1 [Kelsey, Jessica S.; Cataisson, Christophe; Yuspa, Stuart H.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bldg 37,Room 4048B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. [Chen, Jinqiu; Herrmann, Michelle A.] NCI, Collaborat Prot Technol Resource, Ctr Canc Res, Bethesda, MD 20892 USA. [Petersen, Mark E.; Baumann, David O.; McGowan, Kevin M.; Keck, Gary E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bldg 37,Room 4048B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU Intramural Research Program of the National Cancer Institute; Center for Cancer Research [ZiA BC 005270, Z1A BC 005445]; NIH [GM28961] FX Grant sponsor: Intramural Research Program of the National Cancer Institute; Grant sponsor: Center for Cancer Research; Grant numbers: ZiA BC 005270; Z1A BC 005445; Grant sponsor: NIH; Grant number: GM28961 NR 49 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD DEC PY 2016 VL 55 IS 12 BP 2183 EP 2195 DI 10.1002/mc.22460 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EC1GY UT WOS:000387854100024 PM 26859836 ER PT J AU Kimura, MY Thomas, J Tai, XG Guinter, TI Shinzawa, M Etzensperger, R Li, ZH Love, P Nakayama, T Singer, A AF Kimura, Motoko Y. Thomas, Julien Tai, Xuguang Guinter, Terry I. Shinzawa, Miho Etzensperger, Ruth Li, Zhenhu Love, Paul Nakayama, Toshinori Singer, Alfred TI Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; TYROSINE KINASE; RUNX PROTEINS; CD4; THYMOCYTES; DIFFERENTIATION; EXPRESSION; CHOICE; MOLECULES; ANTIGENS AB Major histocompatibility complex class I (MHC I) positive selection of CD8(+) T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8(+) thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8(+) T cells. Consequently, lineage errors did not occur except when MHC I TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection. C1 [Kimura, Motoko Y.; Thomas, Julien; Tai, Xuguang; Guinter, Terry I.; Shinzawa, Miho; Etzensperger, Ruth; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Li, Zhenhu; Love, Paul] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Lab Mammalian Genes & Dev, NIH, Bethesda, MD USA. [Kimura, Motoko Y.; Nakayama, Toshinori] Chiba Univ, Dept Immunol, Chiba, Japan. RP Kimura, MY; Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.; Kimura, MY (reprint author), Chiba Univ, Dept Immunol, Chiba, Japan. EM kimuramo@chiba-u.jp; singera@nih.gov RI Nakayama, Toshinori/E-1067-2017 FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research; Ministry of Education, Culture, Science and Technology [26893033, 15K08524] FX We thank H. Park, D. Singer and N. Taylor for critical reading of the manuscript; M. Nussenzweig (Rockefeller University) for Rag2GFPTg mice; D. Littman (New York University) for Runx3dYFP knock-in reporter mice; R. Bosselut (National Cancer Institute) for ThpokGFP mice; M. Kubo (Tokyo University of Science, Japan) for SOCS1Tg mice; and S. Sharrow and L. Granger for flow cytometry. Supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Ministry of Education, Culture, Science and Technology (Grant-in-Aid for Research Activity Start-up 26893033; and Scientific Research (C) 15K08524). NR 42 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2016 VL 17 IS 12 BP 1415 EP 1423 DI 10.1038/ni.3560 PG 9 WC Immunology SC Immunology GA EC3VY UT WOS:000388056400012 PM 27668801 ER PT J AU Guitart, X Bonaventura, J Rea, W Orru, M Cellai, L Dettori, I Pedata, F Brugarolas, M Cortes, A Casado, V Chang, CP Narayanan, M Chern, Y Ferre, S AF Guitart, Xavier Bonaventura, Jordi Rea, William Orru, Marco Cellai, Lucrezia Dettori, Ilaria Pedata, Felicita Brugarolas, Marc Cortes, Antonio Casado, Vicent Chang, Ching-Pang Narayanan, Manikandan Chern, Yijuang Ferre, Sergi TI Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Adenosine; ENT1; A(2A) receptor; Huntington disease ID ADENOSINE A(2A) RECEPTORS; A(1) RECEPTORS; RAT MODEL; EXPRESSION; ASTROCYTES; DOPAMINE; BEHAVIOR; NEURONS; PROTEIN; BRAIN AB The initial goal of this study was to investigate alterations in adenosine A(2A) receptor (A(2A)R) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENTI) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [H-3]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENTI binding sites were significantly upregulated in zQl 75 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENTI transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENTI and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease. Published by Elsevier Inc. C1 [Guitart, Xavier; Bonaventura, Jordi; Rea, William; Orru, Marco; Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. [Cellai, Lucrezia; Dettori, Ilaria; Pedata, Felicita] Univ Florence, Div Pharmacol & Toxicol, Dept NEUROFARBA, I-50139 Florence, Italy. [Brugarolas, Marc; Cortes, Antonio; Casado, Vicent] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Brugarolas, Marc; Cortes, Antonio; Casado, Vicent] Ctr Biomed Res Neurodegenerat Dis Network, Barcelona 08028, Spain. [Brugarolas, Marc; Cortes, Antonio; Casado, Vicent] Inst Biomed, Barcelona 08028, Spain. [Chang, Ching-Pang; Chern, Yijuang] Acad Sinica, Div Neurosci, Inst Biomed Sci, Taipei 11529, Taiwan. [Narayanan, Manikandan] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, Intramural Res Program,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; OI Ferre, Sergi/0000-0002-1747-1779; Chern, Yijuang/0000-0002-5842-5429 FU NIDA; NIAID; CHDI Foundation [A-6703] FX We thank Dr. Ling-Hui Li for the assistance in data extraction from the GEO database and statistical analyses and Dr. Alessia Melani for her assistance in the microdialysis experiments. Work supported by the Intramural Funds of NIDA and NIAID, and from CHDI Foundation (grant A-6703). NR 43 TC 2 Z9 2 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD DEC PY 2016 VL 96 BP 47 EP 53 DI 10.1016/j.nbd.2016.08.013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EC3WX UT WOS:000388058900006 PM 27567601 ER PT J AU Juczewski, K von Richthofen, H Bagni, C Celikel, T Fisone, G Krieger, P AF Juczewski, Konrad von Richthofen, Helen Bagni, Claudia Celikel, Tansu Fisone, Gilberto Krieger, Patrik TI Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Fragile X syndrome; Barrel cortex; Sensory processing; Hyperexcitation; In vivo electrophysiology; Fmr1 KO; Whisker system; Gap-crossing task; FMRP; Behavior ID MENTAL-RETARDATION PROTEIN; EXPERIENCE-DEPENDENT PLASTICITY; RAT BARREL CORTEX; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; RECEPTIVE-FIELD PROPERTIES; KNOCK-OUT MICE; SYNAPTIC PLASTICITY; LAYER-IV; HOMEOSTATIC PLASTICITY; SENSORIMOTOR SYSTEM AB Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by the absence or reduction of the fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. In humans, one symptom of FXS is hypersensitivity to sensory stimuli, including touch. We used a mouse model of FXS (Fmr1 KO) to study sensory processing of tactile information conveyed via the whisker system. In vivo electrophysiological recordings in somatosensory barrel cortex showed layer-specific broadening of the receptive fields at the level of layer 2/3 but not layer 4, in response to whisker stimulation. Furthermore, the encoding of tactile stimuli at different frequencies was severely affected in layer 2/3. The behavioral effect of this broadening of the receptive fields was tested in the gap-crossing task, a whisker-dependent behavioral paradigm. In this task the Fmr1 KO mice showed differences in the number of whisker contacts with platforms, decrease in the whisker sampling duration and reduction in the whisker touch-time while performing the task. We propose that the increased excitability in the somatosensory barrel cortex upon whisker stimulation may contribute to changes in the whisking strategy as well as to other observed behavioral phenotypes related to tactile processing in Fmr1 KO mice. (C) 2016 Elsevier Inc. All rights reserved. C1 [Juczewski, Konrad; von Richthofen, Helen; Fisone, Gilberto] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Bagni, Claudia] Katholieke Univ Leuven, VIB Ctr Biol Dis, Leuven, Belgium. [Bagni, Claudia] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy. [Celikel, Tansu] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Neurophysiol, Nijmegen, Netherlands. [Krieger, Patrik] Ruhr Univ Bochum, Fac Med, Dept Syst Neurosci, Bochum, Germany. [Bagni, Claudia] Univ Lausanne, Dept Fundamental Neurosci, Lausanne, Switzerland. RP Juczewski, K (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.; Krieger, P (reprint author), Ruhr Univ Bochum, Dept Syst Neurosci, Univ Str 150, D-44801 Bochum, Germany. EM konrad.juczewski@nih.gov; patrik.krieger@rub.de FU Karolinska Institutet-National Institutes of Health [88/10-607]; FWO [G088415N]; Telethon [GGP15257]; Swedish Research Council [13482] FX This research was supported by Karolinska Institutet-National Institutes of Health (grant number 88/10-607); FWO (grant number G088415N) and Telethon (grant number GGP15257) to CB; Swedish Research Council (grant number 13482) to GF. The authors declare no competing financial interests. NR 130 TC 1 Z9 1 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD DEC PY 2016 VL 96 BP 201 EP 215 DI 10.1016/j.nbd.2016.09.007 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EC3WX UT WOS:000388058900019 PM 27616423 ER PT J AU Yang, LY Greig, NH Huang, YN Hsieh, TH Tweedie, D Yu, QS Hoffer, BJ Luo, Y Kao, YC Wang, JY AF Yang, Ling-Yu Greig, Nigel H. Huang, Ya-Ni Hsieh, Tsung-Hsun Tweedie, David Yu, Qian-Sheng Hoffer, Barry J. Luo, Yu Kao, Yu-Chieh Wang, Jia-Yi TI Post-traumatic administration of the p53 inactivator pifithrin-alpha, oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Traumatic brain injury (TBI); p53; Pifithrin-alpha (PFT-alpha); PFT-alpha oxygen analogue (PFT-alpha (o)); Apoptosis; Motor and cognitive deficits; Puma; Controlled cortical impact (CCI) ID FLUORO-JADE-C; PEPTIDE-1 RECEPTOR AGONIST; TUMOR-SUPPRESSOR GENE; NF-KAPPA-B; CELL-DEATH; DEGENERATING NEURONS; FUNCTIONAL OUTCOMES; UNITED-STATES; UP-REGULATION; HEAD-INJURY AB Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippo campus has been detected after TBI. The hippocampal dysfunction may result in cognitive deficits in learning, memory, and spatial information processing. Our previous studies demonstrated that a p53 inhibitor, pifithrin-alpha oxygen analogue (PFT-alpha (O)), significantly reduced cortical cell death, which is substantial following controlled cortical impact (CCI) TBI, and improved neurological functional outcomes via anti-apoptotic mechanisms. In the present study, we examined the effect of PFT-alpha (O) on CCI TBI-induced hippocampal cellular pathophysiology in light of this brain region's role in memory. To investigate whether p53-dependent apoptosis plays a role in hippocampal neuronal loss and associated cognitive deficits and to define underlying mechanisms, SD rats were subjected to experimental CCI TBI followed by the administration of PFT-alpha or PFT-alpha (O) (2 mg/kg, i.v.) or vehicle at 5 h after TBI. Magnetic resonance imaging (MRI) scans were acquired at 24 h and 7 days post-injury to assess evolving structural hippocampal damage. Fluoro-Jade C was used to stain hippocampal sub-regions, including CA1 and dentate gyrus (DG), for cellular degeneration. Neurological functions, including motor and recognition memory, were assessed by behavioral tests at 7 days post injury. p53, p53 upregulated modulator of apoptosis (PUMA), 4-hydroxynonenal (4-HNE), cyclooxygenase-IV (COX IV), annexin V and NeuN were visualized by double immunofluorescence staining with cell-specific markers. Levels of mRNA encoding for caspase-3, p53, PUMA, Bcl-2, Bcl-2-associated X protein (BAX) and superoxide dismutase (SOD) were measured by RT-qPCR. Our results showed that post-injury administration of PFT-alpha and, particularly, PFT-alpha (O) at 5 h dramatically reduced injury volumes in the ipsilateral hippocampus, improved motor outcomes, and ameliorated cognitive deficits at 7 days after TBI, as evaluated by novel object recognition and open-field test. PFT-alpha and especially PFT-alpha (O) significantly reduced the number of FJC-positive cells in hippocampus CA1 and DG subregions, versus vehicle treatment, and significantly decreased caspase-3 and PUMA mRNA expression. PFT-alpha (O), but not PFT-alpha, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-alpha (O) treatment decreased p53, annexin V and 4-HNE positive neurons in the hippocampal CA1 region. Furthermore, PUMA co-localization with the mitochondrial maker COX IV, and the upregulation of PUMA were inhibited by PFT-alpha (O) after TBI. Our data suggest that PFT-alpha and especially PFT-alpha (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties. (C) 2016 Published by Elsevier Inc. C1 [Yang, Ling-Yu; Huang, Ya-Ni; Wang, Jia-Yi] Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Hsing St, Taipei 110, Taiwan. [Greig, Nigel H.; Tweedie, David; Yu, Qian-Sheng] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Huang, Ya-Ni] Hsin Sheng Jr Coll Med Care & Management, Dept Nursing, Taoyuan, Taiwan. [Hsieh, Tsung-Hsun] Chang Gung Univ, Coll Med, Dept Phys Therapy, Taoyuan, Taiwan. [Hsieh, Tsung-Hsun] Chang Gung Univ, Coll Med, Grad Inst Rehabil Sci, Taoyuan, Taiwan. [Hsieh, Tsung-Hsun] Taipei Med Univ, Grad Inst Neural Regenerat Med, Taipei, Taiwan. [Hoffer, Barry J.; Luo, Yu] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. [Kao, Yu-Chieh] Taipei Med Univ, Sch Med, Translat Imaging Res Ctr, Taipei, Taiwan. [Kao, Yu-Chieh] Taipei Med Univ, Sch Med, Dept Radiol, Taipei, Taiwan. [Wang, Jia-Yi] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei, Taiwan. RP Wang, JY (reprint author), Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Hsing St, Taipei 110, Taiwan. EM jywang2010@tmu.edu.tw FU Ministry of Science and Technology [MOST104-2923-B-038-001-MY3 (1-3 2-3)]; National Institutes of Health NINDS [R01NS094152]; Intramural Research Program, National Institute on Aging, National Institutes of Health NINDS, USA [R01NS094152] FX This study was supported in part by grants from (i) the Ministry of Science and Technology (MOST104-2923-B-038-001-MY3 (1-3 & 2-3) (ii) National Institutes of Health NINDS grant R01NS094152 and by (iii) the Intramural Research Program, National Institute on Aging, National Institutes of Health NINDS grant R01NS094152, USA. The authors thank the Translational Imaging Research Center at Taipei Medical University for technical support in relation to animal setup and MRI imaging. For information relating to PFT-alpha. (O) contact NHG 22. In a double-blind, between-groups trial, 31 "restrained" eaters were stabilized on either pexacerfont (300 mg/day for 7 days, then 100 mg/day for 21 days) or placebo. On day 15, they underwent a math-test stressor; during three subsequent visits, they heard personalized craving-induction scripts. In each session, stress-induced food consumption and craving were assessed in a bogus taste test and on visual analog scales. We used digital video to monitor daily ingestion of study capsules and nightly rating of food problems/preoccupation on the Yale Food Addiction Scale (YFAS). The study was stopped early due to an administrative interpretation of US federal law, unrelated to safety or outcome. The bogus taste tests suggested some protective effect of pexacerfont against eating after a laboratory stressor (r (effect) = 0.30, 95 % CL = -0.12, 0.63, Bayes factor 11.30). Similarly, nightly YFAS ratings were lower with pexacerfont than placebo (r (effect) = 0.39, CI 0.03, 0.66), but this effect should be interpreted with caution because it was present from the first night of pill ingestion, despite pexacerfont's slow pharmacokinetics. The findings may support further investigation of the anticraving properties of CRF1 antagonists, especially for food. C1 [Epstein, David H.; Kennedy, Ashley P.; Furnari, Melody; Heilig, Markus; Shaham, Yavin; Phillips, Karran A.; Preston, Kenzie L.] NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,BRC Bldg,Suite 200, Baltimore, MD 21224 USA. RP Epstein, DH (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,BRC Bldg,Suite 200, Baltimore, MD 21224 USA. EM depstein@intra.nida.nih.gov FU NIDA Intramural Research Program FX This study was funded by the NIDA Intramural Research Program. Pexacerfont and placebo capsules were obtained from Bristol-Meyers Squibb (BMS), under an agreement that permitted either BMS or the investigators to publish the results after giving the other party 60 days to check for disclosure of confidential information. BMS had no input into the drafting of this paper and requested no changes. NR 45 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 233 IS 23-24 BP 3921 EP 3932 DI 10.1007/s00213-016-4424-5 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB8RW UT WOS:000387659500009 PM 27595147 ER PT J AU Secci, ME Factor, JA Schindler, CW Panlilio, LV AF Secci, Maria E. Factor, Julie A. Schindler, Charles W. Panlilio, Leigh V. TI Choice between delayed food and immediate oxycodone in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; Animal models; Behavioral economics; Concurrent choice; Delay discounting; Impulsivity ID RHESUS-MONKEYS; DRUG-USE; COCAINE; HEROIN; REINFORCEMENT; REWARD; IMPULSIVITY; ADDICTION; NALOXONE; BEHAVIOR AB The choice to seek immediate drug effects instead of more meaningful but delayed rewards is a defining feature of addiction. To develop a rodent model of this behavior, we allowed rats to choose between immediate intravenous delivery of the prescription opioid oxycodone (50 mu g/kg) and delayed delivery of palatable food pellets. Rats preferred food at delays up to 30 s, but they chose oxycodone and food equally at 60-s delay and preferred oxycodone over food at 120-s delay. Comparison of food-drug choice, food-only, and drug-only conditions indicated that food availability decreased drug intake, but drug availability increased food intake. In the food-only condition, food was effective as a reinforcer even when delayed by 120 s. Pre-session feeding with chow slowed acquisition of food and drug self-administration, but did not affect choice. To establish procedures for testing potential anti-addiction medications, noncontingent pre-treatment with oxycodone or naltrexone (analogous to substitution and antagonist therapies, respectively) were tested on a baseline in which oxycodone was preferred over delayed food. Naltrexone pre-treatment decreased drug intake and increased food intake. Oxycodone pre-treatment decreased drug intake, but also produced extended periods with no food or drug responding. These findings show that the contingencies that induce preference for drugs over more meaningful but less immediate rewards in humans can be modeled in rodents, and they suggest that the model could be useful for assessing the therapeutic potential of treatments and exploring the underlying behavioral and neural mechanisms involved in addiction. C1 [Secci, Maria E.; Factor, Julie A.; Schindler, Charles W.; Panlilio, Leigh V.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Programl,NIH,US Dept HHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Programl,NIH,US Dept HHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM lpanlili@intra.nida.nih.gov FU Intramural Research Program of the NIH, National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. Thanks to Yavin Shaham for invaluable suggestions during planning of the study and preparation of the manuscript. NR 50 TC 0 Z9 0 U1 4 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 DEC PY 2016 VL 233 IS 23-24 BP 3977 EP 3989 DI 10.1007/s00213-016-4429-0 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB8RW UT WOS:000387659500014 PM 27678551 ER PT J AU Ito, Y Clary, R AF Ito, Yoichiro Clary, Robert TI Comparison in Partition Efficiency of Protein Separation between Four Different Tubing Modifications in Spiral High-Speed Countercurrent Chromatography SO SEPARATIONS LA English DT Article DE spiral high-speed countercurrent chromatography; tubing shape modification; protein separation; polymer phase system ID SUPPORT AB High-speed countercurrent chromatography with a spiral tube assembly can retain a satisfactory amount of stationary phase of polymer phase systems used for protein separation. In order to improve the partition efficiency, a simple tool was fabricated to modify the tubing shapes, and the following four different tubing modifications were made: intermittently pressed at 10 mm width, flat, flat-wave, and flat-twist. Partition efficiencies of the separation column made from these modified tubings were examined in protein separation with an aqueous-aqueous polymer phase system at flow rates of 1-2 mL/min under 800 rpm. The results indicated that the column with all modified tubing improved the partition efficiency at a flow rate of 1 mL/min, but at a higher flow rate of 2 mL/min, the columns made of flattened tubing showed lowered partition efficiency, apparently due to the loss of the retained stationary phase. Among all the modified columns, the column with intermittently pressed tubing gave the best peak resolution. It may be concluded that the intermittently pressed and flat-twist improve the partition efficiency in a semi-preparative separation, while other modified tubing of flat and flat-wave configurations may be used for analytical separations with a low flow rate. C1 [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Clary, Robert] NIH, Machine Instrumentat Design & Fabricat, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov; claryrob@od.nih.gov NR 17 TC 0 Z9 0 U1 3 U2 3 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2297-8739 EI 2227-9075 J9 SEPARATIONS JI Separations PD DEC PY 2016 VL 3 IS 4 AR 31 DI 10.3390/separations3040031 PG 7 WC Chemistry, Analytical SC Chemistry GA EC2MQ UT WOS:000387955900004 ER PT J AU Shinomiya, K Zaima, K Harikai, N Ito, Y AF Shinomiya, Kazufusa Zaima, Kazumasa Harikai, Naoki Ito, Yoichiro TI Improved Separations of Proteins and Sugar Derivatives Using the Small-Scale Cross-Axis Coil Planet Centrifuge with Locular Multilayer Coiled Columns SO SEPARATIONS LA English DT Article DE countercurrent chromatography; cross-axis coil planet centrifuge; locular multilayer coil; partition efficiency; proteins; 4-methylumbelliferyl sugar derivatives ID POLYMER PHASE SYSTEMS; PREPARATIVE COUNTERCURRENT CHROMATOGRAPHY; PARTITION EFFICIENCY; TUBING MODIFICATIONS; STATIONARY-PHASE; ROTARY SEALS; APPARATUS; ASSEMBLIES; RETENTION; DESIGN AB (1) Background: Countercurrent chromatography (CCC) is liquid-liquid partition chromatography without using a solid support matrix. This technique requires further improvement of peak resolution and shortening of separation time. (2) Methods: The long-pressed locular multilayer coils with and without mixer glass beads were developed for the separation of proteins and 4-methylumbelliferyl sugar derivatives using a small-scale cross-axis coil planet centrifuge. (3) Results: Proteins were separated from each other and the separation was improved when the flow rate of the mobile phase was decreased from 0.8 to 0.4 mL/min. On the other hand, 4-methylumbelliferyl sugar derivatives were separated at the resolution of almost over 1.5 in short separation time under satisfactory stationary phase retention when the flow rate of the mobile phase was increased from 1.0 to 1.4 mL/min. (4) Conclusion: Better peak resolutions over the previous results were achieved using the long-pressed locular multilayer coil for proteins with aqueous two-phase systems (ATPS) and for 4-methylumbelliferyl sugar derivatives with organic-aqueous two-phase solvent systems by inserting a glass bead into each locule. C1 [Shinomiya, Kazufusa; Zaima, Kazumasa; Harikai, Naoki] Nihon Univ, Sch Pharm, 7-7-1,Narashinodai, Funabashi, Chiba 2748555, Japan. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Sch Pharm, 7-7-1,Narashinodai, Funabashi, Chiba 2748555, Japan. EM shinomiya.kazufusa@nihon-u.ac.jp; zaima.kazumasa@nihon-u.ac.jp; harikai.naoki@nihon-u.ac.jp; itoy@nhlbi.nih.gov NR 18 TC 0 Z9 0 U1 4 U2 4 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2297-8739 EI 2227-9075 J9 SEPARATIONS JI Separations PD DEC PY 2016 VL 3 IS 4 AR 29 DI 10.3390/separations3040029 PG 10 WC Chemistry, Analytical SC Chemistry GA EC2MQ UT WOS:000387955900002 ER PT J AU Yang, Z Holt, HK Fan, JH Ma, L Liu, Y Chen, W Como, P Zhang, L Qiao, YL AF Yang, Zhao Holt, Hunter K. Fan, Jin-Hu Ma, Li Liu, Ying Chen, Wen Como, Peter Zhang, Lin Qiao, You-Lin TI Optimal Cutoff Scores for Alzheimer's Disease Using the Chinese Version of Mini-Mental State Examination Among Chinese Population Living in Rural Areas SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE Alzheimer's disease; Chinese version Mini-Mental State Examination; Chinese population; cutoff scores; rural areas; ROC analysis ID MILD COGNITIVE IMPAIRMENT; GENERAL-POPULATION; CANCER INCIDENCE; DEMENTIA; LINXIAN; DIAGNOSIS; EDUCATION; HEALTH; SUPPLEMENTATION; PREVALENCE AB To explore the optimal cutoff score for initial detection of Alzheimer's Disease (AD) through the Chinese version of Mini-Mental State Examination (CMMSE) in rural areas in China, we conducted a cross-sectional study within the Linxian General Population Nutritional Follow-up study. 16,488 eligible cohort members participated in the survey and 881 completed the CMMSE. Among 881 participants, the median age (Interquartile range) was 69.00 (10.00), 634 (71.92%) were female, 657 (74.57%) were illiterate, 35 (3.97%) had 6 years of education or higher, and 295 (33.48%) were diagnosed with AD. By reducing the CMMSE criteria for illiterate to 16 points, primary school to 19 points, and middle school or higher to 23 points, the efficiency of Chinese version of Mini-Mental State Examination can be significantly improved for initial detection of AD in rural areas in China, especially in those nutrition deficient areas. C1 [Yang, Zhao; Fan, Jin-Hu; Chen, Wen; Qiao, You-Lin] Chinese Acad Med Sci, Canc Hosp Inst, Dept Canc Epidemiol, Beijing, Peoples R China. [Yang, Zhao; Fan, Jin-Hu; Chen, Wen; Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. [Holt, Hunter K.] Rush Univ, Coll Med, Dept Family Med, Chicago, IL 60612 USA. [Holt, Hunter K.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Ma, Li] Dalian Med Univ, Dept Epidemiol, Dalian, Peoples R China. [Liu, Ying] Second Affiliated Hosp Dalian, Dept Neurol, Dalian, Peoples R China. [Como, Peter] US FDA, Silver Spring, MD USA. [Zhang, Lin] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. RP Fan, JH (reprint author), Chinese Acad Med Sci, Canc Hosp Inst, Dept Canc Epidemiol, Beijing, Peoples R China.; Fan, JH (reprint author), Peking Union Med Coll, Beijing, Peoples R China.; Ma, L (reprint author), Dalian Med Univ, Dept Epidemiol, Dalian, Peoples R China. EM fanjh@cicams.ac.cn; mali_lele@sina.com FU NIH [NHHSN261200477001C]; Cancer Institute of the Chinese Academy of Medical Sciences; China National Natural Science Foundation [81200989]; Chinese Academy of Medical Sciences; Intramural Research Program of the US National Cancer Institute, NIH; NIH Fogarty International Center Grant [5R25TW009340] FX This study was supported in part by NIH contract NHHSN261200477001C with the Cancer Institute of the Chinese Academy of Medical Sciences; by funds from the China National Natural Science Foundation No. 81200989; by additional funds from the Chinese Academy of Medical Sciences; by funds from the Intramural Research Program of the US National Cancer Institute, NIH and finally, funds from the NIH Fogarty International Center Grant #5R25TW009340. NR 44 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD DEC PY 2016 VL 31 IS 8 BP 650 EP 657 DI 10.1177/1533317516662336 PG 8 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA EB6IP UT WOS:000387485900006 PM 27659393 ER PT J AU Dickens, C Pfeiffer, RM Anderson, WF Duarte, R Kellett, P Schuz, J Kielkowski, D McCormack, VA AF Dickens, Caroline Pfeiffer, Ruth M. Anderson, William F. Duarte, Raquel Kellett, Patricia Schuz, Joachim Kielkowski, Danuta McCormack, Valerie A. TI Investigation of breast cancer sub-populations in black and white women in South Africa SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Receptors; Age distributions; South Africa ID UNITED-STATES; RISK-FACTORS; TRENDS; AGE; HETEROGENEITY; PREVALENCE; CARCINOMA; DIAGNOSIS; PATTERNS; ESTROGEN AB Bimodal age distributions at diagnosis have been widely observed among US and European female breast cancer populations. To determine whether bimodal breast cancer distributions are also present in a sub-Saharan African population, we investigated female breast cancer in South Africa. Using the South African National Cancer Registry data, we examined age-at-diagnosis frequency distributions (density plots) for breast cancer overall and by their receptor (oestrogen, progesterone and HER2) determinants among black and white women diagnosed during 2009-2011 in the public healthcare sector. For comparison, we also analysed corresponding 2010-2011 US SEER data. We investigated density plots using flexible mixture models, allowing early/late-onset membership to depend on receptor status. We included 8857 women from South Africa, 7176 (81 %) with known oestrogen receptor status, and 95064 US women. Bimodality was present in all races, with an early-onset mode between ages 40-50 years and a late-onset mode among ages 60-70 years. The early-onset mode was younger in South African black women (age 38), compared to other groups (45-54 years). Consistent patterns of bimodality and of its receptor determinants were present across breast cancer patient populations in South Africa and the US. Although the clinical spectrum of breast cancer is well acknowledged as heterogeneous, universal early- and late-onset age distributions at diagnosis suggest that breast cancer etiology consists of a mixture two main types. C1 [Dickens, Caroline; Schuz, Joachim; McCormack, Valerie A.] Int Agcy Res Canc, Sect Environm & Radiat, Lyon, France. [Dickens, Caroline; Duarte, Raquel] Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, 7 York Rd, ZA-2193 Johannesburg, South Africa. [Pfeiffer, Ruth M.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Execut Plaza South Rm 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. [Kellett, Patricia; Kielkowski, Danuta] Natl Canc Registry South Africa, Natl Hlth & Lab Serv, Johannesburg, South Africa. RP Dickens, C (reprint author), Int Agcy Res Canc, Sect Environm & Radiat, Lyon, France.; Dickens, C (reprint author), Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, 7 York Rd, ZA-2193 Johannesburg, South Africa. EM caroline.dickens@wits.ac.za FU International Agency for Research on Cancer; European Commission FP7 Marie Curie Actions - People - Co-funding of regional, national and international programmes (COFUND) FX The work reported in this paper was undertaken during the tenure of a Postdoctoral Fellowship to Dr Dickens from the International Agency for Research on Cancer, partially supported by the European Commission FP7 Marie Curie Actions - People - Co-funding of regional, national and international programmes (COFUND). NR 24 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD DEC PY 2016 VL 160 IS 3 BP 531 EP 537 DI 10.1007/s10549-016-4019-1 PG 7 WC Oncology SC Oncology GA EB4LH UT WOS:000387342800013 PM 27757717 ER PT J AU Neuhouser, ML Smith, AW George, SM Gibson, JT Baumgartner, KB Baumgartner, R Duggan, C Bernstein, L McTiernan, A Ballard, R AF Neuhouser, Marian L. Smith, Ashley Wilder George, Stephanie M. Gibson, James T. Baumgartner, Kathy B. Baumgartner, Richard Duggan, Catherine Bernstein, Leslie McTiernan, Anne Ballard, Rachel TI Use of complementary and alternative medicine and breast cancer survival in the Health, Eating, Activity, and Lifestyle Study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Complementary and alternative medicine; Cancer survivorship; Mortality ID ESTROGENIC BOTANICAL SUPPLEMENTS; QUALITY-OF-LIFE; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; PROSTATE-CANCER; WOMEN; THERAPY; TRIAL; DIET; SOY AB Use of complementary and alternative medicine (CAM) is common among breast cancer patients, but less is known about whether CAM influences breast cancer survival. Health Eating, Activity, and Lifestyle (HEAL) Study participants (n = 707) were diagnosed with stage I-IIIA breast cancer. Participants completed a 30-month post-diagnosis interview including questions on CAM use (natural products such as dietary and botanical supplements, alternative health practices, and alternative medical systems), weight, physical activity, and comorbidities. Outcomes were breast cancer-specific and total mortality, which were ascertained from the Surveillance Epidemiology and End Results registries in Western Washington, Los Angeles County, and New Mexico. Cox proportional hazards regression models were fit to data to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for mortality. Models were adjusted for potential confounding by sociodemographic, health, and cancer-related factors. Among 707 participants, 70 breast cancer-specific deaths and 149 total deaths were reported. 60.2 % of participants reported CAM use post-diagnosis. The most common CAM were natural products (51 %) including plant-based estrogenic supplements (42 %). Manipulative and body-based practices and alternative medical systems were used by 27 and 13 % of participants, respectively. No associations were observed between CAM use and breast cancer-specific (HR 1.04, 95 % CI 0.61-1.76) or total mortality (HR 0.91, 95 % CI 0.63-1.29). Complementary and alternative medicine use was not associated with breast cancer-specific mortality or total mortality. Randomized controlled trials may be needed to definitively test whether there is harm or benefit from the types of CAM assessed in HEAL in relation to mortality outcomes in breast cancer survivors. C1 [Neuhouser, Marian L.; Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North,M4B402, Seattle, WA 98109 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [George, Stephanie M.; Ballard, Rachel] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. [Gibson, James T.] Informat Management Serv Inc, Calverton, MD USA. [Baumgartner, Kathy B.; Baumgartner, Richard] Univ Louisville, James Graham Brown Canc Ctr, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. [Bernstein, Leslie] Beckman Res Inst City Hope, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. RP Neuhouser, ML (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North,M4B402, Seattle, WA 98109 USA. EM mneuhous@fredhutch.org FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010]; National Institutes of Health [M01-RR-00037]; University of New Mexico NCRR [M01-RR-0997]; California Department of Health Services [050Q-8709-S1528] FX The HEAL study was funded by National Cancer Institute (N01-CN-75036-20), N01-CN-05228, N01-PC-67010, National Institutes of Health M01-RR-00037), University of New Mexico NCRR M01-RR-0997, California Department of Health Services 050Q-8709-S1528. NR 48 TC 0 Z9 0 U1 42 U2 42 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 DEC PY 2016 VL 160 IS 3 BP 539 EP 546 DI 10.1007/s10549-016-4010-x PG 8 WC Oncology SC Oncology GA EB4LH UT WOS:000387342800014 PM 27766453 ER PT J AU Wang, W Erbe, AK Gallenberger, M Kim, K Carmichael, L Hess, D Mendonca, EA Song, YQ Hank, JA Cheng, SC Signoretti, S Atkins, M Carlson, A Weiss, JM Mier, J Panka, D McDermott, DF Sondel, PM AF Wang, Wei Erbe, Amy K. Gallenberger, Mikayla Kim, KyungMann Carmichael, Lakeesha Hess, Dustin Mendonca, Eneida A. Song, Yiqiang Hank, Jacquelyn A. Cheng, Su-Chun Signoretti, Sabina Atkins, Michael Carlson, Alexander Weiss, Jonathan M. Mier, James Panka, David McDermott, David F. Sondel, Paul M. TI Killer immunoglobulin-like receptor (KIR) and KIR-ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Renal cell carcinoma; High-dose IL2; Killer immunoglobulin-like receptors; HLA; NK cells ID ACUTE MYELOGENOUS LEUKEMIA; UNLICENSED NK CELLS; RECOMBINANT INTERLEUKIN-2; HLA-C; UNRELATED TRANSPLANTATION; NEUROBLASTOMA PATIENTS; IN-VITRO; ANTIBODY; MISMATCH; TUMOR AB NK cells play a role in many cancer immunotherapies. NK cell activity is tightly regulated by killer immunoglobulin-like receptor (KIR) and KIR-ligand interactions. Inhibitory KIR-ligands have been identified as HLA molecules, while activating KIR-ligands are largely unknown. Individuals that have not inherited the corresponding KIR-ligand for at least one inhibitory KIR gene are termed the "KIR-ligand missing" genotype, and they are thought to have a subset of NK cells that express inhibitory KIRs for which the corresponding KIR-ligand is missing on autologous tissue, and thus will not be inhibited through KIR-ligand recognition. In some settings where an anticancer immunotherapeutic effect is likely mediated by NK cells, individuals with a KIR-ligand missing genotype have shown improved clinical outcome compared to individuals with an "all KIR-ligands present" genotype. In addition, patients receiving hematopoietic stem cell transplants for leukemia may do better if their donor has more activating KIR genes (i.e., KIR haplotype-B). In a recent multi-institution clinical trial of patients with metastatic renal cell carcinoma receiving high-dose IL2 (HD-IL2), 25 % of patients showed a complete or partial tumor response to this therapy. We genotyped KIR and KIR-ligand genes for these patients (n = 107) and tested whether KIR/KIR-ligand genotypes correlated with patient clinical outcomes. In these analyses, we did not find any significant association of KIR/KIR-ligand genotype (either KIR-ligand missing or the presence of KIR haplotype-B) with patient outcome in response to the HD-IL2 therapy. C1 [Wang, Wei; Erbe, Amy K.; Gallenberger, Mikayla; Hess, Dustin; Hank, Jacquelyn A.; Sondel, Paul M.] Univ Wisconsin, Dept Human Oncol, 4159 WIMR Bldg UW Madison Campus, Madison, WI 53705 USA. [Kim, KyungMann; Carmichael, Lakeesha; Mendonca, Eneida A.; Song, Yiqiang] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Cheng, Su-Chun] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Atkins, Michael; Mier, James; McDermott, David F.] Cytokine Working Grp, Rockville, MD USA. [Atkins, Michael] Georgetown Univ, Dept Med, Washington, DC USA. [Carlson, Alexander; Mier, James; Panka, David; McDermott, David F.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Weiss, Jonathan M.] NCI, Biol Resources Branch, Frederick, MD 21701 USA. [Mendonca, Eneida A.; Sondel, Paul M.] Univ Wisconsin, Dept Pediat, Madison, WI 53792 USA. RP Sondel, PM (reprint author), Univ Wisconsin, Dept Human Oncol, 4159 WIMR Bldg UW Madison Campus, Madison, WI 53705 USA.; Sondel, PM (reprint author), Univ Wisconsin, Dept Pediat, Madison, WI 53792 USA. EM pmsondel@humonc.wisc.edu FU Hyundai Hope on Wheels Grant; Midwest Athletes Against Childhood; Stand Up 2 Cancer; The St. Baldrick's Foundation; American Association of Cancer Research; University of Wisconsin-Madison Carbone Cancer Center; NCI-Cytokine Working Group; Public Health Service Grants from the National Cancer Institute [CA014520, CA021115, CA023318, CA066636, CA180820, CA180794, CA021076, CA180799, CA14958, CA180816, CA166105, CA197078]; National Institutes of Health; Department of Health and Human Services FX The authors thank the medical and nursing staff that participated in the care of patients in this study, and especially all patients participating in this study. Thanks also to Bartosz Grzywacz and Patrick Reville for their helpful discussions and input. This research was supported by Hyundai Hope on Wheels Grant; Midwest Athletes Against Childhood; Stand Up 2 Cancer; The St. Baldrick's Foundation; American Association of Cancer Research; University of Wisconsin-Madison Carbone Cancer Center; by NCI-Cytokine Working Group and supported in part by Public Health Service Grants CA014520, CA021115, CA023318, CA066636, CA180820, CA180794, CA021076, CA180799, CA14958, CA180816, CA166105 and CA197078, from the National Cancer Institute; the National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. NR 38 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD DEC PY 2016 VL 65 IS 12 BP 1523 EP 1532 DI 10.1007/s00262-016-1904-8 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA EB7UB UT WOS:000387595000008 PM 27695964 ER PT J AU Zhang, F Zhang, LP Qi, Y Xu, H AF Zhang, Fan Zhang, Liping Qi, Yun Xu, Hong TI Mitochondrial cAMP signaling SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Protein import; Drp1; BH3; Fission; mtDNA; AKAP; TFAM; PKA ID PROTEIN-KINASE-A; SOLUBLE ADENYLYL-CYCLASE; ELEMENT-BINDING PROTEIN; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; STRESS-MEDIATED MODULATION; DOMAIN-CONTAINING PROTEINS; COMPLEX-I; ANCHORING PROTEIN; CELL-DEATH; DEPENDENT PHOSPHORYLATION AB Cyclic adenosine 3, 5'-monophosphate (cAMP) is a ubiquitous second messenger regulating many biological processes, such as cell migration, differentiation, proliferation and apoptosis. cAMP signaling functions not only on the plasma membrane, but also in the nucleus and in organelles such as mitochondria. Mitochondrial cAMP signaling is an indispensable part of the cytoplasm-mitochondrion crosstalk that maintains mitochondrial homeostasis, regulates mitochondrial dynamics, and modulates cellular stress responses and other signaling pathways. Recently, the compartmentalization of mitochondrial cAMP signaling has attracted great attentions. This new input should be carefully taken into account when we interpret the findings of mitochondrial cAMP signaling. In this review, we summarize previous and recent progress in our understanding of mitochondrial cAMP signaling, including the components of the signaling cascade, and the function and regulation of this signaling pathway in different mitochondrial compartments. C1 [Zhang, Fan; Qi, Yun; Xu, Hong] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhang, Liping] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Xu, H (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM xuh5@nhlbi.nih.gov NR 150 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD DEC PY 2016 VL 73 IS 24 BP 4577 EP 4590 DI 10.1007/s00018-016-2282-2 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EB6KK UT WOS:000387491800001 ER PT J AU Oh, H Khodr, ZG Sherman, ME Palakal, M Pfeiffer, RM Linville, L Geller, BM Vacek, PM Weaver, DL Chicoine, RE Falk, RT Horne, HN Papathomas, D Patel, DA Xiang, J Xu, X Veenstra, T Hewitt, SM Shepherd, JA Brinton, LA Figueroa, JD Gierach, GL AF Oh, Hannah Khodr, Zeina G. Sherman, Mark E. Palakal, Maya Pfeiffer, Ruth M. Linville, Laura Geller, Berta M. Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Falk, Roni T. Horne, Hisani N. Papathomas, Daphne Patel, Deesha A. Xiang, Jackie Xu, Xia Veenstra, Timothy Hewitt, Stephen M. Shepherd, John A. Brinton, Louise A. Figueroa, Jonine D. Gierach, Gretchen L. TI Relation of Serum Estrogen Metabolites with Terminal Duct Lobular Unit Involution Among Women Undergoing Diagnostic Image-Guided Breast Biopsy SO HORMONES & CANCER LA English DT Article ID VOLUME MAMMOGRAPHIC DENSITIES; TANDEM MASS-SPECTROMETRY; POSTMENOPAUSAL WOMEN; CANCER RISK; SEX-HORMONES; RADIOIMMUNOASSAY; RELIABILITY; VALIDITY; TISSUE; AREA AB Higher levels of circulating estrogens and estrogen metabolites (EMs) have been associated with higher breast cancer risk. In breast tissues, reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have also been linked to elevated breast cancer risk. However, it is unknown whether reduced TDLU involution mediates the risk associated with circulating EMs. In a cross-sectional analysis of 94 premenopausal and 92 postmenopausal women referred for clinical breast biopsy at an academic facility in Vermont, we examined the associations of 15 EMs, quantified using liquid chromatography-tandem mass spectrometry, with the number of TDLUs and acini count/TDLU using zero-inflated Poisson regression with a robust variance estimator and ordinal logistic regression models, respectively. All analyses were stratified by menopausal status and adjusted for potential confounders. Among premenopausal women, comparing the highest vs. the lowest tertiles, levels of unconjugated estradiol (risk ratio (RR) = 1.74, 95 % confidence interval (CI) = 1.06-2.87, p trend = 0.03), 2-hydroxyestrone (RR = 1.74, 95 % CI = 1.01-3.01, p trend = 0.04), and 4-hydroxyestrone (RR = 1.74, 95 % CI = 0.99-3.06, p trend = 0.04) were associated with significantly higher TDLU count. Among postmenopausal women, higher levels of estradiol (RR = 2.09, 95 % CI = 1.01-4.30, p trend = 0.04) and 16 alpha-hydroxyestrone (RR = 2.27, 95 % CI = 1.29-3.99, p trend = 0.02) were significantly associated with higher TDLU count. Among postmenopausal women, higher levels of EMs, specifically conjugated estrone and 2- and 4-pathway catechols, were also associated with higher acini count/TDLU. Our data suggest that higher levels of serum EMs are generally associated with lower levels of TDLU involution. C1 [Oh, Hannah; Khodr, Zeina G.; Sherman, Mark E.; Palakal, Maya; Pfeiffer, Ruth M.; Linville, Laura; Falk, Roni T.; Horne, Hisani N.; Papathomas, Daphne; Patel, Deesha A.; Xiang, Jackie; Brinton, Louise A.; Figueroa, Jonine D.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Oh, Hannah] 9609 Med Ctr Dr,Rm 7E220, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Univ Vermont, Burlington, VT USA. [Xu, Xia; Veenstra, Timothy] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Shepherd, John A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. RP Oh, H (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Oh, H (reprint author), 9609 Med Ctr Dr,Rm 7E220, Bethesda, MD 20892 USA. EM hannah.oh@nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; Breast Cancer Research Stamp Funds; National Cancer Institute [U01CA70013] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. Breast Cancer Research Stamp Funds (MES, LAB) and cooperative agreement U01CA70013 (BMG, PMV, DLW, REC) from the National Cancer Institute funded some of the data collection for this study. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 44 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD DEC PY 2016 VL 7 IS 5-6 BP 305 EP 315 DI 10.1007/s12672-016-0265-2 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA EB2WZ UT WOS:000387224600003 PM 27138982 ER PT J AU Zhen, DB Griffith, KA Ruch, JM Camphausen, K Savage, JE Kim, EJ Sahai, V Simeone, DM Zalupski, MM AF Zhen, David B. Griffith, Kent A. Ruch, Joshua M. Camphausen, Kevin Savage, Jason E. Kim, Edward J. Sahai, Vaibhav Simeone, Diane M. Zalupski, Mark M. TI A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Cabozantinib; XL-184; Gemcitabine; Pancreatic cancer ID C-MET; CLINICAL-TRIALS; GROWTH-FACTOR; CELLS; METASTASIS; SURVIVAL; MOTILITY; RECEPTOR AB Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with aecurrency sign1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which aecurrency sign25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was > 25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted. C1 [Zhen, David B.; Ruch, Joshua M.; Kim, Edward J.; Sahai, Vaibhav; Zalupski, Mark M.] Univ Michigan, Dept Internal Med, Div Hematol Oncol, 3-219 CC,1500 E Med Ctr Dr,SPC 5934, Ann Arbor, MI 48109 USA. [Griffith, Kent A.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Camphausen, Kevin; Savage, Jason E.] NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Simeone, Diane M.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. RP Zalupski, MM (reprint author), Univ Michigan, Dept Internal Med, Div Hematol Oncol, 3-219 CC,1500 E Med Ctr Dr,SPC 5934, Ann Arbor, MI 48109 USA. EM zalupski@med.umich.edu FU NCI of the National Institutes of Health [P30CA046592]; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; intramural program of the NCI FX The authors thank Bill Reisdorph for his excellent management of the study specific IND 114,716. Young Lee processed urinary samples for the correlative molecular biomarker analysis. Donald Bottaro of the Urologic Oncology Branch at the National Cancer Institute (NCI) provided access to the electrochemiluminescence instrument for the c-Met assay. Exelixis, Inc. provided cabozantinib for this study. Research reported in this publication was supported by the NCI of the National Institutes of Health under award number P30CA046592, Michigan Institute for Clinical and Health Research (MICHR) under award number UL1TR000433, and funded in part by the intramural program of the NCI. NR 29 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 34 IS 6 BP 733 EP 739 DI 10.1007/s10637-016-0376-1 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA EB7QJ UT WOS:000387584100007 PM 27439894 ER PT J AU Blanch-Hartigan, D Chawla, N Moser, RP Rutten, LJF Hesse, BW Arora, NK AF Blanch-Hartigan, Danielle Chawla, Neetu Moser, Richard P. Rutten, Lila J. Finney Hesse, Bradford W. Arora, Neeraj K. TI Trends in cancer survivors' experience of patient-centered communication: results from the Health Information National Trends Survey (HINTS) SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Patient-centered care; Patient-provider communication; Cancer survivorship; Emotions; Uncertainty ID QUALITY-OF-CARE; PERCEPTIONS; ONCOLOGISTS; PHYSICIANS AB Two Institute of Medicine reports almost a decade apart suggest that cancer survivors often feel "lost in transition" and experience suboptimal quality of care. The six core functions of patient-centered communication: managing uncertainty, responding to emotions, making decisions, fostering healing relationships, enabling self-management, and exchanging information, represent a central aspect of survivors' care experience that has not been systematically investigated. Nationally representative data from four administrations of the Health Information National Trends Survey (HINTS) was merged with combined replicate weights using the jackknife replication method. Linear and logistic regression models were used to assess (1) characteristics of cancer survivors (N = 1794) who report suboptimal patient-centered communication and (2) whether survivors' patient-centered communication experience changed from 2007 to 2013. One third to one half of survivors report suboptimal patient-centered communication, particularly on core functions of providers helping manage uncertainty (48 %) and responding to emotions (49 %). In a fully adjusted linear regression model, survivors with more education (Wald F = 2.84, p = .04), without a usual source of care (Wald F = 11.59, p < .001), and in poorer health (Wald F = 9.08, p < .001) were more likely to report less patient-centered communication. Although ratings of patient-centered communication improved over time (p trend = .04), this trend did not remain significant in fully adjusted models. Despite increased attention to survivorship, many survivors continue to report suboptimal communication with their health care providers. Survivorship communication should include managing uncertainty about future risk and address survivors' emotional needs. Efforts to improve patient-centered communication should focus on survivors without a usual source of care and in poorer health. C1 [Blanch-Hartigan, Danielle] Bentley Univ, Dept Nat & Appl Sci, Jennison 103,175 Forest St, Waltham, MA 02452 USA. [Chawla, Neetu] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Moser, Richard P.; Hesse, Bradford W.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Rutten, Lila J. Finney] Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, Rochester, MN USA. [Arora, Neeraj K.] Patient Ctr Outcomes Res Inst, Improving Hlth Syst, Washington, DC USA. RP Blanch-Hartigan, D (reprint author), Bentley Univ, Dept Nat & Appl Sci, Jennison 103,175 Forest St, Waltham, MA 02452 USA. EM danielleblanch@gmail.com FU National Cancer Institute [HHSN26120100064C] FX The Health Information National Trends Survey is supported by contract number HHSN26120100064C from the National Cancer Institute. The views expressed in the manuscript do not necessarily represent the views of the US Federal Government. NR 30 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2016 VL 10 IS 6 BP 1067 EP 1077 DI 10.1007/s11764-016-0550-7 PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EB4JO UT WOS:000387337700011 PM 27193357 ER PT J AU Kenzik, KM Kent, EE Martin, MY Bhatia, S Pisu, M AF Kenzik, Kelly M. Kent, Erin E. Martin, Michelle Y. Bhatia, Smita Pisu, Maria TI Chronic condition clusters and functional impairment in older cancer survivors: a population-based study SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cancer survivor; Comorbidity; Function; Geriatric ID QUALITY-OF-LIFE; CHILDHOOD-CANCER; HEALTH-OUTCOMES; MEDICARE; COMPLICATIONS; PREVALENCE; DISORDER; DISEASE AB The purpose of the study is to identify chronic condition clusters at pre- and post-cancer diagnosis, evaluate predictors of developing clusters post-cancer, and examine the impact on functional impairment among older cancer survivors. We identified 5991 survivors age 65 and older of prostate, breast, colorectal, lung, bladder, kidney, head and neck, and gynecologic cancer and non-Hodgkin lymphoma from the Surveillance, Epidemiology and End Results-Medicare Health Outcomes Survey resource. Survivors completed surveys pre- and post-cancer diagnosis on 13 chronic conditions and functional status. Among those with aeyen2 conditions, exploratory factor analysis identified clusters of conditions. Differences in cluster frequency from pre- to post-cancer diagnosis were evaluated across the top five cancer types using chi-square tests. Modified Poisson regression models estimated the relative risk of developing clusters post-diagnosis. Chi-square tests evaluated associations between function and clusters. Clusters included the following: cardiovascular disease cluster (pre 6.1 % and post 7.7 %), musculoskeletal cluster (28.2 % and 29.3 %), metabolic cluster (14.9 % and 17.6 %), and the major depressive disorder risk (MDDr) + gastrointestinal (GI) + pulmonary condition cluster (5.8 % and 8.7 %). Increases in MDDr + GI + Pulmonary cluster from pre- to post-cancer diagnosis were observed for prostate, lung, and colorectal cancer survivors. Functional impairment was more prevalent in survivors with defined clusters, especially in MDDr + GI + pulmonary, compared to survivors with aeyen2 un-clustered conditions. Distinct condition clusters of two or more chronic conditions are prevalent among older cancer survivors. Cluster prevalence increases from pre- to post-cancer diagnosis and these clusters have a significant impact on functional limitations. Tailored management on specific multimorbidity patterns will have implications for functional outcomes among older survivors. C1 [Kenzik, Kelly M.; Bhatia, Smita] Univ Alabama Birmingham, Inst Canc Outcomes & Survivorship, Birmingham, AL 35233 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Rockville, MD USA. [Martin, Michelle Y.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Pisu, Maria] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL 35233 USA. RP Kenzik, KM (reprint author), Univ Alabama Birmingham, Inst Canc Outcomes & Survivorship, Birmingham, AL 35233 USA. EM kkenzik@uab.edu FU Agency for Healthcare Research and Quality [T32HS013852, K12HS023009] FX KMK was supported by grants T32HS013852 and K12HS023009 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or AHRQ. NR 33 TC 1 Z9 1 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2016 VL 10 IS 6 BP 1096 EP 1103 DI 10.1007/s11764-016-0553-4 PG 8 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EB4JO UT WOS:000387337700014 PM 27229869 ER PT J AU Gozalo, AS Elkins, WR Lambert, LE Stock, F Thomas, ML Woodward, RA AF Gozalo, Alfonso S. Elkins, William R. Lambert, Lynn E. Stock, Frida Thomas, Marvin L., III Woodward, Ruth A. TI Genetic diversity of Klebsiella pneumoniae isolates during an outbreak in a non-human primate research colony SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE Aotus nancymai; automated repetitive extragenic palindromic-polymerase chain reaction; Cebidae; DNA fingerprinting; Klebsiellosis; owl monkey; rep-PCR ID HYPERMUCOVISCOSITY PHENOTYPE; ANTIBIOTIC-RESISTANCE; ENVIRONMENTS; INFECTIONS; PATHOGENS; MONKEYS AB BackgroundKlebsiella pneumoniae can be a serious pathogen in non-human primates, particularly Neotropical monkeys. MethodsDuring a K.pneumoniae outbreak in an owl monkey research colony, 13 K.pneumoniae isolates were DNA fingerprinted by automated repetitive extragenic palindromic-polymerase chain reaction and the profiles compared to isolates obtained from other non-human primate species during the same time period and isolates from previous outbreaks. ResultsEleven different types of K.pneumoniae were circulating in the owl monkey colony at the time of the outbreak. When comparing owl monkey isolates relatedness to previous colony outbreak isolates and squirrel monkey and capuchin monkey isolates, all were different. ConclusionsThese results agree with recent reports where K.pneumoniae nosocomial isolates in hospital settings can have high genetic diversity, and multiple strains can be circulating simultaneously. This potential genetic diversity should be considered when designing strategies for controlling K.pneumoniae outbreaks in captive non-human primate colonies. C1 [Gozalo, Alfonso S.; Elkins, William R.] NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lambert, Lynn E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lambert, Lynn E.] SoBran Inc, Bethesda, MD USA. [Stock, Frida] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Thomas, Marvin L., III] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Woodward, Ruth A.] NICHHD, Res Anim Med Branch, NIH, Bethesda, MD 20892 USA. RP Gozalo, AS (reprint author), NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gozaloa@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch; Laboratory of Malaria Immunology and Vaccinology; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, and the Office of Research Services FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch; Laboratory of Malaria Immunology and Vaccinology; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, and the Office of Research Services. Abstract presented at the 64th AALAS National Meeting, Baltimore, MD, October 27-31, 2013. NR 27 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD DEC PY 2016 VL 45 IS 6 BP 312 EP 317 DI 10.1111/jmp.12229 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA EB4SM UT WOS:000387363700005 ER PT J AU Rosenkrantz, AB Verma, S Choyke, P Eberhardt, SC Eggener, SE Gaitonde, K Haider, MA Margolis, DJ Marks, LS Pinto, P Sonn, GA Taneja, SS AF Rosenkrantz, Andrew B. Verma, Sadhna Choyke, Peter Eberhardt, Steven C. Eggener, Scott E. Gaitonde, Krishnanath Haider, Masoom A. Margolis, Daniel J. Marks, Leonard S. Pinto, Peter Sonn, Geoffrey A. Taneja, Samir S. TI Prostate Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Patients with a Prior Negative Biopsy: A Consensus Statement by AUA and SAR SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; biopsy; magnetic resonance imaging; consensus ID ULTRASOUND FUSION BIOPSY; CANCER; MRI; SYSTEM; LOCALIZATION; GUIDANCE; ANTIGEN; LESION; MEN AB Purpose: After an initial negative biopsy there is an ongoing need for strategies to improve patient selection for repeat biopsy as well as the diagnostic yield from repeat biopsies. Materials and Methods: As a collaborative initiative of the AUA (American Urological Association) and SAR (Society of Abdominal Radiology) Prostate Cancer Disease Focused Panel, an expert panel of urologists and radiologists conducted a literature review and formed consensus statements regarding the role of prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a negative biopsy, which are summarized in this review. Results: The panel recognizes that many options exist for men with a previously negative biopsy. If a biopsy is recommended, prostate magnetic resonance imaging and subsequent magnetic resonance imaging targeted cores appear to facilitate the detection of clinically significant disease over standardized repeat biopsy. Thus, when high quality prostate magnetic resonance imaging is available, it should be strongly considered for any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy. The decision of whether to perform magnetic resonance imaging in this setting must also take into account the results of any other biomarkers and the cost of the examination, as well as the availability of high quality prostate magnetic resonance imaging interpretation. If magnetic resonance imaging is done, it should be performed, interpreted and reported in accordance with PI-RADS version 2 (v2) guidelines. Experience of the reporting radiologist and biopsy operator are required to achieve optimal results and practices integrating prostate magnetic resonance imaging into patient care are advised to implement quality assurance programs to monitor targeted biopsy results. Conclusions: Patients receiving a PI-RADS assessment category of 3 to 5 warrant repeat biopsy with image guided targeting. While transrectal ultrasound guided magnetic resonance imaging fusion or in-bore magnetic resonance imaging targeting may be valuable for more reliable targeting, especially for lesions that are small or in difficult locations, in the absence of such targeting technologies cognitive (visual) targeting remains a reasonable approach in skilled hands. At least 2 targeted cores should be obtained from each magnetic resonance imaging defined target. Given the number of studies showing a proportion of missed clinically significant cancers by magnetic resonance imaging targeted cores, a case specific decision must be made whether to also perform concurrent systematic sampling. However, performing solely targeted biopsy should only be considered once quality assurance efforts have validated the performance of prostate magnetic resonance imaging interpretations with results consistent with the published literature. In patients with negative or low suspicion magnetic resonance imaging (PI-RADS assessment category of 1 or 2, respectively), other ancillary markers (ie PSA, PSAD, PSAV, PCA3, PHI, 4K) may be of value in identifying patients warranting repeat systematic biopsy, although further data are needed on this topic. If a repeat biopsy is deferred on the basis of magnetic resonance imaging findings, then continued clinical and laboratory followup is advised and consideration should be given to incorporating repeat magnetic resonance imaging in this diagnostic surveillance regimen. C1 [Rosenkrantz, Andrew B.] NYU, Dept Radiol, Langone Med Ctr, 560 1St Ave, New York, NY 10016 USA. [Taneja, Samir S.] NYU, Langone Med Ctr, Dept Urol Oncol, New York, NY USA. [Margolis, Daniel J.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Verma, Sadhna] Univ Cincinnati, Coll Med, Dept Radiol, Cincinnati, OH USA. [Gaitonde, Krishnanath] Univ Cincinnati, Coll Med, Dept Urol, Cincinnati, OH USA. [Choyke, Peter] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Pinto, Peter] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Pinto, Peter] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Eberhardt, Steven C.] Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. [Eggener, Scott E.] Univ Chicago Med, Urol Sect, Chicago, IL USA. [Haider, Masoom A.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Med Imaging, Toronto, ON, Canada. [Marks, Leonard S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [Marks, Leonard S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Sonn, Geoffrey A.] Stanford Univ, Dept Urol, Sch Med, Stanford, CA 94305 USA. RP Rosenkrantz, AB (reprint author), NYU, Sch Med, Langone Med Ctr, Dept Radiol,Ctr Biomed Imaging, 660 First Ave,3rd Floor, New York, NY 10016 USA. EM Andrew.Rosenkrantz@nyumc.org NR 29 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD DEC PY 2016 VL 196 IS 6 BP 1613 EP 1618 DI 10.1016/j.juro.2016.06.079 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EB5QS UT WOS:000387436000006 PM 27320841 ER PT J AU Abdel-Wahab, N Lopez-Olivo, MA Pinto-Patarroyo, GP Suarez-Almazor, ME AF Abdel-Wahab, N. Lopez-Olivo, M. A. Pinto-Patarroyo, G. P. Suarez-Almazor, M. E. TI Systematic review of case reports of antiphospholipid syndrome following infection SO LUPUS LA English DT Review DE anticardiolipin antibodies; antiphospholipid antibodies; lupus anticoagulant; infection; systematic review ID INTERNATIONAL CONSENSUS STATEMENT; ANTICARDIOLIPIN ANTIBODIES; LUPUS-ERYTHEMATOSUS; CLASSIFICATION CRITERIA; BETA(2)-GLYCOPROTEIN I; AUTOIMMUNE-DISEASE; APOLIPOPROTEIN-H; POLYMORPHISM; AUTOANTIBODIES; PREVALENCE AB Objective The objective of this study was to conduct a systematic review of case reports documenting the development of antiphospholipid syndrome or antiphospholipid syndrome-related features after an infection. Methods We searched Medline, EMBASE, Web of Science, PubMed ePubs, and The Cochrane Library - CENTRAL through March 2015 without restrictions. Studies reporting cases of antiphospholipid syndrome or antiphospholipid syndrome-related features following an infection were included. Results Two hundred and fifty-nine publications met inclusion criteria, reporting on 293 cases. Three different groups of patients were identified; group 1 included patients who fulfilled the criteria for definitive antiphospholipid syndrome (24.6%), group 2 included patients who developed transient antiphospholipid antibodies with thromboembolic phenomena (43.7%), and group 3 included patients who developed transient antiphospholipid antibodies without thromboembolic events (31.7%). The most common preceding infection was viral (55.6%). In cases that developed thromboembolic events Human immunodeficiency and Hepatitis C viruses were the most frequently reported. Parvovirus B19 was the most common in cases that developed antibodies without thromboembolic events. Hematological manifestations and peripheral thrombosis were the most common clinical manifestations. Positive anticardiolipin antibodies were the most frequent antibodies reported, primarily coexisting IgG and IgM isotypes. Few patients in groups 1 and 2 had persistent antiphospholipid antibodies for more than 6 months. Outcome was variable with some cases reporting persistent antiphospholipid syndrome features and others achieving complete resolution of clinical events. Conclusions Development of antiphospholipid antibodies with all traditional manifestations of antiphospholipid syndrome were observed after variety of infections, most frequently after chronic viral infections with Human immunodeficiency and Hepatitis C. The causal relationship between infection and antiphospholipid syndrome cannot be established, but the possible contribution of various infections in the pathogenesis of antiphospholipid syndrome need further longitudinal and controlled studies to establish the incidence, and better quantify the risk and the outcomes of antiphospholipid-related events after infection. C1 [Abdel-Wahab, N.; Lopez-Olivo, M. A.; Suarez-Almazor, M. E.] Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Sect Rheumatol & Clin Immunol, Houston, TX 77030 USA. [Abdel-Wahab, N.] Assiut Univ Hosp, Rheumatol & Rehabil Dept, Assiut, Egypt. [Pinto-Patarroyo, G. P.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Suarez-Almazor, ME (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Unit 1465,1515 Holcombe Blvd, Houston, TX 77030 USA. EM msalmazor@mdanderson.org FU National Institute for Arthritis, Musculoskeletal and Skin Disorders (NIAMS) [AR053593] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Suarez-Almazor has a K24 career award from the National Institute for Arthritis, Musculoskeletal and Skin Disorders (NIAMS: grant number AR053593). The funding agency had no role in the study's design, conduct, and reporting. NR 42 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0961-2033 EI 1477-0962 J9 LUPUS JI Lupus PD DEC PY 2016 VL 25 IS 14 BP 1520 EP 1531 DI 10.1177/0961203316640912 PG 12 WC Rheumatology SC Rheumatology GA EB5VC UT WOS:000387447700002 PM 27060064 ER PT J AU Quiroz, C Gulyani, S Ruiqian, W Bonaventura, J Cutler, R Pearson, V Allen, RR Earley, CJ Mattson, MP Ferre, S AF Quiroz, Cesar Gulyani, Seema Ruiqian, Wan Bonaventura, Jordi Cutler, Roy Pearson, Virginia Allen, Richard R. Earley, Christopher J. Mattson, Mark P. Ferre, Sergi TI Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome SO NEUROPHARMACOLOGY LA English DT Article DE Restless Legs Syndrome; Brain iron deficiency; Adenosine A(1) receptor; Adenosine A(2A) receptor; Dopamine D-2 receptor ID WILLIS-EKBOM DISEASE; RAT-BRAIN; A(2A) RECEPTORS; DOPAMINE D-1; HOMEOSTATIC SLEEP; A(1) RECEPTORS; EXPRESSION; CAFFEINE; DEPRIVATION; NEUROTRANSMISSION AB Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyper arousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D-2 receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radio-ligand binding saturation experiments in rat brain tissue) of adenosine A(1) receptors (MR) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A(2A) receptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for MR downregulation in the PLMS and hyperarousal in RLS. Published by Elsevier Ltd. C1 [Quiroz, Cesar; Bonaventura, Jordi; Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gulyani, Seema; Ruiqian, Wan; Cutler, Roy; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Pearson, Virginia; Allen, Richard R.; Earley, Christopher J.] Johns Hopkins Sch Med, Dept Neurol, Ctr Restless Legs Study, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, IRP, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse; National Institute on Aging FX Work supported by the intramural funds of the National Institute on Drug Abuse and the National Institute on Aging. NR 43 TC 1 Z9 1 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2016 VL 111 BP 160 EP 168 DI 10.1016/j.neuropharm.2016.09.002 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EB2MS UT WOS:000387197100013 PM 27600688 ER PT J AU Schoenbaum, G Chang, CY Lucantonio, F Takahashi, YK AF Schoenbaum, Geoffrey Chang, Chun-Yun Lucantonio, Federica Takahashi, Yuji K. TI Thinking Outside the Box: Orbitofrontal Cortex, Imagination, and How We Can Treat Addiction SO NEUROPSYCHOPHARMACOLOGY LA English DT Review ID DORSOLATERAL PREFRONTAL CORTEX; REWARD PREDICTION ERRORS; CHRONIC COCAINE; REINFORCER DEVALUATION; AMPHETAMINE EXPOSURE; BASOLATERAL AMYGDALA; DECISION-MAKING; FRONTAL-CORTEX; BEHAVIOR; LESIONS AB Addiction involves an inability to control drug-seeking behavior. While this may be thought of as secondary to an overwhelming desire for drugs, it could equally well reflect a failure of the brain mechanisms that allow addicts to learn about and mentally simulate non-drug consequences. Importantly, this process of mental simulation draws upon, but is not normally bound by, our past experiences. Rather we have the ability to think outside the box of our past, integrating knowledge gained from a variety of similar and not-so-similar life experiences to derive estimates or imagine what might happen next. These estimates influence our current behavior directly and also affect future behavior by serving as the background against which outcomes are evaluated to support learning. Here we will review evidence, from our own work using a Pavlovian over-expectation task as well as from other sources, that the orbitofrontal cortex is a critical node in the neural circuit that generates these estimates. Further we will offer the specific hypothesis that degradation of this function secondary to drug-induced changes is a critical and likely addressable part of addiction. C1 [Schoenbaum, Geoffrey; Chang, Chun-Yun; Lucantonio, Federica; Takahashi, Yuji K.] NIDA, Intramural Res Program, 251 Bayview Dr, Baltimore, MD 21224 USA. RP Schoenbaum, G (reprint author), NIDA, Intramural Res Program, 251 Bayview Dr, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov OI Schoenbaum, Geoffrey/0000-0001-8180-0701 FU Intramural Research Program at the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program at the National Institute on Drug Abuse. The authors declare no conflict of interest. NR 74 TC 0 Z9 0 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2016 VL 41 IS 13 BP 2966 EP 2976 DI 10.1038/npp.2016.147 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700003 PM 27510424 ER PT J AU Barkus, C Korn, C Stumpenhorst, K Laatikainen, LM Ballard, D Lee, S Sharp, T Harrison, PJ Bannerman, DM Weinberger, DR Chen, JS Tunbridge, EM AF Barkus, Chris Korn, Clio Stumpenhorst, Katharina Laatikainen, Linda M. Ballard, Dominic Lee, Sheena Sharp, Trevor Harrison, Paul J. Bannerman, David M. Weinberger, Daniel R. Chen, Jingshan Tunbridge, Elizabeth M. TI Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; REACTION-TIME-TASK; RAT PREFRONTAL CORTEX; VAL(158)MET POLYMORPHISM; PSYCHIATRIC-DISORDERS; EXECUTIVE FUNCTION; GENETIC-VARIATION; DOPAMINE RELEASE; PANIC DISORDER; DEFICIENT MICE AB Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val(158)Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val(158)Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors. C1 [Barkus, Chris; Korn, Clio; Stumpenhorst, Katharina; Laatikainen, Linda M.; Harrison, Paul J.; Tunbridge, Elizabeth M.] Univ Oxford, Dept Psychiat, Oxford, England. [Ballard, Dominic] Univ Oxford, Sch Med, Oxford, England. [Lee, Sheena] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Sharp, Trevor] Univ Oxford, Dept Pharmacol, Oxford, England. [Harrison, Paul J.; Tunbridge, Elizabeth M.] Oxford Hlth NHS Fdn Trust, Oxford, England. [Bannerman, David M.] Univ Oxford, Dept Expt Psychol, Oxford, England. [Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA. [Chen, Jingshan] NIMH, NIH, Bethesda, MD 20892 USA. RP Tunbridge, EM (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, Oxon, England. EM elizabeth.tunbridge@psych.ox.ac.uk FU Intramural Research Program of the NIMH, Bethesda MD, USA; UK Medical Research Council grant [G0700983]; Wellcome Trust; Royal Society [RG100516]; Wellcome Trust Senior Fellowship [087736]; University Research Fellowship - Royal Society FX The authors declare no conflict of interest. This research was funded by the Intramural Research Program of the NIMH, Bethesda MD, USA to the Weinberger Laboratory, and by a UK Medical Research Council grant (G0700983) to PJH and EMT. Additional funding from Wellcome Trust studentships awarded to CK and KS, and a grant to EMT from the Royal Society (RG100516) and a Wellcome Trust Senior Fellowship (087736) awarded to DB. EMT is funded by a University Research Fellowship awarded by the Royal Society. NR 55 TC 1 Z9 1 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2016 VL 41 IS 13 BP 3060 EP 3069 DI 10.1038/npp.2016.119 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700013 PM 27388330 ER PT J AU Kopin, I AF Kopin, Irwin TI Louis Lemberger In Memoriam SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 [Kopin, Irwin] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Kopin, I (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM kopinijk@aol.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2016 VL 41 IS 13 BP 3120 EP 3120 DI 10.1038/npp.2016.204 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700022 PM 27818514 ER PT J AU Kalejaiye, A Giri, N Brewer, CC Zalewski, CK King, KA Adams, CD Rosenberg, PS Kim, HJ Alter, BP AF Kalejaiye, Adedoyin Giri, Neelam Brewer, Carmen C. Zalewski, Christopher K. King, Kelly A. Adams, Charleen D. Rosenberg, Philip S. Kim, H. Jeffrey Alter, Blanche P. TI Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Fanconi anemia; hearing; IBMFS; otology ID ABNORMALITIES; DIAGNOSIS; THERAPY; CANCER AB BackgroundThe inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. MethodsPatients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. ResultsPatients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. ConclusionsFA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss. C1 [Kalejaiye, Adedoyin] Howard Univ Hosp, Washington, DC USA. [Giri, Neelam; Rosenberg, Philip S.; Alter, Blanche P.] NCI, NIH, Rockville, MD USA. [Brewer, Carmen C.; Zalewski, Christopher K.; King, Kelly A.; Kim, H. Jeffrey] NIDCD, NIH, Bethesda, MD USA. [Adams, Charleen D.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Kim, H. Jeffrey] Medstar Georgetown Univ Hosp, Washington, DC USA. RP Giri, N (reprint author), 9609 Med Ctr Dr,Room 6E-538,MSC 9772, Bethesda, MD 20892 USA. EM girin@mail.nih.gov NR 21 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2016 VL 63 IS 12 BP 2139 EP 2145 DI 10.1002/pbc.26155 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EB0HE UT WOS:000387023900010 PM 27428025 ER PT J AU Schepers, SA Haverman, L Zadeh, S Grootenhuis, MA Wiener, L AF Schepers, Sasja A. Haverman, Lotte Zadeh, Sima Grootenhuis, Martha A. Wiener, Lori TI Healthcare Professionals' Preferences and Perceived Barriers for Routine Assessment of Patient-Reported Outcomes in Pediatric Oncology Practice: Moving Toward International Processes of Change SO PEDIATRIC BLOOD & CANCER LA English DT Article DE patient-reported outcomes; pediatric oncology; psychosocial; quality of life ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; CLINICAL-PRACTICE; SUPPORTIVE CARE; CANCER; CHILDREN; QUESTIONNAIRES; COMMUNICATION; PERSPECTIVES; INFORMATION AB BackgroundUsing patient-reported outcomes (PROs) in clinical practice has been shown to enhance detection of health-related quality of life problems and satisfaction with care in children with cancer. This study seeks to identify which PRO information healthcare professionals (HCPs) find useful and what the perceived barriers for routinely assessing PROs are. ProcedureA total of 352 pediatric HCPs (43% male) from 52 countries completed a semistructured online 28-item questionnaire. Descriptive statistics (percentages) were used to identify highly important PRO information and perceived barriers. HCPs' perceived barriers were compared according to gender, years of work experience, and country using a Fishers exact test. ResultsThe five highest ranked PRO topics relevant in routine assessment by HCPs were as follows: pain (98%), feeling sad or depressed (96%), overall physical symptoms (95%), problems with therapy adherence (94%), and overall emotional issues (93%). Five lowest ranked topics were as follows: difficulties praying (50%), other spiritual concerns (55, 56, and 60%), and feeling bored (60%). Barriers for assessing PROs included: time (58%), insufficient staff (49%), logistics (32%), and financial resources (26%). Providers from developing countries more often reported barriers concerning insufficient staff, logistics, and financial resources. ConclusionsHCPs strongly value the use of physical and psychosocial PROs within pediatric oncology practice, but mainly perceive organizational barriers for routine assessment. To successfully integrate PROs, efforts should be made to address HCP-perceived barriers, such that patient-reported problems can be detected and timely referrals made. C1 [Schepers, Sasja A.; Haverman, Lotte; Grootenhuis, Martha A.] Emma Childrens Hosp, Div Pediat, Psychosocial Dept, Acad Med Ctr, Post Box 22660, NL-110 0DD Amsterdam, Netherlands. [Schepers, Sasja A.; Grootenhuis, Martha A.] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Zadeh, Sima; Wiener, Lori] NCI, Behav Hlth Core, Pediat Psychosocial Support & Res Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schepers, SA (reprint author), Emma Childrens Hosp, Div Pediat, Psychosocial Dept, Acad Med Ctr, Post Box 22660, NL-110 0DD Amsterdam, Netherlands. EM s.a.schepers@amc.nl NR 46 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2016 VL 63 IS 12 BP 2181 EP 2188 DI 10.1002/pbc.26135 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EB0HE UT WOS:000387023900016 PM 27511830 ER PT J AU Samala, R Thorsheim, HR Goda, S Taskar, K Gril, B Steeg, PS Smith, QR AF Samala, Ramakrishna Thorsheim, Helen R. Goda, Satyanarayana Taskar, Kunal Gril, Brunilde Steeg, Patricia S. Smith, Quentin R. TI Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer SO PHARMACEUTICAL RESEARCH LA English DT Article DE blood-brain barrier; brain metastases; breast cancer; permeability; vinorelbine ID CENTRAL-NERVOUS-SYSTEM; P-GLYCOPROTEIN; THERAPEUTIC TARGETS; DRUG-DELIVERY; BARRIER; MICE; PERMEABILITY; RESISTANCE; PHARMACOKINETICS; DISPOSITION AB To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis. Brain and systemic metastases were created by administration of cancer cells in female NuNu mice. After metastases developed, animals were administered vinorelbine at the maximal tolerated dose (12 mg/kg), and were evaluated thereafter for total and unbound drug pharmacokinetics, biomarker TUNEL staining, and barrier permeability to Texas red. Median brain metastasis drug exposure was 4-fold greater than normal brain, yet only similar to 8% of non-barrier systemic metastases, which suggests restricted brain exposure. Unbound vinorelbine tissue/plasma partition coefficient, K-p,K-uu, equaled similar to 1.0 in systemic metastases, but 0.03-0.22 in brain metastases, documenting restricted equilibration. In select sub-regions of highest drug-uptake brain metastases, K-p,K-uu approached 1.0, indicating complete focal barrier breakdown. Most vinorelbine-treated brain metastases exhibited little or no positive early apoptosis TUNEL staining in vivo. The in vivo unbound vinorelbine IC50 for TUNEL-positive staining (56 nM) was 4-fold higher than that measured in vitro (14 nM). Consistent with this finding, P-glycoprotein expression was observed to be substantially upregulated in brain metastasis cells in vivo. Vinorelbine exposure at maximum tolerated dose was less than one-tenth that in systemic metastases in > 70% of brain metastases, and was associated with negligible biomarker effect. In small subregions of the highest uptake brain metastases, compromise of blood-tumor barrier appeared complete. The results suggest that restricted delivery accounts for 80% of the compromise in drug efficacy for vinorelbine against this model. C1 [Samala, Ramakrishna; Thorsheim, Helen R.; Goda, Satyanarayana; Taskar, Kunal; Smith, Quentin R.] Texas Tech Univ, Sch Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, 1300 South Coulter Dr, Amarillo, TX 79106 USA. [Goda, Satyanarayana] Formurex Inc, Stockton, CA 95215 USA. [Taskar, Kunal] GlaxoSmithKline, IVIVT, Mechanist Safety & Disposit, Ware SG12 0DP, Herts, England. [Gril, Brunilde; Steeg, Patricia S.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Smith, QR (reprint author), Texas Tech Univ, Sch Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, 1300 South Coulter Dr, Amarillo, TX 79106 USA. EM quentin.smith@ttuhsc.edu FU Department of Defense Breast Cancer Program [W81XWH-06-2-0033]; Cancer Prevention Research Institute of Texas [RP120489, RP110786] FX This work was supported by grants from the Department of Defense Breast Cancer Program (W81XWH-06-2-0033) and the Cancer Prevention Research Institute of Texas (RP120489 and RP110786) NR 49 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD DEC PY 2016 VL 33 IS 12 BP 2904 EP 2919 DI 10.1007/s11095-016-2012-3 PG 16 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EB5DY UT WOS:000387395000004 PM 27541873 ER PT J AU DeCherney, AH Barnett, RL AF DeCherney, Alan H. Barnett, Rebecca L. TI In Vitro Fertilization Research is Translational Research SO REPRODUCTIVE SCIENCES LA English DT Article; Proceedings Paper CT ART of Reproductive Medicine Symposium CY FEB, 2016 CL SPAIN DE IVF; translational research; evidence-based medicine; ART; in vitro fertilization; assisted reproductive technologies AB In vitro fertilization (IVF) is the perfect example of translational research. Changes in IVF and the IVF laboratory have been transmitted to clinical care, showing dramatic improvements in health outcomes, including notable increases in the cumulative pregnancy rate. Current research in the laboratory focusing on culture media, embryo selection criteria, and implementation of genetic testing and manipulation promises to translate to further improvements in our ability to assist human reproduction. The field of IVF and ART remains a large source for clinical and scientific discovery and development, and will require the proper interested and invested personnel, occupational structuring, and funding for continued success. C1 [DeCherney, Alan H.] Natl Inst Child Hlth & Human Dev NICHD, Bethesda, MD USA. [Barnett, Rebecca L.] Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ USA. RP Barnett, RL (reprint author), 125 Paterson St, New Brunswick, NJ 08901 USA. EM barnetrl@rutgers.edu NR 7 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 23 IS 12 BP 1634 EP 1638 DI 10.1177/1933719116667608 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EB6IE UT WOS:000387484600006 PM 27821560 ER PT J AU Liu, BM Yu, MD Graubard, BI Troiano, RP Schenker, N AF Liu, Benmei Yu, Mandi Graubard, Barry I. Troiano, Richard P. Schenker, Nathaniel TI Multiple imputation of completely missing repeated measures data within person from a complex sample: application to accelerometer data in the National Health and Nutrition Examination Survey SO STATISTICS IN MEDICINE LA English DT Article DE accelerometer data; missing; primary sampling units; multiple imputation; alternative conditional expectation models ID PHYSICAL-ACTIVITY; METABOLIC SYNDROME; REGRESSION-MODELS; STEPPING CADENCE; 2005-2006 NHANES; UNITED-STATES; TRANSFORMATIONS; STEPS/DAY; PATTERNS; ADULTS AB The Physical Activity Monitor component was introduced into the 2003-2004 National Health and Nutrition Examination Survey (NHANES) to collect objective information on physical activity including both movement intensity counts and ambulatory steps. Because of an error in the accelerometer device initialization process, the steps data were missing for all participants in several primary sampling units, typically a single county or group of contiguous counties, who had intensity count data from their accelerometers. To avoid potential bias and loss in efficiency in estimation and inference involving the steps data, we considered methods to accurately impute the missing values for steps collected in the 2003-2004 NHANES. The objective was to come up with an efficient imputation method that minimized model-based assumptions. We adopted a multiple imputation approach based on additive regression, bootstrapping and predictive mean matching methods. This method fits alternative conditional expectation (ace) models, which use an automated procedure to estimate optimal transformations for both the predictor and response variables. This paper describes the approaches used in this imputation and evaluates the methods by comparing the distributions of the original and the imputed data. A simulation study using the observed data is also conducted as part of the model diagnostics. Finally, some real data analyses are performed to compare the before and after imputation results. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Liu, Benmei; Yu, Mandi; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Schenker, Nathaniel] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Liu, BM (reprint author), NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. EM liub2@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC PY 2016 VL 35 IS 28 BP 5170 EP 5188 DI 10.1002/sim.7049 PG 19 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EB4PR UT WOS:000387355100004 PM 27488606 ER PT J AU Shardell, M Ferrucci, L AF Shardell, Michelle Ferrucci, Luigi TI Instrumental variable analysis of multiplicative models with potentially invalid instruments SO STATISTICS IN MEDICINE LA English DT Article DE causal inference; generalized method of moments; instrumental variables; structural mean models ID STRUCTURAL-NESTED MODELS; MENDELIAN RANDOMIZATION; CAUSAL INFERENCE; MEAN MODELS; GENERALIZED-METHOD; OUTCOMES; EPIDEMIOLOGISTS; IDENTIFICATION; MOMENTS; TRIALS AB Instrumental variable (IV) methods have potential to consistently estimate the causal effect of an exposure on an outcome in the presence of unmeasured confounding. However, validity of IV methods relies on strong assumptions, some of which cannot be conclusively verified from observational data. One such assumption is that the effect of the proposed instrument on the outcome is completely mediated by the exposure. We consider the situation where this assumption is violated, but the remaining IV assumptions hold; that is, the proposed IV (1) is associated with the exposure and (2) has no unmeasured causes in common with the outcome. We propose a method to estimate multiplicative structural mean models of binary outcomes in this scenario in the presence of unmeasured confounding. We also extend the method to address multiple scenarios, including mediation analysis. The method adapts the asymptotically efficient G-estimation approach that was previously proposed for additive structural mean models, and it can be carried out using off-the-shelf software for generalized method of moments. Monte Carlo simulation studies show that the method has low bias and accurate coverage. We applied the method to a case study of circulating vitamin D and depressive symptoms using season of blood collection as a (potentially invalid) instrumental variable. Potential applications of the proposed method include randomized intervention studies as well as Mendelian randomization studies with genetic variants that affect multiple phenotypes, possibly including the outcome. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Shardell, Michelle; Ferrucci, Luigi] NIA, Harbor Hosp, Rm NM529,3001 S Hanover St, Baltimore, MD 21225 USA. RP Shardell, M (reprint author), NIA, Harbor Hosp, Rm NM529,3001 S Hanover St, Baltimore, MD 21225 USA. EM michelle.shardell@nih.gov FU National Institute on Aging Intramural Program FX The authors would like to thank National Institute on Aging Intramural Program for funding this project. NR 41 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC PY 2016 VL 35 IS 29 BP 5430 EP 5447 DI 10.1002/sim.7069 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EB4QJ UT WOS:000387357400008 PM 27527517 ER PT J AU Mitchell, EM Plowden, TC Schisterman, EF AF Mitchell, Emily M. Plowden, Torie C. Schisterman, Enrique F. TI Estimating relative risk of a log-transformed exposure measured in pools SO STATISTICS IN MEDICINE LA English DT Article DE biomarkers; design; log-transformation; pooled specimens; regression calibration ID ROC CURVE ANALYSIS; REGRESSION-MODELS; EFFICIENT DESIGN; BIOMARKER DATA; NORMAL-WEIGHT; LEPTIN; SERUM; DISTRIBUTIONS; BIOSPECIMENS; SUBJECT AB Pooling biospecimens prior to performing laboratory assays is a useful tool to reduce costs, achieve minimum volume requirements and mitigate assay measurement error. When estimating the risk of a continuous, pooled exposure on a binary outcome, specialized statistical techniques are required. Current methods include a regression calibration approach, where the expectation of the individual-level exposure is calculated by adjusting the observed pooled measurement with additional covariate data. While this method employs a linear regression calibration model, we propose an alternative model that can accommodate log-linear relationships between the exposure and predictive covariates. The proposed model permits direct estimation of the relative risk associated with a log-transformation of an exposure measured in pools. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Mitchell, Emily M.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Plowden, Torie C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Long-Range Research Initiative of the American Chemistry Council FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by the Long-Range Research Initiative of the American Chemistry Council. NR 47 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC PY 2016 VL 35 IS 29 BP 5477 EP 5494 DI 10.1002/sim.7075 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EB4QJ UT WOS:000387357400011 PM 27530506 ER PT J AU Xu, ZZ Proschan, M Lee, S AF Xu, Zhenzhen Proschan, Michael Lee, Shiowjen TI Validity and power considerations on hypothesis testing under minimization SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Xu, Zhenzhen; Lee, Shiowjen] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Proschan, Michael] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Xu, ZZ (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM zhenzhen.xu@fda.hhs.gov NR 5 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC PY 2016 VL 35 IS 29 BP 5527 EP 5528 DI 10.1002/sim.7037 PG 2 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EB4QJ UT WOS:000387357400015 PM 27870128 ER PT J AU Yamada, D Iyoda, T Vizcardo, R Shimizu, K Sato, Y Endo, TA Kitahara, G Okoshi, M Kobayashi, M Sakurai, M Ohara, O Taniguchi, M Koseki, H Fujii, SI AF Yamada, Daisuke Iyoda, Tomonori Vizcardo, Raul Shimizu, Kanako Sato, Yusuke Endo, Takaho A. Kitahara, Genta Okoshi, Momoko Kobayashi, Midori Sakurai, Maki Ohara, Osamu Taniguchi, Masaru Koseki, Haruhiko Fujii, Shin-Ichiro TI Efficient Regeneration of Human V alpha 24(+) Invariant Natural Killer T Cells and Their Anti-Tumor Activity In Vivo SO STEM CELLS LA English DT Article DE Invariant NKT cells; NK cells; Induced pluripotent stem cells; Reprogramming; Immunotherapy ID PLURIPOTENT STEM-CELLS; ACTIVATE NK CELLS; ALPHA-GALACTOSYLCERAMIDE; DENDRITIC CELLS; LUNG-CANCER; PHASE-I; INNATE; CYTOTOXICITY; GENERATION; IMMUNITY AB Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (V alpha 24(+) iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-V alpha 24(+) iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-c upon activation, as much as parental V alpha 24(+) iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-V alpha 24(+) iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-V alpha 24(+) iNKT cells for cancer immunotherapy. C1 [Yamada, Daisuke; Vizcardo, Raul; Kitahara, Genta; Okoshi, Momoko; Kobayashi, Midori; Koseki, Haruhiko] RIKEN Ctr Integrat Med Sci IMS, Lab Dev Genet, Yokohama, Kanagawa, Japan. [Iyoda, Tomonori; Shimizu, Kanako; Sato, Yusuke; Sakurai, Maki; Fujii, Shin-Ichiro] RIKEN Ctr Integrat Med Sci IMS, Lab Immunotherapy, Yokohama, Kanagawa, Japan. [Endo, Takaho A.; Ohara, Osamu] RIKEN Ctr Integrat Med Sci IMS, Lab Integrat Genom, Yokohama, Kanagawa, Japan. [Taniguchi, Masaru] RIKEN Ctr Integrat Med Sci IMS, Lab Immunoregulat, Yokohama, Kanagawa, Japan. [Vizcardo, Raul] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Fujii, SI (reprint author), RIKEN Ctr Integrat Med Sci IMS, Lab Immunotherapy, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.; Koseki, H (reprint author), RIKEN IMS, Lab Dev Genet, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. EM haruhiko.koseki@riken.jp; shin-ichiro.fujii@riken.jp RI Endo, Takaho/B-5763-2017 OI Endo, Takaho/0000-0002-2801-2463 FU Research Center Network for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development (AMED); CREST, Japan Science and Technology Agency FX We are grateful to prof. P.D. Burrows for the critical reading of the manuscript. We thank Masami Kawamura and Chieko Tezuka for their technical supports. This work was supported by the Research Center Network for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development (AMED) and CREST, Japan Science and Technology Agency. NR 32 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD DEC PY 2016 VL 34 IS 12 BP 2852 EP 2860 DI 10.1002/stem.2465 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA EB4NE UT WOS:000387347800005 PM 27422351 ER PT J AU Perosky, JE Khoury, BM Jenks, TN Ward, FS Cortright, K Meyer, B Barton, DK Sinder, BP Marini, JC Caird, MS Kozloff, KM AF Perosky, Joseph E. Khoury, Basma M. Jenks, Terese N. Ward, Ferrous S. Cortright, Kai Meyer, Bethany Barton, David K. Sinder, Benjamin P. Marini, Joan C. Caird, Michelle S. Kozloff, Kenneth M. TI Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/ plus osteogenesis imperfecta model SO BONE LA English DT Article DE Osteogenesis imperfecta; Sclerostin antibody; Cessation; Bisphosphonate; Osteoporosis ID MOUSE MODEL; POSTMENOPAUSAL WOMEN; ALENDRONATE TREATMENT; MINERAL DENSITY; TERIPARATIDE TREATMENT; OVARIECTOMIZED RATS; IN-VIVO; STRENGTH; OSTEOPOROSIS; INCREASES AB Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in 01, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3 week old Brtl/+ and wild type mice for 5 weeks with SclAb, and then withdrew treatment for an additional 6 weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl+ murine model of 01, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6 weeks following cessation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Perosky, Joseph E.; Khoury, Basma M.; Jenks, Terese N.; Ward, Ferrous S.; Cortright, Kai; Meyer, Bethany; Barton, David K.; Sinder, Benjamin P.; Caird, Michelle S.; Kozloff, Kenneth M.] Univ Michigan, Dept Orthopaed Surg, Ann Arbor, MI 48109 USA. [Jenks, Terese N.; Ward, Ferrous S.; Cortright, Kai; Meyer, Bethany; Barton, David K.; Sinder, Benjamin P.; Kozloff, Kenneth M.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Marini, Joan C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Kozloff, KM (reprint author), 2015 Biomed Sci Res Bldg,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM kenkoz@umich.edu FU NIH [AR062522] FX This study was supported by NIH grant AR062522. SclAb was graciously provided by Amgen and UCB. The authors thank Mike Ominsky for feedback on the data and critical review of the manuscript. The authors would like to thank Bonnie Nolan and Kathy Sweet for their technical assistance. Study designed and conducted by KMK, JEP, and MSC. Data collected by JEP, DKB, and BK. Data analyzed and interpreted by all authors. Manuscript was written and approved by all authors. KMK takes responsibility for the integrity of the data analysis. NR 47 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD DEC PY 2016 VL 93 BP 79 EP 85 DI 10.1016/j.bone.2016.09.013 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA9TL UT WOS:000386987500009 PM 27641475 ER PT J AU Marcoline, FV Ishida, Y Mindell, JA Nayak, S Grabe, M AF Marcoline, Frank V. Ishida, Yoichi Mindell, Joseph A. Nayak, Smita Grabe, Michael TI A mathematical model of osteoclast acidification during bone resorption SO BONE LA English DT Article DE Osteoclast; Mathematical model; Acidification; V-ATPase; CIC-7; H(v)1 ID GATED PROTON CHANNELS; CHLORIDE BICARBONATE EXCHANGE; INTRACELLULAR PH REGULATION; RAT-LIVER LYSOSOMES; RUFFLED BORDER; POSTMENOPAUSAL OSTEOPOROSIS; RESORBING OSTEOCLASTS; NA+/H+ ANTIPORTER; AVIAN OSTEOCLAST; PLASMA-MEMBRANE AB Bone resorption by osteoclasts occurs through the creation of a sealed extracellular compartment (ECC), or pit, adjacent to the bone that is subsequently acidified through a complex biological process. The low pH of the pit dissolves the bone mineral and activates acid proteases that further break down the bone matrix. There are many ion channels, transporters, and soluble proteins involved in osteoclast mediated resorption, and in the past few years, there has been an increased understanding of the identity and properties of some key proteins such as the CIC-7 CI-/H+ antiporter and the H(v)1 proton channel. Here we present a detailed mathematical model of osteoclast acidification that includes the influence of many of the key regulatory proteins. The primary enzyme responsible for acidification is the vacuolar H+-ATPase (V-ATPase), which pumps protons from the cytoplasm into the pit Unlike the acidification of small lysosomes, the pit is so large that protons become depleted from the cytoplasm. Hence, proton buffering and production in the cytoplasm by carbonic anhydrase II (CAII) is potentially important for proper acidification. We employ an ordinary differential equations (ODE)-based model that accounts for the changes in ionic species in the cytoplasm and the resorptive pit. Additionally, our model tracks ionic flow between the cytoplasm and the extracellular solution surrounding the cell. Whenever possible, the properties of individual channels and transporters are calibrated based on electrophysiological measurements, and physical properties of the cell, such as buffering capacity, surface areas, and volumes, are estimated based on available data. Our model reproduces many of the experimental findings regarding the role of key proteins in the acidification process, and it allows us to estimate, among other things, number of active pumps, protons moved, and the influence of particular mutations implicated in disease. (C) 2016 Elsevier Inc All rights reserved. C1 [Marcoline, Frank V.; Grabe, Michael] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. [Marcoline, Frank V.; Grabe, Michael] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Ishida, Yoichi] Ohio Univ, Dept Philosophy, Athens, OH 45701 USA. [Mindell, Joseph A.] NINDS, Membrane Transport Biophys Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Nayak, Smita] Swedish Hlth Serv, Swedish Ctr Res & Innovat, Seattle, WA 98122 USA. RP Grabe, M (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. EM michael.grabe@ucsf.edu FU National Institutes of Health [R21-GM100224] FX We would like to thank Thomas DeCoursey, Mary Nakamura, Seth Alper, Diane Barber, Lily Jan, and Neville Bethel for useful discussions. We thank Jianmin Sun for his help early in this study writing the first version of the ODE solver in Matlab (TM). Additionally, we acknowledge Benjamin Hsieh's early help on this study. This work was supported by National Institutes of Health Grant (R21-GM100224). NR 84 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD DEC PY 2016 VL 93 BP 167 EP 180 DI 10.1016/j.bone.2016.09.007 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA9TL UT WOS:000386987500018 PM 27650914 ER PT J AU Welsh, KJ Soldin, SJ AF Welsh, Kerry J. Soldin, Steven J. TI How reliable are free thyroid and total T-3 hormone assays? SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Review ID TANDEM MASS-SPECTROMETRY; FREE-THYROXINE; SUBCLINICAL HYPOTHYROIDISM; FREE TRIIODOTHYRONINE; NONTHYROIDAL ILLNESS; STIMULATING HORMONE; IMMUNOASSAYS; ASSOCIATION; DISEASE; BINDING AB Hypothyroidism is a very common disorder worldwide, for which the usual treatment is monotherapy with levothyroxine (L=T-4). However, a number of patients treated with L=T-4 continue to report symptoms of hypothyroidism despite seemingly normal levels of thyroid-stimulating hormone (TSH), free-T-3 (FT3) and free-T-4 (FT4) measured by immunoassay. This review summarizes the limitations of the immunoassays commonly used to measure thyroid hormone levels and emphasizes the advantages of the role of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Immunoassays for free thyroid hormone are affected by alterations in serum binding proteins that occur in many physiological and disease states. Multiple studies show falsely normal values for T-3, FT3 and FT4 by immunoassay that are below the reference interval when measured by (ultrafiltration) LC-MS/MS, a reference method. We suggest evaluation of thyroid hormone levels by ultrafiltration LC-MS/MS for patients who continue to experience hypothyroid symptoms on LT-4. This may help identify the approximately 20% subset of patients who would benefit from addition of T-3 to their treatment regimen (combination therapy). C1 [Welsh, Kerry J.; Soldin, Steven J.] NIH, Div Clin Chem, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. RP Soldin, SJ (reprint author), NIH, Div Clin Chem, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM steven.soldin@nih.gov FU National Institutes of Health Intramural Research Award FX The authors are supported by the National Institutes of Health Intramural Research Award. NR 55 TC 0 Z9 0 U1 12 U2 12 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD DEC PY 2016 VL 175 IS 6 BP R255 EP R263 DI 10.1530/EJE-16-0193 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA8UV UT WOS:000386915600003 PM 27737898 ER PT J AU Leyva, B Persoskie, A Ottenbacher, A Hamilton, JG Allen, JD Kobrin, SC Taplin, SH AF Leyva, Bryan Persoskie, Alexander Ottenbacher, Allison Hamilton, Jada G. Allen, Jennifer D. Kobrin, Sarah C. Taplin, Stephen H. TI Do Men Receive Information Required for Shared Decision Making About PSA Testing? Results from a National Survey SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Shared decision making; PSA testing; Prostate cancer screening; Uncertainty; Patient-provider communication ID PROSTATE-SPECIFIC ANTIGEN; HEALTH-PROFESSIONALS PERCEPTIONS; AMERICAN-CANCER-SOCIETY; CARE PHYSICIANS USE; CLINICAL-PRACTICE; RANDOMIZED PROSTATE; SCREENING DECISIONS; SELF-REPORTS; FOLLOW-UP; GUIDELINES AB Most professional organizations, including the American College of Physicians and U.S. Preventive Services Task Force, emphasize that screening for prostate cancer with the prostate-specific antigen (PSA) test should only occur after a detailed discussion between the health-care provider and patient about the known risks and potential benefits of the test. In fact, guidelines strongly advise health-care providers to involve patients, particularly those at elevated risk of prostate cancer, in a "shared decision making" (SDM) process about PSA testing. We analyzed data from the National Cancer Institute's Health Information National Trends Survey 2011-2012-a nationally representative, cross-sectional survey-to examine the extent to which health professionals provided men with information critical to SDM prior to PSA testing, including (1) that patients had a choice about whether or not to undergo PSA testing, (2) that not all doctors recommend PSA testing, and (3) that no one is sure if PSA testing saves lives. Over half (55 %) of men between the ages of 50 and 74 reported ever having had a PSA test. However, only 10 % of men, regardless of screening status, reported receiving all three pieces of information: 55 % reported being informed that they could choose whether or not to undergo testing, 22 % reported being informed that some doctors recommend PSA testing and others do not, and 14 % reported being informed that no one is sure if PSA testing actually saves lives. Black men and men with lower levels of education were less likely to be provided this information. There is a need to improve patient-provider communication about the uncertainties associated with the PSA test. Interventions directed at patients, providers, and practice settings should be considered. C1 [Leyva, Bryan; Kobrin, Sarah C.; Taplin, Stephen H.] NCI, Proc Care Res Branch, Behav Res Program, NIH, 9609 Med Ctr Dr 3E230, Bethesda, MD 20892 USA. [Persoskie, Alexander] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Ottenbacher, Allison] NCI, Sci Res & Technol Branch, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Allen, Jennifer D.] Tufts Univ, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. RP Leyva, B (reprint author), NCI, Proc Care Res Branch, Behav Res Program, NIH, 9609 Med Ctr Dr 3E230, Bethesda, MD 20892 USA. EM leyvabryan@gmail.com OI Ottenbacher, Allison/0000-0002-8974-5580 NR 60 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2016 VL 31 IS 4 BP 693 EP 701 DI 10.1007/s13187-015-0870-8 PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA EA5OA UT WOS:000386669200014 PM 26498649 ER PT J AU Commodore-Mensah, Y Sampah, M Berko, C Cudjoe, J Abu-Bonsrah, N Obisesan, O Agyemang, C Adeyemo, A Himmelfarb, CD AF Commodore-Mensah, Yvonne Sampah, Maame Berko, Charles Cudjoe, Joycelyn Abu-Bonsrah, Nancy Obisesan, Olawunmi Agyemang, Charles Adeyemo, Adebowale Himmelfarb, Cheryl Dennison TI The Afro-Cardiac Study: Cardiovascular Disease Risk and Acculturation in West African Immigrants in the United States: Rationale and Study Design SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE African immigrants; Cardiovascular disease; Immigrants; Acculturation ID AMERICAN-HEART-ASSOCIATION; HIGH BLOOD-PRESSURE; PSYCHOLOGICAL ACCULTURATION; EPIDEMIOLOGIC TRANSITION; POPULATION-CHANGE; NATIONAL SAMPLE; PREVALENCE; HEALTH; HYPERTENSION; OBESITY AB Cardiovascular disease (CVD) remains the leading cause of death in the United States (US). African-descent populations bear a disproportionate burden of CVD risk factors. With the increase in the number of West African immigrants (WAIs) to the US over the past decades, it is imperative to specifically study this new and substantial subset of the African-descent population and how acculturation impacts their CVD risk. The Afro-Cardiac study, a community-based cross-sectional study of adult WAIs in the Baltimore-Washington metropolis. Guided by the PRECEDE-PROCEED model, we used a modification of the World Health Organization Steps survey to collect data on demographics, socioeconomic status, migration-related factors and behaviors. We obtained physical, biochemical, acculturation measurements as well as a socio-demographic and health history. Our study provides critical data on the CVD risk of WAIs. The framework used is valuable for future epidemiological studies addressing CVD risk and acculturation among immigrants. C1 [Commodore-Mensah, Yvonne] Emory Univ, Nell Hodgson Woodruff Sch Nursing, 1520 Clifton Rd NE,Rm 368, Atlanta, GA 30322 USA. [Sampah, Maame; Abu-Bonsrah, Nancy] Johns Hopkins Sch Med, 733 N Broadway, Baltimore, MD 21205 USA. [Berko, Charles] St Agnes Hosp, Dept Internal Med, 900 S Caton Ave, Baltimore, MD 21229 USA. [Cudjoe, Joycelyn; Himmelfarb, Cheryl Dennison] Johns Hopkins Sch Nursing, 525 N Wolfe St, Baltimore, MD 21205 USA. [Obisesan, Olawunmi] AT Still Univ, 800 W Jefferson St, Kirksville, MO 63501 USA. [Agyemang, Charles] Univ Amsterdam, Amsterdam Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. RP Commodore-Mensah, Y (reprint author), Emory Univ, Nell Hodgson Woodruff Sch Nursing, 1520 Clifton Rd NE,Rm 368, Atlanta, GA 30322 USA. EM ycommod@emory.edu FU National Institute of Nursing Research (NINR) [1P30NR011409] FX This study was supported by pilot funding from National Institute of Nursing Research (NINR) [1P30NR011409]. We would like to acknowledge all the research assistants (Felicia Sam, Grace Onayiga, Kojo Amoakwah, Audrey Addaquay-Corey, Selase Agudu-Morgan, Loretta Odro and Jonathan Aboagye) who participated in data collection as well as the leaders of the community-based organized organizations that allowed data collection to occur on their premises. Finally, we thank the study participants who dedicated their time to advance our understanding of CVD risk among WAIs. NR 61 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD DEC PY 2016 VL 18 IS 6 BP 1301 EP 1308 DI 10.1007/s10903-015-0291-0 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA3JY UT WOS:000386499600006 PM 26429573 ER PT J AU Varshney, GK Carrington, B Pei, WH Bishop, K Chen, ZL Fan, CX Xu, LS Jones, M LaFave, MC Ledin, J Sood, R Burgess, SM AF Varshney, Gaurav K. Carrington, Blake Pei, Wuhong Bishop, Kevin Chen, Zelin Fan, Chunxin Xu, Lisha Jones, Marypat LaFave, Matthew C. Ledin, Johan Sood, Raman Burgess, Shawn M. TI A high-throughput functional genomics workflow based on CRISPR/Cas9-mediated targeted mutagenesis in zebrafish SO NATURE PROTOCOLS LA English DT Article ID ZINC-FINGER NUCLEASES; GENE-FUNCTION; IN-VIVO; SYSTEM; CRISPR-CAS9; SPECIFICITY; WIDE; CAS9; RESOURCE; SEQUENCE AB The zebrafish is a popular model organism for studying development and disease, and genetically modified zebrafish provide an essential tool for functional genomic studies. Numerous publications have demonstrated the efficacy of gene targeting in zebrafish using CRISPR/Cas9, and they have included descriptions of a variety of tools and methods for guide RNA synthesis and mutant identification. However, most of the published techniques are not readily scalable to increase throughput. We recently described a CRISPR/Cas9-based high-throughput mutagenesis and phenotyping pipeline in zebrafish. Here, we present a complete workflow for this pipeline, including target selection; cloning-free single-guide RNA (sgRNA) synthesis; microinjection; validation of the target-specific activity of the sgRNAs; founder screening to identify germline-transmitting mutations by fluorescence PCR; determination of the exact lesion by Sanger or next-generation sequencing (including software for analysis); and genotyping in the F-1 or subsequent generations. Using these methods, sgRNAs can be evaluated in 3 d, zebrafish germline-transmitting mutations can be identified within 3 months and stable lines can be established within 6 months. Realistically, two researchers can target tens to hundreds of genes per year using this protocol. C1 [Varshney, Gaurav K.; Pei, Wuhong; Chen, Zelin; Xu, Lisha; LaFave, Matthew C.; Burgess, Shawn M.] NHGRI, Dev Genom Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Varshney, Gaurav K.] Oklahoma Med Res Fdn, Funct & Chem Genom Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Carrington, Blake; Bishop, Kevin; Sood, Raman] NHGRI, Zebrafish Core, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Fan, Chunxin] Shanghai Ocean Univ, Minist Educ, Key Lab Explorat & Utilizat Aquat Genet Resource, Shanghai, Peoples R China. [Jones, Marypat] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Ledin, Johan] Uppsala Univ, Sci Life Lab, Dept Organismal Biol, Uppsala, Sweden. [LaFave, Matthew C.] Synthet Genom, San Diego, CA USA. RP Burgess, SM (reprint author), NHGRI, Dev Genom Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI LaFave, Matthew/0000-0001-9165-041X; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health FX We thank J. Fekecs and U. Harper for help with figures, and D. Prebilic, H. Mahon and other staff of the National Institutes of Health zebrafish facility for excellent animal care. This research is funded by the Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health (S.M.B. and R.S.). NR 34 TC 0 Z9 0 U1 36 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD DEC PY 2016 VL 11 IS 12 BP 2357 EP 2375 DI 10.1038/nprot.2016.141 PG 19 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EA9PR UT WOS:000386976800004 PM 27809318 ER PT J AU Lauritzen, KH Hasan-Olive, MM Regnell, CE Kleppa, L Scheibye-Knudsen, M Gjedde, A Klungland, A Bohr, VA Storm-Mathisen, J Bergersen, LH AF Lauritzen, Knut H. Hasan-Olive, Md Mahdi Regnell, Christine E. Kleppa, Liv Scheibye-Knudsen, Morten Gjedde, Albert Klungland, Arne Bohr, Vilhelm A. Storm-Mathisen, Jon Bergersen, Linda H. TI A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain SO NEUROBIOLOGY OF AGING LA English DT Article DE MtDNA damage; Ketogenic diet; Biogenesis; Neurodegeneration ID TEMPORAL-LOBE EPILEPSY; ALZHEIMERS-DISEASE; KETONE-BODIES; BRAIN CANCER; MOUSE-BRAIN; HUMAN-CELLS; DYNAMICS; POLYMERASE; PROTEINS; INFLAMMATION AB Mitochondrial genome maintenance plays a central role in preserving brain health. We previously demonstrated accumulation of mitochondrial DNA damage and severe neurodegeneration in transgenic mice inducibly expressing a mutated mitochondrial DNA repair enzyme (mutUNG1) selectively in forebrain neurons. Here, we examine whether severe neurodegeneration in mutUNG1-expressing mice could be rescued by feeding the mice a ketogenic diet, which is known to have beneficial effects in several neurological disorders. The diet increased the levels of superoxide dismutase 2, and mitochondrial mass, enzymes, and regulators such as SIRT1 and FIS1, and appeared to downregulate N-methyl-Daspartic acid (NMDA) receptor subunits NR2A/B and upregulate gamma-aminobutyric acid A (GABA(A)) receptor subunits alpha(1). However, unexpectedly, the ketogenic diet aggravated neurodegeneration and mitochondrial deterioration. Electron microscopy showed structurally impaired mitochondria accumulating in neuronal perikarya. We propose that aggravation is caused by increased mitochondrial biogenesis of generally dysfunctional mitochondria. This study thereby questions the dogma that a ketogenic diet is unambiguously beneficial in mitochondrial disorders. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lauritzen, Knut H.; Hasan-Olive, Md Mahdi; Regnell, Christine E.; Kleppa, Liv; Storm-Mathisen, Jon; Bergersen, Linda H.] Univ Oslo, Synapt Neurochem Lab, Div Anat, Oslo, Norway. [Lauritzen, Knut H.; Hasan-Olive, Md Mahdi; Regnell, Christine E.; Kleppa, Liv; Storm-Mathisen, Jon; Bergersen, Linda H.] Univ Oslo, CMBN SERTA Hlth Brain Ageing Ctr, Inst Basic Med Sci, Oslo, Norway. [Lauritzen, Knut H.; Hasan-Olive, Md Mahdi; Regnell, Christine E.; Kleppa, Liv; Bergersen, Linda H.] Univ Oslo, Inst Oral Biol, Brain & Muscle Energy Grp, Electron Microscopy Lab, Oslo, Norway. [Regnell, Christine E.; Gjedde, Albert; Bergersen, Linda H.] Univ Copenhagen, Fac Hlth Sci, Ctr Hlth Aging, Copenhagen, Denmark. [Regnell, Christine E.; Gjedde, Albert; Bergersen, Linda H.] Univ Copenhagen, Fac Hlth Sci, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Scheibye-Knudsen, Morten; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Klungland, Arne] Oslo Univ Hosp, Inst Med Microbiol, Oslo, Norway. [Klungland, Arne] Univ Oslo, Oslo, Norway. [Klungland, Arne] Univ Oslo, Inst Basic Med Sci, Dept Mol Med, Oslo, Norway. RP Bergersen, LH (reprint author), Univ Oslo, Div Anat, N-0317 Oslo, Norway.; Bergersen, LH (reprint author), Univ Oslo, CMBN SERTA Hlth Brain Ageing Ctr, N-0317 Oslo, Norway. EM l.h.bergersen@odont.uio.no OI Scheibye-Knudsen, Morten/0000-0002-6637-1280; Gjedde, Albert/0000-0002-3756-7401 FU Research Council of Norway; Norwegian Health Association; Lundbeck Foundation (Denmark); South-Eastern Norway Regional Health Authority FX This study was supported by research grants from The Research Council of Norway, the Norwegian Health Association, The Lundbeck Foundation (Denmark), and The South-Eastern Norway Regional Health Authority. Images for cell counting were acquired at the Norbrain Slidescanning Facility at the Institute of Basic Medical Sciences, University of Oslo, a resource funded by the Research Council of Norway. The authors gratefully acknowledge this help as well as help with protein carbonyl assay from the Regional Core Facility for Mitochondria and Metabolism at the Oslo University Hospital (http://ous-research.no/mito/). NR 60 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2016 VL 48 BP 34 EP 47 DI 10.1016/j.neurobiolaging.2016.08.005 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EA9PW UT WOS:000386977300004 PM 27639119 ER PT J AU Lubbe, SJ Escott-Price, V Brice, A Gasser, T Pittman, AM Bras, J Hardy, J Heutink, P Wood, NM Singleton, AB Grosset, DG Carroll, CB Law, MH Demenais, F Iles, MM Bishop, DT Newton-Bishop, J Williams, NM Morris, HR AF Lubbe, S. J. Escott-Price, V. Brice, A. Gasser, T. Pittman, A. M. Bras, J. Hardy, J. Heutink, P. Wood, N. M. Singleton, A. B. Grosset, D. G. Carroll, C. B. Law, M. H. Demenais, F. Iles, M. M. Bishop, D. T. Newton-Bishop, J. Williams, N. M. Morris, H. R. CA Melanoma Meta-Anal Consortium Int Parkinson's Dis Genomics TI Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's; Cutaneous malignant melanoma; Shared genetic background; Pigmentation; Tyrosinase ID SEQUENCING DATA; SUBSTANTIA-NIGRA; CANCER; RISK; MUTATIONS; PIGMENTATION; ASSOCIATION; NEUROMELANIN; METAANALYSIS; NEURONS AB A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis. (C) 2016 The Author(s). Published by Elsevier Inc. C1 [Lubbe, S. J.; Morris, H. R.] UCL Inst Neurol, Dept Clin Neurosci, London NW3 2PF, England. [Escott-Price, V.; Williams, N. M.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci,Dept Psychol Med, Med Res Council,Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Brice, A.] UPMC Univ Paris 06, UMR S 1127, Inst Cerveau & Moelle Epiniere, INSERM,U 1127,CNRS,UMR 7225,Sorbonne Univ,ICM, Paris, France. [Gasser, T.] Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Gasser, T.] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Pittman, A. M.; Bras, J.; Hardy, J.; Wood, N. M.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Heutink, P.] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Wood, N. M.] UCL Genet Inst, London, England. [Singleton, A. B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Grosset, D. G.] Queen Elizabeth Univ Hosp, Inst Neurol Sci, Dept Neurol, Glasgow, Lanark, Scotland. [Carroll, C. B.] Univ Plymouth, Peninsula Sch Med, Plymouth, Devon, England. [Carroll, C. B.] Univ Plymouth, Peninsula Sch Dent, Plymouth, Devon, England. [Law, M. H.] QIMR Berghofer Med Res Inst, Stat Genet, Brisbane, Qld, Australia. [Demenais, F.] INSERM, UMR 946, Genet Variat & Human Dis Unit, Paris, France. [Demenais, F.] Univ Paris Diderot, Inst Univ Hematol, Paris, France. [Iles, M. M.; Bishop, D. T.; Newton-Bishop, J.] Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds, W Yorkshire, England. RP Morris, HR (reprint author), UCL Inst Neurol, Dept Clin Neurosci, London NW3 2PF, England. EM h.morris@ucl.ac.uk RI Hardy, John/C-2451-2009; Morris, Huw/B-8527-2008; Lubbe, Steven/L-8261-2013; Demenais, Florence/G-3298-2013; OI Morris, Huw/0000-0002-5473-3774; Demenais, Florence/0000-0001-8361-0936; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802 FU Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986]; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986]; Department of Defence [W81XWH-09-2-0128]; Michael J. Fox Foundation for Parkinson's Research; National Institutes of Health [R01NS037167, R01CA141668, P50NS071674]; American Parkinson Disease Association (APDA); Barnes-Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; section of medical genomics, the Prinses Beatrix Fonds; Forschungszentrum fur Umwelt und Gesundheit - German Federal Ministry of Education, Science, Research, and Technology; State of Bavaria; German National Genome Network (NGFNplus, German Ministry for Education and Research) [01GS08134]; German Federal Ministry of Education and Research [NGFN 01GR0468]; ERA-NET NEURON [01EW0908]; Helmholtz Alliance Mental Health in an Ageing Society - Initiative and Networking Fund of the Helmholtz Association [HA-215]; French National Agency of Research [ANR-08-MNP-012]; France-Parkinson Association; French program "Investissements d'avenir" funding [ANR-10-IAIHU-06]; Assistance Publique - Hopitaux de Paris (PHRC) [AOR-08010]; Landspitali University Hospital Research Fund; Icelandic Research Council; European Community [PIAP-GA-2008-230596]; Wellcome Trust [083948/Z/07/Z, 076113, 085475, 090355]; Medical Research Council [G0700943, G1100643, G0501542]; Wellcome Trust disease centre [WT089698/Z/09/Z]; Parkinson's UK [8047, J-0804]; Department of Health's National Institute for Health Research Biomedical Research Centres funding; Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award [WT089698]; Tracking Parkinson's - Parkinson's UK - Glasgow University; National Institute for Health Research (NIHR) DeNDRoN network; NIHR Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University; NIHRBiomedical Research Centre in Cambridge; Parkinson's UK; Paul Hamlyn Foundation; Neurosciences Foundation; Dystonia Society; Michael's Movers; Medical Research Council UK; Ipsen Fund; Motor Neuron Disease Association; Welsh Assembly Government FX The authors would like to thank all the subjects who donated their time and biological samples to be a part of this study. This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers Z01-AG000949-02 and Z01-ES101986. In addition, this work was supported by the Department of Defence (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson's Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, P50NS071674, American Parkinson Disease Association (APDA); Barnes-Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum fur Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by France-Parkinson Association, the French program "Investissements d'avenir" funding (ANR-10-IAIHU-06) and a grant from Assistance Publique - Hopitaux de Paris (PHRC, AOR-08010) for the French clinical data. This study was also sponsored by the Landspitali University Hospital Research Fund (grant to Sigurlaug Sveinbjornsdottir); Icelandic Research Council (grant to Sigurlaug Sveinbjornsdottir); and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to Hjorva Petursson and Johanna Huttenlocher). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. The authors thank the French Parkinson's Disease Genetics Study Group and the Drug Interaction with genes study group: Y. Agid, M. Anheim, A.-M. Bonnet, M. Borg, A. Brice, E. Broussolle, J.-C. Corvol, P. Damier, A. Destee, A. Durr, F. Durif, A. Elbaz, D. Grabil, S. Klebe, P. Krack, E. Lohmann, L. Lacomblez, M. Martinez, V. Mesnage, P. Pollak, O. Rascol, F. Tison, C. Tranchant, M. Verin, F. Viallet, and M. Vidailhet. The authors also thank the members of the French 3C Consortium: A. Alperovitch, C. Berr, C. Tzourio, and P. Amouyel for allowing us to use part of the 3C cohort, and D. Zelenika for support in generating the genome-wide molecular data. The authors thank P.; Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). The authors used genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson's disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). UK population control data was made available through WTCCC1. This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to Nicholas Wood, John Hardy, and Anthony Schapira). As with previous International Parkinson's Disease Genomics Consortium efforts, 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. Funding for the project was provided by the Wellcome Trust under award 076113, 085475, and 090355. This study was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). The authors thank Jeffrey Barrett for assistance with the design of the ImmunoChip. DNA extraction work that was done in the UK was undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson's disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. The work was also supported from the Tracking Parkinson's study, funded by Parkinson's UK, sponsored by Glasgow University, with support from the National Institute for Health Research (NIHR) DeNDRoN network, the NIHR Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and the NIHR funded Biomedical Research Centre in Cambridge. The Molecular Genetic Studies of Neurodegenerative Disorders was part-funded by Medical Research Council (G0501542). Steven Lubbe and Huw R Morris made the conception and design of the study. Steven Lubbe, Valentina Escott-Price, Nigel M. Williams, and HuwR. Morris performed data analysis and editing. Jose Bras, Alexis Brice, Thomas Gasser, John Hardy, Peter Heutink, Nicholas W Wood, Andy B. Singleton, Michael H. Laws, Donald G. Grosset, Camille B. Carroll, Florence Demenais, Mark M. Iles, D. Tom Bishop, Julia Newton-Bishop, and Huw R Morris performed sample and/or data collection. Donald G. Grosset reports grants from Parkinson's UK, the Paul Hamlyn Foundation, the Neurosciences Foundation, the Dystonia Society, and Michael's Movers.; Huw R Morris reports grants from Medical Research Council UK, grants from Wellcome Trust, grants from Parkinson's UK, grants from Ipsen Fund, during the conduct of the study; grants from Motor Neuron Disease Association, grants from Welsh Assembly Government. NR 55 TC 1 Z9 1 U1 18 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2016 VL 48 AR 222.e1 DI 10.1016/j.neurobiolaging.2016.07.013 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EA9PW UT WOS:000386977300023 PM 27640074 ER PT J AU Muterko, A Kalendar, R Salina, E AF Muterko, Alexandr Kalendar, Ruslan Salina, Elena TI Allelic variation at the VERNALIZATION-A1, VRN-B1, VRN-B3, and PHOTOPERIOD-A1 genes in cultivars of Triticum durum Desf. SO PLANTA LA English DT Article DE Cereal; Durum wheat; Genetic variation; Photoperiod response; Vernalization requirement ID SPRING GROWTH HABIT; MOLECULAR CHARACTERIZATION; TETRAPLOID WHEAT; PROMOTER REGION; RESPONSE GENES; HEADING TIME; AESTIVUM L.; IDENTIFICATION; HAPLOTYPES; PPD-A1A AB The durum wheat varieties from Ukraine, Russia, and Kazakhstan are characterized by the specific allelic composition of the VRN genes that sharply distinguish them from the Triticum durum varieties from other countries. For numerous varieties, the VRN alleles which previously were not found in tetraploid wheat were identified. The ability of wheat to adapt to a wide range of environmental conditions is mostly determined by the allelic diversity within genes regulating the vernalization requirement (VRN) and photoperiod response (PPD). In the present study, allelic variation in the VRN1, VRN3, and PPD-A1 genes was investigated for 134 varieties of Triticum durum from different eco-geographic areas. It was shown that varieties from Russia and Ukraine have a specific allelic composition at the VRN genes, which in quantity and quality differed from European and American cultivars. A large number of varieties of T. durum from Russia carry the dominant Vrn-A1a.1 allele, previously identified mainly in hexaploid wheat. For some varieties from Eastern Europe and Asia, Vrn-A1i and vrn-A1b.3 recently revealed in wheat were also identified. Polymorphism of the VRN-B1 promoter region, distinguishing all three variants of this sequence (VRN-B1.f, VRN-B1.s, and VRN-B1.m), was detected. It was found that the dominant Vrn-B1c allele is commonly found in varieties of T. durum from Russia and Ukraine, but not Europe or USA. Furthermore, many Ukrainian and Russian varieties carry the dominant alleles of the both VRN-A1 and VRN-B1 genes simultaneously, while varieties from Europe and America carry the dominant allele of VRN-A1 alone. Finally, a high frequency of the Vrn-B3a allele, which previously was found only in some accessions of hexaploid wheat, was observed for varieties from Ukraine and Russia. It was revealed that the Ukrainian pool of T. durum varieties is currently the largest genetic source of the dominant Vrn-B3a allele in wheat in the worldwide. C1 [Muterko, Alexandr; Salina, Elena] Fed Res Ctr Inst Cytol & Genet, Lavrentyeva Ave 10, Novosibirsk 630090, Russia. [Muterko, Alexandr] Natl Ctr Seed & Cultivar Invest, Plant Breeding & Genet Inst, Ovidiopolskaya Rd 3, UA-65036 Odessa, Ukraine. [Kalendar, Ruslan] RSE Natl Ctr Biotechnol, Sh Valikhanov 13-1, Astana 010000, Kazakhstan. [Kalendar, Ruslan] Univ Helsinki, MTT Plant Genom Lab, Bioctr 3, Viikinkaari 1,POB 65, FIN-00014 Helsinki, Finland. RP Muterko, A (reprint author), Fed Res Ctr Inst Cytol & Genet, Lavrentyeva Ave 10, Novosibirsk 630090, Russia.; Muterko, A (reprint author), Natl Ctr Seed & Cultivar Invest, Plant Breeding & Genet Inst, Ovidiopolskaya Rd 3, UA-65036 Odessa, Ukraine. EM muterko@bionet.nsc.ru RI Kalendar, Ruslan/D-9751-2012; OI Kalendar, Ruslan/0000-0003-3986-2460; Muterko, Alexandr/0000-0002-9083-9162 FU Russian Science Foundation [14-14-00161] FX We are grateful to Carly Schramm for comments and English polishing of the manuscript. The analysis of 63 T. durum varieties (including all varieties from Russia) was supported by the Russian Science Foundation (Project No. 14-14-00161). NR 25 TC 0 Z9 0 U1 18 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0032-0935 EI 1432-2048 J9 PLANTA JI Planta PD DEC PY 2016 VL 244 IS 6 BP 1253 EP 1263 DI 10.1007/s00425-016-2584-5 PG 11 WC Plant Sciences SC Plant Sciences GA EA1ME UT WOS:000386355600007 PM 27522649 ER PT J AU Zanotto, C Bissa, M Illiano, E Mezzanotte, V Marazzi, F Turolla, A Antonelli, M Morghen, CD Radaelli, A AF Zanotto, Carlo Bissa, Massimiliano Illiano, Elena Mezzanotte, Valeria Marazzi, Francesca Turolla, Andrea Antonelli, Manuela Morghen, Carlo De Giuli Radaelli, Antonia TI Identification of antibiotic-resistant Escherichia coli isolated from a municipal wastewater treatment plant SO CHEMOSPHERE LA English DT Article DE Antibiotic resistance; WWTPs; Escherichia coli; bla and cat genes ID ANTIMICROBIAL RESISTANCE; BETA-LACTAMASES; HUMAN HEALTH; GENES; BACTERIA; DISINFECTION; RIVER; WASTEWATERS; ENVIRONMENT; MECHANISMS AB The emergence and diffusion of antibiotic-resistant bacteria has been a major public health problem for many years now. In this study, antibiotic-resistance of coliforms and Escherichia coli were investigated after their isolation from samples collected in a municipal wastewater treatment plant in the Milan area (Italy) along different points of the treatment sequence: inflow to biological treatment; outflow from biological treatment following rapid sand filtration; and outflow from peracetic acid disinfection. The presence of E. coli that showed resistance to ampicillin (AMP) and chloramphenicol (CAF), used as representative antibiotics for the efficacy against Gram-positive and Gram-negative bacteria, was evaluated. After determining E. coli survival using increasing AMP and CAF concentrations, specific single-resistant (AMPR or CAFR) and double-resistant (AMP(R)/CAF(R)) strains were identified among E. coli colonies, through amplification of the beta-lactamase Tern-1 (bla) and acetyl-transferase catA1 (cat) gene sequences. While a limited number of CAF(R) bacteria was observed, most AMP(R) colonies showed the specific resistance genes to both antibiotics, which was mainly due to the presence of the bla gene sequence. The peracetic acid, used as disinfection agent, showed to be very effective in reducing bacteria at the negligible levels of less than 10 CFU/100 mL, compatible with those admitted for the irrigation use of treated waters. (C) 2016 Published by Elsevier Ltd. C1 [Zanotto, Carlo] Univ Milan, Dept Med Biotechnol & Translat Med, Via Vanvitelli 32, I-20129 Milan, Italy. [Bissa, Massimiliano; Illiano, Elena; Radaelli, Antonia] Univ Milan, Dept Pharmacol & Biomol Sci, Via Balzaretti 9, I-20733 Milan, Italy. [Mezzanotte, Valeria; Marazzi, Francesca] Univ Milano Bicocca, Dept Earth & Environm Sci DISAT, Piazza Sci 1, I-20126 Milan, Italy. [Turolla, Andrea; Antonelli, Manuela] Politecn Milan, Dept Civil & Environm Engn DICA, Environm Sect, Piazza Leonardo da Vinci 32, I-20133 Milan, Italy. [Morghen, Carlo De Giuli] Catholic Univ Our Lady Good Counsel, Rr Dritan Hoxha, Tirana, Albania. [Radaelli, Antonia] Univ Milan, Cellular & Mol Pharmacol Sect, Natl Res Council CNR, Inst Neurosci, Via Vanvitelli 32, I-20129 Milan, Italy. [Bissa, Massimiliano] NCI, NIH, Basic Res Lab, AMRVS, Bethesda, MD 20892 USA. RP Radaelli, A (reprint author), Univ Milan, Dept Pharmacol & Biomol Sci, Via Balzaretti 9, I-20733 Milan, Italy.; Morghen, CD (reprint author), Catholic Univ Our Lady Good Counsel, Rr Dritan Hoxha, Tirana, Albania. EM carlo.zanotto@unimi.it; massimiliano.bissa@nih.gov; elena.illiano@unimi.it; valeria.mezzanotte@unimib.it; francesca.marazzi@unimib.it; andrea.turolla@polimi.it; manuela.antonelli@polimi.it; carlo.degiulimorghen@unimi.it; antonia.radaelli@unimi.it OI TUROLLA, ANDREA/0000-0002-2902-5004 FU [18498]; [CUP G42I14001030001] FX The authors thank Dr. Christopher Berrie for editorial assistance with the manuscript. This work was partially founded by the Transition Grant, code no. 18498, CUP G42I14001030001. NR 43 TC 1 Z9 1 U1 92 U2 92 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD DEC PY 2016 VL 164 BP 627 EP 633 DI 10.1016/j.chemosphere.2016.08.040 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA DY7OG UT WOS:000385318200073 PM 27635645 ER PT J AU Hagen, EM Sicko, RJ Kay, DM Rigler, SL Dimopoulos, A Ahmad, S Doleman, MH Fan, RZ Romitti, PA Browne, ML Caggana, M Brody, LC Shaw, GM Jelliffe-Pawlowski, LL Mills, JL AF Hagen, Erin M. Sicko, Robert J. Kay, Denise M. Rigler, Shannon L. Dimopoulos, Aggeliki Ahmad, Shabbir Doleman, Margaret H. Fan, Ruzong Romitti, Paul A. Browne, Marilyn L. Caggana, Michele Brody, Lawrence C. Shaw, Gary M. Jelliffe-Pawlowski, Laura L. Mills, James L. TI Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways SO HUMAN GENETICS LA English DT Article ID CONGENITAL HEART-DISEASE; PRIMARY CILIARY DYSKINESIA; LEFT-RIGHT ASYMMETRY; MOUSE EMBRYOS; DEFECTS; ZEBRAFISH; PREVALENCE; GENETICS; GENES AB Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and near MIR302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axes determination. FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted. C1 [Hagen, Erin M.; Rigler, Shannon L.; Dimopoulos, Aggeliki; Fan, Ruzong; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. [Sicko, Robert J.; Kay, Denise M.; Caggana, Michele] New York State Dept Hlth, Wadsworth Ctr, 120 New Scotland Ave, Albany, NY 12201 USA. [Ahmad, Shabbir; Doleman, Margaret H.] Calif Dept Publ Hlth, Calif Birth Defects Monitoring Program, 1615 Capitol Ave,MS 8304, Sacramento, CA 95899 USA. [Romitti, Paul A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, 145 N Riverside Dr,S416 CPHB, Iowa City, IA 52242 USA. [Browne, Marilyn L.] New York State Dept Hlth, Congenital Malformat Registry, Empire State Plaza Corning Tower, Albany, NY 12237 USA. [Browne, Marilyn L.] SUNY Albany, Sch Publ Hlth, 1400 Washington Ave, Albany, NY 12222 USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bldg 50,50 South Dr,MSC 8004, Bethesda, MD 20892 USA. [Shaw, Gary M.] Stanford Univ, Sch Med, Dept Pediat, Med Off Bldg,1265 Welch Rd Room X159, Stanford, CA 94305 USA. [Jelliffe-Pawlowski, Laura L.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, 550 16th St, San Francisco, CA 94158 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM jamesmills@nih.gov FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201100001I, HHSN27500005, N01-DK-73431]; CDC [5U01DD001033]; NIH [R01HL092330] FX This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts HHSN275201100001I, HHSN27500005, and N01-DK-73431). Dr. Shaw was partially supported for this work by funds from CDC (5U01DD001033) and NIH (R01HL092330). NR 39 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD DEC PY 2016 VL 135 IS 12 BP 1355 EP 1364 DI 10.1007/s00439-016-1727-x PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DY7YT UT WOS:000385345900004 PM 27637763 ER PT J AU Darvishi, E Woldemichael, GM AF Darvishi, Emad Woldemichael, Girma M. TI Cycloheximide Inhibits Actin Cytoskeletal Dynamics by Suppressing Signaling via RhoA SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE CYCLOHEXIMIDE; YEAST KNOCKOUT COLLECTION; ACTIN CYTOSKELETON; MICROFILAMENTS; SMALL GTPase RhoA ID EPIDERMAL-GROWTH-FACTOR; TRANSLATION ELONGATION; YEAST ACTIN; G-PROTEINS; IN-VIVO; GENE; ENDOCYTOSIS; INTEGRITY; INSULIN; COMPLEX AB Genome-wide screening of the yeast Saccharomyces cerevisiae knockout collection was used to characterize chemical-genetic interactions of cycloheximide (CHX). The results showed that while the act1 mutant was the only deletion mutant in the heterozygous essential gene deletion collection that showed hypersensitivity to sub-inhibitory concentrations of CHX, deletion of nonessential genes that work in concert with either cytoplasmic or nuclear actin in the homozygous deletion collection also highly sensitized yeast to CHX. Fluorescence microscopy analysis revealed that CHX disrupts filamentous actin structures and fluid phase endocytosis in the yeast cell. It also showed that CHX disrupts transforming growth factor-1 (TGF-1)-induced actin reorganization and polygonal architecture of microfilaments in mammalian cells. This inhibitory effect is mediated, at least in part, through the actin dynamics signaling pathway via suppression of activation of the small GTPase RhoA. J. Cell. Biochem. 117: 2886-2898, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Darvishi, Emad] NCI, Mol Targets Lab, NIH, Frederick Natl Lab, Frederick, MD 21702 USA. [Woldemichael, Girma M.] Leidos Biomedical Res Inc, Basic Sci Program, Mol Targets Lab, Frederick Natl Lab, Frederick, MD 21702 USA. RP Woldemichael, GM (reprint author), Frederick Natl Lab, Mol Targets Lab, Bldg 538,Rm 131,1050 Boyles St, Frederick, MD 21702 USA. EM woldemichaelg@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX Grant sponsor: Frederick National Laboratory for Cancer Research, National Institutes of Health; Grant number: HHSN261200800001E. NR 43 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD DEC PY 2016 VL 117 IS 12 BP 2886 EP 2898 DI 10.1002/jcb.25601 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DZ4MI UT WOS:000385832400021 PM 27192630 ER PT J AU Saproo, S Shih, V Jangraw, DC Sajda, P AF Saproo, Sameer Shih, Victor Jangraw, David C. Sajda, Paul TI Neural mechanisms underlying catastrophic failure in human-machine interaction during aerial navigation SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE motor control; flight; EEG; boundary avoidance task; pilot induced oscillations; pupillometry; rapid decision making ID ANTERIOR CINGULATE CORTEX; LOCUS-COERULEUS; MENTAL WORKLOAD; EEG; EMG AB Objective. We investigated the neural correlates of workload buildup in a fine visuomotor task called the boundary avoidance task (BAT). The BAT has been known to induce naturally occurring failures of human-machine coupling in high performance aircraft that can potentially lead to a crash-these failures are termed pilot induced oscillations (PIOs). Approach. We recorded EEG and pupillometry data from human subjects engaged in a flight BAT simulated within a virtual 3D environment. Main results. We find that workload buildup in a BAT can be successfully decoded from oscillatory features in the electroencephalogram (EEG). Information in delta, theta, alpha, beta, and gamma spectral bands of the EEG all contribute to successful decoding, however gamma band activity with a lateralized somatosensory topography has the highest contribution, while theta band activity with a fronto-central topography has the most robust contribution in terms of real-world usability. We show that the output of the spectral decoder can be used to predict PIO susceptibility. We also find that workload buildup in the task induces pupil dilation, the magnitude of which is significantly correlated with the magnitude of the decoded EEG signals. These results suggest that PIOs may result from the dysregulation of cortical networks such as the locus coeruleus (LC)-anterior cingulate cortex (ACC) circuit. Significance. Our findings may generalize to similar control failures in other cases of tight man-machine coupling where gains and latencies in the control system must be inferred and compensated for by the human operators. A closed-loop intervention using neurophysiological decoding of workload buildup that targets the LC-ACC circuit may positively impact operator performance in such situations. C1 [Saproo, Sameer; Shih, Victor; Sajda, Paul] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Jangraw, David C.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Saproo, S; Sajda, P (reprint author), Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. EM sameer.saproo@columbia.edu; psajda@columbia.edu OI Sajda, Paul/0000-0002-9738-1342 FU Defense Advanced Research Projects Agency (DARPA); Army Research Office (ARO) [W911NF-11-1-0219]; Army Research Laboratory [W911NF-10-2-0022]; UK Economic and Social Research Council [ES/L012995/1] FX The authors would like to thank Eric Pohlmeyer and Mark Chevillet for their helpful comments and suggestions, and acknowledge Sona Roy and Wha-Yin Hsu for their assistance with data collection. The work was funded by the Defense Advanced Research Projects Agency (DARPA) and Army Research Office (ARO) under grant number W911NF-11-1-0219, the Army Research Laboratory under Cooperative agreement number W911NF-10-2-0022 and the UK Economic and Social Research Council under grant number ES/L012995/1. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the US Government. The US Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein. NR 27 TC 0 Z9 0 U1 7 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD DEC PY 2016 VL 13 IS 6 AR 066005 DI 10.1088/1741-2560/13/6/066005 PG 11 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DZ5XE UT WOS:000385934600005 PM 27705959 ER PT J AU Biggs, ML Doody, DR Trabert, B Starr, JR Chen, C Schwartz, SM AF Biggs, Mary L. Doody, David R. Trabert, Britton Starr, Jacqueline R. Chen, Chu Schwartz, Stephen M. TI Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE alcohol drinking; epidemiology; nonseminoma; seminoma; testicular germ cell tumor ID MARIJUANA USE; TESTIS CANCER; TRENDS; POPULATION; COHORT; ASSOCIATION; MORTALITY; HORMONES; SEX; AGE AB The etiology of testicular germ cell tumor (TGCT) remains obscure and accumulating evidence suggests that postnatal environmental or lifestyle factors may play a role. To investigate whether consumption of alcoholic beverages during adolescence or adulthood is associated with TGCT risk, we analyzed data from a USA population-based case-control study of 540 18-44 year-old TGCT cases and 1,280 age-matched controls. Participants were queried separately about consumption of beer, wine and liquor during grades 7-8, grades 9-12 and the 5 years before reference date (date of diagnosis for cases and corresponding date for controls). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of TGCT risk with alcoholic beverage consumption during the different periods, both total and by specific beverage types and separately for seminomas and nonseminomas. Compared with nondrinkers in the 5 years before reference date, the OR (95% CI) for 1-6, 7-13 and 14 drinks per week were 1.20 (0.85, 1.69), 1.23 (0.81, 1.85) and 1.56 (1.03, 2.37), respectively (p-trend=0.04). The corresponding results for alcohol consumption in grades 9-12 were 1.39 (1.06, 1.82), 1.07 (0.72, 1.60), 1.53 (1.01, 2.31) (p-trend=0.05). Alcohol consumption in grades 7-8 was uncommon and no statistically significant associations with TGCT were observed. Associations with alcohol consumption in the 5 years before reference date appeared stronger for nonseminomas than for seminomas, but the differences were not statistically significant (p0.10). Associations were similar across different alcoholic beverage types. Consumption of alcoholic beverages may be associated with an increased TGCT risk. What's new? Drinking alcohol appears to boost risk of testicular cancer, according to new analysis. Not much is known about the causes of TGCT and these authors wondered if alcohol consumption might play a role. They interviewed 540 cases and 1280 controls about their consumption of beer, wine and liquor during high school and in the 5 years prior to diagnosis (or a randomly assigned reference date, for controls). Those who imbibed two or more drinks per day, in either time period, increased their risk by 50% compared with nondrinkers. C1 [Biggs, Mary L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Doody, David R.; Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, POB 19024, Seattle, WA 98109 USA. [Trabert, Britton] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Starr, Jacqueline R.; Chen, Chu; Schwartz, Stephen M.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Starr, Jacqueline R.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Starr, Jacqueline R.] Harvard Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA USA. RP Schwartz, SM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, POB 19024, Seattle, WA 98109 USA. EM sschwart@fhcrc.org RI Trabert, Britton/F-8051-2015 FU U.S. National Cancer Institute [R01CA085914, N01PC067009, N01PC35142, T32ES007262] FX Grant sponsor: U.S. National Cancer Institute; Grant numbers: R01CA085914; N01PC067009; N01PC35142; T32ES007262 NR 32 TC 0 Z9 0 U1 33 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2016 VL 139 IS 11 BP 2405 EP 2414 DI 10.1002/ijc.30368 PG 10 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200003 PM 27474852 ER PT J AU Liu, ZW Coghill, AE Pfeiffer, RM Hsu, WL Lou, PJ Wang, CP Yu, KJ Niwa, S Brotzman, M Ye, WM Chen, CJ Hildesheim, A AF Liu, Zhiwei Coghill, Anna E. Pfeiffer, Ruth M. Hsu, Wan-Lun Lou, Pei-Jen Wang, Cheng-Ping Yu, Kelly J. Niwa, Shelley Brotzman, Michelle Ye, Weimin Chen, Chien-Jen Hildesheim, Allan TI Birth order and risk of nasopharyngeal carcinoma in multiplex families from Taiwan SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE birth order; Epstein-Barr virus; multiplex family; infant-contact; nasopharyngeal carcinoma; Taiwan ID EPSTEIN-BARR-VIRUS; CD8(+) T-CELLS; INFECTIOUS-MONONUCLEOSIS; HODGKINS LYMPHOMA; EARLY-LIFE; POPULATION; DISEASES; CYTOMEGALOVIRUS; INDIVIDUALS; CHILDHOOD AB A small proportion of individuals infected with Epstein-Barr virus (EBV) develop nasopharyngeal carcinoma (NPC). Timing of initial exposure could alter immunological responses to primary EBV infection and explain variation in cancer risk later in life. We measured early life family structure as a proxy for the timing of primary EBV infection to examine whether earlier age at infection alters NPC risk. We utilized data from 480 NPC cases and 1,291 unaffected siblings from Taiwanese NPC multiplex families ( 2 family members with NPC, N=2,921). Information on birth order within the family was derived from questionnaires. We utilized logistic regression models to examine the association between birth order and NPC, accounting for correlations between relatives. Within these high-risk families, older siblings had an elevated risk of NPC. Compared with being a first-born child, the risk (95% CIs) of NPC associated with a birth order of two, three, four and five or more was 1.00 (0.71, 1.40), 0.88 (0.62, 1.24), 0.74 (0.53, 1.05) and 0.60 (0.43, 0.82), respectively (P for trend=0.002). We observed no associations between NPC risk and the number of younger siblings or cumulative infant-years exposure. These associations were not modified by underlying genetic predisposition or family size. We observed that early life family structure was important for NPC risk in NPC multiplex families, with older siblings having a greater risk of disease. Future studies focusing on more direct measures of the immune response to EBV in early childhood could elucidate the underlying mechanisms. What's new? Got cancer? Blame your baby siblings. New analysis suggests that being an older sibling increase your likelihood of developing nasopharyngeal cancer (NPC) in high-risk populations. Infection with the Epstein-Barr virus can lead to cancer later in life, but whether age at primary infection alters the risk of NPC in endemic areas is unknown. Using the presence of siblings as a proxy for early childhood exposure to the virus, these authors collected birth order information from NPC cases and controls in NPC multiplex families in Taiwan. They found that older siblings did have a higher incidence of NPC than subsequent children, suggesting that timing at EBV infection may pave the way for NPC later in life. C1 [Liu, Zhiwei; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Coghill, Anna E.; Pfeiffer, Ruth M.; Yu, Kelly J.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD USA. [Hsu, Wan-Lun; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Niwa, Shelley; Brotzman, Michelle] Westat Corp, 1600 Res Blvd, Rockville, MD USA. [Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol & Prevent Med, Taipei, Taiwan. RP Liu, ZW (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. EM zhiwei.liu@ki.se FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; Karolinska Institutet (KID) FX Grant sponsors: Intramural Research Program of the National Cancer Institute at the National Institutes of Health and Karolinska Institutet (KID; to Z.L.) NR 30 TC 0 Z9 0 U1 10 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2016 VL 139 IS 11 BP 2467 EP 2473 DI 10.1002/ijc.30390 PG 7 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200009 PM 27537611 ER PT J AU Mascia, F Schloemann, DT Cataisson, C McKinnon, KM Krymskaya, L Wolcott, KM Yuspa, SH AF Mascia, Francesca Schloemann, Derek T. Cataisson, Christophe McKinnon, Katherine M. Krymskaya, Ludmila Wolcott, Karen M. Yuspa, Stuart H. TI Cell autonomous or systemic EGFR blockade alters the immune-environment in squamous cell carcinomas SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE EGFR; SCC; gefitinib; tumor immune-environment; T regulatory cells ID GROWTH-FACTOR RECEPTOR; CANCER; CARCINOGENESIS; KERATINOCYTES; INHIBITORS; MICE AB Targeting mutations and amplifications in the EGFR has been successful precision therapy for cancers of the lung, oral cavity and gastrointestinal track. However, a systemic immune reaction manifested by dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To address the possibility that intra-tumoral immune changes contribute to the anti-cancer activity of EGFR inhibition, squamous cancers were produced by syngeneic orthografts of either EGFR null or wildtype mouse primary keratinocytes transduced with an oncogenic H-ras retrovirus. Flow cytometric, RNA and Bioplex immunoassay analyses of the tumor immune milieu were performed. Cancers forming from keratinocytes genetically depleted of EGFR were smaller than wildtype cancers and had fewer infiltrating FoxP3 Treg cells, lower Foxp3 RNA and a lower percentage of CD4 PD1 positive cells indicating a tumor cell autonomous regulation of its microenvironment. Hosts bearing wildtype cancers treated with gefitinib for 1 week showed a trend for smaller tumors. In this short term pharmacological model, there was also a trend to reduced FoxP3 cells and FoxP3 RNA in the tumors of treated mice as well as a substantial increase in the ratio of IL-1A/IL-1RA transcripts. These results suggest that relatively brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer. Together these data imply that an EGFR dependent Treg function supports the growth of squamous cancers and is a target for the therapeutic activity of EGFR inhibition. What's new? Precision therapy targeting the epidermal growth factor receptor (EGFR) is effective in lung, oral cavity, and gastrointestinal cancer. However, a systemic immune reaction resulting in dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To determine whether immune effectors could contribute to the anti-cancer response, here the authors produced in mice squamous cancers that were either genetically deleted of EGFR or subjected to systemic treatment with gefitinib. Tumor cell autonomous (genetic) or systemic (pharmacologic) inhibition of EGFR signaling reduced tumor growth and Treg infiltration in the microenvironment, suggesting that EGFR-targeted cancer therapy may indeed involve immunomodulation. C1 [Mascia, Francesca; Schloemann, Derek T.; Cataisson, Christophe; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mascia, Francesca] US FDA, Lab Appl Biochem, Div Biotechnol Res & Review 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD USA. [McKinnon, Katherine M.] NCI, FACS Core Facil, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Krymskaya, Ludmila; Wolcott, Karen M.] NCI, FACS Core Facil, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, CCR NIH, 37 Convent Dr,Bldg 37 Rm 4068, Bethesda, MD 20892 USA. EM Yuspas@dc37a.Nci.Nih.Gov FU Intramural Research Program of the NIH, NCI, Center for Cancer Research [BC005445-30] FX Grant sponsor: Intramural Research Program of the NIH, NCI, Center for Cancer Research, Project BC005445-30. NR 15 TC 0 Z9 0 U1 31 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2016 VL 139 IS 11 BP 2593 EP 2597 DI 10.1002/ijc.30376 PG 5 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200021 PM 27509256 ER PT J AU Schiffman, M Hyun, N Raine-Bennett, TR Katki, H Fetterman, B Gage, JC Cheung, LC Befano, B Poitras, N Lorey, T Castle, PE Wentzensen, N AF Schiffman, Mark Hyun, Noorie Raine-Bennett, Tina R. Katki, Hormuzd Fetterman, Barbara Gage, Julia C. Cheung, Li C. Befano, Brian Poitras, Nancy Lorey, Thomas Castle, Philip E. Wentzensen, Nicolas TI A cohort study of cervical screening using partial HPV typing and cytology triage SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervix; HPV; screening; cancer; cytology ID CARCINOGENIC HUMAN-PAPILLOMAVIRUS; 5-YEAR RISKS; CANCER RISK; WOMEN; MANAGEMENT; GUIDELINES; SPECIMENS; PERFORMANCE; PREVENTION; PRECANCER AB HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification (triage) of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed approximate to 9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups (high-grade, ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established benchmark risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV clearance; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology. What's new? Cervical cancer screening includes two elements: cytology and HPV testing. But many women who test positive for HPV won't need further examination; most HPV infections don't lead to cancer. How best to identify those at risk? These authors created a system to simplify risk assessment. By conducting a cohort study to document the likelihood of patients developing CIN3 within three years, they evaluated different patterns of screening results. They were able to stratify risk profiles generated by HPV typing and cytology into four action bands, or further screening recommendations, thus balancing the sensitivity of HPV typing with simplicity of implementation. C1 [Schiffman, Mark; Hyun, Noorie; Katki, Hormuzd; Gage, Julia C.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Raine-Bennett, Tina R.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Fetterman, Barbara; Poitras, Nancy; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.; Befano, Brian] Informat Management Serv Inc, Calverton, MD USA. [Castle, Philip E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Schiffman, M (reprint author), Room 6E544,9609 Med Ctr Dr, Rockville, MD 20850 USA. EM schiffmm@exchange.nih.gov OI Cheung, Li/0000-0003-1625-4331 FU Gen-Probe/Hologic; Roche; Cepheid; ClearPath; Guided Therapeutics; Teva Pharmaceutics; Genticel; Inovio; GE Healthcare FX Drs. Schiffman and Gage report that NCI has received testing of specimens from the PaP cohort at reduced or no cost, for NCI-led studies from Roche and BD. Dr. Wentzensen reports receiving testing of specimens at reduced or no cost for NCI-led studies from Roche, BD, and Hologic. Dr. Castle has received commercial HPV tests for research at a reduced or no cost from Roche, Qiagen, Norchip, Arbor Vita Corporation, BD and mtm. He has been compensated financially as a member of a Merck Data and Safety Monitoring Board for HPV vaccines. Dr. Castle has been paid as consultant for Gen-Probe/Hologic, Roche, Cepheid, ClearPath, Guided Therapeutics, Teva Pharmaceutics, Genticel, Inovio and GE Healthcare. Dr. Castle has received honoraria as a speaker for Roche and Cepheid. NR 38 TC 1 Z9 1 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2016 VL 139 IS 11 BP 2606 EP 2615 DI 10.1002/ijc.30375 PG 10 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200023 PM 27509172 ER PT J AU Akhtar, R Graham, HK Derby, B Sherratt, MJ Trafford, AW Chadwick, RS Gavara, N AF Akhtar, R. Graham, H. K. Derby, B. Sherratt, M. J. Trafford, A. W. Chadwick, R. S. Gavara, N. TI Frequency-modulated atomic force microscopy localises viscoelastic remodelling in the ageing sheep aorta SO JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS LA English DT Article DE Frequency-modulated atomic force; microscopy; Aorta; Ageing; Lamellar; Medial layer ID ELASTIC PROPERTIES; LAMELLAR UNIT; SOFT-TISSUES; NANOINDENTATION; INDENTATION; ARTERIES AB Age-related aortic stiffening is associated with cardiovascular diseases such as heart failure. The mechanical functions of the main structural components of the aorta, such as collagen and elastin, are determined in part by their organisation at the micrometer length scale. With age and disease both components undergo aberrant remodelling, hence, there is a need for accurate characterisation of the biomechanical properties at this length scale. In this study we used a frequency-modulated atomic force microscopy (FM-AFM) technique on a model of ageing in female sheep aorta (young: 18 months, old: >8 years) to measure the micromechanical properties of the medial layer of the ascending aorta. The novelty of our FM-AFM method, operated at 30 kHz, is that it is non-contact and can be performed on a conventional AFM using the 'cantilever tune' mode, with a spatial (areal) resolution of around 1.6 mu m(2). We found significant changes in the elastic and viscoelastic properties within the medial lamellar unit (elastic lamellae and adjacent inter-lamellar space) with age. In particular, there was an increase in elastic modulus (Young; geometric mean (geometric SD)=42.9 (2.26) kPa, Old=113.9 (2.57) kPa, P < 0.0001), G' and G" (storage and loss modulus respectively) (Young; G' = 14.3 (2.26) kPa, Old G' = 38.0 (2.57) kPa, P < 0.0001; Young; G"=14.5 (2.56) kPa, Old G"=32.8 (2.52) kPa, P<0.0001). The trends observed in the elastic properties with FM-AFM matched those we have previously found using scanning acoustic microscopy (SAM). The utility of the FM-AFM method is that it does not require custom AFM hardware and can be used to simultaneously determine the elastic and viscoelastic behaviour of a biological sample. C1 [Akhtar, R.] Univ Liverpool, Sch Engn, Ctr Mat & Struct, Liverpool L69 3GH, Merseyside, England. [Graham, H. K.; Sherratt, M. J.] Univ Manchester, Manchester Acad & Hlth Sci Ctr, Inst Inflammat & Repair, Stopford Bldg, Manchester M13 9PT, Lancs, England. [Derby, B.] Univ Manchester, Sch Mat, Oxford Rd, Manchester M13 9PL, Lancs, England. [Trafford, A. W.] Univ Manchester, Fac Med & Human Sci, Inst Cardiovasc Sci, 46 Grafton St, Manchester M13 9NT, Lancs, England. [Chadwick, R. S.] Natl Inst Deafness & Other Commun Disorders, Auditory Mech Sect, NIH, Bethesda, MD USA. [Gavara, N.] Queen Mary Univ London, Sch Engn & Mat Sci, Mile End Rd, London E1 4NS, England. RP Akhtar, R (reprint author), Univ Liverpool, Sch Engn, Ctr Mat & Struct, Liverpool L69 3GH, Merseyside, England. EM r.akhtar@liverpool.ac.uk RI Derby, Brian/E-3529-2010 OI Derby, Brian/0000-0001-5753-0166 FU Royal Society [R112205]; Wellcome Trust Value in People Award; Medical Research Council [G1001398] FX We gratefully acknowledge funding from the Royal Society for the provision of an International Travel Grant for Collaboration (R112205) to RA, and Wellcome Trust Value in People Award to RA and MJS. MJS and BD gratefully acknowledge the support of the Medical Research Council (www.mrc.ac.uk: grant reference G1001398). NR 28 TC 0 Z9 0 U1 27 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1751-6161 EI 1878-0180 J9 J MECH BEHAV BIOMED JI J. Mech. Behav. Biomed. Mater. PD DEC PY 2016 VL 64 BP 10 EP 17 DI 10.1016/j.jmbbm.2016.07.018 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DW3EY UT WOS:000383526100002 PM 27479890 ER PT J AU Grady, C Fauci, AS AF Grady, Christine Fauci, Anthony S. TI THE ROLE OF THE VIRTUOUS INVESTIGATOR IN PROTECTING HUMAN RESEARCH SUBJECTS SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID CLINICAL-RESEARCH; ETHICS; BOARDS; PHYSICIAN; TRIALS AB In his famous 1966 New England Journal of Medicine article, Henry Beecher concluded that a critical safeguard for protecting human participants, more reliable than informed consent, was the "presence of an intelligent, informed, conscientious, compassionate, responsible investigator."This article examines Beecher's appeal to reliance on the "virtuous" investigator in light of the critical role that investigators play in research ethics and the systems of research protections that have been developed since Beecher's writing. It addresses the extent to which research ethics rely on virtuous investigators; the meaning of virtuous, as distinct from compliance with the rules and regulations that guide ethical research; the particular virtues that it might be important for investigators to have; and the impact of the existing system of human subjects protections on the virtuous investigator.The virtuous investigator who is motivated to take ethical responsibilities seriously is an essential safeguard for the protection of human research participants and an important complement to the system of oversight protections. However, since the current human subjects protection system does not promote virtue or ethical resourcefulness by investigators, attention to enhancing a culture of professional responsibility might serve to forge a synergy between the protections afforded by the current oversight system and those provided by the virtuous investigator. C1 [Grady, Christine] NIH, Dept Bioeth, Clin Res Ctr, Bethesda, MD USA. [Fauci, Anthony S.] NIAID, NIH, Bethesda, MD USA. RP Grady, C (reprint author), Dept Bioeth, NIH Clin Ctr Bldg 10-1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov NR 41 TC 0 Z9 0 U1 14 U2 19 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 EI 1529-8795 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD WIN PY 2016 VL 59 IS 1 BP 122 EP 131 PG 10 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA DT1MW UT WOS:000381247800010 PM 27499489 ER PT J AU Kim, SYH AF Kim, Scott Y. H. TI CLINICAL TRIALS WITHOUT CONSENT? SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID INFORMED-CONSENT; RANDOMIZED-TRIALS; PRAGMATIC TRIALS; MINIMAL RISK; ETHICS; ENROLLMENT; INFANTS AB Fifty years after Beecher's landmark article, an old question is being debated anew: is it ethical to conduct clinical research without consent? This paper provides a systematic analysis of this question. First, it describes five clinical trials that have either been conducted (or proposed) without the subjects providing consent. Second, it reviews a number of conditions that are often provided to justify bypassing of consent and finds that only some of them qualify as necessary conditions for bypassing consent. When those conditions are applied to the clinical trials, only one trial without consent (a type of cluster randomized trial) appears clearly justified; bypassing consent in the remaining four trials is more questionable. The present analysis may be useful in the interpretation of the current U.S. regulations that provide for waivers and alterations of informed consent. C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 32 TC 0 Z9 0 U1 15 U2 23 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 EI 1529-8795 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD WIN PY 2016 VL 59 IS 1 BP 132 EP 146 PG 15 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA DT1MW UT WOS:000381247800011 PM 27499490 ER PT J AU Rathbun, AM Shardell, M Orwig, D Hebel, JR Hicks, GE Beck, T Hochberg, MC Magaziner, J AF Rathbun, Alan M. Shardell, Michelle Orwig, Denise Hebel, J. Richard Hicks, Gregory E. Beck, Thomas Hochberg, Marc C. Magaziner, Jay TI Differences in the trajectory of bone mineral density change measured at the total hip and femoral neck between men and women following hip fracture SO ARCHIVES OF OSTEOPOROSIS LA English DT Article DE Aging; DXA; Osteoporosis; Hip fracture; Sex ID SEMIPARAMETRIC REGRESSION-MODELS; OSTEOPOROTIC FRACTURES; ELDERLY-MEN; OLDER MEN; PERIOSTEAL APPOSITION; RISK-FACTORS; AGE; DETERMINANTS; MASS; POPULATION AB The Summary Research has not examined changes in bone mineral density (BMD) between men and women following hip fracture. The aim was to evaluate sex differences in BMD following hip fracture. Men experienced significant declines in BMD, while not statistically greater than women, underscoring the necessity for better osteoporosis care in men. Introduction Each year in the USA, approximately 260,000 older adults experience a hip fracture. Women experiencing hip fracture have excess decline in BMD in the year following fracture compared to expected decrements due to aging, but few studies have assessed sex differences in the sequelae of hip fracture. Thus, our objective was to examine sex differences in BMD change in the year after hip fracture. Methods The sample (n=286) included persons enrolled in the Baltimore Hip Studies 7th cohort, a study that matched (1: 1) men and women experiencing hip fracture. Weighted estimating equations that accounted for missing data and selective survival were used to estimate sex differences in 12-month total hip (TH) and femoral neck (FN) BMD changes. Results Men had larger average adjusted percent decline in TH and FN BMD. Adjusted 12-month decreases at the FN showed a statistically significant decline of -4.60 % (95 % confidence interval[CI] -7.76 %, -0.20 %) in men and an insignificant change of -1.62 % (95 % CI -4.57 %, 1.32 %) in women. Yet, the difference in change between men and women was not statistically significant (P=0.17). The estimated sex differences for TH BMD loss were smaller in magnitude. Conclusions There is evidence of significant BMD loss among men at the FN in the year after hip fracture. Although not statistically greater than women, these clinically significant findings highlight the need for improved osteoporosis care among men prior to and after hip fracture. C1 [Rathbun, Alan M.; Orwig, Denise; Hebel, J. Richard; Hochberg, Marc C.; Magaziner, Jay] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 W Redwood St,Howard Hall Suite 200, Baltimore, MD 21201 USA. [Shardell, Michelle] NIA, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Hicks, Gregory E.] Univ Delaware, 540 S Coll Ave,Suite 210E, Newark, DE 19713 USA. [Beck, Thomas] Beck Radiol Innovat, 922 Rambling Dr, Catonsville, MD 21228 USA. RP Rathbun, AM (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 W Redwood St,Howard Hall Suite 200, Baltimore, MD 21201 USA. EM arathbun@epi.umaryland.edu NR 40 TC 1 Z9 1 U1 14 U2 27 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1862-3522 EI 1862-3514 J9 ARCH OSTEOPOROS JI Arch. Osteoporos. PD DEC PY 2016 VL 11 IS 1 DI 10.1007/s11657-016-0263-6 PG 9 WC Endocrinology & Metabolism; Orthopedics SC Endocrinology & Metabolism; Orthopedics GA DP1AU UT WOS:000378223400009 ER PT J AU Chamcha, V Kannanganat, S Gangadhara, S Nabi, R Kozlowski, PA Montefiori, DC LaBranche, CC Wrammert, J Keele, BF Balachandran, H Sahu, S Lifton, M Santra, S Basu, R Moss, B Robinson, HL Amara, RR AF Chamcha, Venkateswarlu Kannanganat, Sunil Gangadhara, Sailaja Nabi, Rafiq Kozlowski, Pamela A. Montefiori, David C. LaBranche, Celia C. Wrammert, Jens Keele, Brandon F. Balachandran, Harikrishnan Sahu, Sujata Lifton, Michelle Santra, Sampa Basu, Rahul Moss, Bernard Robinson, Harriet L. Amara, Rama Rao TI Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE age-dependent protection; antibody; DNA/MVA vaccine; HIV vaccine; SIV ID DOSE CHALLENGE EXPERIMENTS; RHESUS MACAQUES; ANTIBODY ACTIVITIES; IMMUNE-RESPONSES; HIV-1 INFECTION; DNA/MVA VACCINE; SIV CHALLENGES; DNA; IMMUNOGENICITY; ACQUISITION AB Background. In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods. The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results. Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5) alpha-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions. The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques. C1 [Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja; Amara, Rama Rao] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Nabi, Rafiq; Kozlowski, Pamela A.] Louisiana State Univ, Dept Microbiol Immunol & Parasitol, Hlth Sci Ctr, New Orleans, LA USA. [Montefiori, David C.; LaBranche, Celia C.] Duke Univ, Med Ctr, Durham, NC USA. [Wrammert, Jens] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Keele, Brandon F.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Baltimore, MD USA. [Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Santra, Sampa] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Basu, Rahul; Robinson, Harriet L.] Geovax Inc, Smyrna, GA USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Amara, RR (reprint author), 954 Gatewood Rd NE, Atlanta, GA 30329 USA. EM ramara@emory.edu NR 41 TC 1 Z9 1 U1 33 U2 47 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofw034 PG 10 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900074 ER PT J AU Gamaletsou, MN Rammaert, B Bueno, MA Sipsas, NV Moriyama, B Kontoyiannis, DP Roilides, E Zeller, V Taj-Aldeen, SJ Miller, AO Petraitiene, R Lortholary, O Walsh, TJ AF Gamaletsou, Maria N. Rammaert, Blandine Bueno, Marimelle A. Sipsas, Nikolaos V. Moriyama, Brad Kontoyiannis, Dimitrios P. Roilides, Emmanuel Zeller, Valerie Taj-Aldeen, Saad J. Miller, Andy O. Petraitiene, Ruta Lortholary, Olivier Walsh, Thomas J. CA Int Osteoarticular Mycoses Consort TI Candida Arthritis: Analysis of 112 Pediatric and Adult Cases SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE antifungal therapy; arthritis; Candida spp; diagnosis; invasive candidiasis ID TOTAL KNEE ARTHROPLASTY; OF-THE-LITERATURE; FUNGAL OSTEOARTICULAR INFECTIONS; ACUTE MYELOGENOUS LEUKEMIA; ALBICANS SEPTIC ARTHRITIS; LIPOSOMAL AMPHOTERICIN-B; RENAL-TRANSPLANT PATIENT; SYSTEMIC CANDIDIASIS; TROPICALIS ARTHRITIS; KRUSEI ARTHRITIS AB Background. Candida arthritis is a debilitating form of deeply invasive candidiasis. However, its epidemiology, clinical manifestations, management, and outcome are not well understood. Methods. Cases of Candida arthritis were reviewed from 1967 through 2014. Variables included Candida spp in joint and/or adjacent bone, underlying conditions, clinical manifestations, inflammatory biomarkers, diagnostic imaging, management, and outcome. Results. Among 112 evaluable cases, 62% were males and 36% were pediatric. Median age was 40 years (range, <1-84 years). Most patients (65%) were not pharmacologically immunosuppressed. Polyarticular infection (>3 joints) occurred in 31% of cases. Clinical manifestations included pain (82%), edema (71%), limited function (39%), and erythema (22%) with knees (75%) and hips (15%) most commonly infected. Median erythrocyte sedimentation rate was 62 mm/hr (10-141) and C reactive protein 26 mg/dL (0.5-95). Synovial fluid median white blood cell count was 27 500/ttL (range, 100-220 000/ttL) with 90% polymorphonuclear neutrophils (range, 24-98). Adjacent osteomyelitis was present in 30% of cases. Candida albicans constituted 63%, Candida tropicalis 14%, and Candida parapsilosis 11%. Most cases (66%) arose de novo, whereas 34% emerged during antifungal therapy. Osteolysis occurred in 42%, joint -effusion in 31%, and soft tissue extension in 21%. Amphotericin and fluconazole were the most commonly used agents. Surgical interventions included debridement in 25%, irrigation 10%, and drainage 12%. Complete or partial response was achieved in 96% and relapse in 16%. Conclusion. Candida arthritis mainly emerges as a de novo infection in usually non-immunosuppressed patients with hips and knees being most commonly infected. Localizing symptoms are frequent, and the most common etiologic agents are C albicans, C tropicalis, and C parapsilosis. Management of Candida arthritis remains challenging with a clear risk of relapse, despite antifungal therapy. C1 [Gamaletsou, Maria N.; Bueno, Marimelle A.; Miller, Andy O.; Petraitiene, Ruta; Walsh, Thomas J.] Cornell Univ, Weill Cornell Med, Dept Med, New York, NY 10021 USA. [Gamaletsou, Maria N.; Bueno, Marimelle A.; Miller, Andy O.; Petraitiene, Ruta; Walsh, Thomas J.] Cornell Univ, Weill Cornell Med, Dept Pediat, New York, NY 10021 USA. [Gamaletsou, Maria N.; Bueno, Marimelle A.; Miller, Andy O.; Petraitiene, Ruta; Walsh, Thomas J.] Cornell Univ, Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10021 USA. [Gamaletsou, Maria N.; Sipsas, Nikolaos V.] Natl & Kapodistrian & Univ Athens, Athens, Greece. [Gamaletsou, Maria N.; Sipsas, Nikolaos V.; Roilides, Emmanuel; Miller, Andy O.; Lortholary, Olivier; Walsh, Thomas J.] Hosp Special Surg, Ctr Osteoarticular Mycoses, 535 E 70th St, New York, NY 10021 USA. [Rammaert, Blandine; Lortholary, Olivier] Univ Paris 05, Hop Necker Enfants Malad, AP HP,Inst Imagine, Sorbonne Paris Cite,Serv Malad Infect & Trop,Ctr, Paris, France. [Rammaert, Blandine] Inst Pasteur, Unite Mycol Mol, Paris, France. [Moriyama, Brad] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Roilides, Emmanuel] Aristotle Univ Thessaloniki, Sch Hlth Sci, Dept Pediat 3, Thessaloniki, Greece. [Roilides, Emmanuel] Hippokrateion Hosp, Thessaloniki, Greece. [Zeller, Valerie] Grp Hosp Diaconesses Croix St Simon, Osteoarticular Reference Ctr, Paris, France. [Taj-Aldeen, Saad J.] Univ Doha, Mycol Lab, Doha, Qatar. [Miller, Andy O.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. RP Walsh, TJ (reprint author), Weill Cornell Med Ctr, Transplantat Oncol Infect Dis Program, 1300 York Ave,A-421, New York, NY 10065 USA.; Walsh, TJ (reprint author), Weill Cornell Med Ctr, Infect Dis Translat Res Lab, 1300 York Ave,A-421, New York, NY 10065 USA.; Walsh, TJ (reprint author), New York Presbyterian Hosp, 1300 York Ave,A-421, New York, NY 10065 USA. EM thw2003@med.cornell.edu NR 112 TC 0 Z9 0 U1 24 U2 69 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofv207 PG 10 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900027 ER PT J AU Nolte, T Brander-Weber, P Dangler, C Deschl, U Elwell, MR Greaves, P Hailey, R Leach, MW Pandiri, AR Rogers, A Shackelford, CC Spencer, A Tanaka, T Ward, JM AF Nolte, Thomas Brander-Weber, Patricia Dangler, Charles Deschl, Ulrich Elwell, Michael R. Greaves, Peter Hailey, Richard Leach, Michael W. Pandiri, Arun R. Rogers, Arlin Shackelford, Cynthia C. Spencer, Andrew Tanaka, Takuji Ward, Jerrold M. TI Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse SO JOURNAL OF TOXICOLOGIC PATHOLOGY LA English DT Article DE diagnostic pathology; nomenclature; diagnostic criteria; digestive system or tract; oral cavity; esophagus; stomach; intestine; small intestine; large intestine; salivary glands; pancreas se ID SPRAGUE-DAWLEY RATS; LARGE-BOWEL DISEASE; SUBMANDIBULAR-GLAND; ACINAR-CELL; EXOCRINE PANCREAS; TRANSGENIC MICE; WISTAR RATS; ANIMAL-MODELS; DUCTAL ADENOCARCINOMA; PAROTID-GLANDS AB The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. C1 [Nolte, Thomas; Deschl, Ulrich] Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, Germany. [Brander-Weber, Patricia] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. [Dangler, Charles] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Dangler, Charles] Sanofi5, Mt Rd, Framingham, MA 01740 USA. [Elwell, Michael R.] Covance Labs Inc, 14500 Avion Pkwy,Ste 125, Chantilly, VA 20151 USA. [Greaves, Peter] Univ Leicester, Leicester Royal Infirm, Dept Canc Studies & Mol Med, Robert Kilpatrick Clin Sci Bldg, Leicester LE2 7LX, Leics, England. [Hailey, Richard] GlaxoSmithKline, POB 14164, Durham, NC 27709 USA. [Leach, Michael W.] Pfizer Inc, One Burtt Rd, Andover, MA 01810 USA. [Pandiri, Arun R.; Shackelford, Cynthia C.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, POB 12766, Res Triangle Pk, NC 27709 USA. [Rogers, Arlin] Tufts Univ, Dept Biomed Sci, 274 Tremont St, Boston, MA 02111 USA. [Spencer, Andrew] Covance Labs Ltd, Alnwick Res Ctr, Willowburn Ave, Alnwick NE66 2JH, Northd, England. [Tanaka, Takuji] Gifu Municipal Hosp, Gifu 5008285, Japan. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD USA. RP Nolte, T (reprint author), Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, Germany. EM thomas.nolte@boehringer-ingelheim.com RI yilmaz, kevser/E-1917-2016 NR 287 TC 1 Z9 1 U1 27 U2 182 PU JAPANESE SOC TOXICOLOGIC PATHOLOGY PI TOKYO PA DEPT ACAD SOC, MEDICAL TRIBUNE INC, ITALIAN CULTURAL INST BLDG 8F 2-1-30, KUDAN MINAMI, CHIYODA, TOKYO, 102-0074, JAPAN SN 0914-9198 EI 1881-915X J9 J TOXICOL PATHOL JI J. Toxicol. Pathol. PD WIN PY 2016 VL 29 IS 1 SU S BP 1S EP 124S DI 10.1293/tox.29.1S PG 124 WC Pathology; Toxicology SC Pathology; Toxicology GA DD7NE UT WOS:000370110600001 PM 26973378 ER PT J AU Kinoshita, Y Yoshizawa, K Emoto, Y Yuki, M Yuri, T Shikata, N Elmore, SA Tsubura, A AF Kinoshita, Yuichi Yoshizawa, Katsuhiko Emoto, Yuko Yuki, Michiko Yuri, Takashi Shikata, Nobuaki Elmore, Susan A. Tsubura, Airo TI A spontaneously occurring malignant ovarian Sertoli cell tumor in a young Sprague Dawley rat SO JOURNAL OF TOXICOLOGIC PATHOLOGY LA English DT Article DE immunohistochemistry; malignant tumor; ovary; Sertoli cell; spontaneous; young rat ID LESIONS; NEOPLASMS; MICE AB Primary ovarian tumors are generally uncommon in rats used in toxicologic studies. A malignant Sertoli cell tumor was present in the ovary of a 19-week-old female Sprague Dawley rat. Macroscopically, the mass was white and firm, 10 x 13 x 17 mm in size, and located in the right ovary. Histopathologically, the mass was composed of nests of pleomorphic cells, which formed seminiferous-like tubules separated by a thin fibrovascular stroma. The tubules were lined by tumor cells, which had basally located nuclei and abundant eosinophilic and vacuolated cytoplasm. In some areas, the tumor cells were arranged in a retiform growth pattern, mimicking a rete testis/ovarii. Disseminated metastases to the surfaces of the mesentery, spleen and liver were also present. Immunohistochemically, many tumor cells were strongly positive for vimentin, estrogen receptor a and Ki 67. Some tumor cells were positive for pancytokeratin and inhibin a. These findings closely resemble those of an ovarian-derived human malignant Sertoli cell tumor. From our review of the literature, we believe this is the first report of a spontaneous malignant Sertoli cell tumor in the ovary of a young laboratory rat. This case might provide useful historical control information for rat toxicity studies. C1 [Kinoshita, Yuichi; Yoshizawa, Katsuhiko; Emoto, Yuko; Yuki, Michiko; Yuri, Takashi; Tsubura, Airo] Kansai Med Univ, Dept Pathol 2, 2-5-1 Shin Machi, Hirakata, Osaka 5731010, Japan. [Kinoshita, Yuichi; Shikata, Nobuaki] Kansai Med Univ, Takii Hosp, Div Diagnost Cytopathol & Histopathol, Fumizono 10-15, Moriguchi, Osaka 5708507, Japan. [Elmore, Susan A.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Yoshizawa, K (reprint author), Kansai Med Univ, Dept Pathol 2, 2-5-1 Shin Machi, Hirakata, Osaka 5731010, Japan. EM yoshizak@hirakata.kmu.co.jp FU MEXT FX The authors would like to thank Dr. Darlene Dixon of the Molecular Pathogenesis Group, National Toxicology Program Laboratory, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, USA, and Dr. Tomo Sasaki and Dr. Takayasu Moroki, Department of Toxicological Research, Research Laboratories, Maruho Co. Ltd., Japan, for their review and critical discussion of this case. In connection with this paper, there is no conflict of interest with any of the author's companies to be disclosed. This project was supported by a grant from MEXT-Supported Programs for the Strategic Research Foundations at Private Universities. NR 27 TC 1 Z9 1 U1 52 U2 119 PU JAPANESE SOC TOXICOLOGIC PATHOLOGY PI TOKYO PA DEPT ACAD SOC, MEDICAL TRIBUNE INC, ITALIAN CULTURAL INST BLDG 8F 2-1-30, KUDAN MINAMI, CHIYODA, TOKYO, 102-0074, JAPAN SN 0914-9198 EI 1881-915X J9 J TOXICOL PATHOL JI J. Toxicol. Pathol. PD WIN PY 2016 VL 29 IS 1 BP 53 EP 59 DI 10.1293/tox.2015-0057 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA DC9TZ UT WOS:000369565300008 PM 26989303 ER PT J AU Malecki, M Putzer, E Quach, C Dodivenaka, C Tombokan, X AF Malecki, Marek Putzer, Emily Quach, Caroline Dodivenaka, Chaitanya Tombokan, Xenia TI Novel paradigm for immunotherapy of ovarian cancer by engaging prophylactic immunity against hepatitis B virus SO CLINICAL AND TRANSLATIONAL MEDICINE LA English DT Article ID SURFACE-ANTIGEN; OVEREXPRESSION; CELLS; HER-2/NEU; SURVIVAL; SINGLE; YEAST AB Background: Only eight women out of one hundred diagnosed with ovarian epithelial cancers, which progressed to the clinical stage IV, survive 10 years. First line therapies: surgery, chemotherapy, and radiation therapy inflict very serious iatrogenic consequences. Passive immunotherapy of ovarian cancers offers only low efficacy. Prophylactic and therapeutic vaccines for ovarian cancers are not available. Interestingly, prophylactic vaccines for Hepatitis B Viruses (HBV) are very effective. Specific aim: The specific aim of this work was to design, synthesize, and administer biomolecules, which would engage prophylactic, vaccination-induced immunity for HBV towards killing of ovarian cancer cells with high specificity and efficacy. Patients: Tissue biopsies, ascites, and blood were acquired from the patients, whose identities were entirely concealed in accordance with the Declaration of Helsinki, pursuant to the Institutional Review Board approval, and with the Patients' informed consent. Methods and results: By biomolecular engineering, we have created a novel family of biomolecules: antibody x vaccine engineered constructs (AVEC: anti-HER-2 x HBsAg). We have collected the blood from the volunteers, and measured the titers of anti-HBV antibodies resulting from the FDA approved and CDC scheduled HBV vaccinations. We have acquired tumor biopsies, ascites, and blood from patients suffering from the advanced ovarian cancers. We have established cultures of HER-2 over-expressing epithelial ovarian cancers: OV-90, TOC-112D, SKOV-3, as well as human ovary surface epithelial (HOSE) and human artery endothelial (HAE) cells. Treatment of the HER-2+ ovarian cancer cells with AVEC: anti-HER-2 x HBsAg, accompanied by administration of blood drawn from patients with high titers of the anti-HBV antibodies, resulted in much higher therapeutic efficacy as compared to treatment with the naked anti-HER-2 antibodies alone and/or with the relevant isotype antibodies. This treatment had practically no effect upon the HOSE and HAE cells. Discussion: Herein, we report attaining the great improvement in eradication efficacy of ovarian epithelial cancer cells' by engaging prophylactic immunity against HBV; thus creating a novel paradigm for immunotherapy of ovarian cancer. We have accomplished that by designing, synthesis, and administration of AVEC. Therefore, the HBV vaccination acquired immunity mounts immune response against the vaccine, but AVEC redirect, accelerate, and amplify this immune response of all the elements of the native and adaptive immune system against ovarian cancer. Our novel paradigm of immunotherapy is currently streamlined to clinical trials also of other cancers, while also engaging prophylactic and acquired immunity. Conclusion: Novel antibody-vaccine engineered constructs (AVEC) create the solid foundation for redirected, accelerated, and amplified prophylactic, HBV vaccination-induced immunity immunotherapy (RAAVIIT) of ovarian cancers. C1 [Malecki, Marek] Phoenix Biomol Engn Fdn, San Francisco, CA 94119 USA. [Malecki, Marek] Univ Wisconsin, Madison, WI 53706 USA. [Malecki, Marek] NIH, Natl Magnet Resonance Facil, Madison, WI 53706 USA. [Putzer, Emily] Dept Hlth, Washington, DC USA. [Quach, Caroline] Long Isl Univ, Brookville, NY USA. [Dodivenaka, Chaitanya] South Dakota State Univ, Brookings, SD 57007 USA. [Tombokan, Xenia] Bruker Biospin Corp, The Woodlands, TX USA. RP Malecki, M (reprint author), Phoenix Biomol Engn Fdn, San Francisco, CA 94119 USA.; Malecki, M (reprint author), Univ Wisconsin, Madison, WI 53706 USA.; Malecki, M (reprint author), NIH, Natl Magnet Resonance Facil, Madison, WI 53706 USA. EM mm@PBMEF.org FU PBMEF [2006070101]; NSF [9420056, 9522771, 9902020, 0094016]; NIH [P41 RR000570, P41 RR002301] FX Parts of this work were supported by the funds from the PBMEF (2006070101), the NSF (9420056, 9522771, 9902020, and 0094016), the NIH (P41 RR000570 and P41 RR002301); to Marek Malecki MD. Ph.D.-the principal investigator. Administrators of the funding institutions had no influence on the data acquisition and the IP. NR 19 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2001-1326 J9 CLIN TRANSL MED JI Clin. Transl. Med. PD NOV 30 PY 2016 VL 5 AR 44 DI 10.1186/s40169-016-0125-2 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EH7KR UT WOS:000391952300001 PM 27905089 ER PT J AU da Cunha, MG Francob, GCN Franchin, M Beutler, JA de Alencar, SM Ikegaki, M Rosalen, PL AF da Cunha, Marcos Guilherme Nobre Francob, Gilson Cesar Franchin, Marcelo Beutler, John A. de Alencar, Severino Matias Ikegaki, Masaharu Rosalen, Pedro Luiz TI Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches SO TOXICOLOGY LETTERS LA English DT Article DE In silico; in vitro; Pharmacokinetics; Genotoxicity; Coumarin; Geopropolis ID MELIPONA-SCUTELLARIS; DRUG-METABOLISM; MISMATCH REPAIR; CISPLATIN; APOPTOSIS; TOXICITY; PRODUCTS; SYSTEM; CELLS AB In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta (TM) and MetaDrug (TM) software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [da Cunha, Marcos Guilherme; Franchin, Marcelo; Rosalen, Pedro Luiz] Univ Campinas UNICAMP, Piracicaba Dent Sch, Dept Physiol Sci, Campinas, SP, Brazil. [Nobre Francob, Gilson Cesar] Univ Estadual Ponta Grossa, Dept Gen Biol, Lab Physiol & Pathophysiol, Ponta Grossa, PR, Brazil. [da Cunha, Marcos Guilherme; Beutler, John A.] NCI, Mol Targets Lab, NIH, Frederick, MD 21701 USA. [de Alencar, Severino Matias] Univ Sao Paulo, Luiz de Queiroz Coll Agr, Dept Agri Food Ind Food & Nutr, Piracicaba, SP, Brazil. [Ikegaki, Masaharu] Univ Fed Alfenas, Coll Pharmaceut Sci, Alfenas, MG, Brazil. RP Rosalen, PL (reprint author), Univ Campinas UNICAMP, Piracicaba Dent Sch, Dept Physiol Sci, Campinas, SP, Brazil. EM rosalen@fop.unicamp.br FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; FAPESP [2011/23635-6, 2012/22002-2] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by FAPESP (#2011/23635-6 and #2012/22002-2). NR 31 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD NOV 30 PY 2016 VL 263 BP 6 EP 10 DI 10.1016/j.toxlet.2016.10.010 PG 5 WC Toxicology SC Toxicology GA EF7CR UT WOS:000390488200002 PM 27773722 ER PT J AU Lee, SB Mao, A Bhattacharya, S Robertson, N Grisshammer, R Tate, CG Vaidehit, N AF Lee, Sangbae Mao, Allen Bhattacharya, Supriyo Robertson, Nathan Grisshammer, Reinhard Tate, Christopher G. Vaidehit, Nagarajan TI How Do Short Chain Nonionic Detergents Destabilize G-Protein-Coupled Receptors? SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ADENOSINE A(2A) RECEPTOR; PHOTOSYNTHETIC REACTION-CENTER; INTEGRAL MEMBRANE-PROTEINS; PARTICLE MESH EWALD; ESCHERICHIA-COLI; MOLECULAR-DYNAMICS; RHODOPSEUDOMONAS-VIRIDIS; STRUCTURAL BASIS; CRYSTALLIZATION; AGONIST AB Stability of detergent-solubilized G-protein coupled receptors (GPCRs) is crucial for their purification in a biologically relevant state, and it is well-known that short chain detergents such as octylglucoside are more denaturing than long chain detergents such as dodecylmaltoside. However, the molecular basis for this phenomenon is poorly understood. To gain insights into the mechanism of detergent destabilization of GPCRs, we used atomistic molecular dynamics simulations of thermostabilized adenosine receptor (A(2A)R) mutants embedded in either a lipid bilayer or detergent micelles of alkylmaltosides and alkylglucosides. A(2A)R mutants in dodecylmaltoside or phospholipid showed low flexibility and good interhelical packing. In contrast, A(2A)R mutants in either octylglucoside or nonylglucoside showed decreased alpha-helicity in transmembrane regions, decreased alpha-helical packing, and the interpenetration of detergent molecules between transmembrane alpha-helices. This was not observed in octylglucoside containing phospholipid. Cholesteryl hemisuccinate in dodecylmaltoside increased the energetic stability of the receptor by wedging into crevices on the hydrophobic surface of A(2A)R, increasing packing interactions within the receptor and stiffening the detergent micelle. The data suggest a three-stage process for the initial events in the destabilization of GPCRs by octylglucoside: (i) highly mobile detergent molecules form small micelles around the receptor; (ii) loss of alpha-helicity and decreased interhelical packing interactions in transmembrane regions are promoted by increased receptor thermal motion; (iii) transient separation of transmembrane helices allowed penetration of detergent molecules into the core of the receptor. The relative hydration of the headgroup and alkyl chain correlates with detergent harshness and suggests new avenues to develop milder versions of octylglucoside for receptor crystallization. C1 [Lee, Sangbae; Mao, Allen; Bhattacharya, Supriyo; Vaidehit, Nagarajan] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Immunol, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Robertson, Nathan] Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England. [Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, US Dept HHS, Rockville, MD 20852 USA. [Tate, Christopher G.] MRC, Mol Biol Lab, Cambridge Biomed Campus,Francis Crick Ave, Cambridge CB2 0QH, England. RP Vaidehit, N (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Immunol, 1500 E Duarte Rd, Duarte, CA 91010 USA.; Tate, CG (reprint author), MRC, Mol Biol Lab, Cambridge Biomed Campus,Francis Crick Ave, Cambridge CB2 0QH, England. EM cgt@mrc-lmb.cam.ac.uk; NVaidehi@coh.org FU NIH [R01-GM097261]; Medical Research Council [MC_U105197215]; ERC [EMPSI 339995]; National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This work was funded by NIH Grant R01-GM097261 to N.V. Work on GPCRs in C.G.T.'s lab is funded by the Medical Research Council (MC_U105197215) and an ERC Advanced Grant (EMPSI 339995). R.G. is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 78 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 30 PY 2016 VL 138 IS 47 BP 15425 EP 15433 DI 10.1021/jacs.6b08742 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA ED8ZV UT WOS:000389160500020 PM 27792324 ER PT J AU Cong, Y Dyall, J Hart, BJ DeWald, LE Johnson, JC Postnikova, E Zhou, H Gross, R Rojas, O Alexander, I Josleyn, N Zhang, T Michelotti, J Janosko, K Glass, PJ Flint, M McMullan, LK Spiropoulou, CF Mierzwa, T Guha, R Shinn, P Michael, S Klumpp-Thomas, C McKnight, C Thomas, C Eakin, AE O'Loughlin, KG Green, CE Catz, P Mirsalis, JC Honko, AN Olinger, GG Bennett, RS Holbrook, MR Hensley, LE Jahrling, PB AF Cong, Yu Dyall, Julie Hart, Brit J. DeWald, Lisa Evans Johnson, Joshua C. Postnikova, Elena Zhou, Huanying Gross, Robin Rojas, Oscar Alexander, Isis Josleyn, Nicole Zhang, Tengfei Michelotti, Julia Janosko, Krisztina Glass, Pamela J. Flint, Mike McMullan, Laura K. Spiropoulou, Christina F. Mierzwa, Tim Guha, Rajarshi Shinn, Paul Michael, Sam Klumpp-Thomas, Carleen McKnight, Crystal Thomas, Craig Eakin, Ann E. O'Loughlin, Kathleen G. Green, Carol E. Catz, Paul Mirsalis, Jon C. Honko, Anna N. Olinger, Gene G., Jr. Bennett, Richard S. Holbrook, Michael R. Hensley, Lisa E. Jahrling, Peter B. TI Evaluation of the Activity of Lamivudine and Zidovudine against Ebola Virus SO PLOS ONE LA English DT Article ID REVERSE-TRANSCRIPTASE; CELL-LINES; MACROPHAGES; 5'-TRIPHOSPHATE; GLYCOPROTEINS; PATHOGENESIS; PREVENTION; DIAGNOSIS; SYNERGY; ENTRY AB In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 mu M). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebolaen-hanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 mu g/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD. C1 [Cong, Yu; Dyall, Julie; Hart, Brit J.; DeWald, Lisa Evans; Johnson, Joshua C.; Postnikova, Elena; Zhou, Huanying; Gross, Robin; Rojas, Oscar; Alexander, Isis; Josleyn, Nicole; Zhang, Tengfei; Michelotti, Julia; Janosko, Krisztina; Honko, Anna N.; Olinger, Gene G., Jr.; Bennett, Richard S.; Holbrook, Michael R.; Hensley, Lisa E.; Jahrling, Peter B.] NIAID, Div Clin Res, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Josleyn, Nicole; Glass, Pamela J.] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Flint, Mike; McMullan, Laura K.; Spiropoulou, Christina F.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Mierzwa, Tim; Guha, Rajarshi; Shinn, Paul; Michael, Sam; Klumpp-Thomas, Carleen; McKnight, Crystal; Thomas, Craig] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Eakin, Ann E.] NIAID, Off Biodef Res Resources & Translat Res, Div Microbiol & Infect Dis, NIH, Rockville, MD USA. [O'Loughlin, Kathleen G.; Green, Carol E.; Catz, Paul; Mirsalis, Jon C.] SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. [Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD USA. [Hart, Brit J.] Assoc Publ Hlth Abstract Labs, Silver Spring, MD USA. [Zhang, Tengfei] Thermo Fisher Sci Inc, Frederick, MD USA. RP Dyall, J (reprint author), NIAID, Div Clin Res, Integrated Res Facil, NIH, Frederick, MD 21702 USA. EM dyallj@niaid.nih.gov OI Honko, Anna/0000-0001-9165-148X; Bennett, Richard/0000-0002-7227-4831 FU SRI International FX SRI International provided support in the form of salaries for authors [KGO, PC, CEG, JCM], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.; We thank IRF Cell Culture staff in preparing the cells used in this study. We appreciate the strong support from Will Sheffield from NCI-Frederick research donor program and Linda Coe (IRF) in obtaining fresh human blood from NIH blood bank (Bethesda, MD, USA). We thank Dr. Gary Kobinger (Public Health Agency of Canada, Winnipeg, CA) for the Makona variant of EBOV (GenBank accession no. KP096420). We thank Dr. Thomas Geisbert (University of Texas Medical Branch at Galveston, Galveston, TX, USA) for the Hartley guinea pig adapted variant of EBOV. We thank Dr. Atsunobu Hiraoka (SCGF Research Laboratory, Kyoto, JP) for the kind gift of conditioned medium from KPB-M15 cells. We thank Dr. Hideki Ebihara (NIAID, Rocky Mountain Laboratories, Hamilton, MT) for Huh 7 (human hepatocellular carcinoma) cells. We thank Dr. William Eugene Dowling (Division of Microbiology and Infectious Diseases, NIH) for providing resources for the pharmacokinetic study. We thank Linh Nguyen and Julie Nop for expert technical assistance in the conduct of the pharmacokinetics study. In addition, we acknowledge Laura Bollinger and Jiro Wada at the IRF for technical writing services and figure preparation, respectively, for this manuscript. NR 34 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 30 PY 2016 VL 11 IS 11 AR e0166318 DI 10.1371/journal.pone.0166318 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3FV UT WOS:000389474100019 PM 27902714 ER PT J AU Noh, JW Kwon, YD Park, J Oh, IH Kim, J AF Noh, Jin-Won Kwon, Young Dae Park, Jumin Oh, In-Hwan Kim, Jinseok TI Relationship between Physical Disability and Depression by Gender: A Panel Regression Model SO PLOS ONE LA English DT Article ID LATE-LIFE; FUNCTIONAL DISABILITY; CHRONIC STRESS; RISK-FACTORS; PREVALENCE; SYMPTOMS; ANXIETY; ADULTS AB Background Depression in persons with physical disabilities may be more common than in the general population. The purpose of this study was to examine the relationship between physical disability and depression by gender among adults, using a large, nationally representative sample. Methods This study used data from the Korean Longitudinal Study of Aging, Wave one through four, and ran a series of random effect panel regression models to test the relationship between physical disability status and depression by gender. We tested the moderating effect of gender on the relationship between disability status and depression level by examining the significance of the cross-product term between disability status and gender. Results After controlling for self-rated health, marital status, employment status, education, and age, subjects who were female or diagnosed as having any disability presented higher levels of depression scores. Further, the difference in terms of their depression level measured by Center for Epidemiologic Studies Short Depression Scale (CES-D 10) scores between those who were diagnosed as having any disability and those who were not was greater for females than for their male counterparts. Conclusion This study reaffirmed that disability is the risk factor of depression, using longitudinal data. In addition, female gender is the effect modifier rather than the risk factor. The effect of gender in the non-disability group, mostly composed of older persons, is limited. On the contrary, the female disability group showed more depressive symptoms than the male disability group. The gender difference in the disability group and the role of culture on these differences need further research. C1 [Noh, Jin-Won] Eulji Univ, Dept Healthcare Management, Seongnam, South Korea. [Noh, Jin-Won] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci, Global Hlth Unit, Groningen, Netherlands. [Kwon, Young Dae] Catholic Univ Korea, Coll Med, Dept Humanities & Social Med, Seoul, South Korea. [Kwon, Young Dae] Catholic Univ Korea, Catholic Inst Healthcare Management, Seoul, South Korea. [Park, Jumin] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Oh, In-Hwan] Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Kim, Jinseok] Seoul Womens Univ, Dept Social Welf, Seoul, South Korea. RP Kim, J (reprint author), Seoul Womens Univ, Dept Social Welf, Seoul, South Korea. EM jskim@swu.ac.kr OI Kwon, Young Dae/0000-0002-8781-6832 FU Seoul Women's University FX This work was supported by a research grant from Seoul Women's University (2016).; This work was supported by a research grant from Seoul Women's University (2016). NR 31 TC 0 Z9 0 U1 0 U2 0 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 NOV 30 PY 2016 VL 11 IS 11 AR e0166238 DI 10.1371/journal.pone.0166238 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3FV UT WOS:000389474100015 PM 27902709 ER PT J AU Ribeiro, TA Prates, KV Pavanello, A Malta, A Tofolo, LP Martins, IP de Oliveira, JC Miranda, RA Gomes, RM Vieira, E Franco, CCD Barella, LF Francisco, FA Alves, VS Silveira, SD Moreira, VM Fabricio, GS Palma-Rigo, K Sloboda, DM Mathias, PCD AF Ribeiro, Tatiane Aparecida Prates, Kelly Valerio Pavanello, Audrei Malta, Ananda Tofolo, Laize Peron Martins, Isabela Peixoto de Oliveira, Julio Cezar Miranda, Rosiane Aparecida Gomes, Rodrigo Mello Vieira, Elaine da Silva Franco, Claudineia Conationi Barella, Luiz Felipe Francisco, Flavio Andrade Alves, Vander Silva Silveira, Sandra da Silva Moreira, Veridiana Mota Fabricio, Gabriel Sergio Palma-Rigo, Kesia Sloboda, Deborah M. de Freitas Mathias, Paulo Cezar TI Acephate exposure during a perinatal life program to type 2 diabetes SO TOXICOLOGY LA English DT Review DE Acephate; Pregnancy; Lactation; Glucose metabolism; Lipid metabolism; Offspring ID NERVOUS-SYSTEM; ORGANOPHOSPHATE INSECTICIDES; PESTICIDE-RESIDUES; RISK-ASSESSMENT; GROWTH; GLUCOSE; OBESITY; RATS; INSULIN; DISEASE AB Acephate has been used extensively as an insecticide in agriculture. Its downstream sequelae are associated with hyperglycemia, lipid metabolism dysfunction, DNA damage, and cancer, which are rapidly growing epidemics and which lead to increased morbidity and mortality rates and soaring healthcare costs. Developing interventions will require a comprehensive understanding of which excess insecticides during perinatal life can cause insulin resistance and type 2 diabetes. A Wistar rat animal model suggests that acephate exposure during pregnancy and lactation causes alterations in maternal glucose metabolism and programs the offspring to be susceptible to type 2 diabetes at adulthood. Therapeutic approaches based on preventive actions to food contaminated with insecticides during pregnancy and lactation could prevent new cases of type 2 diabetes. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Ribeiro, Tatiane Aparecida; Prates, Kelly Valerio; Pavanello, Audrei; Malta, Ananda; Tofolo, Laize Peron; Martins, Isabela Peixoto; Vieira, Elaine; da Silva Franco, Claudineia Conationi; Francisco, Flavio Andrade; Alves, Vander Silva; Silveira, Sandra da Silva; Moreira, Veridiana Mota; Palma-Rigo, Kesia; de Freitas Mathias, Paulo Cezar] State Univ Maringa 5790, Dept Biotechnol Genet & Cell Biol, Lab Secret Cell Biol, BR-87020900 Maringa, PR, Brazil. [Sloboda, Deborah M.] MacMaster Univ, Dept Biochem & Biomed Sci Ob Gyn & Pediat, Hamilton, ON 8S 4L8, Canada. [Barella, Luiz Felipe] Natl Inst Diabet & Digest & Kidney Dis, Mol Signalling Sect, Bioorgan Chem Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Miranda, Rosiane Aparecida] Univ Fed Rio de Janeiro, Carlos Chagas Filho Biophysis Inst, Mol Endocrinol Lab, BR-21941902 Rio De Janeiro, RJ, Brazil. [de Freitas Mathias, Paulo Cezar] UPSP EGEAL Inst Polytech LaSalle Beauvais, BP 30313, F-60026 Beauvais, France. [de Oliveira, Julio Cezar] Univ Fed Mato Grosso, Inst Hlth Sci, BR-78557267 Sinop, MT, Brazil. [Fabricio, Gabriel Sergio] Univ Lille, CNRS, UMR 8576, Unite Glycobiol Struct & Fonctionnelle,UGSF, F-59000 Lille, France. [Gomes, Rodrigo Mello] Univ Fed Goias, Dept Physiol Sci, Lab Neurosci & Cardiovasc Physiol, BR-74690900 Goiania, Go, Brazil. RP Ribeiro, TA (reprint author), Univ Estadual Maringa, Dept Biotechnol Genet & Cell Biol, Block H67,Room 19,UEM Colombo Ave 5790, BR-87020900 Maringa, PR, Brazil. EM tatianeribeiro2@hotmail.com RI Barella, Luiz/C-1181-2014 OI Barella, Luiz/0000-0003-2211-3842 FU Brazilian Federal Foundation, Conselho National de Desenvolvimento Cientifico e Tecnologico (CNPq); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Parana Science Foundation (Fundacao Araucaria) FX This work was supported by the Brazilian Federal Foundation, Conselho National de Desenvolvimento Cientifico e Tecnologico (CNPq), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), and the Parana Science Foundation (Fundacao Araucaria). NR 49 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD NOV 30 PY 2016 VL 372 BP 12 EP 21 DI 10.1016/j.tox.2016.10.010 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE6NY UT WOS:000389730700002 PM 27765684 ER PT J AU White, SF Tyler, P Botkin, ML Erway, AK Thornton, LC Kolli, V Pope, K Meffert, H Blair, J AF White, Stuart F. Tyler, Patrick Botkin, Mary L. Erway, Anna K. Thornton, Laura C. Kolli, Venkata Pope, Kayla Meffert, Harma Blair, James TI Youth with substance abuse histories exhibit dysfunctional representation of expected value during a passive avoidance task SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Substance abuse; Decision-making; Expected value; Prediction error ID VENTROMEDIAL PREFRONTAL CORTEX; DISRUPTIVE BEHAVIOR DISORDERS; REWARD PREDICTION ERRORS; DECISION-MAKING; DEPENDENT INDIVIDUALS; RESPONSE REVERSAL; NEURAL BASIS; HUMAN BRAIN; ADDICTION; FUTURE AB Individuals with substance abuse (SA) histories show impairment in the computations necessary for decision making, including expected value (EV) and prediction error (PE). Neuroimaging findings, however, have been inconsistent. Sixteen youth with (SA(positive)) and 29 youth without (SA(negative)) substance abuse histories completed a passive avoidance task while undergoing functional MRI. The groups did not significantly differ on age, gender composition or IQ. Behavioral results indicated that SA(positive) youth showed significantly less learning than SA(negative) youth over the task. SA(positive) youth show problems representing EV information when attempting to avoid sub-optimal choices in bilateral inferior frontal gyrus and striatum. Furthermore, SA(positive) youth showed a significantly increased differential response to reward versus punishment feedback modulated by PE in posterior cingulate cortex relative to SA(negative) youth. Disrupted decision-making is likely to exacerbate SA as a failure to represent EV during the avoidance of sub-optimal choices is likely to increase the likelihood of SA. With respect to the representation of PE, future work will be needed to clarify the impact of different substances on the neural systems underpinning PE representation. Moreover, interaction of age/development and substance abuse on PE signaling will need to be explored. C1 [White, Stuart F.; Tyler, Patrick; Botkin, Mary L.; Erway, Anna K.; Thornton, Laura C.; Pope, Kayla; Meffert, Harma] Boys Town Natl Res Hosp, Ctr Neurobehav Res, 14100 Crawford St, Boys Town, NE 68010 USA. [Kolli, Venkata] Creighton Univ, Sch Med, Univ Nebraska Med Ctr, Dept Psychiat, 3528 Dodge St, Omaha, NE 68131 USA. [Blair, James] NIMH, Sect Affect Cognit Neurosci, NIH, 15K North Dr,Rm 206,MSC 2670, Bethesda, MD 20814 USA. RP White, SF (reprint author), Boys Town Natl Res Hosp, Ctr Neurobehav Res, 14100 Crawford St, Boys Town, NE 68010 USA. EM stuart.white@boystown.org; patrick.tyler@boystown.org; lormarm@boystown.org; anna.erway@boystown.org; laura.thornton@boystown.org; venkatakolli@creighton.edu; kayla.pope@boystown.org; harma.meffert@boystown.org; jamesblair@mail.nih.gov OI Meffert, Harma/0000-0002-7298-7276 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (1-ZIA-MH002860), Dr. Blair principle investigator. Drs. White and Blair had full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors would like to acknowledge the contributions of Ron Copsey and Kim VanHorn to the collection of this data. The authors would like to thank all subjects and their families for participating. NR 49 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD NOV 30 PY 2016 VL 257 BP 17 EP 24 DI 10.1016/j.pscychresns.2016.08.010 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED8BI UT WOS:000389096500004 PM 27716545 ER PT J AU Patel, DP Nair, S Suhagia, BN Patel, BM AF Patel, Daxesh P. Nair, Sneha Suhagia, Bhanubhai N. Patel, Bhargav M. TI A novel, sensitive and selective method of UPLC/MS-MS for rapid simultaneous determination of midodrine and its active metabolite desglymidodrine in human plasma: Application to support bioequivalence study in healthy human volunteers SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Midodrine; Desglymidodrine; UPLC-MS/MS; Sensitive; High throughput; Incurred sample reanalysis ID PERFORMANCE LIQUID-CHROMATOGRAPHY; PRODRUG MIDODRINE; QUANTIFICATION; DEGLYMIDODRINE; PRESSURE; THERAPY; SYNCOPE; MS/MS; HPLC AB A specific, rapid, sensitive and selective ultra-performance liquid chromatography - tandem mass spectrometry has been developed for the simultaneous determination of midodrine and desglymidodrine in human plasma. The analytes and its deuterated analogs were quantitatively extracted from 100 mu L of human plasma by solid phase extraction technique. Separation of analytes was achieved on the Waters Acquity UPLC BEH C18 (50 x 2.1 mm, 1.7 mu m) column using acetonittile-4.0 mM ammonium formate, pH 2.5(90:10, v/v) as mobile phase. The protonated analytes were quantified by selected reaction monitoring in the positive ionization mode by triple quadrupole mass spectrometer. The calibration plots were linear over the concentration range of 0.050-50.0 ngiml.. The intra-batch and inter-batch precision (%CV) across quality control levels was <4.0 and the% mean relative recovery was >= 96%. Various other parameters like stability in different conditions; matrix effect and reproducibility of the method were performed in accordance with the guidelines specified by the USFDA for bioanalytical method development and validation. The developed method was successfully administered to the pharmacokinetics study of 5 mg midodrine tablet in 12 healthy subjects. Reproducibility of assay was proved by reanalysis of 48 incurred samples. (C) 2016 Elsevier B.V. All rights reserved. C1 [Patel, Daxesh P.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nair, Sneha] Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India. [Suhagia, Bhanubhai N.] Dharamsinh Desai Univ, Nadiad, Gujarat, India. [Patel, Bhargav M.] St Xaviers Coll, Dept Chem, Ahmadabad 380009, Gujarat, India. RP Patel, BM (reprint author), St Xaviers Coll, Dept Chem, Ahmadabad 380009, Gujarat, India. EM bhargavp1001@gmail.com NR 17 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD NOV 30 PY 2016 VL 131 BP 355 EP 363 DI 10.1016/j.jpba.2016.09.005 PG 9 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EB8GB UT WOS:000387628400046 PM 27639073 ER PT J AU Liu, MT Wang, JN Liu, P AF Liu, Mingtao Wang, Jennie Liu, Paul TI HPLC method development, validation, and impurity characterization of a potent antitumor nucleoside, T-dCyd (NSC 764276) SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE 4 '-thio-2 '-deoxycytidine; T-dCyd; NSC 764276; Forced degradation; HPLC validation; Impurity and degradation product characterization ID DNA METHYLTRANSFERASE INHIBITOR; HISTONE DEACETYLATION; BREAST-CANCER; METHYLATION; CELLS; 5-FLUORO-2'-DEOXYCYTIDINE; DEGRADATION; METABOLITES; ZEBULARINE; MECHANISM AB An HPLC method for the assay of an anticancer nucleoside, 4'-thio-2'-deoxycytidine (T-dCyd, NSC 764276), has been developed and validated. The stress testing of T-dCyd was carried out in accordance with ICH guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of T-dCyd from its impurities and degradation products was achieved in 40 min on a Luna (R) Phenyl-Hexyl column (150 mm x 4.6 mm i.d., 3 mu m) with a gradient elution using ammonium phosphate buffer (pH 3.85) and methanol as the mobile phase. The gradient starts from 2% and ends at 80% of methanol. Detection is by UV at 282 nm. LC-QTOF/MS was used to obtain mass data for characterization of impurities and degradation products. The proposed HPLC assay method was validated for specificity, linearity (concentration range 025-0.75 mg/mL, r >= 0.9998), accuracy (recovery 98.1-102.0%), precision (RSD <= 1.5%), and sensitivity (LOD 0.1 mu g/mL). The developed method was suitable for the quality control and stability monitoring of the T-dCyd drug substance. (C) 2016 Elsevier B.V. All rights reserved.d C1 [Liu, Mingtao; Wang, Jennie] SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. [Liu, Paul] NCI, DCTD, Pharmaceut Resources Branch, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Wang, JN (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA.; Liu, P (reprint author), NCI, DCTD, Pharmaceut Resources Branch, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM jennie.wang@sri.com; liup@dtpepn.nci.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261201200028C] FX This work was funded in whole or in part by Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201200028C. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 28 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD NOV 30 PY 2016 VL 131 BP 429 EP 435 DI 10.1016/j.jpba.2016.08.034 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EB8GB UT WOS:000387628400054 PM 27661436 ER PT J AU Ji, J Qin, YF Wang, R Huang, ZY Zhang, Y Zhou, R Song, L Ling, XF Hu, ZB Miao, DS Shen, HB Xia, YK Wang, XR Lu, CC AF Ji, Juan Qin, Yufeng Wang, Rong Huang, Zhenyao Zhang, Yan Zhou, Ran Song, Ling Ling, Xiufeng Hu, Zhibin Miao, Dengshun Shen, Hongbing Xia, Yankai Wang, Xinru Lu, Chuncheng TI Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis SO ONCOTARGET LA English DT Article DE copy number variations; non-obstructive azoospermia ID SEX-CHROMOSOME INACTIVATION; MALE-INFERTILITY; NONOBSTRUCTIVE AZOOSPERMIA; Y-CHROMOSOME; CANCER/TESTIS ANTIGENS; GERM-CELLS; MALE-MICE; VARIANTS; MUTATIONS; FAILURE AB Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis. To uncover the roles of X-linked multi-copy genes in spermatogenesis, we performed systematic analysis of X-linked gene copy number variations (CNVs) and Y chromosome haplogrouping in 447 idiopathic NOA patients and 485 healthy controls. Interestingly, the frequency of individuals with abnormal level copy of Variable charge, X-linked (VCX) was significantly different between cases and controls after multiple test correction (p = 5.10 x 10(-5)). To discriminate the effect of gain/loss copies in these genes, we analyzed the frequency of X-linked multi-copy genes in subjects among subdivided groups. Our results demonstrated that individuals with increased copy numbers of Nuclear RNA export factor 2 (NXF2) (p = 9.21 x 10(-8)) and VCX (p = 1.97 x 10(-4)) conferred the risk of NOA. In vitro analysis demonstrated that increasing copy number of VCX could upregulate the gene expression and regulate cell proliferation and apoptosis. Our study establishes a robust association between the VCX CNVs and NOA risk. C1 [Ji, Juan; Huang, Zhenyao; Zhang, Yan; Zhou, Ran; Song, Ling; Hu, Zhibin; Miao, Dengshun; Shen, Hongbing; Xia, Yankai; Wang, Xinru; Lu, Chuncheng] Nanjing Med Univ, Inst Toxicol, State Key Lab Reprod Med, Nanjing, Jiangsu, Peoples R China. [Ji, Juan; Huang, Zhenyao; Zhang, Yan; Zhou, Ran; Song, Ling; Xia, Yankai; Wang, Xinru; Lu, Chuncheng] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing, Jiangsu, Peoples R China. [Qin, Yufeng] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC USA. [Ji, Juan; Ling, Xiufeng] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Dept Children Hlth Care, Nanjing, Jiangsu, Peoples R China. [Wang, Rong; Miao, Dengshun] Nanjing Med Univ, Dept Anat Histol & Embryol, Res Ctr Bone & Stem Cells, Nanjing, Jiangsu, Peoples R China. [Hu, Zhibin; Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Hu, Zhibin; Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing, Jiangsu, Peoples R China. RP Lu, CC (reprint author), Nanjing Med Univ, Inst Toxicol, State Key Lab Reprod Med, Nanjing, Jiangsu, Peoples R China.; Lu, CC (reprint author), Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing, Jiangsu, Peoples R China. EM chunchenglu@njmu.edu.cn FU National Natural Science Foundation of China [81471500, 81671461, 81322039]; Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine); [BK20130041] FX We thank all the research staff and students who took part in this work. Funding was provided by grants from the National Natural Science Foundation of China (81471500, 81671461 and 81322039), Distinguished Young Scholars of Jiangsu Province (BK20130041) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). NR 54 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 29 PY 2016 VL 7 IS 48 BP 78532 EP 78540 DI 10.18632/oncotarget.12397 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5HH UT WOS:000389636000028 PM 27705943 ER PT J AU Lewis, MJ Liu, JZ Libby, EF Lee, M Crawford, NPS Hurst, DR AF Lewis, Monica J. Liu, Jianzhong Libby, Emily Falk Lee, Minnkyong Crawford, Nigel P. S. Hurst, Douglas R. TI SIN3A and SIN3B differentially regulate breast cancer metastasis SO ONCOTARGET LA English DT Article DE SIN3A; SIN3B; breast cancer; invasion; metastasis ID CHROMATIN REMODELING COMPLEXES; GENE-EXPRESSION; RNA-SEQ; MDA-MB-435 CELLS; COREPRESSOR; SURVIVAL; SUPPRESSION; PROGRESSION; BIOLOGY; PROTEIN AB SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B. C1 [Lewis, Monica J.; Liu, Jianzhong; Libby, Emily Falk; Hurst, Douglas R.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Lee, Minnkyong; Crawford, Nigel P. S.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Hurst, DR (reprint author), Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. EM dhurst@uab.edu OI Hurst, Douglas/0000-0002-1296-2210 FU American Cancer Society [RSG-11-259-01-CSM]; METAvivor Research and Support, Inc; Cancer Prevention and Control Training Program of the University of Alabama at Birmingham [R25 CA047888] FX This study was funded in part by the American Cancer Society RSG-11-259-01-CSM (DRH), METAvivor Research and Support, Inc (DRH) and the Cancer Prevention and Control Training Program of the University of Alabama at Birmingham R25 CA047888 (EFL). NR 44 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 29 PY 2016 VL 7 IS 48 BP 78713 EP 78725 DI 10.18632/oncotarget.12805 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5HH UT WOS:000389636000043 PM 27780928 ER PT J AU Harada, T Nakamura, Y Sato, K Nagaya, T Okuyama, S Ogata, F Choyke, PL Kobayashi, H AF Harada, Toshiko Nakamura, Yuko Sato, Kazuhide Nagaya, Tadanobu Okuyama, Shuhei Ogata, Fusa Choyke, Peter L. Kobayashi, Hisataka TI Near-infrared photoimmunotherapy with galactosyl serum albumin in a model of diffuse peritoneal disseminated ovarian cancer SO ONCOTARGET LA English DT Article DE near-infrared photoimmunotherapy; ovarian cancer; peritoneal cancer metastases; galactosyl serum albumin; beta-D-galactose receptor ID GYNECOLOGIC-ONCOLOGY-GROUP; IN-VIVO; MONOCLONAL-ANTIBODIES; FLUORESCENT PROTEINS; TUMOR; AVIDIN; ANTIGEN; CHASE AB Near-infrared photoimmunotherapy (NIR-PIT) is a highly cell-selective cancer therapy based on an armed antibody conjugated with a phthalocyanine-based photo-absorber, IRDye700DX (IR700). NIR-PIT can quickly kill target cells that express specific proteins on the cellular membrane but only when the antibody-IR700 conjugate binds to the cell membrane and is then exposed to NIR light. NIR-PIT is highly selective based on the specificity of the antibody. Galactosyl serum albumin (GSA) is composed of albumin decorated with galactose molecules conjugated to the carboxyl groups of albumin. GSA binds to beta-D-galactose receptors, a surface lectin, which are overexpressed on the cell surface of many cancers, including ovarian cancers and is quickly internalized after binding. Here, we demonstrate the feasibility of NIR-PIT in a model of disseminated peritoneal ovarian cancer (SHIN3 cells) using GSA-IR700 that binds to beta-D-galactose receptors. GSA-IR700 bound quickly to SHIN3 cells, then accumulated in the endo-lysosomes. Cell-specific killing was observed in vitro, yet a relatively large dose of NIR light exposure was required for cell killing compared to antibody-IR700 conjugates. To evaluate in vivo therapeutic effects of GSA-IR700 NIR-PIT, peritoneal disseminated SHIN3 tumor-bearing mice were separated into four groups: no treatment; NIR light only; GSA-IR700 only; and GSA-IR700 NIR-PIT. Repeated NIR-PIT showed significant suppression of tumor based on bioluminescence compared to the other groups (p < 0.05). Thus, repeated NIR-PIT using GSA-IR700 can achieve efficient antitumor effects, although GSA-IR700 NIR-PIT was less effective than antibody-IR700 NIR-PIT conjugates likely due to the rapid internalization of GSA-IR700. C1 [Harada, Toshiko; Nakamura, Yuko; Sato, Kazuhide; Nagaya, Tadanobu; Okuyama, Shuhei; Ogata, Fusa; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research [ZIA-BC011513] FX This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. (ZIA-BC011513). NR 25 TC 0 Z9 0 U1 5 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 29 PY 2016 VL 7 IS 48 BP 79394 EP 79402 DI 10.18632/oncotarget.12710 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5HH UT WOS:000389636000096 ER PT J AU Lee, JH Cho, HS Lee, JJ Jun, SY Ahn, JH Min, JS Yoon, JY Choi, MH Jeon, SJ Lim, JH Jung, CR Kim, DS Kim, HT Factor, VM Lee, YH Thorgeirsson, SS Kim, CH Kim, NS AF Lee, Jae-Hye Cho, Hyun-Soo Lee, Jeong-Ju Jun, Soo Young Ahn, Jun-Ho Min, Ju-Sik Yoon, Ji-Yong Choi, Min-Hyuk Jeon, Su-Jin Lim, Jung Hwa Jung, Cho-Rok Kim, Dae-Soo Kim, Hyun-Taek Factor, Valentina M. Lee, Yun-Han Thorgeirsson, Snorri S. Kim, Cheol-Hee Kim, Nam-Soon TI Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis SO ONCOTARGET LA English DT Article DE liver cancer; metastasis; PGCP; Wnt/beta-catenin ID EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA; BETA-CATENIN; STEM-CELLS; DICKKOPF 4; TUMOR-METASTASIS; INVASION; ACTIVATION; MIGRATION; PATHWAY AB Tumor metastasis is the leading cause of cancer death. In the metastatic process, EMT is a unique phenotypic change that plays an important role in cell invasion and changes in cell morphology. Despite the clinical significance, the mechanism underlying tumor metastasis is still poorly understood. Here we report a novel mechanism by which secreted plasma glutamate carboxypeptidase(PGCP) negatively involves Wnt/beta-catenin signaling by DKK4 regulation in liver cancer metastasis. Pathway analysis of the RNA sequencing data showed that PGCP knockdown in liver cancer cell lines enriched the functions of cell migration, motility and mesenchymal cell differentiation. Depletion of PGCP promoted cell migration and invasion via activation of Wnt/beta-catenin signaling pathway components such as phospho-LRP6 and beta-catenin. Also, addition of DKK4 antagonized the Wnt/beta-catenin signaling cascade in a thyroxine (T4)-dependent manner. In an in vivo study, metastatic nodules were observed in the lungs of the mice after injection of shPGCP stable cell lines. Our findings suggest that PGCP negatively associates with Wnt/beta-catenin signaling during metastasis. Targeting this regulation may represent a novel and effective therapeutic option for liver cancer by preventing metastatic activity of primary tumor cells. C1 [Lee, Jae-Hye; Cho, Hyun-Soo; Lee, Jeong-Ju; Jun, Soo Young; Ahn, Jun-Ho; Min, Ju-Sik; Yoon, Ji-Yong; Choi, Min-Hyuk; Jeon, Su-Jin; Kim, Dae-Soo; Kim, Nam-Soon] Korea Res Inst Biosci & Biotechnol, Genome Res Ctr, Daejeon 305333, South Korea. [Lim, Jung Hwa; Jung, Cho-Rok] Korea Res Inst Biosci & Biotechnol, Gene Therapy Res Unit, Daejeon 305333, South Korea. [Lee, Jae-Hye; Cho, Hyun-Soo; Jun, Soo Young; Choi, Min-Hyuk; Jeon, Su-Jin; Kim, Dae-Soo; Kim, Nam-Soon] Korea Univ Sci & Technol, Dept Funct Genom, Daejeon 305333, South Korea. [Kim, Hyun-Taek; Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol, Daejeon 305764, South Korea. [Factor, Valentina M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Yun-Han] Keimyung Univ, Dept Mol Med, Sch Med, Daegu 704701, South Korea. [Thorgeirsson, Snorri S.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kim, NS (reprint author), Korea Res Inst Biosci & Biotechnol, Genome Res Ctr, Daejeon 305333, South Korea.; Kim, NS (reprint author), Korea Univ Sci & Technol, Dept Funct Genom, Daejeon 305333, South Korea. EM nskim37@kribb.re.kr FU Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [NRF-2014M3A9A5034157, 2013R1A2A2A01067556, 2014M3C9A2064619, 2014R1A2A1A110 53562]; KRIBB Research Initiative Program FX The PGCP clone was provided by the Korea Human Gene Bank, KRIBB, KOREA. Supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2014M3A9A5034157, 2013R1A2A2A01067556, 2014M3C9A2064619, 2014R1A2A1A110 53562), and by the KRIBB Research Initiative Program. NR 42 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 29 PY 2016 VL 7 IS 48 BP 79760 EP 79772 DI 10.18632/oncotarget.12967 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5HH UT WOS:000389636000124 ER PT J AU Chowella, G Viboud, C AF Chowella, Gerardo Viboud, Cecile TI Pandemic influenza and socioeconomic disparities: Lessons from 1918 Chicago SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MORTALITY PATTERNS; WAVE C1 [Chowella, Gerardo] Georgia State Univ, Sch Publ Hlth, Div Epidemiol & Biostat, Atlanta, GA 30302 USA. [Chowella, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Chowella, G (reprint author), Georgia State Univ, Sch Publ Hlth, Div Epidemiol & Biostat, Atlanta, GA 30302 USA.; Chowella, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@gsu.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 29 PY 2016 VL 113 IS 48 BP 13557 EP 13559 DI 10.1073/pnas.1616537113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700035 PM 27911763 ER PT J AU Yu, GC Cook, TR Li, Y Yan, XZ Wu, D Shao, L Shen, J Tang, GP Huang, FH Chen, XY Stang, PJ AF Yu, Guocan Cook, Timothy R. Li, Yang Yan, Xuzhou Wu, Dan Shao, Li Shen, Jie Tang, Guping Huang, Feihe Chen, Xiaoyuan Stang, Peter J. TI Tetraphenylethene-based highly emissive metallacage as a component of theranostic supramolecular nanoparticles SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE supramolecular coordination complex; self-assembly; discrete metallacage; theranostic; drug delivery ID DRUG-DELIVERY; BIOMEDICAL APPLICATIONS; CANCER-THERAPY; PLATINUM; FUNCTIONALIZATION; THERAPEUTICS; NANOCARRIERS; SELECTIVITY; POLYMERS; PLATFORM AB A theranostic agent combines diagnostic reporter with therapeutic activity in a single entity, an approach that seeks to increase the efficacy of cancer treatment. Herein, we describe the synthesis of a highly emissive tetraphenylethene-based metallacage using multicomponent coordination-driven self-assembly that exhibits a coordination-triggered aggregation-induced emission (AIE) enhancement. The formation of metallacage-loaded nanoparticles (MNPs) occurs when the assembly is treated with two variants of a 1,2-distearoyl-phosphatidylethanolamine (DSPE)/polyethylene glycol (PEG) conjugate, mPEG-DSPE, and biotin-PEG-DSPE. This combination endows the resultant MNPs with excellent stability and targeting ability, specifically enabling selective delivery of the metallacages to cancer cells that overexpress biotin receptors via receptor-mediated endocytosis. Although the mechanism of activity is based on existing Pt(II) anticancer drugs such as oxaliplatin, carboplatin, and cisplatin, in vitro and in vivo studies indicate that the MNPs are more active and show low systemic activity while also possessing emissive properties that allow for fluorescence-based imaging. This pioneering example of a metallacage that combines biologically active components with AIE imaging establishes supra-molecular coordination complexes imbedded within nanoparticles as a promising potential theranostic platform for cancer treatment. C1 [Yu, Guocan; Shao, Li; Huang, Feihe] Zhejiang Univ, State Key Lab Chem Engn, Ctr Chem High Performance & Novel Mat, Dept Chem, Hangzhou 310027, Peoples R China. [Cook, Timothy R.] SUNY Buffalo, Dept Chem, 359 Nat Sci Complex, Buffalo, NY 14260 USA. [Li, Yang; Wu, Dan; Shen, Jie; Tang, Guping] Zhejiang Univ, Dept Chem, Inst Chem Biol & Pharmaceut Chem, Hangzhou 310027, Peoples R China. [Yan, Xuzhou; Stang, Peter J.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Huang, FH (reprint author), Zhejiang Univ, State Key Lab Chem Engn, Ctr Chem High Performance & Novel Mat, Dept Chem, Hangzhou 310027, Peoples R China.; Stang, PJ (reprint author), Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM fhuang@zju.edu.cn; shawn.chen@nih.gov; stang@chem.utah.edu RI Huang, Feihe/A-1020-2012 OI Huang, Feihe/0000-0003-3177-6744 FU National Science Foundation [1212799]; National Basic Research Program [2013CB834502]; National Natural Science Foundation of China [21125417, 21434005, 21620102006]; Fundamental Research Funds for the Central Universities; Key Science Technology Innovation Team of Zhejiang Province [2013TD02]; Open Project of State Key Laboratory of Supramolecular Structure and Materials Grant [sklssm201509] FX Financial support was provided by National Science Foundation Grant 1212799 (to P.J.S.); National Basic Research Program Grant 2013CB834502; National Natural Science Foundation of China Grants 21125417, 21434005, and 21620102006; the Fundamental Research Funds for the Central Universities; Key Science Technology Innovation Team of Zhejiang Province Grant 2013TD02; and Open Project of State Key Laboratory of Supramolecular Structure and Materials Grant sklssm201509 (to F.H.). NR 28 TC 0 Z9 0 U1 52 U2 52 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 29 PY 2016 VL 113 IS 48 BP 13720 EP 13725 DI 10.1073/pnas.1616836113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700062 PM 27856738 ER PT J AU Brouwer, C Jenko, KJ Zoghbi, SS Morse, CL Innis, RB Pike, VW AF Brouwer, Chad Jenko, Kimberly J. Zoghbi, Sami S. Morse, Cheryl L. Innis, Robert B. Pike, Victor W. TI Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Translocator protein; PET; Carbon-11; Ligand; Binding affinity; Lipophilic efficiency ID POSITRON-EMISSION-TOMOGRAPHY; PERIPHERAL BENZODIAZEPINE-RECEPTOR; ALZHEIMERS-DISEASE PATIENTS; 18 KDA; HUMAN-BRAIN; IN-VIVO; BINDING-SITES; GENETIC-POLYMORPHISM; HEALTHY HUMANS; TSPO AB Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinfiammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (K-i = 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11. Published by Elsevier Masson SAS. C1 [Brouwer, Chad; Jenko, Kimberly J.; Zoghbi, Sami S.; Morse, Cheryl L.; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); NIMH [ZIA MH0023793, ZIAMH002852] FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), specifically the NIMH (projects ZIA MH0023793 and ZIAMH002852). We thank the NIH Clinical Center PET Department (Chief: Dr. Peter Herscovitch) for radioisotope production. NR 51 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD NOV 29 PY 2016 VL 124 BP 677 EP 688 DI 10.1016/j.ejmech.2016.08.046 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ED0PO UT WOS:000388544600053 PM 27622910 ER PT J AU Lui, JC Garrison, P Nguyen, Q Ad, M Keembiyehetty, C Chen, WP Jee, YH Landman, E Nilsson, O Barnes, KM Baron, J AF Lui, Julian C. Garrison, Presley Nguyen, Quang Ad, Michal Keembiyehetty, Chithra Chen, Weiping Jee, Youn Hee Landman, Ellie Nilsson, Ola Barnes, Kevin M. Baron, Jeffrey TI EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy SO NATURE COMMUNICATIONS LA English DT Article ID CAUSE WEAVER SYNDROME; GENE-EXPRESSION; SOTOS-SYNDROME; HUMAN HEIGHT; LYSINE 27; MUTATIONS; OVERGROWTH; METHYLATION; H3K27; PLATE AB Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth. C1 [Lui, Julian C.; Garrison, Presley; Nguyen, Quang; Ad, Michal; Jee, Youn Hee; Barnes, Kevin M.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. [Keembiyehetty, Chithra; Chen, Weiping] NIDDK, Genom Core, NIH, Bldg8,Room 1A11,8 Ctr Dr, Bethesda, MD 20892 USA. [Landman, Ellie; Nilsson, Ola] Karolinska Inst, Div Pediat Endocrinol Q2 08, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden. [Landman, Ellie; Nilsson, Ola] Univ Hosp, S-17176 Stockholm, Sweden. [Nilsson, Ola] Univ Orebro, Dept Med Sci, Rm C1213, S-70185 Orebro, Sweden. [Nilsson, Ola] Univ Hosp, S-70185 Orebro, Sweden. RP Lui, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM luichunk@mail.nih.gov RI Lui, Chun Kin Julian/E-2253-2012 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Swedish Research Council [521-2014-3063, 2015-02227]; Swedish Governmental Agency for Innovation Systems (Vinnova) [2014-01438]; Marianne and Marcus Wallenberg Foundation; Stockholm County Council; Byggmastare Olle Engkvist's Foundation; Stiftelsen Frimurare Barnhuset i Stockholm; Karolinska Institutet FX We thank Jeffrey Hanson from LCM core of NCI for advice and guidance of microdissection of growth plate zones with LCM equipment. We thank Dr Yoshiyuki Wakabayashi from DNA Sequencing and Computational Biology Core of NHLBI for help in chromatin shearing and sonication of chondrocytes. We thank Dr Ge Kai from NIDDK for useful advice on Ezh2. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. In addition, O.N. was supported by grants from the Swedish Research Council (grant nos 521-2014-3063 and 2015-02227), the Swedish Governmental Agency for Innovation Systems (Vinnova; 2014-01438), Marianne and Marcus Wallenberg Foundation, the Stockholm County Council, Byggmastare Olle Engkvist's Foundation, Stiftelsen Frimurare Barnhuset i Stockholm and Karolinska Institutet. NR 42 TC 0 Z9 0 U1 12 U2 12 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 NOV 29 PY 2016 VL 7 AR 13685 DI 10.1038/ncomms13685 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED2GN UT WOS:000388662100001 PM 27897169 ER PT J AU Zhang, Q Matsuura, K Kleiner, DE Zamboni, F Alter, HJ Farci, P AF Zhang, Quan Matsuura, Kentaro Kleiner, David E. Zamboni, Fausto Alter, Harvey J. Farci, Patrizia TI Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Hepatocellular carcinoma; Long noncoding RNA; Hepatitis B virus; Hepatitis C virus; Hepatitis D virus ID HEPATITIS-B-VIRUS; LIVER-CANCER; PROMOTES PROLIFERATION; CELL-PROLIFERATION; SIGNALING PATHWAY; TUMOR-GROWTH; METASTASIS; PROGRESSION; CONTRIBUTES; ACTIVATION AB Background: Dysregulation of long noncoding RNA (lncRNA) expression contributes to the pathogenesis of many human diseases, including liver diseases. Several lncRNAs have been reported to play a role in the development of hepatocellular carcinoma (HCC). However, most studies have analyzed lncRNAs only in hepatitis B virus (HBV)-related HCC or in a single group of HCC patients regardless of the viral etiology. Methods: To investigate whether lncRNAs are differentially expressed in HCC of different viral etiology, we profiled 101 disease-related lncRNAs, including 25 lncRNAs previously associated with HCC, in liver specimens obtained from well-characterized patients with HBV-, hepatitis C virus (HCV)-, or hepatitis D virus (HDV)-associated HCC. Results: We identified eight novel HCC-related lncRNAs that were significantly dysregulated in HCC tissues compared to their surrounding non-tumorous tissues. Some of these lncRNAs were significantly dysregulated predominantly in one specific hepatitis virus-related HCC, including PCAT-29 in HBV-related HCC, aHIF and PAR5 in HCV-related HCC, and Y3 in HDV-related HCC. Among the lncRNAs previously reported in HCC, we found that DBH-AS1, hDREH and hPVT1 were differentially expressed in HCC of different viral etiology. Conclusions: Our study suggests that HCC of different viral etiology is regulated by different lncRNAs. The identification of lncRNAs unique to specific hepatitis virus-related HCC may provide new tools for improving the diagnosis of HCC and open new avenues for disease-specific therapeutic interventions. C1 [Zhang, Quan; Farci, Patrizia] NIAID, Infect Dis Lab, Hepat Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Matsuura, Kentaro; Alter, Harvey J.] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zamboni, Fausto] Brotzu Hosp, Liver Transplantat Ctr, Cagliari, Italy. [Zhang, Quan] Nanjing Univ, Dept Expt Med & Infect Dis, Nanjing Drum Tower Hosp, Sch Med, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. RP Farci, P (reprint author), NIAID, Infect Dis Lab, Hepat Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Cancer Institute. NR 53 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 28 PY 2016 VL 14 AR 328 DI 10.1186/s12967-016-1085-4 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG5EB UT WOS:000391065200001 PM 27894309 ER PT J AU Prema, A Thenmozhi, AJ Manivasagam, T Essa, MM Akbar, MD Akbar, M AF Prema, Asokan Thenmozhi, Arokiasamy Justin Manivasagam, Thamilarasan Essa, Musthafa Mohamed Akbar, Mohammed D. Akbar, Mohammed TI Fenugreek Seed Powder Nullified Aluminium Chloride Induced Memory Loss, Biochemical Changes, A beta Burden and Apoptosis via Regulating Akt/GSK3 beta Signaling Pathway SO PLOS ONE LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3-BETA; ALZHEIMERS-DISEASE; RAT-BRAIN; NEURONAL SURVIVAL; PROTEIN-KINASE; PHOSPHORYLATION; ACETYLCHOLINESTERASE; NEUROTOXICITY; EXTRACT; DEATH AB Alzheimer's disease (AD) is the most common form of dementia that mainly affects the cognitive functions of the aged populations. Trigonella foenum-graecum (L.) (fenugreek), a traditionally well utilized medicinal plant ubiquitously used as one of the main food additive worldwide, is known to have numerous beneficial health effects. Fenugreek seed extract could be able to inhibit the activity of acetylcholinesterase (AChE), a key enzyme involved in the pathogenesis of AD, and further shown to have anti-parkinsonic effect. The present study was aimed to explore the neuroprotective effect of fenugreek seed powder (FSP) against aluminium chloride (AlCl3) induced experimental AD model. Administration of germinated FSP (2.5, 5 and 10% mixed with ground standard rat feed) protected AlCl3 induced memory and learning impairments, Al overload, AChE hyperactivity, amyloid beta (A beta) burden and apoptosis via activating Akt/GSK3 beta pathway. Our present data could confirm the neuroprotective effect of fenugreek seeds. Further these results could lead a possible therapeutics for the management of neurodegenerative diseases including AD in future. C1 [Prema, Asokan; Thenmozhi, Arokiasamy Justin; Manivasagam, Thamilarasan] Annamalai Univ, Dept Biochem & Biotechnol, Fac Sci, Annamalainagar 608002, Tamil Nadu, India. [Essa, Musthafa Mohamed] Sultan Qaboos Univ, CAMS, Dept Food Sci & Nutr, Muscat, Oman. [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. [Essa, Musthafa Mohamed] Food & Brain Res Fdn, Madras 600094, Tamil Nadu, India. [Akbar, Mohammed D.; Akbar, Mohammed] NIAAA, SMPT, NIH, Rockville, MD 20852 USA. RP Thenmozhi, AJ (reprint author), Annamalai Univ, Dept Biochem & Biotechnol, Fac Sci, Annamalainagar 608002, Tamil Nadu, India. EM justinthenmozhi@rediffmail.com FU University Grants Commission-Basic Science Research Fellowship, New Delhi, India FX We gratefully acknowledge the University Grants Commission-Basic Science Research Fellowship, New Delhi, India for financial assistance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 28 PY 2016 VL 11 IS 11 AR e0165955 DI 10.1371/journal.pone.0165955 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3FE UT WOS:000389472400013 PM 27893738 ER PT J AU Diarra, B Goita, D Tounkara, S Sanogo, M Baya, B Togo, ACG Maiga, M Sarro, YS Kone, A Kone, B M'Baye, O Coulibaly, N Kassambara, H Cisse, A Belson, M Polis, MA Otu, J Gehre, F Antonio, M Dao, S Siddiqui, S Murphy, RL de Jong, BC Diallo, S AF Diarra, B. Goita, D. Tounkara, S. Sanogo, M. Baya, B. Togo, A. C. G. Maiga, M. Sarro, Y. S. Kone, A. Kone, B. M'Baye, O. Coulibaly, N. Kassambara, H. Cisse, A. Belson, M. Polis, M. A. Otu, J. Gehre, F. Antonio, M. Dao, S. Siddiqui, S. Murphy, R. L. de Jong, B. C. Diallo, S. TI Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014 SO BMC INFECTIOUS DISEASES LA English DT Article DE Tuberculosis Drug resistance; Bamako; Mali AB Background: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. Methods: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. Results: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDRTB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50. 7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. Conclusion: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment. C1 [Diarra, B.; Goita, D.; Tounkara, S.; Sanogo, M.; Baya, B.; Togo, A. C. G.; Maiga, M.; Sarro, Y. S.; Kone, A.; Kone, B.; M'Baye, O.; Coulibaly, N.; Kassambara, H.; Dao, S.; Diallo, S.] USTTB, SEREFO Program, Bamako, Mali. [Cisse, A.] INRSP, Lab Natl Reference Mycobacteries LNR, Bamako, Mali. [Belson, M.; Polis, M. A.; Siddiqui, S.] NIAID, CCRB, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Otu, J.; Gehre, F.; Antonio, M.] MRC, Vaccines & Immun Theme, Atlantic Blvd, Banjul, Gambia. [Diarra, B.; Gehre, F.; de Jong, B. C.] Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. [Antonio, M.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Antonio, M.] Univ Warwick, Warwick Med Sch, Microbiol & Infect Unit, Coventry, W Midlands, England. [Murphy, R. L.] Northwestern Univ, Global Hlth, Chicago, IL 60611 USA. RP Diarra, B (reprint author), USTTB, SEREFO Program, Bamako, Mali.; Diarra, B (reprint author), Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. EM bdiarra@icermali.org FU Northwestern University (Chicago, IL, USA) [ACTG U01AI069471]; University of Sciences, Techniques and Technologies of Bamako (USTTB) through NIH/R01 [R01AI110386]; European & Developing Countries Clinical Trials Partnership (EDCTP); AIDS and Malaria (WANETAM) [CG_cb_07_41700, MSI 2010_10800-01/08/2011-31/07/14]; European Research Council-INTERRUPTB [311725]; TDR fellowship [B40072]; special programme for research and training in tropical diseases; UNICEF; UNDP; World Bank; WHO FX This study was partially funded by the Northwestern University (Chicago, IL, USA) through ACTG U01AI069471, the University of Sciences, Techniques and Technologies of Bamako (USTTB) through NIH/R01 grant R01AI110386, the European & Developing Countries Clinical Trials Partnership (EDCTP) through the West African Node of Excellence for TB, AIDS and Malaria (WANETAM) Grants numbers CG_cb_07_41700 and MSI 2010_10800-01/08/2011-31/07/14 and the European Research Council-INTERRUPTB through grant nr.311725 (to B.d.J.). B.D. was supported by a TDR fellowship, TIMS ID B40072, the special programme for research and training in tropical diseases, co-sponsored by UNICEF, UNDP, World Bank and WHO. NR 13 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD NOV 28 PY 2016 VL 16 AR 714 DI 10.1186/s12879-016-2060-7 PG 8 WC Infectious Diseases SC Infectious Diseases GA ED7WR UT WOS:000389083000001 PM 27894266 ER PT J AU Van Doorslaer, K Porter, S McKinney, C Stepp, WH McBride, AA AF Van Doorslaer, Koenraad Porter, Samuel McKinney, Caleb Stepp, Wesley H. McBride, Alison A. TI Novel recombinant papillomavirus genomes expressing selectable genes SO SCIENTIFIC REPORTS LA English DT Article ID EPITHELIAL-CELL DIFFERENTIATION; IN-VIVO; TRANSGENE EXPRESSION; VIRAL-DNA; VECTORS AB Papillomaviruses infect and replicate in keratinocytes, but viral proteins are initially expressed at low levels and there is no effective and quantitative method to determine the efficiency of infection on a cell-to-cell basis. Here we describe human papillomavirus (HPV) genomes that express marker proteins (antibiotic resistance genes and Green Fluorescent Protein), and can be used to elucidate early stages in HPV infection of primary keratinocytes. To generate these recombinant genomes, the late region of the oncogenic HPV18 genome was replaced by CpG free marker genes. Insertion of these exogenous genes did not affect early replication, and had only minimal effects on early viral transcription. When introduced into primary keratinocytes, the recombinant marker genomes gave rise to drug-resistant keratinocyte colonies and cell lines, which maintained the extrachromosomal recombinant genome long-term. Furthermore, the HPV18 "marker" genomes could be packaged into viral particles (quasivirions) and used to infect primary human keratinocytes in culture. This resulted in the outgrowth of drug-resistant keratinocyte colonies containing replicating HPV18 genomes. In summary, we describe HPV18 marker genomes that can be used to quantitatively investigate many aspects of the viral life cycle. C1 [Van Doorslaer, Koenraad; Porter, Samuel; McKinney, Caleb; Stepp, Wesley H.; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM AMCBRIDE@nih.gov OI Van Doorslaer, Koenraad/0000-0002-2985-0733 FU Intramural Research Program of NIAID, NIH FX The authors acknowledge Jameela Khan for generating the initial plasmids used in this study. This research was supported by the Intramural Research Program of the NIAID, NIH. NR 25 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 28 PY 2016 VL 6 AR 37782 DI 10.1038/srep37782 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4CM UT WOS:000388795000001 PM 27892937 ER PT J AU Seol, HS Lee, SE Song, JS Lee, HY Park, S Kim, I Singh, SR Chang, S Jang, SJ AF Seol, Hyang Sook Lee, Sang Eun Song, Joon Seon Lee, Hye Yong Park, Sojung Kim, Inki Singh, Shree Ram Chang, Suhwan Jang, Se Jin TI Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production SO CANCER LETTERS LA English DT Article DE Hepatocellular carcinoma; Drug repositioning; Riluzole; ROS ID RAF/MEK/ERK PATHWAY; ANTITUMOR-ACTIVITY; CANCER-CELLS; SORAFENIB; ANGIOGENESIS; MIGRATION; INVASION; TUMORS AB Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines. In addition, Riluzole induced caspase-dependent apoptosis and G2/M cell cycle arrest in SNU449 and Huh7 cell lines. In a line with the known function of glutamate release inhibitor, we found Riluzole-treated cells have increased the level of inner cellular glutamate that in turn decrease the glutathione (GSH) level and finally augment the reactive oxygen species (ROS) production. We confirm this finding in vivo by showing the Riluzole-induced GSH and ROS changes in a Huh7 xenograft cancer model. Altogether, these data suggest the anti-cancer effect of Riluzole on hepatocellular carcinoma and the suppression of glutamate signaling might be a new target pathway for HCC therapy. Published by Elsevier Ireland Ltd. C1 [Seol, Hyang Sook; Lee, Sang Eun; Lee, Hye Yong; Park, Sojung; Kim, Inki] Univ Ulsan, Asan Inst Life Sci, Asan Med Ctr, Coll Med, Seoul, South Korea. [Song, Joon Seon] Univ Ulsan, Dept Pathol, Asan Med Ctr, Coll Med, Seoul, South Korea. [Singh, Shree Ram] NCI, Basic Res Lab, Stem Cell Regulat & Anim Aging Sect, Ctr Canc Res, Frederick, MD 21701 USA. [Chang, Suhwan] Univ Ulsan, Dept Biomed Sci, Coll Med, Asan Med Ctr, Seoul, South Korea. [Jang, Se Jin] Univ Ulsan, Asan Inst Life Sci, Dept Pathol, Coll Med,Asan Med Ctr, Seoul, South Korea. RP Chang, S (reprint author), Univ Ulsan, Dept Biomed Sci, Coll Med, Asan Med Ctr, Seoul, South Korea.; Jang, SJ (reprint author), Univ Ulsan, Asan Inst Life Sci, Dept Pathol, Coll Med,Asan Med Ctr, Seoul, South Korea. EM singhshr@mail.nih.gov; suhwan.chang@amc.seoul.kr; jangsejin@amc.seoul.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2015R1A1A3A04001354]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health &Welfare, Republic of Korea [HI06C0868, HI13C1538] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1A1A3A04001354), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) (grant numbers: HI06C0868, HI13C1538), funded by the Ministry of Health &Welfare, Republic of Korea. NR 19 TC 1 Z9 1 U1 12 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD NOV 28 PY 2016 VL 382 IS 2 BP 157 EP 165 DI 10.1016/j.canlet.2016.08.028 PG 9 WC Oncology SC Oncology GA EB2NL UT WOS:000387199000003 ER PT J AU Zhuang, J Kamp, WM Li, J Liu, CY Kang, JG Wang, PY Hwang, PM AF Zhuang, Jie Kamp, William M. Li, Jie Liu, Chengyu Kang, Ju-Gyeong Wang, Ping-Yuan Hwang, Paul M. TI Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SKELETAL-MUSCLE; ENDURANCE EXERCISE; PATHWAY; SIRT1; PHOSPHORYLATION; TRANSLOCATION; HOMEOSTASIS; BIOGENESIS; METABOLISM; TURNOVER AB Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exercise-induced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization. The synergistic increase in nuclear p53 and FOXO3 by exercise can facilitate their known interaction in transactivating Sirtuin 1 (SIRT1), a NAD(+)-dependent histone deacetylase that mediates adaptation to various stresses. Thus, our results reveal one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging. C1 [Zhuang, Jie; Kamp, William M.; Li, Jie; Kang, Ju-Gyeong; Wang, Ping-Yuan; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), 10CRC 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Division of Intramural Research of the NHLBI, National Institutes of Health [HL005101] FX This work was supported by the Division of Intramural Research of the NHLBI, National Institutes of Health Grant HL005101 (to P. M. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 37 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 25 PY 2016 VL 291 IS 48 BP 24819 EP + DI 10.1074/jbc.M116.745737 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5GR UT WOS:000388880100002 PM 27687729 ER PT J AU Liu, X Shu, S Billington, N Williamson, CD Yu, S Brzeska, H Donaldson, JG Sellers, JR Korn, ED AF Liu, Xiong Shu, Shi Billington, Neil Williamson, Chad D. Yu, Shuhua Brzeska, Hanna Donaldson, Julie G. Sellers, James R. Korn, Edward D. TI Mammalian Nonmuscle Myosin II Binds to Anionic Phospholipids with Concomitant Dissociation of the Regulatory Light Chain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; SMOOTH-MUSCLE MYOSIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; TRANSPORT VESICLES; PLASMA-MEMBRANE; GOLGI MEMBRANES; ATPASE ACTIVITY; IN-VITRO; PHOSPHORYLATION; ACTIN AB Mammalian cells express three Class II nonmuscle myosins (NM): NM2A, NM2B, and NM2C. The three NM2s have well established essential roles in cell motility, adhesion, and cytokinesis and less well defined roles in vesicle transport and other processes that would require association of NM2s with cell membranes. Previous evidence for the mechanism of NM2-membrane association includes direct interaction of NM2s with membrane lipids and indirect interaction by association of NM2s with membrane-bound F-actin or peripheral membrane proteins. Direct binding of NM2s to phosphatidylserine-liposomes, but not to phosphatidylcholine-liposomes, has been reported, but the molecular basis of the interaction between NM2s and acidic phospholipids has not been previously investigated. We now show that filamentous, full-length NM2A, NM2B, and NM2C and monomeric, non-filamentous heavy meromyosin bind to liposomes containing one or more acidic phospholipids (phosphatidylserine, phosphatidylinositol 4,5-diphosphate, and phosphatidylinositol 3,4,5-triphosphate) but do not bind to 100% phosphatidylcholine-liposomes. Binding of NM2s to acidic liposomes occurs predominantly through interaction of the liposomes with the regulatory light chain (RLC) binding site in the myosin heavy chain with concomitant dissociation of the RLC. Phosphorylation of myosin-bound RLC by myosin light chain kinase substantially inhibits binding to liposomes of both filamentous NM2 and non-filamentous heavy meromyosin; the addition of excess unbound RLC, but not excess unbound essential light chain, competes with liposome binding. Consistent with the in vitro data, we show that endogenous and expressed NM2A associates with the plasma membrane of HeLa cells and fibrosarcoma cells independently of F-actin. C1 [Liu, Xiong; Shu, Shi; Williamson, Chad D.; Yu, Shuhua; Brzeska, Hanna; Donaldson, Julie G.; Korn, Edward D.] NHLBI, Cell Biol Lab, NIH, Bldg 50,Rm 2517,9000 Rockville Pike, Bethesda, MD 20892 USA. [Billington, Neil; Sellers, James R.] NHLBI, Labs Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Rm 2517,9000 Rockville Pike, Bethesda, MD 20892 USA. EM edk@nih.gov FU Electron and Light Microscopy Cores of the NHLBI, National Institutes of Health FX We acknowledge the support of the Electron and Light Microscopy Cores of the NHLBI, National Institutes of Health. We thank Dr. John Hammer 3rd (NHLBI) for NM2A-mTomato and Dr. Fang Zhang (NHLBI) for purified myosin light chain kinase. NR 44 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 25 PY 2016 VL 291 IS 48 BP 24828 EP 24837 DI 10.1074/jbc.M116.739185 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5GR UT WOS:000388880100003 PM 27697842 ER PT J AU Esser, L Zhou, F Zhou, YH Xiao, YM Tang, WK Yu, CA Qin, ZH Xia, D AF Esser, Lothar Zhou, Fei Zhou, Yihui Xiao, Yumei Tang, Wai-Kwan Yu, Chang-An Qin, Zhaohai Xia, Di TI Hydrogen Bonding to the Substrate Is Not Required for Rieske Iron-Sulfur Protein Docking to the Quinol Oxidation Site of Complex III SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOCHROME BC(1) COMPLEX; BOVINE HEART-MITOCHONDRIA; X-RAY-STRUCTURE; CRYSTAL-STRUCTURE; C REDUCTASE; RESPIRATORY-CHAIN; ELECTRON-TRANSFER; Q-CYCLE; INHIBITORS; BINDING AB Complex III or the cytochrome (cyt) bc(1) complex constitutes an integral part of the respiratory chain of most aerobic organisms and of the photosynthetic apparatus of anoxygenic purple bacteria. The function of cyt bc(1) is to couple the reaction of electron transfer from ubiquinol to cytochrome c to proton pumping across the membrane. Mechanistically, the electron transfer reaction requires docking of its Rieske iron-sulfur protein (ISP) subunit to the quinol oxidation site (Q(P)) of the complex. Formation of an H-bond between the ISP and the bound substrate was proposed to mediate the docking. Here we show that the binding of oxazolidinedione-type inhibitors famoxadone, jg144, and fenamidone induces docking of the ISP to the QP site in the absence of the H-bond formation both in mitochondrial and bacterial cyt bc(1) complexes, demonstrating that ISP docking is independent of the proposed direct ISP-inhibitor interaction. The binding of oxazolidinedione-type inhibitors to cyt bc(1) of different species reveals a toxophore that appears to interact optimally with residues in the Q(P) site. The effect of modifications or additions to the toxophore on the binding to cyt bc(1) from different species could not be predicted from structure-based sequence alignments, as demonstrated by the altered binding mode of famoxadone to bacterial cyt bc(1). C1 [Esser, Lothar; Zhou, Fei; Zhou, Yihui; Xiao, Yumei; Tang, Wai-Kwan; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Zhou, Yihui; Xiao, Yumei; Qin, Zhaohai] China Agr Univ, Coll Sci, Beijing 100193, Peoples R China. [Yu, Chang-An] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Basic Research Science Foundation of China [2010CB126100] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and a grant from the National Basic Research Science Foundation of China (2010CB126100) (to Z. Q.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 44 TC 1 Z9 1 U1 11 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 25 PY 2016 VL 291 IS 48 BP 25019 EP 25031 DI 10.1074/jbc.M116.744391 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5GR UT WOS:000388880100019 PM 27758861 ER PT J AU Speen, AM Kim, HYH Bauer, RN Meyer, M Gowdy, KM Fessler, MB Duncan, KE Liu, W Porter, NA Jaspers, I AF Speen, Adam M. Kim, Hye-Young H. Bauer, Rebecca N. Meyer, Megan Gowdy, Kymberly M. Fessler, Michael B. Duncan, Kelly E. Liu, Wei Porter, Ned A. Jaspers, Ilona TI Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling A POTENTIAL ROLE FOR LIPID-PROTEIN ADDUCTS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AIRWAY EPITHELIAL-CELLS; BIOLOGICALLY-ACTIVE OXYSTEROLS; BRONCHOALVEOLAR LAVAGE FLUID; LEMLI-OPITZ SYNDROME; NF-KAPPA-B; OZONATION PRODUCTS; LUNG SURFACTANT; INNATE IMMUNITY; INFLAMMATORY MEDIATORS; OXIDIZED PHOSPHOLIPIDS AB When inhaled, ozone (O-3) interacts with cholesterols of airway epithelial cell membranes or the lung-lining fluid, generating chemically reactive oxysterols. The mechanism by which O-3-derived oxysterols affect molecular function is unknown. Our data show that in vitro exposure of human bronchial epithelial cells to O-3 results in the formation of oxysterols, epoxy-cholesterol-alpha and -beta and secosterol A and B (Seco A and Seco B), in cell lysates and apical washes. Similarly, bronchoalveolar lavage fluid obtained from human volunteers exposed to O-3 contained elevated levels of these oxysterol species. As expected, O-3-derived oxysterols have a pro-inflammatory effect and increase NF-kappa B activity. Interestingly, expression of the cholesterol efflux pump ATP-binding cassette transporter 1 (ABCA1), which is regulated by activation of the liver X receptor (LXR), was suppressed in epithelial cells exposed to O-3. Additionally, exposure of LXR knock-out mice to O-3 enhanced pro-inflammatory cytokine production in the lung, suggesting LXR inhibits O-3-induced inflammation. Using alkynyl surrogates of O-3-derived oxysterols, our data demonstrate adduction of LXR with Seco A. Similarly, supplementation of epithelial cells with alkynyl-tagged cholesterol followed by O-3 exposure causes observable lipid-LXR adduct formation. Experiments using Seco A and the LXR agonist T0901317 (T09) showed reduced expression of ABCA1 as compared with stimulation with T0901317 alone, indicating that Seco A-LXR protein adduct formation inhibits LXR activation by traditional agonists. Overall, these data demonstrate that O-3-derived oxysterols have pro-inflammatory functions and form lipid-protein adducts with LXR, thus leading to suppressed cholesterol regulatory gene expression and providing a biochemical mechanism mediating O-3-derived formation of oxidized lipids in the airways and subsequent adverse health effects. C1 [Speen, Adam M.; Bauer, Rebecca N.; Meyer, Megan; Duncan, Kelly E.; Jaspers, Ilona] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Dept Pediat, Curriculum Toxicol, Chapel Hill, NC 27599 USA. [Speen, Adam M.; Bauer, Rebecca N.; Meyer, Megan; Duncan, Kelly E.; Jaspers, Ilona] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Dept Microbiol & Immunol, Curriculum Toxicol, Chapel Hill, NC 27599 USA. [Kim, Hye-Young H.; Liu, Wei; Porter, Ned A.] Vanderbilt Univ, Dept Chem, Box 1583, Nashville, TN 37235 USA. [Kim, Hye-Young H.; Liu, Wei; Porter, Ned A.] Vanderbilt Univ, Ctr Mol Toxicol, Nashville, TN 37235 USA. [Gowdy, Kymberly M.] East Carolina Univ, Brody Sch Med, Dept Pharmacol & Toxicol, Greenville, NC 27834 USA. [Fessler, Michael B.] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Jaspers, I (reprint author), Univ North Carolina Chapel Hill, Dept Pediat Microbiol & Immunol, 104 Mason Farm Rd, Chapel Hill, NC 27599 USA.; Jaspers, I (reprint author), Univ North Carolina Chapel Hill, Environm Sci & Engn, 104 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM ilona_jaspers@med.unc.edu FU United States Environmental Protection Agency [CR83346301]; Center for Environmental Medicine, Asthma and Lung Biology at the University of North Carolina at Chapel Hill; National Institutes of Health [T32ES007126, R21ES024666] FX This work was supported in part by the United States Environmental Protection Agency through cooperative agreement CR83346301 with the Center for Environmental Medicine, Asthma and Lung Biology at the University of North Carolina at Chapel Hill (to I. J. and K. E. D.) and National Institutes of Health Grants T32ES007126 (to A. M. S. and R. N. B.) and R21ES024666 (to H. Y. K., N. A. P., and I. J.). The authors declare that they have no conflicts of interest with the contents of this article. This article has not been formally reviewed by EPA. The views expressed in this document are solely those of the authors and do not necessarily reflect those of the Agency. EPA does not endorse any products or commercial services mentioned in this publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 76 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 25 PY 2016 VL 291 IS 48 BP 25192 EP 25206 DI 10.1074/jbc.M116.732362 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5GR UT WOS:000388880100033 PM 27703007 ER PT J AU Koga, T Yao, PL Goudarzi, M Murray, IA Balandaram, G Gonzalez, FJ Perdew, GH Fornace, AJ Peters, JM AF Koga, Takayuki Yao, Pei-Li Goudarzi, Maryam Murray, Iain A. Balandaram, Gayathri Gonzalez, Frank J. Perdew, Gary H. Fornace, Albert J., Jr. Peters, Jeffrey M. TI Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-beta/delta Modulation of SP1 Promoter Occupancy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; PPAR-DELTA AGONIST; NUCLEAR TRANSLOCATION; LIGAND ACTIVATION; CELLS; DISEASE; ALPHA; CAR; MICE; GENE AB Alcoholic liver disease is a pathological condition caused by overconsumption of alcohol. Because of the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Because peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression in Ppar beta/delta(+/+) mice but not in Ppar beta/delta(-/-) mice. Nuclear and cytosolic localization of the constitutive androstane receptor (CAR), a transcription factor known to regulate Cyp2b10 expression, was not different between genotypes. PPAR gamma co-activator 1 alpha, a co-activator of both CAR and PPAR beta/delta, was up-regulated in Ppar beta/delta(+/+) liver following ethanol exposure, but not in Ppar beta/delta(-/-) liver. Functional mapping of the Cyp2b10 promoter and ChIP assays revealed that PPAR beta/delta-dependent modulation of SP1 promoter occupancy up-regulated Cyp2b10 expression in response to ethanol. These results suggest that PPAR beta/delta regulates Cyp2b10 expression indirectly by modulating SP1 and PPAR gamma co-activator 1 alpha expression and/or activity independent of CAR activity. Ligand activation of PPAR beta/delta attenuates ethanol-induced Cyp2b10 expression in Ppar beta/delta(+/+) liver but not in Ppar beta/delta(-/-) liver. Strikingly, Cyp2b10 suppression by ligand activation of PPAR beta/delta following ethanol treatment occurred in hepatocytes and was mediated by paracrine signaling from Kupffer cells. Combined, results from the present study demonstrate a novel regulatory role of PPAR beta/delta in modulating CYP2B10 that may contribute to the etiology of alcoholic liver disease. C1 [Koga, Takayuki; Yao, Pei-Li; Murray, Iain A.; Balandaram, Gayathri; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA. [Koga, Takayuki; Yao, Pei-Li; Murray, Iain A.; Balandaram, Gayathri; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, 312 Life Sci Bldg, University Pk, PA 16802 USA. [Goudarzi, Maryam; Fornace, Albert J., Jr.] Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA.; Peters, JM (reprint author), Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, 312 Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu FU National Institute of Alcohol Abuse and Alcoholism [CA124533, CA141029, AA018863]; National Institutes of Health NCI Intramural Research Program [ZIABC005561, ZIABC005562, ZIABC005708] FX This work was supported by National Institute of Alcohol Abuse and Alcoholism Grants CA124533 and CA141029 (to J. M. P.) and AA018863 (to A. J. F. and J. M. P.) and National Institutes of Health NCI Intramural Research Program Grants ZIABC005561, ZIABC005562, and ZIABC005708 (to F. J. G.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 42 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 25 PY 2016 VL 291 IS 48 BP 25255 EP 25263 DI 10.1074/jbc.M116.755447 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5GR UT WOS:000388880100039 PM 27765815 ER PT J AU Rotroff, DM Joubert, BR Marvel, SW Haberg, SE Wu, MC Nilsen, RM Ueland, PM Nystad, W London, SJ Motsinger-Reif, A AF Rotroff, Daniel M. Joubert, Bonnie R. Marvel, Skylar W. Haberg, Siri E. Wu, Michael C. Nilsen, Roy M. Ueland, Per M. Nystad, Wenche London, Stephanie J. Motsinger-Reif, Alison TI Maternal smoking impacts key biological pathways in newborns through epigenetic modification in Utero SO BMC GENOMICS LA English DT Article DE Smoking; Epigenetics; Pathway analysis; Cancer; In utero ID DNA METHYLATION; PRENATAL EXPOSURE; NORWEGIAN MOTHER; CHILDHOOD-CANCER; PARENTAL SMOKING; WIDE ASSOCIATION; COHORT PROFILE; RECEPTOR-ALPHA; PREGNANCY; ESTROGEN AB Background: Children exposed to maternal smoking during pregnancy exhibit increased risk for many adverse health effects. Maternal smoking influences methylation in newborns at specific CpG sites (CpGs). Here, we extend evaluation of individual CpGs to gene-level and pathway-level analyses among 1062 participants in the Norwegian Mother and Child Cohort Study (MoBa) using the Illumina 450 K platform to measure methylation in newborn DNA and maternal smoking in pregnancy, assessed using the biomarker, plasma cotinine. We used novel implementations of bioinformatics tools to collapse epigenome-wide methylation data into gene-and pathway-level effects to test whether exposure to maternal smoking in utero differentially methylated CpGs in genes enriched in biologic pathways. Unlike most pathway analysis applications, our approach allows replication in an independent cohort. Results: Data on 485,577 CpGs, mapping to a total of 20,199 genes, were used to create gene scores that were tested for association with maternal plasma cotinine levels using Sequence Kernel Association Test (SKAT), and 15 genes were found to be associated (q < 0.25). Six of these 15 genes (GFI1, MYO1G, CYP1A1, RUNX1, LCTL, and AHRR) contained individual CpGs that were differentially methylated with regards to cotinine levels (p < 1.06 x 10(-7)). Nine of the 15 genes (FCRLA, MIR641, SLC25A24, TRAK1, C1orf180, ITLN2, GLIS1, LRFN1, and MIR451) were associated with cotinine at the gene-level (q < 0.25) but had no genome-wide significant individual CpGs (p > 1.06 x 10(-7)). Pathway analyses using gene scores resulted in 51 significantly associated pathways, which we tested for replication in an independent cohort (q < 0.05). Of those 32 replicated in an independent cohort, which clustered into six groups. The largest cluster consisted of pathways related to cancer, cell cycle, ERa receptor signaling, and angiogenesis. The second cluster, organized into five smaller pathway groups, related to immune system function, such as T-cell regulation and other white blood cell related pathways. Conclusions: Here we use novel implementations of bioinformatics tools to determine biological pathways impacted through epigenetic changes in utero by maternal smoking in 1062 participants in the MoBa, and successfully replicate these findings in an independent cohort. The results provide new insight into biological mechanisms that may contribute to adverse health effects from exposure to tobacco smoke in utero. C1 [Joubert, Bonnie R.; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. [Rotroff, Daniel M.; Marvel, Skylar W.; Motsinger-Reif, Alison] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC USA. [Rotroff, Daniel M.] North Carolina State Univ, Dept Stat, Raleigh, NC USA. [Haberg, Siri E.; Nystad, Wenche] Norwegian Inst Publ Hlth, Oslo, Norway. [Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Nilsen, Roy M.] Haukeland Hosp, Ctr Clin Res, Bergen, Norway. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, Lab Clin Biochem, Bergen, Norway. [Motsinger-Reif, Alison] North Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC USA. RP London, SJ (reprint author), NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM London2@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290; Wu, Michael C./0000-0002-3357-6570 FU Norwegian Ministry of Health and Care Services; Ministry of Education and Research; NIH/NIEHS [N01-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019]; Norwegian Research Council/BIOBANK [221097] FX The Norwegian Mother and Child Cohort Study are supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (grant no 221097). We are grateful to all the participating families in Norway who take part in this on-going cohort study. NR 52 TC 1 Z9 1 U1 13 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD NOV 25 PY 2016 VL 17 AR 976 DI 10.1186/s12864-016-3310-1 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA ED3UG UT WOS:000388773400006 PM 27887572 ER PT J AU Shenoy, S Eapen, M Panepinto, JA Logan, BR Wu, J Abraham, A Brochstein, J Chaudhury, S Godder, K Haight, AE Kasow, KA Leung, K Andreansky, M Bhatia, M Dalal, J Haines, H Jaroscak, J Lazarus, HM Levine, JE Krishnamurti, L Margolis, D Megason, GC Yu, LC Pulsipher, MA Gersten, I DiFronzo, N Horowitz, MM Walters, MC Kamani, N AF Shenoy, Shalini Eapen, Mary Panepinto, Julie A. Logan, Brent R. Wu, Juan Abraham, Allistair Brochstein, Joel Chaudhury, Sonali Godder, Kamar Haight, Ann E. Kasow, Kimberly A. Leung, Kathryn Andreansky, Martin Bhatia, Monica Dalal, Jignesh Haines, Hilary Jaroscak, Jennifer Lazarus, Hillard M. Levine, John E. Krishnamurti, Lakshmanan Margolis, David Megason, Gail C. Yu, Lolie C. Pulsipher, Michael A. Gersten, Iris DiFronzo, Nancy Horowitz, Mary M. Walters, Mark C. Kamani, Naynesh TI A trial of unrelated donor marrow transplantation for children with severe sickle cell disease SO BLOOD LA English DT Article ID CORD BLOOD TRANSPLANTATION; VERSUS-HOST-DISEASE; QUALITY-OF-LIFE; APLASTIC-ANEMIA; CONDITIONING REGIMEN; RISK-FACTORS; THALASSEMIA; THERAPY; IMPACT; HEMOGLOBINOPATHIES AB Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), >= 3 vaso-occlusive pain crises per year (n = 12), or >= 2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of >= 75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420. C1 [Shenoy, Shalini] Washington Univ, St Louis Childrens Hosp, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Eapen, Mary; Panepinto, Julie A.; Logan, Brent R.; Horowitz, Mary M.] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Panepinto, Julie A.; Margolis, David] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Wu, Juan; Gersten, Iris] Emmes Corp, Rockville, MD USA. [Abraham, Allistair] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Brochstein, Joel] Steven & Alexandra Cohen Childrens Med Ctr, New Hyde Pk, NY USA. [Chaudhury, Sonali] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Godder, Kamar] Virginia Commonwealth Univ, Dept Pediat, Richmond, VA USA. [Haight, Ann E.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA. [Kasow, Kimberly A.] Univ North Carolina Chapel Hill, Dept Pediat, Chapel Hill, NC USA. [Leung, Kathryn] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Andreansky, Martin] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [Bhatia, Monica] Columbia Univ, Med Ctr, New York, NY USA. [Dalal, Jignesh] Childrens Mercy Hosp & Clin, Kansas City, KS USA. [Haines, Hilary] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Jaroscak, Jennifer] Med Univ South Carolina, Dept Pediat, Charleston, SC USA. [Lazarus, Hillard M.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Dept Internal Med, Cleveland, OH 44106 USA. [Levine, John E.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Levine, John E.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Megason, Gail C.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Yu, Lolie C.] Louisiana State Univ, Med Ctr, Childrens Hosp New Orleans, New Orleans, LA USA. [Pulsipher, Michael A.] Pediat Blood & Marrow Transplant Consortium, Salt Lake City, UT USA. [DiFronzo, Nancy] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Walters, Mark C.] UCSF Benioff Childrens Hosp, Oakland, CA USA. [Kamani, Naynesh] AABB Ctr Cellular Therapies, Bethesda, MD USA. EM shenoy@wustl.edu FU National Institutes of Health, National Heart, Lung, and Blood Institute and National Cancer Institute [U10-HL069294]; National Marrow Donor Program; Sickle Cell Disease Clinical Research Network; National Center on Minority Health and Health Disparities; Pediatric Blood and Marrow Transplant Consortium FX This work was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute and National Cancer Institute (U10-HL069294) to the Blood and Marrow Transplant Clinical Trials Network, the National Marrow Donor Program, the Sickle Cell Disease Clinical Research Network, the National Center on Minority Health and Health Disparities, and the Pediatric Blood and Marrow Transplant Consortium. NR 56 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 24 PY 2016 VL 128 IS 21 BP 2561 EP 2567 DI 10.1182/blood-2016-05-715870 PG 7 WC Hematology SC Hematology GA EI7AO UT WOS:000392649400016 PM 27625358 ER PT J AU Hoppe, T Minton, AP AF Hoppe, Travis Minton, Allen P. TI Incorporation of Hard and Soft Protein-Protein Interactions into Models for Crowding Effects in Binary and Ternary Protein Mixtures. Comparison of Approximate Analytical Solutions with Numerical Simulation SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID BOVINE SERUM-ALBUMIN; IN-VITRO; PHYSIOLOGICAL CONSEQUENCES; LIGHT-SCATTERING; EXCLUDED-VOLUME; STABILITY; ENVIRONMENTS; CELL; ASSOCIATION; DEPENDENCE AB In order to better understand how nonspecific interactions between solutes can modulate specific biochemical reactions taking place in complex media, we introduce a simplified model aimed at elucidating general principles. In this model, solutions containing two or three species of interacting globular proteins are modeled as a fluid of spherical particles interacting through square well potentials that qualitatively capture both steric hard core repulsion and longer-ranged attraction or repulsion. The excess chemical potential, or free energy of solvation, of each particle species is calculated as a function of species concentrations, particle radii, and square well interaction range and depth. The results of analytical models incorporating two-body and three-body interactions are compared with the estimates of free energy obtained via Widom insertion into simulated equilibrium square-well fluids. The analytical models agree well with results of numeric simulations carried out for a variety of model parameters and fluid compositions up to a total particle volume fraction of ca. 0.2. C1 [Hoppe, Travis] NIDDK, Phys Chem Lab, NIH, US PHS, Bethesda, MD 20892 USA. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, US PHS, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIH, Bldg 8,Room 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov FU Division of Inframural Research of the National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Division of Inframural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, and utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 44 TC 0 Z9 0 U1 6 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 24 PY 2016 VL 120 IS 46 BP 11866 EP 11872 DI 10.1021/acs.jpcb.6b07736 PG 7 WC Chemistry, Physical SC Chemistry GA ED5TA UT WOS:000388914000003 PM 27779417 ER PT J AU Bar, KJ Sneller, MC Harrison, LJ Justement, JS Overton, ET Petrone, ME Salantes, DB Seamon, CA Scheinfeld, B Kwan, RW Learn, GH Proschan, MA Kreider, EF Blazkova, J Bardsley, M Refsland, EW Messer, M Clarridge, KE Tustin, NB Madden, PJ Oden, KS O'Dell, SJ Jarocki, B Shiakolas, AR Tressler, RL Doria-Rose, NA Bailer, RT Ledgerwood, JE Capparelli, EV Lynch, RM Graham, BS Moir, S Koup, RA Mascola, JR Hoxie, JA Fauci, AS Tebas, P Chun, TW AF Bar, K. J. Sneller, M. C. Harrison, L. J. Justement, J. S. Overton, E. T. Petrone, M. E. Salantes, D. B. Seamon, C. A. Scheinfeld, B. Kwan, R. W. Learn, G. H. Proschan, M. A. Kreider, E. F. Blazkova, J. Bardsley, M. Refsland, E. W. Messer, M. Clarridge, K. E. Tustin, N. B. Madden, P. J. Oden, K. S. O'Dell, S. J. Jarocki, B. Shiakolas, A. R. Tressler, R. L. Doria-Rose, N. A. Bailer, R. T. Ledgerwood, J. E. Capparelli, E. V. Lynch, R. M. Graham, B. S. Moir, S. Koup, R. A. Mascola, J. R. Hoxie, J. A. Fauci, A. S. Tebas, P. Chun, T-W TI Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; MONOCLONAL-ANTIBODIES; CONTROLLED-TRIAL; COMBINATION; PROTECTION; RESERVOIR; VIREMIA; POTENT AB BACKGROUND The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 mu g per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P = 0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326.) C1 [Bar, K. J.; Salantes, D. B.; Scheinfeld, B.; Learn, G. H.; Kreider, E. F.; Bardsley, M.; Hoxie, J. A.; Tebas, P.] Univ Penn, Philadelphia, PA 19104 USA. [Tustin, N. B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Sneller, M. C.; Justement, J. S.; Petrone, M. E.; Blazkova, J.; Refsland, E. W.; Clarridge, K. E.; Moir, S.; Fauci, A. S.; Chun, T-W] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Proschan, M. A.] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Madden, P. J.; O'Dell, S. J.; Shiakolas, A. R.; Doria-Rose, N. A.; Bailer, R. T.; Ledgerwood, J. E.; Lynch, R. M.; Graham, B. S.; Koup, R. A.; Mascola, J. R.] NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tressler, R. L.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Seamon, C. A.; Kwan, R. W.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Seamon, C. A.; Kwan, R. W.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Oden, K. S.] AIDS Clin Trials Grp, Silver Spring, MD USA. [Tressler, R. L.] Columbus Technol & Serv, Greenbelt, MD USA. [Harrison, L. J.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Overton, E. T.; Messer, M.] Univ Alabama Birmingham, Birmingham, AL USA. [Jarocki, B.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Capparelli, E. V.] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Bar, KJ (reprint author), Univ Penn, Dept Med, 502D Johnson Pavil,3610 Hamilton Walk, Philadelphia, PA 19104 USA.; Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bark@mail.med.upenn.edu; twchun@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) [U01AI068636]; Penn Center for AIDS Research [P30 AI045008]; Penn Clinical Trials Unit [AI069534]; University of Alabama at Birmingham (UAB) Center for AIDS Research [P30 AI027767]; UAB Clinical Trials Unit [AI069452]; AIDS Clinical Trials Group Statistical and Data Analysis Center [UM1 AI068634]; NIAID [1-R21-AI118431]; Ruth L. Kirschstein National Research Service Award [F30 AI112426]; Intramural Research Program of the NIAID, NIH FX Supported by an award from the National Institute of Allergy and Infectious Diseases (NIAID) (U01AI068636); grants from the Penn Center for AIDS Research (P30 AI045008), the Penn Clinical Trials Unit (AI069534), the University of Alabama at Birmingham (UAB) Center for AIDS Research (P30 AI027767), the UAB Clinical Trials Unit (AI069452), the AIDS Clinical Trials Group Statistical and Data Analysis Center (UM1 AI068634), the NIAID (1-R21-AI118431, for A5340 viral analyses); and a Ruth L. Kirschstein National Research Service Award (F30 AI112426, to Dr. Kreider). The National Institutes of Health (NIH) study was funded by the Intramural Research Program of the NIAID, NIH. NR 44 TC 5 Z9 5 U1 5 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 24 PY 2016 VL 375 IS 21 BP 2037 EP 2050 DI 10.1056/NEJMoa1608243 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EC9KU UT WOS:000388464300006 PM 27959728 ER PT J AU Chen, L Wilson, K Goldlust, I Mott, BT Eastman, R Davis, MI Zhang, XH McKnight, C Klumpp-Thomas, C Shinn, P Simmons, J Gormally, M Michael, S Thomas, CJ Ferrer, M Guha, R AF Chen, Lu Wilson, Kelli Goldlust, Ian Mott, Bryan T. Eastman, Richard Davis, Mindy I. Zhang, Xiaohu McKnight, Crystal Klumpp-Thomas, Carleen Shinn, Paul Simmons, John Gormally, Mike Michael, Sam Thomas, Craig J. Ferrer, Marc Guha, Rajarshi TI mQC: A Heuristic Quality-Control Metric for High-Throughput Drug Combination Screening SO SCIENTIFIC REPORTS LA English DT Article ID STATISTICAL PARAMETER; ASSAYS; MODEL; COMPLEXITY; DISCOVERY; SYNERGY AB Quality control (QC) metrics are critical in high throughput screening (HTS) platforms to ensure reliability and confidence in assay data and downstream analyses. Most reported HTS QC metrics are designed for plate level or single well level analysis. With the advent of high throughput combination screening there is a need for QC metrics that quantify the quality of combination response matrices. We introduce a predictive, interpretable, matrix-level QC metric, mQC, based on a mix of data-derived and heuristic features. mQC accurately reproduces the expert assessment of combination response quality and correctly identifies unreliable response matrices that can lead to erroneous or misleading characterization of synergy. When combined with the plate-level QC metric, Z', mQC provides a more appropriate determination of the quality of a drug combination screen. Retrospective analysis on a number of completed combination screens further shows that mQC is able to identify problematic screens whereas plate-level QC was not able to. In conclusion, our data indicates that mQC is a reliable QC filter that can be used to identify problematic drug combinations matrices and prevent further analysis on erroneously active combinations as well as for troubleshooting failed screens. The R source code of mQC is available at http://matrix.ncats.nih.gov/mQC. C1 [Chen, Lu; Wilson, Kelli; Goldlust, Ian; Mott, Bryan T.; Eastman, Richard; Zhang, Xiaohu; McKnight, Crystal; Klumpp-Thomas, Carleen; Shinn, Paul; Gormally, Mike; Michael, Sam; Thomas, Craig J.; Ferrer, Marc; Guha, Rajarshi] Natl Ctr Adv Translat Sci NCATS, Div Preclin Innovat, Rockville, MD 20850 USA. [Davis, Mindy I.] NIAID, Rockville, MD 20852 USA. [Simmons, John] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Guha, R (reprint author), Natl Ctr Adv Translat Sci NCATS, Div Preclin Innovat, Rockville, MD 20850 USA. EM guhar@mail.nih.gov NR 32 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 24 PY 2016 VL 6 AR 37741 DI 10.1038/srep37741 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5PH UT WOS:000388903700001 PM 27883049 ER PT J AU Smith, ME Sanderson, SC Brothers, KB Myers, MF McCormick, J Aufox, S Shrubsole, MJ Garrison, NA Mercaldo, ND Schildcrout, JS Clayton, EW Antommaria, AHM Basford, M Brilliant, M Connolly, JJ Fullerton, SM Horowitz, CR Jarvik, GP Kaufman, D Kitchner, T Li, RL Ludman, EJ McCarty, C McManus, V Stallings, S Williams, JL Holm, IA AF Smith, Maureen E. Sanderson, Saskia C. Brothers, Kyle B. Myers, Melanie F. McCormick, Jennifer Aufox, Sharon Shrubsole, Martha J. Garrison, Nanibaa A. Mercaldo, Nathaniel D. Schildcrout, Jonathan S. Clayton, Ellen Wright Antommaria, Armand H. Matheny Basford, Melissa Brilliant, Murray Connolly, John J. Fullerton, Stephanie M. Horowitz, Carol R. Jarvik, Gail P. Kaufman, Dave Kitchner, Terri Li, Rongling Ludman, Evette J. McCarty, Catherine McManus, Valerie Stallings, Sarah Williams, Janet L. Holm, Ingrid A. TI Conducting a large, multi-site survey about patients' views on broad consent: challenges and solutions SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Survey; Consent; Multi-site; Genomics; Institutional Review Board; Cognitive interviews; Pilot ID INFORMED-CONSENT; EMERGE CONSORTIUM; GENETIC RESEARCH; GENOMIC RESEARCH; PERSPECTIVES; PARTICIPANTS; PREFERENCES; POPULATION; EXPERIENCE; SAMPLES AB Background: As biobanks play an increasing role in the genomic research that will lead to precision medicine, input from diverse and large populations of patients in a variety of health care settings will be important in order to successfully carry out such studies. One important topic is participants' views towards consent and data sharing, especially since the 2011 Advanced Notice of Proposed Rulemaking (ANPRM), and subsequently the 2015 Notice of Proposed Rulemaking (NPRM) were issued by the Department of Health and Human Services (HHS) and Office of Science and Technology Policy (OSTP). These notices required that participants consent to research uses of their de-identified tissue samples and most clinical data, and allowing such consent be obtained in a one-time, open-ended or "broad" fashion. Conducting a survey across multiple sites provides clear advantages to either a single site survey or using a large online database, and is a potentially powerful way of understanding the views of diverse populations on this topic. Methods: A workgroup of the Electronic Medical Records and Genomics (eMERGE) Network, a national consortium of 9 sites (13 separate institutions, 11 clinical centers) supported by the National Human Genome Research Institute (NHGRI) that combines DNA biorepositories with electronic medical record (EMR) systems for large-scale genetic research, conducted a survey to understand patients' views on consent, sample and data sharing for future research, biobank governance, data protection, and return of research results. Results: Working across 9 sites to design and conduct a national survey presented challenges in organization, meeting human subjects guidelines at each institution, and survey development and implementation. The challenges were met through a committee structure to address each aspect of the project with representatives from all sites. Each committee's output was integrated into the overall survey plan. A number of site-specific issues were successfully managed allowing the survey to be developed and implemented uniformly across 11 clinical centers. Conclusions: Conducting a survey across a number of institutions with different cultures and practices is a methodological and logistical challenge. With a clear infrastructure, collaborative attitudes, excellent lines of communication, and the right expertise, this can be accomplished successfully. C1 [Smith, Maureen E.; Aufox, Sharon] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, 645 N Michigan Ave, Chicago, IL 60611 USA. [Sanderson, Saskia C.; Horowitz, Carol R.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Sanderson, Saskia C.] UCL, London, England. [Brothers, Kyle B.] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Myers, Melanie F.; Antommaria, Armand H. Matheny] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [McCormick, Jennifer] Penn State Coll Med, Hershey, PA USA. [Shrubsole, Martha J.; Mercaldo, Nathaniel D.; Schildcrout, Jonathan S.; Clayton, Ellen Wright; Basford, Melissa; Stallings, Sarah] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Shrubsole, Martha J.; Mercaldo, Nathaniel D.; Schildcrout, Jonathan S.; Clayton, Ellen Wright; Basford, Melissa; Stallings, Sarah] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Garrison, Nanibaa A.] Seattle Childrens Res Inst, Seattle, WA USA. [Brilliant, Murray; Kitchner, Terri; McManus, Valerie] Marshfield Clin Res Fdn, Marshfield, WI USA. [Connolly, John J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Fullerton, Stephanie M.; Jarvik, Gail P.] Univ Washington, Seattle, WA 98195 USA. [Kaufman, Dave; Li, Rongling] NHGRI, NIH, Bethesda, MD 20892 USA. [Ludman, Evette J.] Grp Hlth Res Inst, Seattle, WA USA. [McCarty, Catherine] Essentia Inst Rural Hlth, Duluth, MN USA. [Williams, Janet L.] Geisinger Hlth Syst, Danville, PA USA. [Holm, Ingrid A.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. RP Smith, ME (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, 645 N Michigan Ave, Chicago, IL 60611 USA. EM m-smith6@northwestern.edu FU NHGRI [U01HG006828, U01HG006830, U01HG006389, U01HG006382, U01HG006375, 3U01HG006379, U01HG006380, 3U01-HG006388, U01HG006378, 3U01HG006385]; NIH Office of the Director through the NIH Common Fund [3U01HG006828-02S1, 3U01HG006830-02S1, 3U01HG006389-03S1, 3U01HG006382-03S1, 3U01HG006375-03S1, 3U01HG006379-03S1, 3U01HG006380-03S1, 3U01HG006388-03S1, 3U01HG006378-03S1, 3U01HG006385-03S1] FX The CERC Survey project within the eMERGE Network was initiated and funded by NHGRI: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); 3U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); 3U01-HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and 3U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). Additional funding was provided by the NIH Office of the Director through the NIH Common Fund, which is managed by the OD/Office of Strategies Coordination (OSC), award numbers 3U01HG006828-02S1 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); 3U01HG006830-02S1 (Children's Hospital of Philadelphia); 3U01HG006389-03S1 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); 3U01HG006382-03S1 (Geisinger Clinic); 3U01HG006375-03S1 (Group Health Cooperative/University of Washington); 3U01HG006379-03S1 (Mayo Clinic); 3U01HG006380-03S1 (Icahn School of Medicine at Mount Sinai); 3U01HG006388-03S1 (Northwestern University); 3U01HG006378-03S1 (Vanderbilt University Medical Center); and 3U01HG006385-03S1 (Vanderbilt University Medical Center serving as the Coordinating Center). NR 24 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD NOV 24 PY 2016 VL 16 AR 162 DI 10.1186/s12874-016-0263-7 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA ED0ET UT WOS:000388516500001 PM 27881091 ER PT J AU Koren, G Clark, S Hankins, GDV Caritis, SN Umans, JG Miodovnik, M Mattison, DR Matok, I AF Koren, Gideon Clark, Shannon Hankins, Gary D. V. Caritis, Steve N. Umans, Jason G. Miodovnik, Menachem Mattison, Donald R. Matok, Ilan TI Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; MANAGEMENT; BENDECTIN AB Background: Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis r) for NVP, based in part, on the results of a phase III randomized trial demonstrating the efficacy of this drug combination [study drug marketed under the trade name Diclectin r in Canada and Diclegis r in the United States] compared to placebo in pregnant women. Study drug dosing occurred for 14 days, which is substantially longer than what has been performed in similar studies. The objective of this study was to evaluate, through secondary analysis, whether the primary measure of efficacy can be demonstrated after five days of treatment. Methods: Women suffering from NVP were randomized to receive Diclegis r (n = 131) or placebo (n = 125) for 14 days at doses ranging from two to four tablets a day, based on a pre-specified titration protocol. The primary efficacy endpoint was the change in the validated Pregnancy-Unique Quantification of Emesis (PUQE) score at baseline versus Day 15 between Diclegis r -treated and placebo-treated women. For the present study, the change in PUQE score between baseline and Day 15 (end of the study) was compared to the changes observed for Days 3, 4, and 5. Results: The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets show improved NVP symptom control as compared to placebo on Days 3,4 and 5, with sustained efficacy until the end of the trial. Conclusion: A four day study drug dosing trial with Diclegis r is sufficient to document efficacy, as the results are similar to those achieved after 14 study drug dosing days. The benefit seen at the earlier time validates drug efficacy and minimizes the natural course of improvement. C1 [Koren, Gideon; Matok, Ilan] Univ Toronto, Toronto, ON, Canada. [Koren, Gideon; Matok, Ilan] Univ Western Ontario, London, ON, Canada. [Clark, Shannon; Hankins, Gary D. V.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Caritis, Steve N.] Univ Pittsburgh, Med Ctr, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Umans, Jason G.; Miodovnik, Menachem] Medstar Hlth Res Inst, Hyattsville, MD USA. [Umans, Jason G.; Miodovnik, Menachem] Georgetown Howard Univ, Ctr Clin & Translat Sci, Washington, DC USA. [Koren, Gideon; Clark, Shannon; Hankins, Gary D. V.; Caritis, Steve N.; Umans, Jason G.; Miodovnik, Menachem; Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child & Human De, Obstetr Pharmacol Res Unit Network, Bethesda, MD USA. [Matok, Ilan] Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Div Clin Pharm,Inst Drug Res, Jerusalem, Israel. RP Koren, G (reprint author), Univ Toronto, Toronto, ON, Canada.; Koren, G (reprint author), Univ Western Ontario, London, ON, Canada. EM gidiup_2000@yahoo.com FU Duchesnay Inc., Blainville Quebec FX The study was funded by Duchesnay Inc., Blainville Quebec. NR 24 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD NOV 24 PY 2016 VL 16 AR 371 DI 10.1186/s12884-016-1172-9 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EC8XW UT WOS:000388427400003 PM 27881103 ER PT J AU Kumar, A Ganini, D Mason, RP AF Kumar, Ashutosh Ganini, Douglas Mason, Ronald P. TI Role of cytochrome c in a-synuclein radical formation: implications of a-synuclein in neuronal death in Maneb- and paraquat-induced model of Parkinson's disease SO MOLECULAR NEURODEGENERATION LA English DT Article DE Cytochrome c; a-synuclein radical; Peroxidase; Parkinson's disease; Immuno-spin trapping ID LEWY BODY DISEASE; ALPHA-SYNUCLEIN; NEURODEGENERATIVE DISEASES; OXIDATIVE-STRESS; CROSS-LINKING; CELL-DEATH; 2 PARTS; MICE; NITRATION; BRAIN AB Background: The pathological features of Parkinson's disease (PD) include an abnormal accumulation of asynuclein in the surviving dopaminergic neurons. Though PD is multifactorial, several epidemiological reports show an increased incidence of PD with co-exposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and a-synuclein oligomers have been strongly implicated, but the link between the two has not yet been understood. Similarly, the biological effects of a-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. Once in the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or can act as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked out from mitochondria can form radicals on a-synuclein and initiate its oligomerization. Method: Samples from controls, and MP co-exposed wild-type and a-synuclein knockout mice were studied using immuno-spin trapping, confocal microscopy, immunohistochemistry, and microarray experiments. Results: Experiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with a-synuclein. Subsequently, we used immuno-spin trapping method to detect the formation of a-synuclein radical in samples from an in vitro reaction mixture consisting of cytochrome c, a-synuclein, and hydrogen peroxide. These experiments indicated that cytochrome c plays a role in a-synuclein radical formation and oligomerization. Experiments with MP co-exposed a-synuclein knockout mice, in which cytochrome c-a synuclein co-localization and interaction cannot occur, mice showed diminished protein radical formation and neuronal death, compared to wild-type MP coexposed mice. Microarray data from MP co-exposed wild-type and a-synuclein knockout mice further showed that the absence of a-synuclein per se or its co-localization with cytochrome c confers protection from MP co-exposure, as several important pathways were unaffected in a-synuclein knockout mice. Conclusions: Altogether, these results show that peroxidase activity of cytochrome c contributes to a-synuclein radical formation and oligomerization, and that a-synuclein, through its co-localization with cytochrome c or on its own, affects several biological pathways which contribute to increased neuronal death in an MP-induced model of PD. C1 [Kumar, Ashutosh; Ganini, Douglas; Mason, Ronald P.] NIEHS, Free Radical Biol Grp, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr, Durham, NC 27709 USA. RP Kumar, A (reprint author), NIEHS, Free Radical Biol Grp, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr, Durham, NC 27709 USA. EM kumara10@niehs.nih.gov FU Intramural Research Program of the NIEHS, National Institute of Environmental Health Sciences/NIH FX This research was supported by the Intramural Research Program of the NIEHS, National Institute of Environmental Health Sciences/NIH. NR 55 TC 0 Z9 0 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD NOV 24 PY 2016 VL 11 AR 70 DI 10.1186/s13024-016-0135-y PG 12 WC Neurosciences SC Neurosciences & Neurology GA EC8UG UT WOS:000388417700001 PM 27884192 ER PT J AU Faure, LM Fiche, JB Espinosa, L Ducret, A Anantharaman, V Luciano, J Lhospice, S Islam, ST Treguier, J Sotes, M Kuru, E Van Nieuwenhze, MS Brun, YV Theodoly, O Aravind, L Nollmann, M Mignot, T AF Faure, Laura M. Fiche, Jean-Bernard Espinosa, Leon Ducret, Adrien Anantharaman, Vivek Luciano, Jennifer Lhospice, Sebastien Islam, Salim T. Treguier, Julie Sotes, Melanie Kuru, Erkin Van Nieuwenhze, Michael S. Brun, Yves V. Theodoly, Olivier Aravind, L. Nollmann, Marcelo Mignot, Tam TI The mechanism of force transmission at bacterial focal adhesion complexes SO NATURE LA English DT Article ID HIDDEN MARKOV MODEL; PROTON MOTIVE FORCE; MYXOCOCCUS-XANTHUS; GLIDING MOTILITY; ACTIN CYTOSKELETON; ESCHERICHIA-COLI; PROTEIN; SIGNAL; MICROSCOPY; PREDICTION AB Various rod-shaped bacteria mysteriously glide on surfaces in the absence of appendages such as flagella or pili. In the deltaproteobacterium Myxococcus xanthus, a putative gliding motility machinery (the Agl-Glt complex) localizes to so-called focal adhesion sites (FASs) that form stationary contact points with the underlying surface. Here we show that the Agl-Glt machinery contains an inner-membrane motor complex that moves intracellularly along a right-handed helical path; when the machinery becomes stationary at FASs, the motor complex powers a left-handed rotation of the cell around its long axis. At FASs, force transmission requires cyclic interactions between the molecular motor and the adhesion proteins of the outer membrane via a periplasmic interaction platform, which presumably involves contractile activity of motor components and possible interactions with peptidoglycan. Our results provide a molecular model of bacterial gliding motility. C1 [Faure, Laura M.; Espinosa, Leon; Ducret, Adrien; Luciano, Jennifer; Lhospice, Sebastien; Islam, Salim T.; Treguier, Julie; Sotes, Melanie; Mignot, Tam] Aix Marseille Univ, CNRS, Inst Microbiol Mediterranee, Lab Chim Bacterienne,UMR7283, F-13009 Marseille, France. [Fiche, Jean-Bernard; Nollmann, Marcelo] Univ Montpellier, INSERM, CNRS, Ctr Biochim Struct,UMR5048,U1054, 29 Rue Navacelles, F-34090 Montpellier, France. [Ducret, Adrien; Brun, Yves V.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Anantharaman, Vivek] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Kuru, Erkin] Indiana Univ, Interdisciplinary Biochem Program, Bloomington, IN 47405 USA. [Van Nieuwenhze, Michael S.] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. [Theodoly, Olivier] Aix Marseille Univ, INSERM, Adhes & Inflammat Lab, U1067,UMR7333, F-13288 Marseille, France. RP Mignot, T (reprint author), Aix Marseille Univ, CNRS, Inst Microbiol Mediterranee, Lab Chim Bacterienne,UMR7283, F-13009 Marseille, France.; Nollmann, M (reprint author), Univ Montpellier, INSERM, CNRS, Ctr Biochim Struct,UMR5048,U1054, 29 Rue Navacelles, F-34090 Montpellier, France. EM marcelo.nollmann@cbs.cnrs.fr; tmignot@imm.cnrs.fr RI theodoly, olivier/P-5402-2016 FU Fondation ARC; Fondation pour la Recherche Medicale; Canadian Institutes of Health Research; AMIDEX program of Aix-Marseille Universite; IRP funds of the NIH; NIH [GM113172, GM51986]; European Research Council [DOME-261105, 260787]; Bettencourt-Schueller "Coup d'elan pour la recherche Francaise; ANR grant IBM [ANR-14-CE09-0025-01]; ANR grant HiResBacs [ANR-15-CE11-0023]; France-BioImaging ("Investments for the future") [ANR-10-INBS-04]; Imagine Optic FX We thank R. Mercier for suggestions and critical reading of the manuscript, A. Valeri for help with PCA analysis, C. Fiche for help with image analysis and Y. Denis (IMM transcriptomics platform) for help with quantitative PCR and M. Wartel for preliminary experiments. L.M.F. was partially funded by Fondation ARC, L.E. was supported by the Fondation pour la Recherche Medicale (FRM DGE2010221257), S.T.I. was supported by a fellowship from the Canadian Institutes of Health Research and the AMIDEX program of Aix-Marseille Universite, and A.L. and V.A. were supported by the IRP funds of the NIH, NIH grant GM113172 to M.S.V.N. and Y.V.B. and NIH grant GM51986 to Y.V.B. Research in the Mignot laboratory was supported by European Research Council grant DOME-261105 and a Bettencourt-Schueller "Coup d'elan pour la recherche Francaise 2011". Research in the Nollmann laboratory was supported by ANR grants IBM (ANR-14-CE09-0025-01), HiResBacs (ANR-15-CE11-0023), and European Research Council grant smInsulator-260787. We acknowledge support from France-BioImaging (ANR-10-INBS-04, "Investments for the future"), and Imagine Optic. NR 38 TC 1 Z9 1 U1 28 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD NOV 24 PY 2016 VL 539 IS 7630 BP 530 EP + DI 10.1038/nature20121 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED0GI UT WOS:000388520600037 PM 27749817 ER PT J AU Ried, JS Jeff, JM Chu, AY Bragg-Gresham, JL van Dongen, J Huffman, JE Ahluwalia, TS Cadby, G Eklund, N Eriksson, J Esko, T Feitosa, MF Goel, A Gorski, M Hayward, C Heard-Costa, NL Jackson, AU Jokinen, E Kanoni, S Kristiansson, K Kutalik, Z Lahti, J Luan, JA Magi, R Mahajan, A Mangino, M Medina-Gomez, C Monda, KL Nolte, IM Perusse, L Prokopenko, I Qi, L Rose, LM Salvi, E Smith, MT Snieder, H Stancakova, A Sung, YJ Tachmazidou, I Teumer, A Thorleifsson, G van der Harst, P Walker, RW Wang, SR Wild, SH Willems, SM Wong, A Zhang, WH Albrecht, E Alves, AC Bakker, SJL Barlassina, C Bartz, TM Beilby, J Bellis, C Bergman, RN Bergmann, S Blangero, J Bluher, M Boerwinkle, E Bonnycastle, LL Bornstein, SR Bruinenberg, M Campbell, H Chen, YDI Chiang, CWK Chines, PS Collins, FS Cucca, F Cupples, LA D'Avila, F de Geus, EJC Dedoussis, G Dimitriou, M Doring, A Eriksson, JG Farmaki, AE Farrall, M Ferreira, T Fischer, K Forouhi, NG Friedrich, N Gjesing, AP Glorioso, N Graff, M Grallert, H Grarup, N Grassler, J Grewal, J Hamsten, A Harder, MN Hartman, CA Hassinen, M Hastie, N Hattersley, AT Havulinna, AS Heliovaara, M Hillege, H Hofman, A Holmen, O Homuth, G Hottenga, JJ Hui, JN Husemoen, LL Hysi, PG Isaacs, A Ittermann, T Jalilzadeh, S James, AL Jorgensen, T Jousilahti, P Jula, A Justesen, JM Justice, AE Kahonen, M Karaleftheri, M Khaw, KT Keinanen-Kiukaanniemi, SM Kinnunen, L Knekt, PB Koistinen, HA Kolcic, I Kooner, IK Koskinen, S Kovacs, P Kyriakou, T Laitinen, T Langenberg, C Lewin, AM Lichtner, P Lindgren, CM Lindstrom, J Linneberg, A Lorbeer, R Lorentzon, M Luben, R Lyssenko, V Mannisto, S Manunta, P Leach, IM McArdle, WL Mcknight, B Mohlke, KL Mihailov, E Milani, L Mills, R Montasser, ME Morris, AP Muller, G Musk, AW Narisu, N Ong, KK Oostra, BA Osmond, C Palotie, A Pankow, JS Paternoster, L Penninx, BW Pichler, I Pilia, MG Polasek, O Pramstaller, PP Raitakari, OT Rankinen, T Rao, DC Rayner, NW Ribel-Madsen, R Rice, TK Richards, M Ridker, PM Rivadeneira, F Ryan, KA Sanna, S Sarzynski, MA Scholtens, S Scott, RA Sebert, S Southam, L Sparso, TH Steinthorsdottir, V Stirrups, K Stolk, RP Strauch, K Stringham, HM Swertz, MA Swift, AJ Tonjes, A Tsafantakis, E van der Most, PJ Van Vliet-Ostaptchouk, JV Vandenput, L Vartiainen, E Venturini, C Verweij, N Viikari, JS Vitart, V Vohl, MC Vonk, JM Waeber, G Widen, E Willemsen, G Wilsgaard, T Winkler, TW Wright, AF Yerges-Armstrong, LM Zhao, JH Zillikens, MC Boomsma, DI Bouchard, C Chambers, JC Chasman, DI Cusi, D Gansevoort, RT Gieger, C Hansen, T Hicks, AA Hu, F Hveem, K Jarvelin, MR Kajantie, E Kooner, JS Kuh, D Kuusisto, J Laakso, M Lakka, TA Lehtimaki, T Metspalu, A Njolstad, I Ohlsson, C Oldehinkel, AJ Palmer, LJ Pedersen, O Perola, M Peters, A Psaty, BM Puolijoki, H Rauramaa, R Rudan, I Salomaa, V Schwarz, PEH Shudiner, AR Smit, JH Sorensen, TIA Spector, TD Stefansson, K Stumvoll, M Tremblay, A Tuomilehto, J Uitterlinden, AG Uusitupa, M Volker, U Vollenweider, P Wareham, NJ Watkins, H Wilson, JF Zeggini, E Abecasis, GR Boehnke, M Borecki, IB Deloukas, P van Duijn, CM Fox, C Groop, LC Heid, IM Hunter, DJ Kaplan, RC McCarthy, MI North, KE O'Connell, JR Schlessinger, D Thorsteinsdottir, U Strachan, DP Frayling, T Hirschhorn, JN Muller-Nurasyid, M Loos, RJF AF Ried, Janina S. Jeff, Janina M. Chu, Audrey Y. Bragg-Gresham, Jennifer L. van Dongen, Jenny Huffman, Jennifer E. Ahluwalia, Tarunveer S. Cadby, Gemma Eklund, Niina Eriksson, Joel Esko, Tonu Feitosa, Mary F. Goel, Anuj Gorski, Mathias Hayward, Caroline Heard-Costa, Nancy L. Jackson, Anne U. Jokinen, Eero Kanoni, Stavroula Kristiansson, Kati Kutalik, Zoltan Lahti, Jari Luan, Jian'an Maegi, Reedik Mahajan, Anubha Mangino, Massimo Medina-Gomez, Carolina Monda, Keri L. Nolte, Ilja M. Perusse, Louis Prokopenko, Inga Qi, Lu Rose, Lynda M. Salvi, Erika Smith, Megan T. Snieder, Harold Stancakova, Alena Sung, Yun Ju Tachmazidou, Ioanna Teumer, Alexander Thorleifsson, Gudmar van der Harst, Pim Walker, Ryan W. Wang, Sophie R. Wild, Sarah H. Willems, Sara M. Wong, Andrew Zhang, Weihua Albrecht, Eva Alves, Alexessander Couto Bakker, Stephan J. L. Barlassina, Cristina Bartz, Traci M. Beilby, John Bellis, Claire Bergman, Richard N. Bergmann, Sven Blangero, John Blueher, Matthias Boerwinkle, Eric Bonnycastle, Lori L. Bornstein, Stefan R. Bruinenberg, Marcel Campbell, Harry Chen, Yii-Der Ida Chiang, Charleston W. K. Chines, Peter S. Collins, Francis S. Cucca, Fracensco Cupples, L. Adrienne D'Avila, Francesca de Geus, Eco J. C. Dedoussis, George Dimitriou, Maria Doering, Angela Eriksson, Johan G. Farmaki, Aliki-Eleni Farrall, Martin Ferreira, Teresa Fischer, Krista Forouhi, Nita G. Friedrich, Nele Gjesing, Anette Prior Glorioso, Nicola Graff, Mariaelisa Grallert, Harald Grarup, Niels Graessler, Juergen Grewal, Jagvir Hamsten, Anders Harder, Marie Neergaard Hartman, Catharina A. Hassinen, Maija Hastie, Nicholas Hattersley, Andrew Tym Havulinna, Aki S. Heliovaara, Markku Hillege, Hans Hofman, Albert Holmen, Oddgeir Homuth, Georg Hottenga, Jouke-Jan Hui, Jennie Husemoen, Lise Lotte Hysi, Pirro G. Isaacs, Aaron Ittermann, Till Jalilzadeh, Shapour James, Alan L. Jorgensen, Torben Jousilahti, Pekka Jula, Antti Justesen, Johanne Marie Justice, Anne E. Kahonen, Mika Karaleftheri, Maria Khaw, Kay Tee Keinanen-Kiukaanniemi, Sirkka M. Kinnunen, Leena Knekt, Paul B. Koistinen, Heikki A. Kolcic, Ivana Kooner, Ishminder K. Koskinen, Seppo Kovacs, Peter Kyriakou, Theodosios Laitinen, Tomi Langenberg, Claudia Lewin, Alexandra M. Lichtner, Peter Lindgren, Cecilia M. Lindstrom, Jaana Linneberg, Allan Lorbeer, Roberto Lorentzon, Mattias Luben, Robert Lyssenko, Valeriya Mannisto, Satu Manunta, Paolo Leach, Irene Mateo McArdle, Wendy L. Mcknight, Barbara Mohlke, Karen L. Mihailov, Evelin Milani, Lili Mills, Rebecca Montasser, May E. Morris, Andrew P. Mueller, Gabriele Musk, Arthur W. Narisu, Narisu Ong, Ken K. Oostra, Ben A. Osmond, Clive Palotie, Aarno Pankow, James S. Paternoster, Lavinia Penninx, Brenda W. Pichler, Irene Pilia, Maria G. Polasek, Ozren Pramstaller, Peter P. Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rayner, Nigel W. Ribel-Madsen, Rasmus Rice, Treva K. Richards, Marcus Ridker, Paul M. Rivadeneira, Fernando Ryan, Kathy A. Sanna, Serena Sarzynski, Mark A. Scholtens, Salome Scott, Robert A. Sebert, Sylvain Southam, Lorraine Sparso, Thomas Hempel Steinthorsdottir, Valgerdur Stirrups, Kathleen Stolk, Ronald P. Strauch, Konstantin Stringham, Heather M. Swertz, Morris A. Swift, Amy J. Toenjes, Anke Tsafantakis, Emmanouil van der Most, Peter J. Van Vliet-Ostaptchouk, Jana V. Vandenput, Liesbeth Vartiainen, Erkki Venturini, Cristina Verweij, Niek Viikari, Jorma S. Vitart, Veronique Vohl, Marie-Claude Vonk, Judith M. Waeber, Gerard Widen, Elisabeth Willemsen, Gonneke Wilsgaard, Tom Winkler, Thomas W. Wright, Alan F. Yerges-Armstrong, Laura M. Zhao, Jing Hua Zillikens, M. Carola Boomsma, Dorret I. Bouchard, Claude Chambers, John C. Chasman, Daniel I. Cusi, Daniele Gansevoort, Ron T. Gieger, Christian Hansen, Torben Hicks, Andrew A. Hu, Frank Hveem, Kristian Jarvelin, Marjo-Riitta Kajantie, Eero Kooner, Jaspal S. Kuh, Diana Kuusisto, Johanna Laakso, Markku Lakka, Timo A. Lehtimaeki, Terho Metspalu, Andres Njolstad, Inger Ohlsson, Claes Oldehinkel, Albertine J. Palmer, Lyle J. Pedersen, Oluf Perola, Markus Peters, Annette Psaty, Bruce M. Puolijoki, Hannu Rauramaa, Rainer Rudan, Igor Salomaa, Veikko Schwarz, Peter E. H. Shudiner, Alan R. Smit, Jan H. Sorensen, Thorkild I. A. Spector, Timothy D. Stefansson, Kari Stumvoll, Michael Tremblay, Angelo Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti Voelker, Uwe Vollenweider, Peter Wareham, Nicholas J. Watkins, Hugh Wilson, James F. Zeggini, Eleftheria Abecasis, Goncalo R. Boehnke, Michael Borecki, Ingrid B. Deloukas, Panos van Duijn, Cornelia M. Fox, Caroline Groop, Leif C. Heid, Iris M. Hunter, David J. Kaplan, Robert C. McCarthy, Mark I. North, Kari E. O'Connell, Jeffrey R. Schlessinger, David Thorsteinsdottir, Unnur Strachan, David P. Frayling, Timothy Hirschhorn, Joel N. Mueller-Nurasyid, Martina Loos, Ruth J. F. TI A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; DIET-INDUCED OBESITY; MASS INDEX; DISEASE ASSOCIATIONS; FAT DISTRIBUTION; EARLY-ONSET; HIP RATIO; RESOURCE; BIOLOGY; HEIGHT AB Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways. C1 [Ried, Janina S.; Albrecht, Eva; Strauch, Konstantin; Gieger, Christian; Mueller-Nurasyid, Martina] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Jeff, Janina M.; Walker, Ryan W.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Chu, Audrey Y.; Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Bragg-Gresham, Jennifer L.] Univ Michigan, Kidney Epidemiol & Cost Ctr Internal Med Nephrol, Ann Arbor, MI 48109 USA. [van Dongen, Jenny; de Geus, Eco J. C.; Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Huffman, Jennifer E.; Hayward, Caroline; Hastie, Nicholas; Vitart, Veronique; Wright, Alan F.; Wilson, James F.] Univ Edinburgh, MRC Human Genet Unit Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Ahluwalia, Tarunveer S.; Gjesing, Anette Prior; Grarup, Niels; Harder, Marie Neergaard; Justesen, Johanne Marie; Ribel-Madsen, Rasmus; Sparso, Thomas Hempel; Hansen, Torben; Pedersen, Oluf; Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen, Denmark. [Ahluwalia, Tarunveer S.; Lyssenko, Valeriya] Steno Diabet Ctr A S, DK-2820 Gentofte, Denmark. 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[Viikari, Jorma S.] Turku Univ Hosp, Div Med, Turku, Finland. [Vohl, Marie-Claude] Univ Laval, Sch Nutr, Quebec City, PQ G1V 0A6, Canada. [Waeber, Gerard; Vollenweider, Peter] Univ Hosp Lausanne CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Waeber, Gerard; Vollenweider, Peter] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Wilsgaard, Tom; Njolstad, Inger] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, DK-5000 Odense, Denmark. Oulu Univ Hosp, Unit Primary Care, Oys Oulu 90029, Finland. [Jarvelin, Marjo-Riitta] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W12 0NN, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Ctr Life Course Epidemiol, Fac Med, POB 5000, FI-90014 Oulu, Finland. [Kajantie, Eero] Helsinki Univ Hosp, Childrens Hosp, FI-00029 Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, FI-00029 Helsinki, Finland. [Kajantie, Eero] Oulu Univ Hosp, MRC Oulu, Dept Obstet & Gynecol, FI-90029 Oulu, Finland. [Kajantie, Eero] Univ Oulu, FI-90029 Oulu, Finland. [Kooner, Jaspal S.] Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, Kuopio Campus, Kuopio 70210, Finland. [Lehtimaeki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FI-33014 Tampere, Finland. [Lehtimaeki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lehtimaeki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Njolstad, Inger] Univ Tromso, Fac Hlth Sci, Dept Clin Med, N-9037 Tromso, Norway. [Palmer, Lyle J.] Univ Adelaide, Sch Publ Hlth, Adelaide, SA 5005, Australia. [Palmer, Lyle J.] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. [Peters, Annette; Mueller-Nurasyid, Martina] DZHK German Ctr Cardiovasc Res, Partnersite Munich Heart Alliance, D-80802 Munich, Germany. [Tuomilehto, Jaakko] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Washington, DC 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Washington, DC 98101 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Washington, DC 98101 USA. [Puolijoki, Hannu] South Ostrobothnia Cent Hosp, FI-60220 Seinajoki, Finland. [Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio 70211, Finland. [Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, D-01307 Dresden, Germany. [Shudiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21042 USA. [Sorensen, Thorkild I. A.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, FI-00271 Helsinki, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio 70211, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, Kuopio 70029, Finland. [Voelker, Uwe] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany. [Deloukas, Panos] King Abdulaziz Univ, PACER HD, Jeddah 21589, Saudi Arabia. [van Duijn, Cornelia M.] Ctr Med Syst Biol, NL-2300 Leiden, Netherlands. [Groop, Leif C.] Univ Helsinki, Finnish Inst Mol Med FIMM, Helsinki 00014, Finland. [Heid, Iris M.] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Hunter, David J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Popualt Hlth, Bronx, NY 10461 USA. [McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [North, Kari E.] Univ North Carolina Chapel Hill, Dept Epidemiol, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Schlessinger, David] NIA, NIH, Bethesda, MD 20892 USA. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England. [Frayling, Timothy] Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England. [Hirschhorn, Joel N.] Broad Inst, Metab Initiat, Cambridge, MA 02142 USA. [Mueller-Nurasyid, Martina] Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Muller-Nurasyid, M (reprint author), Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.; Loos, RJF (reprint author), Univ Cambridge, Inst Metab Sci, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0QQ, England.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.; Muller-Nurasyid, M (reprint author), Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-81377 Munich, Germany.; Muller-Nurasyid, M (reprint author), DZHK German Ctr Cardiovasc Res, Partnersite Munich Heart Alliance, D-80802 Munich, Germany.; Muller-Nurasyid, M (reprint author), Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM ruth.loos@mssm.edu RI Sarzynski, Mark/A-9798-2014; Hicks, Andrew/E-9518-2017; Justesen, Johanne Marie/L-6023-2015; Wong, Andrew/M-8899-2016; Verweij, Niek/A-4499-2017; Colaus, PsyColaus/K-6607-2013; Grallert, Harald/B-3424-2013; Grarup, Niels/K-2807-2015; Bouchard, Claude/A-7637-2009; Palmer, Lyle/K-3196-2014; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; OI Hicks, Andrew/0000-0001-6320-0411; Justesen, Johanne Marie/0000-0002-0484-8522; Wong, Andrew/0000-0003-2079-4779; Grarup, Niels/0000-0001-5526-1070; Palmer, Lyle/0000-0002-1628-3055; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Linneberg, Allan/0000-0002-0994-0184; Peters, Annette/0000-0001-6645-0985; Lahti, Jari/0000-0002-4310-5297; Havulinna, Aki/0000-0002-4787-8959; Forouhi, Nita/0000-0002-5041-248X; Salvi, Erika/0000-0002-2724-2291; Vandenput, Liesbeth/0000-0002-1712-6131; Jorgensen, Torben/0000-0001-9453-2830; Medina-Gomez, Carolina/0000-0001-7999-5538; Pankow, James/0000-0001-7076-483X; de Geus, Eco/0000-0001-6022-2666 FU Medical Research Council [G0601261, MC_PC_U127561128, MC_UP_A620_1016, MC_UU_12011/3, MC_UU_12015/1, MC_UU_12019/1, MR/J012165/1]; NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [R01 HL117626]; NICHD NIH HHS [P2C HD050924]; NIDDK NIH HHS [P30 DK020541, P30 DK063491, U01 DK062370] NR 48 TC 0 Z9 0 U1 10 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 NOV 23 PY 2016 VL 7 AR 13357 DI 10.1038/ncomms13357 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC7LH UT WOS:000388319700001 PM 27876822 ER PT J AU Chia, CW Shardell, M Tanaka, T Liu, DD Gravenstein, KS Simonsick, EM Egan, JM Ferrucci, L AF Chia, Chee W. Shardell, Michelle Tanaka, Toshiko Liu, David D. Gravenstein, Kristofer S. Simonsick, Eleanor M. Egan, Josephine M. Ferrucci, Luigi TI Chronic Low-Calorie Sweetener Use and Risk of Abdominal Obesity among Older Adults: A Cohort Study SO PLOS ONE LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; DIET SODA INTAKE; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; BODY-WEIGHT; ARTIFICIAL SWEETENERS; BEVERAGE CONSUMPTION; CARDIOVASCULAR RISK; CAUSAL INFERENCE; FOOD-INTAKE AB Introduction Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. Participants and Methods We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0-28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and timevarying low-calorie sweetener use with longitudinal outcomes D body mass index, waist circumference, obesity and abdominal obesity D with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders. Results With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m(2) higher body mass index (95% confidence interval [CI], 0.17-1.44), 2.6 cm larger waist circumference (95% CI, 0.71 +/- 4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10 -1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10 - 2.12) of abdominal obesity than low-calorie sweetener non-users. Conclusions Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control. C1 [Chia, Chee W.; Shardell, Michelle; Tanaka, Toshiko; Liu, David D.; Gravenstein, Kristofer S.; Simonsick, Eleanor M.; Egan, Josephine M.; Ferrucci, Luigi] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Chia, CW (reprint author), NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM chiac@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging, Baltimore, Maryland, USA FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, Baltimore, Maryland, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, Baltimore, Maryland, USA. NR 45 TC 0 Z9 0 U1 19 U2 19 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 NOV 23 PY 2016 VL 11 IS 11 AR e0167241 DI 10.1371/journal.pone.0167241 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5KB UT WOS:000388889500081 PM 27880832 ER PT J AU Swaminathan, S Qiu, J Rupert, AW Hu, ZH Higgins, J Dewar, RL Stevens, R Rehm, CA Metcalf, JA Sherman, BT Baseler, MW Lane, HC Imamichi, T AF Swaminathan, Sanjay Qiu, Ju Rupert, Adam W. Hu, Zonghui Higgins, Jeanette Dewar, Robin L. Stevens, Randy Rehm, Catherine A. Metcalf, Julia A. Sherman, Brad T. Baseler, Michael W. Lane, H. Clifford Imamichi, Tomozumi TI Interleukin-15 (IL-15) Strongly Correlates with Increasing HIV-1 Viremia and Markers of Inflammation SO PLOS ONE LA English DT Article ID T-CELLS; INFECTION AB Objective IL-15 has been postulated to play an important role in HIV-1 infection, yet there are conflicting reports regarding its expression levels in these patients. We sought to measure the level of IL-15 in a large, well characterised cohort of HIV-1 infected patients and correlate this with well known markers of inflammation, including CRP, D-dimer, sCD163 and sCD14. Design and Methods IL-15 levels were measured in 501 people (460 patients with HIV-1 infection and 41 uninfected controls). The HIV-1 infected patients were divided into 4 groups based on viral load: < 50 copies/ml, 51 - 10,000 copies/ml, 10,001 - 100,000 copies/ml and > 100,000 copies/ml. The Mann Whitney test (non-parametric) was used to identify significant relationships between different patient groups. Results IL-15 levels were significantly higher in patients with viral loads > 100,000 copies/ml (3.02 +/- 1.53 pg/ml) compared to both uninfected controls (1.69 +/- 0.37 pg/ml, p< 0.001) or patients with a viral load < 50 copies/ml (1.59 +/- 0.40 pg/ml (p< 0.001). There was a significant correlation between HIV-1 viremia and IL-15 levels (Spearman r = 0.54, p< 0.001) and between CD4+ T cell counts and IL-15 levels (Spearman r =-0.56, p< 0.001). Conclusions IL-15 levels are significantly elevated in HIV-1 infected patients with viral loads > 100,000 copies/ml compared to uninfected controls, with a significant direct correlation noted between IL-15 and HIV-1 viremia and an inverse correlation between IL-15 levels and CD4+ T cell counts. These data support a potential role for IL-15 in the pathogenesis of HIV-associated immune activation. C1 [Swaminathan, Sanjay; Qiu, Ju; Rupert, Adam W.; Higgins, Jeanette; Dewar, Robin L.; Stevens, Randy; Sherman, Brad T.; Baseler, Michael W.; Imamichi, Tomozumi] Frederick Natl Lab Canc Res, Appl & Dev Res Directorate, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Swaminathan, Sanjay] Western Sydney Local Hlth Dist, Dept Clin Immunol, Sydney, NSW, Australia. [Swaminathan, Sanjay] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia. [Swaminathan, Sanjay] Univ Western Sydney, Sch Med, Sydney, NSW, Australia. [Hu, Zonghui] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rehm, Catherine A.; Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Metcalf, Julia A.; Lane, H. Clifford] NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), Frederick Natl Lab Canc Res, Appl & Dev Res Directorate, Leidos Biomed Res Inc, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Disease 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. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the National Institute of Allergy and Infectious Disease. NR 13 TC 0 Z9 0 U1 0 U2 0 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 NOV 23 PY 2016 VL 11 IS 11 AR e0167091 DI 10.1371/journal.pone.0167091 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5KB UT WOS:000388889500066 PM 27880829 ER PT J AU Yang, BY Shebl, FM Sternberg, LR Warner, AC Kleiner, DE Edelman, DC Gomez, A Dagnall, CL Hicks, BD Altekruse, SF Hernandez, BY Lynch, CF Meltzer, PS McGlynn, KA AF Yang, Baiyu Shebl, Fatma M. Sternberg, Lawrence R. Warner, Andrew C. Kleiner, David E. Edelman, Daniel C. Gomez, Allison Dagnall, Casey L. Hicks, Belynda D. Altekruse, Sean F. Hernandez, Brenda Y. Lynch, Charles F. Meltzer, Paul S. McGlynn, Katherine A. TI Telomere Length and Survival of Patients with Hepatocellular Carcinoma in the United States SO PLOS ONE LA English DT Article ID CHRONIC LIVER-DISEASE; HEPATITIS-VIRUS; TRANSARTERIAL CHEMOEMBOLIZATION; QUANTITATIVE PCR; LONG TELOMERES; CANCER; HEPATOCARCINOGENESIS; TISSUES; REACTIVATION; MAINTENANCE AB Background Telomere shortening is an important molecular event in hepatocellular carcinoma (HCC) initiation; however, its role in HCC progression and prognosis is less clear. Our study aimed to examine the association of telomere length with survival of patients with HCC. Methods We measured telomere length in tumor and adjacent non-tumor tissues from 126 persons with HCC in the United States (U.S.) who were followed for mortality outcomes. Relative telomere length (RTL) was measured by a monochrome multiplex quantitative polymerase chain reaction assay. Multivariable Cox proportional hazards modeling was used to calculate hazard ratios (HRs) and 95% CIs for the association between telomere length and allcause mortality. We also examined associations between telomere length and patient characteristics using multiple linear regression. Results During a mean follow-up of 6.0 years, 79 deaths occurred among 114 individuals for whom survival data were available. The ratio of RTL in tumor relative to non-tumor tissue was greater for individuals with regional or distant stage tumors (0.97) than localized stage tumors (0.77), and for individuals with grade III or IV tumors (0.95) than grade II (0.88) or grade I (0.67) tumors. An RTL ratio >= 1 was not associated with survival (HR 0.92, 95% CI 0.55, 1.55) compared to a ratio <1, after adjusting for age at diagnosis, sex, tumor stage and tumor size. Similarly, RTL in the tumor and non-tumor tissue, respectively, were not associated with survival. Conclusions This U.S. based study found that telomeres may be longer in more aggressive HCCs. There was no evidence, however, that telomere length was associated with survival of patients with HCC. Future investigations are warranted to clarify the role of telomere length in HCC prognosis. C1 [Yang, Baiyu; Dagnall, Casey L.; Hicks, Belynda D.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shebl, Fatma M.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Sternberg, Lawrence R.; Warner, Andrew C.] Frederick Natl Lab Canc Res, Pathol Histotechnol Lab, Frederick, MD 21701 USA. [Kleiner, David E.; Edelman, Daniel C.; Gomez, Allison; Meltzer, Paul S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Dagnall, Casey L.; Hicks, Belynda D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD 20892 USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hernandez, Brenda Y.] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Lynch, Charles F.] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. RP Yang, BY (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM baiyu.yang@nih.gov OI Dagnall, Casey/0000-0001-7334-4718 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 38 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 23 PY 2016 VL 11 IS 11 AR e0166828 DI 10.1371/journal.pone.0166828 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5KB UT WOS:000388889500036 PM 27880792 ER PT J AU Collins, FS Riley, WT AF Collins, Francis S. Riley, William T. TI NIH's transformative opportunities for the behavioral and social sciences SO Science Translational Medicine LA English DT Editorial Material C1 [Collins, Francis S.] US Natl Inst Hlth NIH, Bethesda, MD USA. [Riley, William T.] US NIH, Off Behav & Social Sci Res, Bethesda, MD 20191 USA. RP Riley, WT (reprint author), US NIH, Off Behav & Social Sci Res, Bethesda, MD 20191 USA. EM wiriley@mail.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD NOV 23 PY 2016 VL 8 IS 366 AR 366ed14 DI 10.1126/scitranslmed.aai9374 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XQ UT WOS:000389449400001 PM 27881821 ER PT J AU Dey, D Bagarova, J Hatsell, SJ Armstrong, KA Huang, L Ermann, J Vonner, AJ Shen, Y Mohedas, AH Lee, A Eekhoff, EMW van Schie, A Demay, MB Keller, C Wagers, AJ Economides, AN Yu, PB AF Dey, Devaveena Bagarova, Jana Hatsell, Sarah J. Armstrong, Kelli A. Huang, Lily Ermann, Joerg Vonner, Ashley J. Shen, Yue Mohedas, Agustin H. Lee, Arthur Eekhoff, Elisabeth M. W. van Schie, Annelies Demay, Marie B. Keller, Charles Wagers, Amy J. Economides, Aris N. Yu, Paul B. TI Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification SO Science Translational Medicine LA English DT Article ID SMOOTH-MUSCLE-CELLS; SKELETAL-MUSCLE; I RECEPTOR; NATURAL-HISTORY; TRANSGENIC MICE; BONE-FORMATION; PROGRESSIVA; MOUSE; ALK2; CONTRIBUTE AB Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1(R206H) knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx(+) tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1(+) population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1(R206H) in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1(R206H), expression of the man-made, ligand-independent ACVR1(Q207D) mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr(1R206H) knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment. C1 [Dey, Devaveena; Bagarova, Jana; Armstrong, Kelli A.; Vonner, Ashley J.; Shen, Yue; Mohedas, Agustin H.; Yu, Paul B.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Hatsell, Sarah J.; Huang, Lily; Economides, Aris N.] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. [Ermann, Joerg] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Dept Med, Boston, MA 02115 USA. [Lee, Arthur] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Eekhoff, Elisabeth M. W.; van Schie, Annelies] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med, Endocrine Sect, POB 7057, NL-1007 MB Amsterdam, Netherlands. [Eekhoff, Elisabeth M. W.; van Schie, Annelies] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, POB 7057, NL-1007 MB Amsterdam, Netherlands. [Demay, Marie B.] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, 55 Fruit St, Boston, MA 02114 USA. [Keller, Charles] Childrens Canc Therapy Dev Inst, 12655 SW Beaverdam Road West, Beaverton, OR 97005 USA. [Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Wagers, Amy J.] Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Boston, MA 02215 USA. [Economides, Aris N.] Regeneron Genet Ctr, Tarrytown, NY 10591 USA. RP Yu, PB (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM pbyu@partners.org OI Economides, Aris/0000-0002-6508-8942 FU US NIH [HL079943, AR057374, DK036836, HL100402]; Brigham and Women's Hospital Cardiovascular Division T32 [HL007604]; National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 Center for Skeletal Research Core [AR066261]; Department of Defense [MR140072]; Harvard Stem Cell Institute Seed Award; International FOP Association Competitive Grant Award; Harvard Stem Cell Institute; Pulmonary Hypertension Association Clinician Scientist Career Development Award; Leducq Foundation Transatlantic Network of Excellence Award; Howard Hughes Medical Institute Early Career Physician-Scientist Award; Massachusetts Technology Transfer Award FX This work was supported by the US NIH [HL079943 (to P.B.Y.), AR057374 (to P.B.Y.), DK036836 (to A.J.W.), and HL100402 (to A.J.W.)], Brigham and Women's Hospital Cardiovascular Division T32 [HL007604 (to D.D.)], National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 Center for Skeletal Research Core (AR066261), Department of Defense [MR140072 (to P.B.Y.)], Harvard Stem Cell Institute Seed Award (to P.B.Y.), International FOP Association Competitive Grant Award (to P.B.Y. and Y.S.), Harvard Stem Cell Institute funding for the Joslin Diabetes Center Flow Core Facility, Pulmonary Hypertension Association Clinician Scientist Career Development Award (to P.B.Y.), Leducq Foundation Transatlantic Network of Excellence Award (to P.B.Y.), Howard Hughes Medical Institute Early Career Physician-Scientist Award (to P.B.Y.), and Massachusetts Technology Transfer Award (to P.B.Y.). NR 60 TC 2 Z9 2 U1 5 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD NOV 23 PY 2016 VL 8 IS 366 AR 366ra163 DI 10.1126/scitranslmed.aaf1090 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XQ UT WOS:000389449400004 PM 27881824 ER PT J AU Iwanami, N Sikora, K Richter, AS Monnich, M Guerri, L Soza-Ried, C Lawir, DF Mateos, F Hess, I O'Meara, CP Schorpp, M Boehm, T AF Iwanami, Norimasa Sikora, Katarzyna Richter, Andreas S. Moennich, Maren Guerri, Lucia Soza-Ried, Cristian Lawir, Divine-Fondzenyuy Mateos, Fernando Hess, Isabell O'Meara, Connor P. Schorpp, Michael Boehm, Thomas TI Forward Genetic Screens in Zebrafish Identify Pre-mRNA-Processing Pathways Regulating Early T Cell Development SO CELL REPORTS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; DESIGN PRINCIPLES; RECYCLING FACTOR; NUCLEAR IMPORT; B-CELLS; EXPRESSION; PROTEIN; MODEL; HEMATOPOIESIS; COMPONENTS AB Lymphocytes represent basic components of vertebrate adaptive immune systems, suggesting the utility of non-mammalian models to define the molecular basis of their development and differentiation. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. The identification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication and/or repair pathways known from studies of immunocompromisedmammals provided an evolutionary cross-validation of the screen design. Unexpectedly, however, genes encoding proteins required for pre-mRNA processing were enriched in the collection of mutants identified here. In both zebrafish and mice, deficiency of the splice regulator TNPO3 impairs intrathymic T cell differentiation, illustrating the evolutionarily conserved and cell-type-specific functions of certain pre-mRNA-processing factors for T cell development. C1 [Iwanami, Norimasa; Sikora, Katarzyna; Moennich, Maren; Guerri, Lucia; Soza-Ried, Cristian; Lawir, Divine-Fondzenyuy; Mateos, Fernando; Hess, Isabell; O'Meara, Connor P.; Schorpp, Michael; Boehm, Thomas] Max Planck Inst Immunbiol & Epigenet, Dept Dev Immunol, Stubeweg 51, D-79108 Freiburg, Germany. [Sikora, Katarzyna; Richter, Andreas S.] Max Planck Inst Immunbiol & Epigenet, Bioinformat Unit, Stubeweg 51, D-79108 Freiburg, Germany. [Richter, Andreas S.] Genedata AG, CH-4053 Basel, Switzerland. [Moennich, Maren] Univ Copenhagen, Wilhelm Johannsen Ctr Funct Genome Res, Dept Cellular & Mol Med, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. [Guerri, Lucia] NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. [Soza-Ried, Cristian] Fdn Oncoloop, Antonio Varas 710, Santiago, Chile. [Soza-Ried, Cristian] Univ Andres Bellos, Fac Med, Republ 330, Santiago, Chile. RP Boehm, T (reprint author), Max Planck Inst Immunbiol & Epigenet, Dept Dev Immunol, Stubeweg 51, D-79108 Freiburg, Germany. EM boehm@immunbio.mpg.de OI Richter, Andreas S./0000-0002-4166-0991 FU Max Planck Society; European Research Council under the European Union's Seventh Framework Programme (FP7) ERC Grant [323126] FX This project has received funding from the Max Planck Society and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement 323126. The mutant screen was conducted in collaboration with the Tubingen 2000 Screen Consortium and the Freiburg Screening Group; their members are listed in Supplemental Experimental Procedures. We thank W. Wiest for initial identification of the WW18/10 mutant, B. Kanzler for help in the establishment of the mouse Tnpo3 mutant, D. Bonsch for excellent animal care, and U. Bonisch, E. Betancourt, and S. Diehl for help with next-generation sequencing. NR 41 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 22 PY 2016 VL 17 IS 9 BP 2259 EP 2270 DI 10.1016/j.celrep.2016.11.003 PG 12 WC Cell Biology SC Cell Biology GA EG2SE UT WOS:000390893600009 PM 27880902 ER PT J AU Kim, JW Yang, HJ Brooks, MJ Zelinger, L Karakulah, G Gotoh, N Boleda, A Gieser, L Giuste, F Whitaker, DT Walton, A Villasmil, R Barb, JJ Munson, PJ Kaya, KD Chaitankar, V Cogliati, T Swaroop, A AF Kim, Jung-Woong Yang, Hyun-Jin Brooks, Matthew John Zelinger, Lina Karakulah, Gokhan Gotoh, Norimoto Boleda, Alexis Gieser, Linn Giuste, Felipe Whitaker, Dustin Thad Walton, Ashley Villasmil, Rafael Barb, Jennifer Joanna Munson, Peter Jonathan Kaya, Koray Dogan Chaitankar, Vijender Cogliati, Tiziana Swaroop, Anand TI NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors SO CELL REPORTS LA English DT Article ID NUCLEAR RECEPTOR NR2E3; MOUSE RETINA; MAMMALIAN RETINA; INTRON RETENTION; CEREBRAL-CORTEX; LEUCINE-ZIPPER; BIPOLAR CELLS; IN-VITRO; EXPRESSION; DIFFERENTIATION AB Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. Given that the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone-like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal days 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously unannotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor. C1 [Kim, Jung-Woong; Yang, Hyun-Jin; Brooks, Matthew John; Zelinger, Lina; Karakulah, Gokhan; Gotoh, Norimoto; Boleda, Alexis; Gieser, Linn; Giuste, Felipe; Whitaker, Dustin Thad; Walton, Ashley; Kaya, Koray Dogan; Chaitankar, Vijender; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kim, Jung-Woong] Chung Ang Univ, Dept Life Sci, Seoul 06974, South Korea. [Gotoh, Norimoto] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto 6068501, Japan. [Whitaker, Dustin Thad] Texas A&M Univ, Texas A&M Inst Neurosci, College Stn, TX 77843 USA. [Villasmil, Rafael] NEI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Barb, Jennifer Joanna; Munson, Peter Jonathan] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Karakulah, Gokhan] Dokuz Eylul Univ, Izmir Int Biomed & Genome Inst, TR-35340 Inciralti, Turkey. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Karakulah, Gokhan/0000-0001-6706-1375 FU Intramural Research Program of the NEI [EY000450, EY000546]; National Research Foundation of Korea [2015R1C1A1A01055466, 2016R1A4A1008035] FX We thank Julie Laux of the NEI flow cytometry core for assistance. This research was supported by Intramural Research Program of the NEI (grants EY000450 and EY000546) and the National Research Foundation of Korea (grants 2015R1C1A1A01055466 and 2016R1A4A1008035) and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (https://hpc.nih.gov). NR 72 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 22 PY 2016 VL 17 IS 9 BP 2460 EP 2473 DI 10.1016/j.celrep.2016.10.074 PG 14 WC Cell Biology SC Cell Biology GA EG2SE UT WOS:000390893600024 PM 27880916 ER PT J AU Imashimizu, M Afek, A Takahashi, H Lubkowska, L Lukatsky, DB AF Imashimizu, Masahiko Afek, Ariel Takahashi, Hiroki Lubkowska, Lucyna Lukatsky, David B. TI Control of transcriptional pausing by biased thermal fluctuations on repetitive genomic sequences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE repetitive DNA sequence elements; nonconsensus protein-DNA binding; RNA polymerase; backtracking; thermal fluctuations ID RNA-POLYMERASE-II; PROTEIN-DNA BINDING; ESCHERICHIA-COLI; IN-VIVO; ANGSTROM RESOLUTION; STRUCTURAL BASIS; ELONGATION; BACKTRACKING; MECHANISM; TRANSLOCATION AB In the process of transcription elongation, RNA polymerase (RNAP) pauses at highly nonrandom positions across genomic DNA, broadly regulating transcription; however, molecular mechanisms responsible for the recognition of such pausing positions remain poorly understood. Here, using a combination of statistical mechanical modeling and high-throughput sequencing and biochemical data, we evaluate the effect of thermal fluctuations on the regulation of RNAP pausing. We demonstrate that diffusive backtracking of RNAP, which is biased by repetitive DNA sequence elements, causes transcriptional pausing. This effect stems from the increased microscopic heterogeneity of an elongation complex, and thus is entropydominated. This report shows a linkage between repetitive sequence elements encoded in the genome and regulation of RNAP pausing driven by thermal fluctuations. C1 [Imashimizu, Masahiko; Lubkowska, Lucyna] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Imashimizu, Masahiko; Takahashi, Hiroki] Chiba Univ, Med Mycol Res Ctr, Chuo Ku, 1-8-1 Inohana, Chiba 2608673, Japan. [Imashimizu, Masahiko] Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. [Afek, Ariel; Lukatsky, David B.] Ben Gurion Univ Negev, Dept Chem, IL-8410501 Beer Sheva, Israel. [Afek, Ariel] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Takahashi, Hiroki] Chiba Univ, Mol Chiral Res Ctr, Inage Ku, 1-33 Yayoi Cho, Chiba 2638522, Japan. RP Imashimizu, M (reprint author), NCI, Ctr Canc Res, Frederick, MD 21702 USA.; Imashimizu, M (reprint author), Chiba Univ, Med Mycol Res Ctr, Chuo Ku, 1-8-1 Inohana, Chiba 2608673, Japan.; Imashimizu, M (reprint author), Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan.; Lukatsky, DB (reprint author), Ben Gurion Univ Negev, Dept Chem, IL-8410501 Beer Sheva, Israel. EM imashi@ims.u-tokyo.ac.jp; lukatsky@bgu.ac.il FU Intramural Research Program of the NIH/National Cancer Institute; MEXT KAKENHI [16K18671, 16H06279]; Japan Society for the Promotion of Science KAKENHI [16H06692]; Integrated DNA Technologies postdoctoral fellowship FX We thank Mikhail Kashlev and Yoshikazu Nakamura for supporting our research and for helpful discussions, Nobuo Shimamoto and Donald L. Court for critical reading of the manuscript and for insightful comments, and Taku Oshima for helpful discussions regarding the PWM analysis. M.I. is also grateful to Nobuo Shimamoto for discussions regarding chemical kinetics. This work was supported by the Intramural Research Program of the NIH/National Cancer Institute (to Mikhail Kashlev), by MEXT KAKENHI Grants 16K18671 and 16H06279 (to H.T.), and by Japan Society for the Promotion of Science KAKENHI Grant 16H06692 (to M.I.). A. A. is supported by an Integrated DNA Technologies postdoctoral fellowship. NR 52 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 22 PY 2016 VL 113 IS 47 BP E7409 EP E7417 DI 10.1073/pnas.1607760113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4OY UT WOS:000388830700010 PM 27830653 ER PT J AU Yaffe, D Vergara-Jaque, A Forrest, LR Schuldiner, S AF Yaffe, Dana Vergara-Jaque, Ariela Forrest, Lucy R. Schuldiner, Shimon TI Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurotransmitter transporter; ion coupling; reserpine; tetrabenazine ID BOVINE CHROMAFFIN GRANULES; PROTEIN SECONDARY STRUCTURE; AMINE TRANSPORTER; NEUROTRANSMITTER TRANSPORTERS; RESERPINE BINDING; MEMBRANE-PROTEINS; CATECHOLAMINE TRANSPORTER; NONCOMPETITIVE INHIBITOR; SUBSTRATE RECOGNITION; FUCOSE TRANSPORTER AB Neurotransporters located in synaptic vesicles are essential for communication between nerve cells in a process mediated by neurotransmitters. Vesicular monoamine transporter (VMAT), a member of the largest superfamily of transporters, mediates transport of monoamines to synaptic vesicles and storage organelles in a process that involves exchange of two H+ per substrate. VMAT transport is inhibited by the competitive inhibitor reserpine, a second-line agent to treat hypertension, and by the noncompetitive inhibitor tetrabenazine, presently in use for symptomatic treatment of hyperkinetic disorders. During the transport cycle, VMAT is expected to occupy at least three different conformations: cytoplasm-facing, occluded, and lumen-facing. The lumen-to cytoplasm-facing transition, facilitated by protonation of at least one of the essential membrane-embedded carboxyls, generates a binding site for reserpine. Here we have identified residues in the cytoplasmic gate and show that mutations that disrupt the interactions in this gate also shift the equilibrium toward the cytoplasm-facing conformation, emulating the effect of protonation. These experiments provide significant insight into the role of proton translocation in the conformational dynamics of a mammalian H+-coupled antiporter, and also identify key aspects of the mode of action and binding of two potent inhibitors of VMAT2: reserpine binds the cytoplasm-facing conformation, and tetrabenazine binds the lumen-facing conformation. C1 [Yaffe, Dana; Schuldiner, Shimon] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. [Vergara-Jaque, Ariela; Forrest, Lucy R.] NINDS, Computat Struct Biol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Schuldiner, S (reprint author), Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. EM shimon.schuldiner@huji.ac.il OI Schuldiner, Shimon/0000-0002-4874-6237 FU National Institutes of Health Grant [NS16708]; Israel-USA Binational Science Foundation Grant [2013198]; Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH; L'Oreal Chile-UNESCO Women in Science Fellowship; L'Oreal-UNESCO Rising Talent Award FX We thank Dina Listov, Yifat Levine, and Shai Fainsod for help during the course of this work. S.S. is Mathilda Marks-Kennedy Professor of Biochemistry at the Hebrew University of Jerusalem. This research was supported by National Institutes of Health Grant NS16708 (to S.S.); Israel-USA Binational Science Foundation Grant 2013198 (to S.S.); and the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH (L.R.F. and A.V.-J.). A.V.-J. is a recipient of the L'Oreal Chile-UNESCO Women in Science Fellowship and the L'Oreal-UNESCO Rising Talent Award. NR 63 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 22 PY 2016 VL 113 IS 47 BP E7390 EP E7398 DI 10.1073/pnas.1605162113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4OY UT WOS:000388830700008 PM 27821772 ER PT J AU Murai, J Feng, Y Yu, GYK Ru, YB Tang, SW Shen, YQ Pommier, Y AF Murai, Junko Feng, Ying Yu, Guoying K. Ru, Yuanbin Tang, Sai-Wen Shen, Yuqiao Pommier, Yves TI Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition SO Oncotarget LA English DT Article DE PARP-trapping; ATR; PARP inhibitor; BRCA; homologous recombination ID DNA-REPLICATION INITIATION; CELL LUNG-CANCER; BMN 673; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; MOLECULAR PATHWAYS; DRUG-SENSITIVITY; DAMAGING AGENTS; REPAIR; COMBINATION AB Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (similar to 45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs. C1 [Murai, Junko; Tang, Sai-Wen; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Murai, Junko; Tang, Sai-Wen; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Feng, Ying; Yu, Guoying K.; Ru, Yuanbin; Shen, Yuqiao] BioMarin Pharmaceut Inc, Novato, CA USA. [Tang, Sai-Wen] Stanford Univ, Dept Med, Sch Med, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural Program, Center for Cancer Research, of the National Cancer Institute, NIH [BC006150] FX Our studies are supported by the Intramural Program, Center for Cancer Research, of the National Cancer Institute, NIH (BC006150). NR 57 TC 2 Z9 2 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 76534 EP 76550 DI 10.18632/oncotarget.12266 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400016 PM 27708213 ER PT J AU Kwon, M Kim, JH Rybak, Y Luna, A Choi, CH Chung, JY Hewitt, SM Adem, A Tubridy, E Lin, J Libutti, SK AF Kwon, Mijung Kim, Jae-Hoon Rybak, Yevangelina Luna, Alex Choi, Chel Hun Chung, Joon-Yong Hewitt, Stephen M. Adem, Asha Tubridy, Elizabeth Lin, Juan Libutti, Steven K. TI Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer SO Oncotarget LA English DT Article DE ovarian cancer; prognosis; metastasis; chemoresistance; WNT ID EPITHELIAL-MESENCHYMAL TRANSITION; INTERACTING PROTEIN 1-LIKE; BETA-CATENIN; CERVICAL-CANCER; PROGNOSTIC-SIGNIFICANCE; PHENOTYPIC PLASTICITY; COLORECTAL-CANCER; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; DOWN-REGULATION AB Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/beta-catenin signaling and its downstream pathway, epithelial-to- mesenchymal transition (EMT), play a key role in ovarian cancer metastasis and chemoresistance. To study the clinical implications of FILIP1L in regulating the WNT/beta-catenin pathway, the expression of FILIP1L, beta-catenin, SNAIL and SLUG was analyzed by immunohistochemistry on tissue microarrays of 369 ovarian samples ranging from normal to metastatic. In addition, the results were validated in mouse model and in vitro cell culture. In the present study, we demonstrated that FILIP1L expression was inversely correlated with poor prognosis, stage and chemoresistance in ovarian cancer. Notably, low FILIP1L expression was independent negative prognostic factor with respect to overall and disease-free survival. FILIP1L inhibited peritoneal metastases in orthotopic mouse model. FILIP1L knockdown induced chemoresistance in ovarian cancer cells and this phenotype was rescued by simultaneous knockdown of FILIP1L and SLUG, an EMT activator. We also demonstrated that FILIP1L regulates beta-catenin degradation. FILIP1L co-localizes with phospho-beta-catenin and increases phospho-beta-catenin at the centrosomes, destined for proteosomal degradation. Finally, we showed that FILIP1L regulates EMT. Overall, these findings suggest that FILIP1L promotes beta-catenin degradation and suppresses EMT, thereby inhibiting metastases and chemoresistance. Our study provides the first clinical relevance of FILIP1L in human cancer, and suggests that FILIP1L may be a novel prognostic marker for chemotherapy in ovarian cancer patients. Further, the modulation of FILIP1L expression may have the potential to be a target for cancer therapy. C1 [Kwon, Mijung; Rybak, Yevangelina; Luna, Alex; Adem, Asha; Tubridy, Elizabeth; Libutti, Steven K.] Albert Einstein Coll Med, Dept Surg, Bronx, NY 10461 USA. [Lin, Juan] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Div Biostat, Bronx, NY 10461 USA. [Kim, Jae-Hoon] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Kim, Jae-Hoon] Yonsei Univ, Coll Med, Inst Womens Life Med Sci, Seoul 135720, South Korea. [Choi, Chel Hun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135710, South Korea. [Choi, Chel Hun; Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Kwon, M; Libutti, SK (reprint author), Albert Einstein Coll Med, Dept Surg, Bronx, NY 10461 USA. EM mijung.kwon@einstein.yu.edu; slibutti@montefiore.org OI Chung, Joon-Yong/0000-0001-5041-5982 FU Office of the Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer Research Program [W81XWH-15-1-0369]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer Research Program under Award No. W81XWH-15-1-0369. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 82 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 77052 EP 77070 DI 10.18632/oncotarget.12784 PG 19 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400058 PM 27776341 ER PT J AU Maachani, UB Shankavaram, U Kramp, T Tofilon, PJ Camphausen, K Tandle, AT AF Maachani, Uday B. Shankavaram, Uma Kramp, Tamalee Tofilon, Philip J. Camphausen, Kevin Tandle, Anita T. TI FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells SO Oncotarget LA English DT Article DE glioblastoma multiforme; FOXM1; STAT3; glioma stem cells; radio resistance ID FORKHEAD BOX M1; TUMOR STEM-CELLS; DNA-DAMAGE; TRANSCRIPTION FACTOR; ANTICANCER THERAPY; GLIOMA-CELLS; CANCER; REPAIR; EXPRESSION; SURVIVAL AB Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo. Moreover, we observed high expression of Forkhead box protein M1 (FOXM1) in irradiated GBM cells both in vitro and in vivo. Recent evidence of FOXM1 as a master regulator of metastasis and its important role in maintaining neural, progenitor, and GBM stem cells, intrigued us to validate it as a radiosensitizing target. Here we show that FOXM1 inhibition radiosensitizes GBM cells by abrogating genes associated with cell cycle progression and DNA repair, suggesting its role in cellular response to radiation. Further, we demonstrate that radiation induced stimulation of FOXM1 expression is dependent on STAT3 activation. Co-immunoprecipitation and co-localization assays revealed physical interaction of FOXM1 with phosphorylated STAT3 under radiation treatment. In conclusion, we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Collectively our observations might open novel opportunities for targeting FOXM1 for effective GBM therapy. C1 [Maachani, Uday B.; Shankavaram, Uma; Kramp, Tamalee; Tofilon, Philip J.; Camphausen, Kevin; Tandle, Anita T.] NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tandle, AT (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tandlea@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 45 TC 1 Z9 1 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 77365 EP 77377 DI 10.18632/oncotarget.12670 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400084 PM 27764801 ER PT J AU Zhang, SH He, L Dai, N Guan, W Shan, JL Yang, XQ Zhong, ZY Qing, Y Jin, F Chen, C Yang, YX Wang, HY Baugh, L Tell, G Wilson, DM Li, MX Wang, D AF Zhang, Shiheng He, Le Dai, Nan Guan, Wei Shan, Jinlu Yang, Xueqin Zhong, Zhaoyang Qing, Yi Jin, Feng Chen, Chuan Yang, Yuxin Wang, Hongyi Baugh, Laura Tell, Gianluca Wilson, David M., III Li, Mengxia Wang, Dong TI Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients SO Oncotarget LA English DT Article DE APE1; NSCLC; chemotherapy; biomarker ID DNA-REPAIR; BREAST-CANCER; P53 PROTEIN; APE1/REF-1; ANTIBODIES; EXPRESSION; BIOMARKER; ERCC1 AB Purpose: To define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy. Results: Our investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r(2) = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010). Experimental Design: We measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control. Conclusions: Our studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naIve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival. C1 [Zhang, Shiheng; He, Le; Dai, Nan; Guan, Wei; Shan, Jinlu; Yang, Xueqin; Zhong, Zhaoyang; Qing, Yi; Jin, Feng; Chen, Chuan; Yang, Yuxin; Li, Mengxia; Wang, Dong] Third Mil Med Univ, Daping Hosp, Inst Surg Res, Canc Ctr, Chongqing 400042, Peoples R China. [Tell, Gianluca] Univ Udine, Dept Med & Biol Sci, Lab Mol Biol & DNA Repair, I-33100 Udine, Italy. [Wilson, David M., III] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Hongyi; Baugh, Laura] Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX 75246 USA. Tianjin HUABOTE Biotechnol Inc, Tianjin 300350, Peoples R China. RP Li, MX; Wang, D (reprint author), Third Mil Med Univ, Daping Hosp, Inst Surg Res, Canc Ctr, Chongqing 400042, Peoples R China. EM mengxia.li@outlook.com; dongwang64@hotmail.com FU Translational Research Grant from Third Military Medical University [2013XZH01]; Health Care Grant from Health Department of General Logistics Department [ZHBJ201465]; Intramural Research Program of the NIH, National Institute on Aging; Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG14038, IG18400] FX This work was supported by Translational Research Grant from Third Military Medical University [2013XZH01] and Health Care Grant from Health Department of General Logistics Department [ZHBJ201465] to Dr. Dong Wang. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging to Dr. David Wilson III. This research was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC) to Prof Gianluca Tell (grants # IG14038 and IG18400). NR 25 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 77482 EP 77494 DI 10.18632/oncotarget.13030 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400093 PM 27813497 ER PT J AU Cook, MB Drahos, J Wood, S Enewold, L Parsons, R Freedman, ND Taylor, PR Ricker, W Abnet, CC AF Cook, Michael B. Drahos, Jennifer Wood, Shannon Enewold, Lindsey Parsons, Ruth Freedman, Neal D. Taylor, Philip R. Ricker, Winnie Abnet, Christian C. TI Pathogenesis and progression of oesophageal adenocarcinoma varies by prior diagnosis of Barrett's oesophagus SO BRITISH JOURNAL OF CANCER LA English DT Article DE Barrett oesophagus; oesophageal neoplasms; Medicare; SEER program ID CANCER; REFLUX; SENSITIVITY; ENDOSCOPY; SURVIVAL; TIME AB Background: The absolute risk of oesophageal adenocarcinoma (EA) among individuals with Barrett's oesophagus (BE) is low and a majority of EA cases are diagnosed among individuals with no prior BE diagnosis. To ensure that insights from EA case-control studies are transferable to clinical management of BE populations, we conducted a case-case study to compare the clinical presentation, medical history and survival of EA cases with and without a prior BE diagnosis in the Surveillance, Epidemiology and End Results Medicare database. Methods: Eligible EA cases were diagnosed at age >= 68 years during 1994-2009. There were 5271 EA cases in this study, 87% of which did not have a prior diagnosis of BE (EA-no prior BE). Results: Multivariable case-case comparisons evidenced adverse associations of GERD, ever cigarette smoking, hypertension, dyslipidemia, weight loss, peptic ulcer and irritable bowel disease each in EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose and diabetes did not differ between groups. EA-prior BE cases were diagnosed with less advanced disease, were more likely to undergo surgery and less likely to receive chemotherapy and radiotherapy, and had better overall mean survival (2.5 vs 1.4 years). This survival advantage persisted in the multivariable Cox model (HR = 0.69, 95% CI: 0.60, 0.78), despite adjustment for many factors including stage, grade and clinical interventions. Conclusions: This study provides evidence that EA cases occurring among individuals previously diagnosed with BE are different from the large majority of EA cases that occur without a prior BE diagnosis. Regardless of whether these differences emanate from aetiology, biology and/or selection biases, they underscore the importance of a prudent approach in using knowledge from EAC case-control studies in the management of BE populations. C1 [Cook, Michael B.; Drahos, Jennifer; Wood, Shannon; Freedman, Neal D.; Taylor, Philip R.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20850 USA. [Enewold, Lindsey] NCI, Div Canc Control & Populat Sci, NIH, DHHS, Rockville, MD 20850 USA. [Parsons, Ruth; Ricker, Winnie] Informat Management Serv Inc, Rockville, MD 20852 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20850 USA. EM michael.cook@nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 18 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 22 PY 2016 VL 115 IS 11 BP 1383 EP 1390 DI 10.1038/bjc.2016.344 PG 8 WC Oncology SC Oncology GA ED2ZP UT WOS:000388719100016 PM 27780192 ER PT J AU Bjorge, T Gissler, M Ording, AG Engeland, A Glimelius, I Leinonen, M Sorensen, HT Tretli, S Ekbom, A Troisi, R Grotmol, T AF Bjorge, Tone Gissler, Mika Ording, Anne Gulbech Engeland, Anders Glimelius, Ingrid Leinonen, Maarit Sorensen, Henrik Toft Tretli, Steinar Ekbom, Anders Troisi, Rebecca Grotmol, Tom TI Reproductive history and risk of colorectal adenocarcinoma in parous women: a Nordic population-based case-control study SO BRITISH JOURNAL OF CANCER LA English DT Article DE colorectal cancer; reproductive history; case-control study; Nordic countries ID CANCER-RISK; COLON-CANCER; POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES; QUALITY-CONTROL; METAANALYSIS; REGISTRY; COMPLETENESS; ASPIRIN; BETA AB Background: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history. Methods: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders. Results: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found. Conclusions: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women. C1 [Bjorge, Tone; Engeland, Anders] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Bjorge, Tone; Tretli, Steinar; Grotmol, Tom] Canc Registry Norway, Oslo, Norway. [Gissler, Mika] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Ording, Anne Gulbech; Sorensen, Henrik Toft] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. [Engeland, Anders] Norwegian Inst Publ Hlth, Dept Pharmacoepidemiol, Div Mental & Phys Hlth, Bergen, Norway. [Glimelius, Ingrid; Ekbom, Anders] Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden. [Glimelius, Ingrid; Ekbom, Anders] Karolinska Univ Hosp, Stockholm, Sweden. [Glimelius, Ingrid] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Leinonen, Maarit] Finnish Canc Registry, Canc Soc Finland, Helsinki, Finland. [Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Bjorge, T (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.; Bjorge, T (reprint author), Canc Registry Norway, Oslo, Norway. EM Tone.Bjorge@uib.no OI Glimelius, Ingrid/0000-0001-6158-3041 FU Nordic Cancer Union; Program for Clinical Research Infrastructure (PROCRIN); Novo Nordisk Foundation; Danish Cancer Society; Svenska Sallskapet for Medicinsk Forskning (SSMF); Svenska Lakarsallskapet; U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This study was supported by the Nordic Cancer Union, Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation, Danish Cancer Society, Svenska Sallskapet for Medicinsk Forskning (SSMF), Svenska Lakarsallskapet, and the U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 38 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 22 PY 2016 VL 115 IS 11 BP 1416 EP 1420 DI 10.1038/bjc.2016.315 PG 5 WC Oncology SC Oncology GA ED2ZP UT WOS:000388719100020 PM 27701386 ER PT J AU Yang, ZH Emma-Okon, B Remaley, AT AF Yang, Zhi-Hong Emma-Okon, Beatrice Remaley, Alan T. TI Dietary marine-derived long-chain monounsaturated fatty acids and cardiovascular disease risk: a mini review SO LIPIDS IN HEALTH AND DISEASE LA English DT Review DE Long-chain monounsaturated fatty acids; Cardiovascular disease; Atherosclerosis; Peroxisome proliferator-activated receptor signaling pathway; Inflammation ID E-DEFICIENT MICE; SEAL OIL; EICOSAPENTAENOIC ACID; METABOLICALLY HEALTHY; LIPID-COMPOSITION; PARAOXONASE 1; LIVER LIPIDS; PPAR-GAMMA; FISH-OIL; PLASMA AB Regular fish/fish oil consumption is widely recommended for protection against cardiovascular diseases (CVD). Fish and other marine life are rich sources of the cardioprotective long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (C20:5 n-3; EPA) and docosahexaenoic acid (C22:6 n-3; DHA). The lipid content and fatty acid profile of fish, however, vary greatly among different fish species. In addition to n-3 PUFA, certain fish, such as saury, pollock, and herring, also contain high levels of long-chain monounsaturated fatty acids (LCMUFA), with aliphatic tails longer than 18 C atoms (i.e., C20:1 and C22:1 isomers). Compared with well-studied n-3 PUFA, limited information, however, is available on the health benefits of marine-derived LCMUFA, particularly in regard to CVD. Our objective in this review is to summarize the current knowledge and provide perspective on the potential therapeutic value of dietary LCMUFA-rich marine oil for improving CVD risk factors. We will also review the possible mechanisms of LCMUFA action on target tissues. Finally, we describe the epidemiologic data and small-scaled clinical studies that have been done on marine oils enriched in LCMUFA. Although there are still many unanswered questions about LCMUFA, this appears to be promising new area of research that may lead to new insights into the health benefits of a different component of fish oils besides n-3 PUFA. C1 [Yang, Zhi-Hong; Emma-Okon, Beatrice; Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yang, Zhi-Hong] Nippon Suisan Kaisha, Tokyo Innovat Ctr, Cent Res Lab, 32-3 Nanakuni 1 Chome Hachioji, Tokyo 1920991, Japan. RP Remaley, AT (reprint author), NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM aremaley1@nhlbi.nih.gov FU Intramural Research Program of the National Heart, Lung and Blood Institute (NHLBI); Office of Dietary Supplements (ODS) Research Scholars Program at National Institutes of Health FX The authors acknowledge financial support by the Intramural Research Program of the National Heart, Lung and Blood Institute (NHLBI) and the Office of Dietary Supplements (ODS) Research Scholars Program at National Institutes of Health. NR 75 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD NOV 22 PY 2016 VL 15 AR 201 DI 10.1186/s12944-016-0366-5 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA ED3TB UT WOS:000388770300001 PM 27876051 ER PT J AU Bang, A Patel, A Bellad, R Gisore, P Goudar, SS Esamai, F Liechty, EA Meleth, S Goco, N Niermeyer, S Keenan, W Kamath-Rayne, BD Little, GA Clarke, SB Flanagan, VA Bucher, S Jain, M Mujawar, N Jain, V Rukunga, J Mahantshetti, N Dhaded, S Bhandankar, M McClure, EM Carlo, WA Wright, LL Hibberd, PL AF Bang, Akash Patel, Archana Bellad, Roopa Gisore, Peter Goudar, Shivaprasad S. Esamai, Fabian Liechty, Edward A. Meleth, Sreelatha Goco, Norman Niermeyer, Susan Keenan, William Kamath-Rayne, Beena D. Little, George A. Clarke, Susan B. Flanagan, Victoria A. Bucher, Sherri Jain, Manish Mujawar, Nilofer Jain, Vinita Rukunga, Janet Mahantshetti, Niranjana Dhaded, Sangappa Bhandankar, Manisha McClure, Elizabeth M. Carlo, Waldemar A. Wright, Linda L. Hibberd, Patricia L. TI Helping Babies Breathe (HBB) training: What happens to knowledge and skills over time? SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Helping Babies Breathe; Resuscitation; Bag and mask ventilation; Perinatal mortality; Asphyxia; Stillbirth; Training ID EMERGENCY CARDIOVASCULAR CARE; NEONATAL RESUSCITATION; CARDIOPULMONARY-RESUSCITATION; NEWBORN MORTALITY; SAVE LIVES; SCALE-UP; COUNTRIES; DEATHS; PERFORMANCE; STILLBIRTH AB Background: The first minutes after birth are critical to reducing neonatal mortality. Helping Babies Breathe (HBB) is a simulation-based neonatal resuscitation program for low resource settings. We studied the impact of initial HBB training followed by refresher training on the knowledge and skills of the birth attendants in facilities. Methods: We conducted HBB trainings in 71 facilities in the NICHD Global Network research sites (Nagpur and Belgaum, India and Eldoret, Kenya), with a 6: 1 ratio of facility trainees to Master Trainers (MT). Because of staff turnover, some birth attendants (BA) were trained as they joined the delivery room staff, after the initial training was completed (catch-up initial training). We compared pass rates for skills and knowledge pre- and post-initial HBB training and following refresher training among active BAs. An Objective Structured Clinical Examination (OSCE) B tested resuscitation skill retention by comparing post-initial training performance with pre-refresher training performance. We identified factors associated with loss of skills in pre-refresher training performance using multivariable logistic regression analysis. Daily bag and mask ventilation practice, equipment checks and supportive supervision were stressed as part of training. Results: One hundred five MT (1.6 MT per facility) conducted initial and refresher HBB trainings for 835 BAs; 76% had no prior resuscitation training. Initial training improved knowledge and skills: the pass percentage for knowledge tests improved from 74 to 99% (p < 0.001). Only 5% could ventilate a newborn mannequin correctly before initial training but 97% passed the post-initial ventilation training test (p < 0.0001) and 99% passed the OSCE B resuscitation evaluation. During pre-refresher training evaluation, a mean of 6.7 (SD 2.49) months after the initial training, 99% passed the knowledge test, but the successful completion rate fell to 81% for the OSCE B resuscitation skills test. Characteristics associated with deterioration of resuscitation skills were BAs from tertiary care facilities, no prior resuscitation training, and the timing of training (initial vs. catch-up training). Conclusions: HBB training significantly improved neonatal resuscitation knowledge and skills. However, skills declined more than knowledge over time. Ongoing skills practice and monitoring, more frequent retesting, and refresher trainings are needed to maintain neonatal resuscitation skills. C1 [Bang, Akash; Jain, Manish] Mahatma Gandhi Inst Med Sci, Sevagram, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Bellad, Roopa; Goudar, Shivaprasad S.; Mahantshetti, Niranjana; Dhaded, Sangappa; Bhandankar, Manisha] KLE Univ, JN Med Coll, Belgaum, India. [Gisore, Peter; Esamai, Fabian; Rukunga, Janet] Moi Univ, Moi Teaching & Referral Hosp, Eldoret, Kenya. [Liechty, Edward A.; Bucher, Sherri] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Meleth, Sreelatha; Goco, Norman; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Niermeyer, Susan] Univ Colorado, Sch Med, Aurora, CO USA. [Keenan, William] St Louis Univ, St Louis, MO 63103 USA. [Kamath-Rayne, Beena D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Little, George A.; Flanagan, Victoria A.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Clarke, Susan B.] Childrens Hosp Colorado, Aurora, CO USA. [Mujawar, Nilofer] NKP Salve Inst Med Sci, Nagpur, Maharashtra, India. [Jain, Vinita] Daga Mem Govt Womens Hosp, Nagpur, Maharashtra, India. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Wright, Linda L.] George Washington Univ, 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wright, LL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA.; Wright, LL (reprint author), George Washington Univ, 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. EM lindawright.md@gmail.com FU Laerdal Foundation; Norwegian Agency for Development Cooperation (Norad); NICHD [U01 HD040636, U01 HD058322, U10 HD078439, HD U01058326, U01 HD058326-04S1, U10 HD076461, U01 HD042372, U10 HD076457] FX This study was funded with grants from the Laerdal Foundation, Norwegian Agency for Development Cooperation (Norad), and the NICHD (grant numbers U01 HD040636; U01 HD058322 and U10 HD078439; HD U01058326; U01 HD058326-04S1, U10 HD076461, U01 HD042372, U10 HD076457). NR 33 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD NOV 22 PY 2016 VL 16 AR 364 DI 10.1186/s12884-016-1141-3 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EC8XU UT WOS:000388427200002 PM 27875999 ER PT J AU Kavousi, M Desai, CS Ayers, C Blumenthal, RS Budoff, MJ Mahabadi, AA Ikram, MA van der Lugt, A Hofman, A Erbel, R Khera, A Geisel, MH Jockel, KH Lehmann, N Hoffmann, U O'Donnell, CJ Massaro, JM Liu, K Mohlenkamp, S Ning, HY Franco, OH Greenland, P AF Kavousi, Maryam Desai, Chintan S. Ayers, Colby Blumenthal, Roger S. Budoff, Matthew J. Mahabadi, Amir-Abbas Ikram, M. Arfan van der Lugt, Aad Hofman, Albert Erbel, Raimund Khera, Amit Geisel, Marie H. Joeckel, Karl-Heinz Lehmann, Nils Hoffmann, Udo O'Donnell, Christopher J. Massaro, Joseph M. Liu, Kiang Moehlenkamp, Stefan Ning, Hongyan Franco, Oscar H. Greenland, Philip TI Prevalence and Prognostic Implications of Coronary Artery Calcification in Low-Risk Women A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEART-DISEASE; CARDIOVASCULAR-DISEASE; STATIN THERAPY; CALCIUM SCORE; PREDICTION; DESIGN; CLASSIFICATION; INDIVIDUALS; PREVENTION; MARKERS AB IMPORTANCE The role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear. OBJECTIVE To assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women. DESIGN, SETTING, AND PARTICIPANTS Women with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies. EXPOSURES CAC score by computed tomography. MAIN OUTCOMES AND MEASURES Main outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated. RESULTS Among 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC > 0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction. CONCLUSIONS AND RELEVANCE Among women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy. C1 [Kavousi, Maryam; Ikram, M. Arfan; Hofman, Albert; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, Off Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands. [Desai, Chintan S.; Blumenthal, Roger S.] Johns Hopkins Med Inst, Div Cardiol, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21205 USA. [Ayers, Colby] Univ Texas Southwestern Med Ctr Dallas, Div Clin Sci, Dallas, TX 75390 USA. [Budoff, Matthew J.] Harbor Univ Calif Los Angeles Med Ctr, Los Angeles Biomed Res Inst, Div Cardiol, Los Angeles, CA USA. [Mahabadi, Amir-Abbas] Univ Clin Essen, West German Heart & Vasc Ctr, Dept Cardiol, Essen, Germany. [Ikram, M. Arfan; van der Lugt, Aad] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Erbel, Raimund; Geisel, Marie H.; Joeckel, Karl-Heinz; Lehmann, Nils] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Khera, Amit] Univ Texas Southwestern Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Med Sch, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [O'Donnell, Christopher J.; Massaro, Joseph M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liu, Kiang; Ning, Hongyan; Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Moehlenkamp, Stefan] Krankenhaus Bethanien, Dept Cardiol, Moers, Germany. RP Kavousi, M (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Off Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM m.kavousi@erasmusmc.nl FU NCATS NIH HHS [UL1 TR000040, UL1 TR001105]; NHLBI NIH HHS [R01 HL076784, N01 HC025195, R01 HL060040, R01 HL070100, R01 HL071039, R01 HL077447, R01 HL080124, R01 HL107385]; NIA NIH HHS [R01 AG028321] NR 34 TC 1 Z9 1 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 22 PY 2016 VL 316 IS 20 BP 2126 EP 2134 DI 10.1001/jama.2016.17020 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA ED1XD UT WOS:000388637300020 PM 27846641 ER PT J AU Cook, PR Tabor, GT AF Cook, Pamela R. Tabor, G. Travis TI Deciphering fact from artifact when using reporter assays to investigate the roles of host factors on L1 retrotransposition SO MOBILE DNA LA English DT Article DE L1; LINE-1; Reporter; Host factor; p38; HSV-TK; SV40; Promoter; Renilla ID MAP KINASE ISOFORMS; GENE-EXPRESSION; SOMATIC RETROTRANSPOSITION; CYTOMEGALOVIRUS PROMOTER; ALU RETROTRANSPOSITION; TRANSPOSABLE ELEMENTS; SELECTIVE ACTIVATION; RENILLA LUCIFERASE; NERVOUS-SYSTEM; CANCER-THERAPY AB Background: The Long INterspersed Element-1 (L1, LINE-1) is the only autonomous mobile DNA element in humans and has generated as much as half of the genome. Due to increasing clinical interest in the roles of L1 in cancer, embryogenesis and neuronal development, it has become a priority to understand L1-host interactions and identify host factors required for its activity. Apropos to this, we recently reported that L1 retrotransposition in HeLa cells requires phosphorylation of the L1 protein ORF1p at motifs targeted by host cell proline-directed protein kinases (PDPKs), which include the family of mitogen-activated protein kinases (MAPKs). Using two engineered L1 reporter assays, we continued our investigation into the roles of MAPKs in L1 activity. Results: We found that the MAPK p38 delta phosphorylated ORF1p on three of its four PDPK motifs required for L1 activity. In addition, we found that a constitutively active p38d mutant appeared to promote L1 retrotransposition in HeLa cells. However, despite the consistency of these findings with our earlier work, we identified some technical concerns regarding the experimental methodology. Specifically, we found that exogenous expression of p38d appeared to affect at least one heterologous promoter in an engineered L1 reporter, as well as generate opposing effects on two different reporters. We also show that two commercially available non-targeting control (NTC) siRNAs elicit drastically different effects on the apparent retrotransposition reported by both L1 assays, which raises concerns about the use of NTCs as normalizing controls. Conclusions: Engineered L1 reporter assays have been invaluable for determining the functions and critical residues of L1 open reading frames, as well as elucidating many aspects of L1 replication. However, our results suggest that caution is required when interpreting data obtained from L1 reporters used in conjunction with exogenous gene expression or siRNA. C1 [Cook, Pamela R.] NIDDK, Lab Cell & Mol Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. [Tabor, G. Travis] NICHHD, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. RP Cook, PR (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM pamela.cook@nih.gov FU laboratory of Anthony V. Furano at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [1-ZIA-DK057601-19] FX This work was supported by the laboratory of Anthony V. Furano at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Grant 1-ZIA-DK057601-19. NR 95 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1759-8753 J9 MOBILE DNA-UK JI Mob. DNA PD NOV 22 PY 2016 VL 7 AR 23 DI 10.1186/s13100-016-0079-3 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA ED0CP UT WOS:000388510900001 PM 27895722 ER PT J AU Lam, KH Li, Y Li, Y Lim, HG Zhou, QF Shung, KK AF Lam, Kwok Ho Li, Ying Li, Yang Lim, Hae Gyun Zhou, Qifa Shung, Koping Kirk TI Multifunctional single beam acoustic tweezer for non-invasive cell/organism manipulation and tissue imaging SO SCIENTIFIC REPORTS LA English DT Article ID ULTRASONIC TRANSDUCERS; CELLS; FORCE AB Non-contact precise manipulation of single microparticles, cells, and organisms has attracted considerable interest in biophysics and biomedical engineering. Similar to optical tweezers, acoustic tweezers have been proposed to be capable of manipulating microparticles and even cells. Although there have been concerted efforts to develop tools for non-contact manipulation, no alternative to complex, unifunctional tweezer has yet been found. Here we report a simple, low-cost, multifunctional single beam acoustic tweezer (SBAT) that is capable of manipulating an individual micrometer scale non-spherical cell at Rayleigh regime and even a single millimeter scale organism at Mie regime, and imaging tissue as well. We experimentally demonstrate that the SBAT with an ultralow f-number (f# = focal length/aperture size) could manipulate an individual red blood cell and a single 1.6 mm-diameter fertilized Zebrafish egg, respectively. Besides, in vitro rat aorta images were collected successfully at dynamic foci in which the lumen and the outer surface of the aorta could be clearly seen. With the ultralow f-number, the SBAT offers the combination of large acoustic radiation force and narrow beam width, leading to strong trapping and high-resolution imaging capabilities. These attributes enable the feasibility of using a single acoustic device to perform non-invasive multi-functions simultaneously for biomedical and biophysical applications. C1 [Lam, Kwok Ho] Hong Kong Polytech Univ, Dept Elect Engn, Hong Kong, Hong Kong, Peoples R China. [Li, Ying; Li, Yang; Lim, Hae Gyun; Zhou, Qifa; Shung, Koping Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Li, Ying; Li, Yang; Lim, Hae Gyun; Zhou, Qifa; Shung, Koping Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Lam, KH (reprint author), Hong Kong Polytech Univ, Dept Elect Engn, Hong Kong, Hong Kong, Peoples R China. EM kokokh.lam@polyu.edu.hk RI Lam, K.H./B-7765-2014 OI Lam, K.H./0000-0003-1456-9049 FU Hong Kong Research Grants Council (ECS Grant) [253001/14 P]; Hong Kong Polytechnic University [4-ZZDC, 1-ZVCG, G-YBLM]; NIH [R01-EB12058, P41-EB02182] FX We thank Young-Kwon Hong for providing the rat aorta tissue sample; and Yao-Sheng Tung for developing the imaging software. K.H.L. acknowledges support from the Hong Kong Research Grants Council (ECS Grant No. 253001/14 P) and The Hong Kong Polytechnic University (Grant Nos 4-ZZDC, 1-ZVCG, and G-YBLM). K.K.S. acknowledges support from NIH Grant Nos R01-EB12058 and P41-EB02182. NR 23 TC 0 Z9 0 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 22 PY 2016 VL 6 AR 37554 DI 10.1038/srep37554 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC6RI UT WOS:000388263700001 PM 27874052 ER PT J AU Krey, JF Krystofiak, ES Dumont, RA Vijayakumar, S Choi, D Rivero, F Kachar, B Jones, SM Barr-Gillespie, PG AF Krey, Jocelyn F. Krystofiak, Evan S. Dumont, Rachel A. Vijayakumar, Sarath Choi, Dongseok Rivero, Francisco Kachar, Bechara Jones, Sherri M. Barr-Gillespie, Peter G. TI Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid SO JOURNAL OF CELL BIOLOGY LA English DT Article ID HAIR-CELL STEREOCILIA; CUTICULAR PLATE; BIRD COCHLEA; HEARING-LOSS; F-ACTIN; MOUSE STRAINS; CROSS-LINKER; PROTEINS; ESPIN; ORGANIZATION AB With their essential role in inner ear function, stereocilia of sensory hair cells demonstrate the importance of cellular actin protrusions. Actin packing in stereocilia is mediated by cross-linkers of the plastin, fascin, and espin families. Although mice lacking espin (ESPN) have no vestibular or auditory function, we found that mice that either lacked plastin 1 (PLS1) or had nonfunctional fascin 2 (FSCN2) had reduced inner ear function, with double-mutant mice most strongly affected. Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall; ESPN only accounted for similar to 15% of the total cross-linkers in bundles. Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia. Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing. Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter. C1 [Krey, Jocelyn F.; Dumont, Rachel A.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Krey, Jocelyn F.; Dumont, Rachel A.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Choi, Dongseok] Oregon Hlth & Sci Univ, Oregon Hlth & Sci Univ Portland State Univ Sch Pu, Portland, OR 97239 USA. [Krystofiak, Evan S.; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Vijayakumar, Sarath; Jones, Sherri M.] Univ Nebraska, Dept Special Educ & Commun Disorders, Lincoln, NE 68583 USA. [Choi, Dongseok] Kyung Hee Univ, Grad Sch Dent, Seoul 02447, South Korea. [Rivero, Francisco] Univ Hull, Hull York Med Sch, Ctr Cardiovasc & Metab Res, Kingston Upon Hull HU6 7RX, N Humberside, England. RP Barr-Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA.; Barr-Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. EM gillespp@ohsu.edu OI Barr-Gillespie, Peter/0000-0002-9787-5860; Rivero, Francisco/0000-0001-5435-6991; Choi, Dongseok/0000-0002-1552-4072; Vijayakumar, Sarath/0000-0002-4652-2002 FU National Institutes of Health grants [R01 DC002368, R01 DC011034, P30 DC005983, F32 DC012455]; National Institute on Deafness and Other Communication Disorders Intramural Research Program [Z01 DC000002]; Nebraska Tobacco Settlement Biomedical Research Development Fund FX The work described here was supported by National Institutes of Health grants R01 DC002368 (P.G. Barr-Gillespie), R01 DC011034 (P.G. Barr-Gillespie), P30 DC005983 (P.G. Barr-Gillespie), and F32 DC012455 (J.F. Krey). E.S. Krystofiak and B. Kachar were supported by the National Institute on Deafness and Other Communication Disorders Intramural Research Program (Z01 DC000002). S.M. Jones was supported by the Nebraska Tobacco Settlement Biomedical Research Development Fund. We received support from the following core facilities: shotgun and targeted MS from the Oregon Health and Science University (OHSU) Proteomics Shared Resource, confocal and SIM from the OHSU Advanced Light Microscopy Core at The Jungers Center, EM from the OHSU Multiscale Microscopy Core, and EM from the National Institute on Deafness and Other Communication Disorders Advanced Imaging Core (ZIC DC000081). NR 60 TC 0 Z9 0 U1 2 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD NOV 21 PY 2016 VL 215 IS 4 BP 467 EP 482 DI 10.1083/jcb.201606036 PG 16 WC Cell Biology SC Cell Biology GA ED2PT UT WOS:000388690900007 PM 27811163 ER PT J AU Joshi, AS Huang, XF Choudhary, V Levine, TP Hu, JJ Prinz, WA AF Joshi, Amit S. Huang, Xiaofang Choudhary, Vineet Levine, Tim P. Hu, Junjie Prinz, William A. TI A family of membrane-shaping proteins at ER subdomains regulates pre-peroxisomal vesicle biogenesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID TUBULAR ENDOPLASMIC-RETICULUM; SACCHAROMYCES-CEREVISIAE; NUCLEAR-ENVELOPE; SELECTIVE AUTOPHAGY; NETWORK FORMATION; S. CEREVISIAE; GTPASE SEY1P; CELLS; FORM; MECHANISMS AB Saccharomyces cerevisiae contains three conserved reticulon and reticulon-like proteins that help maintain ER structure by stabilizing high membrane curvature in ER tubules and the edges of ER sheets. A mutant lacking all three proteins has dramatically altered ER morphology. We found that ER shape is restored in this mutant when Pex30p or its homologue Pex31p is overexpressed. Pex30p can tubulate membranes both in cells and when reconstituted into proteoliposomes, indicating that Pex30p is a novel ER-shaping protein. In contrast to the reticulons, Pex30p is low abundance, and we found that it localizes to subdomains in the ER. We show that these ER subdomains are the sites where most preperoxisomal vesicles (PPVs) are generated. In addition, overproduction or deletion of Pex30p or Pex31p alters the size, shape, and number of PPVs. Our findings suggest that Pex30p and Pex31p help shape and generate regions of the ER where PPV biogenesis occurs. C1 [Joshi, Amit S.; Choudhary, Vineet; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Huang, Xiaofang; Hu, Junjie] Nankai Univ, Dept Genet & Cell Biol, Coll Life Sci, Tianjin 300071, Peoples R China. [Huang, Xiaofang; Hu, Junjie] Nankai Univ, Tianjin Key Lab Prot Sci, Tianjin 300071, Peoples R China. [Levine, Tim P.] UCL, Inst Ophthalmol, London EC1V 9EL, England. [Hu, Junjie] Chinese Acad Sci, Inst Biophys, Natl Lab Macromol, Beijing 100101, Peoples R China. RP Prinz, WA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov OI HU, JUNJIE/0000-0003-4712-2243 FU Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases; National Natural Science Foundation of China [31225006]; International Early Career Scientist grant from Howard Hughes Medical Institute; Biotechnology and Biological Sciences Research Council Bioinformatics and Biological Resources Fund [BB/M011801]; Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [PA00P3_145358, P300P3_158454] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. J. Hu was supported by the National Natural Science Foundation of China (grant 31225006) and an International Early Career Scientist grant from Howard Hughes Medical Institute. T.P. Levine's laboratory was supported by the Biotechnology and Biological Sciences Research Council Bioinformatics and Biological Resources Fund (grant BB/M011801). V. Choudhary was supported by a fellowship from Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung (grants PA00P3_145358 and P300P3_158454). NR 49 TC 1 Z9 1 U1 4 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD NOV 21 PY 2016 VL 215 IS 4 BP 515 EP 529 DI 10.1083/jcb.201602064 PG 15 WC Cell Biology SC Cell Biology GA ED2PT UT WOS:000388690900010 PM 27872254 ER PT J AU McGowan, ML Ponsaran, RS Silverman, P Harris, LN Marshall, PA AF McGowan, Michelle L. Ponsaran, Roselle S. Silverman, Paula Harris, Lyndsay N. Marshall, Patricia A. TI "A rising tide lifts all boats": establishing a multidisciplinary genomic tumor board for breast cancer patients with advanced disease SO BMC MEDICAL GENOMICS LA English DT Article DE Breast cancer; Genomics; Qualitative research; Patient care; Ethics ID UNIVERSITY-OF-CALIFORNIA; PERSONALIZED MEDICINE; ONCOLOGY; CARE; EXPERIENCE AB Background: Research suggests that multidisciplinary genomic tumor boards (MGTB) can inform cancer patient care, though little is known about factors influencing how MGTBs interpret genomic test results, make recommendations, and perceive the utility of this approach. This study's objective was to observe, describe, and assess the establishment of the Breast Multidisciplinary Genomic Tumor Board, the first MGTB focused on interpreting genomic test results for breast cancer patients with advanced disease. Methods: We conducted a qualitative case study involving participant observation at monthly MGTB meetings from October 2013 through November 2014 and interviews with 12 MGTB members. We analyzed social dynamics and interactions within the MGTB regarding interpretation of genomic findings and participants' views on effectiveness of the MGTB in using genomics to inform patient care. Results: Twenty-two physicians, physician-scientists, basic scientists, bioethicists, and allied care professionals comprised the MGTB. The MGTB reviewed FoundationOne (TM) results for 40 metastatic breast cancer patients. Based on findings, the board mostly recommended referring patients to clinical trials (34) and medical genetics (15), and Food and Drug Administration-approved (FDA) breast cancer therapies (13). Though multidisciplinary, recommendations were driven by medical oncologists. Interviewees described providing more precise care recommendations and professional development as advantages and the limited actionability of genomic test results as a challenge for the MGTB. Conclusions: Findings suggest both feasibility and desirability of pooling professional expertise in genomically-guided breast cancer care and challenges to institutionalizing a Breast MGTB, specifically in promoting interdisciplinary contributions and managing limited actionability of genomic test results for patients with advanced disease. C1 [McGowan, Michelle L.] Univ Cincinnati, Dept Pediat & Womens Gender, Cincinnati Childrens Hosp Med Ctr, Eth Ctr,Div Gen & Community Pediat, 3333 Burnet Ave,MLC 15006, Cincinnati, OH 45229 USA. [McGowan, Michelle L.] Univ Cincinnati, Dept Sexual Studies, Cincinnati Childrens Hosp Med Ctr, Eth Ctr,Div Gen & Community Pediat, 3333 Burnet Ave,MLC 15006, Cincinnati, OH 45229 USA. [Ponsaran, Roselle S.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Silverman, Paula] Case Western Reserve Univ, Sch Med, Univ Hosp, Seidman Canc Ctr, Cleveland, OH USA. [Harris, Lyndsay N.] NCI, Washington, DC USA. RP McGowan, ML (reprint author), Univ Cincinnati, Dept Pediat & Womens Gender, Cincinnati Childrens Hosp Med Ctr, Eth Ctr,Div Gen & Community Pediat, 3333 Burnet Ave,MLC 15006, Cincinnati, OH 45229 USA.; McGowan, ML (reprint author), Univ Cincinnati, Dept Sexual Studies, Cincinnati Childrens Hosp Med Ctr, Eth Ctr,Div Gen & Community Pediat, 3333 Burnet Ave,MLC 15006, Cincinnati, OH 45229 USA. EM michelle.mcgowan@cchmc.org FU National Human Genome Research Institute [P50HG003390] FX Support for this research was provided by National Human Genome Research Institute grant P50HG003390. The funding body was not involved in the design of the study, the collection, analysis and interpretation of data, nor the writing of the manuscript. NR 35 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD NOV 21 PY 2016 VL 9 AR 71 DI 10.1186/s12920-016-0234-1 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EC7SI UT WOS:000388340200001 PM 27871291 ER PT J AU Christensen, CH Barry, KH Andreotti, G Alavanja, MCR Cook, MB Kelly, SP Burdett, LA Yeager, M Freeman, LEB Berndt, SI Koutros, S AF Christensen, Carol H. Barry, Kathryn Hughes Andreotti, Gabriella Alavanja, Michael C. R. Cook, Michael B. Kelly, Scott P. Burdett, Laurie A. Yeager, Meredith Freeman, Laura E. Beane Berndt, Sonja I. Koutros, Stella TI Sex Steroid Hormone Single-Nucleotide Polymorphisms, Pesticide Use, and the Risk of Prostate Cancer: A Nested Case-Control Study within the Agricultural Health Study SO FRONTIERS IN ONCOLOGY LA English DT Article DE prostate cancer; pesticides; sex steroid hormones; single-nucleotide polymorphism; interaction ID DEPLOYMENT-RELATED CHEMICALS; GENOME-WIDE ASSOCIATION; REPAIR PATHWAY GENES; METABOLIC PATHWAY; ANDROGEN RECEPTOR; 3A4 METABOLISM; EXPOSURE; APPLICATORS; VARIANTS; COHORT AB Experimental and epidemiologic investigations suggest that certain pesticides may alter sex steroid hormone synthesis, metabolism or regulation, and the risk of hormone-related cancers. Here, we evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. We evaluated pesticide-SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions, we included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. We translated p-values for interaction into q-values, which reflected the false discovery rate, to account for multiple comparisons. We observed a significant interaction, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 x 10(-5); q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk. C1 [Christensen, Carol H.] US FDA, Off Sci, Ctr Tobacco Prod, Document Control Ctr, Silver Spring, MD USA. [Barry, Kathryn Hughes; Andreotti, Gabriella; Alavanja, Michael C. R.; Freeman, Laura E. Beane; Berndt, Sonja I.; Koutros, Stella] NCI, Occupat & Environm Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20850 USA. [Barry, Kathryn Hughes] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Barry, Kathryn Hughes] Univ Maryland, Program Oncol, Marlene & Stewart Greenebaum Comprehens Canc Ctr, Baltimore, MD 21201 USA. [Cook, Michael B.; Kelly, Scott P.] NCI, Metab Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD USA. [Burdett, Laurie A.; Yeager, Meredith] NCI, Canc Genom Res Lab, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 21701 USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20850 USA. EM koutross@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; Kelly, Scott/D-3195-2013 OI Beane Freeman, Laura/0000-0003-1294-4124; Kelly, Scott/0000-0002-0375-1040 NR 50 TC 0 Z9 0 U1 5 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD NOV 21 PY 2016 VL 6 AR 237 DI 10.3389/fonc.2016.00237 PG 8 WC Oncology SC Oncology GA EC6DN UT WOS:000388226800001 PM 27917368 ER PT J AU Acevedo-Luna, N Marino-Ramirez, L Halbert, A Hansen, U Landsman, D Spouge, JL AF Acevedo-Luna, Natalia Marino-Ramirez, Leonardo Halbert, Armand Hansen, Ulla Landsman, David Spouge, John L. TI Most of the tight positional conservation of transcription factor binding sites near the transcription start site reflects their co-localization within regulatory modules SO BMC BIOINFORMATICS LA English DT Article DE Transcription factor binding site; Positional preference; Transcription start site ID OPEN-ACCESS DATABASE; LARGE GENE LISTS; STATISTICAL SIGNIFICANCE; NUCLEOTIDE-SEQUENCES; FUNCTIONAL-ANALYSIS; HUMAN PROMOTERS; TARGET GENES; MOTIF SITES; GENOME; EXPRESSION AB Background: Transcription factors (TFs) form complexes that bind regulatory modules (RMs) within DNA, to control specific sets of genes. Some transcription factor binding sites (TFBSs) near the transcription start site (TSS) display tight positional preferences relative to the TSS. Furthermore, near the TSS, RMs can co-localize TFBSs with each other and the TSS. The proportion of TFBS positional preferences due to TFBS co-localization within RMs is unknown, however. ChIP experiments confirm co-localization of some TFBSs genome-wide, including near the TSS, but they typically examine only a few TFs at a time, using non-physiological conditions that can vary from lab to lab. In contrast, sequence analysis can examine many TFs uniformly and methodically, broadly surveying the colocalization of TFBSs with tight positional preferences relative to the TSS. Results: Our statistics found 43 significant sets of human motifs in the JASPAR TF Database with positional preferences relative to the TSS, with 38 preferences tight (+/- 5 bp). Each set of motifs corresponded to a gene group of 135 to 3304 genes, with 42/43 (98%) gene groups independently validated by DAVID, a gene ontology database, with FDR < 0.05. Motifs corresponding to two TFBSs in a RM should co-occur more than by chance alone, enriching the intersection of the gene groups corresponding to the two TFs. Thus, a gene-group intersection systematically enriched beyond chance alone provides evidence that the two TFs participate in an RM. Of the 903 = 43*42/2 intersections of the 43 significant gene groups, we found 768/903 (85%) pairs of gene groups with significantly enriched intersections, with 564/768 (73%) intersections independently validated by DAVID with FDR < 0.05. A userfriendly web site at http://go.usa.gov/3kjsH permits biologists to explore the interaction network of our TFBSs to identify candidate subunit RMs. Conclusions: Gene duplication and convergent evolution within a genome provide obvious biological mechanisms for replicating an RM near the TSS that binds a particular TF subunit. Of all intersections of our 43 significant gene groups, 85% were significantly enriched, with 73% of the significant enrichments independently validated by gene ontology. The co-localization of TFBSs within RMs therefore likely explains much of the tight TFBS positional preferences near the TSS. C1 [Acevedo-Luna, Natalia] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. [Marino-Ramirez, Leonardo; Halbert, Armand; Landsman, David; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Hansen, Ulla] Boston Univ, Dept Biol, 5 Cummington Mall, Boston, MA 02215 USA. RP Spouge, JL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM spouge@nih.gov FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and National Center for Biotechnology Information. The National Institutes of Health funded open access charges. The study was performed in part when NAL was at the National Center for Biotechnology Information, NLM, NIH, Bethesda. NR 83 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD NOV 21 PY 2016 VL 17 AR 479 DI 10.1186/s12859-016-1354-5 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA EC4RA UT WOS:000388119900001 PM 27871221 ER PT J AU Brickley, EB Coulibaly, M Gabriel, EE Healy, SA Hume, JCC Sagara, I Traore, SF Doumbo, O Duffy, PE AF Brickley, Elizabeth B. Coulibaly, Mamadou Gabriel, Erin E. Healy, Sara A. Hume, Jen C. C. Sagara, Issaka Traore, Sekou F. Doumbo, Ogobara Duffy, Patrick E. TI Utilizing direct skin feeding assays for development of vaccines that interrupt malaria transmission: A systematic review of methods and case study SO VACCINE LA English DT Review DE Transmission-blocking vaccine; Malaria; Trial design; Direct skin feed; Vaccine activity ID PLASMODIUM-FALCIPARUM; ANOPHELES-GAMBIAE; BLOCKING VACCINE; GAMETOCYTE CARRIERS; WESTERN KENYA; MOSQUITOS; INFECTIVITY; AREA; INFECTIOUSNESS; POPULATION AB Shifting the malaria priorities from a paradigm of control and elimination to a goal of global eradication calls for renewed attention to the interruption of malaria transmission. Sustained progress toward eradication will require both improved understanding of infectious reservoirs and efficient development of novel transmission-blocking interventions, such as rapidly acting and highly efficacious therapeutics and vaccines. Here, we review the direct skin feeding assay (DSF), which has been proposed as a valuable tool for measuring the in ttatura transmission of malaria parasites from human hosts to mosquito vectors across heterogeneous populations. To capture the methodological breadth of this assay's use, we first systematically review and qualitatively synthesize previously published investigations using DSFs to study malaria transmission in humans. Then, using a recent Phase 1 trial in Mali of the Pfs25H-EPA/Alhydrogel (R) vaccine candidate (NCT01867463) designed to interrupt Plasmodium falciparum transmission as a case study, we describe the potential opportunities and current limitations of utilizing the endpoints measured by DSF in making early clinical decisions for individually randomized transmission-interrupting intervention candidates. Using simulations based on the data collected in the clinical trial, we demonstrate that the capacity of the DSF to serve as an evaluative tool is limited by the statistical power constraints of the "effective sample size" (i.e. the number of subjects that are capable of transmitting at the time of feeding). Altogether, our findings suggest DSFs have great potential utility for assessing the public health impacts of emerging antimalarial tools, but additional research is needed to address issues of scalability and to establish correlation with community-wide clinical endpoints as well as complementary in vitro measures, such as standard membrane feeding assays. Published by Elsevier Ltd. C1 [Brickley, Elizabeth B.; Healy, Sara A.; Hume, Jen C. C.; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Room 1111,5640 Fishers Lane, Rockville, MD 20852 USA. [Brickley, Elizabeth B.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, Cambs, England. [Brickley, Elizabeth B.] Geisel Sch Med Dartmouth, Dept Epidemiol, 1 Med Ctr Dr,7927 Rubin Bldg, Lebanon, NH 03756 USA. [Coulibaly, Mamadou; Sagara, Issaka; Traore, Sekou F.; Doumbo, Ogobara] Univ Sci Tech & Technol Bamako, Fac Pharm, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, POB 1805, Bamako, Mali. [Coulibaly, Mamadou; Sagara, Issaka; Traore, Sekou F.; Doumbo, Ogobara] Univ Sci Tech & Technol Bamako, Fac Med & Dent, POB 1805, Bamako, Mali. [Gabriel, Erin E.] NIAID, Biostat Res Branch, NIH, 5601 Fishers Lane, Rockville, MD 20852 USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Room 1111,5640 Fishers Lane, Rockville, MD 20852 USA. EM elizabeth.b.brickley@dartmouth.edu; doudou@icermali.org; erin.gabriel@nih.gov; sara.healy@nih.gov; jennifer.hume@nih.gov; isagara@icermali.org; cheick@icermali.org; okd@icermali.org; patrick.duffy@nih.gov OI Gabriel, Erin/0000-0002-0504-8404; Coulibaly, Mamadou Brahima/0000-0001-9325-2845 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health Oxford Cambridge Scholars Program; National Cancer Institute of the National Institutes of Health [R25CA134286] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [http://www.niaid.nih.gov/]. During the duration of study, EBB was supported by the National Institutes of Health Oxford Cambridge Scholars Program [http://oxcam.gpp.nih.gov/] and by the National Cancer Institute of the National Institutes of Health under Award Number R25CA134286. NR 33 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 21 PY 2016 VL 34 IS 48 BP 5863 EP 5870 DI 10.1016/j.vaccine.2016.10.027 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EC3XG UT WOS:000388059800008 PM 27789147 ER PT J AU Kim, Y Bae, SK Cheng, TM Tao, C Ge, YH Chapman, AB Torres, VE Yu, ASL Mrug, M Bennett, WM Flessner, MF Landsittel, DP Bae, KT AF Kim, Youngwoo Bae, Sonu K. Cheng, Tianming Tao, Cheng Ge, Yinghui Chapman, Arlene B. Torres, Vincente E. Yu, Alan S. L. Mrug, Michal Bennett, William M. Flessner, Michael F. Landsittel, Doug P. Bae, Kyongtae T. TI Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE autosomal dominant kidney disease; polycystic liver disease; image segmentation; prior probability map; level set ID STATISTICAL SHAPE MODEL; PROBABILISTIC ATLAS; HEPATIC CYSTS; CT IMAGES; CONSTRUCTION; INVOLVEMENT; PROGRESSION; ALGORITHMS; CONSORTIUM; VOLUMETRY AB Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC = 0.91 for cyst volumes and ICC = 0.94 for % cyst-to-liver volume. C1 [Kim, Youngwoo; Bae, Sonu K.; Cheng, Tianming; Tao, Cheng; Ge, Yinghui; Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, 3362 Fifth Ave, Pittsburgh, PA 15213 USA. [Chapman, Arlene B.] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA 30307 USA. [Torres, Vincente E.] Mayo Coll Med, Dept Internal Med, Rochester, MN 55905 USA. [Yu, Alan S. L.] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66160 USA. [Mrug, Michal] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL 35487 USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Portland, OR 97210 USA. [Flessner, Michael F.] NIDDK, NIH, Bethesda, MD 20892 USA. [Landsittel, Doug P.] Univ Pittsburgh, Sch Med, Dept Internal Med, Pittsburgh, PA 15213 USA. RP Bae, KT (reprint author), Univ Pittsburgh, Sch Med, Dept Radiol, 3362 Fifth Ave, Pittsburgh, PA 15213 USA. EM baek@upmc.edu FU National Institute of Diabetes and Digestive; Kidney Diseases of the National Institutes of Health [DK056943, DK056956, DK056957, DK056961]; National Center for Research Resources General Clinical Research Centers at Emory University [RR000039]; National Center for Research Resources General Clinical Research Centers at Mayo College of Medicine [RR00585]; National Center for Research Resources General Clinical Research Centers at Kansas University Medical Center [RR23940]; National Center for Research Resources General Clinical Research Centers at University of Alabama at Birmingham [RR000032]; National Center for Research Resources Clinical and Translational Science Awards at Emory [RR025008]; National Center for Research Resources Clinical and Translational Science Awards at Mayo College of Medicine [RR024150]; National Center for Research Resources Clinical and Translational Science Awards at Kansas University Medical Center [RR033179]; National Center for Research Resources Clinical and Translational Science Awards at University of Alabama at Birmingham [RR025777, UL1TR000165]; National Center for Research Resources Clinical and Translational Science Awards at University of Pittsburgh School of Medicine [RR024153, UL1TR000005] FX The CRISP study is supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK056943, DK056956, DK056957, DK056961), by the National Center for Research Resources General Clinical Research Centers at each institution (RR000039, Emory University; RR00585, Mayo College of Medicine; RR23940, Kansas University Medical Center; RR000032, University of Alabama at Birmingham), and the National Center for Research Resources Clinical and Translational Science Awards at each institution (RR025008, Emory; RR024150, Mayo College of Medicine; RR033179, Kansas University Medical Center; RR025777 and UL1TR000165, University of Alabama at Birmingham; RR024153 and UL1TR000005, University of Pittsburgh School of Medicine). The investigators are indebted to the radiologists, nephrologists, radiology technologists, imaging engineers, and study coordinators in CRISP. NR 42 TC 0 Z9 0 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD NOV 21 PY 2016 VL 61 IS 22 BP 7864 EP 7880 DI 10.1088/0031-9155/61/22/7864 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EB1VM UT WOS:000387143900003 ER PT J AU Zhang, D Wlodawer, A Lubkowski, J AF Zhang, Di Wlodawer, Alexander Lubkowski, Jacek TI Crystal Structure of a Complex of the Intracellular Domain of Interferon lambda Receptor 1 (IFNLR1) and the FERM/SH2 Domains of Human JAK1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE JAK/STAT signaling; cytokine receptors; Janus kinases; protein-protein interactions; structure comparisons ID SIGNAL TRANSDUCER GP130; JANUS KINASES; MOLECULAR REPLACEMENT; CYTOKINE RECEPTORS; PROTEIN-KINASE; SH2 DOMAIN; RECOGNITION; ACTIVATION; EXPRESSION; FAMILY AB The crystal structure of a construct consisting of the FERM and SH2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of the interferon-lambda receptor 1 (IFNLR1) has. been determined at the nominal resolution of 2.1 A. In this structure, the receptor peptide forms an 85-angstrom-long extended chain, in which both the previously identified box1 and box2 regions bind simultaneously to the FERM and SH2-like domains of JAK1. Both domains of JAK1 are generally well ordered, with regions not seen in the crystal structure limited to loops located away from the receptor-binding regions. The structure provides a much more complete and accurate picture of the interactions between JAK1 and IFNLR1 than those given in earlier reports, illuminating the molecular basis of the JAK cytokine receptor association. A glutamate residue adjacent to the box2 region in IFNLR1 mimics the mode of binding of a phosphotyrosine in classical SH2 domains. It was shown here that a deletion of residues within the box1 region of the receptor abolishes stable interactions with JAK1, although it was previously shown that box2 alone is sufficient to stabilize a similar complex of the interferon-alpha receptor and TYK2. Published by Elsevier Ltd. C1 [Zhang, Di; Wlodawer, Alexander; Lubkowski, Jacek] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Wlodawer, A; Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM wlodawer@nih.gov; lubkowsj@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 44 TC 2 Z9 2 U1 4 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD NOV 20 PY 2016 VL 428 IS 23 BP 4651 EP 4668 DI 10.1016/j.jmb.2016.10.005 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED8GP UT WOS:000389110300006 PM 27725180 ER PT J AU Mehalko, JL Esposito, D AF Mehalko, Jennifer L. Esposito, Dominic TI Engineering the transposition-based baculovirus expression vector system for higher efficiency protein production from insect cells SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE Baculovirus; Insect cells; Tn7 transposition; Bac-to-Bac; Protein production ID ESCHERICHIA-COLI; RECOMBINANT BACULOVIRUSES; DNA-REPLICATION; TN7; GENERATION; INSERTION; SEQUENCE; ORIGIN; GENES AB One of the most common methods for producing recombinant baculovirus for insect cell protein production involves a transposition mediated system invented over 2 decades ago. This Tn7-mediated system, commercially sold as Bac-to-Bac, has proven highly useful for construction of high quality baculovirus, but suffers from a number of drawbacks which reduce the efficiency of the process and limit its utility for high throughput protein production processes. We describe here the creation of Bac-2-the-Future, a 2nd generation Tn7-based system for recombinant baculovirus production which uses optimized expression vectors, new E. coli strains, and enhanced protocols to dramatically enhance the efficiency of the baculovirus production process. The new system which we describe eliminates the need for additional screening of positive clones, improves the efficiency of transposition, and reduces the cost and time required for high throughput baculovirus production. The system is compatible with multiple cloning methodologies, and has been demonstrated to produce baculovirus with equal or better titer and protein productivity than the currently available systems. (C) 2016 Elsevier B.V. All rights reserved. C1 [Mehalko, Jennifer L.; Esposito, Dominic] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Prot Express Lab, POB B, Frederick, MD 21702 USA. RP Esposito, D (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Prot Express Lab, POB B, Frederick, MD 21702 USA. EM dom.esposito@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We acknowledge the technical support of Ralph Hopkins, Cammi Bittner, and Matt Drew for baculovirus production and insect cell expression culture work. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Vectors and strains described in this manuscript are freely available to academic and non-profit researchers by contacting the authors, and some B2F vectors will shortly be available at Addgene (http://www.acidgene.org). For-profit companies that are interested in obtaining B2F materials should contact the National Cancer Institute Office of Technology Transfer. NR 22 TC 1 Z9 1 U1 13 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 EI 1873-4863 J9 J BIOTECHNOL JI J. Biotechnol. PD NOV 20 PY 2016 VL 238 BP 1 EP 8 DI 10.1016/j.jbiotec.2016.002 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DZ0II UT WOS:000385521100001 PM 27616621 ER PT J AU Kunimatsu, J Tanaka, M AF Kunimatsu, Jun Tanaka, Masaki TI STRIATAL DOPAMINE MODULATES TIMING OF SELF-INITIATED SACCADES SO NEUROSCIENCE LA English DT Article DE self-timing; saccade; dopamine; acetylcholine; basal ganglia; primate ID PRIMATE MOTOR THALAMUS; BASAL GANGLIA; PARKINSONS-DISEASE; NUCLEUS-ACCUMBENS; SUPERIOR COLLICULUS; PROJECTION NEURONS; NONHUMAN-PRIMATES; PREFRONTAL CORTEX; COGNITIVE SIGNALS; SUBSTANTIA-NIGRA AB The ability to adjust movement timing is essential in daily life. Explorations of the underlying neural mechanisms have reported a gradual increase or decrease in neuronal activity prior to self-timed movements within the cortico-basal ganglia loop. Previous studies in both humans and animals have shown that endogenous dopamine (DA) plays a modulatory role in self-timing. However, the specific site of dopaminergic regulation remains elusive because the systemic application of DA-related substances can directly alter both cortical and subcortical neuronal activities. To investigate the role of striatal DA in self-timing, we locally injected DA receptor agonists or antagonists into the striatum of two female monkeys (Macaca fuscata) while they performed two versions of the memory-guided saccade (MS) task. In the conventional, triggered MS task, animals made a saccade to the location of a previously flashed visual cue in response to the fixation point offset. In the self-timed MS task, monkeys were rewarded for making a self-initiated saccade within a predetermined time interval following the cue. Infusion of a small amount of a D-1 or D-2 antagonist led to early saccades in the self-timed, but not the triggered MS tasks, while infusion of DA agonists produced no consistent effect. We also found that local administration of nicotinic but not muscarinic acetylcholine receptor agonists and antagonists altered the timing of self-initiated saccades. Our data suggest that the timing of self-initiated movements may be regulated by the balance of signals in the direct and indirect basal ganglia pathways, as well as that between both hemispheres of the brain. Published by Elsevier Ltd on behalf of IBRO. C1 [Kunimatsu, Jun; Tanaka, Masaki] Hokkaido Univ, Dept Physiol, Sch Med, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. [Kunimatsu, Jun] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Kunimatsu, J; Tanaka, M (reprint author), Hokkaido Univ, Dept Physiol, Sch Med, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM kunimatsu.jun@gmail.com; masa-ki@med.hokudai.ac.jp RI Tanaka, Masaki/D-9199-2011 FU Japan Science and Technology Agency; Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labour and Welfare of Japan; Smoking Research Foundation; Takeda Science Foundation FX The authors thank S. Ohmae, T. Suzuki, and other lab members for valuable comments and discussions; T. Mori and A. Hironaka for their assistance with animal care, training and MRI scanning; and M. Suzuki for her administrative help. We are grateful to M. Takei and Y. Hirata in the Equipment Development Group, Research Institute for Electronic Science, Hokkaido University, for manufacturing some equipment. This work was supported in part by grants from the Japan Science and Technology Agency, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, the Smoking Research Foundation, and the Takeda Science Foundation. NR 80 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD NOV 19 PY 2016 VL 337 BP 131 EP 142 DI 10.1016/j.neuroscience.2016.09.006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EA1FJ UT WOS:000386337600012 PM 27651148 ER PT J AU Medhi, D Goldman, ASH Lichten, M AF Medhi, Darpan Goldman, Alastair S. H. Lichten, Michael TI Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis SO ELIFE LA English DT Article ID DOUBLE-STRAND BREAKS; MEIOTIC GENE CONVERSION; SYNAPTONEMAL COMPLEX-FORMATION; DOUBLE HOLLIDAY JUNCTIONS; SACCHAROMYCES-CEREVISIAE; RECOMBINATION HOTSPOTS; SISTER CHROMATIDS; CHECKPOINT KINASE; HETERODUPLEX DNA; DISTINCT ROLES AB The budding yeast genome contains regions where meiotic recombination initiates more frequently than in others. This pattern parallels enrichment for the meiotic chromosome axis proteins Hop1 and Red1. These proteins are important for Spo11-catalyzed double strand break formation; their contribution to crossover recombination remains undefined. Using the sequence-specific VMA1-derived endonuclease (VDE) to initiate recombination in meiosis, we show that chromosome structure influences the choice of proteins that resolve recombination intermediates to form crossovers. At a Hop1-enriched locus, most VDE-initiated crossovers, like most Spo11-initiated crossovers, required the meiosis-specific MutL gamma resolvase. In contrast, at a locus with lower Hop1 occupancy, most VDE-initiated crossovers were MutL gamma-independent. In pch2 mutants, the two loci displayed similar Hop1 occupancy levels, and VDE-induced crossovers were similarly MutL gamma-dependent. We suggest that meiotic and mitotic recombination pathways coexist within meiotic cells, and that features of meiotic chromosome structure determine whether one or the other predominates in different regions. C1 [Medhi, Darpan; Lichten, Michael] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Medhi, Darpan; Goldman, Alastair S. H.] Univ Sheffield, Sheffield Inst Nucle Acids, Sheffield, S Yorkshire, England. [Medhi, Darpan; Goldman, Alastair S. H.] Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield, S Yorkshire, England. RP Lichten, M (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. EM mlichten@helix.nih.gov OI Lichten, Michael/0000-0001-9707-2956 FU National Cancer Institute Intramural Research Program of the NIH through the Center for Cancer Research at the National Cancer Institute; University of Sheffield FX National Cancer Institute Intramural Research Program of the NIH through the Center for Cancer Research at the National Cancer Institute Michael Lichten; University of Sheffield Graduate tuition grant Darpan Medhi; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 110 TC 1 Z9 1 U1 5 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 18 PY 2016 VL 5 AR e19669 DI 10.7554/eLife.19669 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7GT UT WOS:000393390500001 ER PT J AU Chan, STS Nani, RR Schauer, EA Martin, GE Williamson, RT Sauri, J Buevich, AV Schafer, WA Joyce, LA Goey, AKL Figg, WD Ransom, TT Henrich, CJ Mckee, TC Moser, A MacDonald, SA Khan, S McMahon, JB Schnermann, MJ Gustafson, KR AF Chan, Susanna T. S. Nani, Roger R. Schauer, Evan A. Martin, Gary E. Williamson, R. Thomas Sauri, Josep Buevich, Alexei V. Schafer, Wes A. Joyce, Leo A. Goey, Andrew K. L. Figg, William D. Ransom, Tanya T. Henrich, Curtis J. Mckee, Tawnya C. Moser, Arvin MacDonald, Scott A. Khan, Shabana McMahon, James B. Schnermann, Martin J. Gustafson, Kirk R. TI Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ASSISTED STRUCTURE ELUCIDATION; LR-HSQMBC; NMR; SOFTWARE AB An extract of Eudistoma sp. provided eudistidine C (1), a heterocyclic alkaloid with a novel molecular framework. Eudistidine C (1) is a racemic natural product composed of a tetracyclic core structure further elaborated with a p-methoxyphenyl group and a phenol-substituted aminoimidazole moiety. This compound presented significant structure elucidation challenges due to the large number of heteroatoms and fully substituted carbons. These issues were mitigated by application of a new NMR pulse sequence (LR-EISQMBC) optimized to detect four- and five-bond heteronuclear correlations and the use of computer-assisted structure elucidation software. Synthesis of eudistidine C (1) was accomplished in high yield by treating eudistidine A (2) with 4(2-amino-1H-irnidazol-5-yl)phenol (4) in DMSO. Synthesis of eudistidine C (1) confirmed the proposed structure and provided material for further biological characterization. Treatment of 2 with various nitrogen heterocycles and electron-rich arenes provided a series of analogues (5-10) of eudistidine C. Chiral-phase HPLC resolution of epimeric eudistidine C provided (+)-(R)-eudistidine C (la) and (-)-(S)-eudistidine C (1b). The absolute configuration of these enantiomers was assigned by ECD analysis. (-)-(S)-Eudistidine C (lb) modestly inhibited interaction between the protein binding domains of HIF-1 alpha and p300. Compounds 1, 2, and 6-10 exhibited significant antimalarial activity against Plasmodium falciparum. C1 [Chan, Susanna T. S.; Ransom, Tanya T.; Henrich, Curtis J.; Mckee, Tawnya C.; McMahon, James B.; Gustafson, Kirk R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Nani, Roger R.; Schauer, Evan A.; Schnermann, Martin J.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Martin, Gary E.; Williamson, R. Thomas; Sauri, Josep; Buevich, Alexei V.; Schafer, Wes A.; Joyce, Leo A.] Merck & Co Inc, NMR Struct Elucidat Proc Res & Dev, Rahway, NJ 07065 USA. [Goey, Andrew K. L.; Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Henrich, Curtis J.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Moser, Arvin; MacDonald, Scott A.] Adv Chem Dev Inc, Toronto Dept, ACD Labs, 8 King St East Suite 107, Toronto, ON M5C 1B5, Canada. [Khan, Shabana] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Mckee, Tawnya C.] NCI, Diagnost Biomarkers & Technol Branch, Canc Diag Program, DCTD, Bethesda, MD 20850 USA. [Schauer, Evan A.] Baylor Coll Med, 1 Baylor Plaza, Houston, TX 77030 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA.; Schnermann, MJ (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM martin.schnermann@nih.gov; gustafki@mail.nih.gov OI Sauri, Josep/0000-0002-2706-2426 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Federal funds from National Cancer Institute, National Institutes of Health [HHSN261200800001E]; USDA Agricultural Research Service [58-6408-1-603] FX We gratefully acknowledge D. Newman (NCI) for organizing and documenting the collection, the Natural Products Support Group at NCI Frederick for extraction, T. Bostaph (MTL) and K. Goncharova (MTL) for screening data compilation and analysis, J. Barchi (CBL) for NMR assistance, J. Kelly (CBL) for mass spectrometry analysis, and S. Tarasov and M. Dyba (Biophysics Resource Core, Structural Biophysics Laboratory, CCR) and H. Bokesch (MTL) for assistance with high resolution mass spectrometry. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and by the USDA Agricultural Research Service Specific Cooperative Agreement No. 58-6408-1-603. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 18 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD NOV 18 PY 2016 VL 81 IS 22 BP 10631 EP 10640 DI 10.1021/acs.joc.6b02380 PG 10 WC Chemistry, Organic SC Chemistry GA EG7SI UT WOS:000391248800004 PM 27934476 ER PT J AU Davis, MI Pragani, R Fox, JT Shen, M Parmar, K Gaudiano, EF Liu, L Tanega, C Mcgee, L Hall, MD McKnight, C Shinn, P Nelson, H Chattopadhyay, D D'Andrea, AD Auld, DS DeLucas, LJ Li, ZY Boxer, MB Sinneonov, A AF Davis, Mindy I. Pragani, Rajan Fox, Jennifer T. Shen, Min Parmar, Kalindi Gaudiano, Emily F. Liu, Li Tanega, Cordelle McGee, Lauren Hall, Matthew D. McKnight, Crystal Shinn, Paul Nelson, Henrike Chattopadhyay, Debasish D'Andrea, Alan D. Auld, Douglas S. DeLucas, Larry J. Li, Zhuyin Boxer, Matthew B. Sinneonov, Anton TI Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FATTY-ACID SYNTHASE; PROSTATE-CANCER; DNA-DAMAGE; MAMMALIAN-CELLS; STABILITY; REPAIR; TARGET AB Deubiquitinases are important components of the protein degradation regulatory network. We report the discovery of ML364, a small molecule inhibitor of the deubiquitinase USP2 and its use to interrogate the biology of USP2 and its putative substrate cyclin DL ML364 has an IC50 of 1.1 mu M in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate. Direct binding of ML364 to USP2 was demonstrated using microscale thermophoresis. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest as shown in Western blottings and flow cytometry assays utilizing both Mino and HCT116 cancer cell lines. ML364, and not the inactive analog 2, was antiproliferative in cancer cell lines. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth. C1 [Davis, Mindy I.; Pragani, Rajan; Fox, Jennifer T.; Shen, Min; Liu, Li; Tanega, Cordelle; McGee, Lauren; Hall, Matthew D.; McKnight, Crystal; Shinn, Paul; Nelson, Henrike; Auld, Douglas S.; Li, Zhuyin; Boxer, Matthew B.; Sinneonov, Anton] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Parmar, Kalindi; Gaudiano, Emily F.; D'Andrea, Alan D.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Chattopadhyay, Debasish; DeLucas, Larry J.] Univ Alabama Birmingham, Struct Biol Ctr, Birmingham, AL 35294 USA. [Auld, Douglas S.] Novartis Inst Biomed Res, Ctr Proteorn Chem, Cambridge, MA 02139 USA. RP Boxer, MB; Sinneonov, A (reprint author), NIH, NCATS, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM boxerrn@mail.nih.gov; asimeono@mail.nih.gov FU NCATS Intramural Research Program; Molecular Libraries Initiative of the National Institutes of Health Common Fund; National Institutes of Health [U54 MH 084681]; Alabama Drug Discovery Alliance; National Institutes of Health/NCI Grant [5P30CA13148-37]; Translational Research Grant from the Leukemia & Lymphoma Society [6237-13] FX This work was supported by the NCATS Intramural Research Program, Molecular Libraries Initiative of the National Institutes of Health Common Fund, National Institutes of Health Grant U54 MH 084681, Alabama Drug Discovery Alliance, National Institutes of Health/NCI Grant 5P30CA13148-37, and Translational Research Grant from the Leukemia & Lymphoma Society Grant 6237-13. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 18 PY 2016 VL 291 IS 47 BP 24628 EP 24640 DI 10.1074/jbc.M116.738567 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5EX UT WOS:000388875500024 PM 27681596 ER PT J AU de Vasconcellos, JF Lee, YT Byrnes, C Tumburu, L Rebel, A Miller, JL AF de Vasconcellos, Jaira F. Lee, Y. Terry Byrnes, Colleen Tumburu, Laxminath Rebel, Antoinette Miller, Jeffery L. TI HMGA2 Moderately Increases Fetal Hemoglobin Expression in Human Adult Erythroblasts SO PLOS ONE LA English DT Article ID SICKLE-CELL-DISEASE; BETA-THALASSEMIA; GENE; LET-7; PROTEINS; IDENTIFICATION; TRANSCRIPTION; ERYTHROCYTES; HYDROXYUREA; DETERMINES AB Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with beta-hemoglobin disorders. Previous studies showed that let-7 microRNAs (miRNAs) are highly regulated in erythroid cells during the fetal-to-adult developmental transition, and that targeting let-7 mediated the up-regulation of HbF to greater than 30% of the total globin levels in human adult cultured erythroblasts. HMGA2 is a member of the high-mobility group A family of proteins and a validated target of the let-7 family of miRNAs. Here we investigate whether expression of HMGA2 directly regulates fetal hemoglobin in adult erythroblasts. Let-7 resistant HMGA2 expression was studied after lentiviral transduction of CD34(+) cells. The transgene was regulated by the erythroid-specific gene promoter region of the human SPTA1 gene (HMGA2-OE). HMGA2-OE caused significant increases in gamma-globin mRNA expression and HbF to around 16% of the total hemoglobin levels compared to matched control transductions. Interestingly, no significant changes in KLF1, SOX6, GATA1, ZBTB7A and BCL11A mRNA levels were observed. Overall, our data suggest that expression of HMGA2, a downstream target of let-7 miRNAs, causes moderately increased gamma-globin gene and protein expression in adult human erythroblasts. C1 [de Vasconcellos, Jaira F.; Lee, Y. Terry; Byrnes, Colleen; Rebel, Antoinette; Miller, Jeffery L.] NIDDK, Mol Genom & Therapeut Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Tumburu, Laxminath] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Tumburu, Laxminath] NHLBI, Sickle Cell Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Genom & Therapeut Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases supported this work. NR 42 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 18 PY 2016 VL 11 IS 11 AR e0166928 DI 10.1371/journal.pone.0166928 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC7WC UT WOS:000388350300134 PM 27861570 ER PT J AU Persi, E Wolf, YI Koonin, EV AF Persi, Erez Wolf, Yuri I. Koonin, Eugene V. TI Positive and strongly relaxed purifying selection drive the evolution of repeats in proteins SO NATURE COMMUNICATIONS LA English DT Article ID AMINO-ACID REPEATS; NUCLEAR-PORE COMPLEX; TANDEM REPEATS; ZINC FINGERS; REPETITIVE DNA; ANKYRIN REPEAT; EUKARYOTES; SEQUENCES; GENE; CONSERVATION AB Protein repeats are considered hotspots of protein evolution, associated with acquisition of new functions and novel phenotypic traits, including disease. Paradoxically, however, repeats are often strongly conserved through long spans of evolution. To resolve this conundrum, it is necessary to directly compare paralogous (horizontal) evolution of repeats within proteins with their orthologous (vertical) evolution through speciation. Here we develop a rigorous methodology to identify highly periodic repeats with significant sequence similarity, for which evolutionary rates and selection (dN/dS) can be estimated, and systematically characterize their evolution. We show that horizontal evolution of repeats is markedly accelerated compared with their divergence from orthologues in closely related species. This observation is universal across the diversity of life forms and implies a biphasic evolutionary regime whereby new copies experience rapid functional divergence under combined effects of strongly relaxed purifying selection and positive selection, followed by fixation and conservation of each individual repeat. C1 [Persi, Erez; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Persi, E; Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM erezpersi@gmail.com; koonin@ncbi.nlm.nih.gov FU intramural funds of the US Department of Health and Human Services FX We thank Koonin group members for useful discussions. Our research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 70 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 18 PY 2016 VL 7 AR 13570 DI 10.1038/ncomms13570 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC2ZS UT WOS:000387994100002 PM 27857066 ER PT J AU Gibbs, KD Basson, J Xierali, IM Broniatowski, DA AF Gibbs, Kenneth D., Jr. Basson, Jacob Xierali, Imam M. Broniatowski, David A. TI Decoupling of the minority PhD talent pool and assistant professor hiring in medical school basic science departments in the US SO ELIFE LA English DT Article ID NATIONAL-INSTITUTES; BIOMEDICAL-RESEARCH; RESEARCH WORKFORCE; RESEARCH AWARDS; DIVERSITY; HEALTH; RACE; ETHNICITY; WOMEN; REPRESENTATION AB Faculty diversity is a longstanding challenge in the US. However, we lack a quantitative and systemic understanding of how the career transitions into assistant professor positions of PhD scientists from underrepresented minority (URM) and well-represented (WR) racial/ethnic backgrounds compare. Between 1980 and 2013, the number of PhD graduates from URM backgrounds increased by a factor of 9.3, compared with a 2.6-fold increase in the number of PhD graduates from WR groups. However, the number of scientists from URM backgrounds hired as assistant professors in medical school basic science departments was not related to the number of potential candidates (R-2 = 0.12, p>0.07), whereas there was a strong correlation between these two numbers for scientists from WR backgrounds (R-2 = 0.48, p<0.0001). We built and validated a conceptual system dynamics model based on these data that explained 79% of the variance in the hiring of assistant professors and posited no hiring discrimination. Simulations show that, given current transition rates of scientists from URM backgrounds to faculty positions, faculty diversity would not increase significantly through the year 2080 even in the context of an exponential growth in the population of PhD graduates from URM backgrounds, or significant increases in the number of faculty positions. Instead, the simulations showed that diversity increased as more postdoctoral candidates from URM backgrounds transitioned onto the market and were hired. C1 [Gibbs, Kenneth D., Jr.; Basson, Jacob] NIGMS, Off Program Planning Anal & Evaluat, Bethesda, MD 20892 USA. [Xierali, Imam M.] Assoc Amer Med Coll, Publ Hlth & Divers Initiat, Washington, DC USA. [Broniatowski, David A.] George Washington Univ, Dept Engn Management & Syst Engn, Washington, DC USA. RP Gibbs, KD (reprint author), NIGMS, Off Program Planning Anal & Evaluat, Bethesda, MD 20892 USA. EM kgibbsjr@gmail.com OI Basson, Jacob/0000-0002-0521-3078; Broniatowski, David/0000-0002-3302-9497; Gibbs, Kenneth/0000-0002-3532-5396 NR 61 TC 2 Z9 2 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 17 PY 2016 VL 5 AR e21393 DI 10.7554/eLife.21393 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EG1PU UT WOS:000390805500001 ER PT J AU Abera, MB Xiao, JB Nofziger, J Titus, S Southall, N Zheng, W Moritz, KE Ferrer, M Cherry, JJ Androphy, EJ Wang, A Xu, X Austin, C Fischbeck, KH Marugan, JJ Burnett, BG AF Abera, Mahlet B. Xiao, Jingbo Nofziger, Jonathan Titus, Steve Southall, Noel Zheng, Wei Moritz, Kasey E. Ferrer, Marc Cherry, Jonathan J. Androphy, Elliot J. Wang, Amy Xu, Xin Austin, Christopher Fischbeck, Kenneth H. Marugan, Juan J. Burnett, Barrington G. TI ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice SO JCI INSIGHT LA English DT Article ID SMALL-MOLECULE INHIBITORS; PROTEIN-PROTEIN INTERACTION; SURVIVAL MOTOR-NEURON; MOUSE MODEL; SINGLE NUCLEOTIDE; INCREASES SMN; PHENOTYPE; CANCER; RESCUE; GENE AB Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient-derived cells. We show here that ML372, a representative of this series, almost doubles the half-life of residual SMN protein expressed from the SMN2 locus by blocking its ubiquitination and subsequent degradation by the proteasome. ML372 increased SMN protein levels in muscle, spinal cord, and brain tissue of SMA mice. Importantly, ML372 treatment improved the righting reflex and extended survival of a severe mouse model of SMA. These results demonstrate that slowing SMN degradation by selectively inhibiting its ubiquitination can improve the motor phenotype and lifespan of SMA model mice. C1 [Abera, Mahlet B.; Moritz, Kasey E.; Burnett, Barrington G.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Xiao, Jingbo; Titus, Steve; Southall, Noel; Zheng, Wei; Ferrer, Marc; Wang, Amy; Xu, Xin; Austin, Christopher; Marugan, Juan J.] NIH, NIH Chem Genom Ctr, Discovery Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Cherry, Jonathan J.; Androphy, Elliot J.] Indiana Univ, Sch Med, Dept Dermatol, Indianapolis, IN USA. [Nofziger, Jonathan; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Marugan, JJ (reprint author), 9800 Med Ctr Dr, Rockville, MD 20850 USA.; Burnett, BG (reprint author), 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM maruganj@mail.nih.gov; barrington.burnett@usuhs.edu RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 NR 48 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD NOV 17 PY 2016 VL 1 IS 19 AR e88427 DI 10.1172/jci.insight.88427 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EE7LI UT WOS:000389797700005 PM 27882347 ER PT J AU Booth, DG Beckett, AJ Molina, O Samejima, I Masumoto, H Kouprina, N Larionov, V Prior, IA Earnshaw, WC AF Booth, Daniel G. Beckett, Alison J. Molina, Oscar Samejima, Itaru Masumoto, Hiroshi Kouprina, Natalay Larionov, Vladimir Prior, Ian A. Earnshaw, William C. TI 3D-CLEM Reveals that a Major Portion of Mitotic Chromosomes Is Not Chromatin SO MOLECULAR CELL LA English DT Article ID METAPHASE CHROMOSOMES; ELECTRON-MICROSCOPY; CELL-CYCLE; ORGANIZATION; KINETOCHORE; MITOSIS; PROTEIN; FIBERS; DNA; ULTRASTRUCTURE AB Recent studies have revealed the importance of Ki-67 and the chromosome periphery in chromosome structure and segregation, but little is known about this elusive chromosome compartment. Here we used correlative light and serial block-face scanning electron microscopy, which we term 3D-CLEM, to model the entire mitotic chromosome complement at ultra-structural resolution. Prophase chromosomes exhibit a highly irregular surface appearance with a volume smaller than metaphase chromosomes. This may be because of the absence of the periphery, which associates with chromosomes only after nucleolar disassembly later in prophase. Indeed, the nucleolar volume almost entirely accounts for the extra volume found in metaphase chromosomes. Analysis of wild-type and Ki-67-depleted chromosomes reveals that the periphery comprises 30%-47% of the entire chromosome volume and more than 33% of the protein mass of isolated mitotic chromosomes determined by quantitative proteomics. Thus, chromatin makes up a surprisingly small percentage of the total mass of metaphase chromosomes. C1 [Booth, Daniel G.; Molina, Oscar; Samejima, Itaru; Earnshaw, William C.] Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3BF, Midlothian, Scotland. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Lab Cell Engn, Dept Frontier Res, Kisarazu, Chiba 2920818, Japan. [Kouprina, Natalay; Larionov, Vladimir] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Beckett, Alison J.; Prior, Ian A.] Univ Liverpool, Inst Translat Med, Div Cellular & Mol Physiol, Biomed Electron Microscopy Unit, Crown St, Liverpool L69 3BX, Merseyside, England. RP Booth, DG; Earnshaw, WC (reprint author), Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3BF, Midlothian, Scotland. EM daniel.booth@ed.ac.uk; bill.earnshaw@ed.ac.uk OI Prior, Ian/0000-0002-4055-5161 FU Wellcome Trust [073915, 077707, 092076]; NWCR FX We thank Leonid Mirny for helpful discussions and suggestions. This work was supported by The Wellcome Trust, of which W.C.E. is a Principal Research Fellow (grant number 073915). I.A.P. gratefully acknowledges support from NWCR. The Wellcome Trust Centre for Cell Biology is supported by Wellcome Trust core grants 077707 and 092076. NR 58 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD NOV 17 PY 2016 VL 64 IS 4 BP 790 EP 802 DI 10.1016/j.molcel.2016.10.009 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RR UT WOS:000389515400015 PM 27840028 ER PT J AU Woroniecki, RP Ng, DK Limou, S Winkler, CA Reidy, KJ Mitsnefes, M Sampson, MG Wong, CS Warady, BA Furth, SL Kopp, JB Kaskel, FJ AF Woroniecki, Robert P. Ng, Derek K. Limou, Sophie Winkler, Cheryl A. Reidy, Kimberly J. Mitsnefes, Mark Sampson, Matthew G. Wong, Craig S. Warady, Bradley A. Furth, Susan L. Kopp, Jeffrey B. Kaskel, Frederick J. TI Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis SO FRONTIERS IN PEDIATRICS LA English DT Article DE cardiovascular; left ventricular hypertrophy; chronic renal disease; FSGS; children ID CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; MARGINAL STRUCTURAL MODELS; GENETIC-VARIANTS; BLOOD-PRESSURE; HYPERTENSION; PROGRESSION; RISK; NEPHROPATHY; EPIDEMIOLOGY AB Background and objectives: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children. Design, setting, participants, and measurements: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease. Results: A total of 140 AA children in the CKiD study were genotyped. High risk (HR) APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p < 0.001. FSGS was the most common cause of glomerular disease in children with HR APOL1 (89%; 25/28). Of 32 AA children with FSGS, 25 (78%) had HR APOL1. Compared to children with low risk APOL1 and FSGS (comprising 36 non-AA and 7 AA), children with HR APOL1 developed FSGS at a later age, 12.0 (IQR: 9.5, 12.5) vs. 5.5 (2.5, 11.5) years, p = 0.004, had a higher prevalence of uncontrolled hypertension (52 vs. 33%, p = 0.13), left ventricular hypertrophy (LVH) (53 vs. 12%, p < 0.01), C-reactive protein > 3 mg/l (33 vs. 15%, p = 0.12), and obesity (48 vs. 19%, p = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. Conclusion: AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population. C1 [Woroniecki, Robert P.] Stony Brook Childrens Hosp, Stony Brook, NY 11794 USA. [Ng, Derek K.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Limou, Sophie; Winkler, Cheryl A.] NCI, Basic Res Lab, Frederick Natl Lab, NIH,Leidos Biomed, Frederick, MD 21701 USA. [Reidy, Kimberly J.; Kaskel, Frederick J.] Childrens Hosp Montefiore, Pediat Nephrol, Bronx, NY USA. [Mitsnefes, Mark] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Sampson, Matthew G.] Univ Michigan, Sch Med, Div Pediat Nephrol, Ann Arbor, MI USA. [Wong, Craig S.] Univ New Mexico, Pediat Nephrol, Albuquerque, NM 87131 USA. [Warady, Bradley A.] Childrens Mercy Hosp, Div Pediat Nephrol, Kansas City, MO 64108 USA. [Furth, Susan L.] Univ Penn, Philadelphia, PA 19104 USA. [Kopp, Jeffrey B.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Woroniecki, RP (reprint author), Stony Brook Childrens Hosp, Stony Brook, NY 11794 USA. EM robert.woroniecki@stonybrookmedicine.edu FU NCATS NIH HHS [UL1 TR001425, UL1 TR001073] NR 28 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PD NOV 17 PY 2016 VL 4 AR 122 DI 10.3389/fped.2016.00122 PG 9 WC Pediatrics SC Pediatrics GA EC6IP UT WOS:000388240000001 PM 27900314 ER PT J AU Bloomfield, MAP Ashok, AH Volkow, ND Howes, OD AF Bloomfield, Michael A. P. Ashok, Abhishekh H. Volkow, Nora D. Howes, Oliver D. TI The effects of Delta(9)-tetrahydrocannabinol on the dopamine system SO NATURE LA English DT Review ID D-2/D-3 RECEPTOR AVAILABILITY; POSITRON-EMISSION-TOMOGRAPHY; MARIJUANA SMOKE EXPOSURE; NUCLEUS-ACCUMBENS SHELL; CHRONIC CANNABIS USERS; IN-VIVO MICRODIALYSIS; FREELY-MOVING RATS; WORKING-MEMORY; PREFRONTAL CORTEX; OPIOID RECEPTORS AB The effects of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC. C1 [Bloomfield, Michael A. P.; Ashok, Abhishekh H.; Howes, Oliver D.] Imperial Coll London, Inst Clin Sci, Hammersmith Hosp, Psychiat Imaging Grp,Robert Steiner MR Unit,MRC C, London W12 0NN, England. [Bloomfield, Michael A. P.; Ashok, Abhishekh H.; Howes, Oliver D.] Imperial Coll London, Inst Clin Sci, Psychiat Imaging Grp, Fac Med, Du Cane Rd, London W12 0NN, England. [Bloomfield, Michael A. P.] UCL, Div Psychiat, 6th Floor,Maple House,149 Tottenham Court Rd, London WC1T 7NF, England. [Bloomfield, Michael A. P.; Ashok, Abhishekh H.; Howes, Oliver D.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, De Crespigny Pk, London SE5 8AF, England. [Bloomfield, Michael A. P.] UCL, Clin Psychopharmacol Unit, Res Dept Clin Educ & Hlth Psychol, 1-19 Torrington Pl, London WC1E 6BT, England. [Volkow, Nora D.] NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. RP Howes, OD (reprint author), Imperial Coll London, Inst Clin Sci, Hammersmith Hosp, Psychiat Imaging Grp,Robert Steiner MR Unit,MRC C, London W12 0NN, England.; Howes, OD (reprint author), Imperial Coll London, Inst Clin Sci, Psychiat Imaging Grp, Fac Med, Du Cane Rd, London W12 0NN, England.; Howes, OD (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, De Crespigny Pk, London SE5 8AF, England. EM oliver.howes@csc.mrc.ac.uk FU Medical Research Council (UK) [MC-A656-5QD30] FX We thank V. M. Rajagopal and Nature for assistance with illustrations. This work was funded by a Medical Research Council (UK) Grant to O.D.H. (MC-A656-5QD30). NR 137 TC 0 Z9 0 U1 32 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD NOV 17 PY 2016 VL 539 IS 7629 BP 369 EP 377 DI 10.1038/nature20153 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC5GP UT WOS:000388161700043 PM 27853201 ER PT J AU Witherspoon, JW Meilleur, KG AF Witherspoon, Jessica W. Meilleur, Katherine G. TI Review of RyR1 pathway and associated pathomechanisms SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Review DE RyR1; Myopathies; Skeletal; Muscle; Oxidative; Stress; Excitation-contraction; Pathomechanism; Treatment; Mitochondria; Post-translational modifications ID MUSCLE RYANODINE RECEPTOR; CENTRAL CORE DISEASE; CALCIUM-RELEASE CHANNELS; CONGENITAL NEUROMUSCULAR DISEASE; KING-DENBOROUGH-SYNDROME; COUPLED REDOX REGULATION; CYTOCHROME-C-OXIDASE; UNIFORM TYPE-1 FIBER; KNOCK-IN MICE; II-III LOOP AB Ryanodine receptor isoform-1 (RyR1) is a major calcium channel in skeletal muscle important for excitation-contraction coupling. Mutations in the RYR1 gene yield RyR1 protein dysfunction that manifests clinically as RYR1-related congenital myopathies (RYR1-RM) and/or malignant hyperthermia susceptibility (MHS). Individuals with RYR1-RM and/or MHS exhibit varying symptoms and severity. The symptoms impair quality of life and put patients at risk for early mortality, yet the cause of varying severity is not well understood. Currently, there is no Food and Drug Administration (FDA) approved treatment for RYR1-RM. Discovery of effective treatments is therefore critical, requiring knowledge of the RyR1 pathway. The purpose of this review is to compile work published to date on the RyR1 pathway and to implicate potential regions as targets for treatment. The RyR1 pathway is comprised of protein-protein interactions, protein-ligand interactions, and post-translational modifications, creating an activation/regulatory macromolecular complex. Given the complexity of this pathway, we divided these interactions and modifications into six regulatory groups. Three of several RyR1 interacting proteins, FK506-binding protein 12 (FKBP12), triadin, and calmodulin, were identified as playing important roles across all groups and may serve as promising target sites for treatment. Also, variability in disease severity may be influenced by prolongation or hyperactivity of post-translational modifications resulting from RyR1 dysfunction. C1 [Witherspoon, Jessica W.; Meilleur, Katherine G.] NINR, Tissue Injury Branch, Neuromuscular Symptoms Unit, NIH, Bethesda, MD 20814 USA. RP Witherspoon, JW (reprint author), NINR, Tissue Injury Branch, Neuromuscular Symptoms Unit, NIH, Bethesda, MD 20814 USA. EM jessica.witherspoon@nih.gov NR 159 TC 0 Z9 0 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD NOV 17 PY 2016 VL 4 AR 121 DI 10.1186/s40478-016-0392-6 PG 20 WC Neurosciences SC Neurosciences & Neurology GA EC2BT UT WOS:000387915100001 PM 27855725 ER PT J AU Anderson, ED Gorka, AP Schnermann, MJ AF Anderson, Erin D. Gorka, Alexander P. Schnermann, Martin J. TI Near-infrared uncaging or photosensitizing dictated by oxygen tension SO NATURE COMMUNICATIONS LA English DT Article ID PHOTODYNAMIC THERAPY; ELECTRON-TRANSFER; PHTHALOCYANINE PHOTOSENSITIZERS; SULFONATED PHTHALOCYANINES; SILICON PHTHALOCYANINES; METAL PHTHALOCYANINES; AQUEOUS-SOLUTIONS; TUMOR HYPOXIA; CELL-DEATH; LIGHT AB Existing strategies that use tissue-penetrant near-infrared light for the targeted treatment of cancer typically rely on the local generation of reactive oxygen species. This approach can be impeded by hypoxia, which frequently occurs in tumour microenvironments. Here we demonstrate that axially unsymmetrical silicon phthalocyanines uncage small molecules preferentially in a low-oxygen environment, while efficiently generating reactive oxygen species in normoxic conditions. Mechanistic studies of the uncaging reaction implicate a photoredox pathway involving photoinduced electron transfer to generate a key radical anion intermediate. Cellular studies demonstrate that the biological mechanism of action is O-2-dependent, with reactive oxygen species-mediated phototoxicity in normoxic conditions and small molecule uncaging in hypoxia. These studies provide a near-infrared light-targeted treatment strategy with the potential to address the complex tumour landscape through two distinct mechanisms that vary in response to the local O-2 environment. C1 [Anderson, Erin D.; Gorka, Alexander P.; Schnermann, Martin J.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Schnermann, MJ (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM martin.schnermann@nih.gov FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research; National Cancer Institute, National Institutes of Health FX We thank the Optical Microscopy and Analysis Laboratory (Advanced Technology Program, Frederick National Laboratory for Cancer Research) for assistance in obtaining confocal fluorescence images and the Frederick Center for Cancer Research Flow Cytometry Core (Cancer and Inflammation Program, NCI-Frederick) for help with the cell cycle analysis. We thank Dr Joseph Barchi for NMR assistance and Dr James Kelley for mass spectrometric analysis. Drs Hisataka Kobayashi and Murali Krishna are gratefully acknowledged for assistance with hypoxia experiments and insightful comments. Ms Luxi Qiao is acknowledged for assistance with initial synthetic studies. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research and the National Cancer Institute, National Institutes of Health. NR 56 TC 0 Z9 0 U1 35 U2 35 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 NOV 17 PY 2016 VL 7 AR 13378 DI 10.1038/ncomms13378 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC5CG UT WOS:000388150100001 PM 27853134 ER PT J AU Zarin, DA Tse, T Williams, RJ Carr, S AF Zarin, Deborah A. Tse, Tony Williams, Rebecca J. Carr, Sarah TI Trial Reporting in ClinicalTrials.gov - The Final Rule SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID REGISTRATION; ISSUES C1 [Zarin, Deborah A.; Tse, Tony; Williams, Rebecca J.] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Carr, Sarah] NIH, Off Sci Policy, Bldg 10, Bethesda, MD 20892 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 LM999999] NR 15 TC 7 Z9 7 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 17 PY 2016 VL 375 IS 20 BP 1998 EP 2004 DI 10.1056/NEJMsr1611785 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EC1HS UT WOS:000387856100015 PM 27635471 ER PT J AU Wyss, AB Jones, AC Bolling, AK Kissling, GE Chartier, R Dahlman, HJ Rodes, CE Archer, J Thornburg, J Schwarze, PE London, SJ AF Wyss, Annah B. Jones, Anna Ciesielski Bolling, Anette K. Kissling, Grace E. Chartier, Ryan Dahlman, Hans Jorgen Rodes, Charles E. Archer, Janet Thornburg, Jonathan Schwarze, Per E. London, Stephanie J. TI Particulate Matter 2.5 Exposure and Self-Reported Use of Wood Stoves and Other Indoor Combustion Sources in Urban Nonsmoking Homes in Norway SO PLOS ONE LA English DT Article ID AIR-QUALITY; OUTDOOR; PM2.5; CHANGEOUT; PROGRAM AB Few studies have examined particulate matter (PM) exposure from self-reported use of wood stoves and other indoor combustion sources in urban settings in developed countries. We measured concentrations of indoor PM < 2.5 microns (PM2.5) for one week with the MicroPEM (TM) nephelometer in 36 households in the greater Oslo, Norway metropolitan area. We examined indoor PM2.5 levels in relation to use of wood stoves and other combustion sources during a 7 day monitoring period using mixed effects linear models with adjustment for ambient PM2.5 levels. Mean hourly indoor PM2.5 concentrations were higher (p = 0.04) for the 14 homes with wood stove use (15.6 mu g/m(3)) than for the 22 homes without (12.6 mu g/m(3)). Moreover, mean hourly PM2.5 was higher (p = 0.001) for use of wood stoves made before 1997 (6 homes, 20.2 mu g/m(3)), when wood stove emission limits were instituted in Norway, compared to newer wood stoves (8 homes, 11.9 mu g/m(3)) which had mean hourly values similar to control homes. Increased PM2.5 levels during diary-reported burning of candles was detected independently of concomitant wood stove use. These results suggest that self-reported use of wood stoves, particularly older stoves, and other combustion sources, such as candles, are associated with indoor PM2.5 measurements in an urban population from a high income country. C1 [Wyss, Annah B.; Kissling, Grace E.; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, US Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Jones, Anna Ciesielski; Archer, Janet] Social & Sci Syst Inc, Durham, NC USA. [Bolling, Anette K.; Dahlman, Hans Jorgen; Schwarze, Per E.] Norwegian Inst Publ Hlth, Domain Infect Control & Environm Hlth, Dept Air Pollut & Noise, Oslo, Norway. [Chartier, Ryan; Rodes, Charles E.; Thornburg, Jonathan] Res Triangle Inst Int, Res Triangle Pk, NC USA. RP London, SJ (reprint author), NIEHS, Div Intramural Res, NIH, US Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM london2@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA ES049019]; NIEHS; RTI FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES049019). Anna Ciesielski Jones and Janet Archer are employed by Social & Scientific Systems, Inc., which serves as a contractor to the National Institutes of Health. The support for their effort on this project is provided via contract with NIEHS. Ryan Chartier and Jonathan Thornburg are employed by Research Triangle Institute International, a non-profit organization. RTI provided support in the form of salaries for these authors. Neither RTI nor SSS had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 20 TC 0 Z9 0 U1 13 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 17 PY 2016 VL 11 IS 11 AR e0166440 DI 10.1371/journal.pone.0166440 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC2AC UT WOS:000387910200032 PM 27855223 ER PT J AU Varsano, N Dadosh, T Kapishnikov, S Pereiro, E Shimoni, E Jin, XT Kruth, HS Leiserowitz, L Addadi, L AF Varsano, Neta Dadosh, Tali Kapishnikov, Sergey Pereiro, Eva Shimoni, Eyal Jin, Xueting Kruth, Howard S. Leiserowitz, Leslie Addadi, Lia TI Development of Correlative Cryo-soft X-ray Tomography and Stochastic Reconstruction Microscopy. A Study of Cholesterol Crystal Early Formation in Cells SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN ATHEROSCLEROTIC LESIONS; DIGESTIVE VACUOLE MEMBRANE; MACROPHAGE FOAM CELLS; UNESTERIFIED CHOLESTEROL; CRYOELECTRON TOMOGRAPHY; PLASMODIUM-FALCIPARUM; SUPPORTED MEMBRANES; PLASMA-MEMBRANE; FLUORESCENCE; TRANSPORT AB We have developed a high resolution correlative method involving cryo-soft X-ray tomography (cryo-SXT) and stochastic optical reconstruction microscopy (STORM), which provides information in three dimensions on large cellular volumes at 70 nm resolution. Cryo-SXT morphologically identified and localized aggregations of carbon-rich materials. STORM identified specific markers on the desired epitopes, enabling colocalization between the identified objects, in this case cholesterol crystals, and the cellular environment. The samples were studied under ambient and cryogenic conditions without dehydration or heavy metal staining. The early events of cholesterol crystal development were investigated in relation to atherosclerosis, using as model macrophage cell cultures enriched with LDL particles. Atherosclerotic plaques build up in arteries in a slow process involving cholesterol crystal accumulation. Cholesterol crystal deposition is a crucial stage in the pathological cascade. Our results show that cholesterol crystals can be identified and imaged at a very early stage on the cell plasma membrane and in intracellular locations. This technique can in principle be applied to other biological samples where specific molecular identification is required in conjunction with high resolution 3D-imaging. C1 [Varsano, Neta; Addadi, Lia] Weizmann Inst Sci, Dept Struct Biol, IL-76100 Rehovot, Israel. [Dadosh, Tali; Shimoni, Eyal] Weizmann Inst Sci, Dept Chem Res Support, IL-76100 Rehovot, Israel. [Leiserowitz, Leslie] Weizmann Inst Sci, Dept Mat & Interfaces, IL-76100 Rehovot, Israel. [Kapishnikov, Sergey] Helmholtz Zentrum Berlin, Soft Matter & Funct Mat, Albert Einstein Str 15, D-12489 Berlin, Germany. [Pereiro, Eva] ALBA Synchrotron Light Source, MISTRAL Beamline Expt Div, Barcelona 08290, Spain. [Jin, Xueting; Kruth, Howard S.] NHLBI, Expt Atherosclerosis Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Addadi, L (reprint author), Weizmann Inst Sci, Dept Struct Biol, IL-76100 Rehovot, Israel. EM sergey.kapishnikov@nbi.ku.dk; lia.addadi@weizmann.ac.il FU European Community's Seventh Framework Programme [283570]; Binational Science Foundation [2013045] FX We thank Prof. Benjamin Geiger and Michal Shemesh for their support in the cell culture growth and maintenance. We thank Dr. Sharon G. Wolf for her help with freezing and handling cryo-samples and for many fruitful discussions. We thank Helena Sabanay for her help and guidance with the TEM sample preparation. We thank Moshe Varsano for his great help with programming. Super-resolution microscopy was performed at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. Cryo-SXT experiments were performed at MISTRAL beamline at ALBA Synchrotron with the collaboration of ALBA staff. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 283570. This research was supported by the Binational Science Foundation (grant 2013045 to L.A. and H.S.K.). L.A. is the incumbent of the Dorothy and Patrick Gorman Professorial Chair of Biological Ultrastructure at the Weizmann Institute of Science. NR 58 TC 0 Z9 0 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 16 PY 2016 VL 138 IS 45 BP 14931 EP 14940 DI 10.1021/jacs.6b07584 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA EC8YE UT WOS:000388428200022 PM 27934213 ER PT J AU Wang, Z Zhang, FW Wang, ZT Liu, YJ Fu, X Jin, A Yung, BC Chen, W Fan, J Yang, XY Niu, G Chen, XY AF Wang, Zhe Zhang, Fuwu Wang, Zhantong Liu, Yijing Fu, Xiao Jin, Albert Yung, Bryant C. Chen, Wei Fan, Jing Yang, Xiangyu Niu, Gang Chen, Xiaoyuan TI Hierarchical Assembly of Bioactive Amphiphilic Molecule Pairs into Supramolecular Nanofibril Self-Supportive Scaffolds for Stem Cell Differentiation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NEURAL STEM; DEGRADABLE HYDROGELS; SUBVENTRICULAR ZONE; NEURITE OUTGROWTH; SYNAPSE FORMATION; PROGENITOR CELLS; DENTATE GYRUS; PEPTIDE; ACID; NANOSTRUCTURES AB Molecular design of biomaterials with unique features recapitulating nature's niche to influence biological activities has been a prolific area of investigation in chemistry and material science. The extracellular matrix (ECM) provides a wealth of bioactive molecules in supporting cell proliferation, migration, and differentiation. The well-patterned fibril and intertwining architecture of the ECM profoundly influences cell behavior and development. Inspired by those features from the ECM, we attempted to integrate essential biological factors from the ECM to design bioactive molecules to construct artificial self-supportive ECM mimics to advance stem cell culture. The synthesized biomimic molecules are able to hierarchically self-assemble into nanofibril hydrogels in physiological buffer driven by cooperative effects of electrostatic interaction, van der Waals forces, and intermolecular hydrogen bonds. In addition, the hydrogel is designed to be degradable during cell culture, generating extra space to facilitate cell migration, expansion, and differentiation. We exploited the bioactive hydrogel as a growth factor-free scaffold to support and accelerate neural stem cell adhesion, proliferation, and differentiation into functional neurons. Our study is a successful attempt to entirely use bioactive molecules for bottom-up self-assembly of new biomaterials mimicking the ECM to directly impact cell behaviors. Our strategy provides a new avenue in biomaterial design to advance tissue engineering and cell delivery. C1 [Wang, Zhe; Zhang, Fuwu; Wang, Zhantong; Liu, Yijing; Fu, Xiao; Yung, Bryant C.; Chen, Wei; Fan, Jing; Yang, Xiangyu; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Fu, Xiao; Jin, Albert] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov FU Center for Neuroscience and Regenerative Medicine (CNRM) program grant from the Department of Defense (DoD); Intramural Research Program (IRP) of National Institutes of Health (NIH) FX This study was supported, in part, by the Center for Neuroscience and Regenerative Medicine (CNRM) program grant from the Department of Defense (DoD) and the Intramural Research Program (IRP) of National Institutes of Health (NIH). NR 60 TC 0 Z9 0 U1 46 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 16 PY 2016 VL 138 IS 45 BP 15027 EP 15034 DI 10.1021/jacs.6b09014 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA EC8YE UT WOS:000388428200034 PM 27775895 ER PT J AU Nagy, GN Suardiaz, R Lopata, A Ozohanics, O Vekey, K Brooks, BR Leveles, I Toth, J Vertessy, BG Rosta, E AF Nagy, Gergely N. Suardiaz, Reynier Lopata, Anna Ozohanics, Oliver Vekey, Karoly Brooks, Bernard R. Leveles, Ibolya Toth, Judit Vertessy, Beata G. Rosta, Edina TI Structural Characterization of Arginine Fingers: Identification of an Arginine Finger for the Pyrophosphatase dUTPases SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID INFECTIOUS-ANEMIA VIRUS; MOLECULAR-DYNAMICS; ESCHERICHIA-COLI; GTP-HYDROLYSIS; ACTIVE-SITE; LIGAND-BINDING; DCTP DEAMINASE; FORCE-FIELD; C-TERMINUS; MECHANISM AB Arginine finger is a highly conserved and essential residue in many GTPase and AAA+ ATPase enzymes that completes the active site from a distinct protomer, forming contacts with the gamma-phosphate of the nucleotide. To date, no pyrophosphatase has been identified that employs an arginine finger fulfilling all of the above properties; all essential arginine fingers are used to catalyze the cleavage of the gamma-phosphate. Here, we identify and unveil the role of a conserved arginine residue in trimeric dUTPases that meets all the criteria established for arginine fingers. We found that the conserved arginine adjacent to the P-loop-like motif enables structural organization of the active site for efficient catalysis via its nucleotide coordination, while its direct electrostatic role in transition state stabilization is secondary. An exhaustive structure-based comparison of analogous, conserved arginines from nucleotide hydrolases and transferases revealed a consensus amino acid location and orientation for contacting the gamma-phosphate of the substrate nucleotide. Despite the structurally equivalent position, functional differences between arginine fingers of dUTPases and NTPases are explained on the basis of the unique chemistry performed by the pyrophosphatase dUTPases. C1 [Nagy, Gergely N.; Leveles, Ibolya; Vertessy, Beata G.] Budapest Univ Technol & Econ, Dept Biotechnol & Food Sci, H-1111 Budapest, Hungary. [Nagy, Gergely N.; Lopata, Anna; Leveles, Ibolya; Toth, Judit; Vertessy, Beata G.] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, H-1117 Budapest, Hungary. [Suardiaz, Reynier; Rosta, Edina] Kings Coll London, Dept Chem, London SE1 1DB, England. [Ozohanics, Oliver] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Organ Chem, MS Prote Res Grp, H-1117 Budapest, Hungary. [Vekey, Karoly] Hungarian Acad Sci, Res Ctr Nat Sci, Core Technol Ctr, H-1117 Budapest, Hungary. [Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Lopata, Anna] NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lopata, Anna] Univ Leeds, Fac Biol Sci, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Vekey, Karoly] Szent Istvan Univ, Ybl Miklos Fac Architecture & Civil Engn, H-1442 Budapest, Hungary. RP Nagy, GN; Vertessy, BG (reprint author), Budapest Univ Technol & Econ, Dept Biotechnol & Food Sci, H-1111 Budapest, Hungary.; Nagy, GN; Vertessy, BG (reprint author), Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, H-1117 Budapest, Hungary.; Rosta, E (reprint author), Kings Coll London, Dept Chem, London SE1 1DB, England. EM edina.rosta@kcl.ac.uk; vertessy@mail.bme.hu; edina.rosta@kcl.ac.uk RI Suardiaz, Reynier/B-2962-2008 OI Suardiaz, Reynier/0000-0002-1035-9020 FU EPSRC [EP/L000253/1]; EC [622711]; BBSRC [BB/N007700/1]; National Research, Development and Innovation Office Hungarian Scientific Research Fund [OTKA K115993, K119493, K109486]; MedinProt program of the Hungarian Academy of Sciences; International Centre for Genetic Engineering and Biotechnology [ICGEB CRP/HUN14-01]; European Commission FP7 Biostruct-X project [283570]; Bolyai Janos Research Scholarship of the Hungarian Academy of Sciences FX E.R. gratefully acknowledges Dr. Kei-ichi Okazaki for helpful discussions, and P.G. Jambrina for help with structural alignments. We acknowledge the European Synchrotron Radiation Facility for provision of synchrotron radiation facilities, and we would like to thank Alexander Popov for assistance in using beamline ID23-2. We gratefully thank Veronika Harmat for home source and synchrothron data collection, respectively. We acknowledge computer time on ARCHER granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://www.hecbiosim.ac.uk), supported by EPSRC (Grant EP/L000253/1) and the computational resources of the NIH biowulf cluster. R.S. acknowledges the EC for a Marie Curie fellowship (Project 622711). E.R acknowledges the BB/N007700/1 BBSRC grant. This work was supported by the National Research, Development and Innovation Office Hungarian Scientific Research Fund [OTKA K115993, K119493, K109486], the MedinProt program of the Hungarian Academy of Sciences, the International Centre for Genetic Engineering and Biotechnology [ICGEB CRP/HUN14-01], and the European Commission FP7 Biostruct-X project [Contract 283570]. J.T. is supported by the Bolyai Janos Research Scholarship of the Hungarian Academy of Sciences. NR 74 TC 0 Z9 0 U1 5 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 16 PY 2016 VL 138 IS 45 BP 15035 EP 15045 DI 10.1021/jacs.6b09012 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA EC8YE UT WOS:000388428200035 PM 27740761 ER PT J AU Onozawa, M Aplan, PD AF Onozawa, Masahiro Aplan, Peter D. TI Templated Sequence Insertion Polymorphisms in the Human Genome SO FRONTIERS IN CHEMISTRY LA English DT Review DE templated sequence insertion polymorphisms (TSIPs); mitochondria; polymorphism; human migration; DNA repair; LINE-1 retrotransposon ID INDEPENDENT LINE-1 RETROTRANSPOSITION; DOUBLE-STRAND BREAKS; REVERSE-TRANSCRIPTASE; DNA; REPAIR; CHROMOSOMES; MITOCHONDRIA; EVOLUTION; REPEATS; SITE AB Templated Sequence Insertion Polymorphism (TSIP) is a recently described form of polymorphism recognized in the human genome, in which a sequence that is templated from a distant genomic region is inserted into the genome, seemingly at random. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; Class 1 TSIPs show features of insertions that are mediated via the LINE-1 ORF2 protein, including (1) target-site duplication (TSD), (2) polyadenylation 10-30 nucleotides downstream of a "cryptic" polyadenylation signal, and (3) preference for insertion at a 5'-TTTT/A-3' sequence. In contrast, class 2 TSIPs show features consistent with repair of a DNA double-strand break (DSB) via insertion of a DNA "patch" that is derived from a distant genomic region. Survey of a large number of normal human volunteers demonstrates that most individuals have 25-30 TSIPs, and that these TSIPs track with specific geographic regions. Similar to other forms of human polymorphism, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases. C1 [Onozawa, Masahiro; Aplan, Peter D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Onozawa, Masahiro] Hokkaido Univ, Grad Sch Med, Dept Hematol, Sapporo, Hokkaido, Japan. RP Aplan, PD (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov FU intramural research program of the NCI, NIH; Japan Society for the Promotion of Science (JSPS) [26890001, 16K09836] FX This work was supported by the intramural research program of the NCI, NIH. MO was supported by the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Research Activity Start-up (26890001) and Grant-in-Aid for Scientific Research (C) (16K09836). NR 38 TC 0 Z9 0 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND EI 2296-2646 J9 FRONT CHEM JI Front. Chem. PD NOV 16 PY 2016 VL 4 AR 43 DI 10.3389/fchem.2016.00043 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA EC3IG UT WOS:000388019100001 PM 27900318 ER PT J AU Guo, M Zhang, C Wang, Y Feng, LH Wang, ZP Niu, WB Du, XY Tang, W Li, YN Wang, C Chen, ZW AF Guo, Meng Zhang, Cheng Wang, Yan Feng, Lizhao Wang, Zhengpin Niu, Wanbo Du, Xiaoyan Tang, Wang Li, Yuna Wang, Chao Chen, Zhenwen TI Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis SO SCIENTIFIC REPORTS LA English DT Article ID PREMATURE OVARIAN FAILURE; MOUSE GERM-CELLS; FOLLICLE FORMATION; FETAL OVARY; EARLY OOGENESIS; MPR-ALPHA; EXPRESSION; PGRMC1; PROTEIN; COMPLEX AB Well-timed progression of primordial folliculogenesis is essential for mammalian female fertility. Progesterone (P4) inhibits primordial follicle formation under physiological conditions; however, P4 receptor that mediates this effect and its underlying mechanisms are unclear. In this study, we used an in vitro organ culture system to show that progesterone receptor membrane component 1 (PGRMC1) mediated P4-induced inhibition of oocyte meiotic prophase I and primordial follicle formation. We found that membrane-impermeable BSA-conjugated P4 inhibited primordial follicle formation similar to that by P4. Interestingly, PGRMC1 and its partner serpine1 mRNA-binding protein 1 were highly expressed in oocytes in perinatal ovaries. Inhibition or RNA interference of PGRMC1 abolished the suppressive effect of P4 on follicle formation. Furthermore, P4-PGRMC1 interaction blocked oocyte meiotic progression and decreased intra-oocyte cyclic AMP (cAMP) levels in perinatal ovaries. cAMP analog dibutyryl cAMP reversed P4-PGRMC1 interaction-induced inhibition of meiotic progression and follicle formation. Thus, our results indicated that PGRMC1 mediated P4-induced suppression of oocyte meiotic progression and primordial folliculogenesis by decreasing intra-oocyte cAMP levels. C1 [Guo, Meng; Du, Xiaoyan] Capital Med Univ, Sch Basic Med Sci, Dept Lab Anim Sci, Beijing 100069, Peoples R China. [Zhang, Cheng] Capital Normal Univ, Coll Life Sci, Beijing 100048, Peoples R China. [Wang, Yan; Tang, Wang; Li, Yuna; Chen, Zhenwen] Capital Med Univ, Sch Basic Med Sci, Dept Med Genet & Dev Biol, Beijing 100069, Peoples R China. [Feng, Lizhao; Niu, Wanbo; Wang, Chao] China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100193, Peoples R China. [Wang, Zhengpin] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chen, ZW (reprint author), Capital Med Univ, Sch Basic Med Sci, Dept Med Genet & Dev Biol, Beijing 100069, Peoples R China.; Wang, C (reprint author), China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100193, Peoples R China. EM wangcam@cau.edu.cn; czwenteam@163.com FU National Natural Science Foundation of China [31402027]; Key Projects in the National Science & Technology Pillar Program [2015BAI09B01] FX This work was supported by the National Natural Science Foundation of China (No. 31402027) and Key Projects in the National Science & Technology Pillar Program (No. 2015BAI09B01). NR 50 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 16 PY 2016 VL 6 AR 36869 DI 10.1038/srep36869 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC4FD UT WOS:000388080800001 PM 27848973 ER PT J AU Rhee, DK Lim, JC Hockman, SC Ahmad, F Woo, DH Chung, YW Liu, SW Hockman, AL Manganiello, VC AF Rhee, Dong Keun Lim, Jung Chae Hockman, Steven C. Ahmad, Faiyaz Woo, Dong Ho Chung, Youn Wook Liu, Shiwei Hockman, Allison L. Manganiello, Vincent C. TI Effects of heterologous expression of human cyclic nucleotide phosphodiesterase 3A (hPDE3A) on redox regulation in yeast SO BIOCHEMICAL JOURNAL LA English DT Article ID DEPENDENT PROTEIN-KINASE; DISULFIDE BOND FORMATION; CYSTEINE-SULFINIC ACID; SACCHAROMYCES-CEREVISIAE; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; SIGNALING COMPLEXES; CELLULAR-RESPONSES; CAMP; PATHWAY AB Oxidative stress plays a pivotal role in pathogenesis of cardiovascular diseases and diabetes; however, the roles of protein kinase A (PKA) and human phosphodiesterase 3A (hPDE3A) remain unknown. Here, we show that yeast expressing wild-type (WT) hPDE3A or K13R hPDE3A (putative ubiquitinylation site mutant) exhibited resistance or sensitivity to exogenous hydrogen peroxide (H2O2), respectively. H2O2-stimulated ROS production was markedly increased in yeast expressing K13R hPDE3A (Oxidative stress Sensitive 1, OxiS1), compared with yeast expressing WT hPDE3A (Oxidative stress Resistant 1, OxiR1). In OxiR1, YAP1 and YAP1-dependent antioxidant genes were up-regulated, accompanied by a reduction in thioredoxin peroxidase. In OxiS1, expression of YAP1 and YAP1-dependent genes was impaired, and the thioredoxin system malfunctioned. H2O2 increased cyclic adenosine monophosphate (cAMP)-hydrolyzing activity of WT hPDE3A, but not K13R hPDE3A, through PKA-dependent phosphorylation of hPDE3A, which was correlated with its ubiquitinylation. The changes in antioxidant gene expression did not directly correlate with differences in cAMP-PKA signaling. Despite differences in their capacities to hydrolyze cAMP, total cAMP levels among OxiR1, OxiS1, and mock were similar; PKA activity, however, was lower in OxiS1 than in OxiR1 or mock. During exposure to H2O2, however, Sch9p activity, a target of Rapamycin complex 1-regulated Rps6 kinase and negative-regulator of PKA, was rapidly reduced in OxiR1, and Tpk1p, a PKA catalytic subunit, was diffusely spread throughout the cytosol, with PKA activation. In OxiS1, Sch9p activity was unchanged during exposure to H2O2, consistent with reduced activation of PKA. These results suggest that, during oxidative stress, TOR-Sch9 signaling might regulate PKA activity, and that post-translational modifications of hPDE3A are critical in its regulation of cellular recovery from oxidative stress. C1 [Rhee, Dong Keun; Hockman, Steven C.; Ahmad, Faiyaz; Chung, Youn Wook; Liu, Shiwei; Hockman, Allison L.; Manganiello, Vincent C.] NHLBI, Lab Biochem Physiol, Cardiovasc & Pulm Branch, NIH, Room 5N-307,Bldg 10, Bethesda, MD 20892 USA. [Lim, Jung Chae] NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. [Woo, Dong Ho] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. RP Rhee, DK (reprint author), NHLBI, Lab Biochem Physiol, Cardiovasc & Pulm Branch, NIH, Room 5N-307,Bldg 10, Bethesda, MD 20892 USA. EM rheed2@mail.nih.gov FU National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 64 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 473 BP 4205 EP 4225 DI 10.1042/BCJ20160572 PN 22 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK2LR UT WOS:000393759300009 PM 27647936 ER PT J AU Gueta, K David, A Cohen, T Menuchin-Lasowski, Y Nobel, H Narkis, G Li, LQ Love, P de Melo, J Blackshaw, S Westphal, H Ashery-Padan, R AF Gueta, Keren David, Ahuvit Cohen, Tsadok Menuchin-Lasowski, Yotam Nobel, Hila Narkis, Ginat Li, Liqi Love, Paul de Melo, Jimmy Blackshaw, Seth Westphal, Heiner Ashery-Padan, Ruth TI The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis SO DEVELOPMENT LA English DT Article DE Isl1; Ldb1; Lhx2; Retinogenesis ID HOMEODOMAIN TRANSCRIPTION FACTORS; PHOTORECEPTOR CELL FATE; RETINAL GANGLION-CELLS; HOMEOBOX GENE; MOUSE RETINA; CONTROLS PROLIFERATION; NEURAL DEVELOPMENT; PROGENITOR CELLS; EYE DEVELOPMENT; VERTEBRATE EYE AB The Lim domain-binding proteins are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. Using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the Vsx2 and Rax, and components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2-mediated complex is essential for generation of early-born photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early-and late-stage RPCs and in Muller glia. By contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. An intricate regulatory network exists that is mediated by Ldb1 and Ldb2, and promotes RPC proliferation and multipotency; it also controls specification of mammalian retina cells. C1 [Gueta, Keren; David, Ahuvit; Menuchin-Lasowski, Yotam; Nobel, Hila; Ashery-Padan, Ruth] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Cohen, Tsadok; Narkis, Ginat; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. [Li, Liqi; Love, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [de Melo, Jimmy; Blackshaw, Seth] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Sch Med, Baltimore, MD 21287 USA. RP Ashery-Padan, R (reprint author), Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Fac Med, IL-69978 Tel Aviv, Israel. EM ruthash@post.tau.ac.il FU United States - Israel Binational Science Foundation [2013016]; Israel Academy of Sciences and Humanities [228/14]; Claire and Amedee Maratier Institute for the Study of Blindness and Visual Disorders, Tel-Aviv University; National Institutes of Health [EY02056] FX This work was funded by the United States - Israel Binational Science Foundation (2013016), Israel Academy of Sciences and Humanities (228/14) and by the Claire and Amedee Maratier Institute for the Study of Blindness and Visual Disorders, Tel-Aviv University. The S.B. lab is funded by the National Institutes of Health (EY02056). Deposited in PMC for release after 12 months. NR 75 TC 0 Z9 0 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD NOV 15 PY 2016 VL 143 IS 22 BP 4182 EP 4192 DI 10.1242/dev.129734 PG 11 WC Developmental Biology SC Developmental Biology GA EJ8CY UT WOS:000393453300011 PM 27697904 ER PT J AU Wyss, AB Hashibe, M Lee, YCA Chuang, SC Muscat, J Chen, C Schwartz, SM Smith, E Zhang, ZF Morgenstern, H Wei, QY Li, GJ Kelsey, KT McClean, M Winn, DM Schantz, S Yu, GP Gillison, ML Zevallos, JP Boffetta, P Olshan, AF AF Wyss, Annah B. Hashibe, Mia Lee, Yuan-Chin Amy Chuang, Shu-Chun Muscat, Joshua Chen, Chu Schwartz, Stephen M. Smith, Elaine Zhang, Zuo-Feng Morgenstern, Hal Wei, Qingyi Li, Guojun Kelsey, Karl T. McClean, Michael Winn, Deborah M. Schantz, Stimson Yu, Guo-Pei Gillison, Maura L. Zevallos, Jose P. Boffetta, Paolo Olshan, Andrew F. TI Smokeless Tobacco Use and the Risk of Head and Neck Cancer: Pooled Analysis of US Studies in the INHANCE Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE chewing tobacco; head and neck neoplasms; snuff; tobacco; smokeless ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; ORAL-CANCER; UNITED-STATES; EPIDEMIOLOGY CONSORTIUM; HUMAN-PAPILLOMAVIRUS; ETIOLOGICAL FACTORS; INTERNATIONAL HEAD; PHARYNGEAL CANCER; ALCOHOL-USE AB Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco. C1 [Wyss, Annah B.] NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27599 USA. [Wyss, Annah B.; Olshan, Andrew F.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hashibe, Mia; Lee, Yuan-Chin Amy] Univ Utah, Sch Med, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. [Hashibe, Mia; Lee, Yuan-Chin Amy] Huntsman Canc Inst, Salt Lake City, UT USA. [Chuang, Shu-Chun] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Muscat, Joshua] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Chen, Chu; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Ctr, Durham, NC USA. [Li, Guojun] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Li, Guojun] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Div Surg, Houston, TX 77030 USA. [Kelsey, Karl T.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [McClean, Michael] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schantz, Stimson; Yu, Guo-Pei] New York Eye & Ear Infirm, Dept Otolaryngol, New York, NY 10003 USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing, Peoples R China. [Gillison, Maura L.] Ohio State Univ, Dept Internal Med, Wexner Med Ctr, Columbus, OH 43210 USA. [Zevallos, Jose P.] Univ N Carolina, Sch Med, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. RP Wyss, AB (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27599 USA. EM annah.wyss@nih.gov FU Union for International Cancer Control International Cancer Technology Transfer Fellowship; National Cancer Institute (NCI), National Institutes of Health (NIH) [T32CA09330, R03CA113157]; National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) [T32ES007018, P30ES010126]; National Institutes of Health, NIEHS; NIH [P01CA068384, K07CA104231, R01CA048896, R01DE012609, NIDCR R01DE11979, NIDCR R01DE13110, NIH FIRCA TW01500, R01CA61188, R01CA90731-01, P50CA90388]; Veterans Affairs Merit Review Funds; NIEHS [P30ES010126]; Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; National Institutes of Health, NCI; National Institute of Health [R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667, R01ES11740, R01CA131274, R01CA51845, R01CA078609, R01CA100679, DE016631] FX This work was supported by a Union for International Cancer Control International Cancer Technology Transfer Fellowship; by the National Cancer Institute (NCI) (grants T32CA09330 and R03CA113157) and the National Institute of Environmental Health Sciences (NIEHS) (grants T32ES007018 and P30ES010126), National Institutes of Health (NIH); and by the Intramural Research Program of the National Institutes of Health, NIEHS. The individual studies were funded by the following institutions and grants-New York multicenter study (17): NIH (grants P01CA068384 and K07CA104231); Seattle study (15, 18): NIH (grants R01CA048896 and R01DE012609); Iowa study (19): NIH (grants NIDCR R01DE11979, NIDCR R01DE13110, and NIH FIRCA TW01500) and the Veterans Affairs Merit Review Funds; North Carolina studies (13, 23): NIH (grants R01CA61188 and R01CA90731-01) and (in part) the NIEHS (grant P30ES010126); Los Angeles study (20): NIH (grants P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, and R21ES011667) and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Houston study (21): NIH (grants R01ES11740 and R01CA131274); US multicenter study (16): Intramural Research Program of the National Institutes of Health, NCI; New York Memorial Sloan Kettering Cancer Center study (24): NIH (grant R01CA51845); Boston study (14): NIH (grants R01CA078609 and R01CA100679); Baltimore study (22): NIH (grant DE016631). NR 53 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 15 PY 2016 VL 184 IS 10 BP 703 EP 716 DI 10.1093/aje/kww075 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI7ZW UT WOS:000392724700001 ER PT J AU Freedman, ND AF Freedman, Neal D. TI Invited Commentary: Smokeless Tobacco-An Important Contributor to Cancer, but More Work Is Needed SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE case-control studies; cigarettes; head and neck neoplasms; smokeless tobacco ID CURRENT CIGARETTE-SMOKING; UNITED-STATES; ADULTS; TRENDS AB In this issue of the Journal, Wyss et al. (Am J Epidemiol. 2016; 184(10): 703-716) describe the association between use of smokeless tobacco and head and neck cancer in 11 US case-control studies. Despite use by an estimated 300 million people worldwide and prior evidence for a causal association with cancer, these products remain understudied. Data are particularly needed for persons who do not use cigarettes or other smoking tobacco products. With 6,772 cancer cases and 8,375 controls, the current study is larger than previous efforts, allowing evaluation of associations among never cigarette smokers. Importantly, snuff use was positively associated with head and neck cancer, particularly for cancers of the oral cavity, whereas associations were weaker for chewing tobacco. Associations were observed among never cigarette smokers but not among ever cigarette smokers. Yet, despite the large sample size, only 44 cases and 62 controls had used snuff and only 61 cases and 96 controls had used chewing tobacco in the absence of cigarettes, precluding detailed examinations of dose response and cessation. Future studies set in high-prevalence populations with detailed assessment of lifetime use are needed to better understand the cancer risks of exclusive smokeless tobacco use and dual use of smokeless tobacco with other tobacco products, including cigarettes. C1 [Freedman, Neal D.] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Freedman, ND (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Way,MSC 9768, Rockville, MD 20850 USA. EM freedmanne@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 11 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 15 PY 2016 VL 184 IS 10 BP 717 EP 719 DI 10.1093/aje/kww076 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI7ZW UT WOS:000392724700002 ER PT J AU Peterson, DA Littlewort, GC Bartlett, MS Macerollo, A Perlmutter, JS Jinnah, HA Hallett, M Sejnowski, TJ AF Peterson, David A. Littlewort, Gwen C. Bartlett, Marian S. Macerollo, Antonella Perlmutter, Joel S. Jinnah, H. A. Hallett, Mark Sejnowski, Terrence J. TI Objective, computerized video-based rating of blepharospasm severity SO NEUROLOGY LA English DT Article ID DEEP-BRAIN-STIMULATION; BLINK RATE; DYSTONIA; MULTICENTER; SCALES; TOXIN AB Objective: To compare clinical rating scales of blepharospasm severity with involuntary eye closures measured automatically from patient videos with contemporary facial expression software. Methods: We evaluated video recordings of a standardized clinical examination from 50 patients with blepharospasm in the Dystonia Coalition's Natural History and Biorepository study. Eye closures were measured on a frame-by-frame basis with software known as the Computer Expression Recognition Toolbox (CERT). The proportion of eye closure time was compared with 3 commonly used clinical rating scales: the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale. Results: CERT was reliably able to find the face, and its eye closure measure was correlated with all of the clinical severity ratings (Spearman rho = 0.56, 0.52, and 0.56 for the Burke-FahnMarsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale, respectively, all p < 0.0001). Conclusions: The results demonstrate that CERT has convergent validity with conventional clinical rating scales and can be used with video recordings to measure blepharospasm symptom severity automatically and objectively. Unlike EMG and kinematics, CERT requires only conventional video recordings and can therefore be more easily adopted for use in the clinic. C1 [Peterson, David A.; Sejnowski, Terrence J.] Univ Calif San Diego, Computat Neurobiol Lab, Salk Inst Biol Studies, La Jolla, CA 92093 USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Howard Hughes Med Inst, Salk Inst Biol Studies, La Jolla, CA 92093 USA. [Peterson, David A.; Littlewort, Gwen C.; Bartlett, Marian S.; Sejnowski, Terrence J.] Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA. [Peterson, David A.; Sejnowski, Terrence J.] Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA. [Littlewort, Gwen C.; Bartlett, Marian S.] Univ Calif San Diego, Machine Percept Lab, La Jolla, CA 92093 USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Macerollo, Antonella] UCL, Inst Neurol, Natl Hosp Neurol & Neurosurg, Sobell Dept Motor Neurosci & Movement Disorders, London, England. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Program Phys Therapy, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Program Occupat Therapy, St Louis, MO USA. [Jinnah, H. A.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Peterson, DA (reprint author), Univ Calif San Diego, Computat Neurobiol Lab, Salk Inst Biol Studies, La Jolla, CA 92093 USA.; Peterson, DA (reprint author), Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 USA.; Peterson, DA (reprint author), Univ Calif San Diego, Kavli Inst Brain & Mind, La Jolla, CA 92093 USA. EM dap@salk.edu FU Dystonia Coalition from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences [NS065701, TR001456]; National Institute of Neurologic Disorders and Stroke; Bachmann-Strauss Dystonia & Parkinson Foundation; Benign Essential Blepharospasm Research Foundation; Kavli Institute for Brain and Mind at UCSD; National Institute of Mental Health [NIMH 5T32-MH020002]; National Science Foundation (Temporal Dynamics of Learning Center); National Science Foundation (Science of Learning Center) [SMA-1041755]; National Science Foundation (program in Mind, Machines, Motor Control) [EFRI-1137279]; National Institute of Neurologic Disorders and Stroke Intramural Program FX This study was funded by the Dystonia Coalition (NS065701 and TR001456) from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences and the National Institute of Neurologic Disorders and Stroke, the Bachmann-Strauss Dystonia & Parkinson Foundation, the Benign Essential Blepharospasm Research Foundation, the Kavli Institute for Brain and Mind at UCSD, the National Institute of Mental Health (NIMH 5T32-MH020002), and the National Science Foundation (the Temporal Dynamics of Learning Center, a Science of Learning Center [SMA-1041755] and the program in Mind, Machines, Motor Control [EFRI-1137279]). Dr. Hallett is supported by the National Institute of Neurologic Disorders and Stroke Intramural Program. None of the sponsors were involved in study design, collection, analysis, and interpretation of data; writing the report; or decision to submit the article for publication. NR 27 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 15 PY 2016 VL 87 IS 20 BP 2146 EP 2153 DI 10.1212/WNL.0000000000003336 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1KM UT WOS:000392236100016 PM 27770067 ER PT J AU Haass-Koffler, CL Henry, AT Melkus, G Simms, JA Naemmuddin, M Nielsen, CK Lasek, AW Magill, M Schwandt, ML Momenan, R Hodgkinson, CA Bartlett, SE Swift, RM Bonci, A Leggio, L AF Haass-Koffler, C. L. Henry, A. T. Melkus, G. Simms, J. A. Naemmuddin, M. Nielsen, C. K. Lasek, A. W. Magill, M. Schwandt, M. L. Momenan, R. Hodgkinson, C. A. Bartlett, S. E. Swift, R. M. Bonci, A. Leggio, L. TI Defining the role of corticotropin releasing factor binding protein in alcohol consumption SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID VENTRAL TEGMENTAL AREA; ANXIETY-RELATED BEHAVIOR; STRESS-INDUCED RELAPSE; FACTOR-RECEPTOR; C57BL/6J MICE; ETHANOL DRINKING; BINGE DRINKING; FACTOR CRF; RNA INTERFERENCE; COCAINE SEEKING AB The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD. C1 [Haass-Koffler, C. L.; Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, DICBR, 10 Ctr Dr 10CRC-15330,Room 1-5429, Bethesda, MD 20892 USA. [Haass-Koffler, C. L.; Leggio, L.] NIDA, IRP, NIH, 10 Ctr Dr 10CRC-15330,Room 1-5429, Bethesda, MD 20892 USA. [Haass-Koffler, C. L.; Swift, R. M.] Brown Univ, Dept Psychiat & Human Behav, Ctr Alcohol & Addict Studies, 121 South Main St, Providence, RI 02912 USA. [Haass-Koffler, C. L.; Magill, M.; Leggio, L.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. [Henry, A. T.] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA. [Melkus, G.] Univ Ottawa, Dept Radiol, Ottawa, ON, Canada. [Simms, J. A.; Naemmuddin, M.; Nielsen, C. K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Lasek, A. W.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Schwandt, M. L.] NIAAA, Off Clin Director, NIH, Bethesda, MD USA. [Momenan, R.] NIAAA, Clin Neuroimaging Res Core, NIH, Bethesda, MD USA. [Hodgkinson, C. A.] NIAAA, Lab Neurogenet, NIH, Rockville, MD 20852 USA. [Bartlett, S. E.] Queensland Univ Technol, Brisbane, Qld, Australia. [Bonci, A.] Johns Hopkins Univ, NIDA, Intramural Res Program, Baltimore, MD USA. [Bonci, A.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD USA. [Bonci, A.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, DICBR, 10 Ctr Dr 10CRC-15330,Room 1-5429, Bethesda, MD 20892 USA.; Leggio, L (reprint author), NIDA, IRP, NIH, 10 Ctr Dr 10CRC-15330,Room 1-5429, Bethesda, MD 20892 USA.; Haass-Koffler, CL (reprint author), Brown Univ, Dept Psychiat & Human Behav, Ctr Alcohol & Addict Studies, 121 South Main St, Providence, RI 02912 USA. EM carolina_haass-koffler@brown.edu; lorenzo.leggio@nih.gov FU UCSF Schools of Pharmacy and Medicine, and Strategic Opportunities Exploratory Award; NIAAA Division of Intramural Clinical and Biological Research; NIDA Intramural Research Program; State of California; NIH Fast Track Award; [K01AA023867]; [T-32AA007459] FX The authors would like to thank their funding sources: K01AA023867, T-32AA007459, UCSF Schools of Pharmacy and Medicine, and Strategic Opportunities Exploratory Award (CLH-K); NIAAA Division of Intramural Clinical and Biological Research (MLS, RMS, CAH, LL) and NIDA Intramural Research Program (AB, LL); State of California and NIH Fast Track Award (SEB). The authors also would like to thank Dr Audrey Seasholtz, University of Michigan, for providing the breeding pairs of the CRHBP KO mice; the NIAAA and Clinical Center staff involved in the human data collection at the NIH Intramural Research Program; and Ms. Karen Smith, NIH Library for assistance. NR 45 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD NOV 15 PY 2016 VL 6 DI 10.1038/tp.2016.208 PG 9 WC Psychiatry SC Psychiatry GA EI0AI UT WOS:000392133200006 PM 27845775 ER PT J AU Guardia, CM Farias, GG Jia, R Pu, J Bonifacino, JS AF Guardia, Carlos M. Farias, Ginny G. Jia, Rui Pu, Jing Bonifacino, Juan S. TI BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks SO CELL REPORTS LA English DT Article ID ARF-LIKE GTPASE; RETROGRADE AXONAL-TRANSPORT; SYNAPTIC VESICLE TRANSPORT; ALPHA-TUBULIN; POSTTRANSLATIONAL MODIFICATIONS; CAENORHABDITIS-ELEGANS; SPATIAL-DISTRIBUTION; NONNEURONAL CELLS; MOTOR PROTEINS; LATE ENDOSOMES AB The multiple functions of lysosomes are critically dependent on their ability to undergo bidirectional movement along microtubules between the center and the periphery of the cell. Centrifugal and centripetal movement of lysosomes is mediated by kinesin and dynein motors, respectively. We recently described a multi-subunit complex named BORC that recruits the small GTPase Arl8 to lysosomes to promote their kinesin-dependent movement toward the cell periphery. Here, we show that BORC and Arl8 function upstream of two structurally distinct kinesin types: kinesin-1 (KIF5B) and kinesin-3 (KIF1B beta and KIF1A). Remarkably, KIF5B preferentially moves lysosomes on perinuclear tracks enriched in acetylated alpha-tubulin, whereas KIF1B beta and KIF1A drive lysosome movement on more rectilinear, peripheral tracks enriched in tyrosinated alpha-tubulin. These findings establish BORC as a master regulator of lysosome positioning through coupling to different kinesins and microtubule tracks. Common regulation by BORC enables coordinate control of lysosome movement in different regions of the cell. C1 [Guardia, Carlos M.; Farias, Ginny G.; Jia, Rui; Pu, Jing; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of NICHD, NIH [ZIA HD001607] FX We thank X. Zhu for expert technical assistance, J. Lippincott-Schwartz for kind gifts of reagents, and T. Keren-Kaplan and D. Gershlick for helpful discussions. This work was funded by the Intramural Program of NICHD, NIH (ZIA HD001607). NR 61 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 15 PY 2016 VL 17 IS 8 BP 1950 EP 1961 DI 10.1016/j.celrep.2016.10.062 PG 12 WC Cell Biology SC Cell Biology GA EG2RZ UT WOS:000390893000005 PM 27851960 ER PT J AU Wada, S Neinast, M Jang, C Ibrahim, YH Lee, G Babu, A Li, J Hoshino, A Rowe, GC Rhee, J Martina, JA Puertollano, R Blenis, J Morley, M Baur, JA Seale, P Arany, Z AF Wada, Shogo Neinast, Michael Jang, Cholsoon Ibrahim, Yasir H. Lee, Gina Babu, Apoorva Li, Jian Hoshino, Atsushi Rowe, Glenn C. Rhee, James Martina, Jose A. Puertollano, Rosa Blenis, John Morley, Michael Baur, Joseph A. Seale, Patrick Arany, Zoltan TI The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue SO GENES & DEVELOPMENT LA English DT Article DE adipose tissue; beige fat; mitochondria; FLCN; mTOR; TFE3 ID TRANSCRIPTION FACTOR TFE3; LYSOSOMAL BIOGENESIS; OXIDATIVE-METABOLISM; SIGNAL INTEGRATION; RAG GTPASES; BEIGE FAT; ACTIVATION; FOLLICULIN; AUTOPHAGY; MUSCLE AB Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dube syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1 beta. Conversely, inducible expression of PGC-1 beta in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN mTOR TFE3 PGC-1 beta pathway separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue. C1 [Wada, Shogo; Neinast, Michael; Jang, Cholsoon; Babu, Apoorva; Li, Jian; Hoshino, Atsushi; Morley, Michael; Baur, Joseph A.; Seale, Patrick; Arany, Zoltan] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Wada, Shogo; Neinast, Michael; Jang, Cholsoon; Babu, Apoorva; Li, Jian; Hoshino, Atsushi; Morley, Michael; Baur, Joseph A.; Seale, Patrick; Arany, Zoltan] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Jang, Cholsoon] Princeton Univ, Chem & Integrat Genom, Princeton, NJ 08544 USA. [Ibrahim, Yasir H.; Lee, Gina; Blenis, John] Weill Cornell Med, Meyer Canc Ctr, Dept Pharmacol, New York, NY USA. [Rowe, Glenn C.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Rhee, James] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20814 USA. RP Arany, Z (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.; Arany, Z (reprint author), Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. EM zarany@mail.med.upenn.edu OI Rowe, Glenn/0000-0002-8195-9605 FU American Diabetes Association [1-16-PDF-117]; Toyobo Biotechnology Foundation; University of Pennsylvania [T32 GM-07229]; LAM Foundation; Tuberous Sclerosis Alliance; National Research Foundation of Korea; National Institutes of Health [T32GM007592, GM51405, HL121266]; Foundation for Anesthesia Education and Research; Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [DK098656, DK107667]; National Institute on Aging [AG043483]; National Heart, Lung, and Blood Institute [HL094499] FX We thank Bridget Gosis for technical support and critical discussion; Dr. Antonio Davila Jr. for expert advice; Dr. Eleftheria Maratos-Flier in Beth Israel Deaconess Medical Center/Harvard Medical School for CLAMS and DEXA analyses; Dr. Rexford Ahima, Dr. Frederick Anokye-Danso, and the Diabetes Research Center (DRC) Mouse Phenotyping Core at the University of Pennsylvania for in vivo respiration assay (P30-DK19525); Andrea Stout and Jasmine Zhao from the Cell and Developmental Biology Microscopy Core at the University of Pennsylvania for confocal microscopy imaging; Raymond Meade from the Electron Microscopy Resource laboratory at the Perelman School of Medicine, University of Pennsylvania, for TEM imaging; and Lan Cheng from the Histology and Gene Expression Core at the University of Pennsylvania Cardiovascular Institute for histology sample processing. S.W. is supported by an American Diabetes Association Postdoctoral Fellowship Award (1-16-PDF-117) and was supported by the Toyobo Biotechnology Foundation. M.N. is supported by a University of Pennsylvania Cell and Molecular Biology training grant (T32 GM-07229). G.L. is supported by the LAM Foundation, the Tuberous Sclerosis Alliance, and the National Research Foundation of Korea. J.R. was supported by grants from the National Institutes of Health [T32GM007592] and a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research. J.A.M. and R.P. were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. J.B. is supported by the National Institutes of Health (GM51405 and HL121266). J.A.B. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK098656) and National Institute on Aging (AG043483). Z.A. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK107667) and National Heart, Lung, and Blood Institute (HL094499). S.W. designed and conducted the experiments, analyzed/interpreted the data, and wrote the manuscript. C.J. and M.N. conducted experiments and analyzed data. Y.H.I., G.L., and J.A.B conducted the in vitro kinase assay and gave intellectual input on mTOR signaling. A.B. and M.M. performed bioinformatics analysis on RNA-seq data. J.L. and A.H. generated critical reagents. J.A.M. and R.P. generated the phospho-TFE3 (Ser320)-specific antibody and gave intellectual input on TFE3 biology. G.C.R., J.R., JAB., and P.S. assisted in critical discussion and study design. Z.A. designed the study, interpreted the data, and wrote the manuscript. NR 47 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 30 IS 22 BP 2551 EP 2564 DI 10.1101/gad.287953.116 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EF8XQ UT WOS:000390615700008 PM 27913603 ER PT J AU Si, CP Zhang, RH Wu, TS Lu, GM Hu, Y Zhang, H Xu, FH Wei, P Chen, K Tang, H Yeretssian, G Xiong, HB AF Si, Chuanping Zhang, Ruihua Wu, Tianshu Lu, Geming Hu, Yuan Zhang, Hui Xu, Feihong Wei, Peter Chen, Kang Tang, Hua Yeretssian, Garabet Xiong, Huabao TI Dendritic cell-derived nitric oxide inhibits the differentiation of effector dendritic cells SO ONCOTARGET LA English DT Article DE dendritic cell; iNOS ID KAPPA-B ACTIVATION; NLRP3 INFLAMMASOME; TYROSINE NITRATION; MECHANISM; SYNTHASES; IMMUNITY; DISEASE AB Dendritic cells (DCs) play a pivotal role in the development of effective immune defense while avoiding detrimental inflammation and autoimmunity by regulating the balance of adaptive immunity and immune tolerance. However, the mechanisms that govern the effector and regulatory functions of DCs are incompletely understood. Here, we show that DC-derived nitric oxide (NO) controls the balance of effector and regulatory DC differentiation. Mice deficient in the NO-producing enzyme inducible nitric oxide synthase (iNOS) harbored increased effector DCs that produced interleukin-12, tumor necrosis factor (TNF) and IL-6 but normal numbers of regulatory DCs that expressed IL-10 and programmed cell death-1 (PD-1). Furthermore, an iNOS-specific inhibitor selectively enhanced effector DC differentiation, mimicking the effect of iNOS deficiency in mice. Conversely, an NO donor significantly suppressed effector DC development. Furthermore, iNOS-/-DCs supported enhanced T cell activation and proliferation. Finally iNOS-/-mice infected with the enteric pathogen Citrobacter rodentium suffered more severe intestinal inflammation with concomitant expansion of effector DCs in colon and spleen. Collectively, our results demonstrate that DC-derived iNOS restrains effector DC development, and offer the basis of therapeutic targeting of iNOS in DCs to treat autoimmune and inflammatory diseases. C1 [Si, Chuanping; Zhang, Hui; Xiong, Huabao] Jining Med Coll, Inst Immunol & Mol Med, Rizhao 272067, Shandong, Peoples R China. [Zhang, Ruihua; Wu, Tianshu; Lu, Geming; Hu, Yuan; Xu, Feihong; Wei, Peter; Yeretssian, Garabet; Xiong, Huabao] Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY 10029 USA. [Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Perinatol Res Branch,NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Detroit, MI 48201 USA. [Tang, Hua] Taishan Med Univ, Inst Immunol, Tai An 271000, Shandong, Peoples R China. RP Xiong, HB (reprint author), Jining Med Coll, Inst Immunol & Mol Med, Rizhao 272067, Shandong, Peoples R China.; Zhang, RH; Xiong, HB (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY 10029 USA. EM ruihua.zhang@mssm.edu; huabao.xiong@mssm.edu FU US National Institutes of Health [P01DK072201, R56AI091871, R01AI104688] FX This work was supported by grants from the US National Institutes of Health (P01DK072201, R56AI091871 and R01AI104688 to H.X.). NR 32 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2016 VL 7 IS 46 BP 74834 EP 74845 DI 10.18632/oncotarget.11361 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GF UT WOS:000389632800032 PM 27556858 ER PT J AU Chen, T Xu, J Liu, GQ Liu, H Chen, MJ Qin, YF Wu, W Xia, YK Ji, CB Guo, XR Wen, J Wang, XR AF Chen, Ting Xu, Juan Liu, Guangquan Liu, Heng Chen, Minjian Qin, Yufeng Wu, Wei Xia, Yankai Ji, Chenbo Guo, Xirong Wen, Juan Wang, Xinru TI Genetic variants in PTPRD and risk of gestational diabetes mellitus SO ONCOTARGET LA English DT Article DE PTPRD; polymorphism; gestational diabetes mellitus; susceptibility ID GENOME-WIDE ASSOCIATION; PROTEIN-TYROSINE-PHOSPHATASE; WOMEN; LAR; METAANALYSIS; SIGNALS; DELTA; LEADS; SIGMA; MICE AB Genome-wide association studies (GWASs) showed that two single nucleotide polymorphisms (SNPs) (rs17584499 and rs649891) in the protein tyrosine phosphatase receptor type D (PTPRD) were associated with type 2 diabetes (T2D). We sought to determine the influence of the PTPRD variants on the gestational diabetes mellitus (GDM) risk. In this research, two SNPs in PTPRD reported in T2D GWASs and six PTPRD expression-related SNPs were genotyped in 964 GDM cases and 1,021 controls using the Sequenom platform. Logistic regression analyses in additive models showed consistently significant associations of PTPRD rs10511544 A>C, rs10756026 T>A and rs10809070 C>G with a decreased risk of GDM [ adjusted OR (95% CI) = 0.83 (0.72-0.97) for rs10511544; adjusted OR (95% CI) = 0.81 (0.70-0.94) for rs10756026; adjusted OR (95% CI) = 0.78 (0.65-0.92) for rs10809070]. Furthermore, the risk of GDM was significantly decreased with an increasing number of variant alleles of the three SNPs in a dose-dependent manner (P-trend = 0.008). Moreover, the haplotype containing variant alleles of the three SNPs were significantly associated with a decreased risk of GDM [ adjusted OR (95% CI) = 0.77 (0.64-0.92), P = 0.005], when compared with the most frequent haplotype. However, there were no significant associations for the SNPs reported in the T2D GWASs. Altogether, these findings indicate that the variants of rs10511544, rs10756026 and rs10809070 in PTPRD may contribute to a decreased susceptibility to GDM. Further validation in different ethnic backgrounds and biological function analyses are needed. C1 [Chen, Ting; Chen, Minjian; Wu, Wei; Xia, Yankai; Wang, Xinru] Nanjing Med Univ, Inst Toxicol, State Key Lab Reprod Med, Nanjing 211166, Jiangsu, Peoples R China. [Chen, Ting; Chen, Minjian; Wu, Wei; Xia, Yankai; Wang, Xinru] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing 211166, Jiangsu, Peoples R China. [Chen, Ting; Xu, Juan; Liu, Guangquan; Liu, Heng; Ji, Chenbo; Guo, Xirong; Wen, Juan] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Nanjing Matern & Child Hlth Care Inst, Nanjing 210004, Jiangsu, Peoples R China. [Xu, Juan] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Dept Obstet & Gynecol, Nanjing 210004, Jiangsu, Peoples R China. [Qin, Yufeng] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. [Ji, Chenbo; Guo, Xirong; Wen, Juan] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Dept Children Hlth Care, Nanjing 210004, Jiangsu, Peoples R China. RP Wang, XR (reprint author), Nanjing Med Univ, Inst Toxicol, State Key Lab Reprod Med, Nanjing 211166, Jiangsu, Peoples R China.; Wang, XR (reprint author), Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing 211166, Jiangsu, Peoples R China.; Wen, J (reprint author), Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Nanjing Matern & Child Hlth Care Inst, Nanjing 210004, Jiangsu, Peoples R China.; Wen, J (reprint author), Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Dept Children Hlth Care, Nanjing 210004, Jiangsu, Peoples R China. EM wenj2010@gmail.com; xrwang@njmu.edu.cn FU National Natural Science Foundation of China [81401232, 81600685]; Nanjing Medical Science and technique Development Foundation [QRX11222]; Natural Science Foundation of Jiangsu Province [BK20160141]; Science and Technology Development Fund of the Nanjing Medical University [2015NJMUZD062] FX This work was supported in part by the National Natural Science Foundation of China (81401232, 81600685), Nanjing Medical Science and technique Development Foundation (QRX11222), the Natural Science Foundation of Jiangsu Province (BK20160141), and the Science and Technology Development Fund of the Nanjing Medical University (2015NJMUZD062). NR 22 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2016 VL 7 IS 46 BP 76101 EP 76107 DI 10.18632/oncotarget.12599 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GF UT WOS:000389632800129 PM 27738328 ER PT J AU Galanternik, MV Lush, ME Piotrowski, T AF Galanternik, Marina Venero Lush, Mark E. Piotrowski, Tatjana TI Glypican4 modulates lateral line collective cell migration non cell-autonomously SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Primordium; Wnt/beta-catenin; FGF; Proteoglycans; Lateral line; Morphogenesis; Laminin gamma 1; Sulf1; Heparinase III; extl3/ext2; boxer; dackel ID HEPARAN-SULFATE PROTEOGLYCANS; SLOW MUSCLE PRECURSORS; WNT SIGNALING PATHWAYS; CONVERGENT EXTENSION; WNT/BETA-CATENIN; TISSUE MIGRATION; GASTRULATION MOVEMENTS; ZEBRAFISH MYOTOME; HSPG SYNTHESIS; CHEMOKINE AB Collective cell migration is an essential process during embryonic development and diseases such as cancer, and still much remains to be learned about how cell intrinsic and environmental cues are coordinated to guide cells to their targets. The migration-dependent development of the zebrafish sensory lateral line proves to be an excellent model to study how proteoglycans control collective cell migration in a vertebrate. Proteoglycans are extracellular matrix glycoproteins essential for the control of several signaling pathways including Wnt/beta-catenin, Fgf, BMP and Hh. In the lateral line primordium the modified sugar chains on proteoglycans are important regulators of cell polarity, ligand distribution and Fgf signaling. At least five proteoglycans show distinct expression patterns in the primordium; however, their individual functions have not been studied. Here, we describe the function of glypican4 during zebrafish lateral line development. glypican4 is expressed in neuromasts, interneuromast cells and muscle cells underlying the lateral line. knypek(fr6)/glypican4 mutants show severe primordium migration defects and the primordium often U-turns and migrates back toward the head. Our analysis shows that Glypican4 regulates the feedback loop between Wnt/beta-catenin/Fgf signaling in the primordium redundantly with other Heparan Sulfate Proteoglycans. In addition, the primordium migration defect is caused non-cell autonomously by the loss of cxcl12a-expressing muscle precursors along the myoseptum via downregulation of Hh. Our results show that glypican4 has distinct functions in primordium cells and cells in the environment and that both of these functions are essential for collective cell migration. (C) 2016 Published by Elsevier Inc. C1 [Galanternik, Marina Venero; Piotrowski, Tatjana] Stowers Inst Med Res, 1000 East 50th St, Kansas City, MO 64110 USA. [Galanternik, Marina Venero; Lush, Mark E.; Piotrowski, Tatjana] Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. [Galanternik, Marina Venero] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Piotrowski, T (reprint author), Stowers Inst Med Res, 1000 East 50th St, Kansas City, MO 64110 USA. EM pio@stowers.org FU American Cancer Research Scholar grant [RSG CCG 114528] FX We thank Dr. Solnica-Krezel for sharing the knypekfr6/glypican4 mutants, Dr. Hirsinger for providing the engrailed1a, 1b, 2a and patched2 plasmids and Ana Gabriel for cloning the id1 probe. We are grateful to Joaquin Navajas Acedo and all Piotrowski Lab members for valuable discussions and suggestions. We thank the University of Utah CZAR and Stowers Aquatics Facility for excellent fish husbandry. We also thank Dr. Hua Li from the Stowers Institute Bioinformatics Core for help with statistical analysis and Mark Miller for help with graphical design. This work was supported by an American Cancer Research Scholar grant (RSG CCG 114528) to T.P. and institutional support from the Stowers Institute for Medical Research. NR 71 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 419 IS 2 BP 321 EP 335 DI 10.1016/j.ydbio.2016.09.002 PG 15 WC Developmental Biology SC Developmental Biology GA EE4IV UT WOS:000389566400011 ER PT J AU Hart, GT Akkaya, M Chida, AS Wei, CW Jenks, SA Tipton, C He, CF Wendel, BS Skinner, J Arora, G Kayentao, K Ongoiba, A Doumbo, O Traore, B Narum, DL Jiang, N Crompton, PD Sanz, I Pierce, SK AF Hart, Geoffrey T. Akkaya, Munir Chida, Asiya S. Wei, Chungwen Jenks, Scott A. Tipton, Christopher He, Chenfeng Wendel, Ben S. Skinner, Jeff Arora, Gunjan Kayentao, Kassoum Ongoiba, Aissata Doumbo, Ogobara Traore, Boubacar Narum, David L. Jiang, Ning Crompton, Peter D. Sanz, Ignacio Pierce, Susan K. TI The Regulation of Inherently Autoreactive VH4-34-Expressing B Cells in Individuals Living in a Malaria-Endemic Area of West Africa SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PLASMODIUM-FALCIPARUM; NEUTRALIZING ANTIBODIES; AUTOIMMUNE-DISEASE; ACQUIRED-IMMUNITY; HIV-1 ANTIBODIES; 9G4 IDIOTOPE; GENE SEGMENT; INFECTION; RESPONSES AB Plasmodium falciparum malaria is a deadly infectious disease in which Abs play a critical role in naturally acquired immunity. However, the specificity and nature of Abs elicited in response to malaria are only partially understood. Autoreactivity and polyreactivity are common features of Ab responses in several infections and were suggested to contribute to effective pathogen-specific Ab responses. In this article, we report on the regulation of B cells expressing the inherently autoreactive VH4-34 H chain (identified by the 9G4 mAb) and 9G4(+) plasma IgG in adults and children living in a P. falciparum malaria-endemic area in West Africa. The frequency of 9G4(+) peripheral blood CD19(+) B cells was similar in United States adults and African adults and children; however, more 9G4(+) B cells appeared in classical and atypical memory B cell compartments in African children and adults compared with United States adults. The levels of 9G4(+) IgG increased following acute febrile malaria but did not increase with age as humoral immunity is acquired or correlate with protection from acute disease. This was the case, even though a portion of 9G4(+) B cells acquired phenotypes of atypical and classical memory B cells and 9G4(+) IgG contained equivalent numbers of somatic hypermutations compared with all other VHs, a characteristic of secondary Ab repertoire diversification in response to Ag stimulation. Determining the origin and function of 9G4(+) B cells and 9G4(+) IgG in malaria may contribute to a better understanding of the varied roles of autoreactivity in infectious diseases. C1 [Hart, Geoffrey T.; Akkaya, Munir; Skinner, Jeff; Arora, Gunjan; Crompton, Peter D.; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Chida, Asiya S.; Wei, Chungwen; Jenks, Scott A.; Sanz, Ignacio] Emory Univ, Div Rheumatol, Dept Med, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA. [Tipton, Christopher] Adapt Biotechnol Seattle, Seattle, WA 98102 USA. [He, Chenfeng; Jiang, Ning] Univ Texas Austin, Cockrell Sch Engn, Dept Biomed Engn, Austin, TX 78712 USA. [Wendel, Ben S.] Univ Texas Austin, McKetta Dept Chem Engn, Cockrell Sch Engn, Austin, TX 78712 USA. [Kayentao, Kassoum; Ongoiba, Aissata; Doumbo, Ogobara; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Int Ctr Excellence Res, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. [Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, NIH, Room 200B,MSC 8180,12441 Parklawn Dr, Rockville, MD 20852 USA. EM spierce@nih.gov OI AKKAYA, Munir/0000-0002-9949-9424 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Autoimmunity Center of Excellence - National Institutes of Health [5R37AI049660, U19 AI110483] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by Grants 5R37AI049660 and U19 AI110483 from the Autoimmunity Center of Excellence awarded by the National Institutes of Health (to I.S.). NR 51 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2016 VL 197 IS 10 BP 3841 EP 3849 DI 10.4049/jimmunol.1600491 PG 9 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600010 PM 27798155 ER PT J AU Riteau, N Radtke, AJ Shenderov, K Mittereder, L Oland, SD Hieny, S Jankovic, D Sher, A AF Riteau, Nicolas Radtke, Andrea J. Shenderov, Kevin Mittereder, Lara Oland, Sandra D. Hieny, Sara Jankovic, Dragana Sher, Alan TI Water-in-Oil-Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6-Dependent Pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; ANTIBODY-RESPONSES; DIFFERENTIATION; BCL6; T-HELPER-1; SIGNALS; INFLAMMASOME; MICROBIOTA; INDUCTION; ANTIGEN AB T follicular helper (Tfh) cells are a subset of CD4(+) T lymphocytes that promote the development of humoral immunity. Although the triggers required for the differentiation of the other major Th subsets are well defined, those responsible for Tfh cell responses are still poorly understood. We determined that mice immunized with peptide or protein Ags emulsified in IFA or related water-in-oil adjuvants develop a highly polarized response in which the majority of the Ag-specific CD4(+) T cells are germinal center-homing CXCR5(+)Bcl6(+) Tfh cells. Despite the absence of exogenous microbial pathogen-associated molecular patterns, the Tfh cell responses observed were dependent, in part, on MyD88. Importantly, in addition to IL-6, T cell-intrinsic type I IFN signaling is required for optimal Tfh cell polarization. These findings suggest that water-in-oil adjuvants promote Tfh cell-dominated responses by triggering endogenous alarm signals that, in turn, induce type I IFN-dependent differentiation pathway functioning in T cells. C1 [Riteau, Nicolas; Shenderov, Kevin; Mittereder, Lara; Oland, Sandra D.; Hieny, Sara; Jankovic, Dragana; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,50 South Dr, Bethesda, MD 20892 USA. [Radtke, Andrea J.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov OI Sher, Alan/0000-0001-7053-2895 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research and the Intramural Vaccine Adjuvant Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 32 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2016 VL 197 IS 10 BP 3884 EP 3893 DI 10.4049/jimmunol.1600883 PG 10 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600014 PM 27798160 ER PT J AU Chen, YJ Wilson, R O'Dell, S Guenaga, J Feng, Y Tran, K Chiang, CI Arendt, HE DeStefano, J Mascola, JR Wyatt, RT Li, YX AF Chen, Yajing Wilson, Richard O'Dell, Sijy Guenaga, Javier Feng, Yu Tran, Karen Chiang, Chi-I Arendt, Heather E. DeStefano, Joanne Mascola, John R. Wyatt, Richard T. Li, Yuxing TI An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4 BINDING-SITE; ENVELOPE GLYCOPROTEIN GP120; VIRUS TYPE-1 GP120; MONOCLONAL-ANTIBODY; CD4-BINDING SITE; STRUCTURAL BASIS; CROSS-LINKING; NONHUMAN-PRIMATES; MASS-SPECTROMETRY; IMMUNOGEN DESIGN AB Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120. To preferentially expose the CD4bs and direct the immune response away from the bridging sheet, resulting in an altered angle of approach, we engineered an immunogen consisting of gp120 core in complex with the prototypic CD4-induced Ab, 17b. This mAb directly contacts the bridging sheet but not the CD4bs. The complex was further stabilized by chemical crosslinking to prevent dissociation. Rabbits immunized with the crosslinked complex displayed earlier affinity maturation, achieving tier 1 virus neutralization compared with animals immunized with gp120 core alone. Immunization with the crosslinked complex induced transient Ab responses with binding specificity similar to the CD4bs-directed bNAbs. mAbs derived from complex-immunized rabbits displayed footprints on gp120 more distal from the bridging sheet as compared with previous vaccine-elicited CD4bs Abs, indicating that Env-Ab complexes effectively dampen immune responses to undesired immunodominant bridging sheet determinants. C1 [Chen, Yajing; Wyatt, Richard T.; Li, Yuxing] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Wilson, Richard; Guenaga, Javier; Feng, Yu; Tran, Karen; Wyatt, Richard T.; Li, Yuxing] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [O'Dell, Sijy] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chiang, Chi-I; Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. [Arendt, Heather E.; DeStefano, Joanne] Int AIDS Vaccine Initiat, Brooklyn, NY 11226 USA. [Wyatt, Richard T.] Scripps Ctr HIV Immunogen Discovery, La Jolla, CA 92037 USA. RP Li, YX (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM liy@ibbr.umd.edu FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01AI102766]; National Institute of Allergy and Infectious Diseases Development [P30AI36214, P01 AI104722, UM1 AI100663]; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; International AIDS Vaccine Initiative; United States Agency for International Development; Ministry of Foreign Affairs of the Netherlands; Bill and Melinda Gates Foundation FX This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant R01AI102766 (to Y.L.), National Institute of Allergy and Infectious Diseases Development Grant P30AI36214 to the Center for AIDS Research, University of California, San Diego (to Y.L.), Grants P01 AI104722 (to R.T.W. and Y.L.) and UM1 AI100663 (to R.T.W.), as well as funding from the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to J.R.M.). This work was also supported in part by the International AIDS Vaccine Initiative (to R.T.W.) with the generous support of United States Agency for International Development, the Ministry of Foreign Affairs of the Netherlands, and by the Bill and Melinda Gates Foundation; a full list of International AIDS Vaccine Initiative donors is available at http://www.iavi.org. NR 71 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2016 VL 197 IS 10 BP 3982 EP 3998 DI 10.4049/jimmunol.1601134 PG 17 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600023 PM 27815444 ER PT J AU Hu, X Valentin, A Dayton, F Kulkarni, V Alicea, C Rosati, M Chowdhury, B Gautam, R Broderick, KE Sardesai, NY Martin, MA Mullins, JI Pavlakis, GN Felber, BK AF Hu, Xintao Valentin, Antonio Dayton, Frances Kulkarni, Viraj Alicea, Candido Rosati, Margherita Chowdhury, Bhabadeb Gautam, Rajeev Broderick, Kate E. Sardesai, Niranjan Y. Martin, Malcolm A. Mullins, James I. Pavlakis, George N. Felber, Barbara K. TI DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-LYMPHOCYTE RESPONSES; CONSERVED REGIONS; RHESUS-MONKEYS; VIRAL LOADS; MACAQUES; CHALLENGE; INFECTION; COVERAGE; TYPE-1; CELLS AB HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24(gag) plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27(Gag). Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+CD107a(+)) targeting subdominant CE epitopes, compared with the responses elicited by the p57(gag) pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth. C1 [Hu, Xintao; Dayton, Frances; Kulkarni, Viraj; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Valentin, Antonio; Rosati, Margherita; Chowdhury, Bhabadeb; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Gautam, Rajeev; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut, Plymouth Meeting, PA 19462 USA. [Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Mullins, James I.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Mullins, James I.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Mullins, James I.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Pavlakis, GN; Felber, BK (reprint author), NCI, Vaccine Branch, Ctr Canc Res, POB B,Bldg 535,Room 206, Frederick, MD 21702 USA. EM george.pavlakis@nih.gov; barbara.felber@nih.gov RI bebarta, vikhyat/K-3476-2015 FU Intramural Research Program of the National Cancer Institute; National Institute of Allergy and Infectious Disease, National Institutes of Health (NIAID/NIH) [P01 AI057005]; University of Washington Centers for AIDS Research Molecular Profiling Computational Biology Core (NIH) [P30 AI27757]; NIAID/NIH Division of AIDS [HHSN272200800063C] FX This work was supported by the Intramural Research Program of the National Cancer Institute (to G.N.P. and B.K.F.), National Institute of Allergy and Infectious Disease, National Institutes of Health (NIAID/NIH), Grant P01 AI057005 (to M.A.M.), and the University of Washington Centers for AIDS Research Molecular Profiling Computational Biology Core (NIH Grant P30 AI27757; to J.I.M.). This work also was supported in part by the NIAID/NIH Division of AIDS under HIV Vaccine Design and Development Teams Contract HHSN272200800063C (to N.Y.S.). NR 60 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2016 VL 197 IS 10 BP 3999 EP 4013 DI 10.4049/jimmunol.1600697 PG 15 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600024 PM 27733554 ER PT J AU Bjornstad, ON Viboud, C AF Bjornstad, Ottar N. Viboud, Cecile TI Timing and periodicity of influenza epidemics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID TRANSMISSION; SEASONALITY; HUMIDITY; DYNAMICS; PATTERNS C1 [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bjornstad, ON (reprint author), Penn State Univ, Dept Entomol, University Pk, PA 16802 USA.; Bjornstad, ON (reprint author), Penn State Univ, Dept Biol, University Pk, PA 16802 USA. EM onb1@psu.edu NR 20 TC 1 Z9 1 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 15 PY 2016 VL 113 IS 46 BP 12899 EP 12901 DI 10.1073/pnas.1616052113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100031 PM 27810955 ER PT J AU Rogozin, IB Belinky, F Pavlenko, V Shabalina, SA Kristensen, DM Koonin, EV AF Rogozin, Igor B. Belinky, Frida Pavlenko, Vladimir Shabalina, Svetlana A. Kristensen, David M. Koonin, Eugene V. TI Evolutionary switches between two serine codon sets are driven by selection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tandem nucleotide substitutions; serine codon sets; purifying selection; positive selection; homoplasy ID LONG-BRANCH ATTRACTION; MULTIPLE MUTATIONS; PROTEIN EVOLUTION; DNA-POLYMERASE; SACCHAROMYCES-CEREVISIAE; PHYLOGENETIC ANALYSIS; MOLECULAR EVOLUTION; GENES; HYPERMUTABILITY; SUBSTITUTIONS AB Serine is the only amino acid that is encoded by two disjoint codon sets so that a tandem substitution of two nucleotides is required to switch between the two sets. Previously published evidence suggests that, for the most evolutionarily conserved serines, the codon set switch occurs by simultaneous substitution of two nucleotides. Here we report a genome-wide reconstruction of the evolution of serine codons in triplets of closely related species from diverse prokaryotes and eukaryotes. The results indicate that the great majority of codon set switches proceed by two consecutive nucleotide substitutions, via a threonine or cysteine intermediate, and are driven by selection. These findings imply a strong pressure of purifying selection in protein evolution, which in the case of serine codon set switches occurs via an initial deleterious substitution quickly followed by a second, compensatory substitution. The result is frequent reversal of amino acid replacements and, at short evolutionary distances, pervasive homoplasy. C1 [Rogozin, Igor B.; Belinky, Frida; Pavlenko, Vladimir; Shabalina, Svetlana A.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Kristensen, David M.] Univ Iowa, Biomed Engn Dept, Iowa City, IA 52242 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health FX We thank Michael Galperin, Kira Makarova, David Landsman, Joshua Cherry, and Yuri Wolf for helpful discussions and Olga Batyreva for statistical advice. This research was supported in part by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 47 TC 0 Z9 0 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 15 PY 2016 VL 113 IS 46 BP 13109 EP 13113 DI 10.1073/pnas.1615832113 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100068 PM 27799560 ER PT J AU Xie, ZQ Babiceanu, M Kumar, S Jia, YM Qin, FJ Barr, FG Li, H AF Xie, Zhongqiu Babiceanu, Mihaela Kumar, Shailesh Jia, Yuemeng Qin, Fujun Barr, Frederic G. Li, Hui TI Fusion transcriptome profiling provides insights into alveolar rhabdomyosarcoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE rhabdomyosarcoma; gene fusion; chimeric RNA; myogenesis; PAX3-FOXO1 ID CELL LUNG-CANCER; RNA-SEQ DATA; TARGET GENES; STEM-CELLS; EXPRESSION; IDENTIFICATION; TRANSLOCATION; ONCOPROTEIN; INDIVIDUALS; PROTEINS AB Gene fusions and fusion products were thought to be unique features of neoplasia. However, more and more studies have identified fusion RNAs in normal physiology. Through RNA sequencing of 27 human noncancer tissues, a large number of fusion RNAs were found. By analyzing fusion transcriptome, we observed close clusterings between samples of same or similar tissues, supporting the feasibility of using fusion RNA profiling to reveal connections between biological samples. To put the concept into use, we selected alveolar rhabdomyosarcoma (ARMS), a myogenic pediatric cancer whose exact cell of origin is not clear. PAX3-FOXO1 (paired box gene 3 fused with forkhead box O1) fusion RNA, which is considered a hallmark of ARMS, was recently found during normal muscle cell differentiation. We performed and analyzed RNA sequencing from various time points during myogenesis and uncovered many chimeric fusion RNAs. Interestingly, we found that the fusion RNA profile of RH30, an ARMS cell line, is most similar to the myogenesis time point when PAX3-FOXO1 is expressed. In contrast, full transcriptome clustering analysis failed to uncover this connection. Strikingly, all of the 18 chimeric RNAs in RH30 cells could be detected at the samemyogenic time point(s). In addition, the seven chimeric RNAs that follow the exact transient expression pattern as PAX3-FOXO1 are specific to rhabdomyosarcoma cells. Further testing with clinical samples also confirmed their specificity to rhabdomyosarcoma. These results provide further support for the link between at least some ARMSs and the PAX3-FOXO1-expressing myogenic cells and demonstrate that fusion RNA profiling can be used to investigate the etiology of fusion-gene-associated cancers. C1 [Xie, Zhongqiu; Babiceanu, Mihaela; Kumar, Shailesh; Jia, Yuemeng; Qin, Fujun; Li, Hui] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. [Barr, Frederic G.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Li, Hui] Univ Virginia, Ctr Canc, Charlottesville, VA 22908 USA. RP Li, H (reprint author), Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA.; Li, H (reprint author), Univ Virginia, Ctr Canc, Charlottesville, VA 22908 USA. EM hl9r@virginia.edu RI Qin, Fujun/I-8629-2016 FU St. Baldrick's V Scholar grant; intramural program of the National Cancer Institute FX We thank Drs. Carola Ponzetto and Riccardo Taulli for providing pBABE-PAX3-FOXO1 construct; Dr. Bishwanath Chatterjee for technical assistance; Drs. Dutta, Liang, Triche, Biegel, Mandahl, Ladanyi, Epstein, Shapiro, and Tronick for providing us the tumor cell lines; and Loryn Facemire and Fuming Yi for their technical support. This work is supported by St. Baldrick's V Scholar grant. F.G.B. is supported by the intramural program of the National Cancer Institute. NR 41 TC 1 Z9 1 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 15 PY 2016 VL 113 IS 46 BP 13126 EP 13131 DI 10.1073/pnas.1612734113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100071 PM 27799565 ER PT J AU Rui, LX Drennan, AC Ceribelli, M Zhu, F Wright, GW Huang, DW Xiao, WM Li, YG Grindle, KM Lu, L Hodson, DJ Shaffer, AL Zhao, H Xu, WH Yang, YD Staudt, LM AF Rui, Lixin Drennan, Amanda C. Ceribelli, Michele Zhu, Fen Wright, George W. Huang, Da Wei Xiao, Wenming Li, Yangguang Grindle, Kreg M. Lu, Li Hodson, Daniel J. Shaffer, Arthur L. Zhao, Hong Xu, Weihong Yang, Yandan Staudt, Louis M. TI Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE JAK1; epigenetics; histone modification; lymphoma; oncogene ID NF-KAPPA-B; STAT3; CANCER; MECHANISMS; DISEASE; TRANSCRIPTION; DEREGULATION; SIGNATURES; MUTATIONS; CHROMATIN AB Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials. C1 [Rui, Lixin; Ceribelli, Michele; Huang, Da Wei; Hodson, Daniel J.; Shaffer, Arthur L.; Zhao, Hong; Xu, Weihong; Yang, Yandan; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rui, Lixin; Drennan, Amanda C.; Zhu, Fen; Li, Yangguang; Grindle, Kreg M.; Lu, Li] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. [Rui, Lixin; Drennan, Amanda C.; Zhu, Fen; Li, Yangguang; Grindle, Kreg M.; Lu, Li] Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI 53705 USA. [Wright, George W.] NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Rui, LX; Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Rui, LX (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA.; Rui, LX (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI 53705 USA. EM lrui@medicine.wisc.edu; lstaudt@mail.nih.gov FU Intramural Research Program of the NIH National Cancer Institute; University of Wisconsin-Madison (UW-Madison) start-up funds; KL2 Scholar Awards [UL1TR0000427, KL2TR000428]; National Cancer Institute [1R01 CA187299]; UW-Madison T32 Hematology Training Award [T32 HL07899] FX This research was supported by the Intramural Research Program of the NIH National Cancer Institute, the University of Wisconsin-Madison (UW-Madison) start-up funds, KL2 Scholar Awards UL1TR0000427 and KL2TR000428, the National Cancer Institute Grant 1R01 CA187299 (to L.R.), and the UW-Madison T32 Hematology Training Award T32 HL07899 (to A.C.D.). NR 40 TC 1 Z9 1 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 15 PY 2016 VL 113 IS 46 BP E7260 EP E7267 DI 10.1073/pnas.1610970113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100016 PM 27799566 ER PT J AU Fujikado, N Mann, AO Bansal, K Romito, KR Ferre, EMN Rosenzweig, SD Lionakis, MS Benoist, C Mathis, D AF Fujikado, Noriyuki Mann, Alexander O. Bansal, Kushagra Romito, Kimberly R. Ferre, Elise M. N. Rosenzweig, Sergio D. Lionakis, Michail S. Benoist, Christophe Mathis, Diane TI Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing gamma delta T Cells to Promote Immunologic Tolerance SO IMMUNITY LA English DT Article ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; THYMIC EPITHELIAL-CELLS; ECTODERMAL DYSTROPHY; INTERFERON-GAMMA; IL-17 PRODUCTION; GENE-EXPRESSION; SELF-TOLERANCE; TCR REPERTOIRE; RNA-SEQ; SELECTION AB Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells ( mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A(+)V gamma 6(+) V delta 1(+)T cells, considered to be "early responders'' to tissue stress and drivers of inflammatory reactions. Aire-dependent control of Ii7 expression in mTECs regulated the size of thymic IL-17A(+)V gamma 6(+) V delta 1(+)T compartments. In mice lacking Aire and gd T cells, certain tissues typically targeted in the `` Aire-less'' disease, notably the retina, were only minimally infiltrated. IL-17A(+)V gamma 6(+) V delta 1(+)T cells were present in the retina of wild-type mice and expanded very early in Aire-deficientmice. A putatively parallel population of IL-17A(+)V gamma 6(+) V delta 1(+)T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells. C1 [Fujikado, Noriyuki; Mann, Alexander O.; Bansal, Kushagra; Benoist, Christophe; Mathis, Diane] Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. [Romito, Kimberly R.; Rosenzweig, Sergio D.] NIH, Dept Lab Med, NIH Clin Ctr, Bethesda, MD 20892 USA. [Ferre, Elise M. N.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fujikado, Noriyuki] Eli Lilly Japan KK, Minato Ku, Tokyo 1070052, Japan. RP Benoist, C; Mathis, D (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. EM cb@hms.harvard.edu; dm@hms.harvard.edu FU NIH [R01 DK060027, T32 AI118692]; NIH NIAID Division of Intramural Research; Japan Society for the Promotion of Science; Uehara Memorial Foundation; American Diabetes Association [7-12-MN-51] FX We would like to thank Drs. V. Kuchroo, P. Love, and M. Anderson for mice; Drs. R. Tigelaar and J. Lewis for the 17D1 hybridoma; K. Hattori for expert assistance with mice; Dr. A. Ortiz-Lopez for histological scoring; the NIH Tetramer Core Facility for provision of tetramer reagents; Dr. N. Asinovski for hybridoma culture; and Drs. H. Yoshida and S. Yang for insightful discussions. This work was supported by NIH grant R01 DK060027 to D.M. and in part by the NIH NIAID Division of Intramural Research. N.F. received fellowships from the Japan Society for the Promotion of Science and the Uehara Memorial Foundation, K.B. received a fellowship from the American Diabetes Association (7-12-MN-51), and A.O.M. received a fellowship from the NIH (T32 AI118692). NR 65 TC 0 Z9 0 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD NOV 15 PY 2016 VL 45 IS 5 BP 999 EP 1012 DI 10.1016/j.immuni.2016.10.023 PG 14 WC Immunology SC Immunology GA EE3FP UT WOS:000389473500012 PM 27851927 ER PT J AU Yu, X Cai, BW Wang, MJ Tan, P Ding, XL Wu, J Li, J Li, QT Liu, PH Xing, CS Wang, HY Su, XZ Wang, RF AF Yu, Xiao Cai, Baowei Wang, Mingjun Tan, Peng Ding, Xilai Wu, Jian Li, Jian Li, Qingtian Liu, Pinghua Xing, Changsheng Wang, Helen Y. Su, Xin-zhuan Wang, Rong-Fu TI Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality SO IMMUNITY LA English DT Article ID PERSISTENT LCMV INFECTION; CEREBRAL MALARIA; RESPONSES; DNA; RECOGNITION; AUTOIMMUNITY; PARASITES; BLOCKADE; INSIGHTS; MICE AB Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-alpha and IFN-beta (IFN-a/b) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-alpha/beta production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-alpha/beta-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection. C1 [Yu, Xiao] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510275, Guangdong, Peoples R China. [Wang, Mingjun] Sun Yat Sen Univ, Zhongshan Sch Med, Guangzhou 510275, Guangdong, Peoples R China. [Yu, Xiao; Cai, Baowei; Wang, Mingjun; Tan, Peng; Ding, Xilai; Li, Qingtian; Liu, Pinghua; Xing, Changsheng; Wang, Helen Y.; Wang, Rong-Fu] Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX 77030 USA. [Cai, Baowei; Li, Jian; Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Wu, Jian; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wang, Rong-Fu] Cornell Univ, Dept Microbiol & Immunol, Weill Cornell Med, New York, NY 10065 USA. [Tan, Peng; Wang, Rong-Fu] Texas A&M Univ, Coll Med, Inst Biosci & Technol, Houston, TX 77030 USA. RP Wang, RF (reprint author), Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX 77030 USA.; Su, XZ (reprint author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China.; Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Wang, RF (reprint author), Cornell Univ, Dept Microbiol & Immunol, Weill Cornell Med, New York, NY 10065 USA.; Wang, RF (reprint author), Texas A&M Univ, Coll Med, Inst Biosci & Technol, Houston, TX 77030 USA. EM xsu@niaid.nih.gov; rwang3@houstonmethodist.org OI Su, Xinzhuan/0000-0003-3246-3248 FU China Scholar Council; NCI, NIH [R01CA101795, DA030338]; NIDA, NIH [R01CA101795, DA030338]; Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID) FX We thank Marco Colonna (Washington University School of Medicine) for providing Tlr9-/- mice, Richard A. Flavell (Yale University) for Tlr7-/- mice, Kate Fitzgerald (University of Massachusetts Medical School) and Tadatsugo Taniguchi (The University of Tokyo) for Irf3-/-:Irf7-/- mice, Michael Gale (University of Washington) and Wenxin Wu (University of Oklahoma Health Science Center) for Ddx58-/- mice, and Skip Virgin (Washington University at St. Louis) for Mb21d1-/- mice, Bo Ning for art drawing, and Jana S. Burchfield for editing the manuscript. X.Y. and B.C. were partially supported by the China Scholar Council. This work was supported, in part, by grants (R01CA101795 and DA030338) from the NCI and NIDA, NIH to R.-F.W. and by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID). NR 37 TC 2 Z9 2 U1 9 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD NOV 15 PY 2016 VL 45 IS 5 BP 1093 EP 1107 DI 10.1016/j.immuni.2016.10.001 PG 15 WC Immunology SC Immunology GA EE3FP UT WOS:000389473500019 PM 27793594 ER PT J AU Huang, JH Kang, BH Ishida, E Zhou, TQ Griesman, T Sheng, ZZ Wu, F Doria-Rose, NA Zhang, BS McKee, K O'Dell, S Chuang, GY Druz, A Georgiev, IS Schramm, CA Zheng, AQ Joyce, MG Asokan, M Ransier, A Darko, S Migueles, SA Bailer, RT Louder, MK Alam, SM Parks, R Kelsoe, G Von Holle, T Haynes, BF Douek, DC Hirsch, V Seaman, MS Shapiro, L Mascola, JR Kwong, PD Connors, M AF Huang, Jinghe Kang, Byong H. Ishida, Elise Zhou, Tongqing Griesman, Trevor Sheng, Zizhang Wu, Fan Doria-Rose, Nicole A. Zhang, Baoshan McKee, Krisha O'Dell, Sijy Chuang, Gwo-Yu Druz, Aliaksandr Georgiev, Ivelin S. Schramm, Chaim A. Zheng, Anqi Joyce, M. Gordon Asokan, Mangaiarkarasi Ransier, Amy Darko, Sam Migueles, Stephen A. Bailer, Robert T. Louder, Mark K. Alam, S. Munir Parks, Robert Kelsoe, Garnett Von Holle, Tarra Haynes, Barton F. Douek, Daniel C. Hirsch, Vanessa Seaman, Michael S. Shapiro, Lawrence Mascola, John R. Kwong, Peter D. Connors, Mark TI Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth SO IMMUNITY LA English DT Article ID TYPE-1 INFECTION; ESCAPE; MATURATION; ENVELOPE; EVOLUTION; GLYCOPROTEIN; PATTERNS; POTENCY; GLYCANS; LINEAGE AB Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis. C1 [Huang, Jinghe; Kang, Byong H.; Ishida, Elise; Griesman, Trevor; Migueles, Stephen A.; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhou, Tongqing; Doria-Rose, Nicole A.; Zhang, Baoshan; McKee, Krisha; O'Dell, Sijy; Chuang, Gwo-Yu; Druz, Aliaksandr; Zheng, Anqi; Joyce, M. Gordon; Asokan, Mangaiarkarasi; Ransier, Amy; Darko, Sam; Bailer, Robert T.; Louder, Mark K.; Douek, Daniel C.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wu, Fan; Hirsch, Vanessa] NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sheng, Zizhang; Schramm, Chaim A.; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Alam, S. Munir; Parks, Robert; Kelsoe, Garnett; Von Holle, Tarra; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Seaman, Michael S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Connors, M (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@nih.gov FU Intramural Research Program and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank the members of the Vaccine Research Center for discussions of the manuscript. We thank Lynn Morris for arranging the testing of N6 against an extended clade C pseudovirus panel. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 envelope plasmids used in our neutralization panel. Support for this work was provided by the Intramural Research Program and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science under contract number W-31-109-Eng-38. NR 37 TC 3 Z9 3 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD NOV 15 PY 2016 VL 45 IS 5 BP 1108 EP 1121 DI 10.1016/j.immuni.2016.10.027 PG 14 WC Immunology SC Immunology GA EE3FP UT WOS:000389473500020 PM 27851912 ER PT J AU Lu, Y Biancotto, A Cheung, F Remmers, E Shah, N McCoy, JP Tsang, JS AF Lu, Yong Biancotto, Angelique Cheung, Foo Remmers, Elaine Shah, Naisha McCoy, J. Philip Tsang, John S. TI Systematic Analysis of Cell-to-Cell Expression Variation of T Lymphocytes in a Human Cohort Identifies Aging and Genetic Associations SO IMMUNITY LA English DT Article ID FLUCTUATING ENVIRONMENTS; FLOW-CYTOMETRY; IMMUNE; HETEROGENEITY; DISEASE; ARCHITECTURE; VARIABILITY; RESPONSES; SUBSETS; NOISE AB Cell-to-cell expression variation (CEV) is a prevalent feature of even well-defined cell populations, but its functions, particularly at the organismal level, are not well understood. Using single-cell data obtained via high-dimensional flow cytometry of T cells as a model, we introduce an analysis framework for quantifying CEV in primary cell populations and studying its functional associations in human cohorts. Analyses of 840 CEV phenotypes spanning multiple baseline measurements of 14 proteins in 28 T cell subpopulations suggest that the quantitative extent of CEV can exhibit substantial subject-to-subject differences and yet remain stable within healthy individuals over months. We linked CEV to age and disease-associated genetic polymorphisms, thus implicating CEV as a biomarker of aging and disease susceptibility and suggesting that it might play an important role in health and disease. Our dataset, interactive figures, and software for computing CEV with flow cytometry data provide a resource for exploring CEV functions. C1 [Lu, Yong; Shah, Naisha; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Biancotto, Angelique; Cheung, Foo; McCoy, J. Philip; Tsang, John S.] NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Remmers, Elaine] NHGRI, NIH, Bethesda, MD 20892 USA. [McCoy, J. Philip] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Tsang, JS (reprint author), NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. EM john.tsang@nih.gov FU intramural program of the NIAID; NIH FX We thank Adrian Wiestner for providing healthy samples for age-association validation; Candace Liu for help with figures and software testing; Pamela Schwartzberg, Nicolas van Panhuys, and Ronald Germain for comments on the manuscript; and members of the J.S.T. lab and the Trans-NIH Center for Human Immunology (CHI) for discussions. This work was funded by the intramural program of the NIAID and of NIH institutes supporting the CHI. NR 57 TC 2 Z9 2 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD NOV 15 PY 2016 VL 45 IS 5 BP 1162 EP 1175 DI 10.1016/j.immuni.2016.10.025 PG 14 WC Immunology SC Immunology GA EE3FP UT WOS:000389473500024 PM 27851916 ER PT J AU Crank, MC Wilson, EMP Novik, L Enama, ME Hendel, CS Gu, WJ Nason, MC Bailer, RT Nabel, GJ McDermott, AB Mascola, JR Koup, RA Ledgerwood, JE Graham, BS AF Crank, Michelle C. Wilson, Eleanor M. P. Novik, Laura Enama, Mary E. Hendel, Cynthia S. Gu, Wenjuan Nason, Martha C. Bailer, Robert T. Nabel, Gary J. McDermott, Adrian B. Mascola, John R. Koup, Richard A. Ledgerwood, Julie E. Graham, Barney S. CA VRC012 Study Team TI Safety and Immunogenicity of a rAd35-EnvA Prototype HIV-1 Vaccine in Combination with rAd5-EnvA in Healthy Adults (VRC 012) SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; TEST-OF-CONCEPT; DNA CANDIDATE VACCINE; IMMUNE-RESPONSES; ADENOVIRUS VECTORS; 1ST-IN-HUMAN EVALUATION; NONHUMAN-PRIMATES; PROSTATE-CANCER; PHASE-1 SAFETY; EFFICACY TRIAL AB Background VRC 012 was a Phase I study of a prototype recombinant adenoviral-vector serotype-35 (rAd35) HIV vaccine, the precursor to two recently published clinical trials, HVTN 077 and 083. On the basis of prior evaluation of multiclade rAd5 HIV vaccines, Envelope A (EnvA) was selected as the standard antigen for a series of prototype HIV vaccines to compare various vaccine platforms. In addition, prior studies of rAd5-vectored vaccines suggested preexisting human immunity may be a confounding factor in vaccine efficacy. rAd35 is less seroprevalent across human populations and was chosen for testing alone and in combination with a rAd5-EnvA vaccine in the present two-part phase I study. Methods First, five subjects each received a single injection of 10(9), 10(10), or 10(11) particle units (PU) of rAd35-EnvA in an open-label, dose-escalation study. Next, 20 Ad5/Ad35-seronegative subjects were randomized to blinded, heterologous prime-boost schedules combining rAd5-EnvA and rAd35-EnvA with a three month interval. rAd35-EnvA was given at 10(10) or 10(11) PU to ten subjects each; all rAd5-EnvA injections were 10(10) PU. EnvA-specific immunogenicity was assessed four weeks post-injection. Solicited reactogenicity and clinical safety were followed after each injection. Results Vaccinations were well tolerated at all dosages. Antibody responses measured by ELISA were detected at 4 weeks in 30% and 50% of subjects after single doses of 10(10) or 10(11) PU rAd35, respectively, and in 89% after a single rAd5-EnvA 10(10) PU injection. EnvA-specific IFN-Upsilon ELISpot responses were detected at four weeks in 0%, 70%, and 50% of subjects after the respective rAd35-EnvA dosages compared to 89% of subjects after rAd5. T cell responses were higher after a single rAd5-EnvA 10(10) PU injection than after a single rAd35-EnvA 10(10) PU injection, and humoral responses were low after a single dose of either vector. Of those completing the vaccine schedule, 100% of rAd5-EnvA recipients and 90% of rAd35-EnvA recipients had both T cell and humoral responses after boosting with the heterologous vector. ELISpot response magnitude was similar in both regimens and comparable to a single dose of rAd5. A trend toward more robust CD8 T cell responses using rAd5-EnvA prime and rAd35-EnvA boost was observed. Humoral response magnitude was also similar after either heterologous regimen, but was several fold higher than after a single dose of rAd5. Adverse events (AEs) related to study vaccines were in general mild and limited to one episode of hematuria, Grade two. Activated partial thromboplastin time (aPTT) AEs were consistent with an in vitro effect on the laboratory assay for aPTT due to a transient induction of anti-phospholipid antibody, a phenomenon that has been reported in other adenoviral vector vaccine trials. Conclusions Limitations of the rAd vaccine vectors, including the complex interactions among pre-existing adenoviral immunity and vaccine-induced immune responses, have prompted investigators to include less seroprevalent vectors such as rAd35-EnvA in prime-boost regimens. The rAd35-EnvA vaccine described here was well tolerated and immunogenic. While it effectively primed and boosted antibody responses when given in a reciprocal prime-boost regimen with rAd5-EnvA using a three-month interval, it did not significantly improve the frequency or magnitude of T cell responses above a single dose of rAd5. The humoral and cellular immunogenicity data reported here may inform future vaccine and study design. C1 [Crank, Michelle C.; Wilson, Eleanor M. P.; Novik, Laura; Enama, Mary E.; Hendel, Cynthia S.; Bailer, Robert T.; Nabel, Gary J.; McDermott, Adrian B.; Mascola, John R.; Koup, Richard A.; Ledgerwood, Julie E.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gu, Wenjuan] Leidos Biomed Res Inc, Clin Monitoring Res Program, Clin Res Directorate, NCI Campus,Frederick, Frederick, MD 21702 USA. [Wilson, Eleanor M. P.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Nabel, Gary J.] Sanofi US, Cambridge, MA USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov OI Wilson, Eleanor/0000-0002-4855-514X FU National Institute of Allergy and Infectious Diseases (NIAID) intramural research program; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Funding for the conduct of this clinical trial was provided by the National Institute of Allergy and Infectious Diseases (NIAID) intramural research program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Wenjuan Gu: Ms. Gu is an employee of Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Maryland 21702. 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. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 61 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 15 PY 2016 VL 11 IS 11 AR e0166393 DI 10.1371/journal.pone.0166393 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC0MG UT WOS:000387794600056 PM 27846256 ER PT J AU Mishra, PJ Mishra, PJ Merlino, G AF Mishra, Prasun J. Mishra, Pravin J. Merlino, Glenn TI Integrated Genomics Identifies miR-32/MCL-1 Pathway as a Critical Driver of Melanomagenesis: Implications for miR-Replacement and Combination Therapy SO PLOS ONE LA English DT Article ID ULTRAVIOLET-RADIATION; MALIGNANT-MELANOMA; SITE POLYMORPHISM; TUMOR-SUPPRESSOR; RESISTANCE; CELLS; CANCER; MICE; APOPTOSIS; MCL-1 AB Aims Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAF(V600E) melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous. Methods In this study we integrated gene and microRNA (miRNA) expression data from genetically engineered mouse models of highly and poorly malignant melanocytic tumors, as well as available human melanoma databases, and discovered an important role for a pathway centered on a tumor suppressor miRNA, miR-32. Results Malignant tumors frequently exhibited poor expression of miR-32, whose targets include NRAS, PI3K and notably, MCL-1. Accordingly, MCL-1 was often highly expressed in melanomas, and when knocked down diminished oncogenic potential. Forced MCL-1 overexpression transformed immortalized primary mouse melanocytes, but only when also expressing activating mutations in BRAF, CRAF or PI3K. Importantly, both miR-32 replacement therapy and the MCL-1-specific antagonist sabutoclax demonstrated single-agent efficacy, and acted synergistically in combination with vemurafenib in preclinical melanoma models. Conclusions We here identify miR-32/ MCL-1 pathway members as key early genetic events driving melanoma progression, and suggest that their inhibition may be an effective anti-melanoma strategy irrespective of NRAS, BRAF, and PTEN status. C1 [Mishra, Prasun J.] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA. [Mishra, Prasun J.; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mishra, Pravin J.] Dixie Reg Med Ctr, Precis Genom, Intermt Healthcare, St George, UT USA. RP Mishra, PJ (reprint author), Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA.; Mishra, PJ; Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM mishra.prasun@gene.com; gmerlino@helix.nih.gov FU Intramural Research Program of the Center of Cancer Research, NCI, NIH; NCI Cancer Research Training Award [C5IL039280]; NCI; Genentech FX The work was supported by the Intramural Research Program of the Center of Cancer Research, NCI, NIH, and in part by NCI Cancer Research Training Award C5IL039280, and NCI Director's Innovation Awards in 2009 and 2011 (to PJM). PJM is employed by Genentech Inc. at present. The funder provided support in the form of salaries to PJM (Genentech), GM (NCI), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.; The work was supported by the Intramural Research Program of the Center of Cancer Research, NCI, NIH, and in part by NCI Cancer Research Training Award C5IL039280, and NCI Director's Innovation Awards in 2009 and 2011 (to PJM). PJM is employed by Genentech Inc. at present. The funder provided support in the form of salaries to PJM (Genentech), GM (NCI), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Sabutoclax was a generous gift from Dr. Paul B. Fisher, Virginia Commonwealth University, Richmond, VA and was also purchased from APEXBIO. Some of the human melanocytes and melanoma cell lines were obtained from Dr. Meenhard Herlyn, The Wistar Institute Melanoma Research Center, PA and from Cell Culture Core Facility, Yale Skin Diseases Research Center Core, Department of Dermatology, Yale University School of Medicine. NR 37 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 15 PY 2016 VL 11 IS 11 AR e0165102 DI 10.1371/journal.pone.0165102 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC0MG UT WOS:000387794600008 PM 27846237 ER PT J AU Lee, JJ Yin, XY Hoffmann, U Fox, CS Benjamin, EJ AF Lee, Jane J. Yin, Xiaoyan Hoffmann, Udo Fox, Caroline S. Benjamin, Emelia J. TI Relation of Pericardial Fat, Intrathoracic Fat, and Abdominal Visceral Fat With Incident Atrial Fibrillation (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID EPICARDIAL ADIPOSE-TISSUE; INFLAMMATORY CYTOKINES; CARDIOVASCULAR-DISEASE; RISK-FACTORS; VOLUME; ASSOCIATION; ABLATION AB Obesity is associated with increased risk of developing atrial fibrillation (AF). Different fat depots may have differential associations with cardiac pathology. We examined the longitudinal associations between pericardial, intrathoracic, and visceral fat with incident AF. We studied Framingham Heart Study Offspring and Third-Generation Cohorts who participated in the multidetector computed tomography substudy examination 1. We constructed multivariable-adjusted Cox proportional hazard models for risk of incident AF. Body mass index was included in the multivariable-adjusted model as a secondary adjustment. We included 2,135 participants (53.3% women; mean age 58.8 years). During a median follow-up of 9.7 years, we identified 162 cases of incident AF. Across the increasing tertiles of pericardial fat volume, age- and gender-adjusted incident AF rate per 1,000 person-years of follow-up were 8.4, 7.5, and 10.2. Based on an age- and gender-adjusted model, greater pericardial fat (hazard ratio [BR] 1.17, 95% confidence interval [CI] 1.03 to 1.34) and intrathoracic fat (HR 1.24, 95% CI 1.06 to 1.45) were associated with an increased risk of incident AF. The BRs (95% CI) for incident AF were 1.13 (0.99 to 1.30) for pericardial fat, 1.19 (1.01 to 1.40) for intrathoracic fat, and 1.09 (0.93 to 1.28) for abdominal visceral fat after multivariable adjustment. After additional adjustment of body mass index, none of the associations remained significant (all p >0.05). Our findings suggest that cardiac ectopic fat depots may share common risk factors with AF, which may have led to a lack of independence in the association between pericardial fat with incident AF. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lee, Jane J.; Yin, Xiaoyan; Fox, Caroline S.; Benjamin, Emelia J.] NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA 01702 USA. [Yin, Xiaoyan; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA 01702 USA. [Hoffmann, Udo] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Fox, Caroline S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Benjamin, Emelia J.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Benjamin, EJ (reprint author), NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Boston Univ Framingham Heart Study, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. EM emelia@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study (Framingham, Massachusetts) [N01-HC-25195]; National Institutes of Health [HHSN268201500001I, 2R01HL092577, 1R01 HL128914, 1R01 HL102214, 1RC1HL101056] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Framingham, Massachusetts) (contract N01-HC-25195). Dr. Emelia Benjamin is supported by grants HHSN268201500001I, 2R01HL092577, 1R01 HL128914, 1R01 HL102214, 1RC1HL101056 from the National Institutes of Health. NR 30 TC 1 Z9 1 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 15 PY 2016 VL 118 IS 10 BP 1486 EP 1492 DI 10.1016/j.amjcard.2016.08.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900009 PM 27666172 ER PT J AU Ko, D Riles, EM Marcos, EG Magnani, JW Lubitz, SA Lin, HH Long, MT Schnabel, RB McManus, DD Ellinor, PT Ramachandran, VS Wang, TJ Gerszten, RE Benjamin, EJ Yin, XY Rienstra, M AF Ko, Darae Riles, Eric M. Marcos, Ernaldo G. Magnani, Jared W. Lubitz, Steven A. Lin, Honghuang Long, Michelle T. Schnabel, Renate B. McManus, David D. Ellinor, Patrick T. Ramachandran, Vasan S. Wang, Thomas J. Gerszten, Robert E. Benjamin, Emelia J. Yin, Xiaoyan Rienstra, Michiel TI Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SERUM URIC-ACID; OXIDATIVE STRESS; RISK; BIOMARKER; FAILURE AB Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated.. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 +/- 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ko, Darae] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Gen Internal Med Sect, Boston, MA 02118 USA. [Riles, Eric M.; Magnani, Jared W.; Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Sect Cardiovasc Med, Boston, MA 02118 USA. [Long, Michelle T.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Gastroenterol Sect, Boston, MA 02118 USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Sect Prevent Med, Boston, MA 02118 USA. [Ko, Darae; Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Ko, Darae] Boston Univ, Sch Med, Clin & Translat Sci Inst, Boston, MA 02118 USA. [Marcos, Ernaldo G.; Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Lubitz, Steven A.; Ellinor, Patrick T.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Schnabel, Renate B.] Univ Hamburg, Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [McManus, David D.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Yin, Xiaoyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Rienstra, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. EM m.rienstra@umcg.nl OI Rienstra, Michiel/0000-0002-2581-070X FU NIH/NHLBI [HHSN268201500001I, N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, 1RC1HL101056]; National Institutes of Health [2R01HL092577, 1K24HL105780]; Established Investigator Award from the American Heart Association [13EIA14220013]; Fondation Leducq [14CVD01]; NIH Career Development Award [K23HL114724]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105, 2015084]; European Research Council under the European Union's Horizon research and innovation program [648131]; German Ministry of Research and Education [BMBF 01ZX1408A]; German Research Foundation Emmy Noether Program [SCHN 1149/3-1]; Netherlands Organization for Scientific Research [616.136.055]; NIH [R01-DK-HL081572]; [5T32HL007224-38]; [UL1-TR000157] FX Dr. Ko is supported by 5T32HL007224-38 and UL1-TR000157. Dr. Benjamin is supported in part through NIH/NHLBI HHSN268201500001I; N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, and 1RC1HL101056. Dr. Ellinor is supported by grants from the National Institutes of Health (2R01HL092577, 1K24HL105780), an Established Investigator Award from the American Heart Association (13EIA14220013), and the Fondation Leducq (14CVD01). Dr. Lubitz is supported by an NIH Career Development Award (K23HL114724) and Doris Duke Charitable Foundation Clinical Scientist Development Award (2014105). Dr. Magnani is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award (2015084). Dr. R. Schnabel has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 648131), German Ministry of Research and Education (BMBF 01ZX1408A), German Research Foundation Emmy Noether Program SCHN 1149/3-1. Dr. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 616.136.055). The project was funded by NIH R01-DK-HL081572. NR 25 TC 0 Z9 0 U1 2 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 15 PY 2016 VL 118 IS 10 BP 1493 EP 1496 DI 10.1016/j.amjcard.2016.08.010 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900010 PM 27666170 ER PT J AU Massett, HA Mishkin, G Rubinstein, L Ivy, SP Denicoff, A Godwin, E DiPiazza, K Bolognese, J Zwiebel, JA Abrams, JS AF Massett, Holly A. Mishkin, Grace Rubinstein, Larry Ivy, S. Percy Denicoff, Andrea Godwin, Elizabeth DiPiazza, Kate Bolognese, Jennifer Zwiebel, James A. Abrams, Jeffrey S. TI Challenges Facing Early Phase Trials Sponsoredby the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual SO CLINICAL CANCER RESEARCH LA English DT Review ID CLINICAL-TRIALS; RECRUITMENT AB Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. C1 [Massett, Holly A.; Mishkin, Grace; Rubinstein, Larry; Ivy, S. Percy; Denicoff, Andrea; Zwiebel, James A.; Abrams, Jeffrey S.] NCI, Bethesda, MD 20892 USA. [Godwin, Elizabeth; DiPiazza, Kate] Emmes Corp, Rockville, MD USA. [Bolognese, Jennifer] Westat Corp, Rockville, MD USA. RP Massett, HA (reprint author), NCI, 9609 Med Ctr Dr,Room 5W562, Rockville, MD 20850 USA. EM massetth@mail.nih.gov FU National Cancer Institute at the National Institutes of Health FX The authors acknowledge the support of the National Cancer Institute at the National Institutes of Health. NR 36 TC 1 Z9 1 U1 1 U2 1 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 NOV 15 PY 2016 VL 22 IS 22 BP 5408 EP 5416 DI 10.1158/1078-0432.CCR-16-0338 PG 9 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600004 PM 27401246 ER PT J AU Mansfield, AS Rudek, MA Vulih, D Smith, GL Harris, PJ Ivy, SP AF Mansfield, Aaron S. Rudek, Michelle A. Vulih, Diana Smith, Gary L. Harris, Pamela Jo Ivy, S. Percy CA NCI Organ Dysfunction Working Grp TI The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects SO CLINICAL CANCER RESEARCH LA English DT Article ID DYSFUNCTION WORKING GROUP; ADVANCED SOLID TUMORS; STAGE LIVER-DISEASE; ADVANCED MALIGNANCIES; VARYING DEGREES; AMINOTRANSFERASE LEVELS; PHARMACOKINETIC TRIAL; RENAL DYSFUNCTION; IMATINIB MESYLATE; OXALIPLATIN AB Purpose: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. (C)2016 AACR. C1 [Mansfield, Aaron S.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Rudek, Michelle A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Vulih, Diana] Theradex, Princeton, NJ USA. [Smith, Gary L.] NCI, Clin Trials Monitoring Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Harris, Pamela Jo; Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Mansfield, AS (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM mansfield.aaron@mayo.edu FU NIH [K12CA090628, UM1CA186691, P30CA006973] FX This work was supported by NIH grants K12CA090628 (A.S. Mansfield), UM1CA186691 (M.A. Rudek), and P30CA006973 (M.A. Rudek). NR 30 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2016 VL 22 IS 22 BP 5472 EP 5479 DI 10.1158/1078-0432.CCR-16-0449 PG 8 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600012 PM 27189163 ER PT J AU Xi, LQ Pham, THT Payabyab, EC Sherry, RM Rosenberg, SA Raffeld, M AF Xi, Liqiang Pham, Trinh Hoc-Tran Payabyab, Eden C. Sherry, Richard M. Rosenberg, Steven A. Raffeld, Mark TI Circulating Tumor DNA as an Early Indicator of Response to T-cell Transfer Immunotherapy in Metastatic Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID DROPLET DIGITAL PCR; SERUM; BRAF; MUTATIONS; PLASMA; CANCER; LYMPHOCYTES; RESISTANCE; THERAPY AB Purpose: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma. Responding patients generally do not have significant changes in noncutaneous RECIST targets before 30 to 60 days following TIL infusion, and complete responses are often not confirmed for 1 to 2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of circulating tumor DNA (ctDNA) in separating responding from nonresponding patients. Experimental Design: We studied BRAF V600E ctDNA levels by a sensitive allele-specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the NCI and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. Results: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1 to 2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. Conclusions: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in metastatic melanoma can be used to rapidly identify responding from nonresponding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy. (C)2016 AACR. C1 [Xi, Liqiang; Pham, Trinh Hoc-Tran; Raffeld, Mark] NCI, Mol Diagnost Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 3S235E,10 Ctr Dr, Bethesda, MD 20892 USA. [Payabyab, Eden C.; Sherry, Richard M.; Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Raffeld, M (reprint author), NCI, Mol Diagnost Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 3S235E,10 Ctr Dr, Bethesda, MD 20892 USA. EM mraff@mail.nih.gov NR 28 TC 1 Z9 1 U1 4 U2 4 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 NOV 15 PY 2016 VL 22 IS 22 BP 5480 EP 5486 DI 10.1158/1078-0432.CCR-16-0613 PG 7 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600013 PM 27482033 ER PT J AU Ooms, AHAG Gadd, S Gerhard, DS Smith, MA Auvil, JMG Meerzaman, D Chen, QR Hsu, CH Yan, C Nguyen, C Hu, Y Ma, Y Zong, Z Mungall, AJ Moore, RA Marra, MA Huff, V Dome, JS Chi, YY Tian, J Geller, JI Mullighan, CG Ma, J Wheeler, DA Hampton, OA Walz, AL van den Heuvel-Eibrink, MM de Krijger, RR Ross, N Gastier-Foster, J Perlman, EJ AF Ooms, Ariadne H. A. G. Gadd, Samantha Gerhard, Daniela S. Smith, Malcolm A. Auvil, Jaime M. Guidry Meerzaman, Daoud Chen, Qing-Rong Hsu, Chih Hao Yan, Chunhua Nguyen, Cu Hu, Ying Ma, Yussanne Zong, Zusheng Mungall, Andrew J. Moore, Richard A. Marra, Marco A. Huff, Vicki Dome, Jeffrey S. Chi, Yueh-Yun Tian, Jing Geller, James I. Mullighan, Charles G. Ma, Jing Wheeler, David A. Hampton, Oliver A. Walz, Amy L. van den Heuvel-Eibrink, Marry M. de Krijger, Ronald R. Ross, Nicole Gastier-Foster, JulieM. Perlman, Elizabeth J. TI Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group SO CLINICAL CANCER RESEARCH LA English DT Article ID P53 GENE-MUTATIONS; PROGNOSTIC-FACTOR; POOR-PROGNOSIS; EXPRESSION; ALIGNMENT; GENOME; IMMUNOHISTOCHEMISTRY; TETRAMERIZATION; PATTERNS; GAIN AB Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. Indepth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. (C) 2016 AACR. C1 [Ooms, Ariadne H. A. G.; Gadd, Samantha; Perlman, Elizabeth J.] Northwestern Univ, Dept Pathol & Lab Med, Ann & Robert H Lurie Childrens Hosp Chicago, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Ooms, Ariadne H. A. G.; van den Heuvel-Eibrink, Marry M.; de Krijger, Ronald R.] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Ooms, Ariadne H. A. G.] Pathan BV, Dept Pathol, Rotterdam, Netherlands. [Gerhard, Daniela S.; Auvil, Jaime M. Guidry] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Meerzaman, Daoud; Chen, Qing-Rong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying] NCI, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Ma, Yussanne; Zong, Zusheng; Mungall, Andrew J.; Moore, Richard A.; Marra, Marco A.] BCCA, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Huff, Vicki] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Dome, Jeffrey S.] Childrens Natl Med Ctr, Div Pediat Hematol Oncol, Washington, DC 20010 USA. [Chi, Yueh-Yun; Tian, Jing] Univ Florida, Dept Biostat, Gainesville, FL USA. [Geller, James I.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Pediat Oncol, Cincinnati, OH USA. [Mullighan, Charles G.; Ma, Jing] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Wheeler, David A.; Hampton, Oliver A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Walz, Amy L.] Northwestern Univ, Div Hematol Oncol & Transplantat, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Walz, Amy L.] Northwestern Mem Hosp, Northwestern Med Dev Therapeut Inst, Chicago, IL USA. [de Krijger, Ronald R.] Reinier de Graaf Hosp, Dept Pathol, Delft, Netherlands. [Ross, Nicole; Gastier-Foster, JulieM.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43210 USA. [Gastier-Foster, JulieM.] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Gastier-Foster, JulieM.] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. RP Perlman, EJ (reprint author), Ann & Robert H Lurie Childrens Hosp, 225 East Chicago Ave, Chicago, IL 60611 USA. EM Eperlman@luriechildrens.org RI Marra, Marco/B-5987-2008 FU NCI [U10 CA98543, T32 CA079447]; US NIH [The Children's Oncology Group] [NIH U10CA180886, NIHU10CA180899, NIH U10CA098413, NIHU10CA42326, U10CA98543, U24 CA114766, UO1CA88131, HHSN261200800001E]; Dutch Cancer Society; American and Lebanese Syrian Associated Charities of St. Jude; WGS (CGI, Inc.); WES (Baylor College of Medicine); miRNAseq; RNAseq FX The TARGET initiative is supported by NCI Grant U10 CA98543. Work performed under contracts from the NCI (T32 CA079447, to A.L. Walz), US NIH [The Children's Oncology Group award numbers NIH U10CA180886, NIHU10CA180899; NIH U10CA098413; NIHU10CA42326 (E.J. Perlman); U10CA98543 (to J.S. Dome and E.J. Perlman); U24 CA114766; UO1CA88131 (E.J. Perlman)] within HHSN261200800001E includes specimen processing (the COG BPC), WGS (CGI, Inc.), WES (Baylor College of Medicine), miRNAseq, RNAseq, and target capture sequencing (BCCA Genome Sciences Center). This study was also supported by Dutch Cancer Society (to A.H.A.G. Ooms) and American and Lebanese Syrian Associated Charities of St. Jude (to C.G. Mullighan and Jing Ma). NR 47 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2016 VL 22 IS 22 BP 5582 EP 5591 DI 10.1158/1078-0432.CCR-16-0985 PG 10 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600023 PM 27702824 ER PT J AU Pavlou, HJ Lin, AC Neville, MC Nojima, T Diao, F Chen, BE White, BH Goodwin, SF AF Pavlou, Hania J. Lin, Andrew C. Neville, Megan C. Nojima, Tetsuya Diao, Fengqiu Chen, Brian E. White, Benjamin H. Goodwin, Stephen F. TI Neural circuitry coordinating male copulation SO ELIFE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; MALE COURTSHIP BEHAVIOR; CENTRAL NERVOUS-SYSTEM; DROSOPHILA-MELANOGASTER; SPECTRAL PREFERENCE; FUNCTIONAL-ANALYSIS; EXPRESSING NEURONS; SPERM TRANSFER; DOUBLESEX; FRUITLESS AB Copulation is the goal of the courtship process, crucial to reproductive success and evolutionary fitness. Identifying the circuitry underlying copulation is a necessary step towards understanding universal principles of circuit operation, and how circuit elements are recruited into the production of ordered action sequences. Here, we identify key sex-specific neurons that mediate copulation in Drosophila, and define a sexually dimorphic motor circuit in the male abdominal ganglion that mediates the action sequence of initiating and terminating copulation. This sexually dimorphic circuit composed of three neuronal classes motor neurons, interneurons and mechanosensory neurons controls the mechanics of copulation. By correlating the connectivity, function and activity of these neurons we have determined the logic for how this circuitry is coordinated to generate this male-specific behavior, and sets the stage for a circuit-level dissection of active sensing and modulation of copulatory behavior. C1 [Pavlou, Hania J.; Lin, Andrew C.; Neville, Megan C.; Nojima, Tetsuya; Goodwin, Stephen F.] Univ Oxford, Ctr Neural Circuits & Behav, Oxford, England. [Lin, Andrew C.] Univ Sheffield, Dept Biomed Sci, Sheffield, S Yorkshire, England. [Diao, Fengqiu; White, Benjamin H.] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Chen, Brian E.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Chen, Brian E.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Pavlou, Hania J.] Univ Oxford, Weatherall Inst Mol Med, MRC Ctr Computat Biol, Oxford, England. RP Pavlou, HJ; Goodwin, SF (reprint author), Univ Oxford, Ctr Neural Circuits & Behav, Oxford, England.; Pavlou, HJ (reprint author), Univ Oxford, Weatherall Inst Mol Med, MRC Ctr Computat Biol, Oxford, England. EM hania.pavlou@imm.ox.ac.uk; stephen.goodwin@dpag.ox.ac.uk OI Lin, Andrew/0000-0001-6310-9765 FU EP Abraham Cephalosporin Trust Fund; Brain@McGill Collaboration Fund; National Institute of Mental Health [ZIAMH002800]; Wellcome Trust [WT106189MA] FX EP Abraham Cephalosporin Trust Fund Hania J Pavlou Stephen F Goodwin; Brain@McGill Collaboration Fund Hania J Pavlou Brian E Chen Stephen F Goodwin; National Institute of Mental Health ZIAMH002800 Benjamin H White; Wellcome Trust WT106189MA Stephen F Goodwin; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 60 TC 1 Z9 1 U1 3 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 15 PY 2016 VL 5 AR e20713 DI 10.7554/eLife.20713 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED2NR UT WOS:000388684300001 ER PT J AU Zhao, GH Zhu, PP Renvoise, B Maldonado-Baez, L Park, SH Blackstone, C AF Zhao, Guohua Zhu, Peng-Peng Renvoise, Benoit Maldonado-Baez, Lymarie Park, Seong Hee Blackstone, Craig TI Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Endoplasmic reticulum; Hereditary spastic paraplegia; Lipid droplet; GTPase; CRISPR/Cas9; Morphology ID HEREDITARY SPASTIC PARAPLEGIA; REGULATES SYNAPTIC GROWTH; ENDOPLASMIC-RETICULUM; PHARMACOLOGICAL RESCUE; SENSORY NEUROPATHY; GOLGI-APPARATUS; MEMBRANE-FUSION; ARABIDOPSIS; RHD3; MUTATION AB Atlastins are large, membrane-bound GTPases that participate in the fusion of endoplasmic reticulum (ER) tubules to generate the polygonal ER network in eukaryotes. They also regulate lipid droplet size and inhibit bone morphogenetic protein (BMP) signaling, though mechanisms remain unclear. Humans have three atlastins (ATLI, ATL2, and ATL3), and ATLI and ATL3 are mutated in autosomal dominant hereditary spastic paraplegia and hereditary sensory neuropathies, Cellular investigations of atlastin orthologs in most yeast, plants, flies and worms are facilitated by the presence of a single or predominant isoform, but loss-of-function studies in mammalian cells are complicated by multiple, broadly-expressed paralogs. We have generated mouse NIH-3T3 cells lacking all three mammalian atlastins (Atl 1/2/3) using CRISPR/Cas9-mediated gene knockout (KO). ER morphology is markedly disrupted in these triple KO cells, with prominent impairment in formation of three-way ER tubule junctions. This phenotype can be rescued by expression of distant orthologs from Saccharomyces cereuisiae (Seylp) and Arabidopsis (ROOT HAIR DEFECTIVE3) as well as any one of the three human atlastins. Minimal, if any, changes are observed in the morphology of mitochondria and the Golgi apparatus. Alterations in BMP signaling and increased sensitivity to ER stress are also noted, though effects appear more modest. Finally, atlastins appear required for the proper differentiation of NIH-3T3 cells into an adipocyte-like phenotype. These findings have important implications for the pathogenesis of hereditary spastic paraplegias and sensory neuropathies associated with atlastin mutations. C1 [Zhao, Guohua; Zhu, Peng-Peng; Renvoise, Benoit; Maldonado-Baez, Lymarie; Park, Seong Hee; Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Guohua] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Neurol, Yiwu, Peoples R China. [Zhao, Guohua] Zhejiang Univ, Affiliated Hosp 4, Sch Med, Dept Neurol, Yiwu, Peoples R China. [Park, Seong Hee] Bridge Biotherapeut Inc, Seongnam Si, South Korea. RP Blackstone, C (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 35,Room 2A-201,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS002992] FX We thank Chunxin Wang for assistance in generating the knock out cell lines, Dragan Maric for flow cytometry, and Xufeng Wu for assistance with super-resolution microscopy. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health [ZIA NS002992]. NR 46 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD NOV 15 PY 2016 VL 349 IS 1 BP 32 EP 44 DI 10.1016/j.yexcr.2016.09.015 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA ED0SY UT WOS:000388553400004 PM 27669642 ER PT J AU Goo, L Dowd, KA Lin, TY Mascola, JR Graham, BS Ledgerwood, JE Pierson, TC AF Goo, Leslie Dowd, Kimberly A. Lin, Tsai-Yu Mascola, John R. Graham, Barney S. Ledgerwood, Julie E. Pierson, Theodore C. TI A Virus-Like Particle Vaccine Elicits Broad Neutralizing Antibody Responses in Humans to All Chikungunya Virus Genotypes SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE chikungunya virus; neutralizing antibodies; virus-like particle vaccine ID EMERGENCE; INFECTION; EPIDEMIC AB Chikungunya virus (CHIKV) is an alphavirus that has emerged as a global health burden. There are 3 CHIKV genotypes: Asian, West African, and Eastern/Central/South African. No licensed CHIKV vaccine is available, and whether the antibody response elicited by one genotype can neutralize heterologous genotypes is unclear. We assessed neutralizing antibody (NAb) responses of volunteers in a phase 1 study of a CHIKV vaccine against 9 viral strains representing all 3 genotypes. Minimal differences in vaccine-elicited NAb responses were observed among genotypes, suggesting that vaccination with a single CHIKV strain can elicit cross-protective NAbs against all 3 genotypes. C1 [Goo, Leslie; Dowd, Kimberly A.; Lin, Tsai-Yu; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mascola, John R.; Graham, Barney S.; Ledgerwood, Julie E.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lin, Tsai-Yu] Immune Design, Seattle, WA USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, 33 North Dr,Bldg 33,Rm 2E19A-2, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the intramural research programs of the Division of Intramural Research and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 15 PY 2016 VL 214 IS 10 BP 1487 EP 1491 DI 10.1093/infdis/jiw431 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ED0ZR UT WOS:000388573700006 PM 27655868 ER PT J AU Yu, YW Hsieh, TH Chen, KY Wu, JCC Hoffer, BJ Greig, NH Li, YZ Lai, JH Chang, CF Lin, JW Chen, YH Yang, LY Chiang, YH AF Yu, Yu-Wen Hsieh, Tsung-Hsun Chen, Kai-Yun Wu, John Chung-Che Hoffer, Barry J. Greig, Nigel H. Li, Yazhou Lai, Jing-Huei Chang, Cheng-Fu Lin, Jia-Wei Chen, Yu-Hsin Yang, Liang-Yo Chiang, Yung-Hsiao TI Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats SO JOURNAL OF NEUROTRAUMA LA English DT Article DE amyloid-beta precursor protein; BMX; cognitive dysfunction; controlled cortical impact; GFAP; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; mild traumatic brain injury; neuroinflammation ID GLUCAGON-LIKE PEPTIDE-1; GASTRIC-INHIBITORY POLYPEPTIDE; CENTRAL-NERVOUS-SYSTEM; CLOSED HEAD-INJURY; ALZHEIMERS-DISEASE; GENE-EXPRESSION; NEURODEGENERATIVE DISEASE; SYNAPTIC PLASTICITY; DIABETES-MELLITUS; SIGNALING PATHWAY AB Mild traumatic brain injury (mTBI) is a major public health issue, representing 75-90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13-15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-beta precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment. C1 [Yu, Yu-Wen; Hsieh, Tsung-Hsun; Chen, Kai-Yun; Hoffer, Barry J.; Chiang, Yung-Hsiao] Taipei Med Univ, Coll Med Sci & Technol, PhD Program Neural Regenerat Med, Taipei, Taiwan. [Yu, Yu-Wen; Hsieh, Tsung-Hsun; Chen, Kai-Yun; Hoffer, Barry J.; Chiang, Yung-Hsiao] Natl Hlth Res Inst, Taipei, Taiwan. [Hsieh, Tsung-Hsun; Chen, Kai-Yun; Lai, Jing-Huei; Chiang, Yung-Hsiao] Taipei Med Univ, Ctr Neurotrauma & Neuroregenerat, Taipei, Taiwan. [Hsieh, Tsung-Hsun] Chang Gung Univ, Coll Med, Dept Phys Therapy, Taoyuan, Taiwan. [Hsieh, Tsung-Hsun] Chang Gung Univ, Coll Med, Grad Inst Rehabil Sci, Taoyuan, Taiwan. [Wu, John Chung-Che; Lai, Jing-Huei; Chang, Cheng-Fu; Lin, Jia-Wei; Chiang, Yung-Hsiao] Taipei Med Univ, Coll Med, Dept Surg, Taipei, Taiwan. [Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. [Greig, Nigel H.; Li, Yazhou] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Chen, Yu-Hsin; Yang, Liang-Yo] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei, Taiwan. [Chen, Yu-Hsin] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan. [Yang, Liang-Yo] Taipei Med Univ, Res Ctr Biomed Devices & Prototyping Prod, Taipei, Taiwan. [Chiang, Yung-Hsiao] Taipei Med Univ Hosp, Dept Med Res, Translat Lab, Taipei, Taiwan. [Yang, Liang-Yo] China Med Univ, Sch Med, Coll Med, Taichung, Taiwan. RP Yang, LY (reprint author), China Med Univ, Sch Med, Coll Med, Taichung, Taiwan.; Chiang, YH (reprint author), Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Neural Regenerat Med, 250 Wu Hsing St, Taipei 11031, Taiwan. EM ychiang@tmu.edu.tw FU Ministry of Science and Technology [MOST 103-2321-B-038-003, NSC 101-2321-B-038-004, NSC 102-2321-B-038-004, NSC 101-2632-B-038-001-MY3, MOST 103-2314-B-038-038]; National Institute on Aging FX This study was supported by the Ministry of Science and Technology, grant number MOST 103-2321-B-038-003, NSC 101-2321-B-038-004, NSC 102-2321-B-038-004 and NSC 101-2632-B-038-001-MY3, MOST 103-2314-B-038-038 and the Intramural Research Program of the National Institute on Aging. NR 107 TC 3 Z9 3 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD NOV 15 PY 2016 VL 33 IS 22 BP 2044 EP 2054 DI 10.1089/neu.2015.4229 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EC4OL UT WOS:000388112300008 PM 26972789 ER PT J AU Green, AD Vasu, S McClenaghan, NH Flatt, PR AF Green, Alastair D. Vasu, Srividya McClenaghan, Neville H. Flatt, Peter R. TI Implanting 1.1B4 human beta-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice SO WORLD JOURNAL OF DIABETES LA English DT Article DE Human beta-cell line; 1.1B4; Cell therapy; Insulin; Pseudoislets ID CLINICAL ISLET TRANSPLANTATION; INDUCIBLE INSULIN-SECRETION; FUNCTIONAL-CHARACTERIZATION; B-CELLS; LINE; PANCREAS; GLUCOSE; EXPANSION; RESPONSES; MELLITUS AB AIM To investigate the potential of implanting pseudoislets formed from human insulin-releasing beta-cell lines as an alternative to islet transplantation. METHODS In this study, the anti-diabetic potential of novel human insulin releasing 1.1B4 beta-cells was evaluated by implanting the cells, either as free cell suspensions, or as three-dimensional pseudoislets, into the subscapular region of severe combined immune deficient mice rendered diabetic by single high-dose administration of streptozotocin. Metabolic parameters including food and fluid intake, bodyweight and blood glucose were monitored throughout the study. At the end of the study animals were given an intraperitoneal glucose tolerance test. Animals were then culled and blood and tissues were collected for analysis. Insulin and glucagon contents of plasma and tissues were measured by insulin radioimmunoassay and chemiluminescent enzyme-linked immunosorbance assay respectively. Histological analyses of pancreatic islets were carried out by quantitative fluorescence immunohistochemistry staining. RESULTS Both pseudoislet and cell suspension implants yielded well vascularised beta-cell masses of similar insulin content. This was associated with progressive amelioration of hyperphagia ( P < 0.05), polydipsia ( P < 0.05), body weight loss ( P < 0.05), hypoinsulinaemia ( P < 0.05), hyperglycaemia ( P < 0.05 - P < 0.001) and glucose tolerance ( P < 0.01). Islet morphology was also significantly improved in both groups of transplanted mice, with increased beta-cell ( P < 0.05 - P < 0.001) and decreased alpha cell ( P < 0.05 - P < 0.001) areas. Whereas mice receiving 1.1B4 cell suspensions eventually exhibited hypoglycaemic complications, pseudoislet recipients displayed a more gradual amelioration of diabetes, and achieved stable blood glucose control similar to non-diabetic mice at the end of the study. CONCLUSION Although further work is needed to address safety issues, these results provide proof of concept for possible therapeutic applicability of human beta-cell line pseudoislets in diabetes. C1 [Green, Alastair D.; McClenaghan, Neville H.; Flatt, Peter R.] Univ Ulster, SAAD Ctr Pharm & Diabet, Coleraine BT52 1SA, Londonderry, North Ireland. [Vasu, Srividya] NIDDK, Cell Growth & Metab Sect, NIH, Old Georgetown Rd & Ctr Dr, Bethesda, MD 20892 USA. RP Vasu, S (reprint author), NIDDK, Cell Growth & Metab Sect, NIH, Old Georgetown Rd & Ctr Dr, Bethesda, MD 20892 USA. EM s.vasu@outlook.com NR 53 TC 0 Z9 0 U1 0 U2 0 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1948-9358 J9 WORLD J DIABETES JI World J. Diabetes PD NOV 15 PY 2016 VL 7 IS 19 BP 523 EP 533 DI 10.4239/wjd.v7.i19.523 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EC8BU UT WOS:000388365900003 PM 27895821 ER PT J AU McNeely, J Wu, LT Subramaniam, G Sharma, G Cathers, LA Svikis, D Sleiter, L Russell, L Nordeck, C Sharma, A O'Grady, KE Bouk, LB Cushing, C King, J Wahle, A Schwartz, RP AF McNeely, Jennifer Wu, Li-Tzy Subramaniam, Geetha Sharma, Gaurav Cathers, Lauretta A. Svikis, Dace Sleiter, Luke Russell, Linnea Nordeck, Courtney Sharma, Anjalee O'Grady, Kevin E. Bouk, Leah B. Cushing, Carol King, Jacqueline Wahle, Aimee Schwartz, Robert P. TI Performance of the Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) Tool for Substance Use Screening in Primary Care Patients SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID BEHAVIORAL-COUNSELING INTERVENTIONS; DISORDERS IDENTIFICATION TEST; LONGITUDINAL DATA-ANALYSIS; POSITIVE PREVALENCE RATES; RANDOMIZED CLINICAL-TRIAL; SERVICES-TASK-FORCE; DRUG-USE; TEST ASSIST; PREVENTIVE-SERVICES; SELF-REPORTS AB Background: Substance use, a leading cause of illness and death, is underidentified in medical practice. Objective: The Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool was developed to address the need for a brief screening and assessment instrument that includes all commonly used substances and fits into clinical work-flows. The goal of this study was to assess the performance of the TAPS tool in primary care patients. Design: Multisite study, conducted within the National Drug Abuse Treatment Clinical Trials Network, comparing the TAPS tool with a reference standard measure. (ClinicalTrials.gov: NCT02110693) Setting: 5 adult primary care clinics. Participants: 2000 adult patients consecutively recruited from clinic waiting areas. Measurements: Interviewer-and self-administered versions of the TAPS tool were compared with a reference standard, the modified World Mental Health Composite International Diagnostic Interview (CIDI), which measures problem use and substance use disorder (SUD). Results: Interviewer-and self-administered versions of the TAPS tool had similar diagnostic characteristics. For identifying problem use (at a cutoff of 1+), the TAPS tool had a sensitivity of 0.93 (95% CI, 0.90 to 0.95) and specificity of 0.87 (CI, 0.85 to 0.89) for tobacco and a sensitivity of 0.74 (CI, 0.70 to 0.78) and specificity of 0.79 (CI, 0.76 to 0.81) for alcohol. For problem use of illicit and prescription drugs, sensitivity ranged from 0.82 (CI, 0.76 to 0.87) for marijuana to 0.63 (CI, 0.47 to 0.78) for sedatives; specificity was 0.93 or higher. For identifying any SUD (at a cutoff of 2+), sensitivity was lower. Limitations: The low prevalence of some drug classes led to poor precision in some estimates. Research assistants were not blinded to participants' TAPS tool responses when they administered the CIDI. Conclusion: In a diverse population of adult primary care patients, the TAPS tool detected clinically relevant problem substance use. Although it also may detect tobacco, alcohol, and marijuana use disorders, further refinement is needed before it can be recommended broadly for SUD screening. C1 [McNeely, Jennifer] NYU, Sch Med, Dept Populat Hlth, 550 First Ave,VZ30 6th Floor, New York, NY 10016 USA. [McNeely, Jennifer] Dept Med, Div Gen Internal Med, 550 First Ave,VZ30 6th Floor, New York, NY 10016 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Dept Med, Durham, NC 27710 USA. [Wu, Li-Tzy] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Subramaniam, Geetha; Cushing, Carol] NIDA, Ctr Clin Trials Network, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Sharma, Anjalee; King, Jacqueline; Wahle, Aimee] EMMES Corp, 401 North Washington St, Rockville, MD 20850 USA. [Cathers, Lauretta A.] Virginia Commonwealth Univ, 730 East Broad St,Room 3076, Richmond, VA 23298 USA. [Svikis, Dace] Virginia Commonwealth Univ, POB 98034,1001 East Broad St,Room 305, Richmond, VA 23298 USA. [Sleiter, Luke; Russell, Linnea] NYU, Sch Med, 227 East 30th St,7th Floor, New York, NY 10016 USA. [Nordeck, Courtney; Sharma, Anjalee; Schwartz, Robert P.] Friends Res Inst, 1040 Pk Ave,Suite 103, Baltimore, MD 21201 USA. [O'Grady, Kevin E.] Univ Maryland, College Pk, MD 20742 USA. [Bouk, Leah B.] Duke Univ, Sch Med, Duke Translat Res Inst, Kannapolis, NC USA. RP McNeely, J (reprint author), NYU, Sch Med, Dept Populat Hlth, 550 First Ave,VZ30 6th Floor, New York, NY 10016 USA. EM Jennifer.McNeely@nyumc.org OI McNeely, Jennifer/0000-0003-4601-6940 FU National Institute on Drug Abuse FX National Institute on Drug Abuse. NR 70 TC 0 Z9 0 U1 3 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 15 PY 2016 VL 165 IS 10 BP 690 EP + DI 10.7326/M16-0317 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EC2RB UT WOS:000387970500013 PM 27595276 ER PT J AU Gamaldo, AA Beydoun, MA Beydoun, HA Liang, HL Sales, RE Zonderman, AB Gamaldo, CE Eid, SM AF Gamaldo, Alyssa A. Beydoun, May A. Beydoun, Hind A. Liang, Hailun Sales, Rachel E. Zonderman, Alan B. Gamaldo, Charlene E. Eid, Shaker M. TI Sleep Disturbances among Older Adults in the United States, 2002-2012: Nationwide Inpatient Rates, Predictors, and Outcomes SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE sleep disturbances; sleep disorders; inpatient sample; co-morbidity; length of stay; health care cost; mortality; older adults ID ALL-CAUSE MORTALITY; INSOMNIA-RELATED SYMPTOMS; AFRICAN-AMERICANS; FOLLOW-UP; APNEA; DURATION; COHORT; RISK; POPULATION; HEALTH AB Objective/Background: We examined the rates, predictors, and outcomes [mortality risk (MR), length of stay (LOS), and total charges (TC)] of sleep disturbances in older hospitalized patients. Patients/Methods: Using the U.S. Nationwide Inpatient Sample database (2002-2012), older patients (>= 60 years) were selected and rates of insomnia, obstructive sleep apnea (OSA) and other sleep disturbances (OSD) were estimated using ICD-9CM. TC, adjusted for inflation, was of primary interest, while MR and LOS were secondary outcomes. Multivariable regression analyses were conducted. Results: Of 35,258,031 older adults, 263,865 (0.75%) had insomnia, 750,851 (2.13%) OSA and 21,814 (0.06%) OSD. Insomnia rates increased significantly (0.27% in 2002 to 1.29 in 2012, P-trend < 0.001), with a similar trend observed for OSA (1.47 in 2006 to 5.01 in 2012, P-trend < 0.001). TC (2012 $) for insomnia-related hospital admission increased over time from $22,250 in 2002 to $31,527 in 2012, and increased similarly for OSA and OSD; while LOS and MR both decreased. Women with any sleep disturbance had lower MR and TC than men, while Whites had consistently higher odds of insomnia, OSA, and OSD than older Blacks and Hispanics. Co-morbidities such as depression, cardiovascular risk factors, and neurological disorders steadily increased over time in patients with sleep disturbances. Conclusion: TC increased over time in patients with sleep disturbances while LOS and MR decreased. Further, research should focus on identifying the mechanisms that explain the association between increasing sleep disturbance rates and expenditures within hospital settings and the potential hospital expenditures of unrecognized sleep disturbances in the elderly. C1 [Gamaldo, Alyssa A.] Univ S Florida, Sch Aging Studies, Tampa, FL USA. [Gamaldo, Alyssa A.; Beydoun, May A.; Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Lab Epidemiol & Populat Sci, NIH,IRP, Baltimore, MD 21224 USA. [Gamaldo, Alyssa A.] Penn State Univ, Human Dev & Family Studies, State Coll, PA USA. [Beydoun, Hind A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Liang, Hailun] Johns Hopkins Univ, Dept Hlth Policy & Management, Sch Publ Hlth, Baltimore, MD 21218 USA. [Sales, Rachel E.; Gamaldo, Charlene E.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Beydoun, MA (reprint author), NIA, Behav Epidemiol Sect, Lab Epidemiol & Populat Sci, NIH,IRP, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov FU NIA/NIH/IRP FX This study was supported in part by the NIA/NIH/IRP in collaboration with Johns Hopkins University School of Medicine. We would like to thank Ms. Danielle Shaked and Dr. Greg Dore for their internal review of the manuscript. NR 66 TC 0 Z9 0 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD NOV 15 PY 2016 VL 8 AR 266 DI 10.3339/fnagi.2016.00266 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EB9OI UT WOS:000387724500001 PM 27895576 ER PT J AU Bibbins-Domingo, K Grossman, DC Curry, SJ Davidson, K Epling, JW Garcia, FAR Gillman, MW Kemper, AR Krist, AH Kurth, AE Landefeld, CS LeFevre, ML Mangione, CM Phillips, WR Owens, DK Phipps, MG Pignone, MP AF Bibbins-Domingo, Kirsten Grossman, David C. Curry, Susan J. Davidson, KarinaW. Epling, John W., Jr. Garcia, Francisco A. R. Gillman, Matthew W. Kemper, Alex R. Krist, Alex H. Kurth, Ann E. Landefeld, C. Seth LeFevre, Michael L. Mangione, Carol M. Phillips, William R. Owens, Douglas K. Phipps, Maureen G. Pignone, Michael P. CA US Preventive Serv Task Force TI Statin Use for the Primary Prevention of Cardiovascular Disease in Adults US Preventive Services Task Force Recommendation Statement SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; WOMENS HEALTH; RISK; CHOLESTEROL; EVENTS; COHORT; INTERVENTIONS; DYSLIPIDEMIA; GUIDELINES AB IMPORTANCE Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States, accounting for 1 of every 3 deaths among adults. OBJECTIVE To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for lipid disorders in adults. EVIDENCE REVIEW The USPSTF reviewed the evidence on the benefits and harms of screening for and treatment of dyslipidemia in adults 21 years and older; the benefits and harms of statin use in reducing CVD events and mortality in adults without a history of CVD events; whether the benefits of statin use vary by subgroup, clinical characteristics, or dosage; and the benefits of various treatment strategies in adults 40 years and older without a history of CVD events. CONCLUSIONS AND RECOMMENDATIONS The USPSTF recommends initiating use of low-to moderate-dose statins in adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a calculated 10-year CVD event risk of 10% or greater (B recommendation). The USPSTF recommends that clinicians selectively offer low-to moderate-dose statins to adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 7.5% to 10% (C recommendation). The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older (I statement). C1 [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossman, David C.] Grp Hlth Res Inst, Seattle, WA USA. [Curry, Susan J.] Univ Iowa, Iowa City, IA USA. [Davidson, KarinaW.] Columbia Univ, New York, NY USA. [Epling, John W., Jr.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Garcia, Francisco A. R.] Pima Cty Dept Hlth, Tucson, AZ USA. [Gillman, Matthew W.] Harvard Med Sch, Boston, MA USA. [Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Gillman, Matthew W.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kemper, Alex R.] Duke Univ, Durham, NC USA. [Krist, Alex H.] Fairfax Family Practice Residency, Fairfax, VA USA. [Krist, Alex H.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Kurth, Ann E.] Yale Univ, New Haven, CT USA. [Landefeld, C. Seth] Univ Alabama Birmingham, Birmingham, AL USA. [LeFevre, Michael L.] Univ Missouri, Columbia, MO 65211 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Phillips, William R.] Univ Washington, Seattle, WA 98195 USA. [Owens, Douglas K.] Stanford Univ, Stanford, CA 94305 USA. [Phipps, Maureen G.] Brown Univ, Providence, RI 02912 USA. [Pignone, Michael P.] Univ Texas Austin, Austin, TX 78712 USA. RP Bibbins-Domingo, K (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM chair@uspstf.net FU USPSTF FX The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF. NR 44 TC 9 Z9 9 U1 5 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 15 PY 2016 VL 316 IS 19 BP 1997 EP 2007 DI 10.1001/jama.2016.15450 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EB8XC UT WOS:000387673800018 ER PT J AU Dobbin, KK Cesano, A Alvarez, J Hawtin, R Janetzki, S Kirsch, I Masucci, GV Robbins, PB Selvan, SR Streicher, HZ Zhang, J Butterfield, LH Thurin, M AF Dobbin, Kevin K. Cesano, Alessandra Alvarez, John Hawtin, Rachael Janetzki, Sylvia Kirsch, Ilan Masucci, Giuseppe V. Robbins, Paul B. Selvan, Senthamil R. Streicher, Howard Z. Zhang, Jenny Butterfield, Lisa H. Thurin, Magdalena TI Validation of biomarkers to predict response to immunotherapy in cancer: Volume II - clinical validation and regulatory considerations SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Review DE Biomarker; Immunotherapy; Cancer; Assay; Validation; Regulatory ID CELL LUNG-CANCER; COMPANION DIAGNOSTICS; CHEMOTHERAPY; EXPRESSION; TRIALS AB There is growing recognition that immunotherapy is likely to significantly improve health outcomes for cancer patients in the coming years. Currently, while a subset of patients experience substantial clinical benefit in response to different immunotherapeutic approaches, the majority of patients do not but are still exposed to the significant drug toxicities. Therefore, a growing need for the development and clinical use of predictive biomarkers exists in the field of cancer immunotherapy. Predictive cancer biomarkers can be used to identify the patients who are or who are not likely to derive benefit from specific therapeutic approaches. In order to be applicable in a clinical setting, predictive biomarkers must be carefully shepherded through a step-wise, highly regulated developmental process. Volume I of this two-volume document focused on the pre-analytical and analytical phases of the biomarker development process, by providing background, examples and "good practice" recommendations. In the current Volume II, the focus is on the clinical validation, validation of clinical utility and regulatory considerations for biomarker development. Together, this two volume series is meant to provide guidance on the entire biomarker development process, with a particular focus on the unique aspects of developing immune-based biomarkers. Specifically, knowledge about the challenges to clinical validation of predictive biomarkers, which has been gained from numerous successes and failures in other contexts, will be reviewed together with statistical methodological issues related to bias and overfitting. The different trial designs used for the clinical validation of biomarkers will also be discussed, as the selection of clinical metrics and endpoints becomes critical to establish the clinical utility of the biomarker during the clinical validation phase of the biomarker development. Finally, the regulatory aspects of submission of biomarker assays to the U.S. Food and Drug Administration as well as regulatory considerations in the European Union will be covered. C1 [Dobbin, Kevin K.] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, 101 Buck Rd, Athens, GA 30602 USA. [Cesano, Alessandra] NanoString Inc, 530 Fairview Ave N, Seattle, WA 98109 USA. [Alvarez, John] Janssen Res & Dev LLC, Spring House, PA 19477 USA. [Hawtin, Rachael] Nodality Inc, 170 Harbor Way, San Francisco, CA 94080 USA. [Janetzki, Sylvia] ZellNet Consulting Inc, 555 North Ave, Ft Lee, NJ 07024 USA. [Kirsch, Ilan] Adapt Biotechnol Inc, 1551 Eastlake Ave E, Seattle, WA 98102 USA. [Masucci, Giuseppe V.] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Robbins, Paul B.] Pfizer, San Diego, CA USA. [Selvan, Senthamil R.] Omni Array Biotechnol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. [Streicher, Howard Z.] NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Zhang, Jenny] Covaris Inc, 14 Gill St, Woburn, MA 01801 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. [Thurin, Magdalena] NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Thurin, M (reprint author), NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM thurinm@mail.nih.gov NR 36 TC 2 Z9 2 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD NOV 15 PY 2016 VL 4 AR 77 DI 10.1186/s40425-016-0179-0 PG 14 WC Oncology SC Oncology GA EC3RL UT WOS:000388043200003 PM 27891226 ER PT J AU Masucci, GV Cesano, A Hawtin, R Janetzki, S Zhang, J Kirsch, I Dobbin, KK Alvarez, J Robbins, PB Selvan, SR Streicher, HZ Butterfield, LH Thurin, M AF Masucci, Giuseppe V. Cesano, Alessandra Hawtin, Rachael Janetzki, Sylvia Zhang, Jenny Kirsch, Ilan Dobbin, Kevin K. Alvarez, John Robbins, Paul B. Selvan, Senthamil R. Streicher, Howard Z. Butterfield, Lisa H. Thurin, Magdalena TI Validation of biomarkers to predict response to immunotherapy in cancer: Volume I - pre-analytical and analytical validation SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Review DE Biomarker; Immunotherapy; Cancer; Assay; Validation; Standardization ID TUMOR-INFILTRATING LYMPHOCYTES; ASSAYS PRACTICE GUIDELINES; ADVANCED MELANOMA PATIENTS; RESISTANT PROSTATE-CANCER; PARAFFIN-EMBEDDED TISSUE; GENE-EXPRESSION ANALYSIS; BLOOD MONONUCLEAR-CELLS; ACUTE MYELOID-LEUKEMIA; PD-1 BLOCKADE; METASTATIC MELANOMA AB Immunotherapies have emerged as one of the most promising approaches to treat patients with cancer. Recently, there have been many clinical successes using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). Despite demonstrated successes in a variety of malignancies, responses only typically occur in a minority of patients in any given histology. Additionally, treatment is associated with inflammatory toxicity and high cost. Therefore, determining which patients would derive clinical benefit from immunotherapy is a compelling clinical question. Although numerous candidate biomarkers have been described, there are currently three FDA-approved assays based on PD-1 ligand expression (PD-L1) that have been clinically validated to identify patients who are more likely to benefit from a single-agent anti-PD-1/PD-L1 therapy. Because of the complexity of the immune response and tumor biology, it is unlikely that a single biomarker will be sufficient to predict clinical outcomes in response to immune-targeted therapy. Rather, the integration of multiple tumor and immune response parameters, such as protein expression, genomics, and transcriptomics, may be necessary for accurate prediction of clinical benefit. Before a candidate biomarker and/or new technology can be used in a clinical setting, several steps are necessary to demonstrate its clinical validity. Although regulatory guidelines provide general roadmaps for the validation process, their applicability to biomarkers in the cancer immunotherapy field is somewhat limited. Thus, Working Group 1 (WG1) of the Society for Immunotherapy of Cancer (SITC) Immune Biomarkers Task Force convened to address this need. In this two volume series, we discuss pre-analytical and analytical (Volume I) as well as clinical and regulatory (Volume II) aspects of the validation process as applied to predictive biomarkers for cancer immunotherapy. To illustrate the requirements for validation, we discuss examples of biomarker assays that have shown preliminary evidence of an association with clinical benefit from immunotherapeutic interventions. The scope includes only those assays and technologies that have established a certain level of validation for clinical use (fit-for-purpose). Recommendations to meet challenges and strategies to guide the choice of analytical and clinical validation design for specific assays are also provided. C1 [Masucci, Giuseppe V.] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Cesano, Alessandra] NanoString Inc, 500 Fairview Ave North, Seattle, WA 98109 USA. [Hawtin, Rachael] Nodality Inc, 170 Harbor Way, San Francisco, CA 94080 USA. [Janetzki, Sylvia] ZellNet Consulting Inc, 555 North Ave, Ft Lee, NJ 07024 USA. [Zhang, Jenny] Covaris Inc, 14 Gill St, Woburn, MA 01801 USA. [Kirsch, Ilan; Thurin, Magdalena] Adapt Biotechnol Inc, 1551 Eastlake Ave E, Seattle, WA 98102 USA. [Dobbin, Kevin K.] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, 101 Buck Rd, Athens, GA 30602 USA. [Alvarez, John] Janssen Res & Dev LLC, Spring House, PA 19477 USA. [Robbins, Paul B.] Pfizer, San Diego, CA USA. [Selvan, Senthamil R.] Omni Array Biotechnol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. [Streicher, Howard Z.] NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Dept Med Surg & Immunol, Inst Canc, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. [Thurin, Magdalena] NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP Thurin, M (reprint author), Adapt Biotechnol Inc, 1551 Eastlake Ave E, Seattle, WA 98102 USA.; Thurin, M (reprint author), NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM thurinm@mail.nih.gov NR 177 TC 2 Z9 2 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD NOV 15 PY 2016 VL 4 AR 76 DI 10.1186/s40425-016-0178-1 PG 25 WC Oncology SC Oncology GA EC3RL UT WOS:000388043200002 PM 27895917 ER PT J AU Ascierto, PA Agarwala, S Botti, G Cesano, A Ciliberto, G Davies, MA Demaria, S Dummer, R Eggermont, AM Ferrone, S Fu, YX Gajewski, TF Garbe, C Huber, V Khleif, S Krauthammer, M Lo, RS Masucci, G Palmieri, G Postow, M Puzanov, I Silk, A Spranger, S Stroncek, DF Tarhini, A Taube, JM Testori, A Wang, E Wargo, JA Yee, C Zarour, H Zitvogel, L Fox, BA Mozzillo, N Marincola, FM Thurin, M AF Ascierto, Paolo A. Agarwala, Sanjiv Botti, Gerardo Cesano, Alessandra Ciliberto, Gennaro Davies, Michael A. Demaria, Sandra Dummer, Reinhard Eggermont, Alexander M. Ferrone, Soldano Fu, Yang Xin Gajewski, Thomas F. Garbe, Claus Huber, Veronica Khleif, Samir Krauthammer, Michael Lo, Roger S. Masucci, Giuseppe Palmieri, Giuseppe Postow, Michael Puzanov, Igor Silk, Ann Spranger, Stefani Stroncek, David F. Tarhini, Ahmad Taube, Janis M. Testori, Alessandro Wang, Ena Wargo, Jennifer A. Yee, Cassian Zarour, Hassane Zitvogel, Laurence Fox, Bernard A. Mozzillo, Nicola Marincola, Francesco M. Thurin, Magdalena TI Future perspectives in melanoma research SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HERPES-SIMPLEX-VIRUS; STAGE-III MELANOMA; CD8(+) T-CELLS; METASTATIC MELANOMA; UNTREATED MELANOMA; ADJUVANT THERAPY; TUMOR MICROENVIRONMENT; ANTITUMOR IMMUNITY; BRAF INHIBITION; CTLA-4 BLOCKADE AB The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients' population. This meeting's specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays. C1 [Ascierto, Paolo A.; Botti, Gerardo; Ciliberto, Gennaro; Mozzillo, Nicola] Fdn G Pascale, IRCCS Ist Nazl Tumori, Naples, Italy. [Agarwala, Sanjiv] St Lukes Univ Hosp, Dept Hematol & Oncol, Bethlehem, PA USA. [Agarwala, Sanjiv] Temple Univ, Bethlehem, PA USA. [Cesano, Alessandra] Nanostring Inc, 500 Fairview Ave N, Seattle, WA 98109 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Dummer, Reinhard] Univ Hosp Zurich, Skin Canc Unit, Dept Dermatol, CH-8091 Zurich, Switzerland. [Eggermont, Alexander M.] Gustave Roussy Canc Campus Grand Paris, Villejuif, France. [Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Fu, Yang Xin] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Med, Immunol & Canc Program, Chicago, IL USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Pathol, Immunol & Canc Program, Chicago, IL USA. [Garbe, Claus] Univ Tubingen, Dept Dermatol, Ctr Dermato Oncol, Tubingen, Germany. [Huber, Veronica] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Khleif, Samir] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Krauthammer, Michael] Yale Univ, Sch Med, New Haven, CT USA. [Lo, Roger S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lo, Roger S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Lo, Roger S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Masucci, Giuseppe] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Postow, Michael] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Postow, Michael] Weill Cornell Med Coll, New York, NY USA. [Puzanov, Igor] Roswell Pk Canc Inst, Dept Med, Early Phase Clin Trials Program, New York, NY USA. [Silk, Ann] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Spranger, Stefani] Univ Chicago, Chicago, IL 60637 USA. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15260 USA. [Taube, Janis M.] Johns Hopkins Univ SOM, Dept Dermatol, Baltimore, MD USA. [Testori, Alessandro] Ist Europeo Oncol, Milan, Italy. [Wang, Ena] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Genom Med & Surg Oncol, Houston, TX 77030 USA. [Yee, Cassian; Marincola, Francesco M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Zitvogel, Laurence] Gustave Roussy Canc Ctr, INSERM, U1015, Villejuif, France. [Zitvogel, Laurence] Univ Paris 11, Le Kremlin Bicetre, France. [Fox, Bernard A.] Providence Portland Med Ctr, Robert W Franz Canc Res Ctr, Earle A Chiles Res Inst, Providence Canc Ctr, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Ascierto, Paolo A.] Fdn G Pascale, Unit Med Oncol & Innovat Therapy, Ist Nazl Studio & Cura Tumori, Via Mariano Semmola, I-80131 Naples, Italy. RP Thurin, M (reprint author), NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA.; Ascierto, PA (reprint author), Fdn G Pascale, Unit Med Oncol & Innovat Therapy, Ist Nazl Studio & Cura Tumori, Via Mariano Semmola, I-80131 Naples, Italy. EM paolo.ascierto@gmail.com; thurinm@mail.nih.gov FU Fondazione Melanoma Onlus; Society of ImmunoTherapy of Cancer (SITC); 3P Solution of Napoli FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to 3P Solution of Napoli for their support and cooperation in organizing the meeting and especially to Lucia Politi. NR 145 TC 0 Z9 0 U1 26 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 15 PY 2016 VL 14 AR 313 DI 10.1186/s12967-016-1070-y PG 25 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB9QX UT WOS:000387732200001 PM 27846884 ER PT J AU Chen, G Shin, YW Taylor, PA Glen, DR Reynolds, RC Israel, RB Cox, RW AF Chen, Gang Shin, Yong-Wook Taylor, Paul A. Glen, Daniel R. Reynolds, Richard C. Israel, Robert B. Cox, Robert W. TI Untangling the relatedness among correlations, part I: Nonparametric approaches to inter-subject correlation analysis at the group level SO NEUROIMAGE LA English DT Article ID HUMAN BRAIN; INTERSUBJECT CORRELATIONS; HEMODYNAMIC-RESPONSE; PERMUTATION TESTS; FMRI; CORTEX; SYNCHRONIZATION; SOFTWARE; SYSTEMS; REVEAL AB FMRI data acquisition under naturalistic and continuous stimuli (e.g., watching a video or listening to music) has become popular recently due to the fact that it entails less manipulation and more realistic/complex contexts involved in the task, compared to the conventional task-based experimental designs. The synchronization or response similarities among subjects are typically measured through inter-subject correlation (ISC) between any pair of subjects. At the group level, summarizing the collection of ISC values is complicated by their intercorrelations, which necessarily lead to the violation of independence assumed in typical parametric approaches such as Student's t-test. Nonparametric methods, such as bootstrapping and permutation testing, have previously been adopted for testing purposes by resampling the time series of each subject, but the quantitative validity of these specific approaches in terms of controllability of false positive rate (FPR) has never been explored before. Here we survey the methods of ISC group analysis that have been employed in the literature, and discuss the issues involved in those methods. We then propose less computationally intensive nonparametric methods that can be performed at the group level (for both one-and two-sample analyses), as compared to the popular method of circularly shifting the EPI time series at the individual level. As part of the new approaches, subject-wise (SW) resampling is adopted instead of element-wise (EW) resampling, so that exchangeability and independence assumptions are satisfied, and the patterned correlation structure among the ISC values can be more accurately captured. We examine the FPR controllability and power achievement of all the methods through simulations, as well as their performance when applied to a real experimental dataset. Published by Elsevier Inc. C1 [Chen, Gang; Taylor, Paul A.; Glen, Daniel R.; Reynolds, Richard C.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shin, Yong-Wook] Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, Ulsan, South Korea. [Israel, Robert B.] Univ British Columbia, Dept Math, Vancouver, BC V5Z 1M9, Canada. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.; Shin, YW (reprint author), Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, Ulsan, South Korea. EM gangchen@mail.nih.gov; shaman_korea@mac.com OI Chen, Gang/0000-0002-2960-089X FU NIMH Program of the NIH/HHS, USA [1ZICMH002888]; NINDS Intramural Research Program of the NIH/HHS, USA [1ZICMH002888]; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea [2012-0230] FX Our work benefited significantly from the statistical computational language and environment R, its many packages, and the great support of the R community. All the plots were created in R with the base graphics library. We gratefully acknowledge the advice of J.-P. Kauppi, J. Tohka, and J. Pajula for using the ISC Toolbox. The research and writing of the paper were supported by the NIMH and NINDS Intramural Research Programs (1ZICMH002888) of the NIH/HHS, USA, and by a grant (2012-0230) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 49 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2016 VL 142 BP 238 EP 249 DI 10.1016/j.neuroimage.2016.05.023 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EC2WW UT WOS:000387986000020 PM 27195792 ER PT J AU Liu, JJ Loncar, I Collee, JM Bolla, MK Dennis, J Michailidou, K Wang, Q Andrulis, IL Barile, M Beckmann, MW Behrens, S Benitez, J Blomqvist, C Boeckx, B Bogdanova, NV Bojesen, SE Brauch, H Brennan, P Brenner, H Broeks, A Burwinkel, B Chang-Claude, J Chen, ST Chenevix-Trench, G Cheng, CY Choi, JY Couch, FJ Cox, A Cross, SS Cuk, K Czene, K Dork, T Dos-Santos-Silva, I Fasching, PA Figueroa, J Flyger, H Garcia-Closas, M Giles, GG Glendon, G Goldberg, MS Gonzalez-Neira, A Guenel, P Haiman, CA Hamann, U Hart, SN Hartman, M Hatse, S Hopper, JL Ito, H Jakubowska, A Kabisch, M Kang, D Kosma, VM Kristensen, VN Le Marchand, L Lee, E Li, JM Lophatananon, A Lubinski, J Mannermaa, A Matsuo, K Milne, RL Neuhausen, SL Nevanlinna, H Orr, N Perez, JIA Peto, J Putti, TC Pylkas, K Radice, P Sangrajrang, S Sawyer, EJ Schmidt, MK Schneeweiss, A Shen, CY Shrubsole, MJ Shu, XO Simard, J Southey, MC Swerdlow, A Teo, SH Tessier, DC Thanasitthichai, S Tomlinson, I Torres, D Truong, T Tseng, CC Vachon, C Winqvist, R Wu, AH Yannoukakos, D Zheng, W Hall, P Dunning, AM Easton, DF Hooning, MJ van den Ouweland, AMW Martens, JWM Hollestelle, A AF Liu, Jingjing Loncar, Ivona Collee, J. Margriet Bolla, Manjeet K. Dennis, Joe Michailidou, Kyriaki Wang, Qin Andrulis, Irene L. Barile, Monica Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Blomqvist, Carl Boeckx, Bram Bogdanova, Natalia V. Bojesen, Stig E. Brauch, Hiltrud Brennan, Paul Brenner, Hermann Broeks, Annegien Burwinkel, Barbara Chang-Claude, Jenny Chen, Shou-Tung Chenevix-Trench, Georgia Cheng, Ching Y. Choi, Ji-Yeob Couch, Fergus J. Cox, Angela Cross, Simon S. Cuk, Katarina Czene, Kamila Doerk, Thilo Dos-Santos-Silva, Isabel Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Garcia-Closas, Montserrat Giles, Graham G. Glendon, Gord Goldberg, Mark S. Gonzalez-Neira, Anna Guenel, Pascal Haiman, Christopher A. Hamann, Ute Hart, Steven N. Hartman, Mikael Hatse, Sigrid Hopper, John L. Ito, Hidemi Jakubowska, Anna Kabisch, Maria Kang, Daehee Kosma, Veli-Matti Kristensen, Vessela N. Le Marchand, Loic Lee, Eunjung Li, Jingmei Lophatananon, Artitaya Lubinski, Jan Mannermaa, Arto Matsuo, Keitaro Milne, Roger L. Neuhausen, Susan L. Nevanlinna, Heli Orr, Nick Perez, Jose I. A. Peto, Julian Putti, Thomas C. Pylkas, Katri Radice, Paolo Sangrajrang, Suleeporn Sawyer, Elinor J. Schmidt, Marjanka K. Schneeweiss, Andreas Shen, Chen-Yang Shrubsole, Martha J. Shu, Xiao-Ou Simard, Jacques Southey, Melissa C. Swerdlow, Anthony Teo, Soo H. Tessier, Daniel C. Thanasitthichai, Somchai Tomlinson, Ian Torres, Diana Truong, Therese Tseng, Chiu-Chen Vachon, Celine Winqvist, Robert Wu, Anna H. Yannoukakos, Drakoulis Zheng, Wei Hall, Per Dunning, Alison M. Easton, Douglas F. Hooning, Maartje J. van den Ouweland, Ans M. W. Martens, John W. M. Hollestelle, Antoinette CA NBCS Collaborators TI rs2735383, located at a microRNA binding site in the 3 ' UTR of NBS1, is not associated with breast cancer risk SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; DOUBLE-STRAND BREAKS; GLU185GLN POLYMORPHISM; FUNCTIONAL POLYMORPHISM; PATHWAY GENES; LUNG-CANCER; METAANALYSIS; SUSCEPTIBILITY; REPAIR; POPULATIONS AB NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r(2) > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility. C1 [Liu, Jingjing; Loncar, Ivona; Hooning, Maartje J.; Martens, John W. M.; Hollestelle, Antoinette] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Collee, J. Margriet; van den Ouweland, Ans M. W.] Erasmus Univ, Dept Clin Genet, Med Ctr, Rotterdam, Netherlands. [Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Comprehens Canc Ctr Erlangen EMN, Erlangen, Germany. [Behrens, Sabine; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Behrens, Sabine; Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hamburg, Germany. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain. [Blomqvist, Carl] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. [Boeckx, Bram] VIB, Res Ctr, Leuven, Belgium. [Boeckx, Bram] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bogdanova, Natalia V.; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia V.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Brenner, Hermann; Cuk, Katarina] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Burwinkel, Barbara; Schneeweiss, Andreas] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany. [Chen, Shou-Tung] Changhua Christian Hosp, Dept Surg, Changhua, Taiwan. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia. [Cheng, Ching Y.] Singapore Eye Res Inst, Singapore, Singapore. [Cheng, Ching Y.] Singapore Natl Eye Ctr, Singapore, Singapore. [Cheng, Ching Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore. [Cheng, Ching Y.] Natl Univ Hlth Syst, Singapore, Singapore. [Cheng, Ching Y.] Duke NUS Grad Med Sch, Singapore, Singapore. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Biol Sci, Seoul, South Korea. [Choi, Ji-Yeob; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cox, Angela] Univ Sheffield, Dept Oncol & Metab, Acad Unit Mol Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Czene, Kamila; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. [Guenel, Pascal; Truong, Therese] Univ Paris Saclay, Univ Paris Sud, INSERM, Canc & Environm Grp,Ctr Res Epidemiol & Populat H, Villejuif, France. [Haiman, Christopher A.; Lee, Eunjung; Tseng, Chiu-Chen; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hart, Steven N.; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Hartman, Mikael] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Hatse, Sigrid] Univ Hosp Leuven, Leuven Canc Inst, Dept Oncol, Leuven Multidisciplinary Breast Ctr, Leuven, Belgium. [Ito, Hidemi] Aichi Canc Ctr, Div Epidemiol & Prevent, Res Inst, Nagoya, Aichi, Japan. [Ito, Hidemi; Matsuo, Keitaro] Nagoya Univ, Grad Sch Med, Dept Epidemiol, Nagoya, Aichi, Japan. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Kristensen, Vessela N.] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway. [Kristensen, Vessela N.] Oslo Univ Hosp, Univ Oslo, Dept Clin Mol Biol, Oslo, Norway. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA. [Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Lophatananon, Artitaya] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Orr, Nick; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Perez, Jose I. A.] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Putti, Thomas C.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pathol, Singapore, Singapore. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Pylkas, Katri; Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Radice, Paolo] Fdn IRCCS Ist Ricovero & Cura Carattere Sci, INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Taiwan Biobank, Inst Biomed Sci, Taipei, Taiwan. [Shrubsole, Martha J.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Simard, Jacques] Univ Laval, Res Ctr, Ctr Hosp Univ Quebec, Genom Ctr, Quebec City, PQ, Canada. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Teo, Soo H.] Canc Res Malaysia, Subang Jaya, Selangor, Malaysia. [Teo, Soo H.] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Tessier, Daniel C.] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Thanasitthichai, Somchai] Natl Canc Inst, Res & Technol Assessment Dept, Bangkok, Thailand. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece. [Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Martens, John W. M.] Canc Genom Netherlands, Utrecht, Netherlands. RP Hollestelle, A (reprint author), Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. EM a.hollestelle@erasmusmc.nl RI Li, Jingmei/I-2904-2012; Brenner, Hermann/B-4627-2017; Dork, Thilo/J-8620-2012 OI Li, Jingmei/0000-0001-8587-7511; Brenner, Hermann/0000-0002-6129-1572; FU Department Director-General of Disease Control; NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA); Breast Cancer Now; Institute of Cancer Research; NHS; Cancer Genomics Netherlands (CGC.nl); grant for the Netherlands Organization of Scientific Research (NWO); China Scholarship Council (Beijing, China); Cancer Research UK [C1287/A12014, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C490/A10124]; European Community [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978, R01 CA77398, UM1 CA164917, U01 CA199277]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, DDHK 2004-3124, DDHK 2009-4318]; Breast Cancer Research Trust, UK; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Agence Nationale de Securite Sanitaire; de l'Alimentation; de l'Environnement et du Travail (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev and Gentofte Hospital; Instituto de Salud Carlos III (CEGEN); Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]; FEDER funds; H2020 (BRIDGES project); California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; California Department of Public Health [103885]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715, 251314]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; MEXT Kakenhi from the Ministry of Education, Science, Sports, Culture and Technology of Japan [170150181, 26253041]; Ministry Health, Labour and Welfare of Japan; Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; "Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development [15ck0106177h0001]; AMED; Cancer Bio Bank Aichi; Friends of Hannover Medical School; Rudolf Bartling Foundation; Merit and Hans Rausings Initiative Against Breast Cancer; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; 'Stichting tegen Kanker'; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA192393, CA116167, CA176785, CA63464, CA54281, CA098758, CA132839, CA164973, R01CA100374, R01CA64277, R01CA148667, UMCA182910, R37CA70867]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the " CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06, RP046B-15HTM]; Cancer Research Malaysia; Yayasan Sime Darby LPGA Tournament; Research Council of Norway [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346, 27208]; Norwegian Cancer Society [419616-71248 -PR-2006-0282]; K. G. Jebsen Centre for Breast Cancer Research; Finnish Cancer Foundation; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds for Oulu University Hospital-based research activities; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Survey and Biospecimen Shared Resource [P30 CA68485]; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; National Cancer Institute Thailand; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Hellenic Cooperative Oncology Group [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Institute of Cancer Research (ICR), London; [PBZ_KBN_122/P05/2004] FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: Paul Pharoah (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai and Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Andrew Lee, Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, Francois Bacot, Daniel Vincent, Sylvie La Boissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility; ABCFS: Maggie Angelakos, Judi Maskiell, Gillian Dite; ABCS: Blood bank Sanquin (The Netherlands); ACP: The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special Thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the study would like to thank Dr Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout; BBCS: Eileen Williams, Elaine Ryder-Mills, Kara Sargus; BIGGS: Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones; BSUCH: Peter Bugert, Medical Faculty Mannheim; CGPS: Staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases; CNIO-BCS: Guillermo Pita, Charo Alonso, Nuria Alvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO); CTS: The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, and Eunjung Lee at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine, and Fred Schumacher at Case Western University. Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach; GENICA: The GENICA Network: Dr.; Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany [Hiltrud Brauch, Wing-Yee Lo, Christina Justenhoven], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [Hiltrud Brauch], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [HansPeter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [Thomas Bruning, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]; HEBCS: Kristiina Aittomaki, Sofia Khan, Taru A. Muranen, Kirsimari Aaltonen, Karl von Smitten, Irja Erkkila; HMBCS: Peter Hillemanns, Hans Christiansen and Johann H. Karstens; pKARMA: The Swedish Medical Research Counsel; KBCP: Eija Myohanen, Helena Kemilainen; kConFab/AOCS: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; LAABC: We thank all the study participants and the entire data collection team, especially Annie Fung and June Yashiki; LMBC: Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts; MARIE: Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Ursula Eilber, Muhabbet Celik; MBCSG: Paolo Peterlongo of IFOM, the FIRC Institute of Molecular Oncology; Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Daniela Zaffaroni and Lidia Pezzani of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory; MTLGEBCS: We would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. We thank study partcipants and research staff (particularly Patsy Ng, Nurhidayu Hassan, Yoon Sook-Yee, Daphne Lee, Lee Sheau Yee, Phuah Sze Yee and Norhashimah Hassan) for their contributions and commitment to this study; NBCS: OSBREAC Investigators: Prof. Solveig Hofvind, PhD (Cancer Registry of Norway, Oslo, Norway, Oslo and Akershus University College of Applied Sciences, Faculty of Health Science, Oslo, Norway), Prof. Tone F. Bathen, PhD (Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU), Trondheim, Norway), Dr. Elin Borgen, MD (Department of Pathology, Division of Diagnostics and Intervention, Oslo University Hospital, Oslo, Norway), Prof. Em. Oystein Fodstad, MD (Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Dr.; Oystein Garred, MD (Department of Pathology, Oslo University Hospital, Oslo, Norway), Gry Aarum Geitvik, Unit leader (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Prof. Gunhild Mari Maelandsmo, PhD (Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway, Department of Pharmacy, Faculty of Health Sciences, University of Tromso, Tromso, Norway), Dr. Hege G Russnes, MD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway and Department of Pathology, Oslo University Hospital, Oslo, Norway), Dr. Therese Sorlie, PhD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Prof. Ole Christian Lingjorde, PhD (Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway and Department of Computer Science, University of Oslo, Oslo, Norway), Dr. Helle Kristine Skjerven, MD (Breast and Endocrine Surgery, Department of Breast and Endocrine Surgery, Vestre Viken Hospital, Drammen, Norway), Dr. Britt Fritzman, MD (Ostfold Hospital, Ostfold, Norway); NBHS: We thank study participants and research staff for their contributions and commitment to this study; OBCS: We thank Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Meeri Otsukka, Leena Keskitalo and Kari Mononen for their contributions to this study; OFBCR: Teresa Selander, Nayana Weerasooriya; PBCS: Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner; RBCS: Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic; SASBAC: The Swedish Medical Research Counsel; SBCGS: We thank study partcipants and research staff for their contributions and commitment to this study; SBCS: Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed; SEARCH: The SEARCH and EPIC teams; SGBCC: We thank the participants and research coordinator Ms Tan Siew Li; SKKDKFZS: We thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study; SZBCS: Ewa Putresza; UKBGS: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre.; This study was funded by the Cancer Genomics Netherlands (CGC.nl) and a grant for the Netherlands Organization of Scientific Research (NWO). J Liu received a scholarship from the China Scholarship Council (Beijing, China). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). 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 USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III (CEGEN) and grants from the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070) with FEDER funds and H2020 (BRIDGES project).; The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and "Practical Research for Innovative Cancer Control (15ck0106177h0001)" from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The pKARMA study was supported by Merit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program.; Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the 'Stichting tegen Kanker'. Diether Lambrechts is supported by the FWO. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the " CIHR Team in Familial Risks of Breast Cancer" program grant #CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale and 27208 to V. N. Kristensen) and the Norwegian Cancer Society (to A-L Borresen-Dale and 419616-71248 -PR-2006-0282 to V. N. Kristensen). It has received funding from the K. G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA).; 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 USA Government or the BCFR. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now. SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies- Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute Thailand. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation; the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, 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) - ARISTEIA. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 29 TC 0 Z9 0 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 15 PY 2016 VL 6 AR 36874 DI 10.1038/srep36874 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8QC UT WOS:000387654800001 PM 27845421 ER PT J AU Nakagawa-Goto, K Taniguchi, Y Watanabe, Y Oda, A Ohkoshi, E Hamel, E Lee, KH Goto, M AF Nakagawa-Goto, Kyoko Taniguchi, Yukako Watanabe, Yurie Oda, Akifumi Ohkoshi, Emika Hamel, Ernest Lee, Kuo-Hsiung Goto, Masuo TI Triethylated chromones with substituted naphthalenes as tubulin inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Triethylated chromones; Naphthalene; Mitotic inhibitors ID DESMOSDUMOTIN-B ANALOGS; COLCHICINE; AGENTS AB Previously synthesized 2-(benzo[b]thiophene-3'-yI)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1'-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3-5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4'-acetoxynaphthalen-1'-yl derivative, displayed the most potent antiproliferative activity (IC50, 0.2-5.7 mu M). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Nakagawa-Goto, Kyoko; Taniguchi, Yukako; Watanabe, Yurie; Oda, Akifumi] Kanazawa Univ, Sch Pharmaceut Sci, Coll Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa 9201192, Japan. [Nakagawa-Goto, Kyoko; Ohkoshi, Emika; Lee, Kuo-Hsiung; Goto, Masuo] Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, 2 Yuh Der Rd, Taichung 40447, Taiwan. RP Nakagawa-Goto, K (reprint author), Kanazawa Univ, Sch Pharmaceut Sci, Coll Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa 9201192, Japan.; Nakagawa-Goto, K; Goto, M (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. EM kngoto@p.kanazawa-u.ac.jp; goto@med.unc.edu RI GOTO, Kyoko/D-8389-2015 OI GOTO, Kyoko/0000-0002-1642-6538 FU Ministry of Education, Culture, Sports, Science, and Technology (MEXT KAKENHI, Japan) [25293024, 25670054, 26460034, 15H01064]; Terumo Life Science Foundation; NIH grant from the National Cancer Institute [CA177584]; University Research Council (UNC); IBM Junior Faculty Development Award; Eshelman Institute for Innovation, Chapel Hill, North Carolina FX We wish to thank the Microscopy Service Laboratory (UNC-CH) for their expertise in fluorescence and confocal microscopy. In addition, we appreciate critical comments, suggestions, and editing of the manuscript by Dr. Susan L. Morris-Natschke (UNC-CH). This study was supported by Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT KAKENHI, Japan), awarded to K.N.G. (Grant Numbers 25293024 & 25670054) and A.O. (Grant Numbers 26460034 & 15H01064), as well as by a grant from the Terumo Life Science Foundation awarded to K.N.G. This work was supported in part by NIH grant CA177584 from the National Cancer Institute awarded to K.H.L. This work was also supported by a grant from the University Research Council (UNC), and the IBM Junior Faculty Development Award, as well as the Eshelman Institute for Innovation, Chapel Hill, North Carolina, awarded to M.G. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. NR 14 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 15 PY 2016 VL 24 IS 22 BP 6048 EP 6057 DI 10.1016/j.bmc.2016.09.062 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA EB2NV UT WOS:000387200000037 PM 27707623 ER PT J AU Farrand, AQ Gregory, RA Backman, CM Helke, KL Boger, HA AF Farrand, Ariana Q. Gregory, Rebecca A. Backman, Cristina M. Helke, Kristi L. Boger, Heather A. TI Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease SO BRAIN RESEARCH LA English DT Article DE In vivo electrochemistry; Glutamate; Striatum; Neurodegeneration; MitoPark; Dopamine ID SUBSTANTIA-NIGRA; INDUCED DYSKINESIAS; PREFRONTAL CORTEX; BASAL GANGLIA; ANIMAL-MODELS; RAT STRIATUM; MICE; MICROELECTRODE; RECEPTORS; GDNF AB Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson's disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients. These mice display the same phenotypic characteristics as PD, including accelerated decline in motor function and DAergic systems with age. Previously, these mice have responded to L-Dopa treatment and develop L-Dopa induced dyskinesia (LID) as they age. A potential mechanism involved in the formation of LID is greater glutamate release into the dorsal striatum as a result of altered basal ganglia neurocircuitry due to reduced nigrostriatal DA neurotransmission. Therefore, the focus of this study was to assess various indicators of glutamate neurotransmission in the dorsal striatum of MitoPark mice at an age in which nigrostriatal DA has degenerated. At 28 weeks of age, MitoPark mice had, upon KCl stimulation, greater glutamate release in the dorsal striatum compared to control mice. In addition, uptake kinetics were slower in MitoPark mice. These findings were coupled with reduced expression of the glutamate re-uptake transporter, GLT-1, thus providing an environment suitable for glutamate excitotoxic events, leading to altered physiological function in these mice. (C) 2016 Elsevier B.V. All rights reserved. C1 [Farrand, Ariana Q.; Gregory, Rebecca A.; Boger, Heather A.] Med Univ South Carolina, Dept Neurosci, 173 Ashley Ave,BSB 403,MSC 510, Charleston, SC 29425 USA. [Farrand, Ariana Q.; Gregory, Rebecca A.; Boger, Heather A.] Med Univ South Carolina, Ctr Aging, 173 Ashley Ave,BSB 403,MSC 510, Charleston, SC 29425 USA. [Gregory, Rebecca A.; Helke, Kristi L.] Med Univ South Carolina, Dept Comparat Med, 114 Doughty St,STB 648,MSC 777, Charleston, SC 29425 USA. [Backman, Cristina M.] NIH, Integrat Neurosci Sect, Natl Inst Drug Abuse Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Boger, HA (reprint author), Med Univ South Carolina, Dept Neurosci, 173 Ashley Ave,BSB 403,MSC 510, Charleston, SC 29425 USA.; Boger, HA (reprint author), Med Univ South Carolina, Ctr Aging, 173 Ashley Ave,BSB 403,MSC 510, Charleston, SC 29425 USA. EM boger@musc.edu OI Helke, Kris/0000-0001-9746-0764 FU MUSC Barmore Fund, Charleston, SC; National Institute on Aging at the National Institutes of Health [4R00AG033687] FX This work was supported by the MUSC Barmore Fund, Charleston, SC and the National Institute on Aging at the National Institutes of Health (Grant 4R00AG033687). NR 41 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD NOV 15 PY 2016 VL 1651 BP 88 EP 94 DI 10.1016/j.brainres.2016.09.025 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EB6WU UT WOS:000387527100010 PM 27659966 ER PT J AU Bakir, M Nelson, MD Jones, E Li, QL Wei, J Sharif, B Minissian, M Shufelt, C Sopko, G Pepine, CJ Merz, CNB AF Bakir, May Nelson, Michael D. Jones, Erika Li, Quanlin Wei, Janet Sharif, Behzad Minissian, Margo Shufelt, Chrisandra Sopko, George Pepine, Carl J. Merz, C. Noel Bairey TI Heart failure hospitalization in women with signs and symptoms of ischemia: A report from the women's ischemia syndrome evaluation study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Heart failure; Heart failure with preserved ejection fraction; Coronary microvascular disease; Women; Coronary artery disease ID SYNDROME EVALUATION WISE; CORONARY-ARTERY-DISEASE; PRESERVED EJECTION FRACTION; NATIONAL-HEART; RISK-FACTORS; EPIDEMIOLOGY; REACTIVITY; HEALTH; LUNG AB Background: Women with signs and symptoms of ischemia, no obstructive coronary artery disease, and preserved left ventricular ejection fraction enrolled in the National Heart Lung and Blood Institute (NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study have an unexpectedly high rate of subsequent heart failure (HF) hospitalization. We sought to verify and characterize the HF hospitalizations. Methods: A retrospective chart review was performed on 223 women with signs and symptoms of ischemia, undergoing coronary angiography for suspected coronary artery disease followed for 6 +/- 2.6 years. Data were collected from a single site in the WISE study. Results: At the time of study enrollment, the women were 57 +/- 11 years of age, all had preserved left ventricular ejection fraction, and 81 (36%) had obstructive CAD (defined as >50% stenosis in at least one epicardial artery). Among the 223 patients, 25 (11%) reported HF hospitalizations, of which 14/25 (56%) had recurrent HF hospitalizations (>2 hospitalizations). Medical records were available in 13/25 (52%) women. Left ventricular ejection fraction was measured in all verified cases and was found to be preserved in 12/13 (92%). HF hospitalization was not related to obstructive CAD. Conclusion: Among women with signs and symptoms of ischemia undergoing coronary angiography for suspected obstructive CAD, HF hospitalization at 6-year follow-up was predominantly characterized by a preserved ejection fraction and not associated with obstructive CAD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Bakir, May; Nelson, Michael D.; Jones, Erika; Wei, Janet; Minissian, Margo; Shufelt, Chrisandra; Merz, C. Noel Bairey] Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Los Angeles, CA USA. [Li, Quanlin] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Biostat & Bioinformat, Los Angeles, CA 90048 USA. [Sharif, Behzad] Cedars Sinai Med Ctr, Biomed Imaging Res Inst, Los Angeles, CA 90048 USA. [Sopko, George] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Pepine, Carl J.] Univ Florida, Gainesville, FL USA. RP Merz, CNB (reprint author), Cedars Sinai Med Ctr, Womens Heart Ctr, 127 S San Vicente Blvd,A3906, Los Angeles, CA 90048 USA. EM merz@cshs.org OI Bakir, May/0000-0002-8924-425X FU National Heart, Lung and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, T32HL116273, R01 HL090957, 1R03AG032631]; National Institute on Aging; GCRC [MO1-RR00425]; National Center for Research Resources; National Center for Advancing Translational Sciences Grant [UL1TR000124, UL1TR000064]; Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc., Laurence Harbor, NJ; Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California; Constance Austin Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California; Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles; Society for Women's Health Research (SWHR), Washington, D.C.; Linda Joy Pollin Women's Heart Health Program, Cedars-Sinai Medical Center, Los Angeles, California; American Heart Association [16SDG27260115]; Harry S. Moss Heart Trust; Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California FX This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, T32HL116273, R01 HL090957, and 1R03AG032631; from the National Institute on Aging; from GCRC grant MO1-RR00425; from the National Center for Research Resources; from the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR000064; and from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women's Health Research (SWHR), Washington, D.C., The Linda Joy Pollin Women's Heart Health Program, the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California, the American Heart Association (16SDG27260115) and the Harry S. Moss Heart Trust. NR 18 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD NOV 15 PY 2016 VL 223 BP 936 EP 939 DI 10.1016/j.ijcard.2016.07.301 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200240 PM 27589041 ER PT J AU Knudsen, GA Hughes, MF Sanders, JM Hall, SM Birnbaum, LS AF Knudsen, Gabriel A. Hughes, Michael F. Sanders, J. Michael Hall, Samantha M. Birnbaum, Linda S. TI Estimation of human percutaneous bioavailability for two novel brominated flame retardants, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Dermal bioavailability; Brominated flame retardant; 2-Ethylhexyl 2-3,4,5-tetrabromobenzoate; Bis(2-ethylhexyl) tetrabromophthalate; Parallelogram method; Persistent organic pollutant ID IN-HOUSE DUST; ENDOCRINE DISRUPTING CHEMICALS; POLYBROMINATED DIPHENYL ETHERS; MIXTURE FIREMASTER(R) 550; VITRO DERMAL ABSORPTION; GREAT-LAKES ATMOSPHERE; RAT SKIN ABSORPTION; EARLY-LIFE EXPOSURE; INDOOR DUST; PARALLELOGRAM METHOD AB 2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP) are novel brominated flame retardants used in consumer products. A parallelogram approach was used to predict human dermal absorption and flux for EH-TBB and BEH-TEBP. [C-14]-EH-TBB or [C-14]-BEH-TEBP was applied to human or rat skin at 100 nmol/cm(2) using a flow-through system. Intact rats received analogous dermal doses. Treated skin was washed and tape-stripped to remove "unabsorbed" [C-14]-radioactivity after continuous exposure (24 h). "Absorbed" was quantified using dermally retained [C-14]-radioactivity; "penetrated" was calculated based on [C-14]-radioactivity in media (in vitro) or excreta + tissues (in vivo). Human skin absorbed EH-TBB (24 +/- 1%) while 0.2 +/- 0.1% penetrated skin. Rat skin absorbed more (51 +/- 10%) and was more permeable (2 +/- 0.5%) to EH-TBB in vitro; maximal EH-TBB flux was 11 +/- 7 and 102 +/- 24 pmol-eq/cm(2)/h for human and rat skin, respectively. In vivo, 27 +/- 5% was absorbed and 13% reached systemic circulation after 24 h (maximum flux was 464 +/- 65 pmol-eq/cm(2)/h). BEH-TEBP in vitro penetrance was minimal (<0.01%) for rat or human skin. BEH-TEBP absorption was 12 +/- 11% for human skin and 41 +/- 3% for rat skin. In vivo, total absorption was 27 +/- 9%; 12% reached systemic circulation. In vitro maximal BEH-TEBP flux was 0.3 +/- 0.2 and 1 +/- 0.3 pmol-eq/cm2/h for human and rat skin; in vivo maximum flux for rat skin was 16 +/- 7 pmol-eq/cm2/h. EH-TBB was metabolized in rat and human skin to tetrabromobenzoic acid. BEH-TEBP-derived [C-14] -radioactivity in the perfusion media could not be characterized. <1% of the dose of EH-TBB and BEH-TEHP is estimated to reach the systemic circulation following human dermal exposure under the conditions tested. Chemical compounds studied in this article: 2-Ethylhexyl 2,3,4,5-tetrabromobenzoate (PubChem CID: 71316600; CAS No. 183658-27-7 FW: 549.92 g/mol logP(est): 7.73-8.75 (12)) Abdallah et al., 2015a. Other published abbreviations for 2-ethylhexyl-2,3,4,5-tetrabromobenzoate are TBB EHTeBB or EHTBB Abdallah and Harrad, 2011. bis(2-ethylhexyl) tetrabromophthalate (PubChem CID: 117291; CAS No. 26040-51-7 FW: 706.14 g/mol logP(est): 9.48-11.95 (12)). Other published abbreviations for bis(2-ethylhexyl)tetrabromophthalate are TeBrDEPH TBPH or BEHTBP. Published by Elsevier Inc. C1 [Knudsen, Gabriel A.; Sanders, J. Michael; Hall, Samantha M.; Birnbaum, Linda S.] NCI, Lab Toxicol & Toxicokinet, 111 TW Alexander Dr, Res Triangle Pk, NC USA. [Hughes, Michael F.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Knudsen, GA (reprint author), 111 TW Alexander Dr,BG 101 Rm C220A, Res Triangle Pk, NC 27709 USA. EM gabriel.knudsen@nih.gov OI Hall, Samantha M./0000-0003-1608-9508 FU Intramural Research Program of NIH/NCI [ZIA BC 011476] FX The authors would like to thank Ms. Brenda Edwards, Mr. Ethan Hull, Ms. Katelyn McIntosh and Mr. Vivek Miyani, for technical assistance. This article has been reviewed in accordance with the policy of 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 in part by the Intramural Research Program of NIH/NCI (Project ZIA BC 011476). NR 96 TC 0 Z9 0 U1 7 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD NOV 15 PY 2016 VL 311 BP 117 EP 127 DI 10.1016/j.taap.2016.10.005 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EA9VI UT WOS:000386992400013 PM 27732871 ER PT J AU Kaczkurkin, AN Moore, TM Ruparel, K Ciric, R Calkins, ME Shinohara, RT Elliott, MA Hopson, R Roalf, DR Vandekar, SN Gennatas, ED Wolf, DH Scott, JC Pine, DS Leibenluft, E Detre, JA Foa, EB Gur, RE Gur, RC Satterthwaite, TD AF Kaczkurkin, Antonia N. Moore, Tyler M. Ruparel, Kosha Ciric, Rastko Calkins, Monica E. Shinohara, Russell T. Elliott, Mark A. Hopson, Ryan Roalf, David R. Vandekar, Simon N. Gennatas, Efstathios D. Wolf, Daniel H. Scott, J. Cobb Pine, Daniel S. Leibenluft, Ellen Detre, John A. Foa, Edna B. Gur, Raquel E. Gur, Ruben C. Satterthwaite, Theodore D. TI Elevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Adolescence; Amygdala; Anxiety; Cerebral blood flow; Depression; Insula; Perfusion ID CEREBRAL-BLOOD-FLOW; PHILADELPHIA NEURODEVELOPMENTAL COHORT; POSTTRAUMATIC-STRESS-DISORDER; MESSENGER-RNA EXPRESSION; COMMON MENTAL-DISORDERS; FUNCTIONAL CONNECTIVITY; FEARFUL FACES; WHITE-MATTER; HUMAN BRAIN; INDIVIDUAL-DIFFERENCES AB BACKGROUND: Adolescence is a critical period for emotional maturation and is a time when clinically significant symptoms of anxiety and depression increase, particularly in females. However, few studies relate developmental differences in symptoms of anxiety and depression to brain development. Cerebral blood flow is one brain phenotype that is known to have marked developmental sex differences. METHODS: We investigated whether developmental sex differences in cerebral blood flow mediated sex differences in anxiety and depression symptoms by capitalizing on a large sample of 875 youths who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. Perfusion was quantified on a voxelwise basis using arterial spin-labeled magnetic resonance imaging at 3T. Perfusion images were related to trait and state anxiety using general additive models with penalized splines, while controlling for gray matter density on a voxelwise basis. Clusters found to be related to anxiety were evaluated for interactions with age, sex, and puberty. RESULTS: Trait anxiety was associated with elevated perfusion in a network of regions including the amygdala, anterior insula, and fusiform cortex, even after accounting for prescan state anxiety. Notably, these relationships strengthened with age and the transition through puberty. Moreover, higher trait anxiety in postpubertal females was mediated by elevated perfusion of the left amygdala. CONCLUSIONS: Taken together, these results demonstrate that differences in the evolution of cerebral perfusion during adolescence may be a critical element of the affective neurobiological characteristics underlying sex differences in anxiety and mood symptoms. C1 [Kaczkurkin, Antonia N.; Moore, Tyler M.; Ruparel, Kosha; Ciric, Rastko; Calkins, Monica E.; Hopson, Ryan; Roalf, David R.; Gennatas, Efstathios D.; Wolf, Daniel H.; Scott, J. Cobb; Foa, Edna B.; Gur, Raquel E.; Gur, Ruben C.; Satterthwaite, Theodore D.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Shinohara, Russell T.; Vandekar, Simon N.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Elliott, Mark A.; Detre, John A.; Gur, Raquel E.; Gur, Ruben C.] Univ Penn, Perelman Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Detre, John A.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Scott, J. Cobb; Gur, Ruben C.] Philadelphia Vet Adm Med Ctr, Philadelphia, PA USA. [Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Satterthwaite, TD (reprint author), Hosp Univ Penn, Dept Psychiat, 34th & Spruce St,10th Floor,Gates Bldg, Philadelphia, PA 19104 USA. EM sattertt@upenn.edu FU National Institute of Mental Health RC2 Grant [MH089983, MH089924, R01MH07703]; National Institutes of Health [K23MH098130, R01MH101111, K01MH102609, K08MH079364, R01NS085211, P50mh096891, T32MH065218]; Dowshen Program for Neuroscience; Center for Biomedical Computing and Image Analysis (CBICA) at the University of Pennsylvania; Oxford University Press FX This work was supported by the National Institute of Mental Health RC2 Grant Nos. MH089983, MH089924, and R01MH07703. Additional support was provided by the National Institutes of Health Grant Nos. K23MH098130 (to TDS), R01MH101111 (to DHW), K01MH102609 (to DRR), K08MH079364 (to MEC), R01NS085211 (to RTS), P50mh096891 (to REG), and T32MH065218 (to SNV); and the Dowshen Program for Neuroscience. Support for developing statistical analyses (to RTS and TDS) was provided by a seed grant by the Center for Biomedical Computing and Image Analysis (CBICA) at the University of Pennsylvania. The data reported in this article have been deposited in the database of Genotypes and Phenotypes (dbGaP), available at: www.ncbi.nlm.nih.gov/gap (accession no. phs000607.v1.p1).; REG participated in an advisory board for Otsuka Pharmaceuticals. RCG receives royalties from the Brain Resource Centre and serves without compensation on an advisory board for Lumosity. EBF receives royalties from the sale of the books Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences Therapist Guide and Reclaiming Your Life From a Traumatic Experience Workbook by Oxford University Press and receives payment for training workshops she conducts on prolonged exposure therapy. All other authors reported no biomedical financial interests or potential conflicts of interest. NR 98 TC 2 Z9 2 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 15 PY 2016 VL 80 IS 10 BP 775 EP 785 DI 10.1016/j.biopsych.2016.04.021 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0FS UT WOS:000385513500008 PM 27395327 ER PT J AU Chung, EJ Sowers, A Thetford, A McKay-Corkum, G Chung, SI Mitchell, JB Citrin, DE AF Chung, Eun Joo Sowers, Anastasia Thetford, Angela McKay-Corkum, Grace Chung, Su I. Mitchell, James B. Citrin, Deborah E. TI Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID MTOR INHIBITORS; CELLULAR SENESCENCE; THORACIC IRRADIATION; SECRETORY PHENOTYPE; CANCER-CELLS; LIFE-SPAN; LUNG; MICE; BINDING; RADIOSENSITIVITY AB Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF. Methods and Materials: C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for beta-galactosidase activity. Results: Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days (P = .006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 +/- 11.8 mu g per lung; irradiation plus rapamycin, 21.4 +/- 6.0 mu g per lung; P = .001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1 beta and transforming growth factor beta induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P < .001). Conclusions: Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes. Published by Elsevier Inc. C1 [Chung, Eun Joo; McKay-Corkum, Grace; Chung, Su I.; Citrin, Deborah E.] NIH, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Sowers, Anastasia; Thetford, Angela; Mitchell, James B.] NIH, Radiat Biol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Radiat Oncol Branch, Bldg 10 CRC,B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU Intramural Research Program of the National Institutes of Health-National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health-National Cancer Institute. NR 54 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2016 VL 96 IS 4 BP 857 EP 866 DI 10.1016/j.ijrobp.2016.07.026 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0JG UT WOS:000385524000019 PM 27663762 ER PT J AU Shen, CC Li, XZ Rasooly, A Guo, LY Zhang, KN Yang, MH AF Shen, Congcong Li, Xiangzhi Rasooly, Avraham Guo, Linyan Zhang, Kaina Yang, Minghui TI A single electrochemical biosensor for detecting the activity and inhibition of both protein kinase and alkaline phosphatase based on phosphate ions induced deposition of redox precipitates SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Protein kinase; Alkaline phosphatase; Electrochemical; Biosensor; Inhibitor ID ELECTROGENERATED CHEMILUMINESCENCE BIOSENSOR; CARBON QUANTUM DOTS; SIGNAL AMPLIFICATION; FLUORESCENT ASSAY; CANCER-THERAPY; A ACTIVITY; PHOS-TAG; GRAPHENE; PHOSPHORYLATION; NANOPARTICLES AB Protein kinase (PIGS) and alkaline phosphatase (ALP) are clinically relevant enzymes for a number of diseases. In this work, we developed a new simple electrochemical biosensor for the detection of the activity and inhibition of both PICA and ALP. One common feature of the PICA and ALP catalyzing process is that PICA can hydrolysis adenosine-5'-triphosphate (ATP) and ALP can hydrolysis pyrophosphate, both reactions produce phosphate ions, and the amount of phosphate ion produced is proportional to enzyme activity. Our assay is based on the principle that phosphate ions react with molybdate to form redox molybdophosphate precipitates on the electrode surface, thus generating electrochemical current. The detection limit for PICA and ALP were much lower than existing assays. The biosensor has good specificity and was used to measure drug-stimulated PICA from lysates of HeLa cells. We also evaluated the use of the biosensor as a screening tool for enzyme inhibitors. To the best of our knowledge, this is the first report of a biosensor capable of detecting the activity of both PICA and ALP. This tool has the potential to simplify PICA and ALP clinical measurement, thereby improving diagnostics of relevant diseases. It also may serve as the basis for a simple screening method for new enzyme inhibitors for disease treatment. (C) 2016 Elsevier B.V. All rights reserved. C1 [Shen, Congcong; Li, Xiangzhi; Guo, Linyan; Zhang, Kaina; Yang, Minghui] Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China. [Rasooly, Avraham] NCI, NIH, Rockville, MD 20850 USA. RP Yang, MH (reprint author), Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China. EM yangminghui@csu.edu.cn FU National Key Basic Research Program of China [2014CB744502]; National Natural Science Foundation of China [21575165]; Natural Science Foundation of Hunan Province, China [2015JJ1019] FX The authors thank the support of this work by the National Key Basic Research Program of China (2014CB744502), the National Natural Science Foundation of China (No. 21575165) and the Natural Science Foundation of Hunan Province, China (No. 2015JJ1019). NR 54 TC 6 Z9 6 U1 104 U2 128 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD NOV 15 PY 2016 VL 85 BP 220 EP 225 DI 10.1016/j.bios.2016.05.025 PG 6 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA DU7QQ UT WOS:000382410100029 ER PT J AU Pastor, M Song, J Hoang, DT Jo, J AF Pastor, Marissa Song, Juyong Danh-Tai Hoang Jo, Junghyo TI Minimal perceptrons for memorizing complex patterns SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE Perceptrons; Network complexity; Binary patterns; Memory storage; Network architecture ID FEEDFORWARD NEURAL-NETWORKS; STORAGE CAPACITY; HIDDEN UNITS; NUMBER; CLASSIFICATION; ALGORITHMS AB Feedforward neural networks have been investigated to understand learning and memory, as well as applied to numerous practical problems in pattern classification. It is a rule of thumb that more complex tasks require larger networks. However, the design of optimal network architectures for specific tasks is still an unsolved fundamental problem. In this study, we consider three-layered neural networks for memorizing binary patterns. We developed a new complexity measure of binary patterns, and estimated the minimal network size for memorizing them as a function of their complexity. We formulated the minimal network size for regular, random, and complex patterns. In particular, the minimal size for complex patterns, which are neither ordered nor disordered, was predicted by measuring their Hamming distances from known ordered patterns. Our predictions agree with simulations based on the back-propagation algorithm. (C) 2016 Elsevier B.V. All rights reserved. C1 [Pastor, Marissa; Song, Juyong; Danh-Tai Hoang; Jo, Junghyo] Asia Pacific Ctr Theoret Phys, Pohang, South Korea. [Pastor, Marissa] Univ San Carlos Talamban, Dept Phys, Cebu, Philippines. [Song, Juyong; Jo, Junghyo] Pohang Univ Sci & Technol, Dept Phys, Pohang, South Korea. [Danh-Tai Hoang] Quang Binh Univ, Dept Nat Sci, Dong Hoi, Vietnam. [Danh-Tai Hoang] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Jo, J (reprint author), Asia Pacific Ctr Theoret Phys, Pohang, South Korea. EM jojunghyo@apctp.org FU Basic Science Research Program through the National Foundation of Korea funded by the Ministry of Science, ICT & Future Planning [2013R1A1A1006655]; Max Planck Society; Korea Ministry of Education, Science and Technology, Gyeongsangbuk-Do and Pohang City FX We thank V. Periwal for discussions and hospitality during our stay at National Institutes of Health in the US. M. Pastor acknowledges the Office of Research, University of San Carlos, Cebu City, Philippines. This research was supported by Basic Science Research Program through the National Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (No. 2013R1A1A1006655) and by the Max Planck Society, the Korea Ministry of Education, Science and Technology, Gyeongsangbuk-Do and Pohang City. NR 23 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 EI 1873-2119 J9 PHYSICA A JI Physica A PD NOV 15 PY 2016 VL 462 BP 31 EP 37 DI 10.1016/j.physa.2016.06.025 PG 7 WC Physics, Multidisciplinary SC Physics GA DT9SF UT WOS:000381841900004 ER PT J AU Gobl, C Resch, M Strickland, M Hartlmuller, C Viertler, M Tjandra, N Madl, T AF Goebl, Christoph Resch, Moritz Strickland, Madeleine Hartlmueller, Christoph Viertler, Martin Tjandra, Nico Madl, Tobias TI Increasing the Chemical-Shift Dispersion of Unstructured Proteins with a Covalent Lanthanide Shift Reagent SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE chemical-shift dispersion; intrinsically disordered proteins; lanthanides; NMR; pseudo-contact shifts ID INTRINSICALLY DISORDERED PROTEINS; BACKBONE RESONANCE ASSIGNMENT; NMR-SPECTROSCOPY; UNFOLDED PROTEINS; BIOMOLECULAR NMR; LOW-COMPLEXITY; REGIONS; BINDING; FUS; TRANSPORTIN AB The study of intrinsically disordered proteins (IDPs) by NMR often suffers from highly overlapped resonances that prevent unambiguous chemical-shift assignments, and data analysis that relies on well-separated resonances. We present a covalent paramagnetic lanthanide-binding tag (LBT) for increasing the chemical-shift dispersion and facilitating the chemical-shift assignment of challenging, repeat-containing IDPs. Linkage of the DOTA-based LBT to a cysteine residue induces pseudo-contact shifts (PCS) for resonances more than 20 residues from the spin-labeling site. This leads to increased chemical-shift dispersion and decreased signal overlap, thereby greatly facilitating chemical-shift assignment. This approach is applicable to IDPs of varying sizes and complexity, and is particularly helpful for repeat-containing IDPs and low-complexity regions. This results in improved efficiency for IDP analysis and binding studies. C1 [Goebl, Christoph; Resch, Moritz; Strickland, Madeleine; Hartlmueller, Christoph; Viertler, Martin; Tjandra, Nico; Madl, Tobias] Tech Univ Munich, Ctr Integrated Prot Sci Munich, Dept Chem, Lichtenbergstr 4, D-85748 Garching, Germany. [Goebl, Christoph; Resch, Moritz; Hartlmueller, Christoph; Viertler, Martin; Madl, Tobias] Helmholtz Zentrum Munchen, Inst Biol Struct, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Madl, Tobias] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria. [Strickland, Madeleine; Tjandra, Nico] NHLBI, Lab Struct Biophys, Biochem & Biophys Ctr, NIH, Bldg 50, Bethesda, MD 20814 USA. RP Tjandra, N; Madl, T (reprint author), Tech Univ Munich, Ctr Integrated Prot Sci Munich, Dept Chem, Lichtenbergstr 4, D-85748 Garching, Germany.; Madl, T (reprint author), Helmholtz Zentrum Munchen, Inst Biol Struct, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany.; Madl, T (reprint author), Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria. EM tjandran@nhlbi.nih.gov; tobias.madl@medunigraz.at RI Madl, Tobias/B-1682-2012; Goebl, Christoph/G-7578-2016; OI Madl, Tobias/0000-0002-9725-5231; Gobl, Christoph/0000-0001-8614-1434; Strickland, Madeleine/0000-0001-8160-070X; Resch, Moritz/0000-0003-3477-3565 FU Intramural Research Program of the NIH, NHLBI; Bavarian Ministry of Sciences, Research and the Arts (Bavarian Molecular Biosystems Research Network); German Research Foundation (Emmy Noether program) [MA 5703/1-1]; Center for Integrated Protein Science Munich (CIPSM); Austrian Science Fund [FWF: P28854, W1226-B18] FX Part of this work was supported by the Intramural Research Program of the NIH, NHLBI. T.M. was supported by the Bavarian Ministry of Sciences, Research and the Arts (Bavarian Molecular Biosystems Research Network), the German Research Foundation (Emmy Noether program MA 5703/1-1), the Center for Integrated Protein Science Munich (CIPSM), and the Austrian Science Fund (FWF: P28854, W1226-B18). We thank the Imaging Probe Development Group of the NIH for synthesizing the Yb-M8 tag. Critical reading of the manuscript by Ashley C. Barnes, Sam Asami, and Vanessa Morris is gratefully acknowledged. NR 48 TC 0 Z9 0 U1 3 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD NOV 14 PY 2016 VL 55 IS 47 BP 14847 EP 14851 DI 10.1002/anie.201607261 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EC6NH UT WOS:000388252700067 PM 27763708 ER PT J AU Weeraratna, AT Gorospe, M AF Weeraratna, Ashani T. Gorospe, Myriam TI UNRelenting Translation UNRestrains Melanoma Migration SO CANCER CELL LA English DT Editorial Material ID EXPRESSION; PROTEINS; CELLS; UNR AB The cytoplasmic RNA-binding protein UNR influences key developmental processes by controlling mRNA turnover and translation initiation. In this issue of Cancer Cell, Wurth et al. report that UNR is highly expressed in melanoma and enhances invasion and metastasis at least partly by inducing translation elongation of VIM and RAC1 mRNAs. C1 [Weeraratna, Ashani T.] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, 3601 Spruce St, Philadelphia, PA 19104 USA. [Gorospe, Myriam] NIA, Lab Genet & Genom, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Lab Genet & Genom, IRP, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov FU NCI NIH HHS [P30 CA010815, R01 CA174746] NR 10 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD NOV 14 PY 2016 VL 30 IS 5 BP 655 EP 657 DI 10.1016/j.ccell.2016.10.012 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EC3ZE UT WOS:000388064800002 PM 27846383 ER PT J AU Ceribelli, M Hou, ZE Kelly, PN Huang, DW Wright, G Ganapathi, K Evbuomwan, MO Pittaluga, S Shaffer, AL Marcucci, G Forman, SJ Xiao, WM Guha, R Zhang, XH Ferrer, M Chaperot, L Plumas, J Jaffe, ES Thomas, CJ Reizis, B Staudt, LM AF Ceribelli, Michele Hou, Zhiying Esther Kelly, Priscilla N. Huang, Da Wei Wright, George Ganapathi, Karthik Evbuomwan, Moses O. Pittaluga, Stefania Shaffer, Arthur L. Marcucci, Guido Forman, Stephen J. Xiao, Wenming Guha, Rajarshi Zhang, Xiaohu Ferrer, Marc Chaperot, Laurence Plumas, Joel Jaffe, Elaine S. Thomas, Craig J. Reizis, Boris Staudt, Louis M. TI A Druggable TCF4-and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm SO CANCER CELL LA English DT Article ID INTERFERON-PRODUCING CELLS; SELECTIVE-INHIBITION; SEQUENCING REVEALS; FACTOR E2-2; SPI-B; LYMPHOMA; EXPRESSION; MUTATIONS; CANCER; RECURRENT AB Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy. C1 [Ceribelli, Michele; Kelly, Priscilla N.; Huang, Da Wei; Shaffer, Arthur L.; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Hou, Zhiying Esther; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Wright, George] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Ganapathi, Karthik; Evbuomwan, Moses O.; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Marcucci, Guido; Forman, Stephen J.] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplant, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Xiao, Wenming] NCTR FDA, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Guha, Rajarshi; Zhang, Xiaohu; Ferrer, Marc; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Chaperot, Laurence; Plumas, Joel] EFS Rhone Alpes Grenoble, R&D Lab, F-38701 La Tronche, France. [Chaperot, Laurence; Plumas, Joel] CNRS, INSERM, Inst Adv Biosci UGA, U1209,UMR 5309, F-38000 Grenoble, France. [Reizis, Boris] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Ganapathi, Karthik] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA.; Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA.; Reizis, B (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. EM boris.reizis@nyumc.org; lstaudt@mail.nih.gov OI Reizis, Boris/0000-0003-1140-7853 FU NIH, National Cancer Institute, Center for Cancer Research; National Human Genome Research Institute; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E, U54CA143930]; Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; NIH [AI072571]; Feinberg Lymphoma Research Pilot award FX This research was supported by the Intramural Research Programs of the NIH, National Cancer Institute, Center for Cancer Research, and the National Human Genome Research Institute; the Frederick National Laboratory for Cancer Research, NIH including contract HHSN261200800001E and grant #U54CA143930; the Division of Preclinical Innovation, National Center for Advancing Translational Sciences; the Molecular Libraries Initiative of the NIH Roadmap for Medical Research; and by NIH grant AI072571 and the Feinberg Lymphoma Research Pilot award to B.R. We thank Kathleen Meyer for help with the GEO submission. NR 57 TC 4 Z9 4 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD NOV 14 PY 2016 VL 30 IS 5 BP 764 EP 778 DI 10.1016/j.ccell.2016.10.002 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EC3ZE UT WOS:000388064800015 PM 27846392 ER PT J AU Queiros, AC Beekman, R Vilarrasa-Blasi, R Duran-Ferrer, M Clot, G Merkel, A Raineri, E Russinol, N Castellano, G Bea, S Navarro, A Kulis, M Verdaguer-Dot, N Jares, P Enjuanes, A Calasanz, MJ Bergmann, A Vater, I Salaverria, I van de Werken, HJG Wilson, WH Datta, A Flicek, P Royo, R Martens, J Gine, E Lopez-Guillermo, A Stunnenberg, HG Klapper, W Pott, C Heath, S Gut, IG Siebert, R Campo, E Martin-Subero, JI AF Queiros, Ana C. Beekman, Renee Vilarrasa-Blasi, Roser Duran-Ferrer, Marti Clot, Guillem Merkel, Angelika Raineri, Emanuele Russinol, Nuria Castellano, Giancarlo Bea, Silvia Navarro, Alba Kulis, Marta Verdaguer-Dot, Nuria Jares, Pedro Enjuanes, Anna Jose Calasanz, Maria Bergmann, Anke Vater, Inga Salaverria, Itziar van de Werken, Harmen J. G. Wilson, Wyndham H. Datta, Avik Flicek, Paul Royo, Romina Martens, Joost Gine, Eva Lopez-Guillermo, Armando Stunnenberg, Hendrik G. Klapper, Wolfram Pott, Christiane Heath, Simon Gut, Ivo G. Siebert, Reiner Campo, Elias Martin-Subero, Jose I. TI Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage SO CANCER CELL LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MOLECULAR PATHOGENESIS; CANCER-CELLS; METHYLATION; MUTATIONS; ENHANCERS; EPIGENOME; REVEALS; GENOME; DIFFERENTIATION AB We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome. C1 [Queiros, Ana C.; Vilarrasa-Blasi, Roser; Duran-Ferrer, Marti; Russinol, Nuria; Kulis, Marta; Verdaguer-Dot, Nuria; Jares, Pedro; Campo, Elias; Martin-Subero, Jose I.] Univ Barcelona, Dept Fundamentos Clin, E-08036 Barcelona, Spain. [Beekman, Renee; Clot, Guillem; Russinol, Nuria; Castellano, Giancarlo; Bea, Silvia; Navarro, Alba; Verdaguer-Dot, Nuria; Salaverria, Itziar; Campo, Elias; Martin-Subero, Jose I.] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain. [Merkel, Angelika; Raineri, Emanuele; Heath, Simon; Gut, Ivo G.] Ctr Nacl Anal Genom, Parc Cient Barcelona, Barcelona 08028, Spain. [Jares, Pedro; Enjuanes, Anna] IDIBAPS, Unidad Genom, Barcelona 08036, Spain. [Jose Calasanz, Maria] Univ Navarra, Dept Genet, Pamplona 31008, Spain. [Bergmann, Anke; Vater, Inga; Siebert, Reiner] Univ Kiel, Inst Human Genet, D-24105 Kiel, Germany. [Bergmann, Anke] Univ Kiel, Dept Pediat, D-24105 Kiel, Germany. [Bergmann, Anke] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany. [van de Werken, Harmen J. G.] Erasmus MC, Dept Cell Biol, NL-3015 CN Rotterdam, Netherlands. [van de Werken, Harmen J. G.] Erasmus MC, Canc Computat Biol Ctr, NL-3015 CN Rotterdam, Netherlands. [van de Werken, Harmen J. G.] Erasmus MC, Dept Urol, NL-3015 CN Rotterdam, Netherlands. [Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Datta, Avik; Flicek, Paul] EBI, EMBL, Wellcome Trust Genome Campus, Hinxton CB10 1SD, England. [Royo, Romina] BSC, Joint Program Computat Biol, Barcelona Sci Pk, Barcelona 08034, Spain. [Royo, Romina] IRB, Barcelona Sci Pk, Barcelona 08034, Spain. [Martens, Joost; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, FNWI, NCMLS, Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Gine, Eva; Lopez-Guillermo, Armando] IDIBAPS, Hosp Clin, Serv Hematol, Barcelona 08036, Spain. [Klapper, Wolfram] Christian Albrecht Univ, Hematopathol Sect, D-24105 Kiel, Germany. [Klapper, Wolfram] Christian Albrecht Univ, Lymph Node Registry, D-24105 Kiel, Germany. [Pott, Christiane] Univ Hosp Schleswig Holstein, Dept Med 2, D-24116 Kiel, Germany. [Campo, Elias] Hosp Clin Barcelona, Serv Anat Patol, Unidad Hematopatol, E-08036 Barcelona, Spain. RP Martin-Subero, JI (reprint author), Univ Barcelona, Dept Fundamentos Clin, E-08036 Barcelona, Spain.; Martin-Subero, JI (reprint author), Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain. EM imartins@clinic.ub.es RI Klapper, Wolfram/S-6314-2016; Siebert, Reiner/A-8049-2010; OI Beekman, Renee/0000-0001-7081-7874; Flicek, Paul/0000-0002-3897-7955; van de Werken, Harmen/0000-0002-9794-1477 FU European Union through the Blueprint Consortium [282510]; European Hematology Association; Worldwide Cancer Research [16-1285]; Spanish Ministerio de Economia y Competitividad (MINECO) [SAF2015-64885-R]; Generalitat de Catalunya Suport Grups de Recerca AGAUR [2014-SGR-795]; Portuguese Fundacao para a Ciencia e a Tecnologia (FCT); Netherlands Organisation for Scientific Research (NWO); EU (Marie Curie); MINECO FX This work was funded by the European Union's Seventh Framework Program through the Blueprint Consortium (grant agreement 282510), the European Hematology Association (Non-Clinical Advanced Research Fellowships to J.I.M.-S.), the Worldwide Cancer Research (grant number 16-1285, to J.I.M.-S.), Spanish Ministerio de Economia y Competitividad (MINECO), grant no. SAF2015-64885-R (to E.C.) and Generalitat de Catalunya Suport Grups de Recerca AGAUR 2014-SGR-795 (to E.C.). Methylation microarrays were out-sourced to the Spanish Centro Nacional de Genotipado (CEGEN-ISCIII). We are indebted to the Genomics core facility of the Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) for technical help. This work was partially developed at the Centro Esther Koplowitz (CEK; Barcelona, Spain). J.I.M.-S. is a Ramon y Cajal researcher of MINECO, E.C. is an Academia Researcher of the "Institucio Catalana de Recerca i Estudis Avancats" (ICREA) of the Generalitat de Catalunya, A.C.Q. is supported by a Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) fellowship, R.B. by fellowships from the Netherlands Organisation for Scientific Research (NWO) and the EU (Marie Curie), and R.V.-B by a pre-doctoral fellowship of the MINECO. Paul Flicek is a member of the Scientific Advisory Board for Omicia, Inc. NR 52 TC 1 Z9 1 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD NOV 14 PY 2016 VL 30 IS 5 BP 806 EP 821 DI 10.1016/j.ccell.2016.09.014 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EC3ZE UT WOS:000388064800018 PM 27846393 ER PT J AU Luo, ZP AF Luo, Zhipu TI Selenourea: a convenient phasing vehicle for macromolecular X-ray crystal structures SO SCIENTIFIC REPORTS LA English DT Article ID ANOMALOUS DIFFRACTION; CRYSTALLOGRAPHY; PROTEINS; SIGNAL; DNA; DERIVATIZATION; SULFUR; MAD AB Majority of novel X-ray crystal structures of proteins are currently solved using the anomalous diffraction signal provided by selenium after incorporation of selenomethionine instead of natural methionine by genetic engineering methods. However, selenium can be inserted into protein crystals in the form of selenourea (SeC(NH2)(2)), by adding the crystalline powder of selenourea into mother liquor or cryo-solution with native crystals, in analogy to the classic procedure of heavy-atom derivatization. Selenourea is able to bind to reactive groups at the surface of macromolecules primarily through hydrogen bonds, where the selenium atom may serve as acceptor and amide groups as donors. Selenourea has different chemical properties than heavy-atom reagents and halide ions and provides a convenient way of phasing crystal structures of macromolecules. C1 [Luo, Zhipu] Argonne Natl Lab, Natl Canc Inst, Synchrotron Radiat Res Sect, 9700 S Cass Ave, Argonne, IL 60439 USA. RP Luo, ZP (reprint author), Argonne Natl Lab, Natl Canc Inst, Synchrotron Radiat Res Sect, 9700 S Cass Ave, Argonne, IL 60439 USA. EM luozhipu@anl.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. The help of Zbigniew Dauter in preparation of this manuscript is gratefully appreciated. The instruction for CFP expression and purification and growth of HPP crystals by Milosz Ruszkowski are appreciated. Provision of thaumatin and trypsin crystals by Miroslawa Dauter is gratefully acknowledged. NR 29 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 14 PY 2016 VL 6 AR 37123 DI 10.1038/srep37123 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC1GJ UT WOS:000387852600001 PM 27841370 ER PT J AU Greer, RL Dong, XX Moraes, ACF Zielke, RA Fernandes, GR Peremyslova, E Vasquez-Perez, S Schoenborn, AA Gomes, EP Pereira, AC Ferreira, SRG Yao, M Fuss, IJ Strober, W Sikora, AE Taylor, GA Gulati, AS Morgun, A Shulzhenko, N AF Greer, Renee L. Dong, Xiaoxi Moraes, Ana Carolina F. Zielke, Ryszard A. Fernandes, Gabriel R. Peremyslova, Ekaterina Vasquez-Perez, Stephany Schoenborn, Alexi A. Gomes, Everton P. Pereira, Alexandre C. Ferreira, Sandra R. G. Yao, Michael Fuss, Ivan J. Strober, Warren Sikora, Aleksandra E. Taylor, Gregory A. Gulati, Ajay S. Morgun, Andrey Shulzhenko, Natalia TI Akkermansia muciniphila mediates negative effects of IFN gamma on glucose metabolism SO NATURE COMMUNICATIONS LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; DIET-INDUCED OBESITY; GUT MICROBIOTA; INTERFERON-GAMMA; ADIPOSE-TISSUE; BODY-WEIGHT; ADAPTIVE IMMUNITY; MICE LACKING; T-CELLS; INFLAMMATION AB Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease. Here, we show that the gut microbe Akkermansia muciniphila can mediate negative effects of IFN gamma on glucose tolerance. In IFN gamma-deficient mice, A. muciniphila is significantly increased and restoration of IFN gamma levels reduces A. muciniphila abundance. We further show that IFN gamma-knockout mice whose microbiota does not contain A. muciniphila do not show improvement in glucose tolerance and adding back A. muciniphila promoted enhanced glucose tolerance. We go on to identify Irgm1 as an IFN gamma-regulated gene in the mouse ileum that controls gut A. muciniphila levels. A. muciniphila is also linked to IFN gamma-regulated gene expression in the intestine and glucose parameters in humans, suggesting that this trialogue between IFN gamma, A. muciniphila and glucose tolerance might be an evolutionally conserved mechanism regulating metabolic health in mice and humans. C1 [Greer, Renee L.; Vasquez-Perez, Stephany; Shulzhenko, Natalia] Oregon State Univ, Coll Vet Med, 105 Dryden Hall,450 SW 30th St, Corvallis, OR 97331 USA. [Dong, Xiaoxi; Zielke, Ryszard A.; Peremyslova, Ekaterina; Sikora, Aleksandra E.; Morgun, Andrey] Oregon State Univ, Coll Pharm, 1601 SW Jefferson Way, Corvallis, OR 97331 USA. [Moraes, Ana Carolina F.; Ferreira, Sandra R. G.] Univ Sao Paulo, Sch Publ Hlth, Dept Epidemiol, Ave Dr Arnaldo 715, BR-01246904 Sao Paulo, SP, Brazil. [Fernandes, Gabriel R.] Fundacao Oswaldo Cruz, Rene Rachou Res Ctr, Ave Augusto de Lima 1715, BR-30190002 Belo Horizonte, MG, Brazil. [Schoenborn, Alexi A.; Gulati, Ajay S.] Univ N Carolina, Div Pediat Gastroenterol, 260 MacNider Bldg,CB 7220, Chapel Hill, NC 27599 USA. [Gomes, Everton P.; Pereira, Alexandre C.] Univ Sao Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, Ave Dr Eneas de Carvalho Aguiar,44, BR-05403000 Sao Paulo, SP, Brazil. [Yao, Michael; Fuss, Ivan J.; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Immune Def, Bethesda, MD 20892 USA. [Taylor, Gregory A.] Duke Univ, Med Ctr, Geriatr Res Educ & Clin Ctr, VA Med Ctr,Dept Med,Div Geriatr, Duke Box 3003, Durham, NC 27710 USA. [Taylor, Gregory A.] Duke Univ, Med Ctr, Geriatr Res Educ & Clin Ctr, VA Med Ctr,Dept Mol Genet,Div Geriatr, Duke Box 3003, Durham, NC 27710 USA. [Taylor, Gregory A.] Duke Univ, Med Ctr, Geriatr Res Educ & Clin Ctr, VA Med Ctr,Dept Microbiol & Immunol,Div Geriatr, Duke Box 3003, Durham, NC 27710 USA. [Taylor, Gregory A.] Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Duke Box 3003, Durham, NC 27710 USA. RP Shulzhenko, N (reprint author), Oregon State Univ, Coll Vet Med, 105 Dryden Hall,450 SW 30th St, Corvallis, OR 97331 USA.; Morgun, A (reprint author), Oregon State Univ, Coll Pharm, 1601 SW Jefferson Way, Corvallis, OR 97331 USA. EM anemorgun@hotmail.com; natalia.shulzhenko@oregonstate.edu FU Oregon State University (OSU), USA [NIH U01 AI109695, R01 DK103761]; Intramural Research Program of the NIH, NIAID; FAPESP (Sao Paulo Research Foundation) of ADVENTO Study [12/12626-9, 12/03880-9] FX This research was supported by startup funds for AM and NS from Oregon State University (OSU), USA; NIH U01 AI109695 (AM) and R01 DK103761 (NS) and by the Intramural Research Program of the NIH, NIAID (MY, IJF, WS). We also thank the FAPESP (Sao Paulo Research Foundation) for financial support (12/12626-9 and 12/03880-9) of ADVENTO Study. We thank Oregon State University Center for Genome Research and Biocomputing (CGRB) for sequencing services and technical support; Dr Daniel Cawley and the Oregon Health and Science University Monoclonal Antibody Core for production of IFN gamma antibodies; and the personnel of Oregon State University Laboratory Animal Resources Center. NR 68 TC 5 Z9 5 U1 20 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 NOV 14 PY 2016 VL 7 AR 13329 DI 10.1038/ncomms13329 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7IF UT WOS:000387559600001 PM 27841267 ER PT J AU Iranzo, J Buldu, JM Aguirre, J AF Iranzo, Jaime Buldu, Javier M. Aguirre, Jacobo TI Competition among networks highlights the power of the weak SO NATURE COMMUNICATIONS LA English DT Article ID COMPLEX NETWORKS; EVOLUTIONARY GAMES; SOCIAL NETWORKS; DYNAMICS; COOPERATION AB The unpreventable connections between real networked systems have recently called for an examination of percolation, diffusion or synchronization phenomena in multilayer networks. Here we use network science and game theory to explore interactions in networks-of-networks and model these as a game for gaining importance. We propose a viewpoint where networks choose the connection strategies, in contrast with classical approaches where nodes are the active players. Specifically, we investigate how creating paths between networks leads to different Nash equilibria that determine their structural and dynamical properties. In a wide variety of cases, selecting adequate connections leads to a cooperative solution that allows weak networks to overcome the strongest opponent. Counterintuitively, each weak network can induce a global transition to such cooperative configuration regardless of the actions of the strongest network. This power of the weak reveals a critical dominance of the underdogs in the fate of networks-of-networks. C1 [Iranzo, Jaime] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Buldu, Javier M.] Ctr Biomed Technol UPM, Lab Biol Networks, Madrid 28223, Spain. [Buldu, Javier M.] Univ Rey Juan Carlos, Complex Syst Grp, Madrid 28933, Spain. [Buldu, Javier M.; Aguirre, Jacobo] GISC, Madrid, Spain. [Aguirre, Jacobo] CSIC, Ctr Nacl Biotecnol, C Darwin 3, E-28049 Madrid, Spain. RP Aguirre, J (reprint author), GISC, Madrid, Spain.; Aguirre, J (reprint author), CSIC, Ctr Nacl Biotecnol, C Darwin 3, E-28049 Madrid, Spain. EM jaguirre@cnb.csic.es RI Iranzo, Jaime/H-5197-2011 OI Iranzo, Jaime/0000-0002-4538-7726 FU Spanish MINECO [FIS2011-27569, FIS2014-57686, FIS2013-41057]; intramural funds of the US Department of Health and Human Services FX We thank S. Ahnert, A. Arenas, S. Boccaletti, D. Crespo, J. Cuesta, L. Dudbridge, J. Garcia-Ojalvo, S. Manrubia, Y. Moreno, F. Pablo-Marti, D. Papo, M.A. Porter, F. Puente-Sanchez, A. Sanchez and A. Sanz for fruitful conversations, and J.F. Nash for being a source of inspiration. J. A. acknowledges financial support from Spanish MINECO (projects FIS2011-27569 and FIS2014-57686), J. I. is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine) and J.M.B. is funded by Spanish MINECO (project FIS2013-41057). NR 44 TC 0 Z9 0 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 14 PY 2016 VL 7 AR 13273 DI 10.1038/ncomms13273 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7IA UT WOS:000387559100001 PM 27841258 ER PT J AU Molina, O Vargiu, G Abad, MA Zhiteneva, A Jeyaprakash, AA Masumoto, H Kouprina, N Larionov, V Earnshaw, WC AF Molina, Oscar Vargiu, Giulia Abad, Maria Alba Zhiteneva, Alisa Jeyaprakash, A. Arockia Masumoto, Hiroshi Kouprina, Natalay Larionov, Vladimir Earnshaw, William C. TI Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance SO NATURE COMMUNICATIONS LA English DT Article ID CENP-A; CHROMOSOME SEGREGATION; CENTROMERIC CHROMATIN; H3; DOMAIN; RNA; ORGANIZATION; NUCLEOSOMES; ACETYLATION; COMPONENT AB Centromeres consist of specialized centrochromatin containing CENP-A nucleosomes intermingled with H3 nucleosomes carrying transcription-associated modifications. We have designed a novel synthetic biology 'in situ epistasis' analysis in which H3 dimethylated on lysine 4 (H3K4me2) demethylase LSD2 plus synthetic modules with competing activities are simultaneously targeted to a synthetic alphoid(tetO) HAC centromere. This allows us to uncouple transcription from histone modifications at the centromere. Here, we report that H3K4me2 loss decreases centromeric transcription, CENP-A assembly and stability and causes spreading of H3K9me3 across the HAC, ultimately inactivating the centromere. Surprisingly, CENP-28/Eaf6-induced transcription of the alphoidtetO array associated with H4K12 acetylation does not rescue the phenotype, whereas p65-induced transcription associated with H3K9 acetylation does rescue. Thus mitotic transcription plus histone modifications including H3K9ac constitute the 'epigenetic landscape' allowing CENP-A assembly and centrochromatin maintenance. H3K4me2 is required for the transcription and H3K9ac may form a barrier to prevent heterochromatin spreading and kinetochore inactivation at human centromeres. C1 [Molina, Oscar; Vargiu, Giulia; Abad, Maria Alba; Zhiteneva, Alisa; Jeyaprakash, A. Arockia; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3QR, Midlothian, Scotland. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Lab Cell Engn, Dept Frontier Res, Kisarazu 2920818, Japan. [Kouprina, Natalay; Larionov, Vladimir] NCI, Genome Struct & Funct Grp, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3QR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk OI Arulanandam, Arockia Jeyaprakash/0000-0002-1889-8635 FU European Molecular Biology Organization (long-term EMBO fellowship) [ALTF-453-2012]; Wellcome Trust [073915]; Intramural Research Program of the NIH, NCI Center for Cancer Research; MEXT KAKENHI grant [23247030, 23114008]; Kazusa DNA Research Institute Foundation; Career development grant [095822]; Marie Curie career integration grant [334291]; Wellcome Trust Centre for Cell Biology [077707, 092076] FX We thank Drs Patrick Heun, Pauline Audergon, Manu Shukla and Dan Booth for critical discussions and feedback on the manuscript. O.M. was funded by the European Molecular Biology Organization (long-term EMBO fellowship; ALTF-453-2012). This work was funded by the Wellcome Trust, of which W.C.E. is a Principal Research Fellow (grant number 073915), the Intramural Research Program of the NIH, NCI Center for Cancer Research (V.L. and N.K.) and MEXT KAKENHI grant numbers 23247030, 23114008 and the Kazusa DNA Research Institute Foundation (H.M.). Career development grant 095822 and Marie Curie career integration grant 334291 (A.A.J.). The Wellcome Trust Centre for Cell Biology is supported by core grant numbers 077707 and 092076. NR 65 TC 1 Z9 1 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 14 PY 2016 VL 7 AR 13334 DI 10.1038/ncomms13334 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7IH UT WOS:000387559800001 PM 27841270 ER PT J AU Janakiram, NB Mohammed, A Bryant, T Zhang, YT Brewer, M Duff, A Biddick, L Singh, A Lightfoot, S Steele, VE Rao, CV AF Janakiram, Naveena B. Mohammed, Altaf Bryant, Taylor Zhang, Yuting Brewer, Misty Duff, Ashley Biddick, Laura Singh, Anil Lightfoot, Stan Steele, Vernon E. Rao, Chinthalapally V. TI Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer SO SCIENTIFIC REPORTS LA English DT Article ID ORNITHINE-DECARBOXYLASE; COLORECTAL-CANCER; ALPHA-DIFLUOROMETHYLORNITHINE; DOUBLE-BLIND; STATINS; MICE; CARCINOGENESIS; PREVENTION; INHIBITOR; ADENOMAS AB Colorectal cancer (CRC) is the second highest cause of cancer-related deaths. A successful strategy to improve chemopreventive efficacies is by down-regulating tumor polyamines and enhancing NK cell activities. Colonic carcinogenesis was induced by azoxymethane (AOM) in male F344 rats. Eight weeks after AOM treatment, animals were fed diets containing Rosuvastatin and difluromethylornithine (DFMO) individually and in combination for 40 weeks. Both agents showed significant suppression of adenocarcinoma multiplicity and incidence with no toxicity compared to untreated rats. Low-dose Rosuvastatin plus DFMO suppressed colon adenocarcinoma multiplicity by 76% compared to low-dose Rosuvastatin (29%) and DFMO (46%), suggesting additive efficacy. Furthermore, low-dose combination caused a delay in colonic adenocarcinoma progression. DFMO, Rosuvastatin and/or combinations significantly decreased polyamine content and increased intra-tumoral NK cells expressing perforin plus IFN-gamma compared to untreated colon tumors. Further ex-vivo analysis of splenic NK cells exposed to DFMO, Rosuvastatin or combination resulted in an increase of NKs with perforin expression. This is the first report on Rosuvastatin alone or combination strategy using clinically relevant statin plus DFMO doses which shows a significant suppression of colon adenocarcinomas, and their potential in increasing functional NK cells. This strategy has potential for further testing in high risk individuals for colon cancer. C1 [Janakiram, Naveena B.; Mohammed, Altaf; Bryant, Taylor; Zhang, Yuting; Brewer, Misty; Duff, Ashley; Biddick, Laura; Singh, Anil; Lightfoot, Stan; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Dept Med,Hematol Oncol Sect,Stephenson Canc Ctr, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Janakiram, NB; Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Dept Med,Hematol Oncol Sect,Stephenson Canc Ctr, Oklahoma City, OK 73104 USA. EM njanakir@ouhsc.edu; cv-rao@ouhsc.edu FU [NCI R01-CA-094962]; [NCI-CN-N01-53300] FX The authors thank Ms. Agata Bien and Ms. Kathy Kyler, Staff Editor, for editorial assistance with this article. The authors also thank Jim Henthorn at the Flow Cytometry Core for his assistance with flow work and the OUHSC Rodent Barrier Facility staff for the valuable support in bioassay studies. This study was supported by grants NCI R01-CA-094962 & NCI-CN-N01-53300. NR 48 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 14 PY 2016 VL 6 AR 37046 DI 10.1038/srep37046 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7AE UT WOS:000387536300001 PM 27841323 ER PT J AU Lipsitch, M Barclay, W Raman, R Russell, CJ Belser, JA Cobey, S Kasson, PM Lloyd-Smith, JO Maurer-Stroh, S Riley, S Beauchemin, CAA Bedford, T Friedrich, TC Handel, A Herfst, S Murcia, PR Roche, B Wilke, CO Russell, CA AF Lipsitch, Marc Barclay, Wendy Raman, Rahul Russell, Charles J. Belser, Jessica A. Cobey, Sarah Kasson, Peter M. Lloyd-Smith, James O. Maurer-Stroh, Sebastian Riley, Steven Beauchemin, Catherine A. A. Bedford, Trevor Friedrich, Thomas C. Handel, Andreas Herfst, Sander Murcia, Pablo R. Roche, Benjamin Wilke, Claus O. Russell, Colin A. TI Viral factors in influenza pandemic risk assessment SO ELIFE LA English DT Article ID RECEPTOR-BINDING PROPERTIES; UPPER RESPIRATORY-TRACT; SINGLE AMINO-ACID; A H7N9 VIRUS; MEMBRANE-FUSION; HEMAGGLUTININ PROTEIN; HONG-KONG; POULTRY WORKERS; HUMAN INFECTION; A(H7N9) VIRUS AB The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk. C1 [Lipsitch, Marc] Harvard TH Chan Sch Pub Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard TH Chan Sch Pub Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard TH Chan Sch Pub Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Barclay, Wendy] Imperial Coll, Fac Med, Div Infect Dis, London, England. [Raman, Rahul] MIT, Dept Biol Engn, Koch Inst Intergrat Canc Res, Cambridge, MA 02139 USA. [Russell, Charles J.] St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. [Belser, Jessica A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Cobey, Sarah] Univ Chicago, Dept Ecol & Evolut Biol, Chicago, IL 60637 USA. [Kasson, Peter M.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. [Kasson, Peter M.] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Maurer-Stroh, Sebastian] Agcy Sci Technol & Res, Bioinformat Inst, Singapore, Singapore. [Maurer-Stroh, Sebastian] Minist Hlth, Communicable Dis Div, Natl Publ Hlth Lab, Singapore, Singapore. [Maurer-Stroh, Sebastian] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore. [Riley, Steven] Imperial Coll London, Sch Publ Hlth, MRC Ctr Outbreak Anal & Modelling, London, England. [Riley, Steven] Imperial Coll London, Sch Publ Hlth, Dept Infect Dis Epidemiol, London, England. [Beauchemin, Catherine A. A.] Ryerson Univ, Dept Phys, Toronto, ON, Canada. [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Friedrich, Thomas C.] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Handel, Andreas] Univ Georgia, Coll Publ Hlth, Dept Edidemiol & Biostat, Athens, GA 30602 USA. [Herfst, Sander] Erasmus MC, Dept Virosci, Rotterdam, Netherlands. [Murcia, Pablo R.] MRC Univ Glasgow, Ctr Virus Res, Glasgow, Lanark, Scotland. [Roche, Benjamin] IRD UPMC UMMISCO, Montpellier, France. [Wilke, Claus O.] Univ Texas Austin, Inst Cellular & Mol Biol, Ctr Computat Biol & Bioinformat, Austin, TX 78712 USA. [Wilke, Claus O.] Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA. [Russell, Colin A.] Univ Cambridge, Dept Vet Med, Cambridge, England. RP Lipsitch, M (reprint author), Harvard TH Chan Sch Pub Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA.; Lipsitch, M (reprint author), Harvard TH Chan Sch Pub Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Lipsitch, M (reprint author), Harvard TH Chan Sch Pub Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. EM mlipsitc@hsph.harvard.edu OI Lipsitch, Marc/0000-0003-1504-9213 FU National Institutes of Health [U54 GM088558, R01 GM098304, R01 GM088344]; National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance [HHSN272201400006C]; National Health and Medical Research Council [12/1/06/24/5793]; Agency for Science, Technology and Research [12/1/06/24/5793]; Wellcome [093488/Z/10/Z, 200187/Z/15/Z, 200861/Z/16/Z]; Medical Research Council [MR/J008761/1, G0801822]; National Institute of General Medical Sciences [MIDAS U01 GM110721-01]; Natural Sciences and Engineering Research Council of Canada [355837-2013]; Ministry of Research and Innovation of Ontario [ER13-09-040]; Nederlandse Organisatie voor Wetenschappelijk Onderzoek VIDI grant [91715372]; Royal Society University FX National Institutes of Health U54 GM088558 Marc Lipsitch; National Institutes of Health RAPIDD program, Science and Technology Directorate, U.S Department of Homeland Security, and the Fogarty International Center Marc Lipsitch; National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (Contract HHSN272201400006C) Charles J Russel; National Institutes of Health R01 GM098304 Peter M Kasson; National Health and Medical Research Council 12/1/06/24/5793 Sebastian Maurer-Stroh; Agency for Science, Technology and Research 12/1/06/24/5793 Sebastian Maurer-Stroh; Wellcome Project 093488/Z/10/Z Steven Riley; Wellcome 200187/Z/15/Z Steven Riley; Wellcome 200861/Z/16/Z Steven Riley; Medical Research Council MR/J008761/1 Steven Riley; National Institute of General Medical Sciences MIDAS U01 GM110721-01 Steven Riley; Natural Sciences and Engineering Research Council of Canada 355837-2013 Catherine AA Beauchemin; Ministry of Research and Innovation of Ontario ER13-09-040 Catherine AA Beauchemin; Nederlandse Organisatie voor Wetenschappelijk Onderzoek VIDI grant 91715372 Sander Herfst; Medical Research Council G0801822 Pablo R Murcia; National Institutes of Health R01 GM088344 Claus O Wilke; Royal Society University Research Fellowship Colin A Russell; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 240 TC 2 Z9 2 U1 5 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 11 PY 2016 VL 5 AR e18491 DI 10.7554/eLife.18491 PG 38 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EG8AB UT WOS:000391276700001 ER PT J AU Rebbeck, TR Friebel, TM Mitra, N Wan, F Chen, S Andrulis, IL Apostolou, P Arnold, N Arun, BK Barrowdale, D Benitez, J Berger, R Berthet, P Borg, A Buys, SS Caldes, T Carter, J Chiquette, J Claes, KBM Couch, FJ Cybulski, C Daly, MB de la Hoya, M Diez, O Domchek, SM Nathanson, KL Durda, K Ellis, S Evans, DG Foretova, L Friedman, E Frost, D Ganz, PA Garber, J Glendon, G Godwin, AK Greene, MH Gronwald, J Hahnen, E Hallberg, E Hamann, U Hansen, TVO Imyanitov, EN Isaacs, C Jakubowska, A Janavicius, R Jaworska-Bieniek, K John, EM Karlan, BY Kaufman, B Kwong, A Laitman, Y Lasset, C Lazaro, C Lester, J Loman, N Lubinski, J Manoukian, S Mitchell, G Montagna, M Neuhausen, SL Nevanlinna, H Niederacher, D Nussbaum, RL Offit, K Olah, E Olopade, OI Park, SK Piedmonte, M Radice, P Rappaport-Fuerhauser, C Rookus, MA Seynaeve, C Simard, J Singer, CF Soucy, P Southey, M Stoppa-Lyonnet, D Sukiennicki, G Szabo, CI Tancredi, M Teixeira, MR Teo, SH Terry, MB Thomassen, M Tihomirova, L Tischkowitz, M Toland, AE Toloczko-Grabarek, A Tung, N van Rensburg, EJ Villano, D Wang-Gohrke, S Wappenschmidt, B Weitzel, JN Zidan, J Zorn, KK McGuffog, L Easton, D Chenevix-Trench, G Antoniou, AC Ramus, SJ AF Rebbeck, Timothy R. Friebel, Tara M. Mitra, Nandita Wan, Fei Chen, Stephanie Andrulis, Irene L. Apostolou, Paraskevi Arnold, Norbert Arun, Banu K. Barrowdale, Daniel Benitez, Javier Berger, Raanan Berthet, Pascaline Borg, Ake Buys, Saundra S. Caldes, Trinidad Carter, Jonathan Chiquette, Jocelyne Claes, Kathleen B. M. Couch, Fergus J. Cybulski, Cezary Daly, Mary B. de la Hoya, Miguel Diez, Orland Domchek, Susan M. Nathanson, Katherine L. Durda, Katarzyna Ellis, Steve Evans, D. Gareth Foretova, Lenka Friedman, Eitan Frost, Debra Ganz, Patricia A. Garber, Judy Glendon, Gord Godwin, Andrew K. Greene, Mark H. Gronwald, Jacek Hahnen, Eric Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna John, Esther M. Karlan, Beth Y. Kaufman, Bella Kwong, Ava Laitman, Yael Lasset, Christine Lazaro, Conxi Lester, Jenny Loman, Niklas Lubinski, Jan Manoukian, Siranoush Mitchell, Gillian Montagna, Marco Neuhausen, Susan L. Nevanlinna, Heli Niederacher, Dieter Nussbaum, Robert L. Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Park, Sue Kyung Piedmonte, Marion Radice, Paolo Rappaport-Fuerhauser, Christine Rookus, Matti A. Seynaeve, Caroline Simard, Jacques Singer, Christian F. Soucy, Penny Southey, Melissa Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Szabo, Csilla I. Tancredi, Mariella Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tihomirova, Laima Tischkowitz, Marc Toland, Amanda Ewart Toloczko-Grabarek, Aleksandra Tung, Nadine van Rensburg, Elizabeth J. Villano, Danylo Wang-Gohrke, Shan Wappenschmidt, Barbara Weitzel, Jeffrey N. Zidan, Jamal Zorn, Kristin K. McGuffog, Lesley Easton, Douglas Chenevix-Trench, Georgia Antoniou, Antonis C. Ramus, Susan J. CA EMBRACE HEBON KConFab Investigators TI Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women SO BREAST CANCER RESEARCH LA English DT Article DE Hereditary breast and ovarian cancer; Transheterozygosity; BRCA1; BRCA2 ID UNKNOWN CLINICAL-SIGNIFICANCE; CANCER SUSCEPTIBILITY GENE; SPORADIC BREAST-CANCER; DNA-SEQUENCE VARIANTS; WILD-TYPE CHROMOSOME; OVARIAN-CANCER; FANCONI-ANEMIA; DOUBLE HETEROZYGOSITY; GERMLINE MUTATIONS; HETEROGENIC LOSS AB Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2. C1 [Rebbeck, Timothy R.; Friebel, Tara M.; Garber, Judy] Dana Farber Canc Inst, Dept Epidemiol, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02115 USA. [Rebbeck, Timothy R.; Friebel, Tara M.; Garber, Judy] Harvard TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA USA. [Mitra, Nandita] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Wan, Fei] Grp Hlth, Biostat Unit, Res Inst, Seattle, WA USA. [Chen, Stephanie; Ramus, Susan J.] Univ So Calif, Keck Sch Med, USC Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Barrowdale, Daniel; Chenevix-Trench, Georgia] QIMR Berghofer Inst Med Res, Dept Genet & Computat Biol, Brisbane, Qld, Australia. [McGuffog, Lesley; Easton, Douglas; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet & Lab Med, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Pathobiol, Toronto, ON, Canada. [Apostolou, Paraskevi] Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str Aghia Paras, Athens, Greece. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Campus Kiel, Kiel, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Pressler St,CBP 5, Houston, TX USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Clin Canc Genet Program, 1515 Pressler St,CBP 5, Houston, TX USA. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Berger, Raanan; Kaufman, Bella] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Ramat Gan 52621, Israel. [Berthet, Pascaline] Ctr Francois Baclesse, 3 Ave General Harris, Caen, France. [Borg, Ake] Lund Univ, Dept Oncol Clin Sci, Lund, Sweden. [Borg, Ake] Skane Univ Hosp, Lund, Sweden. [Buys, Saundra S.] Huntsman Canc Inst, Dept Med, 2000 Circle Hope, Salt Lake City, UT 84112 USA. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, IdISSC El Inst Invest Sanit Hosp Clin San Carlos, Mol Oncol Lab, Martin Lagos S N, Madrid, Spain. [Carter, Jonathan] Univ Sydney, Ctr Canc, Royal Prince Alfred Hosp, Gynaecol Oncol, Sydney, NSW, Australia. [Chiquette, Jocelyne] Hop St Sacrement, Ctr Malad Sein Deschenes Fabia, Unite Rech SantePopulat, 1050 Chemin Sainte Foy, Quebec City, PQ, Canada. [Claes, Kathleen B. M.] Univ Ghent, Ctr Med Genet, Pintelaan 185, B-9000 Ghent, Belgium. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN USA. [Cybulski, Cezary; Durda, Katarzyna; Gronwald, Jacek; Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan; Sukiennicki, Grzegorz; Toloczko-Grabarek, Aleksandra] Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland. [Daly, Mary B.] Fox Chase Canc Ctr, Div Populat Sci, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Diez, Orland] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Oncogenet Grp, Clinical & Mol Genet Area, Barcelona 11929, Spain. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA USA. [Ellis, Steve; Frost, Debra; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge, England. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Inst Human Dev, Genom Med, Manchester, Lancs, England. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Zluty Kopec 7, Brno 65653, Czech Republic. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel. [Friedman, Eitan; Laitman, Yael] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel. [Ganz, Patricia A.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Godwin, Andrew K.] Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall EastMS 3040, Kansas City, KS USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Greene, Mark H.] NIH, NCI, DCEG, Clin Genet Branch, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD USA. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Cologne, Ctr Hereditary Breast & Ovarian Canc CIO, Cologne, Germany. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Hosp Cologne, Cologne, Germany. [Hallberg, Emily] Mayo Clin, Dept Hlth Sci Res, 13400 E Scottsdale Blvd, Scottsdale, AZ USA. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. [Hansen, Thomas V. O.] Univ Copenhagen Hosp, Rigshosp, Ctr Genom Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [HEBON] Netherlands Canc Inst, Amsterdam, Netherlands. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Santariskiu St, Vilnius, Lithuania. [Janavicius, Ramunas] State Res Inst Ctr Innovat Med, Zygymantu St 9, Vilnius, Lithuania. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA USA. [KConFab Investigators] Peter MacCallum Canc Ctr, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Vic, Australia. [Kwong, Ava] Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Lasset, Christine] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, 28 Rue Laennec, Lyon, France. [Lazaro, Conxi] IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Catalan Inst Oncol, Mol Diagnost Unit,LHosp Barcelona, Gran Via Hosp 199-203, Barcelona 08908, Spain. [Loman, Niklas] Univ Lund Hosp, Dept Oncol, Lund, Sweden. [Manoukian, Siranoush] Fdn IRCCS, Dept Prevent & Predict Med, Ist Nazl Tumori, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy. [Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. [Mitchell, Gillian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Montagna, Marco] IRCCS, Veneto Inst Oncol IOC, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Nevanlinna, Heli] HUS, Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Nussbaum, Robert L.] 62513 Parnassus Ave,HSE 901E, San Francisco, CA 94143 USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] 5841 South Maryland Ave, Chicago, IL USA. [Park, Sue Kyung] Seoul Natl Univ, Coll Med, Dept Prevent Med, 103 Daehak Ro, Seoul 110799, South Korea. [Piedmonte, Marion] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA. [Radice, Paolo] Fdn IRCCS, Dept Prevent & Predicted Med, Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Amaedeolab Via GA Amadeo 42, I-20133 Milan, Italy. [Rappaport-Fuerhauser, Christine] Med Univ Vienna, Dept OB GYN, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, POB 902031000, Amsterdam, Netherlands. [Seynaeve, Caroline] Erasmus MC, Inst Canc, Family Canc Clin, Dept Med Oncol, POB 52013008, Rotterdam, Netherlands. [Simard, Jacques; Soucy, Penny] Univ Quebec, Res Ctr, Ctr Hosp, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Simard, Jacques; Soucy, Penny] Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Singer, Christian F.] Med Univ Vienna, Dept OB GYN, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Singer, Christian F.] Med Univ Vienna, Ctr Comprehens Canc, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Stoppa-Lyonnet, Dominique] Inst Curie, Serv Genet Oncol, 26 Rue dUlm, Paris 05, France. [Szabo, Csilla I.] Natl Inst Hlth, NHGRI, Bldg 50,Room 5312,50 South Dr,MSC 004, Bethesda, MD 20892 USA. [Tancredi, Mariella] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Tancredi, Mariella] Univ Hosp Pisa, Pisa, Italy. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino Almeida, P-4200072 Oporto, Portugal. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Canc Res Inst, Kuala Lumpur 50603, Malaysia. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia. [Tischkowitz, Marc] McGill Univ, Dept Human Genet & Oncol, Program Canc Genet, Montreal, PQ, Canada. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med & Mol Virol, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol & Med Genet, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, 330 Brookline Ave, Boston, MA 02215 USA. [van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa. [Villano, Danylo] Mem Sloan Kettering Canc Ctr, Clin Canc Genet Lab, New York, NY USA. [Wang-Gohrke, Shan] Univ Hosp Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Zidan, Jamal] Inst Oncol, Rivka Ziv Med Ctr, IL-13000 Safed, Israel. [Zidan, Jamal] Bar Ilan Univ, Fac Med, Safed, Israel. [Zorn, Kristin K.] 934301 West Markham St,Slot 793, Little Rock, AR 72205 USA. [Ramus, Susan J.] Univ New South Wales, Sch Womens & Childrens Hlth, 384 Victoria St, Darlinghurst, NSW 2010, Australia. [Ramus, Susan J.] Garvan Inst Med Res, Kinghorn Canc Ctr, 384 Victoria St, Darlinghurst, NSW 2010, Australia. RP Rebbeck, TR (reprint author), Dana Farber Canc Inst, Dept Epidemiol, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02115 USA.; Rebbeck, TR (reprint author), Harvard TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA USA. EM Timothy_Rebbeck@dfci.harvard.edu RI Gronwald, Jacek/A-4576-2017; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Arnold, Norbert/E-3012-2010; manoukian, siranoush/E-7132-2017; montagna, marco/E-2225-2012 OI Gronwald, Jacek/0000-0002-3643-2871; Arnold, Norbert/0000-0003-4523-8808; manoukian, siranoush/0000-0002-6034-7562; montagna, marco/0000-0002-4929-2150 FU National Cancer Institute [UM1 CA164920, RC4CA153828]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [SEN-18/2015]; Breast Cancer Research Foundation; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); Office of the Director, National Institutes of Health; Italian citizens of the Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research UK [C12292/A20861, C1287/A11990C5047/A8385C1287/A10118 C1287/A 10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565]; 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 [SYN11_10_19 NBCA]; DKFZ; NIHR; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Cancer Aid [110837]; Center for Molecular Medicine Cologne (CMMC); Ligue Nationale Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research; French National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant) [P30-CA051008]; Fisher Center for Familial Cancer Research; Swing Fore the Cure; ISCIII (Spain) [RD12/0036/0006, 15/00059]; European Regional Development FEDER funds; Helsinki University Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research grant [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201, CA125183, R01 CA142996, 1U01CA161032]; NIH [CA116167, CA128978, CA176785]; MH CZ - DRO (MMCI) [00209805]; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague project [UNCE204024]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Inc, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Russian Federation for Basic Research [14-04-93959, 15-04-01744]; NRG Oncology Operations grant [U10 CA180868]; NRG SDMC grant [U10 CA180822]; Gynecologic Oncology Group (GOG) Administrative Office; GOG Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; Intramural Research Program, NCI; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori) grants; Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06)]; Cancer Research Initiatives Foundation; Israel cancer association; funding for the Israeli Inherited breast cancer consortium; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program; Helen Diller Family Comprehensive Cancer Center; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation for the cure; Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh; Victorian Cancer Agency; Cancer Australia; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; European Community [223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Ovarian Cancer Research Fund; [SAF2010-20493]; [5U01CA113916]; [R01CA140323]; [PBZ_KBN_122/P05/2004] FX 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 US Government or the BCFR.; BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015; BIDMC is supported by the Breast Cancer Research Foundation; BRCA gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; SLN was partially supported by the Morris and Horowitz Families Endowed Professorship.; This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493; City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) 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; 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.; The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow.; 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: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund.; The DKFZ study was supported by the DKFZ.; EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust; The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship.; The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC); The study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa).; CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure.; Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds; The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.; 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. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection.; HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9; ICO: Contract grant sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364.; The IHCC was supported by Grant PBZ_KBN_122/P05/2004; 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.; IOCHBOCS is supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant.; This study was in part supported by Liga Portuguesa Contra o Cancro.; kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia;; MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation.; MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ).; MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund.; The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. For CIMBA PRS paper: The research of Drs. MH Greene and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.; This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744).; This study was supported by NRG Oncology Operations grant number U10 CA180868 as well as NRG SDMC grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469) and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI.; OSUCCG is supported by the Ohio State University Comprehensive Cancer Center.; This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013.; Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; This project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortium; SWE-BRCA collaborators are supported by the Swedish Cancer Society; 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.; Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation; UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center; UKFOCR was supported by a project grant from CRUK to Paul Pharoah.; National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh; Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation; Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME- ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund NR 39 TC 1 Z9 1 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD NOV 11 PY 2016 VL 18 AR 112 DI 10.1186/s13058-016-0768-3 PG 19 WC Oncology SC Oncology GA EG2UM UT WOS:000390899600001 PM 27836010 ER PT J AU Gladyshev, VN Arner, ES Berry, MJ Brigelius-Flohe, R Bruford, EA Burk, RF Carlson, BA Castellano, S Chavatte, L Conrad, M Copeland, PR Diamond, AM Driscoll, DM Ferreiro, A Flohe, L Green, FR Guigo, R Handy, DE Hatfield, DL Hesketh, J Hoffmann, PR Holmgren, A Hondal, RJ Howard, MT Huang, K Kim, HY Kim, IY Kohrle, J Krol, A Kryukov, GV Lee, BJ Lee, BC Lei, XG Liu, Q Lescure, A Lobanov, AV Loscalzo, J Maiorino, M Mariotti, M Prabhu, KS Rayman, MP Rozovsky, S Salinas, G Schmidt, EE Schomburg, L Schweizer, U Simonovic, M Sunde, RA Tsuji, PA Tweedie, S Ursini, F Whanger, PD Zhang, Y AF Gladyshev, Vadim N. Arner, Elias S. Berry, Marla J. Brigelius-Flohe, Regina Bruford, Elspeth A. Burk, Raymond F. Carlson, Bradley A. Castellano, Sergi Chavatte, Laurent Conrad, Marcus Copeland, Paul R. Diamond, Alan M. Driscoll, Donna M. Ferreiro, Ana Flohe, Leopold Green, Fiona R. Guigo, Roderic Handy, Diane E. Hatfield, Dolph L. Hesketh, John Hoffmann, Peter R. Holmgren, Arne Hondal, Robert J. Howard, Michael T. Huang, Kaixun Kim, Hwa-Young Kim, Ick Young Koehrle, Josef Krol, Alain Kryukov, Gregory V. Lee, Byeong Jae Lee, Byung Cheon Lei, Xin Gen Liu, Qiong Lescure, Alain Lobanov, Alexei V. Loscalzo, Joseph Maiorino, Matilde Mariotti, Marco Sandeep Prabhu, K. Rayman, Margaret P. Rozovsky, Sharon Salinas, Gustavo Schmidt, Edward E. Schomburg, Lutz Schweizer, Ulrich Simonovic, Miljan Sunde, Roger A. Tsuji, Petra A. Tweedie, Susan Ursini, Fulvio Whanger, Philip D. Zhang, Yan TI Selenoprotein Gene Nomenclature SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE genomics; selenium; selenocysteine; selenoprotein; structure-function; function; gene name; nomenclature ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; AMINO-ACID-SEQUENCE; THIOREDOXIN REDUCTASE; RAT-LIVER; IODOTHYRONINE 5-DEIODINASE; EUKARYOTIC SELENOPROTEINS; SELENIUM METABOLISM; CONTAINING PROTEINS; MESSENGER-RNA; SELENOCYSTEINE AB The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates. C1 [Gladyshev, Vadim N.; Lobanov, Alexei V.; Mariotti, Marco] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Arner, Elias S.; Holmgren, Arne] Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys MBB, SE-17177 Stockholm, Sweden. [Berry, Marla J.; Hoffmann, Peter R.] Univ Hawaii Manoa, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96813 USA. [Brigelius-Flohe, Regina] German Inst Human Nutr Potsdam Rehbrucke, D-14558 Nuthetal, Germany. [Bruford, Elspeth A.; Tweedie, Susan] HUGOGene Nomenclature Comm HGNC, European Bioinformat Inst European Mol Biol Lab E, Hinxton CB10 1SD, England. [Burk, Raymond F.] Vanderbilt Univ, Div Gastroenterol Hepatol & Nutr, Dept Med, Sch Med, Nashville, TN 37232 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] Ctr Canc Res, NIH, Mouse Canc Genet Program, Mol Biol Selenium Sect, Bethesda, MD 20892 USA. [Castellano, Sergi] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany. [Chavatte, Laurent] INSERM, CIRI, U1111, F-69007 Lyon, France. [Chavatte, Laurent] CNRS, ENS UMR5308, F-69007 Lyon, France. [Conrad, Marcus] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany. [Copeland, Paul R.] Rutgers Robert Wood Johnson Med Sch, Dept Biochem & Mol Biol, Piscataway, NJ 08854 USA. [Diamond, Alan M.] Univ Illinois, Dept Pathol, Chicago, IL 60607 USA. [Driscoll, Donna M.] Cleveland Clin Fdn, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44195 USA. [Ferreiro, Ana] Univ Paris Diderot, Sorbonne Paris Cite, Pathophysiol Striated Muscles Lab, Unit Funct & Adapt Biol BFA,UMR CNRS 8251 BFA, F-75250 Paris, France. [Ferreiro, Ana] Grp Hosp Pitie Salpetriere, AP HP, Ctr Reference Malad Neuromusculaires Paris Est, F-75013 Paris, France. [Flohe, Leopold] Univ Republica, Facultad Med, Dept Bioquim, Montevideo 11800, Uruguay. [Flohe, Leopold] Univ Padua, Dept Mol Med, I-35121 Padua, Italy. [Green, Fiona R.] Univ Manchester, Div Cardiovasc Sci, Sch Med Sci, Fac Biol Med & Hlth, Manchester, Lancs, England. [Guigo, Roderic] Ctr Genom Regulat CRG, Barcelona 08003, Spain. [Guigo, Roderic] UPF, Barcelona 08002, Spain. [Handy, Diane E.] Brigham & Womens Hosp, Dept Med, Cardiovasc Div, Boston, MA 02115 USA. [Handy, Diane E.] Harvard Med Sch, Boston, MA 02115 USA. [Hesketh, John] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Hesketh, John] Newcastle Univ, Human Nutr Res Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Hesketh, John] Newcastle Univ, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Hondal, Robert J.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Howard, Michael T.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Huang, Kaixun] Huazhong Univ Sci & Technol, Hubei Key Lab Bioinorgan Chem & Mat Med, Sch Chem & Chem Engn, Wuhan 430074, Peoples R China. [Kim, Hwa-Young] Yeungnam Univ, Dept Biochem & Mol Biol, Coll Med, Daegu 42415, South Korea. [Kim, Ick Young; Lee, Byung Cheon] Korea Univ, Coll Life Sci & Biotechnol, Seoul 02841, South Korea. [Koehrle, Josef; Schomburg, Lutz] Charite, Inst Expt Endocrinol, D-13353 Berlin, Germany. [Krol, Alain; Lescure, Alain] Univ Strasbourg, Architecture & Reactivite ARN, Ctr Natl Rech Sci, Inst Biol Mol & Cellulaire, F-67084 Strasbourg, France. [Kryukov, Gregory V.] KSQ Therapeut, Cambridge, MA 02139 USA. [Lee, Byeong Jae] Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. [Lei, Xin Gen] Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA. [Liu, Qiong; Zhang, Yan] Shenzhen Univ, Shenzhen Key Lab Marine Biotechnol & Ecol, Coll Life Sci, Shenzhen 518060, Guangdong Provi, Peoples R China. [Lescure, Alain] Ctr Natl Rech Sci, F-75794 Paris, France. [Loscalzo, Joseph] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Sandeep Prabhu, K.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Rayman, Margaret P.] Univ Surrey, Dept Nut Sci, Fac Hlth & Med Sci, Guildford GU2 7XH, Surrey, England. [Rozovsky, Sharon] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Salinas, Gustavo] Inst Higiene, Catedra Inmunol, Fac Quim, Montevideo 11600, Uruguay. [Schmidt, Edward E.] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA. [Schweizer, Ulrich] Rhein Friedrich Wilhelms Univ Bonn, Inst Biochem & Molekularbiol, D-53115 Bonn, Germany. [Simonovic, Miljan] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Sunde, Roger A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. [Whanger, Philip D.] Oregon State Univ, Dept Environm & Mol Toxicol, Coll Agr Sci, Corvallis, OR 97331 USA. RP Gladyshev, VN (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA.; Gladyshev, VN (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM vgladyshev@rics.bwh.harvard.edu RI Guigo, Roderic/D-1303-2010; rozovsky, sharon/S-4534-2016; OI Guigo, Roderic/0000-0002-5738-4477; rozovsky, sharon/0000-0003-4902-0777; Kohrle, Josef/0000-0002-9187-9078; Arner, Elias/0000-0002-4807-6114 FU National Institutes of Health [GM061603] FX This work was supported, in whole or in part, by National Institutes of Health Grant GM061603. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 49 TC 1 Z9 1 U1 15 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 11 PY 2016 VL 291 IS 46 BP 24036 EP 24040 DI 10.1074/jbc.M116.756155 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC9XR UT WOS:000388498100020 PM 27645994 ER PT J AU Sharma, AK Arora, D Singh, LK Gangwal, A Sajid, A Molle, V Singh, Y Nandicoori, VK AF Sharma, Aditya K. Arora, Divya Singh, Lalit K. Gangwal, Aakriti Sajid, Andaleeb Molle, Virginie Singh, Yogendra Nandicoori, Vinay Kumar TI Serine/Threonine Protein Phosphatase PstP of Mycobacterium tuberculosis Is Necessary for Accurate Cell Division and Survival of Pathogen SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell division; cell signaling; mycobacteria; Mycobacterium tuberculosis; phosphatase; phosphorylation; protein serine; threonine phosphatase (PSP); PstP; cell division ID 2-COMPONENT SIGNAL-TRANSDUCTION; VACUOLAR-H+-ATPASE; CORYNEBACTERIUM-GLUTAMICUM; TYROSINE PHOSPHATASES; BACILLUS-ANTHRACIS; GENOME SEQUENCE; GENE-EXPRESSION; KINASES PKNA; IN-VITRO; PHOSPHORYLATION AB Protein phosphatases play vital roles in phosphorylation-mediated cellular signaling. Although there are 11 serine/threonine protein kinases in Mycobacterium tuberculosis, only one serine/threonine phosphatase, PstP, has been identified. Although PstP has been biochemically characterized and multiple in vitro substrates have been identified, its physiological role has not yet been elucidated. In this study, we have investigated the impact of PstP on cell growth and survival of the pathogen in the host. Overexpression of PstP led to elongated cells and partially compromised survival. We find that depletion of PstP is detrimental to cell survival, eventually leading to cell death. PstP depletion results in elongated multiseptate cells, suggesting a role for PstP in regulating cell division events. Complementation experiments performed with PstP deletion mutants revealed marginally compromised survival, suggesting that all of the domains, including the extracellular domain, are necessary for complete rescue. On the other hand, the catalytic activity of PstP is absolutely essential for the in vitro growth. Mice infection experiments establish a definitive role for PstP in pathogen survival within the host. Depletion of PstP from established infections causes pathogen clearance, indicating that the continued presence of PstP is necessary for pathogen survival. Taken together, our data suggest an important role for PstP in establishing and maintaining infection, possibly via the modulation of cell division events. C1 [Arora, Divya; Nandicoori, Vinay Kumar] Natl Inst Immunol, Aruna Asaf Ali Marg, New Delhi 110067, India. [Sharma, Aditya K.; Singh, Lalit K.; Sajid, Andaleeb; Singh, Yogendra] CSIR Inst Genom & Integrat Biol, Mall Rd, Delhi 110007, India. [Gangwal, Aakriti; Singh, Yogendra] Univ Delhi, Dept Zool, Delhi 110007, India. [Molle, Virginie] Univ Montpellier 2, CNRS, Lab Dynam Interact Membranaires Normales & Pathol, UMR 5235, Montpellier, France. [Sharma, Aditya K.] CSIR IGIB, Acad Sci & Innovat Res AcSIR, Delhi 110025, India. [Sajid, Andaleeb] NIAID, NIH, Bethesda, MD 20814 USA. RP Nandicoori, VK (reprint author), Natl Inst Immunol, Aruna Asaf Ali Marg, New Delhi 110067, India.; Singh, Y (reprint author), CSIR Inst Genom & Integrat Biol, Mall Rd, Delhi 110007, India.; Singh, Y (reprint author), Univ Delhi, Dept Zool, Delhi 110007, India. EM ysingh@igib.res.in; vinaykn@nii.ac.in FU Indo French Centre for the Promotion of Advanced Research Grant [5303-1, BSC0104] FX This work was supported by Indo French Centre for the Promotion of Advanced Research Grant 5303-1 (to V.K.N., Y.S., and V.M.) and BSC0104 (CSIR) (to Y.S.). The authors declare that they have no conflicts of interest with the contents of this article. NR 68 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 11 PY 2016 VL 291 IS 46 BP 24215 EP 24230 DI 10.1074/jbc.M116.754531 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC9XR UT WOS:000388498100035 PM 27758870 ER PT J AU Sassa, A Caglayan, M Rodriguez, Y Beard, WA Wilson, SH Nohmi, T Honma, M Yasui, M AF Sassa, Akira Caglayan, Melike Rodriguez, Yesenia Beard, William A. Wilson, Samuel H. Nohmi, Takehiko Honma, Masamitsu Yasui, Manabu TI Impact of Ribonucleotide Backbone on Translesion Synthesis and Repair of 7,8-Dihydro-8-oxoguanine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE 8-oxoguanine (8-oxoG); base excision repair (BER); DNA damage; DNA polymerase; oxidative stress; ribonucleotide; translesion DNA synthesis ID DNA-POLYMERASE-KAPPA; IN-VITRO; EXCISION-REPAIR; LESION BYPASS; ERROR-FREE; HUMAN-CELLS; ETA; EXTENSION; 8-OXOGUANINE; SUBSTRATE AB Numerous ribonucleotides are incorporated into the genome during DNA replication. Oxidized ribonucleotides can also be erroneously incorporated into DNA. Embedded ribonucleotides destabilize the structure of DNA and retard DNA synthesis by DNA polymerases (pols), leading to genomic instability. Mammalian cells possess translesion DNA synthesis (TLS) pols that bypass DNA damage. The mechanism of TLS and repair of oxidized ribonucleotides remains to be elucidated. To address this, we analyzed the miscoding properties of the ribonucleotides riboguanosine (rG) and 7,8-dihydro-8-oxo-riboguanosine (8-oxo-rG) during TLS catalyzed by the human TLS pols and in vitro. The primer extension reaction catalyzed by human replicative pol was strongly blocked by 8-oxo-rG. pol inefficiently bypassed rG and 8-oxo-rG compared with dG and 7,8-dihydro-8-oxo-2-deoxyguanosine (8-oxo-dG), whereas pol easily bypassed the ribonucleotides. pol exclusively inserted dAMP opposite 8-oxo-rG. Interestingly, pol preferentially inserted dCMP opposite 8-oxo-rG, whereas the insertion of dAMP was favored opposite 8-oxo-dG. In addition, pol accurately bypassed 8-oxo-rG. Furthermore, we examined the activity of the base excision repair (BER) enzymes 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1 on the substrates, including rG and 8-oxo-rG. Both BER enzymes were completely inactive against 8-oxo-rG in DNA. However, OGG1 suppressed 8-oxo-rG excision by RNase H2, which is involved in the removal of ribonucleotides from DNA. These results suggest that the different sugar backbones between 8-oxo-rG and 8-oxo-dG alter the capacity of TLS and repair of 8-oxoguanine. C1 [Sassa, Akira; Nohmi, Takehiko; Honma, Masamitsu; Yasui, Manabu] Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, 1-18-1 Kamiyoga, Tokyo 1588501, Japan. [Caglayan, Melike; Rodriguez, Yesenia; Beard, William A.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Sassa, A; Yasui, M (reprint author), Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, 1-18-1 Kamiyoga, Tokyo 1588501, Japan. EM a-sassa@nihs.go.jp; m-yasui@nihs.go.jp FU Ministry of Education, Culture, Sports, Science and Technology in Japan [16K16195, 25281022]; Intramural Research Program of the National Institutes of Health, NIEHS [Z01 ES050158, Z01 ES050159] FX This work was supported by Grant-in-Aid for Young Scientists B (16K16195) and for Scientific Research B (25281022) from the Ministry of Education, Culture, Sports, Science and Technology in Japan and the Intramural Research Program of the National Institutes of Health, NIEHS Grants Z01 ES050158 and Z01 ES050159. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 54 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 11 PY 2016 VL 291 IS 46 BP 24314 EP 24323 DI 10.1074/jbc.M116.738732 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC9XR UT WOS:000388498100042 PM 27660390 ER PT J AU Young, DJ Guydosh, NR AF Young, David J. Guydosh, Nicholas R. TI UNFOLDED PROTEIN RESPONSE Silence without stress SO ELIFE LA English DT Editorial Material ID TRANSCRIPTION FACTOR; ENDOPLASMIC-RETICULUM; TRANSLATION C1 [Young, David J.; Guydosh, Nicholas R.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Guydosh, NR (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM nicholas.guydosh@nih.gov NR 9 TC 0 Z9 0 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 11 PY 2016 VL 5 AR e22073 DI 10.7554/eLife.22073 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EC9YV UT WOS:000388501100001 ER PT J AU Joshi, AA Lerman, JB Aberra, TM Afshar, M Teague, HL Rodante, JA Krishnamoorthy, P Ng, Q Aridi, TZ Salahuddin, T Natarajan, B Lockshin, BN Ahlman, MA Chen, MY Rader, DJ Reilly, MP Remaley, AT Bluemke, DA Playford, MP Gelfand, JM Mehta, NN AF Joshi, Aditya A. Lerman, Joseph B. Aberra, Tsion M. Afshar, Mehdi Teague, Heather L. Rodante, Justin A. Krishnamoorthy, Parasuram Ng, Qimin Aridi, Tarek Z. Salahuddin, Taufiq Natarajan, Balaji Lockshin, Benjamin N. Ahlman, Mark A. Chen, Marcus Y. Rader, Daniel J. Reilly, Muredach P. Remaley, Alan T. Bluemke, David A. Playford, Martin P. Gelfand, Joel M. Mehta, Nehal N. TI GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis SO CIRCULATION RESEARCH LA English DT Article DE cardiovascular disease; coronary artery disease; FDG PET CT; GlycA; inflammation; psoriasis; risk factors ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; COMPUTED TOMOGRAPHIC ANGIOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; ACUTE-PHASE GLYCOPROTEINS; TYPE-2 DIABETES-MELLITUS; ACUTE CORONARY SYNDROME; C-REACTIVE PROTEIN; FDG-PET/CT; VASCULAR INFLAMMATION; RISK AB Rationale: GlycA, an emerging inflammatory biomarker, predicted cardiovascular events in population-based studies. Psoriasis, an inflammatory disease associated with increased cardiovascular risk, provides a model to study inflammatory biomarkers in cardiovascular disease (CVD). Whether GlycA associates with psoriasis and how it predicts subclinical CVD beyond high-sensitivity C-reactive protein in psoriasis is unknown. Objective: To investigate the relationships between GlycA and psoriasis and between GlycA and subclinical CVD. Methods and Results: Patients with psoriasis and controls (n=412) participated in a 2-stage study. We measured GlycA by nuclear magnetic resonance spectroscopy. National Institutes of Health (NIH) participants underwent 18-F Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18-FDG PET/CT) scans to assess vascular inflammation (VI) and coronary computed tomographic angiography to quantify coronary artery disease burden. Psoriasis cohorts were young (mean age=47.9), with low cardiovascular risk and moderate skin disease. high-sensitivity C-reactive protein and GlycA were increased in psoriasis compared with controls (GlycA: [PENN: 408.8 +/- 75.4 versus 289.4 +/- 60.2, P<0.0001; NIH: 415.8 +/- 63.2 versus 346.2 +/- 46, P<0.0001]) and demonstrated a doseresponse with psoriasis severity. In stage 2, VI (beta=0.36, P<0.001) and coronary artery disease (beta=0.29, P=0.004) associated with GlycA beyond CV risk factors in psoriasis. In receiver operating characteristic analysis, GlycA added value in predicting VI (P=0.01) and coronary artery disease (P<0.01). Finally, initiating anti-tumor necrosis factor therapy (n=16) reduced psoriasis severity (P<0.001), GlycA (463.7 +/- 92.5 versus 370.1 +/- 78.5, P<0.001) and VI (1.93 +/- 0.36 versus 1.76 +/- 0.19, P<0.001), whereas GlycA remained associated with VI (beta=0.56, P<0.001) post treatment. Conclusions: GlycA associated with psoriasis severity and subclinical CVD beyond traditional CV risk and highsensitivity C-reactive protein. Moreover, psoriasis treatment reduced GlycA and VI. These findings support the potential use of GlycA in subclinical CVD risk assessment in psoriasis and potentially other inflammatory diseases. C1 [Joshi, Aditya A.; Lerman, Joseph B.; Aberra, Tsion M.; Teague, Heather L.; Rodante, Justin A.; Ng, Qimin; Aridi, Tarek Z.; Salahuddin, Taufiq; Natarajan, Balaji; Chen, Marcus Y.; Remaley, Alan T.; Bluemke, David A.; Playford, Martin P.; Mehta, Nehal N.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Joshi, Aditya A.; Lerman, Joseph B.; Aberra, Tsion M.; Teague, Heather L.; Rodante, Justin A.; Ng, Qimin; Aridi, Tarek Z.; Salahuddin, Taufiq; Natarajan, Balaji; Remaley, Alan T.; Playford, Martin P.; Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bldg 10, Bethesda, MD 20892 USA. [Joshi, Aditya A.] Allegheny Gen Hosp, Dept Internal Med, Pittsburgh, PA 15212 USA. [Afshar, Mehdi] McGill Univ, Dept Med, Montreal, PQ, Canada. [Krishnamoorthy, Parasuram] Albert Einstein Med Ctr, Einstein Inst Heart & Vasc Hlth, Dept Cardiol, Philadelphia, PA 19141 USA. [Salahuddin, Taufiq] Univ Colorado, Dept Internal Med, Denver, CO USA. [Natarajan, Balaji] Univ Arizona, Coll Med South Campus, Dept Internal Med, Tucson, AZ USA. [Lockshin, Benjamin N.] Derm Associates, Silver Spring, MD USA. [Ahlman, Mark A.] NIH, Dept Radiol & Imaging Sci, Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gelfand, Joel M.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Gelfand, Joel M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Columbia Univ, Dept Med, Div Cardiol, Irving Inst Clin & Translat Res, New York, NY USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Clin Res Ctr, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) FX The study was supported by the National Institutes of Health (NIH) intramural research program. NR 41 TC 2 Z9 2 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD NOV 11 PY 2016 VL 119 IS 11 BP 1242 EP + DI 10.1161/CIRCRESAHA.116.309637 PG 15 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EC4NN UT WOS:000388108900018 PM 27654120 ER PT J AU Henley, SJ Thomas, CC Sharapova, SR Momin, B Massetti, GM Winn, DM Armour, BS Richardson, LC AF Henley, S. Jane Thomas, Cheryll C. Sharapova, Saida R. Momin, Behnoosh Massetti, Greta M. Winn, Deborah M. Armour, Brian S. Richardson, Lisa C. TI Vital Signs: Disparities in Tobacco-Related Cancer Incidence and Mortality - United States, 2004-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID AFFORDABLE CARE ACT; SMOKING; DEATHS AB Background: Tobacco use causes at least 12 types of cancer and is the leading preventable cause of cancer.. Methods: Data from the United States Cancer Statistics dataset for 2004-2013 were used to assess incidence and death rates and trends for cancers that can be caused by tobacco use (tobacco-related cancers: oral cavity and pharynx; esophagus; stomach; colon and rectum; liver; pancreas; larynx; lung, bronchus, and trachea; kidney and renal pelvis; urinary bladder; cervix; and acute myeloid leukemia) by sex, age, race, ethnicity; state, county-level poverty and educational attainment, and cancer site: Results: Each year during 2009-2013, on average, 660,000 persons in the United States received a diagnosis of a tobacco-related cancer, and 343,000 persons died from these cancers. Tobacco-related cancer incidence and death rates were higher among men than women; highest among black men and women; higher in counties with low proportion of college graduates or high level of poverty; lowest in the West; and differed two-fold among states. During 2004-2013, incidence of tobacco-related cancer decreased 1.3% per year and mortality decreased 1.6% per year, with decreases observed across most groups, hot not at the same rate. Conclusions: Tobacco-related cancer declined during 2004-2013. However, the burden remains high, and disparities persist among certain groups with higher rates or slower declines in rates. Implications far Public Health Practice: The burden of tobacco-related cancers can be reduced through efforts to prevent and control tobacco use and other comprehensive cancer control efforts focused on reducing cancer risk, detecting cancer early, improving cancer treatments, helping more persons survive cancer, and improving cancer survivors' quality of life, and better assisting communities disproportionately impacted by cancer. C1 [Henley, S. Jane; Thomas, Cheryll C.; Momin, Behnoosh; Massetti, Greta M.; Richardson, Lisa C.] CDC, Div Canc Prevent & Control, Atlanta, GA 30333 USA. [Sharapova, Saida R.; Armour, Brian S.] CDC, Off Smoking & Hlth, Atlanta, GA 30333 USA. [Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Henley, SJ (reprint author), CDC, Div Canc Prevent & Control, Atlanta, GA 30333 USA. EM shenley@cdc.gov NR 15 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 11 PY 2016 VL 65 IS 44 BP 1212 EP 1218 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC3XJ UT WOS:000388060100003 PM 27832048 ER PT J AU Vallabhaneni, S Kallen, A Tsay, S Chow, N Welsh, R Kerins, J Kemble, SK Pacilli, M Black, SR Landon, E Ridgway, J Palmore, TN Zelzany, A Adams, EH Quinn, M Chaturvedi, S Greenko, J Fernandez, R Southwick, K Furuya, EY Calfee, DP Hamula, C Patel, G Barrett, P Lafaro, P Berkow, EL Moulton-Meissner, H Noble-Wang, J Fagan, RP Jackson, BR Lockhart, SR Litvintseva, AP Chiller, TM AF Vallabhaneni, Snigdha Kallen, Alex Tsay, Sharon Chow, Nancy Welsh, Rory Kerins, Janna Kemble, Sarah K. Pacilli, Massimo Black, Stephanie R. Landon, Emily Ridgway, Jessica Palmore, Tara N. Zelzany, Adrian Adams, Eleanor H. Quinn, Monica Chaturvedi, Sudha Greenko, Jane Fernandez, Rafael Southwick, Karen Furuya, E. Yoko Calfee, David P. Hamula, Camille Patel, Gopi Barrett, Patricia Lafaro, Patricia Berkow, Elizabeth L. Moulton-Meissner, Heather Noble-Wang, Judith Fagan, Ryan P. Jackson, Brendan R. Lockhart, Shawn R. Litvintseva, Anastasia P. Chiller, Tom M. TI Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus - United States, May 2013-August 2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Vallabhaneni, Snigdha; Tsay, Sharon; Chow, Nancy; Welsh, Rory; Berkow, Elizabeth L.; Jackson, Brendan R.; Lockhart, Shawn R.; Litvintseva, Anastasia P.; Chiller, Tom M.] CDC, Mycot Dis Branch, Div Food Water & Environm Dis, Atlanta, GA 30333 USA. [Kallen, Alex; Moulton-Meissner, Heather; Noble-Wang, Judith; Fagan, Ryan P.] CDC, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Tsay, Sharon; Kerins, Janna] CDC, Epidem Intelligence Serv, Ctr Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. [Kerins, Janna; Kemble, Sarah K.; Pacilli, Massimo; Black, Stephanie R.] Chicago Dept Publ Hlth, Chicago, IL USA. [Landon, Emily; Ridgway, Jessica] Univ Chicago, Chicago, IL 60637 USA. [Palmore, Tara N.; Zelzany, Adrian] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Adams, Eleanor H.; Quinn, Monica; Chaturvedi, Sudha; Greenko, Jane; Fernandez, Rafael; Southwick, Karen] New York State Dept Hlth, New York, NY USA. [Furuya, E. Yoko] Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Calfee, David P.] Weill Cornell Med, New York, NY USA. [Hamula, Camille; Patel, Gopi] Icahn Sch Med Mt Sinai, Mt Sinai Hlth Syst, New York, NY 10029 USA. [Barrett, Patricia] New Jersey Dept Hlth, Trenton, NJ USA. [Lafaro, Patricia] Robert Wood Johnson Univ Hosp, New Brunswick, NJ USA. RP Vallabhaneni, S (reprint author), CDC, Mycot Dis Branch, Div Food Water & Environm Dis, Atlanta, GA 30333 USA. EM svallabhaneni@cdc.gov NR 10 TC 1 Z9 1 U1 2 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 11 PY 2016 VL 65 IS 44 BP 1234 EP 1237 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC3XJ UT WOS:000388060100007 PM 27832049 ER PT J AU Smith, JL Lee, LC Read, A Li, QN Yu, B Lee, CS Luo, J AF Smith, Jordan L. Lee, Liam C. Read, Abigail Li, Qiuning Yu, Bing Lee, Chih-Shia Luo, Ji TI One-step immortalization of primary human airway epithelial cells capable of oncogenic transformation SO CELL AND BIOSCIENCE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; HUMAN TUMOR-CELLS; LUNG ADENOCARCINOMA; LIFE-SPAN; TELOMERASE ACTIVITY; CANCER GENOME; MECHANISMS; KERATINOCYTES; SUFFICIENT; SENESCENCE AB Background: The ability to transform normal human cells into cancer cells with the introduction of defined genetic alterations is a valuable method for understanding the mechanisms of oncogenesis. Easy establishment of immortalized but non-transformed human cells from various tissues would facilitate these genetic analyses. Results: We report here a simple, one-step immortalization method that involves retroviral vector mediated co-expression of the human telomerase protein and a shRNA targeting the CDKN2A gene locus. We demonstrate that this method could successfully immortalize human small airway epithelial cells while maintaining their chromosomal stability. We further showed that these cells retain p53 activity and can be transformed by the KRAS oncogene. Conclusions: Our method simplifies the immortalization process and is broadly applicable for establishing immortalized epithelial cell lines from primary human tissues for cancer research. C1 [Smith, Jordan L.; Lee, Liam C.; Read, Abigail; Li, Qiuning; Yu, Bing; Lee, Chih-Shia; Luo, Ji] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smith, Jordan L.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Smith, Jordan L.] Univ Massachusetts, Grad Sch Biomed Sci, Worcester, MA 01605 USA. [Lee, Liam C.] Univ Cambridge, Grad Program, Cambridge, England. [Li, Qiuning] ShanghaiTech Univ, Shanghai, Peoples R China. [Yu, Bing] Janssen R&D Shanghai Discovery Ctr, Shanghai, Peoples R China. RP Luo, J (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ji.luo@nih.gov OI Smith , Jordan /0000-0003-0460-0647 FU NCI Intramural Award [ZIA BC 011304] FX This work was supported by a NCI Intramural Award ZIA BC 011304 to JL. NR 33 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD NOV 11 PY 2016 VL 6 AR 57 DI 10.1186/s13578-016-0122-6 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB6PO UT WOS:000387507300001 PM 27891214 ER PT J AU Johnson, KA Lovinger, DM AF Johnson, Kari A. Lovinger, David M. TI Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction? SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE addiction; self-administration; presynaptic; GPCR; dopamine receptor; CB1 receptor; metabotropic glutamate receptor; allosteric modulator ID METABOTROPIC GLUTAMATE RECEPTORS; LONG-TERM DEPRESSION; VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; CANNABINOID CB1 RECEPTOR; POSITIVE ALLOSTERIC MODULATOR; NICOTINE-SEEKING BEHAVIOR; MEDIAL PREFRONTAL CORTEX; DOPAMINE D2 RECEPTORS; MGLUR(2/3) AGONIST LY379268 AB Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the G(i/o), class of G protein. There is increasing evidence that these presynaptic G(i/o)-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D-1 and D-2 -like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on development of mGlu(2) positive allosteric modulators (PAMs). C1 [Johnson, Kari A.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacolocy, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacolocy, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov FU Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health [ZIA AA000416]; National Institute of General Medical Sciences FX This article was supported by funding from the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, project number ZIA AA000416, and a Postdoctoral Research Associate Fellowship from the National Institute of General Medical Sciences (to KAJ.). We thank Dr. David Kupferschmidt for comments on the manuscript. NR 290 TC 0 Z9 0 U1 21 U2 21 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD NOV 11 PY 2016 VL 10 AR 264 DI 10.3339/fncel.2016.00264 PG 22 WC Neurosciences SC Neurosciences & Neurology GA EB8AK UT WOS:000387612900001 PM 27891077 ER PT J AU Viboud, C Epstein, SL AF Viboud, Cecile Epstein, Suzanne L. TI First flu is forever SO SCIENCE LA English DT Editorial Material ID INFLUENZA VACCINES; INFECTION; IMMUNITY; VIRUS C1 [Viboud, Cecile] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Epstein, Suzanne L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov NR 10 TC 0 Z9 0 U1 14 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 11 PY 2016 VL 354 IS 6313 BP 706 EP 707 DI 10.1126/science.aak9816 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4FS UT WOS:000387326300018 PM 27846592 ER PT J AU Gostic, KM Ambrose, M Worobey, M Lloyd-Smith, JO AF Gostic, Katelyn M. Ambrose, Monique Worobey, Michael Lloyd-Smith, James O. TI Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting SO SCIENCE LA English DT Article ID A VIRUS; INFECTION; HUMANS; AGE; ANTIBODIES; IMMUNITY; A(H7N9); CHINA; EPIDEMIOLOGY; VACCINATION AB Two zoonotic influenza A viruses (IAV) of global concern, H5N1 and H7N9, exhibit unexplained differences in age distribution of human cases. Using data from all known human cases of these viruses, we show that an individual's first IAV infection confers lifelong protection against severe disease from novel hemagglutinin (HA) subtypes in the same phylogenetic group. Statistical modeling shows that protective HA imprinting is the crucial explanatory factor, and it provides 75% protection against severe infection and 80% protection against death for both H5N1 and H7N9. Our results enable us to predict age distributions of severe disease for future pandemics and demonstrate that a novel strain's pandemic potential increases yearly when a group-mismatched HA subtype dominates seasonal influenza circulation. These findings open new frontiers for rational pandemic risk assessment. C1 [Gostic, Katelyn M.; Ambrose, Monique; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 90095 USA. [Worobey, Michael] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 90095 USA.; Worobey, M (reprint author), Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA.; Lloyd-Smith, JO (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM worobey@email.arizona.edu; jlloydsmith@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU National Institute of General Medical Sciences of the National Institutes of Health [T32GM008185]; National Science Foundation Graduate Research Fellowship [DGE-1144087]; David and Lucile Packard Foundation; National Science Foundation [EF-0928690]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank the Lloyd-Smith lab and the Worobey lab for helpful comments, C. Viboud for providing insight into historic influenza data, T. Mega and S. Wu for assistance compiling data, B. Cowling for sharing poultry exposure data, and P. Horby for sharing Vietnam contact data. K.M.G. is supported by the National Institute of General Medical Sciences of the National Institutes of Health (T32GM008185). M.A. is supported by the National Science Foundation Graduate Research Fellowship (DGE-1144087). M.W. is supported by the David and Lucile Packard Foundation. J.O.L-S. is supported by the National Science Foundation (EF-0928690); the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; and Fogarty International Center, 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. The authors declare no competing financial interests. Case data and code for model fitting are available as supplementary data files. Requests for materials should be addressed to M.W. or J.O.L.-S. NR 34 TC 2 Z9 2 U1 15 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 11 PY 2016 VL 354 IS 6313 BP 722 EP 726 AR aag1322 DI 10.1126/science.aag1322 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4FS UT WOS:000387326300030 PM 27846599 ER PT J AU Hu, B Jin, CC Li, HB Tong, JY Ouyang, XS Cetinbas, NM Zhu, S Strowig, T Lam, FC Zhao, C Henao-Mejia, J Yilmaz, O Fitzgerald, KA Eisenbarth, SC Elinav, E Flavell, RA AF Hu, Bo Jin, Chengcheng Li, Hua-Bing Tong, Jiyu Ouyang, Xinshou Cetinbas, Naniye Malli Zhu, Shu Strowig, Till Lam, Fred C. Zhao, Chen Henao-Mejia, Jorge Yilmaz, Omer Fitzgerald, Katherine A. Eisenbarth, Stephanie C. Elinav, Eran Flavell, Richard A. TI The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury SO SCIENCE LA English DT Article ID GASTROINTESTINAL SYNDROME; MEDICAL-MANAGEMENT; SENSOR AIM2; MICE; APOPTOSIS; P53; ACTIVATION; EXPOSURE AB Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure. C1 [Hu, Bo; Jin, Chengcheng; Li, Hua-Bing; Tong, Jiyu; Zhu, Shu; Strowig, Till; Henao-Mejia, Jorge; Eisenbarth, Stephanie C.; Elinav, Eran; Flavell, Richard A.] Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. [Tong, Jiyu] Jinan Univ, Biomed Translat Res Inst, Guangzhou 510632, Guangdong, Peoples R China. [Ouyang, Xinshou] Yale Univ, Sect Digest Dis, New Haven, CT 06520 USA. [Cetinbas, Naniye Malli; Lam, Fred C.; Yilmaz, Omer] MIT, Koch Inst Integrat Canc Biol, 500 Main St, Cambridge, MA 02139 USA. [Zhao, Chen] NIH, Hematol Oncol Fellowship Program, Bldg 10, Bethesda, MD 20892 USA. [Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Program Innate Immun, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [Eisenbarth, Stephanie C.] Yale Univ, Dept Lab Med, Sch Med, New Haven, CT 06520 USA. [Flavell, Richard A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Strowig, Till] Helmholtz Ctr Infect Res, Inhoffenstr 7, D-38124 Braunschweig, Germany. [Henao-Mejia, Jorge] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Elinav, Eran] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel. RP Flavell, RA (reprint author), Yale Univ, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA.; Flavell, RA (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM richard.flavell@yale.edu OI Strowig, Till/0000-0003-0185-1459; Li, Huabing/0000-0003-3573-6803 FU NIH [T32 2T32DK007356]; Howard Hughes Medical Institute FX We thank V. M. Dixit, N. Kayagaki, and E. S. Alnemri for sharing materials and reagents, and V. A. Rathinam for technical advice. We thank P. Bongiorni for assistance with radiation experiments. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. H.-B.L. is supported by NIH T32 2T32DK007356. This work was supported by the Howard Hughes Medical Institute (R.A.F.). NR 24 TC 1 Z9 1 U1 15 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 11 PY 2016 VL 354 IS 6313 BP 765 EP 768 DI 10.1126/science.aaf7532 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4FS UT WOS:000387326300041 PM 27846608 ER PT J AU Kitajima, N Numaga-Tomita, T Watanabe, M Kuroda, T Nishimura, A Miyano, K Yasuda, S Kuwahara, K Sato, Y Ide, T Birnbaumer, L Sumimoto, H Mori, Y Nishida, M AF Kitajima, Naoyuki Numaga-Tomita, Takuro Watanabe, Masahiko Kuroda, Takuya Nishimura, Akiyuki Miyano, Kei Yasuda, Satoshi Kuwahara, Koichiro Sato, Yoji Ide, Tomomi Birnbaumer, Lutz Sumimoto, Hideki Mori, Yasuo Nishida, Motohiro TI TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling SO SCIENTIFIC REPORTS LA English DT Article ID SMALL GTPASE RAC; HEART-FAILURE; NADPH OXIDASES; CA2+ INFLUX; CHANNELS; ACTIVATION; HYPERTROPHY; SUPEROXIDE; BETA; ANGIOTENSIN AB Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities. C1 [Kitajima, Naoyuki; Numaga-Tomita, Takuro; Nishimura, Akiyuki; Nishida, Motohiro] Natl Inst Nat Sci, Natl Inst Physiol Sci, Okazaki Inst Integrat Biosci, Div Cardiocirculatory Signaling, Okazaki, Aichi 4448787, Japan. [Kitajima, Naoyuki; Sato, Yoji; Nishida, Motohiro] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Translat Pharmaceut Sci, Fukuoka 8128582, Japan. [Numaga-Tomita, Takuro; Nishimura, Akiyuki; Nishida, Motohiro] Grad Univ Adv Studies, Sch Life Sci, SOKENDAI, Dept Physiol Sci, Okazaki, Aichi 4448787, Japan. [Watanabe, Masahiko] Hokkaido Univ, Dept Anat, Sch Med, Sapporo, Hokkaido 0608638, Japan. [Kuroda, Takuya; Yasuda, Satoshi; Sato, Yoji] Natl Inst Hlth Sci, Div Cell Based Therapeut Prod, Setagaya Ku, Tokyo 1588501, Japan. [Miyano, Kei; Sumimoto, Hideki] Kyoto Univ, Grad Sch Med Sci, Dept Biochem, Fukuoka 8128582, Japan. [Kuwahara, Koichiro] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto 6068507, Japan. [Ide, Tomomi] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka 8128582, Japan. [Birnbaumer, Lutz] NIEHS, Neurosci Lab, NIH, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Catholic Univ Argentina, Inst Biomed Res BIOMED, C1107AFF, Buenos Aires, DF, Argentina. [Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto 6158510, Japan. [Nishida, Motohiro] JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan. RP Nishida, M (reprint author), Natl Inst Nat Sci, Natl Inst Physiol Sci, Okazaki Inst Integrat Biosci, Div Cardiocirculatory Signaling, Okazaki, Aichi 4448787, Japan.; Nishida, M (reprint author), Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Translat Pharmaceut Sci, Fukuoka 8128582, Japan.; Nishida, M (reprint author), Grad Univ Adv Studies, Sch Life Sci, SOKENDAI, Dept Physiol Sci, Okazaki, Aichi 4448787, Japan.; Nishida, M (reprint author), JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan. EM nishida@nips.ac.jp RI WATANABE, Masahiko/A-4055-2012 FU Comprehensive Brain Science Network (CBSN); Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology Program; Ministry of Education, Culture, Sports, Science, and Technology of Japan [25293018, 16H05092, 12J05497, 26670144]; Daiko Foundation; Naito Memorial Foundation; Intramural Research Program of the NIH [ZO1-ES-101684] FX TRPC3(-/-) mice and TRPC(1-7) deficient MEFs were kindly provided from Dr. Lutz Birnbaumer of the NIEHS, Research Triangle Park, NC, USA. This research was supported by Comprehensive Brain Science Network (CBSN) for anti-TRPC3 antibody, and funded by grants from the Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology Program (to M.N.); Grants-in-Aid for Scientific Research (No. 25293018 and No. 16H05092 to M.N.; No. 12J05497 to N.K., No. 26670144 to T.N-T.) and Scientific Research on Innovative Areas (Research in a Proposed Research Area 'Oxygen Biology' to M.N. and 'Living in Space' to T.N-T.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Daiko Foundation and Naito Memorial Foundation (to M.N.); and by the Intramural Research Program of the NIH (Project ZO1-ES-101684 to L.B.). NR 33 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 11 PY 2016 VL 6 AR 37001 DI 10.1038/srep37001 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB6FE UT WOS:000387476100001 PM 27833156 ER PT J AU Park, JY Jo, Y Ko, E Luckey, MA Park, YK Park, SH Park, JH Hong, C AF Park, Joo-Young Jo, Yuna Ko, Eunhee Luckey, Megan A. Park, Yoo Kyoung Park, Se-Ho Park, Jung-Hyun Hong, Changwan TI Soluble gamma c cytokine receptor suppresses IL-15 signaling and impairs iNKT cell development in the thymus SO SCIENTIFIC REPORTS LA English DT Article ID DOUBLE-POSITIVE THYMOCYTES; FUNCTIONALLY DISTINCT SUBSETS; V-ALPHA-14I NKT CELLS; REGULATORY T-CELLS; NATURAL-KILLER; TRANSCRIPTION FACTOR; LINEAGE FATE; TERMINAL MATURATION; HOMEOSTASIS; DIFFERENTIATION AB The soluble gamma c protein (s gamma c) is a naturally occurring splice isoform of the gamma c cytokine receptor that is produced by activated T cells and inhibits gamma c cytokine signaling. Here we show that s gamma c expression is also highly upregulated in immature CD4(+)CD8(+) thymocytes but then downregulated in mature thymocytes. These results indicate a developmentally controlled mechanism for s gamma c expression and suggest a potential role for s gamma c in regulating T cell development in the thymus. Indeed, s gamma c overexpression resulted in significantly reduced thymocyte numbers and diminished expansion of immature thymocytes, concordant to its role in suppressing signaling by IL-7, a critical gamma c cytokine in early thymopoiesis. Notably, s gamma c overexpression also impaired generation of iNKT cells, resulting in reduced iNKT cell percentages and numbers in the thymus. iNKT cell development requires IL-15, and we found that s gamma c interfered with IL-15 signaling to suppress iNKT cell generation in the thymus. Thus, s gamma c represents a new mechanism to control cytokine availability during T cell development that constrains mature T cell production and specifically iNKT cell generation in the thymus. C1 [Park, Joo-Young; Luckey, Megan A.; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Jo, Yuna; Ko, Eunhee; Hong, Changwan] Pusan Natl Univ, Dept Anat, Sch Med, Yangsan 626870, South Korea. [Park, Yoo Kyoung] Kyung Hee Univ, Grad Sch East West Med Sci, Dept Med Nutr, Yongin 446701, South Korea. [Park, Se-Ho] Korea Univ, Sch Life Sci & Biotechnol, Seoul 136701, South Korea. RP Hong, C (reprint author), Pusan Natl Univ, Dept Anat, Sch Med, Yangsan 626870, South Korea. EM chong@pusan.ac.kr RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 FU Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI14C2512]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank members of the Hong lab for critical review of this manuscript. This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2512), and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 57 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 11 PY 2016 VL 6 AR 36962 DI 10.1038/srep36962 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7FD UT WOS:000387550900001 PM 27833166 ER PT J AU Harris, LN Ismaila, N McShane, LM Andre, F AF Harris, Lyndsay N. Ismaila, Nofisat McShane, Lisa M. Andre, Fabrice TI Providing Balance in ASCO Clinical Practice Guidelines: CYP2D6 Genotyping and Tamoxifen Efficacy Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID POSITIVE BREAST-CANCER; LATE-DISTANT RECURRENCE; MOLECULAR GRADE INDEX; ADJUVANT TAMOXIFEN; TRIAL; POPULATION; BIOMARKERS; SIGNATURE; SURVIVAL; THERAPY C1 [Harris, Lyndsay N.; McShane, Lisa M.] NCI, Bethesda, MD 20892 USA. [Ismaila, Nofisat] Amer Soc Clin Oncol, Alexandria, VA USA. [Andre, Fabrice] Inst Gustave Roussy, Paris, France. RP Harris, LN (reprint author), NCI, Bethesda, MD 20892 USA. NR 25 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 10 PY 2016 VL 34 IS 32 BP 3946 EP + DI 10.1200/JCO.2016.68.7020 PG 4 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900024 ER PT J AU Cheng, JJ McCorvy, JD Giguere, PM Zhu, H Kenakin, T Roth, BL Kozikowski, AP AF Cheng, Jianjun McCorvy, John D. Giguere, Patrick M. Zhu, Hu Kenakin, Terry Roth, Bryan L. Kozikowski, Alan P. TI Design and Discovery of Functionally Selective Serotonin 2C (5-HT2c) Receptor Agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LIGANDS; IDENTIFICATION; TRANSDUCTION; DISEASE; MODELS; POTENT; AGENTS; DRUG; 2B AB On the basis of the structural similarity of our previous 5-HT2c agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5HT(2c) receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2c agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus beta-arrestin recruitment. The most functionally selective compound (+)-7e produced weak beta-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2c agonists possessing weak beta-arrestin recruitment can produce distinct receptor desensitization properties. C1 [Cheng, Jianjun; Kozikowski, Alan P.] Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Drug Discovery Program, Chicago, IL 60612 USA. [McCorvy, John D.; Giguere, Patrick M.; Zhu, Hu; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Kenakin, Terry] Univ N Carolina, Sch Med, Div Pharmacol, Chapel Hill, NC 27599 USA. [Kenakin, Terry] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Cheng, Jianjun] ShanghaiTech Univ, iHuman Inst, 99 Haike Rd, Shanghai 201210, Peoples R China. [Giguere, Patrick M.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada. [Zhu, Hu] NCATS, Div Preclin Innovat, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Kozikowski, AP (reprint author), Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Drug Discovery Program, Chicago, IL 60612 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; kozikowa@uic.edu FU National Institute of Mental Health (NIMH) [R01MH99993]; Psychoactive Drug Screening Program (PDSP) [HHSN-271-2013-00017-C] FX Financial support from the National Institute of Mental Health (NIMH) (Grant R01MH99993) and Psychoactive Drug Screening Program (PDSP, Contract HHSN-271-2013-00017-C) is gratefully acknowledged. NR 36 TC 0 Z9 0 U1 11 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD NOV 10 PY 2016 VL 59 IS 21 BP 9866 EP 9880 DI 10.1021/acs.jmedchem.6b01194 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EB9SO UT WOS:000387737600018 PM 27726356 ER PT J AU Johnson, TL Fischer, RJ Raffel, SJ Schwan, TG AF Johnson, Tammi L. Fischer, Robert J. Raffel, Sandra J. Schwan, Tom G. TI Host associations and genomic diversity of Borrelia hermsii in an endemic focus of tick-borne relapsing fever in western North America SO PARASITES & VECTORS LA English DT Article DE Ornithodoros hermsi; Tick-borne zoonosis; Montana; Argasidae ID LYME-DISEASE RISK; INTERSTATE OUTBREAK; ORNITHODOROS-HERMSI; SPECIES-DIVERSITY; UNITED-STATES; GRAND-CANYON; CALIFORNIA; SPIROCHETE; INFECTION; BURGDORFERI AB Background: An unrecognized focus of tick-borne relapsing fever caused by Borrelia hermsii was identified in 2002 when five people became infected on Wild Horse Island in Flathead Lake, Montana. The terrestrial small mammal community on the island is composed primarily of pine squirrels (Tamiasciurus hudsonicus) and deer mice (Peromyscus maniculatus), neither of which was known as a natural host for the spirochete. Thus a 3-year study was performed to identify small mammals as hosts for B. hermsii. Methods: Small mammals were captured alive on two island and three mainland sites, blood samples were collected and examined for spirochetes, and serological tests performed to detect anti-B. hermsii antibodies. Ornithodoros hermsi ticks were collected and fed on laboratory mice to assess infection. Genomic DNA samples from spirochetes isolated from infected mammals and ticks were analyzed by multilocus sequence typing. Results: Eighteen pine squirrels and one deer mouse had detectable spirochetemias when captured, from which 12 isolates of B. hermsii were established. Most pine squirrels were seropositive, and the five species of sciurids combined had a significantly higher prevalence of seropositive animals than did the other six small mammal species captured. The greater diversity of small mammals on the mainland in contrast to the islands demonstrated that other species in addition to pine squirrels were also involved in the maintenance of B. hermsii at Flathead Lake. Ornithodoros hermsi ticks produced an additional 12 isolates of B. hermsii and multilocus sequence typing identified both genomic groups of B. hermsii described previously, and identified a new genomic subdivision. Experimental infections of deer mice with two strains of B. hermsii demonstrated that these animals were susceptible to infection with spirochetes belonging to Genomic Group II but not Genomic Group I. Conclusions: Pine squirrels are the primary hosts for the maintenance of B. hermsii on the islands in Flathead Lake, however serological evidence showed that numerous additional species are also involved on the mainland. Future studies testing the susceptibility of several small mammal species to infection with different genetic types of B. hermsii will help define their role as hosts in this and other endemic foci. C1 [Johnson, Tammi L.; Fischer, Robert J.; Raffel, Sandra J.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Johnson, Tammi L.] Ctr Dis Control & Prevent, Div Vector Borne Dis, Ft Collins, CO USA. [Fischer, Robert J.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Schwan, TG (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU Montana Ecology of Infectious Diseases Program; National Science Foundation Integrative Graduate Education and Research Traineeship; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Montana Ecology of Infectious Diseases Program, National Science Foundation Integrative Graduate Education and Research Traineeship, and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 76 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD NOV 10 PY 2016 VL 9 AR 575 DI 10.1186/s13071-016-1863-0 PG 17 WC Parasitology SC Parasitology GA EC5AL UT WOS:000388145400001 PM 27832805 ER PT J AU Loftfield, E O'Brien, TR Pfeiffer, RM Howell, CD Horst, R Prokunina-Olsson, L Weinstein, SJ Albanes, D Morgan, TR Freedman, ND AF Loftfield, Erikka O'Brien, Thomas R. Pfeiffer, Ruth M. Howell, Charles D. Horst, Ron Prokunina-Olsson, Ludmila Weinstein, Stephanie J. Albanes, Demetrius Morgan, Timothy R. Freedman, Neal D. TI Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials SO PLOS ONE LA English DT Article ID CHRONIC HEPATITIS-C; GENOTYPE 1 INFECTION; PEGINTERFERON ALPHA-2A; ANTIVIRAL THERAPY; 25-HYDROXYVITAMIN D; AMERICAN PATIENTS; VIRUS THERAPY; RIBAVIRIN; INTERFERON; METAANALYSIS AB More than 150 million people worldwide are chronically infected with hepatitis C virus (HCV) and face higher risk of cirrhosis and hepatocellular carcinoma. Highly effective HCV treatments have recently been developed; however, they are costly and therefore poorly suited for application in resource-limited settings where HCV burden is high. Pegylated-interferon alpha (PEG-IFN alpha) and ribavirin (RBV) therapy is far less costly, but also less effective. Vitamin D supplementation has been proposed as an inexpensive adjuvant to treatment, however, prior epidemiological evidence on its effectiveness is inconsistent, with little data available among African Americans who naturally have lower vitamin D concentrations. We thus evaluated associations between baseline vitamin D status, measured by circulating 25-hydroxyvitamin D (25(OH)D), which is considered to be the best marker of vitamin D status in humans, and subsequent response to PEG-IFN alpha/RBV therapy in two large clinical trials that together included 1292 patients infected with HCV genotype 1. We used race-stratified logistic regression models to evaluate multivariable-adjusted associations of 25(OH)D with early virologic response (EVR; 2-log10 HCV RNA decline at week 12) and sustained virologic response (SVR). Among African Americans, we saw no associations. Among European Americans, we saw no association with low vitamin D (<= 20 ng/mL) versus sufficient concentrations (20-<30 ng/mL). However, patients with 25(OH) D >= 30 ng/mL were actually less likely to attain EVR (OR = 0.64, 95% CI = 0.43-0.94) than those with sufficient concentrations, with a similar but non-significant association observed for SVR (OR = 0.49, 95% CI = 0.20-1.17). C1 [Loftfield, Erikka; O'Brien, Thomas R.; Pfeiffer, Ruth M.; Prokunina-Olsson, Ludmila; Weinstein, Stephanie J.; Albanes, Demetrius; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Howell, Charles D.] Howard Univ, Coll Med, Dept Med, Washington, DC USA. [Horst, Ron] Heartland Assays, Ames, IA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Long Beach, CA USA. RP Loftfield, E (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM erikka.loftfield@nih.gov FU Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Heartland Assays; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. Heartland Assays provided support in the form of salaries for author [RH], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section.; This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Heartland Assays provided support in the form of salaries for author [RH], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section. The VIRAHEP-C and HALT-C studies were conducted, respectively, by the VIRAHEP-C and HALT-C Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The data and samples from the VIRAHEP-C and HALT-C studies reported here were supplied by the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories. This manuscript was not prepared in collaboration with the VIRAHEP-C study group or the HALT-C study group and does not necessarily reflect the opinions or views of the VIRAHEP-C Trial and HALT-C Trial, the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories or the National Institute of Diabetes and Digestive and Kidney Diseases. NR 51 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 10 PY 2016 VL 11 IS 11 AR 0166036 DI 10.1371/journal.pone.0166036 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9ON UT WOS:000387725000056 ER PT J AU Rienstra, M Geelhoed, B Yin, XY Siland, JE Vermond, RA Mulder, BA Van Der Harst, P Hillege, HL Benjamin, EJ Van Gelder, IC AF Rienstra, Michiel Geelhoed, Bastiaan Yin, Xiaoyan Siland, Joylene E. Vermond, Rob A. Mulder, Bart A. Van Der Harst, Pim Hillege, Hans L. Benjamin, Emelia J. Van Gelder, Isabelle C. TI Cluster Individuals Based on Phenotype and Determine the Risk for Atrial Fibrillation in the PREVEND and Framingham Heart Study Populations SO PLOS ONE LA English DT Article ID ASSOCIATION CONSENSUS CONFERENCE; LATENT CLASS ANALYSIS; PROGNOSIS; COHORT AB Background Risk prediction of atrial fibrillation (AF) is of importance to improve the early diagnosis and treatment of AF. Latent class analysis takes into account the possible existence of classes of individuals each with shared risk factors, and maybe a better method of incorporating the phenotypic heterogeneity underlying AF. Methods and findings Two prospective community-based cohort studies from Netherlands and United States were used. Prevention of Renal and Vascular End-stage Disease (PREVEND) study, started in 1997, and the Framingham Heart Study (FHS) Offspring cohort started in 1971, both with 10-years follow-up. The main objective was to determine the risk of AF using a latent class analysis, and compare the discrimination and reclassification performance with traditional regression analysis. Mean age in PREVEND was 49 13 years, 49.8% were men. During follow-up, 250(3%) individuals developed AF. We built a latent class model based on 18 risk factors. A model with 7 distinct classes (ranging from 341 to 1517 individuals) gave the optimum tradeoff between a high statistical model-likelihood and a low number of model parameters. All classes had a specific profile. The incidence of AF varied; class 1 0.0%, class 2 0.3%, class 3 7.5%, class 4 0.2%, class 5 1.3%, class 6 4.2%, class 7 21.7% (p<0.001). The discrimination (C-statistic 0.830 vs. 0.842, delta-C -0.013, p = 0.22) and reclassification (IDI-0.028, p<0.001, NRI-0.090, p = 0.049, and category-less-NRI -0.049, p = 0.495) performance of both models was comparable. The results were successfully replicated in a sample of the FHS study (n = 3162; mean age 58 9 years, 46.3% men). Conclusions Latent class analysis to build an AF risk model is feasible. Despite the heterogeneity in number and severity of risk factors between individuals at risk for AF, latent class analysis produces distinguishable groups. C1 [Rienstra, Michiel; Geelhoed, Bastiaan; Siland, Joylene E.; Vermond, Rob A.; Mulder, Bart A.; Van Der Harst, Pim; Hillege, Hans L.; Van Gelder, Isabelle C.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Yin, Xiaoyan; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Yin, Xiaoyan; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Rienstra, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. EM m.rienstra@umcg.nl OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU Dutch Kidney Foundation [E0.13]; Netherlands Heart Foundation [NHS2010B280]; Netherlands Organization for Scientific Research (Veni) [016.136.055]; EHRA Academic Fellowship program; [HHSN268201500001I]; [N01-HC 25195]; [2R01HL092577]; [1R01HL128914] FX The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by grants from the Netherlands Organization for Scientific Research (Veni grant 016.136.055) and from the EHRA Academic Fellowship program. The FHS is supported by HHSN268201500001I, N01-HC 25195, 2R01HL092577, and 1R01HL128914. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 10 PY 2016 VL 11 IS 11 AR e0165828 DI 10.1371/journal.pone.0165828 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9ON UT WOS:000387725000036 PM 27832125 ER PT J AU Manson, JE Brannon, PM Rosen, CJ Taylor, CL AF Manson, JoAnn E. Brannon, Patsy M. Rosen, Clifford J. Taylor, Christine L. TI Vitamin D Deficiency - Is There Really a Pandemic? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID EUROPE C1 [Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Manson, JoAnn E.] Harvard Med Sch, Boston, MA 02115 USA. [Brannon, Patsy M.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Rosen, Clifford J.] Maine Med Ctr Res Inst, Ctr Clin & Translat Med, Scarborough, ME USA. [Taylor, Christine L.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Manson, JE (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Manson, JE (reprint author), Harvard Med Sch, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA138962] NR 5 TC 2 Z9 2 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 10 PY 2016 VL 375 IS 19 BP 1817 EP 1820 DI 10.1056/NEJMp1608005 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EB6ZK UT WOS:000387534200004 PM 27959647 ER PT J AU Shehata, MA Nohr, AC Lissa, D Bisig, C Isberg, V Andersen, KB Harpsoe, K Bjorkling, F Brauner-Osborne, H Gloriam, DE AF Shehata, Mohamed A. Nohr, Anne C. Lissa, Delphine Bisig, Christoph Isberg, Vignir Andersen, Kirsten B. Harpsoe, Kasper Bjorkling, Fredrik Brauner-Osborne, Hans Gloriam, David E. TI Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139 SO SCIENTIFIC REPORTS LA English DT Article ID FINGERPRINTS; LIGANDS; TARGETS AB GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids (L)-Trp and (L)-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization. C1 [Shehata, Mohamed A.; Nohr, Anne C.; Lissa, Delphine; Bisig, Christoph; Isberg, Vignir; Andersen, Kirsten B.; Harpsoe, Kasper; Bjorkling, Fredrik; Brauner-Osborne, Hans; Gloriam, David E.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark. [Andersen, Kirsten B.] H Lundbeck & Co AS, Dept Neurodegenerat 1, Ottiliavej 9, DK-2500 Valby, Denmark. [Lissa, Delphine] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Bisig, Christoph] Univ Fribourg, Adolphe Merkle Inst, Chemin Verdiers 4, CH-1700 Fribourg, Switzerland. [Isberg, Vignir] Novozymes AS, Krogshojvej 36, DK-2880 Bagsvaerd, Denmark. [Andersen, Kirsten B.] Danish Vet & Food Adm, Minist Environm & Food Denmark, Stn Pk 31-33, DK-2600 Glostrup, Denmark. RP Brauner-Osborne, H; Gloriam, DE (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark. EM hbo@sund.ku.dk; david.gloriam@sund.ku.dk OI Shehata, Mohamed/0000-0001-5475-1967; Brauner-Osborne, Hans/0000-0001-9495-7388; Gloriam, David/0000-0002-4299-7561; Harpsoe, Kasper/0000-0002-9326-9644 FU Lundbeck Foundation [R163-2013-16327]; Danish Council for Independent Research (DFF) [1331-00180]; European Research Council [DE-ORPHAN 639125]; A. P. Moller Foundation for the Advancement of Medical Sciences; Lundbeck Foundation; Faculty of Health and Medical Sciences FX This work was supported by grants from the Lundbeck Foundation (R163-2013-16327 to D.E.G.), The Danish Council for Independent Research (DFF - 1331-00180 to D.E.G.) and European Research Council (DE-ORPHAN 639125 to D.E.G.); and the A. P. Moller Foundation for the Advancement of Medical Sciences and the Lundbeck Foundation (H.B.-O.). M.A.S. and A.C.N. acknowledge funding from the Faculty of Health and Medical Sciences. NR 30 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 10 PY 2016 VL 6 AR 36681 DI 10.1038/srep36681 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB6QX UT WOS:000387510900001 PM 27830715 ER PT J AU Xu, H Li, ZY Yu, Y Sizdahkhani, S Ho, WS Yin, FC Wang, L Zhu, GL Zhang, M Jiang, L Zhuang, ZP Qin, JH AF Xu, Hui Li, Zhongyu Yu, Yue Sizdahkhani, Saman Ho, Winson S. Yin, Fangchao Wang, Li Zhu, Guoli Zhang, Min Jiang, Lei Zhuang, Zhengping Qin, Jianhua TI A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors SO SCIENTIFIC REPORTS LA English DT Article ID MICROVASCULAR ENDOTHELIAL-CELLS; VITRO MODEL; ELECTRICAL-RESISTANCE; BBB; CANCER; CHIP; RAT; PERMEABILITY; EXPRESSION; SYSTEM AB The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research. C1 [Xu, Hui; Li, Zhongyu; Yu, Yue; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Qin, Jianhua] Chinese Acad Sci, Dalian Inst Chem Phys, Div Biotechnol, Dalian, Peoples R China. [Xu, Hui; Li, Zhongyu; Yu, Yue; Yin, Fangchao; Zhu, Guoli] Univ Chinese Acad Sci, Beijing, Peoples R China. [Sizdahkhani, Saman; Ho, Winson S.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Qin, JH (reprint author), Chinese Acad Sci, Dalian Inst Chem Phys, Div Biotechnol, Dalian, Peoples R China. EM jhqin@dicp.ac.cn OI Yu, Yue/0000-0003-0633-9577 FU National Nature Science Foundation of China [91543121, 31671038, 81573394, 81273483]; International Science & Technology Cooperation Program of China [2015DFA00740]; Key Laboratory of Separation Science for Analytical Chemistry (Dalian Institute of Chemical Physics, Chinese Academy of Sciences) FX This research was supported by National Nature Science Foundation of China (Nos 91543121, 31671038, 81573394, 81273483), International Science & Technology Cooperation Program of China (2015DFA00740), Key Laboratory of Separation Science for Analytical Chemistry (Dalian Institute of Chemical Physics, Chinese Academy of Sciences). NR 48 TC 0 Z9 0 U1 20 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 10 PY 2016 VL 6 AR 36670 DI 10.1038/srep36670 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB6QW UT WOS:000387510800001 PM 27830712 ER PT J AU Baker, PM Jhou, T Li, B Matsumoto, M Mizumori, SJY Stephenson-Jones, M Vicentic, A AF Baker, Phillip M. Jhou, Thomas Li, Bo Matsumoto, Masayuki Mizumori, Sheri J. Y. Stephenson-Jones, Marcus Vicentic, Aleksandra TI The Lateral Habenula Circuitry: Reward Processing and Cognitive Control SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anterior cingulate cortex; cognition; globus pallidus; lateral habenula; punishment; reward; rostromedial tegmental nucleus ID VENTRAL TEGMENTAL AREA; ANTERIOR CINGULATE CORTEX; MIDBRAIN DOPAMINE NEURONS; NEGATIVE MOTIVATIONAL VALUE; OPPONENT-PROCESS THEORY; BASAL GANGLIA; NONHUMAN-PRIMATES; SUBSTANTIA-NIGRA; DECISION-MAKING; MOTOR-RESPONSES AB There has been a growing interest in understanding the role of the lateral habenula (LHb) in reward processing, affect regulation, and goal-directed behaviors. The LHb gets major inputs from the habenula-projecting globus pallidus and the mPFC, sending its efferents to the dopaminergic VTA and SNc, serotonergic dorsal raphe nuclei, and the GABAergic rostromedial tegmental nucleus. Recent studies have made advances in our understanding of the LHb circuit organization, yet the precise mechanisms of its involvement in complex behaviors are largely unknown. To begin to address this unresolved question, we present here emerging cross-species perspectives with a goal to provide a more refined understanding of the role of the LHb circuits in reward and cognition. We begin by highlighting recent findings from rodent experiments using optogenetics, electrophysiology, molecular, pharmacology, and tracing techniques that reveal diverse neural phenotypes in the LHb circuits that may underlie previously undescribed behavioral functions. We then discuss results from electrophysiological studies in macaques that suggest that the LHb cooperates with the anterior cingulate cortex to monitor action outcomes and signal behavioral adjustment. Finally, weprovide an integrated summary of cross-species findings and discuss how further research on the connectivity, neural signaling, and physiology of the LHb circuits can deepen our understanding of the role of the LHb in normal and maladaptive behaviors associated with mental illnesses and drug abuse. C1 [Baker, Phillip M.; Mizumori, Sheri J. Y.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Jhou, Thomas] Med Univ South Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Li, Bo; Stephenson-Jones, Marcus] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. [Matsumoto, Masayuki] Univ Tsukuba, Div Biomed Sci, Fac Med, Ibaraki 3058577, Japan. [Vicentic, Aleksandra] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Li, B (reprint author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA.; Vicentic, A (reprint author), NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. EM bli@cshl.edu; vicentica@mail.nih.gov OI Baker, Phillip/0000-0002-3023-2983 FU National Institute of Drug Abuse Grant [T32 DA07278 - 20]; National Institute of Mental Health [R01MH108924, R01MH58755]; National Institute of Drug Abuse [1R01DA037327]; National Institute on Drug Abuse [1R21DA032898]; Cabinet Office, Government of Japan Funding Program for Next Generation World-Leading Researchers [LS074]; Ministry of Education, Culture, Sports, Science and Technology of Japan [26120707]; Takeda Science Foundation; Inamori Foundation; Uehara Memorial Foundation; University of Washington Research Royalty Fund Grant; National Alliance for Research on Schizophrenia and Depression; EMBO Long-Term Fellowship Awards FX This work was supported by National Institute of Drug Abuse Grant T32 DA07278 - 20 to P.M.B., National Institute of Mental Health Grant R01MH108924 to B.L., National Institute of Drug Abuse Grants 1R01DA037327 and National Institute on Drug Abuse 1R21DA032898 to T.J., Cabinet Office, Government of Japan Funding Program for Next Generation World-Leading Researchers LS074, Ministry of Education, Culture, Sports, Science and Technology of Japan Grants-in-Aid for Scientific Research 26120707, Takeda Science Foundation, Inamori Foundation, and Uehara Memorial Foundation to M.M., National Institute of Mental Health Grant R01MH58755 and University of Washington Research Royalty Fund Grant to S.J.Y.M., and National Alliance for Research on Schizophrenia and Depression and EMBO Long-Term Fellowship Awards to M.S.-J. NR 72 TC 0 Z9 0 U1 7 U2 7 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 NOV 9 PY 2016 VL 36 IS 45 BP 11482 EP 11488 DI 10.1523/JNEUROSCI.2350-16.2016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EG5AC UT WOS:000391054300013 PM 27911751 ER PT J AU Aron, AR Herz, DM Brown, P Forstmann, BU Zaghloul, K AF Aron, Adam R. Herz, Damian M. Brown, Peter Forstmann, Birte U. Zaghloul, Kareem TI Frontosubthalamic Circuits for Control of Action and Cognition SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal ganglia; conflict; oscillations; response inhibition; stopping; surprise ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN SUBTHALAMIC NUCLEUS; SUPPLEMENTARY MOTOR AREA; DEEP BRAIN-STIMULATION; CORTICOSUBTHALAMIC INPUT ZONES; SIGNAL RESPONSE-INHIBITION; INFERIOR FRONTAL GYRUS; BASAL-GANGLIA; PARKINSONS-DISEASE; FUNCTIONAL-ANATOMY AB The subthalamic nucleus (STN) of the basal ganglia appears to have a potent role in action and cognition. Anatomical and imaging studies show that different frontal cortical areas directly project to the STN via so-called hyperdirect pathways. This review reports some of the latest findings about such circuits, including simultaneous recordings from cortex and the STN in humans, single-unit recordings in humans, high-resolution fMRI, and neurocomputational modeling. We argue that a major function of the STN is to broadly pause behavior and cognition when stop signals, conflict signals, or surprise signals occur, and that the fronto-STN circuits for doing this, at least for stopping and conflict, are dissociable anatomically and in terms of their spectral reactivity. Wealso highlight recent evidence for synchronization of oscillations between prefrontal cortex and the STN, which may provide a preferential "window in time" for single neuron communication via long-range connections. C1 [Aron, Adam R.] Univ Calif San Diego, Dept Psychol, San Diego, CA 92093 USA. [Herz, Damian M.; Brown, Peter] Univ Oxford, MRC, Brain Network Dynam Unit, Oxford OX1 3TH, England. [Herz, Damian M.; Brown, Peter] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX1 3TH, England. [Forstmann, Birte U.] Univ Amsterdam, Amsterdam Brain & Cognit Ctr, Psychol, Roetersstr 15, NL-1018 Amsterdam, Netherlands. [Zaghloul, Kareem] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Aron, AR (reprint author), Univ Calif San Diego, Dept Psychol, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM adamaron@ucsd.edu OI Brown, Peter/0000-0002-5201-3044 FU National Institutes of Health [DA DA026452]; James S. McDonnell Grant [220020375]; European Union [655605]; Medical Research Council of Great Britain [MC_UU_12024/1]; European Research Council; Netherlands Organization for Scientific Research FX A.R.A. was supported by National Institutes of Health DA DA026452 and James S. McDonnell Grant 220020375. D.M.H. was supported by European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement 655605. P.B. was supported by Medical Research Council of Great Britain MC_UU_12024/1. B.U.F. was supported by the European Research Council and Netherlands Organization for Scientific Research. We thank Nader Pouratian for discussion, Navarre Guiterrez-Read for assistance with the figure, and Johanna Wagner and Eleonora Bartoli for comments on the manuscript. NR 98 TC 1 Z9 1 U1 12 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 9 PY 2016 VL 36 IS 45 BP 11489 EP 11495 DI 10.1523/JNEUROSCI.2348-16.2016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EG5AC UT WOS:000391054300014 PM 27911752 ER PT J AU Ji, B Kaneko, H Minamimoto, T Inoue, H Takeuchi, H Kumata, K Zhang, MR Aoki, I Seki, C Ono, M Tokunaga, M Tsukamoto, S Tanabe, K Shin, RM Minamihisamatsu, T Kito, S Richmond, BJ Suhara, T Higuchi, M AF Ji, Bin Kaneko, Hiroyuki Minamimoto, Takafumi Inoue, Haruhisa Takeuchi, Hiroki Kumata, Katsushi Zhang, Ming-Rong Aoki, Ichio Seki, Chie Ono, Maiko Tokunaga, Masaki Tsukamoto, Satoshi Tanabe, Koji Shin, Ryong-Moon Minamihisamatsu, Takeharu Kito, Seiji Richmond, Barry J. Suhara, Tetsuya Higuchi, Makoto TI Multimodal Imaging for DREADD-Expressing Neurons in Living Brain and Their Application to Implantation of iPSC-Derived Neural Progenitors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cell replacement therapy; clozapine-N-oxide (CNO); designer receptor exclusively activated by designer drugs (DREADD); induced pluripotent stem cell (iPSC); positron emission tomography (PET) ID SPINAL-CORD-INJURY; PLURIPOTENT STEM-CELLS; PROTEIN-COUPLED RECEPTORS; CENTRAL-NERVOUS-SYSTEM; CLOZAPINE-N-OXIDE; PARKINSONS-DISEASE; MOUSE MODEL; IN-VIVO; CANNABINOID RECEPTORS; MUSCARINIC RECEPTORS AB Chemogenetic manipulation of neuronal activities has been enabled by a designer receptor (designer receptor exclusively activated by designer drugs, DREADD) that is activated exclusively by clozapine-N-oxide (CNO). Here, we applied CNO as a functional reporter probe to positron emission tomography (PET) of DREADD in living brains. Mutant human M4 DREADD (hM4Di) expressed in transgenic (Tg) mouse neurons was visualized by PET with microdose [C-11] CNO. Deactivation of DREADD-expressing neurons in these mice by nonradioactive CNO at a pharmacological dose could also be captured by arterial spin labeling MRI (ASL-MRI). Neural progenitors derived from hM4Di Tg-induced pluripotent stem cells were then implanted into WT mouse brains and neuronal differentiation of the grafts could be imaged by [C-11] CNO-PET. Finally, ASL-MRI captured chemogenetic functional manipulation of the graft neurons. Our data provide the first demonstration of multimodal molecular/functional imaging of cells expressing a functional gene reporter in the brain, which would be translatable to humans for therapeutic gene transfers and cell replacements. C1 [Ji, Bin; Kaneko, Hiroyuki; Minamimoto, Takafumi; Seki, Chie; Ono, Maiko; Tokunaga, Masaki; Shin, Ryong-Moon; Minamihisamatsu, Takeharu; Suhara, Tetsuya; Higuchi, Makoto] Natl Inst Quantum & Radiol Sci & Technol, Dept Funct Brain Imaging Res, Chiba 2638555, Japan. [Kumata, Katsushi; Zhang, Ming-Rong] Natl Inst Quantum & Radiol Sci & Technol, Dept Radiopharmaceut Dev, Chiba 2638555, Japan. [Aoki, Ichio] Natl Inst Quantum & Radiol Sci & Technol, Dept Mol Imaging & Theranost, Chiba 2638555, Japan. [Tsukamoto, Satoshi; Kito, Seiji] Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Lab Anim & Genome Sci Sect, Chiba 2638555, Japan. [Inoue, Haruhisa; Takeuchi, Hiroki; Tanabe, Koji] Kyoto Univ, Ctr iPS Cell Res & Applicat CiRA, Kyoto, Kyoto 6068507, Japan. [Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ji, Bin; Inoue, Haruhisa; Suhara, Tetsuya; Higuchi, Makoto] Japan Sci & Technol Agcy JST, CREST, Kawaguchi, Saitama 3320012, Japan. RP Higuchi, M (reprint author), Natl Inst Radiol Sci, Mol Imaging Ctr, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. EM mhiguchi@nirs.go.jp OI Aoki, Ichio/0000-0002-4429-5053; Ji, BIn/0000-0002-9672-6441; Minamimoto, Takafumi/0000-0003-4305-0174 FU Ministry of Education, Culture, Sports, Science and Technology, Japan [23111009]; Japan Agency for Medical Research and Development [14533254]; JST Yamanaka iPS Cell Special Project; CREST FX This work was supported by Grants-in-Aid for the Japan Advanced Molecular Imaging Program and Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan ("Brain Environment" 23111009 to M.H.), for Brain Mapping by Integrated Neurotechnologies for Disease Studies from the Japan Agency for Medical Research and Development (Grant 14533254 to M.H.), the JST Yamanaka iPS Cell Special Project (H.I.), and CREST (H.I. and T.S.). NR 52 TC 0 Z9 0 U1 1 U2 1 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 NOV 9 PY 2016 VL 36 IS 45 BP 11544 EP 11558 DI 10.1523/JNEUROSCI.1279-16.2016 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EG5AC UT WOS:000391054300020 PM 27911758 ER PT J AU Saxena, P He, L Malyutin, A Datta, SAK Rein, A Bond, KM Jarrold, MF Spilotros, A Svergun, D Douglas, T Dragnea, B AF Saxena, Pooja He, Li Malyutin, Andrey Datta, Siddhartha A. K. Rein, Alan Bond, Kevin M. Jarrold, Martin F. Spilotros, Alessandro Svergun, Dmitri Douglas, Trevor Dragnea, Bogdan TI Virus Matryoshka: A Bacteriophage Particle-Guided Molecular Assembly Approach to a Monodisperse Model of the Immature Human Immunodeficiency Virus SO SMALL LA English DT Article ID DETECTION MASS-SPECTROMETRY; IN-VITRO; CRYOELECTRON MICROSCOPY; GAG PROTEIN; SPHERICAL CRYSTALLOGRAPHY; BIOLOGICAL MACROMOLECULES; RETROVIRUS PARTICLES; HIV-1 MORPHOGENESIS; ANGSTROM RESOLUTION; SOLUTION SCATTERING AB Immature human immunodeficiency virus type 1 (HIV-1) is approximately spherical, but is constructed from a hexagonal lattice of the Gag protein. As a hexagonal lattice is necessarily flat, the local symmetry cannot be maintained throughout the structure. This geometrical frustration presumably results in bending stress. In natural particles, the stress is relieved by incorporation of packing defects, but the magnitude of this stress and its significance for the particles is not known. In order to control this stress, we have now assembled the Gag protein on a quasi-spherical template derived from bacteriophage P22. This template is monodisperse in size and electron-transparent, enabling the use of cryo-electron microscopy in structural studies. These templated assemblies are far less polydisperse than any previously described virus-like particles (and, while constructed according to the same lattice as natural particles, contain almost no packing defects). This system gives us the ability to study the relationship between packing defects, curvature and elastic energy, and thermodynamic stability. As Gag is bound to the P22 template by single-stranded DNA, treatment of the particles with DNase enabled us to determine the intrinsic radius of curvature of a Gag lattice, unconstrained by DNA or a template. We found that this intrinsic radius is far larger than that of a virion or P22-templated particle. We conclude that Gag is under elastic strain in a particle; this has important implications for the kinetics of shell growth, the stability of the shell, and the type of defects it will assume as it grows. C1 [Saxena, Pooja; Malyutin, Andrey; Bond, Kevin M.; Jarrold, Martin F.; Douglas, Trevor; Dragnea, Bogdan] Indiana Univ, Dept Chem, 800 E Kirkwood Ave, Bloomington, IN 47405 USA. [He, Li] Indiana Univ, Dept Mol & Cellular Biochem, Bloomington, IN 47405 USA. [Datta, Siddhartha A. K.; Rein, Alan] NCI, POB B,Bldg 535, Frederick, MD 21702 USA. [Spilotros, Alessandro; Svergun, Dmitri] European Mol Biol Lab DESY, Notkestr 85,Geb 25a, D-22603 Hamburg, Germany. RP Dragnea, B (reprint author), Indiana Univ, Dept Chem, 800 E Kirkwood Ave, Bloomington, IN 47405 USA. EM dragnea@indiana.edu RI Douglas, Trevor/F-2748-2011 FU Human Frontier Science Program [RGP0017/2012]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; U.S. Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0010507] FX P.S. and L.H. contributed equally to this work. The authors gratefully acknowledge Dr. John A. G. Briggs (European Molecular Biology Laboratory, Heidelberg, Germany) and Dr. Peter E. Prevelige Jr. (Department of Microbiology, University of Alabama, Birmingham, USA) for insightful discussions on this project. The IU Nanoscale Characterization Facility is thanked for access to instrumentation. This work was supported by the Human Frontier Science Program research grant RGP0017/2012 (to B.D., A.R., D.S., and Dr. Paul van der Schoot, Technische Universiteit Eindhoven, The Netherlands) for work on cryo-EM, SAXS, molecular biology and numerical simulations; by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to A.R.); and by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, under award DE-SC0010507 (to B.D.) for work on data processing algorithms. NR 69 TC 0 Z9 0 U1 7 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD NOV 9 PY 2016 VL 12 IS 42 BP 5862 EP 5872 DI 10.1002/smll.201601712 PG 11 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 EE2HF UT WOS:000389403900008 ER PT J AU Sun, W Weingarten, RA Xu, M Southall, N Dai, S Shinn, P Sanderson, PE Williamson, PR Frank, KM Zheng, W AF Sun, Wei Weingarten, Rebecca A. Xu, Miao Southall, Noel Dai, Sheng Shinn, Paul Sanderson, Philip E. Williamson, Peter R. Frank, Karen M. Zheng, Wei TI Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria SO EMERGING MICROBES & INFECTIONS LA English DT Article DE antimicrobial susceptibility testing; drug repositioning; drug repurposing; Klebsiella pneumoniae; multidrug-resistant bacteria; targeted drug combination; ultra-high-throughput screen ID ACINETOBACTER-BAUMANNII; ANTIBIOTIC-RESISTANCE; CYSTIC-FIBROSIS; CLINICAL-TRIAL; INFECTIONS; THERAPY; PNEUMONIAE; MECHANISMS; CHALLENGES; DISCOVERY AB Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pneumoniae. To further improve the efficacy and reduce the effective drug concentrations, we applied a targeted drug combination approach that integrates drugs' clinical antimicrobial susceptibility breakpoints, achievable plasma concentrations, clinical toxicities and mechanisms of action to identify optimal drug combinations. Three sets of three-drug combinations were identified with broad-spectrum activities against 10 MDR clinical isolates including K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Colistin-auranofin-ceftazidime and colistin-auranofin- rifabutin suppressed > 80% growth of all 10 MDR strains; while rifabutin-colistin-imipenem inhibited > 75% of these strains except two Acinetobacter baumannii isolates. The results demonstrate this new assay has potential as a real-time method to identify new drugs and effective drug combinations to combat severe clinical infections with MDR organisms. C1 [Sun, Wei; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E.; Zheng, Wei] Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20892 USA. [Weingarten, Rebecca A.; Frank, Karen M.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20892 USA.; Frank, KM (reprint author), NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA.; Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov; karen.frank@nih.gov; wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of National Center for Advancing Translational Sciences, National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA FX We thank the compound management group at National Center for Advancing Translational Sciences, National Institutes of Health (NM), for their professional support. We also thank the clinical microbiology laboratory technologists at the National Institutes of Health Clinical Center for preparing and testing patient isolates. This work was supported by the Intramural Research Program of National Center for Advancing Translational Sciences, National Institutes of Health Clinical Center, and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NR 50 TC 0 Z9 0 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2222-1751 J9 EMERG MICROBES INFEC JI Emerg. Microbes Infect. PD NOV 9 PY 2016 VL 5 AR e116 DI 10.1038/emi.2016.123 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA EC8XP UT WOS:000388426700004 PM 27826141 ER PT J AU Hensch, NR Karim, ZA Druey, KM Tansey, MG Khasawneh, FT AF Hensch, Nicole R. Karim, Zubair A. Druey, Kirk M. Tansey, Malu G. Khasawneh, Fadi T. TI RGS10 Negatively Regulates Platelet Activation and Thrombogenesis SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; OUTSIDE-IN; THROMBUS FORMATION; VASCULAR INJURY; KAPPA-B; AGONISTS; PHOSPHORYLATION; SECRETION; NEURONS; COMPLEX AB Regulators of G protein signaling (RGS) proteins act as GTPase activating proteins to negatively regulate G protein-coupled receptor (GPCR) signaling. Although several RGS proteins including RGS2, RGS16, RGS10, and RGS18 are expressed in human and mouse platelets, the respective unique function(s) of each have not been fully delineated. RGS10 is a member of the D/R12 subfamily of RGS proteins and is expressed in microglia, macrophages, megakaryocytes, and platelets. We used a genetic approach to examine the role (s) of RGS10 in platelet activation in vitro and hemostasis and thrombosis in vivo. GPCRinduced aggregation, secretion, and integrin activation was much more pronounced in platelets from Rgs10(-/-) mice relative to wild type (WT). Accordingly, these mice had markedly reduced bleeding times and were more susceptible to vascular injury-associated thrombus formation than control mice. These findings suggest a unique, non-redundant role of RGS10 in modulating the hemostatic and thrombotic functions of platelets in mice. RGS10 thus represents a potential therapeutic target to control platelet activity and/or hypercoagulable states. C1 [Hensch, Nicole R.; Karim, Zubair A.; Khasawneh, Fadi T.] Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Pomona, CA 91766 USA. [Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11S244B, Bethesda, MD 20892 USA. [Tansey, Malu G.] Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA. [Karim, Zubair A.; Khasawneh, Fadi T.] Univ Texas El Paso, Sch Pharm, Dept Pharmaceut Sci, 1101 N Campbell St, El Paso, TX 79902 USA. RP Khasawneh, FT (reprint author), Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Pomona, CA 91766 USA.; Khasawneh, FT (reprint author), Univ Texas El Paso, Sch Pharm, Dept Pharmaceut Sci, 1101 N Campbell St, El Paso, TX 79902 USA. EM khasawneh@westemu.edu FU College of Pharmacy, Western University of Health Sciences, Pomona, CA FX This work was supported by funds from the College of Pharmacy, Western University of Health Sciences, Pomona, CA (to F.T.K.). NR 34 TC 0 Z9 0 U1 0 U2 0 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 NOV 9 PY 2016 VL 11 IS 11 AR e0165984 DI 10.1371/journal.pone.0165984 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9OG UT WOS:000387724300071 PM 27829061 ER PT J AU Walther, S Tietze, M Czerny, CP Konig, S Diesterbeck, US AF Walther, Stefanie Tietze, Manfred Czerny, Claus-Peter Koenig, Sven Diesterbeck, Ulrike S. TI Development of a Bioinformatics Framework for the Detection of Gene Conversion and the Analysis of Combinatorial Diversity in Immunoglobulin Heavy Chains in Four Cattle Breeds SO PLOS ONE LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; COMPLEMENTARITY-DETERMINING REGION-3; BOVINE IGG REPERTOIRE; V-H FAMILY; VARIABLE REGION; SOMATIC DIVERSIFICATION; ANTIBODY DIVERSITY; CHICKEN; GERMLINE; LOCUS AB We have developed a new bioinformatics framework for the analysis of rearranged bovine heavy chain immunoglobulin (Ig) variable regions by combining and refining widely used alignment algorithms. This bioinformatics framework allowed us to investigate alignments of heavy chain framework regions (FRHs) and the separate alignments of FRHs and heavy chain complementarity determining regions (CDRHs) to determine their germline origin in the four cattle breeds Aubrac, German Black Pied, German Simmental, and Holstein Friesian. Now it is also possible to specifically analyze Ig heavy chains possessing exceptionally long CDR3Hs. In order to gain more insight into breed specific differences in Ig combinatorial diversity, somatic hypermutations and putative gene conversions of IgG, we compared the dominantly transcribed variable (IGHV), diversity (IGHD), and joining (IGHJ) segments and their recombination in the four cattle breeds. The analysis revealed the use of 15 different IGHV segments, 21 IGHD segments, and two IGHJ segments with significant different transcription levels within the breeds. Furthermore, there are preferred rearrangements within the three groups of CDR3H lengths. In the sequences of group 2 (CDR3H lengths (L) of 11-47 amino acid residues (aa)) a higher number of recombination was observed than in sequences of group 1 (L <= 10 aa) and 3 (L >= 48 aa). The combinatorial diversity of germline IGHV, IGHD, and IGHJ-segments revealed 162 rearrangements that were significantly different. The few preferably rearranged gene segments within group 3 CDR3H regions may indicate specialized antibodies because this length is unique in cattle. The most important finding of this study, which was enabled by using the bioinformatics framework, is the discovery of strong evidence for gene conversion as a rare event using pseudogenes fulfilling all definitions for this particular diversification mechanism. C1 [Walther, Stefanie; Czerny, Claus-Peter; Diesterbeck, Ulrike S.] Georg August Univ Goettingen, Inst Vet Med, Fac Agr Sci, Dept Anim Sci,Div Microbiol & Anim Hyg, Gottingen, Germany. [Tietze, Manfred; Koenig, Sven] Univ Kassel, Dept Anim Breeding, Witzenhausen, Germany. [Diesterbeck, Ulrike S.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Diesterbeck, US (reprint author), Georg August Univ Goettingen, Inst Vet Med, Fac Agr Sci, Dept Anim Sci,Div Microbiol & Anim Hyg, Gottingen, Germany.; Diesterbeck, US (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM ulrike.diesterbeck@nih.gov FU Georg-August University Goettingen [GAUGIVM9100010893]; German Research Foundation (DFG); Open Access Publication Funds of the Gottingen University FX Stefanie Walther was supported by a scholarship provided by the Georg-August University Goettingen (GAUGIVM9100010893). We acknowledge support by the German Research Foundation (DFG) and the Open Access Publication Funds of the Gottingen University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 0 Z9 0 U1 9 U2 9 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 NOV 9 PY 2016 VL 11 IS 11 AR e0164567 DI 10.1371/journal.pone.0164567 PG 31 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9OG UT WOS:000387724300018 PM 27828971 ER PT J AU Dinh, L Chowell, G Mizumoto, K Nishiura, H AF Dinh, Linh Chowell, Gerardo Mizumoto, Kenji Nishiura, Hiroshi TI Estimating the subcritical transmissibility of the Zika outbreak in the State of Florida, USA, 2016 SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Article DE Prediction; Zika virus; Epidemic; Mathematical model; Basic reproduction number ID EPIDEMIC AB Background: Florida State has reported autochthonous transmission of Zika virus since late July 2016. Here we assessed the transmissibility associated with the outbreak and generated a short-term forecast. Methods: Time-dependent dynamics of imported cases reported in the state of Florida was approximated by a logistic growth equation. We estimated the reproduction number using the renewal equation in order to predict the incidence of local cases arising from both local and imported primary cases. Using a bootstrap method together with the logistic and renewal equations, a short-term forecast of local and imported cases was carried out. Results: The reproduction number was estimated at 0.16 (95 % Confidence Interval: 0.13, 0.19). Employing the logistic equation to capture a drastic decline in the number of imported cases expected through the course of 2016, together with the low estimate of the local reproduction number in Florida, the expected number of local reported cases was demonstrated to show an evident declining trend for the remainder of 2016. Conclusions: The risk of local transmission in the state of Florida is predicted to dramatically decline by the end of 2016. C1 [Dinh, Linh; Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, 1 Pk Pl, Atlanta, GA 30303 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Mizumoto, Kenji; Nishiura, Hiroshi] Hokkaido Univ, Grad Sch Med, Kita Ku, Kita 15 Jo Nishi 7 Chome, Sapporo, Hokkaido 0608638, Japan. [Mizumoto, Kenji; Nishiura, Hiroshi] Japan Sci & Technol Agcy, CREST, 4-1-8,Honcho, Kawaguchi, Saitama 3320012, Japan. RP Nishiura, H (reprint author), Hokkaido Univ, Grad Sch Med, Kita Ku, Kita 15 Jo Nishi 7 Chome, Sapporo, Hokkaido 0608638, Japan.; Nishiura, H (reprint author), Japan Sci & Technol Agcy, CREST, 4-1-8,Honcho, Kawaguchi, Saitama 3320012, Japan. EM nishiurah@med.hokudai.ac.jp FU Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [16KT0130, 16 K15356, 26700028]; Program for Advancing Strategic International Networks; Japan Science and Technology Agency (JST) CREST program; RISTEX program for Science of Science, Technology and Innovation Policy; NSF [1414374]; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1]; NSF-IIS RAPID [1518939]; NSF: Small: Data Management for Real-Time Data Driven Epidemic simulation [1318788 III]; Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health FX HN received funding support from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 16KT0130, 16 K15356 and 26700028, Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, the Japan Science and Technology Agency (JST) CREST program and RISTEX program for Science of Science, Technology and Innovation Policy. GC acknowledges financial support from the NSF grant 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program; UK Biotechnology and Biological Sciences Research Council grant BB/M008894/1, NSF-IIS RAPID award # 1518939, and NSF grant 1318788 III: Small: Data Management for Real-Time Data Driven Epidemic simulation, and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 12 TC 1 Z9 1 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD NOV 9 PY 2016 VL 13 AR 20 DI 10.1186/s12976-016-0046-1 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA EC2EJ UT WOS:000387922200001 PM 27829439 ER PT J AU Bielekova, B Tintore, M AF Bielekova, Bibiana Tintore, Mar TI Sustained reduction of MS disability New player in comparing disease-modifying treatments SO NEUROLOGY LA English DT Editorial Material ID REMITTING MULTIPLE-SCLEROSIS; CONTROLLED PHASE-3 TRIAL; ALEMTUZUMAB; INFLAMMATION C1 [Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Tintore, Mar] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Dept Neurol Neuroimmunol, Ctr Esclerosi Multiple Catalunya Cemcat, E-08193 Barcelona, Spain. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU intramural research program of the National Institute of Neurologic Disorders and Stroke FX The work of Dr. Bielekova was supported by the intramural research program of the National Institute of Neurologic Disorders and Stroke. NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 8 PY 2016 VL 87 IS 19 BP 1966 EP 1967 DI 10.1212/WNL.0000000000003314 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JP UT WOS:000392233600006 PM 27733564 ER PT J AU Nadkarni, NK Boudreau, RM Studenski, SA Lopez, OL Liu, G Kritchevsky, S Yaffe, K Newman, AB Rosano, C AF Nadkarni, Neelesh K. Boudreau, Robert M. Studenski, Stephanie A. Lopez, Oscar L. Liu, Ge Kritchevsky, Stephen Yaffe, Kristine Newman, Anne B. Rosano, Caterina TI Slow gait, white matter characteristics, and prior 10-year interleukin-6 levels in older adults SO NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; INFLAMMATORY MARKERS; CARDIOVASCULAR HEALTH; PHYSICAL PERFORMANCE; MR-IMAGES; DECLINE; BRAIN; HYPERINTENSITIES; DIFFUSION; MOBILITY AB Objective: To examine the relationship between gait speed and prior 10 years interleukin-6 (IL-6) burden in older adults. We then assessed whether white matter characteristics influence this relationship. Methods: In 179 community-dwelling older adults, gait speed was assessed on an automated walkway and serum IL-6 was assayed on ELISA. Concurrently, white matter characteristics were assessed on MRI by quantifying volume of white matter hyperintensities (WMH), a marker of small vessel disease, and normal-appearing white matter on fractional anisotropy (NAWM-FA), a marker of axonal integrity. IL-6 was assayed at regular intervals at gait assessment and over the prior 10 years and estimates of sustained 10-year IL-6 exposure and the rate of change in IL-6 over 10 years were obtained. Multivariate linear regressions were used to examine the relationships among sustained IL-6 exposure, rate of change in IL-6, gait speed, and white matter characteristics. Results: In this sample (age 83 years, 58% female, 41% black, gait speed 0.9 m/s), higher sustained IL-6 levels, but not the rate of change in IL-6 or IL-6 at gait assessment, was significantly related to slower gait (beta = -20.27, p < 0.001) and to higher WMH (beta = 0.23, p = 0.002), but not NAWM-FA, withstanding covariate adjustments. WMH accounted for 30% attenuation in the relationship between higher sustained IL-6 levels and slower gait speed (p = 0.043) in the mediation analyses. Conclusions: Sustained exposure to high IL-6 over 10 years rather than the rate of change in IL-6 or an isolated high IL-6 level may adversely affect gait speed by influencing cerebral WMH. C1 [Nadkarni, Neelesh K.] Univ Pittsburgh, Div Geriatr Med & Gerontol, Dept Med, Sch Med, Pittsburgh, PA 15260 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15260 USA. [Nadkarni, Neelesh K.; Lopez, Oscar L.] Univ Pittsburgh, Pittsburgh Alzheimers Dis Res Ctr, Sch Med, Pittsburgh, PA 15260 USA. [Boudreau, Robert M.; Liu, Ge; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Kritchevsky, Stephen] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Nadkarni, NK (reprint author), Univ Pittsburgh, Div Geriatr Med & Gerontol, Dept Med, Sch Med, Pittsburgh, PA 15260 USA.; Nadkarni, NK (reprint author), Univ Pittsburgh, Pittsburgh Alzheimers Dis Res Ctr, Sch Med, Pittsburgh, PA 15260 USA. EM nkn3@pitt.edu FU National Institute on Aging [K23AG049945, R01AG029232, N01AG62101, N01AG62103, N01AG 62106]; Intramural Research Program of the NIH; Pittsburgh Pepper Center [P30 AG024827]; Pittsburgh Alzheimer's Disease Research Center [P50 AG005133] FX This research was supported by National Institute on Aging awards K23AG049945, R01AG029232, N01AG62101, N01AG62103, and N01AG 62106; the Intramural Research Program of the NIH; the Pittsburgh Pepper Center (P30 AG024827); and the Pittsburgh Alzheimer's Disease Research Center (P50 AG005133). NR 40 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 8 PY 2016 VL 87 IS 19 BP 1993 EP 1999 DI 10.1212/WNL.0000000000003304 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JP UT WOS:000392233600010 PM 27733566 ER PT J AU Luoni, A Massart, R Nieratschker, V Nemoda, Z Blasi, G Gilles, M Witt, SH Suderman, MJ Suomi, SJ Porcelli, A Rizzo, G Fazio, L Torretta, S Rampino, A Berry, A Gass, P Cirulli, F Rietschel, M Bertolino, A Deuschle, M Szyf, M Riva, MA AF Luoni, A. Massart, R. Nieratschker, V. Nemoda, Z. Blasi, G. Gilles, M. Witt, S. H. Suderman, M. J. Suomi, S. J. Porcelli, A. Rizzo, G. Fazio, L. Torretta, S. Rampino, A. Berry, A. Gass, P. Cirulli, F. Rietschel, M. Bertolino, A. Deuschle, M. Szyf, M. Riva, M. A. TI Ankyrin-3 as a molecular marker of early-life stress and vulnerability to psychiatric disorders SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CONVERGENT FUNCTIONAL GENOMICS; DNA METHYLATION; BIPOLAR DISORDER; PREFRONTAL CORTEX; WORKING-MEMORY; POSTSYNAPTIC DENSITY; PRENATAL STRESS; NEUROPSYCHIATRIC DISORDERS; ASSOCIATION ANALYSIS; BRAIN-DEVELOPMENT AB Exposure to early-life stress (ELS) may heighten the risk for psychopathology at adulthood. Here, in order to identify common genes that may keep the memory of ELS through changes in their methylation status, we intersected methylome analyses performed in different tissues and time points in rats, non-human primates and humans, all characterized by ELS. We identified Ankyrin-3 (Ank3), a scaffolding protein with a strong genetic association for psychiatric disorders, as a gene persistently affected by stress exposure. In rats, Ank3 methylation and mRNA changes displayed a specific temporal profile during the postnatal development. Moreover, exposure to prenatal stress altered the interaction of ankyrin-G, the protein encoded by Ank3 enriched in the post-synaptic compartment, with PSD95. Notably, to model in humans a gene by early stress interplay on brain phenotypes during cognitive performance, we demonstrated an interaction between functional variation in Ank3 gene and obstetric complications on working memory in healthy adult subjects. Our data suggest that alterations of Ank3 expression and function may contribute to the effects of ELS on the development of psychiatric disorders. C1 [Luoni, A.; Riva, M. A.] Univ Milan, Dept Pharmacol & Biomol Sci, Via Balzaretti 9, I-20133 Milan, Italy. [Massart, R.; Nemoda, Z.; Suderman, M. J.; Szyf, M.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. [Nieratschker, V.; Witt, S. H.; Rietschel, M.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Nieratschker, V.] Univ Tubingen, Dept Psychiat & Psychotherapy, Tubingen, Germany. [Nemoda, Z.; Suderman, M. J.; Szyf, M.] McGill Univ, Sackler Inst Epigenet & Psychobiol, Montreal, PQ, Canada. [Blasi, G.; Porcelli, A.; Rizzo, G.; Fazio, L.; Torretta, S.; Rampino, A.; Bertolino, A.] Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy. [Gilles, M.; Gass, P.; Deuschle, M.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany. [Suderman, M. J.] McGill Univ, McGill Ctr Bioinformat, Montreal, PQ, Canada. [Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Bethesda, MD USA. [Berry, A.; Cirulli, F.] Ist Super Sanita, Dept Cell Biol & Neurosci, Rome, Italy. RP Riva, MA (reprint author), Univ Milan, Dept Pharmacol & Biomol Sci, Via Balzaretti 9, I-20133 Milan, Italy. EM M.Riva@unimi.it OI Blasi, Giuseppe/0000-0003-0878-1131 FU ERANET Neuron grant; Italian Ministry of University and Research (PRIN) [20107MSMA4_002]; Fondazione CARIPLO [2012-0503]; Dietmar Hopp Foundation; Olympia-Morata-Programme of the University of Heidelberg; Boehringer-Ingelheim Fonds; Fondazione Umberto Veronesi Fellowship; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme; Canadian Institute of Health Research [MOP-42411] FX This work was supported by an ERANET Neuron grant to MD, MS, MAR and PG, as well as by grants from the Italian Ministry of University and Research to MAR (PRIN - grant number 20107MSMA4_002) and from Fondazione CARIPLO (grant number 2012-0503) to MAR, FC and A Bertolino. In addition, characterization of the human cohort was supported by a grant of the Dietmar Hopp Foundation. VN received support from the Olympia-Morata-Programme of the University of Heidelberg and the Boehringer-Ingelheim Fonds. AL was supported by a Fondazione Umberto Veronesi Fellowship. ZN was supported by Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. Work in MS's laboratory was supported by Canadian Institute of Health Research Grant MOP-42411. We are grateful to Elisa Zianni and Dr Jennifer Stanic for the help with co-immunoprecipitation. NR 83 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD NOV 8 PY 2016 VL 6 AR e943 DI 10.1038/tp.2016.211 PG 9 WC Psychiatry SC Psychiatry GA EI0AD UT WOS:000392132700004 PM 27824361 ER PT J AU Marusak, HA Thomason, ME Peters, C Zundel, C Elrahal, F Rabinak, CA AF Marusak, H. A. Thomason, M. E. Peters, C. Zundel, C. Elrahal, F. Rabinak, C. A. TI You say 'prefrontal cortex' and I say 'anterior cingulate': meta-analysis of spatial overlap in amygdala-to-prefrontal connectivity and internalizing symptomology SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; GENERALIZED ANXIETY DISORDER; FUNCTIONAL CONNECTIVITY; BIPOLAR DISORDER; NETWORK; ACTIVATION; MATTER; BRAIN; SCALE; SPECIALIZATION AB Connections between the amygdala and medial prefrontal cortex (mPFC) are considered critical for the expression and regulation of emotional behavior. Abnormalities in frontoamygdala circuitry are reported across several internalizing conditions and associated risk factors (for example, childhood trauma), which may underlie the strong phenotypic overlap and co-occurrence of internalizing conditions. However, it is unclear if these findings converge on the same localized areas of mPFC or adjacent anterior cingulate cortex (ACC). Examining 46 resting-state functional connectivity magnetic resonance imaging studies of internalizing conditions or risk factors (for example, early adversity and family history), we conducted an activation likelihood estimation meta-analysis of frontoamygdala circuitry. We included all reported amygdala to frontal coordinate locations that fell within a liberal anatomically defined frontal mask. Peak effects across studies were centered in two focal subareas of the ACC: pregenual (pgACC) and subgenual (sgACC). Using publicly available maps and databases of healthy individuals, we found that observed subareas have unique connectivity profiles, patterns of neural co-activation across a range of neuropsychological tasks, and distribution of tasks spanning various behavioral domains within peak regions, also known as 'functional fingerprints'. These results suggest disruptions in unique amygdala-ACC subcircuits across internalizing, genetic and environmental risk studies. Based on functional characterizations and the studies contributing to each peak, observed amygdala-ACC subcircuits may reflect separate transdiagnostic neural signatures. In particular, they may reflect common neurobiological substrates involved in developmental risk (sgACC), or the broad expression of emotional psychopathology (pgACC) across disease boundaries. C1 [Marusak, H. A.; Peters, C.; Elrahal, F.; Rabinak, C. A.] Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48202 USA. [Thomason, M. E.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA. [Thomason, M. E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Thomason, M. E.] NICHD, Unit Perinatal Neural Connect, Perinatol Res Branch, NIH,DHHS, Bethesda, MD USA. [Zundel, C.] Boston Univ, Behav Neurosci, Boston, MA 02215 USA. RP Marusak, HA (reprint author), Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48202 USA. EM hmarusak@med.wayne.edu FU American Cancer Society award [129368-PF-16-057-01-PCSM]; National Institutes of Health (NIH) National Institute of Mental Health [K01 MH101123]; NIH National Institute of Environmental Health Sciences [P30 ES020957, R21 ES026022]; NIH National Institute of Mental Health [R01 MH110793] FX Dr Marusak is supported by American Cancer Society award 129368-PF-16-057-01-PCSM. Dr Rabinak is supported by National Institutes of Health (NIH) National Institute of Mental Health award K01 MH101123. Dr Thomason is supported by NIH National Institute of Environmental Health Sciences awards P30 ES020957 and R21 ES026022, and NIH National Institute of Mental Health award R01 MH110793. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and design to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 54 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD NOV 8 PY 2016 VL 6 AR e944 DI 10.1038/tp.2016.218 PG 10 WC Psychiatry SC Psychiatry GA EI0AD UT WOS:000392132700005 PM 27824358 ER PT J AU Carlson, VR Sheehan, FT Boden, BP AF Carlson, Victor R. Sheehan, Frances T. Boden, Barry P. TI VIDEO ANALYSIS OF ANTERIOR CRUCIATE LIGAMENT (ACL) INJURIES A Systematic Review SO JBJS REVIEWS LA English DT Article ID FEMALE TEAM HANDBALL; TIBIAL PLATEAU; BONE CONTUSION; SAGITTAL PLANE; PROFESSIONAL FOOTBALL; VALGUS COLLAPSE; KNEE KINEMATICS; RISK-FACTORS; MECHANISMS; PREVENTION AB Background: As the most viable method for investigating in vivo anterior cruciate ligament (ACL) rupture, video analysis is critical for understanding ACL injury mechanisms and advancing preventative training programs. Despite the limited number of published studies involving video analysis, much has been gained through evaluating actual injury scenarios. Methods: Studies meeting criteria for this systematic review were collected by performing a broad search of the ACL literature with use of variations and combinations of video recordings and ACL injuries. Both descriptive and analytical studies were included. Results: Descriptive studies have identified specific conditions that increase the likelihood of an ACL injury. These conditions include close proximity to opposing players or other perturbations, high shoe-surface friction, and landing on the heel or the flat portion of the foot. Analytical studies have identified high-risk joint angles on landing, such as a combination of decreased ankle plantar flexion, decreased knee flexion, and increased hip flexion. Conclusions: The high-risk landing position appears to influence the likelihood of ACL injury to a much greater extent than inherent risk factors. As such, on the basis of the results of video analysis, preventative training should be applied broadly. Kinematic data from video analysis have provided insights into the dominant forces that are responsible for the injury (i.e., axial compression with potential contributions from quadriceps contraction and valgus loading). With the advances in video technology currently underway, video analysis will likely lead to enhanced understanding of non-contact ACL injury. C1 [Carlson, Victor R.; Sheehan, Frances T.; Boden, Barry P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Carlson, Victor R.; Sheehan, Frances T.] NIH, Funct & Appl Biomech, Bldg 10, Bethesda, MD 20892 USA. [Boden, Barry P.] Orthopaed Ctr, Rockville, MD USA. RP Sheehan, FT (reprint author), NIH, Funct & Appl Biomech, Bldg 10, Bethesda, MD 20892 USA. EM gavellif@cc.nih.gov FU National Institutes of Health (NIH), Clinical Center, Functional and Applied Biomechanics Section; NIH FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Clinical Center, Functional and Applied Biomechanics Section. This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, the Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, visit the website at http://fnih.org. The authors also thank informationist Judith Welsh, NIH Library, for editing this manuscript. NR 66 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2329-9185 J9 JBJS REV JI JBJS Rev. PD NOV 8 PY 2016 VL 4 IS 11 AR e5 DI 10.2106/JBJS.RVW.15.00116 PG 12 WC Surgery SC Surgery GA EG4SN UT WOS:000391034100005 ER PT J AU Lin, WHW Nish, SA Yen, B Chen, YH Adams, WC Kratchmarov, R Rothman, NJ Bhandoola, A Xue, HH Reiner, SL AF Lin, Wen-Hsuan W. Nish, Simone A. Yen, Bonnie Chen, Yen-Hua Adams, William C. Kratchmarov, Radomir Rothman, Nyanza J. Bhandoola, Avinash Xue, Hai-Hui Reiner, Steven L. TI CD8(+) T Lymphocyte Self-Renewal during Effector Cell Determination SO CELL REPORTS LA English DT Article ID DNA METHYLATION; VIRAL-INFECTION; MEMORY; DIFFERENTIATION; DIVISION; SPECIFICATION; TCF-1; FATES; ACTIVATION; EXPRESSION AB Selected CD8(+) T cells must divide, produce differentiated effector cells, and self-renew, often repeatedly. We now show that silencing expression of the transcription factor TCF1 marks loss of self-renewal by determined effector cells and that this requires cell division. In acute infections, the first three CD8(+) T cell divisions produce daughter cells with unequal proliferative signaling but uniform maintenance of TCF1 expression. The more quiescent initial daughter cells resemble canonical central memory cells. The more proliferative, effector-prone cells from initial divisions can subsequently undergo division-dependent production of a TCF1-negative effector daughter cell along with a self-renewing TCF1-positive daughter cell, the latter also contributing to the memory cell pool upon resolution of infection. Self-renewal in the face of effector cell determination may promote clonal amplification and memory cell formation in acute infections, sustain effector regeneration during persistent subclinical infections, and be rate limiting, but remediable, in chronic active infections and cancer. C1 [Lin, Wen-Hsuan W.; Nish, Simone A.; Yen, Bonnie; Chen, Yen-Hua; Adams, William C.; Kratchmarov, Radomir; Rothman, Nyanza J.; Reiner, Steven L.] Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA. [Lin, Wen-Hsuan W.; Nish, Simone A.; Yen, Bonnie; Chen, Yen-Hua; Adams, William C.; Kratchmarov, Radomir; Rothman, Nyanza J.; Reiner, Steven L.] Columbia Univ, Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA. [Bhandoola, Avinash] NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. [Xue, Hai-Hui] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. RP Reiner, SL (reprint author), Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA.; Reiner, SL (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA. EM sr2978@cumc.columbia.edu FU NIH [AI061699, AI113365, AI076458, AI112579, AI115149, AI119160, AI121080]; U.S. Department of Veteran Affairs Merit Review Award [I01 BX002903]; Charles H. Revson Foundation FX We are grateful to E.J. Wherry (University of Pennsylvania) for advice and reagents. This study was supported by NIH grants AI061699, AI113365, and AI076458 (to S.L.R.), AI112579, AI115149, AI119160, and AI121080 (to H.-H.X.); the U.S. Department of Veteran Affairs Merit Review Award I01 BX002903 (to H.-H.X.); and the Charles H. Revson Foundation. NR 34 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 8 PY 2016 VL 17 IS 7 BP 1773 EP 1782 DI 10.1016/j.celrep.2016.10.032 PG 10 WC Cell Biology SC Cell Biology GA EF7YS UT WOS:000390545900008 PM 27829149 ER PT J AU Zheng, XF Yang, PY Lackford, B Bennett, BD Wang, L Li, H Wang, Y Miao, YL Foley, JF Fargo, DC Jin, Y Williams, CJ Jothi, R Hu, G AF Zheng, Xiaofeng Yang, Pengyi Lackford, Brad Bennett, Brian D. Wang, Li Li, Hui Wang, Yu Miao, Yiliang Foley, Julie F. Fargo, David C. Jin, Ying Williams, Carmen J. Jothi, Raja Hu, Guang TI CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; CCR4-NOT COMPLEX; SELF-RENEWAL; FACILITATES PLURIPOTENCY; IN-VIVO; PROTEINS; GENOME; CNOT3; DIFFERENTIATION; IDENTIFICATION AB Poly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for mouse epiblast maintenance. It is highly expressed in blastocysts and its deletion leads to peri-implantation lethality. The epiblast cells in Cnot3 deletion embryos are quickly lost during diapause and fail to outgrow in culture. Mechanistically, CNOT3 C terminus is required for its interaction with the complex and its function in embryonic stem cells (ESCs). Furthermore, Cnot3 deletion results in increases in the poly(A) tail lengths, half-lives, and steady-state levels of differentiation gene mRNAs. The half-lives of CNOT3 target mRNAs are shorter in ESCs and become longer during normal differentiation. Together, we propose that CNOT3 maintains the pluripotent state by promoting differentiation gene mRNA deadenylation and degradation, and we identify poly(A) tail-length regulation as a post-transcriptional mechanism that controls pluripotency. C1 [Zheng, Xiaofeng; Yang, Pengyi; Lackford, Brad; Wang, Li; Jothi, Raja; Hu, Guang] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. [Bennett, Brian D.; Fargo, David C.] Natl Inst Environm Hlth Sci, Integrat Bioinformat Support Grp, Res Triangle Pk, NC 27709 USA. [Li, Hui; Jin, Ying] Shanghai Jiao Tong Univ, Lab Mol Dev Biol, Sch Med, Shanghai 200025, Peoples R China. [Wang, Yu; Foley, Julie F.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Miao, Yiliang; Williams, Carmen J.] Natl Inst Environm Hlth Sci, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. RP Hu, G (reprint author), Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov OI Yang, Pengyi/0000-0003-1098-3138 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01ES102745, Z01ES102985, Z01ES102625] FX We thank Dr. Anna-Katerina Hadjantonakis for helpful discussions. We thank the NIEHS Animal, Epigenomics, Bioinformatics, Protein Expression, Imaging, and Histology core facility for assistance with various techniques and experiments. This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Z01ES102745 (to G.H.), Z01ES102985 (to C.J.W.), and Z01ES102625 (to R.J.). NR 56 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD NOV 8 PY 2016 VL 7 IS 5 BP 897 EP 910 DI 10.1016/j.stemcr.2016.09.007 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3QH UT WOS:000389509000007 PM 27746116 ER PT J AU Kishton, RJ Sukumar, M Restifo, NP AF Kishton, Rigel J. Sukumar, Madhusudhanan Restifo, Nicholas P. TI Arginine Arms T Cells to Thrive and Survive SO Cell Metabolism LA English DT Editorial Material ID METABOLISM; MEMORY; PATHWAYS AB A clear role for cellular metabolism in regulating immune cell function has recently been established. In a recent issue of Cell, Geiger et al. (2016) demonstrate a role for intracellular arginine abundance in T cells for the promotion of oxidative metabolism, increased cell viability, persistence, and in vivo antitumor response. C1 [Kishton, Rigel J.; Sukumar, Madhusudhanan; Restifo, Nicholas P.] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. [Kishton, Rigel J.; Sukumar, Madhusudhanan; Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA.; Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM restifo@nih.gov NR 9 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD NOV 8 PY 2016 VL 24 IS 5 BP 647 EP 648 DI 10.1016/j.cmet.2016.10.019 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EE3QC UT WOS:000389508000003 PM 27829132 ER PT J AU Gui, DY Sullivan, LB Luengo, A Hosios, AM Bush, LN Gitego, N Davidson, SM Freinkman, E Thomas, CJ Vander Heiden, MG AF Gui, Dan Y. Sullivan, Lucas B. Luengo, Alba Hosios, Aaron M. Bush, Lauren N. Gitego, Nadege Davidson, Shawn M. Freinkman, Elizaveta Thomas, Craig J. Vander Heiden, Matthew G. TI Environment Dictates Dependence on Mitochondrial Complex I for NAD plus and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin SO Cell Metabolism LA English DT Article ID RESPIRATORY-CHAIN; DIABETIC-PATIENTS; PROSTATE-CANCER; BREAST-CANCER; LUNG-CANCER; METABOLISM; BIGUANIDES; INHIBITION; PHARMACOKINETICS; TUMORIGENESIS AB Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. C1 [Gui, Dan Y.; Sullivan, Lucas B.; Luengo, Alba; Hosios, Aaron M.; Bush, Lauren N.; Gitego, Nadege; Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Gui, Dan Y.; Sullivan, Lucas B.; Luengo, Alba; Hosios, Aaron M.; Bush, Lauren N.; Gitego, Nadege; Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Freinkman, Elizaveta] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Thomas, Craig J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu FU Burroughs Wellcome Fund [SU2C]; Ludwig Center at the Massachusetts Institute of Technology; NIH [P30CA1405141, GG006413, R01 CA168653, R01 CA201276, T32 GM007753]; American Cancer Society [PF-15-096-01-TBE]; National Science Foundation [GRFP DGE-1122374] FX This work was supported by the Burroughs Wellcome Fund, SU2C, the Ludwig Center at the Massachusetts Institute of Technology, and the NIH (P30CA1405141, GG006413, R01 CA168653, and R01 CA201276) to M.G.V.H., NIH (T32 GM007753) to D.Y.G., a postdoctoral fellowship (PF-15-096-01-TBE) from the American Cancer Society to L.B.S., and the National Science Foundation (GRFP DGE-1122374) to A.L. and S.M.D. We thank members of the M.G.V.H. laboratory for thoughtful discussion. NR 54 TC 2 Z9 2 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD NOV 8 PY 2016 VL 24 IS 5 BP 716 EP 727 DI 10.1016/j.cmet.2016.09.006 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EE3QC UT WOS:000389508000012 PM 27746050 ER PT J AU Leng, YK Wu, WJ Li, L Lin, K Sun, K Chen, XY Li, WW AF Leng, Yuankui Wu, Weijie Li, Li Lin, Kun Sun, Kang Chen, Xiaoyuan Li, Wanwan TI Magnetic/Fluorescent Barcodes Based on Cadmium-Free Near-Infrared-Emitting Quantum Dots for Multiplexed Detection SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article ID MAGNETIC SEPARATION; SUSPENSION ARRAY; FLOW-CYTOMETRY; BEADS; NANOCRYSTALS; MICROSPHERES; ENRICHMENT; MICROBEADS; CELLS; NANOPARTICLES AB Magnetic/fluorescent barcodes, which combine quantum dots (QDs) and superparamagnetic nanoparticles in micrometer-sized host microspheres, are promising for automatic high-throughput multiplexed biodetection applications and "point of care" biodetection. However, the fluorescence intensity of QDs sharply decreases after addition of magnetic nanoparticles (MNPs) due to absorption by MNPs, and thus, the encoding capacity of QDs becomes more limited. Furthermore, the intrinsic toxicity of cadmium-based QDs, the most commonly used QD in barcodes, has significant risks to human health and the environment. In this work, to alleviate fluorescence quenching and intrinsic toxicity, cadmium-free NIR-emitting CuInS2/ZnS QDs and Fe3O4 MNPs are successfully incorporated into poly(styrene-co-maleic anhydride) microspheres by using the Shirasu porous glass membrane emulsification technique. A "single-wavelength" encoding model is successfully constructed to guide the encoding of NIR QDs with wide emission spectra. Then, a "single-wavelength" encoding combined with size encoding is used to produce different optical codes by simply changing the wavelength and the intensity of the QDs as well as the size of the barcode microspheres. 48 barcodes are easily created due to the greatly reduced energy transfer between the NIR-emitting QDs and MNPs. The resulting bifunctional barcodes are also combined with a flow cytometer using one laser for multiplexed detection of five tumor markers in one test. Assays based on these barcodes are significantly more sensitive than non-magnetic and traditional ELISA assays. Moreover, validating experiments also show good performance of the bifunctional barcodes-based suspension array when dealing with patient serum samples. Thus, magnetic/fluorescent barcodes based on NIR-emitting CuInS2/ZnS QDs are promising for multiplexed bioassay applications. C1 [Leng, Yuankui; Wu, Weijie; Sun, Kang; Li, Wanwan] Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. [Li, Li; Lin, Kun] Shanghai Jiao Tong Univ, Sch Med, Peoples Hosp 1, Shanghai 200080, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Li, WW (reprint author), Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. EM wwli@sjtu.edu.cn FU National Natural Science Foundation of China [81371645]; Science and Technology Committee of Shanghai [15PJD020, 15441905800, 16JC1400604]; Medicine and Engineering Cross Research Foundation of Shanghai Jiao Tong University [YG2012MS61, YG2014MS33] FX This work was financially supported by National Natural Science Foundation of China (Project No. 81371645), Science and Technology Committee of Shanghai (Project Nos. 15PJD020, 15441905800, and 16JC1400604), and Medicine and Engineering Cross Research Foundation of Shanghai Jiao Tong University (Project Nos. YG2012MS61 and YG2014MS33). The authors thank Instrumental Analysis Center of SJTU for the assistance with TEM, SEM, VSM, and XRD characterizations. NR 44 TC 0 Z9 0 U1 35 U2 35 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1616-301X EI 1616-3028 J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD NOV 8 PY 2016 VL 26 IS 42 BP 7581 EP 7589 DI 10.1002/adfm.201602900 PG 9 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 EC5IC UT WOS:000388166700004 ER PT J AU Srimuang, K Miotto, O Lim, P Fairhurst, RM Kwiatkowski, DP Woodrow, CJ Imwong, M AF Srimuang, Krongkan Miotto, Olivo Lim, Pharath Fairhurst, Rick M. Kwiatkowski, Dominic P. Woodrow, Charles J. Imwong, Mallika CA Tracking Resistance Artemisinin TI Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration SO MALARIA JOURNAL LA English DT Article DE Malaria; Plasmodium falciparum; Anti-malarial resistance; Chloroquine; Amodiaquine; Mefloquine; Artemisinin; Combination therapy; pfcrt; pfmdr1 ID PLASMODIUM-FALCIPARUM MALARIA; THAI-MYANMAR BORDER; GENE COPY NUMBER; CHLOROQUINE-RESISTANCE; DIHYDROARTEMISININ-PIPERAQUINE; IN-VITRO; ARTESUNATE-AMODIAQUINE; COMBINATION THERAPY; ARTEMETHER-LUMEFANTRINE; MEFLOQUINE RESISTANCE AB Background: Declining anti-malarial efficacy of artemisinin-based combination therapy, and reduced Plasmodium falciparum susceptibility to individual anti-malarials are being documented across an expanding area of Southeast Asia (SEA). Genotypic markers complement phenotypic studies in assessing the efficacy of individual anti-malarials. Methods: The markers pfmdr1 and pfcrt were genotyped in parasite samples obtained in 2011-2014 at 14 TRAC (Tracking Resistance to Artemisinin Collaboration) sites in mainland Southeast Asia using a combination of PCR and next-generation sequencing methods. Results: Pfmdr1 amplification, a marker of mefloquine and lumefantrine resistance, was highly prevalent at Mae Sot on the Thailand-Myanmar border (59.8% of isolates) and common (more than 10%) at sites in central Myanmar, eastern Thailand and western Cambodia; however, its prevalence was lower than previously documented in Pailin, western Cambodia. The pfmdr1 Y184F mutation was common, particularly in and around Cambodia, and the F1226Y mutation was found in about half of samples in Mae Sot. The functional significance of these two mutations remains unclear. Other previously documented pfmdr1 mutations were absent or very rare in the region. The pfcrt mutation K76T associated with chloroquine resistance was found in 98.2% of isolates. The CVIET haplotype made up 95% or more of isolates in western SEA while the CVIDT haplotype was common (30-40% of isolates) in north and northeastern Cambodia, southern Laos, and southern Vietnam. Conclusions: These findings generate cause for concern regarding the mid-term efficacy of artemether-lumefantrine in Myanmar, while the absence of resistance-conferring pfmdr1 mutations and SVMNT pfcrt haplotypes suggests that amodiaquine could be an efficacious component of anti-malarial regimens in SEA. C1 [Srimuang, Krongkan; Imwong, Mallika] Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand. [Miotto, Olivo; Woodrow, Charles J.; Imwong, Mallika] Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Miotto, Olivo; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Hinxton, England. [Miotto, Olivo; Kwiatkowski, Dominic P.] Univ Oxford, MRC, Ctr Genom & Global Hlth, Oxford, England. [Lim, Pharath; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Woodrow, Charles J.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England. RP Imwong, M (reprint author), Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand. EM noi@tropmedres.ac FU Royal Golden Jubilee Ph.D. Programme; Thailand Research Fund; Mahidol University; Wellcome Trust of Great Britain; Wellcome Trust through core funding of the Wellcome Trust Sanger Institute [098051]; Wellcome Trust Centre for Human Genetics [090532/Z/09/Z]; Resource Centre for Genomic Epidemiology of Malaria [090770/Z/09/Z]; UK Medical Research Council [G0600718, MR/M006212/1]; Bill and Melinda Gates Foundation [OPP1040463]; UK Department for International Development; Worldwide Anti-malarial Resistance Network (WWARN); Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX PCR work in Thailand was funded by the Royal Golden Jubilee Ph.D. Programme, the Thailand Research Fund, and Mahidol University. The Mahidol-Oxford Tropical Medicine Research Programme is funded by the Wellcome Trust of Great Britain. Whole-genome sequencing for this study was funded by the Wellcome Trust through core funding of the Wellcome Trust Sanger Institute (098051). The Wellcome Trust also supports the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z) and the Resource Centre for Genomic Epidemiology of Malaria (090770/Z/09/Z). The Centre for Genomics and Global Health is supported by the UK Medical Research Council (G0600718, MR/M006212/1). This work was funded in part by the Bill and Melinda Gates Foundation (OPP1040463). The fieldwork to obtain samples was supported by grants from the UK Department for International Development, the Worldwide Anti-malarial Resistance Network (WWARN), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. The views expressed and information contained in this article are not necessarily those of or endorsed by the UK Department for International Development or by the other funders, which can accept no responsibility for such views or for any reliance placed on them. NR 62 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD NOV 8 PY 2016 VL 15 AR 541 DI 10.1186/s12936-016-1598-6 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EC5AA UT WOS:000388144300006 PM 27825353 ER PT J AU Kong, L Lee, DE Kadam, RU Liu, T Giang, E Nieusma, T Garces, F Tzarum, N Woods, VL Ward, AB Li, S Wilson, IA Law, M AF Kong, Leopold Lee, David E. Kadam, Rameshwar U. Liu, Tong Giang, Erick Nieusma, Travis Garces, Fernando Tzarum, Netanel Woods, Virgil L., Jr. Ward, Andrew B. Li, Sheng Wilson, Ian A. Law, Mansun TI Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis C virus; E2; CD81-binding site; conformational flexibility; protein dynamics ID BROADLY NEUTRALIZING ANTIBODIES; AMIDE HYDROGEN/DEUTERIUM EXCHANGE; SUSTAINED VIROLOGICAL RESPONSE; ENVELOPE GLYCOPROTEIN COMPLEX; MOLECULAR-DYNAMICS; HIV-1 GP120; MEDIATED NEUTRALIZATION; MONOCLONAL-ANTIBODIES; ELECTRON-MICROSCOPY; MASS-SPECTROMETRY AB Hepatitis C virus (HCV) is a major cause of liver disease, affecting over 2% of the world's population. The HCV envelope glycoproteins E1 and E2 mediate viral entry, with E2 being the main target of neutralizing antibody responses. Structural investigations of E2 have produced templates for vaccine design, including the conserved CD81 receptor-binding site (CD81bs) that is a key target of broadly neutralizing antibodies (bNAbs). Unfortunately, immunization with recombinant E2 and E1E2 rarely elicits sufficient levels of bNAbs for protection. To understand the challenges for eliciting bNAb responses against the CD81bs, we investigated the E2 CD81bs by electron microscopy (EM), hydrogen-deuterium exchange (HDX), molecular dynamics (MD), and calorimetry. By EM, we observed that HCV1, a bNAb recognizing the N-terminal region of the CD81bs, bound a soluble E2 core construct from multiple angles of approach, suggesting components of the CD81bs are flexible. HDX of multiple E2 constructs consistently indicated the entire CD81bs was flexible relative to the rest of the E2 protein, which was further confirmed by MD simulations. However, E2 has a high melting temperature of 84.8 degrees C, which is more akin to proteins from thermophilic organisms. Thus, recombinant E2 is a highly stable protein overall, but with an exceptionally flexible CD81bs. Such flexibility may promote induction of nonneutralizing antibodies over bNAbs to E2 CD81bs, underscoring the necessity of rigidifying this antigenic region as a target for rational vaccine design. C1 [Kong, Leopold; Kadam, Rameshwar U.; Nieusma, Travis; Garces, Fernando; Tzarum, Netanel; Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Lee, David E.; Liu, Tong; Woods, Virgil L., Jr.; Li, Sheng] Univ Calif San Diego, Dept Med, La Jolla, CA 92037 USA. [Giang, Erick; Law, Mansun] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Kong, Leopold] NIDDK, Struct Cell Biol Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20814 USA. RP Wilson, IA (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.; Law, M (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Wilson, IA (reprint author), Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. EM wilson@scripps.edu; mlaw@scripps.edu FU Swiss National Science Foundation; NIH [AI079031, AI123861, AI106005, AI123365, GM094586, AI117905, GM020501, AI101436]; Skaggs Institute FX R.U.K. thanks the Swiss National Science Foundation for a postdoctoral fellowship. This work is supported by NIH Grants AI079031 and AI123861 (to M.L.); NIH Grants AI106005 and AI123365 (to M.L. and I.A.W.); NIH Grant GM094586 (to I.A.W.); and NIH Grants AI117905, GM020501, and AI101436 (to S.L.), as well as the Skaggs Institute (I.A.W.). This article is manuscript 29353 from The Scripps Research Institute. NR 72 TC 1 Z9 1 U1 8 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 8 PY 2016 VL 113 IS 45 BP 12768 EP 12773 DI 10.1073/pnas.1609780113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC4CL UT WOS:000388073300067 ER PT J AU Kerbl, A Fofanova, EG Mayorova, TD Voronezhskaya, EE Worsaae, K AF Kerbl, Alexandra Fofanova, Elizaveta G. Mayorova, Tatiana D. Voronezhskaya, Elena E. Worsaae, Katrine TI Comparison of neuromuscular development in two dinophilid species (Annelida) suggests progenetic origin of Dinophilus gyrociliatus SO FRONTIERS IN ZOOLOGY LA English DT Article DE Meiofauna evolution; Paedomorphosis; Sexual dimorphism; Sister species; Nervous system; Musculature; Ciliation; Interstitial ID VENTRAL PHARYNGEAL ORGANS; POLYCHAETA ANNELIDA; NERVOUS-SYSTEM; PHYLOGENETIC IMPORTANCE; SEX-RATIO; SP-NOV.; HETEROCHRONY; EVOLUTION; ARCHIANNELIDA; ULTRASTRUCTURE AB Background: Several independent meiofaunal lineages are suggested to have originated through progenesis, however, morphological support for this heterochronous process is still lacking. Progenesis is defined as an arrest of somatic development (synchronously in various organ systems) due to early maturation, resulting in adults resembling larvae or juveniles of the ancestors. Accordingly, we established a detailed neuromuscular developmental atlas of two closely related Dinophilidae using immunohistochemistry and CLSM. This allows us to test for progenesis, questioning whether i) the adult smaller, dimorphic Dinophilus gyrociliatus resembles a younger developmental stage of the larger, monomorphic D. taeniatus and whether ii) dwarf males of D. gyrociliatus resemble an early developmental stage of D. gyrociliatus females. Results: Both species form longitudinal muscle bundles first, followed by circular muscles, creating a grid of body wall musculature, which is the densest in adult D. taeniatus, while the architecture in adult female D. gyrociliatus resembles that of prehatching D. taeniatus. Both species display a subepidermal ganglionated nervous system with an anterior dorsal brain and five longitudinal ventral nerve bundles with six sets of segmental commissures (associated with paired ganglia). Neural differentiation of D. taeniatus and female D. gyrociliatus commissures occurs before hatching: both species start out forming one transverse neurite bundle per segment, which are thereafter joined by additional thin bundles. Whereas D. gyrociliatus arrests its development at this stage, adult D. taeniatus condenses the thin commissures again into one thick commissural bundle per segment. Generally, D. taeniatus adults demonstrate a seemingly more organized (= segmental) pattern of serotonin-like and FMRFamide-like immunoreactive elements. The dwarf male of D. gyrociliatus displays a highly aberrant neuromuscular system, showing no close resemblance to any early developmental stage of female Dinophilus, although the onset of muscular development mirrors the early myogenesis in females. Conclusion: The apparent synchronous arrest of nervous and muscular development in adult female D. gyrociliatus, resembling the prehatching stage of D. taeniatus, suggests that D. gyrociliatus have originated through progenesis. The synchrony in arrest of three organ systems, which show opposing reduction and addition of elements, presents one of the morphologically best-argued cases of progenesis within Spiralia. C1 [Kerbl, Alexandra; Worsaae, Katrine] Univ Copenhagen, Dept Biol, Marine Biol Sect, Univ Parken 4, DK-2100 Copenhagen, Denmark. [Fofanova, Elizaveta G.; Mayorova, Tatiana D.; Voronezhskaya, Elena E.] RAS, Koltzov Inst Dev Biol, Lab Dev Neurobiol, 26 Vavilova Str, Moscow, Russia. [Mayorova, Tatiana D.] NINDS, Lab Neurobiol, NIH, 49 Convent Dr, Bethesda, MD 20824 USA. RP Worsaae, K (reprint author), Univ Copenhagen, Dept Biol, Marine Biol Sect, Univ Parken 4, DK-2100 Copenhagen, Denmark.; Mayorova, TD (reprint author), RAS, Koltzov Inst Dev Biol, Lab Dev Neurobiol, 26 Vavilova Str, Moscow, Russia.; Mayorova, TD (reprint author), NINDS, Lab Neurobiol, NIH, 49 Convent Dr, Bethesda, MD 20824 USA. EM mayorova@wsbs-msu.ru; kworsaae@bio.ku.dk OI Kerbl, Alexandra/0000-0002-9454-6359 FU Russian Foundation for Basic Research [15-04-04298, 15-29-02650]; Villum Foundation [1025442] FX A. Martinez, M. DiDomenico, N. Bekkouche, B. Gonzalez and RM. Kristensen are thanked for their help collecting specimens of D. taeniatus in Disko Island, Greenland and in Lysekil, Sweden. Furthermore, K. Kvindebjerg is thanked for her help with unravelling myogenesis in the dwarf male of D. gyrociliatus. We are furthermore grateful to the staff of the Pertsov White Sea Biological Station, Russia as well as the people of the Arctic Station, Disko Island, West Greenland for their generous assistance. The authors thank the Optical Research Group of IDB RAS for technical assistance. We are very grateful for the detailed comments provided by E. Seaver, G. Purschke and two anonymous reviewers, which significantly improved the manuscript. This work was partially supported by the Russian Foundation for Basic Research (grants. 15-04-04298 to TDM and No 15-29-02650 to EEV) and by the Villum Foundation (grant No 1025442 to K. Worsaae). NR 83 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-9994 J9 FRONT ZOOL JI Front. Zool. PD NOV 8 PY 2016 VL 13 AR 49 DI 10.1186/s12983-016-0181-x PG 39 WC Zoology SC Zoology GA EB9TN UT WOS:000387740100001 PM 27833644 ER PT J AU Twitchell, EL Tin, C Wen, K Zhang, HS Becker-Dreps, S Azcarate-Peril, MA Vilchez, S Li, GH Ramesh, A Weiss, M Lei, SH Bui, T Yang, XD Schultz-Cherry, S Yuan, LJ AF Twitchell, Erica L. Tin, Christine Wen, Ke Zhang, Husen Becker-Dreps, Sylvia Azcarate-Peril, M. Andrea Vilchez, Samuel Li, Guohua Ramesh, Ashwin Weiss, Mariah Lei, Shaohua Bui, Tammy Yang, Xingdong Schultz-Cherry, Stacey Yuan, Lijuan TI Modeling human enteric dysbiosis and rotavirus immunity in gnotobiotic pigs SO GUT PATHOGENS LA English DT Article DE Enteric dysbiosis; Gnotobiotic pig; Rotavirus; Vaccine; Enteric immunity ID ISOTYPE ANTIBODY-RESPONSES; POLYMERASE-CHAIN-REACTION; ENVIRONMENTAL ENTEROPATHY; GUT MICROBIOTA; KLEBSIELLA-PNEUMONIAE; MATERNAL ANTIBODIES; CELL RESPONSES; PROTECTIVE IMMUNITY; PCR ASSAYS; INFECTION AB Background: Rotavirus vaccines have poor efficacy in infants from low- and middle-income countries. Gut microbiota is thought to influence the immune response to oral vaccines. Thus, we developed a gnotobiotic (Gn) pig model of enteric dysbiosis to study the effects of human gut microbiota (HGM) on immune responses to rotavirus vaccination, and the effects of rotavirus challenge on the HGM by colonizing Gn pigs with healthy HGM (HHGM) or unhealthy HGM (UHGM). The UHGM was from a Nicaraguan infant with a high enteropathy score (ES) and no seroconversion following administration of oral rotavirus vaccine, while the converse was characteristic of the HHGM. Pigs were vaccinated, a subset was challenged, and immune responses and gut microbiota were evaluated. Results: Significantly more rotavirus-specific IFN-gamma producing T cells were in the ileum, spleen, and blood of HHGM than those in UHGM pigs after three vaccine doses, suggesting HHGM induces stronger cell-mediated immunity than UHGM. There were significant correlations between multiple Operational Taxonomic Units (OTUs) and frequencies of IFN-gamma producing T cells at the time of challenge. There were significant positive correlations between Collinsella and CD8+ T cells in blood and ileum, as well as CD4+ T cells in blood, whereas significant negative correlations between Clostridium and Anaerococcus, and ileal CD8+ and CD4+ T cells. Differences in alpha diversity and relative abundances of OTUs were detected between the groups both before and after rotavirus challenge. Conclusion: Alterations in microbiome diversity and composition along with correlations between certain microbial taxa and T cell responses warrant further investigation into the role of the gut microbiota and certain microbial species on enteric immunity. Our results support the use of HGM transplanted Gn pigs as a model of human dysbiosis during enteric infection, and oral vaccine responses. C1 [Twitchell, Erica L.; Tin, Christine; Wen, Ke; Li, Guohua; Ramesh, Ashwin; Weiss, Mariah; Lei, Shaohua; Bui, Tammy; Yang, Xingdong; Yuan, Lijuan] Virginia Polytech Inst & State Univ, Virginia Maryland Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA. [Zhang, Husen] NCI, Microbiome Core, Canc Inflammat Program, Bethesda, MD 20892 USA. [Becker-Dreps, Sylvia] Univ N Carolina, Sch Med, Dept Family Med, Chapel Hill, NC USA. [Azcarate-Peril, M. Andrea] Univ N Carolina, Dept Cell Biol & Physiol, Sch Med, Chapel Hill, NC USA. [Azcarate-Peril, M. Andrea] Univ N Carolina, Microbiome Core Facil, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA. [Vilchez, Samuel] Natl Autonomous Univ Nicaragua, Dept Microbiol & Parasitol, Fac Med Sci, Leon, Nicaragua. [Schultz-Cherry, Stacey] St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Yuan, LJ (reprint author), Virginia Polytech Inst & State Univ, Virginia Maryland Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA 24061 USA. EM lyuan@vt.edu FU Bill and Melinda Gates Foundation [OPP1108188]; Virginia Tech Graduate Student Assembly Graduate Research and Development Fund; Ruth L. Kirschstein Institutional National Research Service Award from the National Institutes of Health FX This work was supported by the Bill and Melinda Gates Foundation (http://www.gatesfoundation.org) Grant # OPP1108188 to LY. A Virginia Tech Graduate Student Assembly Graduate Research and Development Fund Award (Spring 2015) provided financial support for the porcine enteropathy ELISA kits. Erica Twitchell is supported by a Ruth L. Kirschstein Institutional National Research Service Award from the National Institutes of Health. The funding body had no role in the design of the study, or collection, analysis, or interpretation of data, or writing the manuscript. NR 60 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-4749 J9 GUT PATHOG JI Gut Pathogens PD NOV 8 PY 2016 VL 8 AR 51 DI 10.1186/s13099-016-0136-y PG 18 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA EB3ON UT WOS:000387275000001 PM 27826359 ER PT J AU Clayton, JA Tannenbaum, C AF Clayton, Janine Austin Tannenbaum, Cara TI Reporting Sex, Gender, or Both in Clinical Research? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, 6707 Democracy Blvd, Bethesda, MD 20817 USA. [Tannenbaum, Cara] Canadian Inst Hlth Res, Inst Gender & Hlth, Montreal, PQ, Canada. RP Clayton, JA (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd, Bethesda, MD 20817 USA. EM janine.clayton@nih.gov NR 5 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 8 PY 2016 VL 316 IS 18 BP 1863 EP 1864 DI 10.1001/jama.2016.16405 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EB1MN UT WOS:000387116500008 PM 27802482 ER PT J AU Geng, S Chen, KQ Yuan, RX Peng, L Maitra, U Diao, N Chen, C Zhang, Y Hu, Y Qi, CF Pierce, S Ling, WH Xiong, HB Li, LW AF Geng, Shuo Chen, Keqiang Yuan, Ruoxi Peng, Liang Maitra, Urmila Diao, Na Chen, Chun Zhang, Yao Hu, Yuan Qi, Chen-Feng Pierce, Susan Ling, Wenhua Xiong, Huabao Li, Liwu TI The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis SO NATURE COMMUNICATIONS LA English DT Article ID BREAST-CANCER CELLS; LOW-DOSE ENDOTOXIN; IRAK-M EXPRESSION; B TYPE-I; UP-REGULATION; LIPOPOLYSACCHARIDE LPS; KAPPA-B; MACROPHAGES; TOLERANCE; RECEPTOR AB Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis. C1 [Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi; Maitra, Urmila; Diao, Na; Chen, Chun; Zhang, Yao; Li, Liwu] Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. [Peng, Liang; Hu, Yuan; Xiong, Huabao] Icahn Sch Med Mt Sinai, Dept Med, Inst Immunol, New York, NY 10029 USA. [Qi, Chen-Feng; Pierce, Susan] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Ling, Wenhua] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou 510080, Guangdong, Peoples R China. RP Li, LW (reprint author), Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA.; Xiong, HB (reprint author), Icahn Sch Med Mt Sinai, Dept Med, Inst Immunol, New York, NY 10029 USA. EM Huabao.Xiong@mssm.edu; lwli@vt.edu OI Li, Liwu/0000-0001-8870-5299 FU National Institute of Health grants [R01 HL115835, R56AI108264, RO1 AI104688, R56AI091871]; American Heart Association Award [15POST25860003] FX This work was supported by the National Institute of Health grants R01 HL115835, R56AI108264 to L.L., RO1 AI104688 and R56AI091871 to H.X., and American Heart Association Award 15POST25860003 to S.G. NR 68 TC 0 Z9 0 U1 5 U2 5 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 NOV 8 PY 2016 VL 7 AR 13436 DI 10.1038/ncomms13436 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB3JJ UT WOS:000387260200001 PM 27824038 ER PT J AU Permuth, JB Reid, B Earp, M Chen, YA Monteiro, ANA Chen, ZH Chenevix-Trench, G Fasching, PA Beckmann, MW Lambrechts, D Vanderstichele, A Van Niewenhuyse, E Vergote, I Rossing, MA Doherty, JA Chang-Claude, J Moysich, K Odunsi, K Goodman, MT Shvetsov, YB Wilkens, LR Thompson, PJ Dork, T Bogdanova, N Butzow, R Nevanlinna, H Pelttari, L Leminen, A Modugno, F Edwards, RP Ness, RB Kelley, J Heitz, F Karlan, B Lester, J Kjaer, SK Jensen, A Giles, G Hildebrandt, M Liang, D Lu, KH Wu, XF Levine, DA Bisogna, M Berchuck, A Cramer, DW Terry, KL Tworoger, SS Poole, EM Bandera, EV Fridley, B Cunningham, J Winham, SJ Olson, SH Orlow, I Bjorge, L Kiemeney, LA Massuger, L Pejovic, T Moffitt, M Le, N Cook, LS Brooks-Wilson, A Kelemen, LE Gronwald, J Lubinski, J Wentzensen, N Brinton, LA Lissowska, J Yang, HN Hogdall, E Hogdall, C Lundvall, L Pharoah, PDP Song, HL Campbell, I Eccles, D McNeish, I Whittemore, A McGuire, V Sieh, W Rothstein, J Phelan, CM Risch, H Narod, S McLaughlin, J Anton-Culver, H Ziogas, A Menon, U Gayther, S Ramus, SJ Gentry-Maharaj, A Pearce, CL Wu, AH Kupryjanczyk, J Dansonka-Mieszkowska, A Schildkraut, JM Cheng, JQ Goode, EL Sellers, TA AF Permuth, Jennifer B. Reid, Brett Earp, Madalene Chen, Y. Ann Monteiro, Alvaro N. A. Chen, Zhihua Chenevix-Trench, Georgia Fasching, Peter A. Beckmann, Matthias W. Lambrechts, Diether Vanderstichele, Adriaan Van Niewenhuyse, Els Vergote, Ignace Rossing, Mary Anne Doherty, Jennifer Anne Chang-Claude, Jenny Moysich, Kirsten Odunsi, Kunle Goodman, Marc T. Shvetsov, Yurii B. Wilkens, Lynne R. Thompson, Pamela J. Doerk, Thilo Bogdanova, Natalia Butzow, Ralf Nevanlinna, Heli Pelttari, Liisa Leminen, Arto Modugno, Francesmary Edwards, Robert P. Ness, Roberta B. Kelley, Joseph Heitz, Florian Karlan, Beth Lester, Jenny Kjaer, Susanne K. Jensen, Allan Giles, Graham Hildebrandt, Michelle Liang, Dong Lu, Karen H. Wu, Xifeng Levine, Douglas A. Bisogna, Maria Berchuck, Andrew Cramer, Daniel W. Terry, Kathryn L. Tworoger, Shelley S. Poole, Elizabeth M. Bandera, Elisa V. Fridley, Brooke Cunningham, Julie Winham, Stacey J. Olson, Sara H. Orlow, Irene Bjorge, Line Kiemeney, Lambertus A. Massuger, Leon Pejovic, Tanja Moffitt, Melissa Le, Nhu Cook, Linda S. Brooks-Wilson, Angela Kelemen, Linda E. Gronwald, Jacek Lubinski, Jan Wentzensen, Nicolas Brinton, Louise A. Lissowska, Jolanta Yang, Hanna Hogdall, Estrid Hogdall, Claus Lundvall, Lene Pharoah, Paul D. P. Song, Honglin Campbell, Ian Eccles, Diana McNeish, Iain Whittemore, Alice McGuire, Valerie Sieh, Weiva Rothstein, Joseph Phelan, Catherine M. Risch, Harvey Narod, Steven McLaughlin, John Anton-Culver, Hoda Ziogas, Argyrios Menon, Usha Gayther, Simon Ramus, Susan J. Gentry-Maharaj, Aleksandra Pearce, Celeste Leigh Wu, Anna H. Kupryjanczyk, Jolanta Dansonka-Mieszkowska, Agnieszka Schildkraut, Joellen M. Cheng, Jin Q. Goode, Ellen L. Sellers, Thomas A. CA AOCS Study Grp TI Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration SO ONCOTARGET LA English DT Article DE polymorphisms; RNA editing; ovarian cancer risk ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; ADENOSINE-DEAMINASE; ANALYSES REVEAL; LOCI; DISEASE; GENES; RARE AB RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P = 1.0x10(-4)) in ADAR3 and rs185455523 in SND1 (OR (95% CI) = 0.68 (0.56-0.83), P = 2.0x10(-4)). When restricting to serous histology (n = 6,500), the magnitude of association strengthened for rs185455523 (OR = 0.60, P = 1.0x10(-4)). Gene-level analyses revealed that variation in ADAR was associated (P < 0.05) with EOC susceptibility, with P-AML = 0.022 and PSKAT-CR = 0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P < 0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing. C1 [Permuth, Jennifer B.; Reid, Brett; Monteiro, Alvaro N. A.; Phelan, Catherine M.; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Earp, Madalene; Cunningham, Julie; Winham, Stacey J.; Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Chen, Y. Ann; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia. [Campbell, Ian; AOCS Study Grp] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Australia. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Beckmann, Matthias W.] Friedrich Alexander Univers Erlangen Nuremberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Ctr Comprehens Canc, Erlangen, Germany. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Vanderstichele, Adriaan; Van Niewenhuyse, Els; Vergote, Ignace] Univ Hosp Leuven, Div Gynecol Oncol, Dept Obstet & Gynaecol, Leuven, Belgium. [Vanderstichele, Adriaan; Van Niewenhuyse, Els; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Doherty, Jennifer Anne] Dartmouth Coll, Geisel Sch Med, Dept Epidemiol, Hanover, NY USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Canc Prevent & Control, Samuel Oshin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI USA. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia] Hannover Med Sch, Radiaton Oncol Res Unit, Hannover, Germany. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf] Helsinki Univ Hosp, Helsinki, Finland. [Nevanlinna, Heli; Pelttari, Liisa; Leminen, Arto] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Pelttari, Liisa; Leminen, Arto] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Modugno, Francesmary; Edwards, Robert P.; Kelley, Joseph] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Modugno, Francesmary; Edwards, Robert P.] Magee Womens Res Inst, Ovarian Canc Ctr Excellence, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary; Edwards, Robert P.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Heitz, Florian] Knappschaft GmbH, Evang Huyssens Stiftung, Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Heitz, Florian] Dr Horst Schmidt Klin Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Karlan, Beth; Lester, Jenny] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Kjaer, Susanne K.; Jensen, Allan; Hogdall, Estrid] Danish Canc Soc, Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Kjaer, Susanne K.] Univ Copenhagen, Dept Gynaecol, Rigshosp, Copenhagen, Denmark. [Giles, Graham] Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Giles, Graham] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Hildebrandt, Michelle; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Levine, Douglas A.; Bisogna, Maria] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Tworoger, Shelley S.; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tworoger, Shelley S.; Poole, Elizabeth M.] Harvard Med Sch, Boston, MA USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Fridley, Brooke] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Olson, Sara H.; Orlow, Irene] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Bjorge, Line] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway. [Bjorge, Line] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Massuger, Leon] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, Nijmegen, Netherlands. [Pejovic, Tanja; Moffitt, Melissa] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Moffitt, Melissa] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Le, Nhu] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Kelemen, Linda E.] Med Univ South Carolina, Coll Med, Dept Publ Hlth Sci, Charleston, SC USA. [Gronwald, Jacek; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Wentzensen, Nicolas; Brinton, Louise A.; Yang, Hanna] NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Hogdall, Claus; Lundvall, Lene] Rigshosp, Dept Obstet & Gynecol, Juliane Marie Ctr, Copenhagen, Denmark. [Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Pharoah, Paul D. P.; Song, Honglin] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic, Australia. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton, Hants, England. [McNeish, Iain] Unvers Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Glasgow, Lanark, Scotland. [Whittemore, Alice; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA. [Risch, Harvey; Menon, Usha] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Narod, Steven] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Genet Epidemiol Res Inst, UCI Sch Med, Irvine, CA USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Gayther, Simon; Ramus, Susan J.; Pearce, Celeste Leigh; Wu, Anna H.] Univ Southern Calif, Norris Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA. [Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Womens Canc, London, England. [Pearce, Celeste Leigh] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Cheng, Jin Q.] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USA. [Sellers, Thomas A.] Ovarian Canc Assoc Consortium, New York, NY USA. RP Permuth, JB (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. EM jenny.permuth@moffitt.org RI Gronwald, Jacek/A-4576-2017; Bjorge, Line/C-1307-2017; Brooks-Wilson, Angela/E-9399-2012; Dork, Thilo/J-8620-2012; OI Gronwald, Jacek/0000-0002-3643-2871; Bjorge, Line/0000-0002-0240-2770; Brooks-Wilson, Angela/0000-0003-1009-6408; Winham, Stacey/0000-0002-8492-9102 FU US National Institute of Health [R01-CA-11343, R01-CA114343-S1]; Genetic Associations and Mechanisms in Oncology (GAME-ON), a NCI Cancer Post-GWAS Initiative [U19-CA148112]; NHMRC; Medical Research Council; University of Erlangen-Nuremberg; Programme of Clinical Biomedical Research [01 GB 9401]; Helsinki University Research Fund; NIH/National Center for Research Resources/General Clinical Research Center [M01-RR000056, R01-CA126841]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; National Cancer Institute, Bethesda, MD [R01-CA61107]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; VicHealth; Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; DOD Ovarian Cancer Research Program [W81XWH-07-0449]; NCI CCSG award [P30-CA008748]; Canadian Institutes of Health Research [MOP-86727]; NIH/NCI [1 R01CA160669-01A1]; NIH [R01 CA063678, CA063682, CA149429]; Lon V Smith Foundation [VLS-39420]; Eve Appeal (The Oak Foundation); National Institute for Health Research University College London Hospitals Biomedical Research Centre; California Cancer Research Program [00-01389V-20170, 2II0200]; Biostatistics and Cancer Informatics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center [P30-CA076292] FX Funding for this study was supported in part by the US National Institute of Health (R01-CA-11343 and R01-CA114343-S1) and the Genetic Associations and Mechanisms in Oncology (GAME-ON), a NCI Cancer Post-GWAS Initiative (U19-CA148112). In addition, we acknowledge the following: AUS: U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia, Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia (199600 and 400281). The Australian Ovarian Cancer Study Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) and ACS Investigators (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all the clinical and scientific collaborators (see http://www.aocstudy.org/) and the women for their contribution. GCT & PW are supported by Fellowships from NHMRC; AP is funded by a Medical Research Council studentship; BAV: ELAN funds of the University of Erlangen-Nuremberg. BEL: Nationaal Kankerplan, we would like to thank Gilian Peuteman, Thomas Van Brussel, Annick Van den Broeck and Joke De Roover for technical assistance; DOV: U.S. National Institutes of Health R01-CA112523 and R01-CA87538; GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ). GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056. HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HJO and HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: DOD DAMD17-02-1-0669 and NCI K07-CA080668, R01-CA95023, P50-CA159981; NIH/National Center for Research Resources/General Clinical Research Center grant M01-RR000056; R01-CA126841; LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAL: Funding for this study was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project.; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393), Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database;; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: National Institute of Health (UM1-CA176726, and R01-CA67262).; The NHS would like to thank the participants and staff for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey, and NCI CCSG award (P30-CA008748); NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; POC: Pomeranian Medical University; POL: Intramural Research Program of the NCI; PVD: Herlev Hospitals Forskningsrad, Direktor Jacob Madsens og Hustru Olga Madsens fond, Arvid Nilssons fond, Gangsted fonden, Herlev Hospitals Forskningsrad and Danish Cancer Society; RMH: Cancer Research UK (no grant number is available); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589) and to thank all members of Scottish Gynaecological Clinical Trials group and COTROC1 investigators; STA: US National Institutes of Health U01-CA71966, R01-CA16056, K07-CA143047, and U01-CA69417 for recruitment of controls by the Cancer Prevention Institute of California; TOR: NIH grants R01 CA063678, CA063682, and CA149429; UCI: NIH R01-CA058860, and the Lon V Smith Foundation grant VLS-39420; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We particularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study; UKR: Cancer Research UK (C490/A6187); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01-CA17054, P30-CA14089, R01-CA61132, N01-PC67010, R03-CA113148, R03-CA115195, N01-CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200). WOC: National Science Centren (N N301 5645 40) The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. This study was supported in part by the Biostatistics and Cancer Informatics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). NR 28 TC 1 Z9 1 U1 7 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 8 PY 2016 VL 7 IS 45 BP 72381 EP 72394 DI 10.18632/oncotarget.10546 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5WT UT WOS:000387452100001 PM 27911851 ER PT J AU Sun, Y Zhang, HM Kazemian, M Troy, JM Seward, C Lu, XC Stubbs, L AF Sun, Younguk Zhang, Huimin Kazemian, Majid Troy, Joseph M. Seward, Christopher Lu, Xiaochen Stubbs, Lisa TI ZSCAN5B and primate-specific paralogs bind RNA polymerase III genes and extra-TFIIIC (ETC) sites to modulate mitotic progression SO ONCOTARGET LA English DT Article DE zinc finger transcription factor; primate-specific duplication; RNA Polymerase III transcription; chromatin architecture; cell cycle ID CARTILAGE-HAIR HYPOPLASIA; POL-II; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; HUMAN GENOME; HUMAN-CELLS; TRANSCRIPTION; EXPRESSION; CHROMATIN; PROMOTERS AB Mammalian genomes contain hundreds of genes transcribed by RNA Polymerase III (Pol III), encoding noncoding RNAs and especially the tRNAs specialized to carry specific amino acids to the ribosome for protein synthesis. In addition to this well-known function, tRNAs and their genes (tDNAs) serve a variety of other critical cellular functions. For example, tRNAs and other Pol III transcripts can be cleaved to yield small RNAs with potent regulatory activities. Furthermore, from yeast to mammals, active tDNAs and related "extra-TFIIIC" (ETC) loci provide the DNA scaffolds for the most ancient known mechanism of three-dimensional chromatin architecture. Here we identify the ZSCAN5 TF family - including mammalian ZSCAN5B and its primate-specific paralogs - as proteins that occupy mammalian Pol III promoters and ETC sites. We show that ZSCAN5B binds with high specificity to a conserved subset of Pol III genes in human and mouse. Furthermore, primate-specific ZSCAN5A and ZSCAN5D also bind Pol III genes, although ZSCAN5D preferentially localizes to MIR SINE-and LINE2-associated ETC sites. ZSCAN5 genes are expressed in proliferating cell populations and are cell-cycle regulated, and siRNA knockdown experiments suggested a cooperative role in regulation of mitotic progression. Consistent with this prediction, ZSCAN5A knockdown led to increasing numbers of cells in mitosis and the appearance of cells. Together, these data implicate the role of ZSCAN5 genes in regulation of Pol III genes and nearby Pol II Ioci, ultimately influencing cell cycle progression and differentiation in a variety of tissues. C1 [Sun, Younguk; Zhang, Huimin; Kazemian, Majid; Troy, Joseph M.; Seward, Christopher; Lu, Xiaochen; Stubbs, Lisa] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. [Sun, Younguk; Zhang, Huimin; Seward, Christopher; Lu, Xiaochen; Stubbs, Lisa] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA. [Troy, Joseph M.] Univ Illinois, Illinois Informat Program, Urbana, IL USA. [Kazemian, Majid] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kazemian, Majid] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Stubbs, L (reprint author), Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA.; Stubbs, L (reprint author), Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA. EM ljstubbs@illinois.edu OI Stubbs, Lisa/0000-0002-9556-1972; Kazemian, Majid/0000-0001-7080-8820 FU March of Dimes Foundation [FY2011-393]; National Institutes of General Medical Sciences [R01-GM078368] FX This work was supported by March of Dimes Foundation, grant FY2011-393, and by the National Institutes of General Medical Sciences grants R01-GM078368 (awarded to L.S.). NR 68 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 8 PY 2016 VL 7 IS 45 BP 72571 EP 72592 DI 10.18632/oncotarget.12508 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5WT UT WOS:000387452100015 PM 27732952 ER PT J AU Lin, H Mueller-Nurasyid, M Smith, AV Arking, DE Barnard, J Bartz, TM Lunetta, KL Lohman, K Kleber, ME Lubitz, SA Geelhoed, B Trompet, S Niemeijer, MN Kacprowski, T Chasman, DI Klarin, D Sinner, MF Waldenberger, M Meitinger, T Harris, TB Launer, LJ Soliman, EZ Chen, LY Smith, JD Van Wagoner, DR Rotter, JI Psaty, BM Xie, Z Hendricks, AE Ding, J Delgado, GE Verweij, N van der Harst, P Macfarlane, PW Ford, I Hofman, A Uitterlinden, A Heeringa, J Franco, OH Kors, JA Weiss, S Volzke, H Rose, LM Natarajan, P Kathiresan, S Kaab, S Gudnason, V Alonso, A Chung, MK Heckbert, SR Benjamin, EJ Liu, Y Marz, W Rienstra, M Jukema, JW Stricker, BH Dorr, M Albert, CM Ellinor, PT AF Lin, Honghuang Mueller-Nurasyid, Martina Smith, Albert V. Arking, Dan E. Barnard, John Bartz, Traci M. Lunetta, Kathryn L. Lohman, Kurt Kleber, Marcus E. Lubitz, Steven A. Geelhoed, Bastiaan Trompet, Stella Niemeijer, Maartje N. Kacprowski, Tim Chasman, Daniel I. Klarin, Derek Sinner, Moritz F. Waldenberger, Melanie Meitinger, Thomas Harris, Tamara B. Launer, Lenore J. Soliman, Elsayed Z. Chen, Lin Y. Smith, Jonathan D. Van Wagoner, David R. Rotter, Jerome I. Psaty, Bruce M. Xie, Zhijun Hendricks, Audrey E. Ding, Jingzhong Delgado, Graciela E. Verweij, Niek van der Harst, Pim Macfarlane, Peter W. Ford, Ian Hofman, Albert Uitterlinden, Andre Heeringa, Jan Franco, Oscar H. Kors, Jan A. Weiss, Stefan Volzke, Henry Rose, Lynda M. Natarajan, Pradeep Kathiresan, Sekar Kaab, Stefan Gudnason, Vilmundur Alonso, Alvaro Chung, Mina K. Heckbert, Susan R. Benjamin, Emelia J. Liu, Yongmei Marz, Winfried Rienstra, Michiel Jukema, J. Wouter Stricker, Bruno H. Dorr, Marcus Albert, Christine M. Ellinor, Patrick T. TI Gene-gene Interaction Analyses for Atrial Fibrillation SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-INTERACTION MAPS; FAMILIAL AGGREGATION; MISSING HERITABILITY; BREAST-CANCER; ASSOCIATION; RISK; VARIANTS; DISEASE; SUSCEPTIBILITY; METAANALYSIS AB Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 x 10(-8)). Eight additional gene-gene interactions were also marginally significant (P < 5 x 10(-7)). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF. C1 [Lin, Honghuang; Lunetta, Kathryn L.; Hendricks, Audrey E.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lin, Honghuang; Lunetta, Kathryn L.; Hendricks, Audrey E.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Lin, Honghuang; Xie, Zhijun] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Sinner, Moritz F.; Kaab, Stefan] Ludwig Maximilians Univ Munchen, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina; Waldenberger, Melanie; Meitinger, Thomas; Kaab, Stefan] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Barnard, John; Smith, Jonathan D.; Van Wagoner, David R.; Chung, Mina K.] Cleveland Clin, Cleveland, OH 44106 USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lohman, Kurt] Wake Forest Sch Med, Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Kleber, Marcus E.; Waldenberger, Melanie; Delgado, Graciela E.] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.; Natarajan, Pradeep; Kathiresan, Sekar; Ellinor, Patrick T.] Harvard Med Sch, Boston, MA USA. [Geelhoed, Bastiaan; Verweij, Niek; van der Harst, Pim; Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Niemeijer, Maartje N.; Hofman, Albert; Heeringa, Jan; Franco, Oscar H.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Kacprowski, Tim; Weiss, Stefan] Univ Med, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Kacprowski, Tim; Weiss, Stefan] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Kacprowski, Tim; Weiss, Stefan; Volzke, Henry; Dorr, Marcus] Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Chasman, Daniel I.; Rose, Lynda M.; Albert, Christine M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Klarin, Derek] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Dept Med, Cardiovasc Div, Minneapolis, MN 55455 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci JIR, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Dept Med, Inst Translat Genom & Populat Sci JIR, Torrance, CA 90509 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hendricks, Audrey E.] Univ Colorado, Math & Stat Sci, Denver, CO 80202 USA. [Ding, Jingzhong] Wake Forest Sch Med, Dept Gerontol & Geriatr Med, Winston Salem, NC USA. [Macfarlane, Peter W.] Univ Glasgow, Coll Vet Med & Life Sci, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Uitterlinden, Andre; Stricker, Bruno H.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol & Internal Med, Rotterdam, Netherlands. [Kors, Jan A.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med & Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Liu, Yongmei] Wake Forest Sch Med, Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Marz, Winfried] Synlab Acad, Synlab Serv, GmbH P5,7, D-68161 Mannheim, Germany. [Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Marz, Winfried] Heidelberg Univ, Med Fac Mannheim, Med Clin Nephrol 5, Hypertensiol,Rheumatol,Endocrinol,Diabetol, Mannheim, Germany. [Stricker, Bruno H.] Inspectorate Hlth Care, Utrecht, Netherlands. [Dorr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. RP Lin, H (reprint author), NHLBI, Framingham, MA USA.; Lin, H (reprint author), Boston Univ, Framingham Heart Study, Framingham, MA USA.; Lin, H (reprint author), Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. EM hhlin@bu.edu RI Alonso, Alvaro/A-4917-2010; Verweij, Niek/A-4499-2017; OI Alonso, Alvaro/0000-0002-2225-8323; Hendricks, Audrey/0000-0002-7152-0287; Rienstra, Michiel/0000-0002-2581-070X FU German Federal Ministry of Education and Research (BMBF); German National Competence network on atrial fibrillation (AFNET); Leducq Foundation [07-CVD 03]; D.W. Reynolds Foundation Clinical Cardiovascular Research Center at Johns Hopkins University; Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) [01GS0499, 01GI0204, 01GS0838]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; State of Bavaria; Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat; German Heart Foundation; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; American Heart Association [16EIA26410001, 13EIA14220013]; NIH Roadmap for Medical Research; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058]; NIH [R01HL090620, R01HL111314, 1RO1HL092577, 2R01LM010098, HL104156, HL105780, HL065962, K23HL114724]; NIH/NCRR CTSA grant [1UL-RR024989]; Heart and Vascular Institute Philanthropic grant, Department of Cardiovascular Medicine, Cleveland Clinic (Chung); Leducq Fondation [07-CVD-03]; Boston University [N01-HC-25195, HHSN268201500001I]; Benjamin and Ellinor [1R01HL128914]; 7th Framework Program (AtheroRemo) [201668, 305739]; Dutch Kidney Foundation [E0.13]; Netherlands organization for health research and development [175.010.2007.006, 90.700.441]; Dutch Inter University Cardiology Institute Netherlands (ICIN); Netherlands Heart Foundation [NHS2010B280]; Netherlands Organization for Scientific Research [016.136.055]; Bristol-Myers Squibb; Established Clinical Investigator of the Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; 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; 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)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus MC; Erasmus University Rotterdam; Netherlands Organisation for Scientific Research (NWO); Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; European Commission (DG XII); Municipality of Rotterdam; Fondation Leducq [14CVD01]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; [N01-HC-85239]; [N01-HC-85079]; [N01-HC-85080]; [N01-HC-85081]; [N01-HC-85082]; [N01-HC-85083]; [N01-HC-85084]; [N01-HC-85085]; [N01-HC-85086]; [N01-HC-35129]; [N01 HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [HHSN268200800007C]; [HHSN268201200036C]; [HL080295]; [HL087652]; [HL103612]; [HL105756]; [HL120393] FX The study was supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET), the Leducq Foundation (07-CVD 03), the D.W. Reynolds Foundation Clinical Cardiovascular Research Center at Johns Hopkins University, and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) by grants to Stefan Kaab (01GS0499, 01GI0204, 01GS0838). The KORA study 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 (BMBF) 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. Dr. Sinner is supported by the German Heart Foundation. 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,), R01HL087641, R01HL59367, R01HL086694, and R01HL111314; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Dr. Alonso is supported by grant 16EIA26410001 from the American Heart Association. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268200800007C, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL103612, HL105756, HL120393 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. The Cleveland Clinic AF study was supported by NIH grants to Drs. Chung, Barnard, Smith, and Van Wagoner (R01HL090620, R01HL111314), an NIH/NCRR CTSA grant (1UL-RR024989), Heart and Vascular Institute Philanthropic grant, Department of Cardiovascular Medicine, Cleveland Clinic (Chung), and a Leducq Fondation grant 07-CVD-03 (Van Wagoner). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195; HHSN268201500001I). This project also was supported by NIH grants to Drs. Ellinor, Benjamin, and Lunetta (1RO1HL092577) and Benjamin and Ellinor (1R01HL128914). LURIC was supported by the 7th Framework Program (AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the EU. The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13), the National Institutes of Health (grant 2R01LM010098), The Netherlands organization for health research and development (NWO-Groot grant 175.010.2007.006, ZonMw grant 90.700.441), and the Dutch Inter University Cardiology Institute Netherlands (ICIN), and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.; 055). There are no relations with industry. The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. 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). SHIP 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' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Ellinor is supported by grants from the National Institutes of Health (HL104156, HL105780, HL065962). Dr. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). Dr. Lubitz is supported by NIH grants K23HL114724, and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. NR 32 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 8 PY 2016 VL 6 AR 35371 DI 10.1038/srep35371 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB3RL UT WOS:000387283300001 PM 27824142 ER PT J AU Perner, J Provaznik, J Schrenkova, J Urbanova, V Ribeiro, JMC Kopacek, P AF Perner, Jan Provaznik, Jan Schrenkova, Jana Urbanova, Veronika Ribeiro, Jose M. C. Kopacek, Petr TI RNA-seq analyses of the midgut from blood- and serum-fed Ixodes ricinus ticks SO SCIENTIFIC REPORTS LA English DT Article ID GLUTATHIONE-PEROXIDASE GENE; BOOPHILUS-MICROPLUS; SALIVARY-GLANDS; CATTLE TICK; HAEMAPHYSALIS-LONGICORNIS; MOLECULAR-CLONING; AEDES-AEGYPTI; LYME-DISEASE; HARD TICK; ORNITHODOROS-MOUBATA AB Adult females of the genus Ixodes imbibe blood meals exceeding about 100 times their own weight within 7-9 days. During this period, ticks internalise components of host blood by endocytic digest cells that line the tick midgut epithelium. Using RNA-seq, we aimed to characterise the midgut transcriptome composition in adult Ixodes ricinus females during early and late phase of engorgement. To address specific adaptations to the haemoglobin-rich diet, we compared the midgut transcriptomes of genetically homogenous female siblings fed either bovine blood or haemoglobin-depleted serum. We noted that tick gut transcriptomes are subject to substantial temporal-dependent expression changes between day 3 and day 8 of feeding. In contrast, the number of transcripts significantly affected by the presence or absence of host red blood cells was low. Transcripts relevant to the processes associated with blood-meal digestion were analysed and involvement of selected encoded proteins in the tick midgut physiology discussed. A total of 7215 novel sequences from I. ricinus were deposited in public databases as an additional outcome of this study. Our results broaden the current knowledge of tick digestive system and may lead to the discovery of potential molecular targets for efficient tick control. C1 [Perner, Jan; Schrenkova, Jana; Urbanova, Veronika; Kopacek, Petr] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Branisovska 31, Ceske Budejovice 37005, Czech Republic. [Provaznik, Jan] Acad Sci Czech Republic, Ctr Biol, Inst Entomol, Branisovska 31, Ceske Budejovice 37005, Czech Republic. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Perner, J (reprint author), Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Branisovska 31, Ceske Budejovice 37005, Czech Republic. EM perner@paru.cas.cz OI Ribeiro, Jose/0000-0002-9107-0818 FU Czech Science Foundation [13-11043S, 15-12006Y]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health [ZIA AI000810-19] FX This project was primarily supported by the Czech Science Foundation-grant No. 13-11043S to P.K. V.U. was supported by the Czech Science Foundation grant. No. 15-12006Y and J.M.R. by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health grant ZIA AI000810-19. The authors gratefully acknowledge the assistance of Prof. Vladimir Benes (Genomics Core Facility, EMBL Heidelberg) during the experimental design. NR 82 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 8 PY 2016 VL 6 AR 36695 DI 10.1038/srep36695 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4FC UT WOS:000387324300001 PM 27824139 ER PT J AU Kellman, P Xue, H Olivieri, LJ Cross, RR Grant, EK Fontana, M Ugander, M Moon, JC Hansen, MS AF Kellman, Peter Xue, Hui Olivieri, Laura J. Cross, Russell R. Grant, Elena K. Fontana, Marianna Ugander, Martin Moon, James C. Hansen, Michael S. TI Dark blood late enhancement imaging SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Late enhancement; Gadolinium; Myocardial infarction; Dark blood; Ablation; Scar; PSIR; MOCO; LGE ID LATE-GADOLINIUM-ENHANCEMENT; MYOCARDIAL-INFARCTION; MAGNETIC-RESONANCE; IRREVERSIBLE INJURY; CONTRAST; MRI; HEART; RECONSTRUCTION; DISTINCTION; DISEASE AB Background: Bright blood late gadolinium enhancement (LGE) imaging typically achieves excellent contrast between infarcted and normal myocardium. However, the contrast between the myocardial infarction (MI) and the blood pool is frequently suboptimal. A large fraction of infarctions caused by coronary artery disease are subendocardial and thus adjacent to the blood pool. It is not infrequent that sub-endocardial MIs are difficult to detect or clearly delineate. Methods: In this present work, an inversion recovery (IR) T2 preparation was combined with single shot steady state free precession imaging and respiratory motion corrected averaging to achieve dark blood LGE images with good signal to noise ratio while maintaining the desired spatial and temporal resolution. In this manner, imaging was conducted free-breathing, which has benefits for image quality, patient comfort, and clinical workflow in both adults and children. Furthermore, by using a phase sensitive inversion recovery reconstruction the blood signal may be made darker than the myocardium (i.e., negative signal values) thereby providing contrast between the blood and both the MI and remote myocardium. In the proposed approach, a single T1-map scout was used to measure the myocardial and blood T1 using a MOdified Look-Locker Inversion recovery (MOLLI) protocol and all protocol parameters were automatically calculated from these values within the sequence thereby simplifying the user interface. Results: The contrast to noise ratio (CNR) between MI and remote myocardium was measured in n = 30 subjects with subendocardial MI using both bright blood and dark blood protocols. The CNR for the dark blood protocol had a 13 % loss compared to the bright blood protocol. The CNR between the MI and blood pool was positive for all dark blood cases, and was negative in 63 % of the bright blood cases. The conspicuity of subendocardial fibrosis and MI was greatly improved by dark blood (DB) PSIR as well as the delineation of the subendocardial border. Conclusions: Free-breathing, dark blood PSIR LGE imaging was demonstrated to improve the visualization of subendocardial MI and fibrosis in cases with low contrast with adjacent blood pool. The proposed method also improves visualization of thin walled fibrous structures such as atrial walls and valves, as well as papillary muscles. C1 [Kellman, Peter; Xue, Hui; Hansen, Michael S.] NHLBI, NIH, DHHS, 10 Ctr Dr MSC 1061, Bethesda, MD 20892 USA. [Olivieri, Laura J.; Cross, Russell R.; Grant, Elena K.] Childrens Natl Med Ctr, 111 Michigan Ave,NW, Washington, DC 20010 USA. [Fontana, Marianna] UCL, Royal Free Hosp, Natl Amyloidosis Ctr, Sch Med, London, England. [Ugander, Martin] Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden. [Ugander, Martin] Karolinska Univ Hosp, Stockholm, Sweden. [Moon, James C.] St Bartholomews Hosp, Barts Heart Ctr, London, England. RP Kellman, P (reprint author), NHLBI, NIH, DHHS, 10 Ctr Dr MSC 1061, Bethesda, MD 20892 USA. EM kellman@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research. NR 30 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD NOV 7 PY 2016 VL 18 AR 77 DI 10.1186/s12968-016-0297-3 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EC3RP UT WOS:000388043600001 PM 27817748 ER PT J AU Murugesan, S Hong, JS Yi, J Li, D Beach, JR Shao, L Meinhardt, J Madison, G Wu, XF Betzig, E Hammer, JA AF Murugesan, Sricharan Hong, Jinsung Yi, Jason Li, Dong Beach, Jordan R. Shao, Lin Meinhardt, John Madison, Grey Wu, Xufeng Betzig, Eric Hammer, John A. TI Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse SO JOURNAL OF CELL BIOLOGY LA English DT Article ID IMMUNOLOGICAL SYNAPSE; ACTIN CYTOSKELETON; F-ACTIN; SIGNAL-TRANSDUCTION; RETROGRADE FLOW; MYOSIN IIA; ACTIVATION; ORGANIZATION; MOLECULES; ADHESION AB Actin assembly and inward flow in the plane of the immunological synapse (IS) drives the centralization of T cell receptor microclusters (TCR MCs) and the integrin leukocyte functional antigen 1 (LFA-1). Using structured-illumination microscopy (SIM), we show that actin arcs populating the medial, lamella-like region of the IS arise from linear actin filaments generated by one or more formins present at the IS distal edge. After traversing the outer, Arp2/3-generated, lamellipodia-like region of the IS, these linear filaments are organized by myosin II into antiparallel concentric arcs. Three-dimensional SIM shows that active LFA-1 often aligns with arcs, whereas TCR MCs commonly reside between arcs, and total internal reflection fluorescence SIM shows TCR MCs being swept inward by arcs. Consistently, disrupting actin arc formation via formin inhibition results in less centralized TCR MCs, missegregated integrin clusters, decreased T-B cell adhesion, and diminished TCR signaling. Together, our results define the origin, organization, and functional significance of a major actomyosin contractile structure at the IS that directly propels TCR MC transport. C1 [Murugesan, Sricharan; Hong, Jinsung; Yi, Jason; Beach, Jordan R.; Meinhardt, John; Madison, Grey; Wu, Xufeng; Hammer, John A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Li, Dong; Shao, Lin; Betzig, Eric] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Li, Dong] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China. RP Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov OI Murugesan, Sricharan/0000-0003-3045-3513 FU Intramural National Heart, Lung, and Blood Institute [1ZIAHL006121-04] FX This work was supported by Intramural National Heart, Lung, and Blood Institute grant 1ZIAHL006121-04 to J.A. Hammer. NR 62 TC 2 Z9 2 U1 4 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD NOV 7 PY 2016 VL 215 IS 3 BP 383 EP 399 DI 10.1083/jcb.201603080 PG 17 WC Cell Biology SC Cell Biology GA EB8JI UT WOS:000387636900013 PM 27799367 ER PT J AU Gopinath, C Law, WD Rodreguez-Molina, JF Prasad, AB Song, LY Crawford, GE Mullikin, JC Svaren, J Antonellis, A AF Gopinath, Chetna Law, William D. Rodriguez-Molina, Jose F. Prasad, Arjun B. Song, Lingyun Crawford, Gregory E. Mullikin, James C. Svaren, John Antonellis, Anthony TI Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation SO BMC GENOMICS LA English DT Article DE Comparative sequence analysis; Transcriptional regulation; Ultra-conserved sequences; Myelination; Schwann cells; SOX10 ID TRANSCRIPTION FACTOR SOX10; MYELIN-ASSOCIATED GLYCOPROTEIN; PERIPHERAL-NERVE MYELINATION; MARIE-TOOTH-DISEASE; SCHWANN-CELLS; OLIGODENDROCYTE DIFFERENTIATION; PROTEIN; GENE; EXPRESSION; IDENTIFICATION AB Background: The transcription factor SOX10 is essential for all stages of Schwann cell development including myelination. SOX10 cooperates with other transcription factors to activate the expression of key myelin genes in Schwann cells and is therefore a context-dependent, pro-myelination transcription factor. As such, the identification of genes regulated by SOX10 will provide insight into Schwann cell biology and related diseases. While genome-wide studies have successfully revealed SOX10 target genes, these efforts mainly focused on myelinating stages of Schwann cell development. We propose that less-biased approaches will reveal novel functions of SOX10 outside of myelination. Results: We developed a stringent, computational-based screen for genome-wide identification of SOX10 response elements. Experimental validation of a pilot set of predicted binding sites in multiple systems revealed that SOX10 directly regulates a previously unreported alternative promoter at SOX6, which encodes a transcription factor that inhibits glial cell differentiation. We further explored the utility of our computational approach by combining it with DNase-seq analysis in cultured Schwann cells and previously published SOX10 ChIP-seq data from rat sciatic nerve. Remarkably, this analysis enriched for genomic segments that map to loci involved in the negative regulation of gliogenesis including SOX5, SOX6, NOTCH1, HMGA2, HES1, MYCN, ID4, and ID2. Functional studies in Schwann cells revealed that: (1) all eight loci are expressed prior to myelination and down-regulated subsequent to myelination; (2) seven of the eight loci harbor validated SOX10 binding sites; and (3) seven of the eight loci are down-regulated upon repressing SOX10 function. Conclusions: Our computational strategy revealed a putative novel function for SOX10 in Schwann cells, which suggests a model where SOX10 activates the expression of genes that inhibit myelination during non-myelinating stages of Schwann cell development. Importantly, the computational and functional datasets we present here will be valuable for the study of transcriptional regulation, SOX protein function, and glial cell biology. C1 [Gopinath, Chetna; Antonellis, Anthony] Univ Michigan, Sch Med, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. [Law, William D.; Antonellis, Anthony] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Rodriguez-Molina, Jose F.] Univ Wisconsin, Cellular & Mol Pathol Program, Madison, WI 53706 USA. [Prasad, Arjun B.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Song, Lingyun; Crawford, Gregory E.] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC 27708 USA. [Crawford, Gregory E.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27708 USA. [Svaren, John] Univ Wisconsin, Waisman Ctr, Madison, WI 53706 USA. [Svaren, John] Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53706 USA. [Antonellis, Anthony] Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI 48109 USA. RP Antonellis, A (reprint author), Univ Michigan, Sch Med, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA.; Antonellis, A (reprint author), Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA.; Antonellis, A (reprint author), Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI 48109 USA. EM antonell@umich.edu OI Svaren, John/0000-0003-2963-7921 FU National Institute of Neurological Diseases and Stroke [NS073748, NS083841]; Intramural Research Program of the National Human Genome Research Institute; Cellular and Molecular Biology Program at the University of Michigan; National Institutes of Health Genetics Training Grant [GM007544]; EDGE Award from the Endowment for the Basic Sciences at the University of Michigan; National Science Foundation FX This project was funded by the National Institute of Neurological Diseases and Stroke (NS073748 to A.A. and NS083841 to J.S.) and the Intramural Research Program of the National Human Genome Research Institute. C.G. was supported by funds from the Cellular and Molecular Biology Program at the University of Michigan. W.D.L. was supported by the National Institutes of Health Genetics Training Grant (GM007544) and an EDGE Award from the Endowment for the Basic Sciences at the University of Michigan. J.F.R-.M. was supported by a National Science Foundation Pre-Doctoral Fellowship. NR 60 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD NOV 7 PY 2016 VL 17 AR 887 DI 10.1186/s12864-016-3167-3 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EB2IO UT WOS:000387183000008 PM 27821050 ER PT J AU Faison, SL Schindler, CW Goldberg, SR Wang, JB AF Faison, Shamia L. Schindler, Charles W. Goldberg, Steven R. Wang, Jia Bei TI l-tetrahydropalmatine reduces nicotine self-administration and reinstatement in rats SO BMC PHARMACOLOGY & TOXICOLOGY LA English DT Article DE levo-Tetrahydropalmatine; Nicotine; Addiction ID LEVO-TETRAHYDROPALMATINE; SMOKING-CESSATION; DOPAMINE RELEASE; PARTIAL AGONIST; ADDICTION; COCAINE; DEPENDENCE; BRAIN; REINFORCEMENT; VARENICLINE AB Background: The negative consequences of nicotine use are well known and documented, however, abstaining from nicotine use and achieving abstinence poses a major challenge for the majority of nicotine users trying to quit. l-Tetrahydropalmatine (l-THP), a compound extracted from the Chinese herb Corydalis, displayed utility in the treatment of cocaine and heroin addiction via reduction of drug-intake and relapse. The present study examined the effects of l-THP on abuse-related effects of nicotine. Methods: Self-administration and reinstatement testing was conducted. Rats trained to self-administer nicotine (0.03 mg/kg/injection) under a fixed-ratio 5 schedule (FR5) of reinforcement were pretreated with l-THP (3 or 5 mg/kg), varenicline (1 mg/kg), bupropion (40 mg/kg), or saline before daily 2-h sessions. Locomotor, food, and microdialysis assays were also conducted in separate rats. Results: l-THP significantly reduced nicotine self-administration (SA). l-THP's effect was more pronounced than the effect of varenicline and similar to the effect of bupropion. In reinstatement testing, animals were pretreated with the same compounds, challenged with nicotine (0.3 mg/kg, s.c.), and reintroduced to pre-extinction conditions. l-THP blocked reinstatement of nicotine seeking more effectively than either varenicline or bupropion. Locomotor data revealed that therapeutic doses of l-THP had no inhibitory effects on ambulatory ability and that l-THP (3 and 5 mg/kg) significantly blocked nicotine induced hyperactivity when administered before nicotine. In in-vivo microdialysis experiments, l-THP, varenicline, and bupropion alone elevated extracellular dopamine (DA) levels in the nucleus accumbens shell (nAcb). Conclusions: Since l-THP reduces nicotine taking and blocks relapse it could be a useful alternative to varenicline and bupropion as a treatment for nicotine addiction. C1 [Faison, Shamia L.; Wang, Jia Bei] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Faison, Shamia L.; Schindler, Charles W.; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,US Dept HHS, Baltimore, MD USA. RP Wang, JB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. EM jwang@rx.umaryland.edu FU National Institutes of Health National Institute on Drug Abuse [DP1DA031401, 3DP1DA031401-02S1]; Intramural Research Program of NIDA, NIH, DHHS FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Avant-Garde Award DP1DA031401] to J.B.W. with diversity supplemental grant to S.L.F (3DP1DA031401-02S1). This research was also supported in part by the Intramural Research Program of NIDA, NIH, DHHS. NR 34 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2050-6511 J9 BMC PHARMACOL TOXICO JI BMC Pharmacol. Toxicol. PD NOV 7 PY 2016 VL 17 AR 49 DI 10.1186/s40360-016-0093-6 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EB3RH UT WOS:000387282900001 PM 27817750 ER PT J AU Yi, J Manna, A Barr, VA Hong, J Neuman, KC Samelson, LE AF Yi, Jason Manna, Asit Barr, Valarie A. Hong, Jennifer Neuman, Keir C. Samelson, Lawrence E. TI madSTORM: a superresolution technique for large-scale multiplexing at single-molecule accuracy SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID T-CELL-RECEPTOR; OPTICAL RECONSTRUCTION MICROSCOPY; PAIR CORRELATION-ANALYSIS; FLUORESCENT-PROBES; LOCALIZATION MICROSCOPY; IMMUNOLOGICAL SYNAPSE; ACTIN; ORGANIZATION; STORM; PALM AB Investigation of heterogeneous cellular structures using single-molecule localization microscopy has been limited by poorly defined localization accuracy and inadequate multiplexing capacity. Using fluorescent nanodiamonds as fiducial markers, we define and achieve localization precision required for single-molecule accuracy in dSTORM images. Coupled with this advance, our new multiplexing strategy, madSTORM, allows accurate targeting of multiple molecules using sequential binding and elution of fluorescent antibodies. madSTORM is used on an activated T-cell to localize 25 epitopes, 14 of which are on components of the same multimolecular T-cell receptor complex. We obtain an average localization precision of 2.6 nm, alignment error of 2.0 nm, and < 0.01% cross-talk. Combining these technical advances affords the ability to move beyond obtaining superresolved structures to defining spatial relationships among constituent molecules within structures. Probing the molecular topology of complex signaling cascades and other heterogeneous networks is feasible with madSTORM. C1 [Yi, Jason; Manna, Asit; Barr, Valarie A.; Samelson, Lawrence E.] NHLBI, Lab Cellular & Mol Biol, NCI, NIH, Bethesda, MD 20892 USA. [Hong, Jennifer; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NHLBI, Lab Cellular & Mol Biol, NCI, NIH, Bethesda, MD 20892 USA. EM samelsonl@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural Research Program of the National Cancer Institute Center for Cancer Research FX We thank Connie Sommers for providing CD4+ mouse T-cells, Sunmee Huh for help with illustration, Xufeng Wu for access to the Nikon N-STORM microscope, and Hari Shroff for comments on the manuscript. This research was supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research. NR 44 TC 1 Z9 1 U1 8 U2 8 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 7 PY 2016 VL 27 IS 22 BP 3591 EP 3600 DI 10.1091/mbc.E16-05-0330 PG 10 WC Cell Biology SC Cell Biology GA EB5CR UT WOS:000387391400020 PM 27708141 ER PT J AU Zhou, ZJ Hu, R Wang, LR Sun, CJ Fu, G Gao, JH AF Zhou, Zijian Hu, Rong Wang, Lirong Sun, Chengjie Fu, Gang Gao, Jinhao TI Water bridge coordination on the metal-rich facets of Gd2O3 nanoplates confers high T-1 relaxivity SO NANOSCALE LA English DT Article ID MRI CONTRAST AGENTS; GADOLINIUM-BASED CONTRAST; IRON-OXIDE NANOPARTICLES; EXPOSED 001 FACETS; SELECTIVE HYDROGENATION; RELAXATION; NANOSHEETS; NANOCRYSTALS; THERAPY; DESIGN AB The realization of the nature of water coordination on the solid surfaces may provoke an essential understanding of T-1 relaxation enhancement, especially in nanoparticulate systems. We report herein that the T-1 relaxivity of Gd2O3 nanoplates is highly dependent on water coordinating behaviors on different surfaces. Gd2O3 nanoplates with metal-rich {100} facets showed an approximately 4-fold higher r(1) value compared to that with oxygen-terminated {111} facets. Density functional theory (DFT) calculations show that the enhanced T-1 relaxivity of Gd2O3 {100} nanoplates may be ascribed to the high density of accessible Gd3+, fast exchange of water, and more importantly, multicenter (one-to-two) coordination for water molecules with magnetic centers on the metal-rich surface. C1 [Zhou, Zijian; Hu, Rong; Wang, Lirong; Sun, Chengjie; Fu, Gang; Gao, Jinhao] Xiamen Univ, State Key Lab Phys Chem Solid Surfaces, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China. [Zhou, Zijian; Hu, Rong; Wang, Lirong; Sun, Chengjie; Fu, Gang; Gao, Jinhao] Xiamen Univ, Key Lab Chem Biol Fujian Prov, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. [Zhou, Zijian] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Gao, JH (reprint author), Xiamen Univ, State Key Lab Phys Chem Solid Surfaces, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China.; Gao, JH (reprint author), Xiamen Univ, Key Lab Chem Biol Fujian Prov, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. EM jhgao@xmu.edu.cn FU National Key Basic Research Program of China [2013CB933901, 2014CB744502, 2014CB932004]; National Natural Science Foundation of China [21222106, 21521004, 81370042, 81430041]; Fok Ying Tung Education Foundation [142012]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the National Key Basic Research Program of China (2013CB933901, 2014CB744502, and 2014CB932004), the National Natural Science Foundation of China (21222106, 21521004, 81370042, and 81430041), Fok Ying Tung Education Foundation (142012), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 48 TC 0 Z9 0 U1 27 U2 27 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PD NOV 7 PY 2016 VL 8 IS 41 BP 17887 EP 17894 DI 10.1039/c6nr06444b PG 8 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EB4HI UT WOS:000387331100021 PM 27722744 ER PT J AU Kim, SH Vlijm, R van der Torre, J Dalal, Y Dekker, C AF Kim, Sung Hyun Vlijm, Rifka van der Torre, Jaco Dalal, Yamini Dekker, Cees TI CENP-A and H3 Nucleosomes Display a Similar Stability to Force-Mediated Disassembly SO PLOS ONE LA English DT Article ID HISTONE CHAPERONE NAP1; CENTROMERIC NUCLEOSOME; SINGLE-MOLECULE; MAGNETIC TWEEZERS; CRYSTAL-STRUCTURE; CHROMATIN FIBERS; KINETOCHORE; DNA; DYNAMICS; CORE AB Centromere-specific nucleosomes are a central feature of the kinetochore complex during mitosis, in which microtubules exert pulling and pushing forces upon the centromere. CENP-A nucleosomes have been assumed to be structurally unique, thereby providing resilience under tension relative to their H3 canonical counterparts. Here, we directly test this hypothesis by subjecting CENP-A and H3 octameric nucleosomes, assembled on random or on centromeric DNA sequences, to varying amounts of applied force by using single-molecule magnetic tweezers. We monitor individual disassembly events of CENP-A and H3 nucleosomes. Regardless of the DNA sequence, the force-mediated disassembly experiments for CENP-A and H3 nucleosomes demonstrate similar rupture forces, life time residency and disassembly steps. From these experiments, we conclude that CENP-A does not, by itself, contribute unique structural features to the nucleosome that lead to a significant resistance against force-mediated disruption. The data present insights into the mechanistic basis for how CENP-A nucleosomes might contribute to the structural foundation of the centromere in vivo. C1 [Kim, Sung Hyun; Vlijm, Rifka; van der Torre, Jaco; Dekker, Cees] Delft Univ Technol, Kavli Inst Nanosci Delft, Dept Bionanosci, Delft, Netherlands. [Dalal, Yamini] NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, Ctr Canc Res,NHI, Bethesda, MD 20892 USA. [Vlijm, Rifka] German Canc Res Ctr, Div Opt Nanoscopy, Heidelberg, Germany. RP Dekker, C (reprint author), Delft Univ Technol, Kavli Inst Nanosci Delft, Dept Bionanosci, Delft, Netherlands.; Dalal, Y (reprint author), NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, Ctr Canc Res,NHI, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov; C.Dekker@tudelft.nl FU ERC Advanced Grant SynDiv [669598]; Netherlands Organization for Scientific Research (NWO/OCW) [as part of the Frontiers of Nanoscience program]; intramural research program of the Center for Cancer Research under the auspices of the National Cancer Institute at the NIH FX This work was supported by the ERC Advanced Grant SynDiv [grant number 669598 to C.D.]; the Netherlands Organization for Scientific Research (NWO/OCW) [as part of the Frontiers of Nanoscience program]. YD is funded by the intramural research program of the Center for Cancer Research under the auspices of the National Cancer Institute at the NIH. NR 71 TC 1 Z9 1 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 7 PY 2016 VL 11 IS 11 AR e0165078 DI 10.1371/journal.pone.0165078 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8BB UT WOS:000387614800006 PM 27820823 ER PT J AU Weth-Malsch, D Langeslag, M Beroukas, D Zangrandi, L Kastenberger, I Quarta, S Malsch, P Kalpachidou, T Schwarzer, C Proia, RL Haberberger, RV Kress, M AF Weth-Malsch, Daniela Langeslag, Michiel Beroukas, Dimitra Zangrandi, Luca Kastenberger, Iris Quarta, Serena Malsch, Philipp Kalpachidou, Theodora Schwarzer, Christoph Proia, Richard L. Haberberger, Rainer V. Kress, Michaela TI Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE sphingosine 1-phosphate; S1P receptor 3; hippocampus; working memory; neuron excitability ID PROTEIN-COUPLED RECEPTOR; MOUSE VENTRICULAR FIBROBLASTS; CENTRAL-NERVOUS-SYSTEM; MOSSY FIBER TERMINALS; SENSORY NEURONS; MICE LACKING; SPHINGOSINE-1-PHOSPHATE; BRAIN; ALTERNATION; LESIONS AB Understanding the role of the bioactive lipid mediator sphingosine 1-phosphate (S1P) within the central nervous system has recently gained more and more attention, as it has been connected to major diseases such as multiple sclerosis and Alzheimer's disease. Even though much data about the functions of the five S1P receptors has been collected for other organ systems, we still lack a complete understanding for their specific roles, in particular within the brain. Therefore, it was the aim of this study to further elucidate the role of S1P receptor subtype 3 (S1P(3)) in vivo and in vitro with a special focus on the hippocampus. Using an S1P(3) knock-out mouse model we applied a range of behavioral tests, performed expression studies, and whole cell patch clamp recordings in acute hippocampal slices. We were able to show that S1P(3) deficient mice display a significant spatial working memory deficit within the T-maze test, but not in anxiety related tests. Furthermore, S1p3 mRNA was expressed throughout the hippocampal formation. Principal neurons in area CA3 lacking S1P(3) showed significantly increased interspike intervals and a significantly decreased input resistance. Upon stimulation with S1P CA3 principal neurons from both wildtype and S1P(3)(-/-) mice displayed significantly increased evoked EPSC amplitudes and decay times, whereas rise times remained unchanged. These results suggest a specific involvement of S1P(3) for the establishment of spatial working memory and neuronal excitability within the hippocampus. C1 [Weth-Malsch, Daniela; Langeslag, Michiel; Quarta, Serena; Malsch, Philipp; Kalpachidou, Theodora; Kress, Michaela] Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria. [Beroukas, Dimitra; Haberberger, Rainer V.] Flinders Univ S Australia, Anat & Histol, Adelaide, SA, Australia. [Beroukas, Dimitra; Haberberger, Rainer V.] Flinders Univ S Australia, Ctr Neurosci, Adelaide, SA, Australia. [Zangrandi, Luca; Kastenberger, Iris; Schwarzer, Christoph] Med Univ Innsbruck, Dept Pharmacol, Innsbruck, Austria. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. RP Kress, M (reprint author), Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria. EM Michaela.Kress@i-med.ac.at OI Haberberger, Rainer Viktor/0000-0001-8043-3786 FU Intramural Research Programs of the National Instituts of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Austrian Research Funding Agency FWF [P20562, P25345, SPIN-01206-B6]; European FP7 programme (ncRNAPain) [GA 602133] FX This work was supported by the Intramural Research Programs of the National Instituts of Health, National Institute of Diabetes and Digestive and Kidney Diseases to RP, the Austrian Research Funding Agency FWF (project grants P20562, P25345, and SPIN-01206-B6) and the European FP7 programme (ncRNAPain - GA 602133) to MK. The authors thank Markus Doblander for expert technical assistance. NR 48 TC 0 Z9 0 U1 5 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD NOV 7 PY 2016 VL 10 AR 258 DI 10.3389/fncel.2016.00258 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EA9QA UT WOS:000386977700001 PM 27872583 ER PT J AU Chin, PY Dorian, CL Hutchinson, MR Olson, DM Rice, KC Moldenhauer, LM Robertson, SA AF Chin, Peck Yin Dorian, Camilla L. Hutchinson, Mark R. Olson, David M. Rice, Kenner C. Moldenhauer, Lachlan M. Robertson, Sarah A. TI Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth SO SCIENTIFIC REPORTS LA English DT Article ID FETAL-GROWTH RESTRICTION; FUSOBACTERIUM-NUCLEATUM; BLOOD MONOCYTES; LABOR; EXPRESSION; NALOXONE; PARTURITION; MEMBRANES; LIPOPOLYSACCHARIDE; RESPONSES AB Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (-)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting. C1 [Chin, Peck Yin; Dorian, Camilla L.; Moldenhauer, Lachlan M.; Robertson, Sarah A.] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. [Chin, Peck Yin; Dorian, Camilla L.; Hutchinson, Mark R.; Moldenhauer, Lachlan M.; Robertson, Sarah A.] Univ Adelaide, Adelaide Med Sch, Adelaide, SA 5005, Australia. [Hutchinson, Mark R.] Australian Res Council, Ctr Excellence Nanoscale BioPhoton, Adelaide, SA 5005, Australia. [Olson, David M.] Univ Alberta, Dept Obstet & Gynecol, Edmonton, AB T6G 2S2, Canada. [Olson, David M.] Univ Alberta, Dept Pediat, Edmonton, AB T6G 2S2, Canada. [Olson, David M.] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2S2, Canada. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Robertson, SA (reprint author), Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia.; Robertson, SA (reprint author), Univ Adelaide, Adelaide Med Sch, Adelaide, SA 5005, Australia. EM sarah.robertson@adelaide.edu.au OI Hutchinson, Mark/0000-0003-2154-5950 FU National Health and Medical Research Council of Australia [APP1026178, APP465423]; Canadian Institutes of Health Research [2011-09-15]; Australian Research Council [DP110100297]; NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism (NIAAA) FX This work was supported by project and fellowship grants from the National Health and Medical Research Council of Australia (APP1026178 and APP465423), the Canadian Institutes of Health Research (2011-09-15) and the Australian Research Council (DP110100297). A portion of this work was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). NR 65 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 7 PY 2016 VL 6 AR 36112 DI 10.1038/srep36112 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA9ZD UT WOS:000387002300001 PM 27819333 ER PT J AU Xu, XQ Zhang, B Yang, SL An, S Ribeiro, JMC Andersen, JF AF Xu, Xueqing Zhang, Bei Yang, Shilong An, Su Ribeiro, Jose M. C. Andersen, John F. TI Structure and Function of FS50, a salivary protein from the flea Xenopsylla cheopis that blocks the sodium channel Na(V)1.5 SO SCIENTIFIC REPORTS LA English DT Article ID BETA-SCORPION TOXIN; ACTIVATION; INHIBITOR; BINDING; INSECT; PEPTIDE; GLANDS; TOOLS; SITE AB Naturally occurring toxins have been invaluable tools for the study of structural and functional relationships of voltage-gated sodium channels (VGSC). Few studies have been made of potential channel-modulating substances from blood-feeding arthropods. He we describe the characterization FS50, a salivary protein from the flea, Xenopsylla cheopis, that exhibits an inhibitory activity against the Na(V)1.5 channel with an IC50 of 1.58 mu M. The pore-blocking mechanism of this toxin is evident from the kinetics of activation and inactivation suggesting that FS50 does not interfere with the voltage sensor of Na(V)1.5. FS50 exhibits high specificity for Na(V)1.5, since 10 mu M FS50 had no discernable effect on voltage-gated Na+, K+ and Ca2+ channels in rat dorsal root ganglia or VGSC forms individually expressed in HEK 293T cells. Furthermore, intravenous injection of FS50 into rats and monkeys elicited recovery from arrhythmia induced by BaCl2, as would be expected from a blockade of Na(V)1.5. The crystal structure of FS50 revealed a beta alpha beta beta domain similar to that of scorpion beta toxin and a small N-terminal beta alpha beta domain. Site-directed mutagenesis experiments have implicated a basic surface including the side chains of Arg 6, His 11 and Lys 32 as potentially important in the FS50 Na(V)1.5 interaction. C1 [Xu, Xueqing; Zhang, Bei] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Guangdong, Peoples R China. [Xu, Xueqing; Ribeiro, Jose M. C.; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Yang, Shilong; An, Su] Chinese Acad Sci, Kunming Inst Zool, Lab Anim Models & Human Dis Mech, Kunming 650223, Yunnan, Peoples R China. RP Xu, XQ (reprint author), Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Guangdong, Peoples R China.; Xu, XQ; Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM xu2003@smu.edu.cn; jandersen@niaid.nih.gov FU Chinese National Natural Science Foundation [3137078]; Chinese Ministry of Science and Technology [2010CB529800]; National Institutes of Health intramural research program of NIAID FX The authors thank the staff of the Southeast Regional Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory for assistance with X-ray data collection. This work was supported in part by the Chinese National Natural Science Foundation (3137078), the Chinese Ministry of Science and Technology (2010CB529800) and the National Institutes of Health intramural research program of NIAID. NR 30 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 7 PY 2016 VL 6 AR 36574 DI 10.1038/srep36574 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB0VJ UT WOS:000387064000001 PM 27819327 ER PT J AU Lee, J Chowell, G Jung, E AF Lee, Jonggul Chowell, Gerardo Jung, Eunok TI A dynamic compartmental model for the Middle East respiratory syndrome outbreak in the Republic of Korea: A retrospective analysis on control interventions and superspreading events SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE MERS; Superspreader; Nosocomial infections; Mathematical modeling; Republic of Korea; Infectious diseases ID HEALTH-CARE FACILITIES; MERS-COV; INFECTIOUS-DISEASES; CORONAVIRUS; TRANSMISSION; SARS; EPIDEMIOLOGY AB The 2015 Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea has provided an opportunity to improve our understanding of the spread of MERS linked to healthcare settings. Here we designed a dynamic transmission model to analyze the MERS outbreak in the Republic of Korea based on confirmed cases reported during the period May 20 July 4, 2015. Our model explicitly incorporates superspreading events and time-dependent transmission and isolation rates. Our model was able to provide a good fit to the trajectory of the outbreak and was useful to analyze the role of hypothetical control scenarios. Specifically, we assessed the impact of the timing of control measures, especially associated with a reduction of the transmission rate and diagnostic delays on outbreak size and duration. Early interventions within 1 week after the epidemic onset, for instance, including the initial government announcement to the public about the list of hospitals exposed to MERS coronavirus (MERS-CoV), show a promising means to reduce the size (>71%) and duration (>35%) of the MERS epidemic. Finally, we also present results of an uncertainty analysis focused on the role of superspreading events. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Lee, Jonggul; Jung, Eunok] Konkuk Univ, Dept Math, Seoul 05029, South Korea. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Jung, E (reprint author), Konkuk Univ, Dept Math, Seoul 05029, South Korea. EM jack9872@konkuk.ac.kr; gchowell@gsu.edu; junge@konkuk.ac.kr FU Korea National Research Foundation (NRF) - Korea government (MEST) [NRF-2015R1A2A1A15054463]; Konkuk University FX The research work of Jung was supported by the Korea National Research Foundation (NRF) grant funded by the Korea government (MEST) (NRF-2015R1A2A1A15054463). Jung's work is also resulted from the Konkuk University research support program. NR 32 TC 0 Z9 0 U1 8 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD NOV 7 PY 2016 VL 408 BP 118 EP 126 DI 10.1016/j.jtbi.2016.08.009 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA DX8IG UT WOS:000384630700012 PM 27521523 ER PT J AU Lewis, DEA Gussin, GN Adhya, S AF Lewis, Dale E. A. Gussin, Gary N. Adhya, Sankar TI New Insights into the Phage Genetic Switch: Effects of Bacteriophage Lambda Operator Mutations on DNA Looping and Regulation of P-R, P-L, and P-RM SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE prophage lambdagenetic switch; DNA looping; CI repressor; transcription ID OPEN COMPLEX-FORMATION; RNA-POLYMERASE; TRANSCRIPTION INITIATION; PRM PROMOTER; REPRESSOR SYNTHESIS; NEGATIVE CONTROL; PAIR DELETION; CI REPRESSOR; IN-VITRO; ACTIVATION AB One of the best understood systems in genetic regulatory biology is the so-called "genetic switch" that determines the choice the phage-encoded CI repressor binds cooperatively to tripartite operators, O-L and O-R, in a defined pattern, thus blocking the transcription at two lytic promoters, P-L and P-R, and auto-regulating the promoter, P-RM, which directs CI synthesis by the prophage. Fine-tuning of the maintenance of lysogeny is facilitated by interactions between CI dimers bound to O-R and O-L through the formation of a loop by the intervening DNA segment. By using a purified in vitro transcription system, we have genetically dissected the roles of individual operator sites in the formation of the DNA loop and thus have gained several new and unexpected insights into the system. First, although both O-R and O-L are tripartite, the presence of only a single active CI binding site in one of the two operators is sufficient for DNA loop formation. Second, in PL, unlike in P-R, the promoter distal operator site, O(L)3, is sufficient to directly repress PL. Third, DNA looping mediated by the formation of CI octamers arising through the interaction of pairs of dimers bound to adjacent operator sites in OR and OL does not require OR and OL to be aligned "in register", that is, CI bound to "out-of-register" sub-operators, for example, O(L)1 similar to O(1)2 and O(R)2 similar to O(R)3, can also mediate loop formation. Finally, based on an examination of the mechanism of activation of PRM when only O(R)1 or O(R)2 are wild type, we hypothesize that RNA polymerase bound at P-R interferes with DNA loop formation. Thus, the formation of DNA loops involves potential interactions between proteins bound at numerous cis-acting sites, which therefore very subtly contribute to the regulation of the "switch". (C) 2016 Published by Elsevier Ltd. C1 [Lewis, Dale E. A.; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gussin, Gary N.] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank our colleagues in the laboratory for helpful discussions. NR 49 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD NOV 6 PY 2016 VL 428 IS 22 BP 4438 EP 4456 DI 10.1016/j.jmb.2016.08.027 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC1AG UT WOS:000387835300003 PM 27670714 ER PT J AU Oronsky, B Caroen, S Zeman, K Quinn, M Brzezniak, C Scicinski, J Cabrales, P Reid, TR Trepel, JB Abrouk, ND Larson, C Oronsky, A Lybeck, HE Day, RM Carter, CA AF Oronsky, Bryan Caroen, Scott Zeman, Karen Quinn, Mary Brzezniak, Christina Scicinski, Jan Cabrales, Pedro Reid, Tony R. Trepel, Jane B. Abrouk, Nacer D. Larson, Christopher Oronsky, Arnold Lybeck, Harry E. Day, Regina M. Carter, Corey A. TI A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient After Priming with RRx-001 SO CLINICAL MEDICINE INSIGHTS-ONCOLOGY LA English DT Article DE resistant SCLC; RRx-001; resistance reversal; resensitization; platinum doublets; epigenetic ID MELANOMA BRAIN METASTASES; DRUG-RESISTANCE; TOPOTECAN; THERAPY; RADIOTHERAPY; MECHANISMS; UPDATE; TRIALS AB As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high-and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT; NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status. C1 [Oronsky, Bryan; Caroen, Scott; Scicinski, Jan] EpicentRx, Mountain View, CA 94040 USA. [Zeman, Karen; Quinn, Mary; Brzezniak, Christina; Carter, Corey A.] Walter Reed Mil Med Ctr, Bethesda, MD USA. [Cabrales, Pedro] UCSD, Dept Bioengn, La Jolla, CA USA. [Reid, Tony R.; Larson, Christopher] UCSD, Moores Canc Ctr, La Jolla, CA USA. [Trepel, Jane B.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Abrouk, Nacer D.] Innovexe, Palo Alto, CA USA. [Oronsky, Arnold] InterWest Partners, Menlo Pk, CA USA. [Lybeck, Harry E.] Univ Helsinki, Helsinki, Finland. [Day, Regina M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Caroen, S (reprint author), EpicentRx, Mountain View, CA 94040 USA. EM scaroen@epicentrx.com NR 26 TC 0 Z9 0 U1 4 U2 4 PU LIBERTAS ACAD PI AUCKLAND PA PO BOX 300-874, ALBANY 0752, AUCKLAND, 00000, NEW ZEALAND SN 1179-5549 J9 CLIN MED INSIGHTS-ON JI Clin. Med. Insights-Oncol. PD NOV 6 PY 2016 VL 10 BP 105 EP 108 DI 10.4137/CMO.S40429 PG 4 WC Oncology SC Oncology GA EA9CL UT WOS:000386938600001 PM 27840583 ER PT J AU Blanquart, F Grabowski, MK Herbeck, J Nalugoda, F Serwadda, D Eller, MA Robb, ML Gray, R Kigozi, G Laeyendecker, O Lythgoe, KA Nakigozi, G Quinn, TC Reynolds, SJ Wawer, MJ Fraser, C AF Blanquart, Francois Grabowski, Mary Kate Herbeck, Joshua Nalugoda, Fred Serwadda, David Eller, Michael A. Robb, Merlin L. Gray, Ronald Kigozi, Godfrey Laeyendecker, Oliver Lythgoe, Katrina A. Nakigozi, Gertrude Quinn, Thomas C. Reynolds, Steven J. Wawer, Maria J. Fraser, Christophe TI A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda SO ELIFE LA English DT Article ID GENITAL ULCER DISEASE; SIMPLEX-VIRUS TYPE-2; VIRAL LOAD; PROGNOSTIC MARKERS; PROSPECTIVE COHORT; SET-POINT; PROGRESSION; POPULATION; INFECTION; RAKAI AB Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals. C1 [Blanquart, Francois; Lythgoe, Katrina A.; Fraser, Christophe] Imperial Coll London, MRC Ctr Outbreak Anal & Modelling, London, England. [Blanquart, Francois; Lythgoe, Katrina A.; Fraser, Christophe] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Blanquart, Francois; Lythgoe, Katrina A.; Fraser, Christophe] Imperial Coll London, Sch Publ Hlth, London, England. [Grabowski, Mary Kate; Gray, Ronald; Wawer, Maria J.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Grabowski, Mary Kate; Gray, Ronald; Wawer, Maria J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Herbeck, Joshua] Univ Washington, Int Clin Res Ctr, Seattle, WA 98195 USA. [Herbeck, Joshua] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Nalugoda, Fred; Serwadda, David; Gray, Ronald; Kigozi, Godfrey; Nakigozi, Gertrude] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Eller, Michael A.; Robb, Merlin L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Eller, Michael A.; Robb, Merlin L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Laeyendecker, Oliver; Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lythgoe, Katrina A.] Univ Oxford, Dept Zool, Oxford, England. [Fraser, Christophe] Univ Oxford, Big Data Inst, Nuffield Dept Med, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England. RP Blanquart, F (reprint author), Imperial Coll London, MRC Ctr Outbreak Anal & Modelling, London, England.; Blanquart, F (reprint author), Imperial Coll London, Dept Infect Dis Epidemiol, London, England.; Blanquart, F (reprint author), Imperial Coll London, Sch Publ Hlth, London, England. EM f.blanguart@imperial.ac.uk OI Fraser, Christophe/0000-0003-2399-9657 FU European Commission [657768]; National Institute of Allergy and Infectious Diseases [R01 AI29314, R01 A134826, U01 AI11171-01-02]; National Institute of Child Health and Development [5P30 HD 06268]; John E. Fogarty Foundation for Persons with Intellectual and Developmental Disabilities [5D43TW00010]; John Snow Inc. [5024-30]; Pfizer [5024-30]; Rockefeller Foundation; World Bank Group; National Institutes of Health [P30AI027757, R01AI108490]; U.S. Department of Defense [W81XWH-07-2-0067]; Henry M. Jackson Foundation [W81XWH-07-2-0067]; European Research Council [PBDR-339251] FX European Commission Intra European Fellowship 657768 Francois Blanquart; National Institute of Allergy and Infectious Diseases R01 AI29314 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; National Institute of Child Health and Development 5P30 HD 06268 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; John E. Fogarty Foundation for Persons with Intellectual and Developmental Disabilities 5D43TW00010 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; John Snow Inc. 5024-30 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; Pfizer 5024-30 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; Rockefeller Foundation Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; World Bank Group Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; National Institute of Allergy and Infectious Diseases R01 A134826 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; National Institute of Allergy and Infectious Diseases U01 AI11171-01-02 Mary Kate Grabowski Fred Nalugoda David Serwadda Michael A Eller Merlin L Robb Ronald Gray Godfrey Kigozi Oliver Laeyendecker Gertrude Nakigozi Thomas C Quinn Steven J Reynolds Maria J Wawer; National Institutes of Health P30AI027757 Joshua Herbeck; National Institutes of Health R01AI108490 Joshua Herbeck; U.S. Department of Defense W81XWH-07-2-0067 Michael A Eller Merlin L Robb; Henry M. Jackson Foundation W81XWH-07-2-0067 Michael A Eller Merlin L Robb; European Research Council PBDR-339251 Christophe Fraser NR 67 TC 3 Z9 3 U1 3 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 5 PY 2016 VL 5 AR e20492 DI 10.7554/eLife.20492 PG 31 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED2NJ UT WOS:000388683400001 ER PT J AU Ratha, BN Ghosh, A Brender, JR Gayen, N Ilyas, H Neeraja, C Das, KP Mandal, AK Bhunia, A AF Ratha, Bhisma N. Ghosh, Anirban Brender, Jeffrey R. Gayen, Nilanjan Ilyas, Humaira Neeraja, Chilukoti Das, Kali P. Mandal, Atin K. Bhunia, Anirban TI Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide: MECHANISTIC DETAILS STUDIED BY SPECTROSCOPY IN COMBINATION WITH MICROSCOPY SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE amyloid; atomic force microscopy (AFM); fluorescence anisotropy; inhibitor; insulin ID TRANSFER DIFFERENCE NMR; AGGREGATION PATHWAYS; ALZHEIMERS-DISEASE; BETA FIBRILS; PROTEINS; KINETICS; HEXAMER; BINDING; LIGAND; HELIX AB The aggregation of insulin into amyloid fibers has been a limiting factor in the development of fast acting insulin analogues, creating a demand for excipients that limit aggregation. Despite the potential demand, inhibitors specifically targeting insulin have been few in number. Here we report a non-toxic and serum stable-designed heptapeptide, KR7 (KPWWPRR-NH2), that differs significantly from the primarily hydrophobic sequences that have been previously used to interfere with insulin amyloid fibrillation. Thioflavin T fluorescence assays, circular dichroism spectroscopy, and one-dimensional proton NMR experiments suggest KR7 primarily targets the fiber elongation step with little effect on the early oligomerization steps in the lag time period. From confocal fluorescence and atomic force microscopy experiments, the net result appears to be the arrest of aggregation in an early, non-fibrillar aggregation stage. This mechanism is noticeably different from previous peptide-based inhibitors, which have primarily shifted the lag time with little effect on later stages of aggregation. As insulin is an important model system for understanding protein aggregation, the new peptide may be an important tool for understanding peptide-based inhibition of amyloid formation. C1 [Ratha, Bhisma N.; Ghosh, Anirban; Ilyas, Humaira; Bhunia, Anirban] Bose Inst, Dept Biophys, P 1-12 CIT Scheme 7 M, Kolkata 700054, India. [Gayen, Nilanjan; Mandal, Atin K.] Bose Inst, Dept Mol Med, P 1-12 CIT Scheme 7 M, Kolkata 700054, India. [Brender, Jeffrey R.] NIH, Radiat Biol Branch, Bethesda, MD 20814 USA. [Neeraja, Chilukoti] TIFR Ctr Interdisciplinary Sci TCIS, Hyderabad 500075, Andhra Pradesh, India. [Das, Kali P.] Bose Inst, Dept Chem, 93-1 APC Rd, Kolkata 700009, India. RP Bhunia, A (reprint author), Bose Inst, Dept Biophys, P 1-12 CIT Scheme 7 M, Kolkata 700054, India. EM anirbanbhunia@gmail.com FU DBT, Government of India [BT/PR3106/INF/22/138/2011] FX A. B. acknowledges DBT, Government of India, for infrastructure development Fund BT/PR3106/INF/22/138/2011 to the Bose Institute for procuring a 700-MHz NMR spectrometer with cryoprobe. Central Instrument Facility (CIF) of Bose Institute is greatly acknowledged. NR 66 TC 0 Z9 0 U1 15 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 4 PY 2016 VL 291 IS 45 BP 23545 EP 23556 DI 10.1074/jbc.M116.742460 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC1RH UT WOS:000387884400016 PM 27679488 ER PT J AU Dougherty, EJ Elinoff, JM Ferreyra, GA Hou, A Cai, RM Sun, JF Blaine, KP Wang, SB Danner, RL AF Dougherty, Edward J. Elinoff, Jason M. Ferreyra, Gabriela A. Hou, Angela Cai, Rongman Sun, Junfeng Blaine, Kevin P. Wang, Shuibang Danner, Robert L. TI Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling: DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE AP1 transcription factor (AP-1); glucocorticoid receptor; inflammation; mineralocorticoid receptor; NF-B transcription factor; nuclear receptor; trans-repression ID NF-KAPPA-B; COMPOSITE RESPONSE ELEMENT; STEROID-HORMONE RECEPTORS; PROSTATE CARCINOMA-CELLS; GLUCOCORTICOID-RECEPTOR; ACTIVATOR PROTEIN-1; VASCULAR INFLAMMATION; MYOCARDIAL-INFARCTION; NEGATIVE REGULATION; HEART-FAILURE AB Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature. C1 [Dougherty, Edward J.; Elinoff, Jason M.; Ferreyra, Gabriela A.; Hou, Angela; Cai, Rongman; Sun, Junfeng; Blaine, Kevin P.; Wang, Shuibang; Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Hou, Angela] NYU, Langone Med Ctr, 550 1st Ave, New York, NY 10016 USA. RP Dougherty, EJ; Danner, RL (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Rm 2C145, Bethesda, MD 20892 USA. EM doughertye@cc.nih.gov; rdanner@nih.gov FU National Institutes of Health intramural funds FX This work was supported by National Institutes of Health intramural funds. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 76 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 4 PY 2016 VL 291 IS 45 BP 23628 EP 23644 DI 10.1074/jbc.M116.732248 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC1RH UT WOS:000387884400023 PM 27650495 ER PT J AU Ritter, DI Roychowdhury, S Roy, A Rao, S Landrum, MJ Sonkin, D Shekar, M Davis, CF Hart, RK Micheel, C Weaver, M Van Allen, EM Parsons, DW McLeod, HL Watson, MS Plon, SE Kulkarni, S Madhavan, S AF Ritter, Deborah I. Roychowdhury, Sameek Roy, Angshumoy Rao, Shruti Landrum, Melissa J. Sonkin, Dmitriy Shekar, Mamatha Davis, Caleb F. Hart, Reece K. Micheel, Christine Weaver, Meredith Van Allen, Eliezer M. Parsons, Donald W. McLeod, Howard L. Watson, Michael S. Plon, Sharon E. Kulkarni, Shashikant Madhavan, Subha CA ClinGen Somatic Canc Working Grp TI Somatic cancer variant curation and harmonization through consensus minimum variant level data SO GENOME MEDICINE LA English DT Article DE Cancer genomics; Somatic variant interpretation; Data standard; Somatic variant curation ID MICROARRAY EXPERIMENT MIAME; DECISION-SUPPORT; MEDICINE; GENOME; INFORMATION; PLATFORM; CHALLENGES; STANDARDS; ONCOLOGY; TUMOR AB Background: To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods: We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD. Results: Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions: We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice. C1 [Ritter, Deborah I.; Roy, Angshumoy; Parsons, Donald W.; Plon, Sharon E.; Kulkarni, Shashikant] Baylor Coll Med, Houston, TX 77030 USA. [Ritter, Deborah I.; Roy, Angshumoy; Parsons, Donald W.; Plon, Sharon E.; Kulkarni, Shashikant] Texas Childrens Hosp, Houston, TX 77030 USA. [Roychowdhury, Sameek] Ohio State Univ, Columbus, OH 43210 USA. [Rao, Shruti; Madhavan, Subha] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [Rao, Shruti; Madhavan, Subha] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Landrum, Melissa J.] Natl Ctr Biotechnol Informat, Bethesda, MD USA. [Sonkin, Dmitriy] NCI, Rockville, MD USA. [Shekar, Mamatha] Illumina, San Diego, CA USA. [Davis, Caleb F.] MolecularMatch, Houston, TX USA. [Hart, Reece K.] Invitae, San Francisco, CA USA. [Micheel, Christine] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Weaver, Meredith] Amer Coll Med Genet & Genom, Bethesda, MD USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McLeod, Howard L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Madhavan, S (reprint author), Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA.; Madhavan, S (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. EM sm696@georgetown.edu OI Micheel, Christine/0000-0002-7744-9039; Hart, Reece/0000-0003-3463-0775 FU National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute [U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E]; Intramural Research Program of the NIH, National Library of Medicine; NHGRI, BD2K Program [01HG008390]; NHGRI/NCI [1U01HG006485]; [U01HG006492]; [K08CA188615] FX ClinGen is funded by the National Human Genome Research Institute, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E). ClinVar is supported by the Intramural Research Program of the NIH, National Library of Medicine. Additional funding: 01HG008390 (NHGRI, BD2K Program) to SM; U01HG006492 and K08CA188615 to EMV. The BASIC3 study is a Clinical Sequencing Exploratory Research (CSER) program project supported by NHGRI/NCI 1U01HG006485 to AR, SEP, and DWP. NR 33 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD NOV 4 PY 2016 VL 8 AR 117 DI 10.1186/s13073-016-0367-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EB8DS UT WOS:000387621800001 PM 27814769 ER PT J AU Feunang, YD Eisner, R Knox, C Chepelev, L Hastings, J Owen, G Fahy, E Steinbeck, C Subramanian, S Bolton, E Greiner, R Wishart, DS AF Feunang, Yannick Djoumbou Eisner, Roman Knox, Craig Chepelev, Leonid Hastings, Janna Owen, Gareth Fahy, Eoin Steinbeck, Christoph Subramanian, Shankar Bolton, Evan Greiner, Russell Wishart, David S. TI ClassyFire: automated chemical classification with a comprehensive, computable taxonomy SO JOURNAL OF CHEMINFORMATICS LA English DT Article DE Structure-based classification; Ontology; Taxonomy; Text-based search; Inference; Annotation; Database; Data integration ID METABOLOME DATABASE; SMALL MOLECULES; ONTOLOGY; DESIGN; CHEMISTRY; GENE; TOOL AB Background: Scientists have long been driven by the desire to describe, organize, classify, and compare objects using taxonomies and/or ontologies. In contrast to biology, geology, and many other scientific disciplines, the world of chemistry still lacks a standardized chemical ontology or taxonomy. Several attempts at chemical classification have been made; but they have mostly been limited to either manual, or semi-automated proof-of-principle applications. This is regrettable as comprehensive chemical classification and description tools could not only improve our understanding of chemistry but also improve the linkage between chemistry and many other fields. For instance, the chemical classification of a compound could help predict its metabolic fate in humans, its druggability or potential hazards associated with it, among others. However, the sheer number (tens of millions of compounds) and complexity of chemical structures is such that any manual classification effort would prove to be near impossible. Results: We have developed a comprehensive, flexible, and computable, purely structure-based chemical taxonomy (ChemOnt), along with a computer program (ClassyFire) that uses only chemical structures and structural features to automatically assign all known chemical compounds to a taxonomy consisting of >4800 different categories. This new chemical taxonomy consists of up to 11 different levels (Kingdom, SuperClass, Class, SubClass, etc.) with each of the categories defined by unambiguous, computable structural rules. Furthermore each category is named using a consensus-based nomenclature and described (in English) based on the characteristic common structural properties of the compounds it contains. The ClassyFire webserver is freely accessible at http://classyfire.wishartlab.com/. Moreover, a Ruby API version is available at https://bitbucket.org/wishartlab/classyfire_api, which provides programmatic access to the ClassyFire server and database. ClassyFire has been used to annotate over 77 million compounds and has already been integrated into other software packages to automatically generate textual descriptions for, and/or infer biological properties of over 100,000 compounds. Additional examples and applications are provided in this paper. Conclusion: ClassyFire, in combination with ChemOnt (ClassyFire's comprehensive chemical taxonomy), now allows chemists and cheminformaticians to perform large-scale, rapid and automated chemical classification. Moreover, a freely accessible API allows easy access to more than 77 million "ClassyFire" classified compounds. The results can be used to help annotate well studied, as well as lesser-known compounds. In addition, these chemical classifications can be used as input for data integration, and many other cheminformatics-related tasks. C1 [Feunang, Yannick Djoumbou; Wishart, David S.] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E8, Canada. [Eisner, Roman] Jobber Field Serv Software, 10520 Jasper Ave, Edmonton, AB T5J 1Z7, Canada. [Knox, Craig; Greiner, Russell; Wishart, David S.] Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2E8, Canada. [Wishart, David S.] Natl Inst Nanotechnol NINT, Natl Res Council, Edmonton, AB T6G 2M9, Canada. [Chepelev, Leonid] Univ Ottawa, Ottawa Hosp, Dept Med Imaging, Civ Campus,1053 Carling Ave, Ottawa, ON K1Y 4E9, Canada. [Hastings, Janna; Owen, Gareth; Steinbeck, Christoph] European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England. [Fahy, Eoin; Subramanian, Shankar] Univ Calif La Jolla, Dept Bioengn, San Diego, CA 92093 USA. [Bolton, Evan] Natl Lib Med, Dept Hlth & Human Serv, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. [Greiner, Russell] Univ Alberta, Alberta Innovates Ctr Machine Learning AICML, Dept Comp Sci, 2-21 Athabasca Hall, Edmonton, AB T6G 2E8, Canada. [Wishart, David S.] Univ Alberta, Metabol Innovat Ctr, Edmonton, AB T6G 2E9, Canada. RP Wishart, DS (reprint author), Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E8, Canada.; Wishart, DS (reprint author), Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2E8, Canada.; Wishart, DS (reprint author), Natl Inst Nanotechnol NINT, Natl Res Council, Edmonton, AB T6G 2M9, Canada.; Wishart, DS (reprint author), Univ Alberta, Metabol Innovat Ctr, Edmonton, AB T6G 2E9, Canada. EM david.wishart@ualberta.ca OI Steinbeck, Christoph/0000-0001-6966-0814 FU Genome Canada; Genome Alberta; Canadian Institutes of Health Research; Alberta Innovates; National Research Council; National Institute of Nanotechnology FX Funding for this research has been provided by Genome Canada, Genome Alberta, The Canadian Institutes of Health Research, Alberta Innovates, The National Research Council and The National Institute of Nanotechnology. The funders had no role in study design, data collection. Data analysis, decision to publish, or preparation of the manuscript. NR 46 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD NOV 4 PY 2016 VL 8 AR 61 DI 10.1186/s13321-016-0174-y PG 20 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA EB1DJ UT WOS:000387086800001 ER PT J AU Kim, S Bolton, EE Bryant, SH AF Kim, Sunghwan Bolton, Evan E. Bryant, Stephen H. TI Similar compounds versus similar conformers: complementarity between PubChem 2-D and 3-D neighboring sets SO JOURNAL OF CHEMINFORMATICS LA English DT Article DE PubChem; PubChem3D; Molecular similarity; Neighboring; Neighbor Preference Index (NPI) ID MOLECULAR DESCRIPTOR SPACE; GAUSSIAN DESCRIPTION; SHAPE; 2D; COEFFICIENTS; INFORMATION; DIVERSITY; RESOURCE; DATABASE AB Background: PubChem is a public repository for biological activities of small molecules. For the efficient use of its vast amount of chemical information, PubChem performs 2-dimensional (2-D) and 3-dimensional (3-D) neighborings, which precompute "neighbor" relationships between molecules in the PubChem Compound database, using the PubChem subgraph fingerprints-based 2-D similarity and the Gaussian-shape overlay-based 3-D similarity, respectively. These neighborings allow PubChem to provide the user with immediate access to the list of 2-D and 3-D neighbors (also called "Similar Compounds" and "Similar Conformers", respectively) for each compound in PubChem. However, because 3-D neighboring is much more time-consuming than 2-D neighboring, how different the results of the two neighboring schemes are is an important question, considering limited computational resources. Results: The present study analyzed the complementarity between the PubChem 2-D and 3-D neighbors. When all compounds in PubChem were considered, the overlap between 2-D and 3-D neighbors was only 2% of the total neighbors. For the data sets containing compounds with annotated information, the overlap increased as the data sets became smaller. However, it did not exceed 31% and substantial fractions of neighbors were still recognized by either PubChem 2-D or 3-D similarity, but not by both. The Neighbor Preference Index (NPI) of a molecule for a given data set was introduced, which quantified whether a molecule had more 2-D or 3-D neighbors in the data set. The NPI histogram for all PubChem compounds had a bimodal shape with two maxima at NPI = +/- 1 and a minimum at NPI = 0. However, the NPI histograms for the subsets containing compounds with annotated information had a greater fraction of compounds with a strong preference for one neighboring method to the other (at NPI = +/- 1) as well as compounds with a neutral preference (at NPI = 0). Conclusion: The results of our study indicate that, for the majority of the compounds in PubChem, their structural similarity to other compounds can be recognized predominantly by either 2-D or 3-D neighborings, but not by both, showing a strong complementarity between 2-D and 3-D neighboring results. Therefore, despite its heavy requirements for computational resources, 3-D neighboring provides an alternative way in which the user can instantly access structurally similar molecules that cannot be detected if only 2-D neighboring is used. C1 [Kim, Sunghwan; Bolton, Evan E.; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Kim, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU Intramural Research Program of the National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services FX We are grateful to the NCBI Systems staff, especially Ron Patterson, Charlie Cook, and Don Preuss, whose efforts helped make the PubChem3D project possible. We also thank Cindy Clark, NIH Library Editing Service, for reviewing the manuscript. This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. NR 35 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD NOV 4 PY 2016 VL 8 AR 62 DI 10.1186/s13321-016-0163-1 PG 17 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA EB1DJ UT WOS:000387086800002 PM 27872662 ER PT J AU Goodyear, K Parasuraman, R Chernyak, S Madhavan, P Deshpande, G Krueger, F AF Goodyear, Kimberly Parasuraman, Raja Chernyak, Sergey Madhavan, Poornima Deshpande, Gopikrishna Krueger, Frank TI Advice Taking from Humans and Machines: An fMRI and Effective Connectivity Study SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE expert advice; functional magnetic resonance imaging (fMRI); effective connectivity; Granger causality; precuneus; posterior insula ID GRANGER CAUSALITY ANALYSIS; ROSTROLATERAL PREFRONTAL CORTEX; DECISION-MAKING; INDIVIDUAL-DIFFERENCES; SOCIAL COGNITION; DETECTION TASK; EXPERT ADVICE; BRAIN; TRUST; SYSTEMS AB With new technological advances, advice can come from different sources such as machines or humans, but how individuals respond to such advice and the neural correlates involved need to be better understood. We combined functional MRI and multivariate Granger causality analysis with an X-ray luggage-screening task to investigate the neural basis and corresponding effective connectivity involved with advice utilization from agents framed as experts. Participants were asked to accept or reject good or bad advice from a human or machine agent with low reliability (high false alarm rate). We showed that unreliable advice decreased performance overall and participants interacting with the human agent had a greater depreciation of advice utilization during bad advice compared to the machine agent. These differences in advice utilization can be perceivably due to reevaluation of expectations arising from association of dispositional credibility for each agent. We demonstrated that differences in advice utilization engaged brain regions that may be associated with evaluation of personal characteristics and traits (precuneus, posterior cingulate cortex, temporoparietal junction) and interoception (posterior insula). We found that the right posterior insula and left precuneus were the drivers of the advice utilization network that were reciprocally connected to each other and also projected to all other regions. Our behavioral and neuroimaging results have significant implications for society because of progressions in technology and increased interactions with machines. C1 [Goodyear, Kimberly] Brown Univ, Dept Behav & Social Sci, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Goodyear, Kimberly] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD USA. [Goodyear, Kimberly] NIDA, Bethesda, MD 20892 USA. [Parasuraman, Raja; Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Chernyak, Sergey; Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Madhavan, Poornima] Inst Def Anal, Alexandria, VA USA. [Deshpande, Gopikrishna] Auburn Univ, Dept Elect & Comp Engn, MRI Res Ctr, Auburn, AL 36849 USA. [Deshpande, Gopikrishna] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Deshpande, Gopikrishna] Auburn Univ, Alabama Adv Imaging Consortium, Birmingham, AL USA. [Deshpande, Gopikrishna] Univ Alabama Birmingham, Birmingham, AL USA. RP Krueger, F (reprint author), George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA.; Krueger, F (reprint author), George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. EM fkrueger@gmu.edu OI Deshpande, Gopikrishna/0000-0001-7471-5357 FU Air Force of Scientific Research [202857] FX This work was supported by the Air Force of Scientific Research [202857]. NR 102 TC 0 Z9 0 U1 14 U2 14 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD NOV 4 PY 2016 VL 10 AR 542 DI 10.3389/fnhum.2016.00542 PG 15 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EA9IF UT WOS:000386955600001 PM 27867351 ER PT J AU Park, T Chen, HZ Kevala, K Lee, JW Kim, HY AF Park, Taeyeop Chen, Huazhen Kevala, Karl Lee, Ji-Won Kim, Hee-Yong TI N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Synaptamide; Microglia; NF-kappa B; Docosahexaenoic acid; Cytokine; iNOS; CCL2; Iba-1; GFAP; FAA ID NITRIC-OXIDE SYNTHASE; TUMOR-NECROSIS-FACTOR; KAPPA-B; TRANSCRIPTIONAL ACTIVITY; PROSTAGLANDIN E-2; CELL ACTIVATION; NERVOUS-SYSTEM; BRAIN; MICROGLIA; LIPOPOLYSACCHARIDE AB Background: Brain inflammation has been implicated as a critical mechanism responsible for the progression of neurodegeneration and characterized by glial cell activation accompanied by production of inflammation-related cytokines and chemokines. Growing evidence also suggests that metabolites derived from docosahexaenoic acid (DHA) have anti-inflammatory and pro-resolving effects; however, the possible role of N-docosahexaenoylethanolamine (synaptamide), an endogenous neurogenic and synaptogenic metabolite of DHA, in inflammation, is largely unknown. (The term "synaptamide" instead of "DHEA" was used for N-docosahexaenoylethanolamine since DHEA is a widely used and accepted term for the steroid, dehydroepiandrosterone.) In the present study, we tested this possibility using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. Methods: For in vitro studies, we used P3 primary rat microglia and immortalized murine microglia cells (BV2) to assess synaptamide effects on LPS-induced cytokine/chemokine/iNOS (inducible nitric oxide synthase) expression by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). To evaluate in vivo effects, mice were intraperitoneally (i.p.) injected with LPS followed by synaptamide, and expression of proinflammatory mediators was measured by qPCR and western blot analysis. Activation of microglia and astrocyte in the brain was examined by Iba-1 and GFAP immunostaining. Results: Synaptamide significantly reduced LPS-induced production of TNF-alpha and NO in cultured microglia cells. Synaptamide increased intracellular cAMP levels, phosphorylation of PKA, and phosphorylation of CREB but suppressed LPS-induced nuclear translocation of NF-kappa B p65. Conversely, adenylyl cyclase or PKA inhibitors abolished the synaptamide effect on p65 translocation as well as TNF-alpha and iNOS expression. Administration of synaptamide following LPS injection (i.p.) significantly reduced neuroinflammatory responses, such as microglia activation and mRNA expression of inflammatory cytokines, chemokine, and iNOS in the brain. Conclusions: DHA-derived synaptamide is a potent suppressor of neuroinflammation in an LPS-induced model, by enhancing cAMP/PKA signaling and inhibiting NF-kappa B activation. The anti-inflammatory capability of synaptamide may provide a new therapeutic avenue to ameliorate the inflammation-associated neurodegenerative conditions. C1 [Park, Taeyeop; Chen, Huazhen; Kevala, Karl; Lee, Ji-Won; Kim, Hee-Yong] NIAAA, Mol Signalling Lab, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. [Kim, Hee-Yong] NIAAA, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.; Kim, HY (reprint author), NIAAA, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health FX This study was funded by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. The funding agencies did not participate in planning the experiments, data analysis, or preparing the manuscript. NR 53 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD NOV 4 PY 2016 VL 13 AR 284 DI 10.1186/s12974-016-0751-z PG 15 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EB1DO UT WOS:000387087600001 PM 27809877 ER PT J AU Tripathi, V Sixt, KM Gao, SJ Xu, X Huang, J Weigert, R Zhou, M Zhang, YE AF Tripathi, Veenu Sixt, Katherine M. Gao, Shaojian Xu, Xuan Huang, Jing Weigert, Roberto Zhou, Ming Zhang, Ying E. TI Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-beta SO MOLECULAR CELL LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; CANCER PROGRESSION; TRANSCRIPTION; METASTASIS; PHOSPHORYLATION; ASSOCIATION; TRANSLATION; EXPRESSION; PATHWAYS; CD44 AB In advanced stages of cancers, TGF-beta promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, mechanisms that underpin the signaling cooperation and convert TGF-beta from a potent growth inhibitor to a tumor promoter are not fully understood. We report here that TGF-beta directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF-beta and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35-positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E. We further show that the SMAD3-mediated alternative splicing is essential to the tumor-promoting role of TGF-beta and has a global influence on protein products of genes instrumental to epithelial-to-mesenchymal transition and metastasis. C1 [Tripathi, Veenu; Sixt, Katherine M.; Xu, Xuan; Weigert, Roberto; Zhang, Ying E.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Gao, Shaojian] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Huang, Jing] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Zhou, Ming] Leidos Biomed Res Inc, Lab Prot Characterizat, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Zhang, YE (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. B. O'Malley and R. Kumar for PCBP1 plasmids, Jing Yang for HMLE cells, Chonghui Cheng for the CD44v plasmid, and Fang Liu for SMAD3 pT208 antibodies. This research was supported by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 35 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD NOV 3 PY 2016 VL 64 IS 3 BP 549 EP 564 DI 10.1016/j.molcel.2016.09.013 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RQ UT WOS:000389515300013 PM 27746021 ER PT J AU Ren, JQ Stroncek, DF AF Ren, Jiaqiang Stroncek, David F. TI Gene therapy simplified SO BLOOD LA English DT Editorial Material C1 [Ren, Jiaqiang; Stroncek, David F.] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Ren, JQ (reprint author), NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 3 PY 2016 VL 128 IS 18 BP 2194 EP 2195 DI 10.1182/blood-2016-09-736983 PG 4 WC Hematology SC Hematology GA EC4LA UT WOS:000388099600002 PM 27811188 ER PT J AU Goldin, LR McMaster, ML Rotunno, M Herman, SEM Jones, K Zhu, B Boland, J Burdett, L Hicks, B Ravichandran, S Luke, BT Yeager, M Fontaine, L Goldstein, AM Chanock, SJ Tucker, MA Wiestner, A Marti, G Caporaso, NE AF Goldin, Lynn R. McMaster, Mary L. Rotunno, Melissa Herman, Sarah E. M. Jones, Kristine Zhu, Bin Boland, Joseph Burdett, Laurie Hicks, Belynda Ravichandran, Sarangan Luke, Brian T. Yeager, Meredith Fontaine, Laura Goldstein, Alisa M. Chanock, Stephen J. Tucker, Margaret A. Wiestner, Adrian Marti, Gerald Caporaso, Neil E. TI Whole exome sequencing in families with CLL detects a variant in Integrin beta 2 associated with disease susceptibility SO BLOOD LA English DT Letter ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LYMPHOPROLIFERATIVE DISORDERS; EXPRESSION; RISK C1 [Goldin, Lynn R.; McMaster, Mary L.; Goldstein, Alisa M.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rotunno, Melissa] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Herman, Sarah E. M.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Jones, Kristine; Zhu, Bin; Boland, Joseph; Burdett, Laurie; Hicks, Belynda; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ravichandran, Sarangan; Luke, Brian T.] Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Fontaine, Laura] Westat Corp, Rockville, MD USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Tucker, Margaret A.] NCI, Human Genet Program, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E432, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov NR 13 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 3 PY 2016 VL 128 IS 18 BP 2261 EP 2263 DI 10.1182/blood-2016-02-697771 PG 3 WC Hematology SC Hematology GA EC4LA UT WOS:000388099600011 PM 27629550 ER PT J AU Ngwa, JS Cabral, HJ Cheng, DM Pencina, MJ Gagnon, DR LaValley, MP Cupples, LA AF Ngwa, Julius S. Cabral, Howard J. Cheng, Debbie M. Pencina, Michael J. Gagnon, David R. LaValley, Michael P. Cupples, L. Adrienne TI A comparison of time dependent Cox regression, pooled logistic regression and cross sectional pooling with simulations and an application to the Framingham Heart Study SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Time dependent covariate model (TDCM); Cross sectional pooling (CSP); Pooled logistic regression (PLR); Longitudinal and survival data ID PROPORTIONAL-HAZARDS; ATRIAL-FIBRILLATION; SURVIVAL ANALYSIS; AGE; WOMEN; SCORE; MODEL AB Background: Typical survival studies follow individuals to an event and measure explanatory variables for that event, sometimes repeatedly over the course of follow up. The Cox regression model has been used widely in the analyses of time to diagnosis or death from disease. The associations between the survival outcome and time dependent measures may be biased unless they are modeled appropriately. Methods: In this paper we explore the Time Dependent Cox Regression Model (TDCM), which quantifies the effect of repeated measures of covariates in the analysis of time to event data. This model is commonly used in biomedical research but sometimes does not explicitly adjust for the times at which time dependent explanatory variables are measured. This approach can yield different estimates of association compared to a model that adjusts for these times. In order to address the question of how different these estimates are from a statistical perspective, we compare the TDCM to Pooled Logistic Regression (PLR) and Cross Sectional Pooling (CSP), considering models that adjust and do not adjust for time in PLR and CSP. Results: In a series of simulations we found that time adjusted CSP provided identical results to the TDCM while the PLR showed larger parameter estimates compared to the time adjusted CSP and the TDCM in scenarios with high event rates. We also observed upwardly biased estimates in the unadjusted CSP and unadjusted PLR methods. The time adjusted PLR had a positive bias in the time dependent Age effect with reduced bias when the event rate is low. The PLR methods showed a negative bias in the Sex effect, a subject level covariate, when compared to the other methods. The Cox models yielded reliable estimates for the Sex effect in all scenarios considered. Conclusions: We conclude that survival analyses that explicitly account in the statistical model for the times at which time dependent covariates are measured provide more reliable estimates compared to unadjusted analyses. We present results from the Framingham Heart Study in which lipid measurements and myocardial infarction data events were collected over a period of 26 years. C1 [Ngwa, Julius S.; Cabral, Howard J.; Cheng, Debbie M.; Gagnon, David R.; LaValley, Michael P.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave,CT 3rd Floor, Boston, MA 02118 USA. [Ngwa, Julius S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, 615 N Wolfe St, Baltimore, MD 21205 USA. [Pencina, Michael J.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, 2400 Pratt St,7021 North Pavil, Durham, NC 27705 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. RP Ngwa, JS; Cupples, LA (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave,CT 3rd Floor, Boston, MA 02118 USA. EM ngwaj@bu.edu; adrienne@bu.edu FU National Heart, Lung and Blood Institute's Framingham Heart Study of the National Institutes of Health [N01-HC-25195, HHSN268201500001I]; Boston University School of Medicine; National Center for Research Resources (NIH NCRR) FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contracts N01-HC-25195 and HHSN268201500001I) of the National Institutes of Health and Boston University School of Medicine. A portion of this research was conducted using Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the National Center for Research Resources (NIH NCRR). NR 28 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD NOV 3 PY 2016 VL 16 AR 148 DI 10.1186/s12874-016-0248-6 PG 12 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EC2FT UT WOS:000387925800001 PM 27809784 ER PT J AU Guan, B Welch, JM Sapp, JC Ling, H Li, YL Johnston, JJ Kebebew, E Biesecker, LG Simonds, WF Marx, SJ Agarwal, SK AF Guan, Bin Welch, James M. Sapp, Julie C. Ling, Hua Li, Yulong Johnston, Jennifer J. Kebebew, Electron Biesecker, Leslie G. Simonds, William F. Marx, Stephen J. Agarwal, Sunita K. TI GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM; AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM; PARATHYROID-GLAND DEVELOPMENT; CELLS-MISSING-HOMOLOG; TRANSCRIPTION FACTOR; GCMB MUTATION; GENE; HORMONE; EXPRESSION; MANAGEMENT AB Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP. C1 [Guan, Bin; Welch, James M.; Li, Yulong; Simonds, William F.; Marx, Stephen J.; Agarwal, Sunita K.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. [Sapp, Julie C.; Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Bethesda, MD 20892 USA. [Ling, Hua] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. [Kebebew, Electron] NCI, Bethesda, MD 20892 USA. [Marx, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Guan, B; Agarwal, SK (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. EM bin.guan@nih.gov; sunitaa@mail.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU NIH; NIDDK; National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute FX The authors are grateful to the participants in this study. We thank members at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Clinical Laboratory Core for storage of DNA samples. We would like to thank Mr. Craig Cochran and the NIH 5NW nursing staff for their expert patient care. We also thank our colleagues Drs. Lee Weinstein, Monica Skarulis, and Michael Collins, as well as the past and present fellows of the National Institute of Child Health and Human Development (NICHD)-NIDDK Interinstitute Endocrine Training Program. This work was supported by the Intramural Research Program of the NIH, the NIDDK (S.J.M., S.K.A., and W.F.S.), the National Human Genome Research Institute (L.G.B., J.C.S., and J.J.J.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (S.J.M.), and the National Cancer Institute (E.K.). NR 42 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD NOV 3 PY 2016 VL 99 IS 5 BP 1034 EP 1044 DI 10.1016/j.ajhg.2016.08.018 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EB6XT UT WOS:000387529600003 PM 27745835 ER PT J AU O'Grady, GL Best, HA Sztal, TE Schartner, V Sanjuan-Vazquez, T Donkervoort, S Neto, OA Sutton, RB Ilkovski, B Romero, NB Stojkovic, T Dastgir, J Waddell, LB Boland, A Hu, Y Williams, C Ruparelia, AA Maisonobe, T Peduto, AJ Reddel, SW Lek, M Tukiainen, T Cummings, BB Joshi, H Nectoux, J Brammah, S Deleuze, JF Ing, VO Ramm, G Ardicli, D Nowak, KJ Talim, B Topaloglu, H Laing, NG North, KN MacArthur, DG Friant, S Clarke, NF Bryson-Richardson, RJ Bonnemann, CG Laporte, J Cooper, ST AF O'Grady, Gina L. Best, Heather A. Sztal, Tamar E. Schartner, Vanessa Sanjuan-Vazquez, Tvlyriam Donkervoort, Sandra Neto, Osorio Abath Sutton, Roger Bryan Ilkovski, Biljana Romero, Norma Beatriz Stojkovic, Tanya Dastgir, Jahannaz Waddell, Leigh B. Boland, Anne Hu, Ying Williams, Caitlin Ruparelia, Avnika A. Maisonobe, Thierry Peduto, Anthony J. Reddel, Stephen W. Lek, Monkol Tukiainen, Tam Cummings, Beryl B. Joshi, Himanshu Nectoux, Juliette Brammah, Susan Deleuze, Jean-Francois Ing, Viola Oorschot Ramm, Georg Ardicli, Didem Nowak, Kristen J. Talim, Beril Topaloglu, Haluk Laing, Nigel G. North, Kathryn N. MacArthur, Daniel G. Friant, Sylvie Clarke, Nigel F. Bryson-Richardson, Robert J. Bonnemann, Carsten G. Laporte, Jocelyn Cooper, Sandra T. TI Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CONGENITAL MYOPATHIES; PHYLOGENETIC ANALYSIS; NEMALINE MYOPATHY; ZEBRAFISH MODELS; GENETIC-VARIANTS; GENERATION; DIAGNOSIS; DISEASE; MUSCLE AB This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase girl show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease. C1 [O'Grady, Gina L.; Best, Heather A.; Ilkovski, Biljana; Waddell, Leigh B.; Joshi, Himanshu; North, Kathryn N.; Clarke, Nigel F.; Cooper, Sandra T.] Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [O'Grady, Gina L.; Best, Heather A.; Clarke, Nigel F.; Cooper, Sandra T.] Univ Sydney, Discipline Paediat & Child Hlth, Fac Med, Sydney, NSW 2006, Australia. [O'Grady, Gina L.] Starship Childrens Hlth, Paediat Neurol Serv, Auckland 1023, New Zealand. [Sztal, Tamar E.; Williams, Caitlin; Ruparelia, Avnika A.; Bryson-Richardson, Robert J.] Monash Univ, Sch Biol Sci, Melbourne, Vic 3800, Australia. [Schartner, Vanessa; Neto, Osorio Abath; Laporte, Jocelyn] IGBMC, F-67400 Illkirch Graffenstaden, France. [Sanjuan-Vazquez, Tvlyriam; Friant, Sylvie] Univ Strasbourg, CNRS, UMR7156, Dept Mol & Cellular Genet, F-67081 Strasbourg, France. [Donkervoort, Sandra; Dastgir, Jahannaz; Hu, Ying; Bonnemann, Carsten G.] NINDS, Neurogenet Branch, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Sutton, Roger Bryan] Texas Tech Univ, Hlth Sci Ctr, Dept Cell Physiol & Mol Biophys, Lubbock, TX 79430 USA. [Sutton, Roger Bryan] Texas Tech Univ, Hlth Sci Ctr, Ctr Membrane Prot Res, Lubbock, TX 79430 USA. [Romero, Norma Beatriz] UPMC Univ Paris 06, INSERM, UMRS974,CNRS FRE3617, Sorbonne Univ,Ctr Res Myol,GH Pitie Salpetriere, 47 Blvd Hop, F-75013 Paris, France. [Romero, Norma Beatriz; Stojkovic, Tanya; Maisonobe, Thierry] GHU La Pitie Salpetriere, AP HP, Inst Myol, Ctr Reference Pathol Neuromusculaire Paris Est, F-7503 Paris, France. [Boland, Anne; Deleuze, Jean-Francois] CEA, Ctr Natl Genotypage, Inst Genom, CP5721, F-91057 Evry, France. [Peduto, Anthony J.] Univ Sydney, Dept Radiol, Westmead Hosp, Western Clin Sch, Sydney, NSW 1024, Australia. [Reddel, Stephen W.] Univ Sydney, Concord Clin Sch, Dept Neurol, Sydney, NSW 2139, Australia. [Lek, Monkol; Tukiainen, Tam; Cummings, Beryl B.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Tukiainen, Tam; Cummings, Beryl B.; MacArthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Nectoux, Juliette] HUPC Hop Cochin, Serv Biochim & Genet Mol, F-75014 Paris, France. [Nectoux, Juliette] Univ Paris 05, INSERM, U1016, Inst Cochin,CNRS UMR8104, F-75014 Paris, France. [Brammah, Susan] Concord Repatriat Gen Hosp, Electron Microscope Unit, Concord, NSW 2139, Australia. [Ing, Viola Oorschot; Ramm, Georg] Monash Univ, Clive & Vera Ramaciotti Ctr Struct Cryoelectron M, Melbourne, Vic 3800, Australia. [Ramm, Georg] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia. [Ardicli, Didem; Talim, Beril; Topaloglu, Haluk] Hacettepe Univ, Dept Pediat Neurol, Childrens Hosp, TR-06100 Ankara, Turkey. [Nowak, Kristen J.; Laing, Nigel G.] Univ Western Australia, Ctr Med Res, Perth, WA 6009, Australia. [Nowak, Kristen J.; Laing, Nigel G.] Harry Perkins Inst Med Res, Perth, WA 6009, Australia. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. [Laporte, Jocelyn] Univ Strasbourg, F-67081 Illkirch Graffenstaden, France. RP Cooper, ST (reprint author), Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia.; Cooper, ST (reprint author), Univ Sydney, Discipline Paediat & Child Hlth, Fac Med, Sydney, NSW 2006, Australia. EM sandra.cooper@sydney.edu.au RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Friant, Sylvie/0000-0002-5412-6288 FU Australian National Health and Medical Research Council (NHMRC) [1080587, 1022707, 1031893, 1048816, 1056285]; Muscular Dystrophy New South Wales; Royal Australasian College of Physicians; Australian Research Council [FT100100734]; National Human Genome Research Institute of the NIH [U54 HG003067]; Division of Intramural Research of the National Institutes of Neurological Disorders and Stroke, France Genomique National infrastructure grant Investissements d'Avenir and Agence Nationale pour la Recherche [ANR-10-INBS-09, ANR-11-BSV1-026]; Fondation Maladies Rares "Myocapture" sequencing project; Association Frangaise contre les Myopathies [AFM-15352, AFM-16551]; Muscular Dystrophy Association [MDA-186985]; Myotubular Trust; IDEX-Universite de Strasbourg PhD fellowship; NINDS/NIH FX This study was supported by the following funding: The Australian National Health and Medical Research Council (NHMRC) 1080587 (S.T.C., N.F.C., D.G.M., K.N.N., R.B.R., K.J.N., N.G.L.), 1022707 and 1031893 (K.N.N., N.F.C., and N.G.L.), 1048816 (S.T.C.), and 1056285 (G.L.O.), Muscular Dystrophy New South Wales (G.L.O.), Royal Australasian College of Physicians (G.L.O.), Australian Research Council FT100100734 (K.J.N.), National Human Genome Research Institute of the NIH (D.G.M., Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander), Division of Intramural Research of the National Institutes of Neurological Disorders and Stroke, France Genomique National infrastructure grant Investissements d'Avenir and Agence Nationale pour la Recherche (ANR-10-INBS-09 and ANR-11-BSV1-026), Fondation Maladies Rares "Myocapture" sequencing project, Association Frangaise contre les Myopathies (AFM-15352 and AFM-16551), Muscular Dystrophy Association (MDA-186985), Myotubular Trust and IDEX-Universite de Strasbourg PhD fellowship (M.S.-V), and intramural funds of the NINDS/NIH (C.G.B. and S.D.). NR 35 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD NOV 3 PY 2016 VL 99 IS 5 BP 1086 EP 1105 DI 10.1016/j.ajhg.2016.09.005 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA EB6XT UT WOS:000387529600007 PM 27745833 ER PT J AU Rubio-Tapia, A Ludvigsson, JF Choung, RS Brantner, TL Rajkumar, SV Landgren, O Murray, JA AF Rubio-Tapia, Alberto Ludvigsson, Jonas F. Choung, Rok Seon Brantner, Tricia L. Rajkumar, S. Vincent Landgren, Ola Murray, Joseph A. TI Increased mortality among men aged 50 years old or above with elevated IgA anti-transglutaminase antibodies: NHANES III SO BMC GASTROENTEROLOGY LA English DT Article DE Epidemiology; Survival; Transglutaminase ID POPULATION-BASED COHORT; UNDIAGNOSED CELIAC-DISEASE; UNITED-STATES; NATIONAL-HEALTH; INDIVIDUALS; PREVALENCE; MALIGNANCY; RISK AB Background: Immunoglobulin A (IgA) antibodies to tissue transglutaminase (tTG) are the serologic test of choice for diagnosing celiac disease (CD). Our aim was to determine if elevated IgA anti-tTG were associated with increased mortality risk. Methods: Stored serum samples of National Health and Nutrition Examination Survey (NHANES) III (1988-1992) were available for 6032 individuals aged 50 years old or above, which were screened for IgA anti-tTG, and if positive, for IgA endomysial antibodies. Mortality was determined from the National Death Index records through 2006. Hazard ratios were calculated through Cox proportional hazards regression. Results: From a total of 6032, 85 participants tested positive for IgA anti-tTG (1.4 %) and 5947 tested negative. After a median follow-up of 13 years, IgA anti-tTG positive participants were at increased risk of death in both crude (HR = 1.68; 95 % CI = 1.30-2.18) and adjusted analyses (adjusted hazard ratio = 1.43; 95 % CI = 1.10-1.85) as compared to IgA anti-tTG negative participants. The excess mortality was restricted to IgA anti-tTG positive males (adjusted hazard ratio = 1.69 (95 % CI = 1.26-2.29), as opposed to a hazard ratio of 0.96 (95 % CI = 0.57-1.62) among IgA anti-tTG positive females. Although the most common cause of death in IgA anti-tTG positive participants was cardiovascular disease (36 %), the increased hazard ratio was only observed in respiratory cause of death as compared to IgA anti-tTG negative participants (adjusted hazard ratio = 5.11; 2.76-9.46). Conclusion: Men aged 50 years old or above participants of NHANES III with elevated IgA anti-tTG antibodies had increased mortality risk. Elevated IgA anti-tTG antibodies could be a nonspecific marker of serious disease in older men. C1 [Rubio-Tapia, Alberto; Choung, Rok Seon; Brantner, Tricia L.; Murray, Joseph A.] Mayo Clin, Div Gastroenterol & Hepatol, Dept Med, Rochester, MN 55905 USA. [Ludvigsson, Jonas F.] Orebro Univ Hosp, Dept Pediat, Orebro, Sweden. [Ludvigsson, Jonas F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Rajkumar, S. Vincent] Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA. [Landgren, Ola] NCI, Multiple Myeloma Sect, Lymphoid Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. [Landgren, Ola] NIDDK, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Murray, JA (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, Dept Med, Rochester, MN 55905 USA. EM murray.joseph@mayo.edu FU Centers for Disease Control and Prevention [M26561]; American College of Gastroenterology Junior Faculty Development Award; Swedish Research Council; Fulbright Commission FX This work was supported by the Centers for Disease Control and Prevention Contract #M26561 (J.A.M.), American College of Gastroenterology Junior Faculty Development Award (A.R-T.), and the Swedish Research Council and the Fulbright Commission (J.F.L.). NR 24 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-230X J9 BMC GASTROENTEROL JI BMC Gastroenterol. PD NOV 3 PY 2016 VL 16 AR 136 DI 10.1186/s12876-016-0547-8 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EB7AK UT WOS:000387537200001 PM 27809801 ER PT J AU Schmidt, T Situ, AJ Ulmer, TS AF Schmidt, Thomas Situ, Alan J. Ulmer, Tobias S. TI Direct Evaluation of Protein-Lipid Contacts Reveals Protein Membrane Immersion and Isotropic Bicelle Structure SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID ALPHA-IIB-BETA-3 TRANSMEMBRANE COMPLEX; PHOSPHOLIPID BICELLES; NMR-SPECTROSCOPY; MIXED MICELLES; DYNAMICS; BILAYERS; HELICES; THREONINE; SEGMENT; MOTIFS AB The solvation of membrane proteins by both lipids and water makes their membrane immersion difficult to predict and the choice of a membrane mimic challenging. To characterize protein-lipid contacts and bicelle membrane mimics, we examined protein-lipid cross-relaxation of integrin alpha IIb and beta 3(A711P) transmembrane helices in isotropic phospholipid bicelles (q = 0.5 and 0.7). Long-chain bicelle lipids dominated contacts with central helix segments, whereas both short- and long-chain lipids contacted the terminal turns of each helix in corroboration of the mixed bicelle model. The saturation transfer profiles from long chain lipids directly established helix midpoints in the lipid bilayer. Lipid headgroups and water molecules engaged the side chains of buried serine and threonine in competition with intrahelical hydrogen bonding, illustrating that polar side chains seek the most favorable electrostatic contacts. C1 [Ulmer, Tobias S.] Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Med, 1501 San Pablo St, Los Angeles, CA 90033 USA. Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, 1501 San Pablo St, Los Angeles, CA 90033 USA. [Schmidt, Thomas] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Ulmer, TS (reprint author), Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Med, 1501 San Pablo St, Los Angeles, CA 90033 USA. EM tulmer@usc.edu FU American Heart Association [15GRNT23200010] FX This work was supported by American Heart Association Grant 15GRNT23200010. NR 33 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD NOV 3 PY 2016 VL 7 IS 21 BP 4420 EP 4426 DI 10.1021/acs.jpclett.6b02159 PG 7 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EB2PT UT WOS:000387205000029 PM 27776216 ER PT J AU Fowler, MG Qin, M Fiscus, SA Currier, JS Flynn, PM Chipato, T McIntyre, J Gnanashanmugam, D Siberry, GK Coletti, AS Taha, TE Klingman, KL Martinson, FE Owor, M Violari, A Moodley, D Theron, GB Bhosale, R Bobat, R Chi, BH Strehlau, R Mlay, P Loftis, AJ Browning, R Fenton, T Purdue, L Basar, M Shapiro, DE Mofenson, LM AF Fowler, M. G. Qin, M. Fiscus, S. A. Currier, J. S. Flynn, P. M. Chipato, T. McIntyre, J. Gnanashanmugam, D. Siberry, G. K. Coletti, A. S. Taha, T. E. Klingman, K. L. Martinson, F. E. Owor, M. Violari, A. Moodley, D. Theron, G. B. Bhosale, R. Bobat, R. Chi, B. H. Strehlau, R. Mlay, P. Loftis, A. J. Browning, R. Fenton, T. Purdue, L. Basar, M. Shapiro, D. E. Mofenson, L. M. CA IMPAACT 1077BF 1077FF PROMISE Stud TI Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TENOFOVIR DISOPROXIL FUMARATE; ADVERSE BIRTH OUTCOMES; INFECTED WOMEN; PROGESTERONE LEVELS; LOPINAVIR EXPOSURE; PRETERM DELIVERY; CHILD-MORTALITY; PREGNANCY; PROTEASE; LOPINAVIR/RITONAVIR AB BACKGROUND Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P = 0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P = 0.03). Adverse events did not differ significantly between the ART groups (P > 0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P < 0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P = 0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P < 0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P = 0.04) and early infant death (4.4% vs. 0.6%, P = 0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P = 0.10 and P = 0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538.) C1 [Fowler, M. G.] Johns Hopkins Univ, Sch Med, Dept Pathol, 600 N Wolfe St,443 Carnegie, Baltimore, MD 21287 USA. [Taha, T. E.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gnanashanmugam, D.; Klingman, K. L.; Browning, R.; Purdue, L.] NIAID, Div Aids, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Siberry, G. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Qin, M.; Fenton, T.; Shapiro, D. E.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Fiscus, S. A.; Loftis, A. J.] Univ N Carolina, Sch Med, Retrovirol Core Lab, Chapel Hill, NC 27599 USA. [Coletti, A. S.] FHI 360, Durham, NC USA. [Currier, J. S.] Univ Calif Los Angeles, Ctr Clin AIDS Res & Educ, Los Angeles, CA USA. [Flynn, P. M.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chipato, T.] Univ Zimbabwe, Coll Hlth Sci, Dept Obstet & Gynecol, Harare, Zimbabwe. [McIntyre, J.] Univ Witwatersrand, Fac Hlth Sci, Anova Hlth Inst, Perinatal HIV Res, Johannesburg, South Africa. [Violari, A.] Univ Witwatersrand, Fac Hlth Sci, Perinatal HIV Res Unit, Johannesburg, South Africa. [Strehlau, R.] Empilweni Serv & Res Unit, Johannesburg, South Africa. [McIntyre, J.] Univ Cape Town, Sch Publ Hlth & Family Med, ZA-7700 Rondebosch, South Africa. [Theron, G. B.] Univ Stellenbosch, Dept Obstet & Gynaecol, Cape Town, South Africa. [Moodley, D.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa Umlazi Clin R, Nelson R Mandela Sch Med, Durban, South Africa. [Bobat, R.] Univ KwaZulu Natal, Durban Paediat HIV, Nelson R Mandela Sch Med, Durban, South Africa. [Martinson, F. E.] Univ North Carolina Project Kamuzu Cent Hosp Tidz, Lilongwe, Malawi. [Owor, M.] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Bhosale, R.] BJ Med Coll, Dept Obstet & Gynecol, Pune, Maharashtra, India. [Chi, B. H.] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Mlay, P.] Kilimanjaro Christian Med Center Duke Univ Collab, Moshi, Tanzania. [Basar, M.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Mofenson, L. M.] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. RP Fowler, MG (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 600 N Wolfe St,443 Carnegie, Baltimore, MD 21287 USA. EM mgfowler@mujhu.org FU National Institute of Allergy and Infectious Diseases of the NIH [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; Janssen; Gilead Sciences; ViiV Healthcare FX Supported by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health.; Dr. Violari reports receiving consulting fees from Janssen and grant support from Gilead Sciences and ViiV Healthcare, all paid to her institution. No other potential conflict of interest relevant to this article was reported. NR 27 TC 2 Z9 2 U1 5 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 3 PY 2016 VL 375 IS 18 BP 1726 EP 1737 DI 10.1056/NEJMoa1511691 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EB0BB UT WOS:000387007300006 PM 27806243 ER PT J AU Tripathi, A Gottesman, S AF Tripathi, Arti Gottesman, Susan TI CELL BIOLOGY Phosphate on, rubbish out SO NATURE LA English DT News Item ID QUALITY-CONTROL; PROTEIN; DESTRUCTION; MCSB AB A previously unknown way in which cells mark proteins for destruction has been found in bacteria - phosphorylation of the amino acid arginine targets proteins for degradation by protease enzymes. SEE ARTICLE p.48 C1 [Tripathi, Arti; Gottesman, Susan] Natl Canc Inst, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), Natl Canc Inst, Mol Biol Lab, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov NR 13 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD NOV 3 PY 2016 VL 539 IS 7627 BP 38 EP 39 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA5OJ UT WOS:000386670100022 PM 27808186 ER PT J AU Si, H Lu, H Yang, X Mattox, A Jang, M Bian, Y Sano, E Viadiu, H Yan, B Yau, C Ng, S Lee, SK Romano, RA Davis, S Walker, RL Xiao, W Sun, H Wei, L Sinha, S Benz, CC Stuart, JM Meltzer, PS Van Waes, C Chen, Z AF Si, H. Lu, H. Yang, X. Mattox, A. Jang, M. Bian, Y. Sano, E. Viadiu, H. Yan, B. Yau, C. Ng, S. Lee, S. K. Romano, R-A Davis, S. Walker, R. L. Xiao, W. Sun, H. Wei, L. Sinha, S. Benz, C. C. Stuart, J. M. Meltzer, P. S. Van Waes, C. Chen, Z. TI TNF-alpha modulates genome-wide redistribution of Delta Np63 alpha/TAp73 and NF-kappa B cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer SO ONCOGENE LA English DT Article ID CELL CARCINOMA; C-JUN; TRANSCRIPTION FACTORS; TUMOR SUPPRESSION; SIGNAL PATHWAYS; GROWTH-FACTOR; NECK-CANCER; P53 HOMOLOG; HUMAN HEAD; P63 AB The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform Delta Np63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs comodulated by cREL/Delta Np63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCCs). However, how inflammatory gene signatures and cREL/p63/p73 targets are comodulated genome wide is unclear. Here, we examined how the inflammatory factor tumor necrosis factor-alpha (TNF-alpha) broadly modulates redistribution of cREL with Delta Np63 alpha/TAp73 complexes and signatures genome wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-alpha enhanced genome-wide co-occupancy of cREL with Delta Np63 alpha on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to activator protein-1 (AP-1) sites. cREL, Delta Np63 alpha and TAp73 binding and oligomerization on NF-kappa B-, TP53- or AP-1-specific sequences were independently validated by ChIP-qPCR (quantitative PCR), oligonucleotide-binding assays and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53-, AP-1- and NF-kappa B-specific REs or p21, SERPINE1 and IL-6 promoter luciferase reporter activities. Concurrently, TNF-alpha regulated a broad gene network with cobinding activities for cREL, Delta Np63 alpha and TAp73 observed upon array profiling and reverse transcription-PCR. Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing Delta Np63 alpha. Furthermore, multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF-kappa B complexes through an AP-1 hub, further supporting our findings. Thus, inflammatory cytokine TNF-a mediates genome-wide redistribution of the cREL/p63/p73, and AP-1 interactome, to diminish TAp73 tumor suppressor function and reciprocally activate NF-kappa B and AP-1 gene programs implicated in malignancy. C1 [Si, H.; Lu, H.; Yang, X.; Mattox, A.; Jang, M.; Bian, Y.; Lee, S. K.; Van Waes, C.; Chen, Z.] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Lu, H.] Zhujiang Hosp Guangzhou, Orthopaed Ctr, Guangzhou, Guangdong, Peoples R China. [Sano, E.] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA. [Viadiu, H.] Univ Nacl Autonoma Mexico, Inst Quim, Ciudad Univ, Mexico City, DF, Mexico. [Yan, B.] Univ Hong Kong, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China. [Yan, B.] Univ Hong Kong, LKS Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Yan, B.] Univ Hong Kong, Ctr Genome Sci, Hong Kong, Hong Kong, Peoples R China. [Yau, C.; Benz, C. C.] Buck Inst Res Aging, Novato, CA USA. [Ng, S.; Stuart, J. M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Romano, R-A; Sinha, S.] SUNY Buffalo, Ctr Excellence Bioinformat & Life Sci, Dept Biochem, Buffalo, NY USA. [Davis, S.; Walker, R. L.] NCI, Canc Genet Branch, Bethesda, MD 20892 USA. [Xiao, W.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AK USA. [Sun, H.] NIAMSD, Biodata Min & Discovery Sect, Bethesda, MD 20892 USA. [Wei, L.] NEI, Clin Immunol Sect, NIH, Bethesda, MD 20892 USA. [Wei, L.] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou, Guangdong, Peoples R China. RP Van Waes, C (reprint author), NIDCD, NIH, Bldg 10-CRC,4-2732,10 Ctr Dr, Bethesda, MD 20892 USA.; Chen, Z (reprint author), NIDCD, Clin Genom Unit, Head & Neck Surg Branch, NIH, Bldg 10-5D55,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov; chenz@nidcd.nih.gov FU NIH [R01AR049238]; NCI [R01-CA180778, U24-CA143858]; Stand Up to Cancer; Prostate Cancer Foundation; Movember Foundation; [ZIA-DC-000073]; [ZIA-DC-000074] FX We thank Dr Fan Yang (NCI/NIH), Dr Kairong Cui (NHLBI/NIH), Dr Bingmei Zhu (NIDDK/NIH), Jeffery Burnett (NIDCD/NIH), Jamie Coupar (NIDCD/NIH), Guanmei Liang (Thomas Jefferson High School for Science and Technology, Alexandria, VA, USA) and Eric Nicolson (Ithaca High School, Ithaca, New York, NY, USA) for their technical assistance and suggestions. The authors express appreciation to Drs James W Rocco and Leif W Ellisen (Harvard University) for providing Delta Np63 and TAp63 expression vectors, Dr Thomas Gilmore (Boston University) for cRel expression plasmids, Professor Gerry Melino (University of Leicester) for TAp73 alpha expression plasmids, Dr J Silvio Gutkind (NIDCR/NIH) for IL-6 promoter reporter plasmids, Dr Gourisankar Ghosh (UCSD) for the cRel expression plasmid, and Drs Michal Karin (University of California, San Diego), Cheng-Ming Chiang (University of Texas, Southwestern) and Xuan Liu (University of California, Riverside) for critique of and helpful suggestions for the manuscript. HL, HS, XY, AM, MJ, YB, CVW and ZC are supported by intramural projects ZIA-DC-000073, ZIA-DC-000074 and RAR and SS are supported by a grant from NIH (R01AR049238). JMS acknowledges support from NCI (R01-CA180778 and U24-CA143858), Stand Up to Cancer, Prostate Cancer Foundation and the Movember Foundation. NR 55 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 3 PY 2016 VL 35 IS 44 BP 5781 EP 5794 DI 10.1038/onc.2016.112 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EA9XQ UT WOS:000386998400009 PM 27132513 ER PT J AU Sekine, Y Zyryanova, A Crespillo-Casado, A Amin-Wetzel, N Harding, HP Ron, D AF Sekine, Yusuke Zyryanova, Alisa Crespillo-Casado, Ana Amin-Wetzel, Niko Harding, Heather P. Ron, David TI Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TRANSLATION INITIATION; DISEASE; EIF2B; PHOSPHORYLATION; EIF2-ALPHA; METABOLISM; REPRESSION; DISORDERS AB The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2's alpha subunit (eIF2 alpha) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4 A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2 alpha on GEF by a contravening EIF2S1/eIF2 alpha(S51A) mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4(A391D) and the related severe VWM EIF2B4(R483W) cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2 alpha genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR. C1 [Sekine, Yusuke; Zyryanova, Alisa; Crespillo-Casado, Ana; Amin-Wetzel, Niko; Harding, Heather P.; Ron, David] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Sekine, Yusuke] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Sekine, Y; Ron, D (reprint author), Univ Cambridge, Cambridge Inst Med Res, Cambridge, England.; Sekine, Y (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM yusuke.sekine@nih.gov; dr360@medschl.cam.ac.uk OI Sekine, Yusuke/0000-0003-0345-1416; Ron, David/0000-0002-3014-5636 FU Wellcome Trust [200848/Z/16/Z, 100140]; European Commission (EU FP7 Beta-Bat) [277713]; Medical Research Council FX Supported by grants from the Wellcome Trust (Wellcome 200848/Z/16/Z) and the European Commission (EU FP7 Beta-Bat No: 277713) and, a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (Wellcome 100140). YS is a Japanese Society for the Promotion of Science Postdoctoral Fellow for Research Abroad. NAW is a Medical Research Council supported PhD student. DR is a Wellcome Trust Principal Research Fellow. Wellcome Trust URL; http://www.wellcome.ac.uk, JSPS URL; https://www.jsps.go.jp, MRC URL; http://www.mrc.ac.uk. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 3 PY 2016 VL 11 IS 11 AR e0166278 DI 10.1371/journal.pone.0166278 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8SX UT WOS:000386910000107 PM 27812215 ER PT J AU Ader, NR AF Ader, Nicholas R. TI Seeking an In Vivo Neuronal Context for the PINK1/Parkin Pathway SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID MITOCHONDRIAL QUALITY-CONTROL; PARKINSONS-DISEASE; MAMMALIAN-CELLS; REQUIRES PINK1; MITOPHAGY; DEGRADATION; MUTATIONS; AUTOPHAGY; DROSOPHILA; STRESS C1 [Ader, Nicholas R.] Med Res Council Lab Mol Biol, Div Cell Biol, Cambridge CB2 0QH, England. [Ader, Nicholas R.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Ader, NR (reprint author), MRC Lab Mol Biol, Francis Crick Ave,Cambridge Biomed Campus, Cambridge CB2 0QH, England. EM nader@mrc-lmb.cam.ac.uk FU Medical Research Council [MC_UP_1201/8] NR 31 TC 0 Z9 0 U1 1 U2 1 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 NOV 2 PY 2016 VL 36 IS 44 BP 11165 EP 11167 DI 10.1523/JNEUROSCI.2525-16.2016 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EG4YN UT WOS:000391050100005 PM 27807159 ER PT J AU Suzuki, TW Kunimatsu, J Tanaka, M AF Suzuki, Tomoki W. Kunimatsu, Jun Tanaka, Masaki TI Correlation between Pupil Size and Subjective Passage of Time in Non-Human Primates SO JOURNAL OF NEUROSCIENCE LA English DT Article DE eye movements; monkeys; pupil diameter; self-timing; temporal processing ID RAT PREFRONTAL CORTEX; LOCUS-COERULEUS; NEURONAL-ACTIVITY; NORADRENERGIC MODULATION; ELECTRICAL-STIMULATION; CINGULATE CORTEX; DECISION-MAKING; ADAPTIVE GAIN; MOTOR CORTEX; NEURAL BASIS AB Our daily experience of time is strongly influenced by internal states, such as arousal, attention, and mood. However, the underlying neuronal mechanism remains largely unknown. To investigate this, we recorded pupil diameter, which is closely linked to internal factors and neuromodulatory signaling, in monkeys performing the oculomotor version of the time production paradigm. In the self-timed saccade task, animals were required to make a memory-guided saccade during a predetermined time interval following a visual cue. We found that pupil diameter was negatively correlated with trial-by-trial latency of self-timed saccades. Because no significant correlation was found for visually guided saccades, correlation of self-timed saccades could not be explained solely by the facilitation of saccade execution. As the reward amount was manipulated, pupil diameter and saccade latency altered in opposite directions and the magnitudes of modulation correlated strongly across sessions, further supporting the close link between pupil diameter and the subjective passage of time. When the animals were trained to produce two different intervals depending on the instruction, the pupil size again correlated with the trial-by-trial variation of saccade latency in each condition; however, pupil diameter differed significantly for saccades with similar latencies generated under different conditions. Our results indicate that internal brain states indexed by pupil diameter, which parallel noradrenergic neuronal activity (Aston-Jones and Cohen, 2005), may bias trial-by-trial variation in the subjective passage of time. C1 [Suzuki, Tomoki W.; Kunimatsu, Jun; Tanaka, Masaki] Hokkaido Univ, Dept Physiol, Sch Med, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. [Kunimatsu, Jun] NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tanaka, M (reprint author), Hokkaido Univ, Dept Physiol, Sch Med, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM masaki@med.hokudai.ac.jp RI Tanaka, Masaki/D-9199-2011 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labour and Welfare of Japan; Takeda Science Foundation FX This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, and the Takeda Science Foundation. Animals were provided by the National Bio-Resource Project. We thank A. Narumi and H. Arime for participating in the early part of the experiments; T. Mori and A. Hironaka for assistance with animal care and surgery; M. Suzuki for administrative help; M. Takei and Y. Hirata for manufacturing equipment; K. Matsuda (Human Informatics Research Institute, AIST) for providing software for the eye tracking system; and all laboratory members for comments and discussions. NR 62 TC 1 Z9 1 U1 2 U2 2 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 NOV 2 PY 2016 VL 36 IS 44 BP 11331 EP 11337 DI 10.1523/JNEUROSCI.2533-16.2016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EG4YN UT WOS:000391050100019 PM 27807173 ER PT J AU Lambrughi, M De Gioia, L Gervasio, FL Lindorff-Larsen, K Nussinov, R Urani, C Bruschi, M Papaleo, E AF Lambrughi, Matteo De Gioia, Luca Gervasio, Francesco Luigi Lindorff-Larsen, Kresten Nussinov, Ruth Urani, Chiara Bruschi, Maurizio Papaleo, Elena TI DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; TUMOR-SUPPRESSOR P53; FULL-LENGTH P53; FREE-ENERGY LANDSCAPE; CRYSTAL-STRUCTURE; CORE DOMAIN; INDUCED FIT; COMMUNICATION PATHWAYS; FORCE-FIELD; MUTANT P53 AB Binding-induced conformational changes of a protein at regions distant from the binding site may play crucial roles in protein function and regulation. The p53 tumour suppressor is an example of such an allosterically regulated protein. Little is known, however, about how DNA binding can affect distal sites for transcription factors. Furthermore, the molecular details of how a local perturbation is transmitted through a protein structure are generally elusive and occur on timescales hard to explore by simulations. Thus, we employed state-of-the-art enhanced sampling atomistic simulations to unveil DNA-induced effects on p53 structure and dynamics that modulate the recruitment of cofactors and the impact of phosphorylation at Ser215. We show that DNA interaction promotes a conformational change in a region 3 nm away from the DNA binding site. Specifically, binding to DNA increases the population of an occluded minor state at this distal site by more than 4-fold, whereas phosphorylation traps the protein in its major state. In the minor conformation, the interface of p53 that binds biological partners related to p53 transcription-independent functions is not accessible. Significantly, our study reveals a mechanism of DNA-mediated protection of p53 from interactions with partners involved in the p53 transcription-independent signalling. This also suggests that conformational dynamics is tightly related to p53 signalling. C1 [Lambrughi, Matteo; Papaleo, Elena] Unit Stat Bioinformat & Registry, Computat Biol Lab, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. [Lambrughi, Matteo; Lindorff-Larsen, Kresten; Papaleo, Elena] Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, Copenhagen, Denmark. [De Gioia, Luca] Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy. [Gervasio, Francesco Luigi] UCL, Dept Chem, London WC1H 0AJ, England. [Gervasio, Francesco Luigi] UCL, Inst Struct & Mol Biol, London WC1H 0AJ, England. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Urani, Chiara; Bruschi, Maurizio] Univ Milano Bicocca, Dept Earth & Environm Sci, Piazza Sci 1, I-20126 Milan, Italy. RP Papaleo, E (reprint author), Unit Stat Bioinformat & Registry, Computat Biol Lab, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.; Papaleo, E (reprint author), Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, Copenhagen, Denmark. EM elenap@cancer.dk RI Lindorff-Larsen, Kresten/K-6469-2014 OI Lindorff-Larsen, Kresten/0000-0002-4750-6039 FU PRACE-DECI project DyNet; ISCRA-CINECA HPC [HP10BLFPW4, HP10C8LO8N]; HECBioSim allocation on Archer; Danish Cancer Society Research Center (DCRC); Novo Nordisk Foundation; EPSRC [EP/M013898/1]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX PRACE-DECI project DyNet, the ISCRA-CINECA HPC Grants [HP10BLFPW4 and HP10C8LO8N]; HECBioSim allocation on Archer; Danish Cancer Society Research Center (DCRC) [to E.P.]; Hallas-Moller stipend from the Novo Nordisk Foundation [K.L.-L. and E.P.]; EPSRC [EP/M013898/1 to F.L.G. in part]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [in part]. Funding for open access charge: PRACE-DECI project DyNet, the ISCRA-CINECA HPC Grants [HP10BLFPW4 and HP10C8LO8N]; HECBioSim allocation on Archer; Danish Cancer Society Research Center (DCRC) [to E.P.]; Hallas-Moller stipend from the Novo Nordisk Foundation [K.L.-L. and E.P.]; EPSRC [EP/M013898/1 to F.L.G. in part]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [in part]. NR 98 TC 1 Z9 1 U1 17 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV 2 PY 2016 VL 44 IS 19 BP 9096 EP 9109 DI 10.1093/nar/gkw770 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC3HK UT WOS:000388016900011 PM 27604871 ER PT J AU Kent, T Rusanov, TD Hoang, TM Velema, WA Krueger, AT Copeland, WC Kool, ET Pomerantz, RT AF Kent, Tatiana Rusanov, Timur D. Hoang, Trung M. Velema, Willem A. Krueger, Andrew T. Copeland, William C. Kool, Eric T. Pomerantz, Richard T. TI DNA polymerase theta specializes in incorporating synthetic expanded-size (xDNA) nucleotides SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE-PAIRS; ERRONEOUS INCORPORATION; CANCER PATIENTS; GENETIC SYSTEM; BREAST-CANCER; UP-REGULATION; POLQ; REPLICATION; FIDELITY; BYPASS AB DNA polymerase theta (Pol theta) is a unique A-family polymerase that is essential for alternative end-joining (alt-EJ) of double-strand breaks (DSBs) and performs translesion synthesis. Because Pol theta is highly expressed in cancer cells, confers resistance to ionizing radiation and chemotherapy agents, and promotes the survival of homologous recombination (HR) deficient cells, it represents a promising new cancer drug target. As a result, identifying substrates that are selective for this enzyme is a priority. Here, we demonstrate that Pol theta efficiently and selectively incorporates into DNA large benzo-expanded nucleotide analogs (dxAMP, dxGMP, dxTMP, dxAMP) which exhibit canonical base-pairing and enhanced base stacking. In contrast, functionally related Y-family translesion polymerases exhibit a severely reduced ability to incorporate dxNMPs, and all other human polymerases tested from the X, B and A families fail to incorporate them under the same conditions as Pol theta. We further find that Pol theta is inhibited after multiple dxGMP incorporation events, and that Pol theta efficiency for dxGMP incorporation approaches that of native dGMP. These data demonstrate a unique function for Pol theta in incorporating synthetic large-sized nucleotides and suggest the future possibility of the use of dxG nucleoside or related prodrug analogs as selective inhibitors of Pol theta activity. C1 [Kent, Tatiana; Rusanov, Timur D.; Hoang, Trung M.; Pomerantz, Richard T.] Temple Univ, Lewis Katz Sch Med, Dept Med Genet & Mol Biochem, Fels Inst Canc Res, Philadelphia, PA 19140 USA. [Velema, Willem A.; Krueger, Andrew T.; Kool, Eric T.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Copeland, William C.] NIEHS, Lab Mol Genet, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Pomerantz, RT (reprint author), Temple Univ, Lewis Katz Sch Med, Dept Med Genet & Mol Biochem, Fels Inst Canc Res, Philadelphia, PA 19140 USA. EM richard.pomerantz@temple.edu FU National Institutes of Health [4R00CA160648-03, 1R21CA209281-01]; Army Research Office [W911NF-13-1-0181]; Netherlands Organisation for Scientific Research; EMBO [ALTF 934-2014]; NIH FX National Institutes of Health [4R00CA160648-03 and 1R21CA209281-01 awarded to R.T.P.]. Army Research Office [W911NF-13-1-0181 to E.T.K.]; The Netherlands Organisation for Scientific Research and EMBO [ALTF 934-2014 to W.A.V.]. Funding for open access charge: NIH. NR 43 TC 1 Z9 1 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV 2 PY 2016 VL 44 IS 19 BP 9381 EP 9392 DI 10.1093/nar/gkw721 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC3HK UT WOS:000388016900033 PM 27591252 ER PT J AU Greely, HT Ramos, KM Grady, C AF Greely, Henry T. Ramos, Khara M. Grady, Christine TI Neuroethics in the Age of Brain Projects SO NEURON LA English DT Editorial Material AB Neuroscience advances have brought important ethical questions. The recent launch of two large brain projects, the United States BRAIN Initiative and the European Union Human Brain Project, should accelerate progress in understanding the brain. This article examines neuroethics in those two projects, as well as its exploration by other efforts. C1 [Greely, Henry T.] Stanford Univ, Ctr Law & Biosci, Stanford, CA 94305 USA. [Greely, Henry T.] Stanford Univ, Stanford Program Neurosci & Soc, Stanford, CA 94305 USA. [Ramos, Khara M.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Greely, HT (reprint author), Stanford Univ, Ctr Law & Biosci, Stanford, CA 94305 USA.; Greely, HT (reprint author), Stanford Univ, Stanford Program Neurosci & Soc, Stanford, CA 94305 USA. EM hgreely@stanford.edu NR 10 TC 1 Z9 1 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD NOV 2 PY 2016 VL 92 IS 3 BP 637 EP 641 DI 10.1016/j.neuron.2016.10.048 PG 5 WC Neurosciences SC Neurosciences & Neurology GA EA6TU UT WOS:000386762700018 PM 27810008 ER PT J AU Sam-Agudu, NA Paintsil, E Aliyu, MH Kwara, A Ogunsola, F Afrane, YA Onoka, C Awandare, GA Amponsah, G Cornelius, LJ Mendy, G Sturke, R Ghansah, A Siberry, GK Ezeanolue, EE AF Sam-Agudu, Nadia A. Paintsil, Elijah Aliyu, Muktar H. Kwara, Awewura Ogunsola, Folasade Afrane, Yaw A. Onoka, Chima Awandare, Gordon A. Amponsah, Gladys Cornelius, Llewellyn J. Mendy, Gabou Sturke, Rachel Ghansah, Anita Siberry, George K. Ezeanolue, Echezona E. TI Building Sustainable Local Capacity for Global Health Research in West Africa SO ANNALS OF GLOBAL HEALTH LA English DT Article DE western Africa; capacity-building; financial support; global health; research ID DEVELOPING-COUNTRIES; CLINICAL-TRIALS; EPIDEMIOLOGY; EDCTP; SOUTH; BIOSTATISTICS; PARTNERSHIP; EXCELLENCE; PROGRAM AB BACKGROUND Global health research in resource-limited countries has been largely sponsored and led by foreign institutions. Thus, these countries' training capacity and productivity in global health research is limited. Local participation at all levels of global health knowledge generation promotes equitable access to evidence-based solutions. Additionally, leadership inclusive of competent local professionals promotes best outcomes for local contextualization and implementation of successful global health solutions. Among the sub-Saharan African regions, West Africa in particular lags in research infrastructure, productivity, and impact in global health research. OBJECTIVE In this paper, experts discuss strategies for scaling up West Africa's participation in global health evidence generation using examples from Ghana and Nigeria. METHODS We conducted an online and professional network search to identify grants awarded for global health research and research education in Ghana and Nigeria. Principal investigators, global health educators, and representatives of funding institutions were invited to add their knowledge and expertise with regard to strengthening research capacity in West Africa. FINDINGS While there has been some progress in obtaining foreign funding, foreign institutions still dominate local research. Local research funding opportunities in the 2 countries were found to be insufficient, disjointed, poorly sustained, and inadequately publicized, indicating weak infrastructure. As a result, research training programs produce graduates who ultimately fail to launch independent investigator careers because of lack of mentoring and poor infrastructural support. CONCLUSIONS Research funding and training opportunities in Ghana and Nigeria remain inadequate. RECOMMENDATIONS We recommend systems-level changes in mentoring, collaboration, and funding to drive the global health research agenda in these countries. Additionally, research training programs should be evaluated not only by numbers of individuals graduated but also by numbers of independent investigators and grants funded. Through equitable collaborations, infrastructure, and mentoring, West Africa can match the rest of Africa in impactful global health research. C1 [Sam-Agudu, Nadia A.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Sam-Agudu, Nadia A.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Sam-Agudu, Nadia A.] Int Res Ctr Excellence, Inst Human Virol Nigeria, Abuja, Nigeria. [Sam-Agudu, Nadia A.] Univ Cape Coast, Sch Med Sci, Dept Paediat, Cape Coast, Ghana. [Paintsil, Elijah] Yale Sch Med, Dept Pediat, New Haven, CT USA. [Aliyu, Muktar H.] Vanderbilt Inst Global Hlth, Nashville, TN USA. [Aliyu, Muktar H.] Vanderbilt Univ, Med Ctr, Dept Prevent Med, Nashville, TN USA. [Kwara, Awewura] Univ Florida, Coll Med, Dept Med, Gainesville, FL USA. [Ogunsola, Folasade] Univ Lagos, Dept Med Microbiol & Parasitol, Coll Med, Lagos, Nigeria. [Afrane, Yaw A.] Univ Ghana, Coll Hlth Sci, Dept Med Microbiol, Legon, Ghana. [Onoka, Chima] Univ Nigeria, Dept Community Med, Enugu, Nigeria. [Awandare, Gordon A.] Univ Ghana, West African Ctr Cell Biol Infect Pathogens, Dept Biochem Cell & Mol Biol, Legon, Ghana. [Amponsah, Gladys] Ridge Reg Hosp, Sch Anaesthesia, Accra, Ghana. [Cornelius, Llewellyn J.] Univ Georgia, Sch Social Work, Athens, GA USA. [Mendy, Gabou] Healing Healthcare, New Orleans, LA USA. [Sturke, Rachel] NIH, Div Int Policy Planning & Evaluat, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sturke, Rachel] NIH, Ctr Global Hlth Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Ghansah, Anita] Noguchi Mem Inst Med Res, Legon, Ghana. [Ezeanolue, Echezona E.] Univ Nevada, Sch Community Hlth Sci, Las Vegas, NV 89154 USA. [Ezeanolue, Echezona E.] Univ Nigeria, Coll Med, Enugu, Nigeria. RP Sam-Agudu, NA (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA.; Sam-Agudu, NA (reprint author), Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA.; Sam-Agudu, NA (reprint author), Int Res Ctr Excellence, Inst Human Virol Nigeria, Abuja, Nigeria.; Sam-Agudu, NA (reprint author), Univ Cape Coast, Sch Med Sci, Dept Paediat, Cape Coast, Ghana. EM nsam-agudu@ihv.umaryland.edu OI Awandare, Gordon/0000-0002-8793-3641 NR 60 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-9996 J9 ANN GLOB HEALTH JI Ann. Glob. Health PD NOV-DEC PY 2016 VL 82 IS 6 BP 1010 EP 1025 DI 10.1016/j.aogh.2016.10.011 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO4VA UT WOS:000396691200008 PM 28314488 ER PT J AU Hoge, CW Ivany, CG Schoenbaum, M AF Hoge, Charles W. Ivany, Christopher G. Schoenbaum, Michael TI Death by suicide in US military during the Afghanistan and Iraq wars SO LANCET PSYCHIATRY LA English DT Editorial Material ID SERVICE MEMBERS; MENTAL-HEALTH; RISK; VETERANS; ARMY C1 [Hoge, Charles W.] Walter Reed Army Inst Res, Ctr Psychiat & Neurosci, Silver Spring, MD 20910 USA. [Ivany, Christopher G.] Off Army Surgeon Gen, Falls Church, VA USA. [Schoenbaum, Michael] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Hoge, CW (reprint author), Walter Reed Army Inst Res, Ctr Psychiat & Neurosci, Silver Spring, MD 20910 USA. EM charles.w.hoge.civ@mail.mil NR 12 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD NOV PY 2016 VL 3 IS 11 BP 1001 EP 1003 DI 10.1016/S2215-0366(16)30305-4 PG 4 WC Psychiatry SC Psychiatry GA EN9UL UT WOS:000396345000008 PM 27697515 ER PT J AU Thrift, AP Anderson, LA Murray, LJ Cook, MB Shaheen, NJ Rubenstein, JH El-Serag, HB Vaughan, TL Schneider, JL Whiteman, DC Corley, DA AF Thrift, Aaron P. Anderson, Lesley A. Murray, Liam J. Cook, Michael B. Shaheen, Nicholas J. Rubenstein, Joel H. El-Serag, Hashem B. Vaughan, Thomas L. Schneider, Jennifer L. Whiteman, David C. Corley, Douglas A. TI Nonsteroidal Anti-Inflammatory Drug Use is Not Associated With Reduced Risk of Barrett's Esophagus SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID ADENOCARCINOMA SEQUENCE; CYCLOOXYGENASE-2; INHIBITION; ASPIRIN; CANCER; METAANALYSIS; EXPRESSION; MORTALITY; TRENDS AB OBJECTIVES: Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of esophageal adenocarcinoma. Epidemiological studies examining the association between NSAID use and the risk of the precursor lesion, Barrett's esophagus, have been inconclusive. METHODS: We analyzed pooled individual-level participant data from six case-control studies of Barrett's esophagus in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). We compared medication use from 1,474 patients with Barrett's esophagus separately with two control groups: 2,256 population-based controls and 2,018 gastroesophageal reflux disease (GERD) controls. Study-specific odds ratio (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models and were combined using a random-effects meta-analytic model. RESULTS: Regular (at least once weekly) use of any NSAIDs was not associated with the risk of Barrett's esophagus (vs. population-based controls, adjusted OR=1.00, 95% CI=0.76-1.32, I-2=61%; vs. GERD controls, adjusted OR=0.99, 95% CI=0.82-1.19, I-2=19%). Similar null findings were observed among individuals who took aspirin or non-aspirin NSAIDs. We also found no association with highest levels of frequency (at least daily use) and duration (>= 5 years) of NSAID use. There was evidence of moderate between-study heterogeneity; however, associations with NSAID use remained non-significant in "leave-one-out" sensitivity analyses. CONCLUSIONS: Use of NSAIDs was not associated with the risk of Barrett's esophagus. The previously reported inverse association between NSAID use and esophageal adenocarcinoma may be through reducing the risk of neoplastic progression in patients with Barrett's esophagus. C1 [Thrift, Aaron P.; Cook, Michael B.; Shaheen, Nicholas J.; Schneider, Jennifer L.] Baylor Coll Med, Sect Gastroenterol & Hepatol, Dept Med, Houston, TX 77030 USA. [Thrift, Aaron P.; El-Serag, Hashem B.; Schneider, Jennifer L.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. [Murray, Liam J.; Vaughan, Thomas L.; Whiteman, David C.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Murray, Liam J.; El-Serag, Hashem B.; Schneider, Jennifer L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Murray, Liam J.; El-Serag, Hashem B.; Whiteman, David C.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Cook, Michael B.; Vaughan, Thomas L.; Schneider, Jennifer L.] Ann Arbor Vet Affairs Med Ctr, Ctr Clin Management Res, Ann Arbor, MI USA. [Cook, Michael B.; El-Serag, Hashem B.; Whiteman, David C.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Barretts Esophagus Program, Ann Arbor, MI USA. [Murray, Liam J.; El-Serag, Hashem B.; Whiteman, David C.] Houston VA HSR Ctr Innovat Qual, Dept Med, Michael DeBakey VA Med Ctr, Effectiveness & Safety, Houston, TX USA. [Cook, Michael B.; Vaughan, Thomas L.; Whiteman, David C.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA USA. [Murray, Liam J.; El-Serag, Hashem B.; Schneider, Jennifer L.] Calif & San Francisco Med Ctr, Kaiser Permanente Div Res, Oakland, CA USA. [Murray, Liam J.; El-Serag, Hashem B.; Corley, Douglas A.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. RP Thrift, AP (reprint author), Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. EM aaron.thrift@bcm.edu OI Anderson, Lesley/0000-0002-1000-3649; Whiteman, David/0000-0003-2563-9559 FU National Institutes of Health [RO1 DK63616, 1R21DK077742, K23DK59311, R03 DK75842, K23DK079291, R01 CA116845, K24-04-107]; Intramural Program of the National Institutes of Health; Ireland-Northern Ireland cooperation research project grant - the Northern Ireland Research and Development Office; Health Research Board, Ireland (FINBAR) [RES/1699/01N/S]; Study of Digestive Health [NCI RO1 CA 001833]; Study of Reflux Disease [NCI R01 CA72866]; Established Investigator Award in Cancer Prevention and Control [K05 CA124911]; US Department of Veterans Affairs CSRD Merit [I01-CX000899] FX This work was supported by the National Institutes of Health RO1 DK63616 (D.A.C.); 1R21DK077742 (N.J.S. and D.A.C.); K23DK59311 (N.J.S.); R03 DK75842 (N.J.S.); K23DK079291 (J.H.R.); R01 CA116845 (H.B.E.-S.); K24-04-107 (H.B.E.-S.); the Intramural Program of the National Institutes of Health (M.B.C.); an Ireland-Northern Ireland cooperation research project grant sponsored by the Northern Ireland Research and Development Office and the Health Research Board, Ireland (FINBAR; L.J.M.: RES/1699/01N/S); the Study of Digestive Health, NCI RO1 CA 001833 (D.C.W.); the Study of Reflux Disease, NCI R01 CA72866 (T.L.V.), the Established Investigator Award in Cancer Prevention and Control, K05 CA124911 (T.L.V.), and the US Department of Veterans Affairs CSRD Merit I01-CX000899 (J.H.R.). NR 28 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD NOV PY 2016 VL 111 IS 11 BP 1528 EP 1535 DI 10.1038/ajg.2016.348 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6PT UT WOS:000394047300014 PM 27575711 ER PT J AU Harada, M Kamijo, Y Nakajima, T Hashimoto, K Yamada, Y Shimojo, H Gonzalez, FJ Aoyama, T AF Harada, Makoto Kamijo, Yuji Nakajima, Takero Hashimoto, Koji Yamada, Yosuke Shimojo, Hisashi Gonzalez, Frank J. Aoyama, Toshifumi TI Peroxisome proliferator-activated receptor alpha-dependent renoprotection of murine kidney by irbesartan SO CLINICAL SCIENCE LA English DT Article DE angiotensin II type 1 receptor blocker; fatty acid metabolism; irbesartan (Irbe); peroxisome proliferator-activated receptor alpha (PPAR alpha) ID PPAR-ALPHA; TUBULOINTERSTITIAL DAMAGE; GENE-EXPRESSION; DIABETIC-NEPHROPATHY; HYPERTENSIVE-RATS; PROXIMAL TUBULES; OXIDATIVE STRESS; GAMMA AGONIST; RENAL-DISEASE; FATTY-ACIDS AB Activation of renal peroxisome proliferator-activated receptor alpha (PPAR alpha) is renoprotective, but there is no safe PPARa activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPAR alpha. However, Irbe's renal PPAR alpha-activating effects and the role of PPAR alpha signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy kidneys of wild-type (WT) and Ppara-null (KO) mice and in the murine protein-overload nephropathy (PON) model respectively. The results were compared with those of losartan (Los), another ARB that does not activate PPAR alpha. PPAR alpha and its target gene expression were significantly increased only in the kidneys of Irbe-treated WT mice and not in KO or Los-treated mice, suggesting that the renal PPAR alpha-activating effect was Irbe-specific. Irbe-treated-PON-WT mice exhibited decreased urine protein excretion, tubular injury, oxidative stress (OS), and pro-inflammatory and apoptosis-stimulating responses, and they exhibited maintenance of fatty acid metabolism. Furthermore, the expression of PPAR alpha and that of its target mRNAs encoding proteins involved in OS, pro-inflammatory responses, apoptosis and fatty acid metabolism was maintained upon Irbe treatment. These renoprotective effects of Irbe were reversed by the PPAR alpha antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPAR alpha and that the resultant increased PPAR alpha signalling mediates its renoprotective effects. C1 [Harada, Makoto; Kamijo, Yuji; Hashimoto, Koji; Yamada, Yosuke] Shinshu Univ, Dept Nephrol, Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. [Harada, Makoto; Kamijo, Yuji; Nakajima, Takero; Yamada, Yosuke; Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Inst Pathogenesis & Dis Prevent, Dept Metab Regulat, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. [Shimojo, Hisashi] Shinshu Univ, Sch Med, Dept Pathol, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Kamijo, Y (reprint author), Shinshu Univ, Dept Nephrol, Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan.; Kamijo, Y (reprint author), Shinshu Univ, Grad Sch Med, Inst Pathogenesis & Dis Prevent, Dept Metab Regulat, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. EM yujibeat@shinshu-u.ac.jp FU Sumitomo Dainippon Pharma Co.; [25460329] FX This work was supported by the Sumitomo Dainippon Pharma Co. and Grants-in-Aid for Scientific Research (KAKENHI) in Japan [grant number 25460329]. NR 45 TC 0 Z9 0 U1 0 U2 0 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD NOV 1 PY 2016 VL 130 IS 21 BP 1969 EP 1981 DI 10.1042/CS20160343 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK2PR UT WOS:000393769700011 PM 27496805 ER PT J AU Schuebel, K Gitik, M Domschke, K Goldman, D AF Schuebel, Kornel Gitik, Miri Domschke, Katharina Goldman, David TI Making Sense of Epigenetics SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE epigenetics; DNA methylation; chromatin; neuropsychiatric disorders ID HISTONE DEACETYLASE INHIBITORS; SUBSTANCE USE DISORDERS; LONG-TERM-MEMORY; DNA METHYLATION; SYNAPTIC PLASTICITY; GENE-EXPRESSION; BIPOLAR DISORDER; MONOZYGOTIC TWINS; MONOAMINE-OXIDASE; BRAIN-DEVELOPMENT AB The gene-environment interactions that underlie development and progression of psychiatric illness are poorly understood. Despite a century of progress, genetic approaches have failed to identify new treatment modalities, perhaps because of the heterogeneity of the disorders and lack of understanding of mechanisms. Recent exploration into epigenetic mechanisms in health and disease has uncovered changes in DNA methylation and chromatin structure that may contribute to psychiatric disorders. Epigenetic changes suggest a variety of new therapeutic options due to their reversible chemistry. However, distinguishing causal links between epigenetic changes and disease from changes consequent to life experience has remained problematic. Here we define epigenetics and explore aspects of epigenetics relevant to causes and mechanisms of psychiatric disease, and speculate on future directions. C1 [Schuebel, Kornel; Gitik, Miri; Goldman, David] NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Rm 3s-32, Rockville, MD 20852 USA. [Schuebel, Kornel; Gitik, Miri; Goldman, David] NIAAA, Off Clin Director, NIH, Rockville, MD 20852 USA. [Domschke, Katharina] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Rm 3s-32, Rockville, MD 20852 USA. EM david.goldman@nih.gov FU National Institutes of Health, National Institute for Alcohol Abuse and Alcoholism; German Research Foundation (DFG) [SFB-TRR-58]; German Ministry of Research and Education (BMBF) [01EE1402A] FX The present work was supported by intramural funding from the National Institutes of Health, National Institute for Alcohol Abuse and Alcoholism, the German Research Foundation (DFG, SFB-TRR-58, C02 to K.D.), and the German Ministry of Research and Education (BMBF, 01EE1402A, PROTECT-AD, P5 to K.D.). We apologize to those whose work has not been cited due to space constraints. NR 89 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD NOV PY 2016 VL 19 IS 11 DI 10.1093/ijnp/pyw058 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EK4QO UT WOS:000393912100001 ER PT J AU Allen, NE Travis, RC Appleby, PN Albanes, D Barnett, MJ Black, A Bueno-De-Mesquita, HB Deschasaux, M Galan, P Goodman, GE Goodman, PJ Gunter, MJ Heliovaara, M Helzlsouer, KJ Henderson, BE Hercberg, S Knekt, P Kolonel, LN Lasheras, C Linseisen, J Metter, EJ Neuhouser, ML Olsen, A Pala, V Platz, EA Rissanen, H Reid, ME Schenk, JM Stampfer, MJ Stattin, P Tangen, CM Touvier, M Trichopoulou, A van den Brandt, PA Key, TJ AF Allen, Naomi E. Travis, Ruth C. Appleby, Paul N. Albanes, Demetrius Barnett, Matt J. Black, Amanda Bueno-de-Mesquita, H. Bas Deschasaux, Melanie Galan, Pilar Goodman, Gary E. Goodman, Phyllis J. Gunter, Marc J. Heliovaara, Markku Helzlsouer, Kathy J. Henderson, Brian E. Hercberg, Serge Knekt, Paul Kolonel, Laurence N. Lasheras, Christina Linseisen, Jakob Metter, E. Jeffrey Neuhouser, Marian L. Olsen, Anja Pala, Valeria Platz, Elizabeth A. Rissanen, Harri Reid, Mary E. Schenk, Jeannette M. Stampfer, Meir J. Stattin, Par Tangen, Catherine M. Touvier, Mathilde Trichopoulou, Antonia van den Brandt, Piet A. Key, Timothy J. CA Endogenous Hormones Nutr Biomakers TI Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SERUM SELENIUM; SUBSEQUENT RISK; SELENOPROTEIN P; TRIAL; ASSOCIATION; TOENAILS; MEN; SUPPLEMENTATION; PREVENTION; POLYMORPHISMS AB Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, P-heterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, P-trend <.001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, P-heterogeneity =.08). Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-termselenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation. C1 [Allen, Naomi E.] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg, Oxford OX3 7LF, England. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Richard Doll Bldg, Oxford OX3 7LF, England. [Travis, Ruth C.; Appleby, Paul N.; Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Albanes, Demetrius; Black, Amanda] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Barnett, Matt J.; Goodman, Gary E.; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Goodman, Phyllis J.; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, SWOG, Seattle, WA 98104 USA. [Schenk, Jeannette M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Schenk, Jeannette M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Tangen, Catherine M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas; Gunter, Marc J.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Deschasaux, Melanie; Galan, Pilar; Hercberg, Serge; Touvier, Mathilde] Univ Paris 07, Univ Paris 05,Nutr Epidemiol Res Team, Univ Paris 13,Inserm U1153,Inra U1125,Cnam, Sorbonne Paris Cite Epidemiol & Biostat, Bobigny, France. [Heliovaara, Markku; Knekt, Paul; Rissanen, Harri] Natl Inst Hlth & Welf, Helsinki, Finland. [Helzlsouer, Kathy J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Henderson, Brian E.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lasheras, Christina] Univ Oviedo, Fac Med, Dept Funct Biol, Asturias, Spain. [Linseisen, Jakob] Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Linseisen, Jakob] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Metter, E. Jeffrey] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Intramural Res Programm,Natl Inst Aging, Memphis, TN 38163 USA. [Olsen, Anja] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Pala, Valeria] IRCCS, Ist Nazl Tumori, Epidemiol & Prevent Unit, I-20133 Milan, Italy. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Reid, Mary E.] Roswell Pk Canc Inst, New York, NY USA. [Stampfer, Meir J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Stampfer, Meir J.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci, Urol & Androl, Umea, Sweden. [Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [van den Brandt, Piet A.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. RP Allen, NE (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg, Oxford OX3 7LF, England.; Allen, NE (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Richard Doll Bldg, Oxford OX3 7LF, England. EM naomi.allen@ndph.ox.ac.uk FU Cancer Research UK [C570/A11691, C8221/A19170]; National Institute on Aging Intramural Research Program, Prostate Spore Grant [CA58236]; US Department of Health and Human Services; National Institutes of Health [U01 CA63673, P01 CA 33619, R37 CA 54281, RO1 CA49764, CA37429, CA42182, CA58684, CA57374, CA94028, CA55075]; Clinical Nutrition Research Unit [P30 DK35816]; Department of Defense [DAMD1-94-J-4265]; Europe Against Cancer Programme of the European Commission; German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund of the Spanish Ministry of Health; Centros de Investigacion Biomedica en Red Epidemiologia y Salud Publica, Barcelona, Spain; Medical Research Council, UK; Stroke Association (UK); British Heart Foundation; Department of Health (UK); Food Standards Agency (UK); Greek Ministry of Education; Greek Ministry of Health and Social Solidarity; Hellenic Health Foundation; Italian Association for Research on Cancer; Italian National Research Council; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; German Federal Ministry of Education and Research [FK 0313846A]; Deutsche Krebshilfe [10-1793 Scholl]; Cancer Society of Finland; National Heart, Lung, and Blood Institute [HL35464]; US National Cancer Institute; Dutch Cancer Society [UM 2009-4556]; Intramural Research Program; French Ministry of Health/Direction Generale de la Sante FX This work was supported by Cancer Research UK (grant numbers C570/A11691, C8221/A19170). We thank the men who participated in the collaborating studies, the research staff, the collaborating laboratories, and the funding agencies in each of the studies. BLSA was supported by the National Institute on Aging Intramural Research Program, Prostate Spore Grant (CA58236). CARET was supported by the US Department of Health and Human Services and the National Institutes of Health (U01 CA63673), Clinical Nutrition Research Unit (P30 DK35816). Campaign against Cancer and Stroke was supported by the US National Cancer Institute, the National Institutes of Health (CA94028), and the Department of Defense (DAMD1-94-J-4265). European Investigation into Cancer and Nutrition was supported by Cancer Research UK; Europe Against Cancer Programme of the European Commission; German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund of the Spanish Ministry of Health; Centros de Investigacion Biomedica en Red Epidemiologia y Salud Publica, Barcelona, Spain; the participating regional governments and institutions of Spain; Medical Research Council, UK; the Stroke Association (UK); British Heart Foundation; Department of Health (UK); Food Standards Agency (UK); Greek Ministry of Education; Greek Ministry of Health and Social Solidarity; Hellenic Health Foundation; Italian Association for Research on Cancer; Italian National Research Council; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skane, Sweden. EPIC-Heidelberg was supported by the German Federal Ministry of Education and Research (FK 0313846A), Deutsche Krebshilfe (10-1793 Scholl). Finnish Mobile Clinic Health Examination was supported by the Cancer Society of Finland. Health Professionals Follow-up Study was supported by the US National Cancer Institute, the National Institutes of Health (CA55075), and the National Heart, Lung, and Blood Institute (HL35464). Multiethnic Cohort was supported by the US National Cancer Institute and the National Institutes of Health (P01 CA 33619, R37 CA 54281). Nutritional Prevention of Cancer Trial was supported by the US National Cancer Institute and the National Institutes of Health (RO1 CA49764). Netherlands Cohort Study was supported by the Dutch Cancer Society (UM 2009-4556). Prostate Cancer Prevention Trial and Selenium and Vitamin E Cancer Prevention Trial (SouthWest Oncology Group) were supported by the US National Cancer Institute and the National Institutes of Health (CA37429). Physicians' Health Study was supported by the US National Cancer Institute and the National Institutes of Health (CA42182, CA58684, CA57374). Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial was supported by the US National Cancer Institute, the National Institutes of Health (PLCO Cancer Screening Trial), and the Intramural Research Program. SUpplementation en Vitamines et Mineraux Anti-oXydants Trial was supported by the French Ministry of Health/Direction Generale de la Sante. NR 49 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD NOV PY 2016 VL 108 IS 11 AR djw153 DI 10.1093/jnci/djw153 PG 8 WC Oncology SC Oncology GA EK4LD UT WOS:000393897300012 ER PT J AU Miyake, K Suzuki, A Morita, C Goto, M Newman, DJ O'Keefe, BR Morris-Natschke, SL Lee, KH Nakagawa-Goto, K AF Miyake, Katsunori Suzuki, Airi Morita, Chihiro Goto, Masuo Newman, David J. O'Keefe, Barry R. Morris-Natschke, Susan L. Lee, Kuo-Hsiung Nakagawa-Goto, Kyoko TI Acetophenone Monomers from Acronychia trifoliolata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID PEDUNCULATA; DERIVATIVES AB Seven new [acronyculatins I-0 (1-7)] and four known acetophenone monomers were isolated from a CH3OH/CH2C12 (1:1) extract (N089419) of Acronychia trifoliolata provided by the U.S. National Cancer Institute (NCI, Frederick, MD, USA). Their structures were characterized by using various NMR and HEMS techniques. Among the known compounds, the structure of acronyculatin B (8) was revised. Some of the isolated compounds were evaluated for antiproliferative activity against human cancer cell lines. While most of the tested compounds were not cytotoxic, acronyculatins I (1) and J (2) showed moderate antiproliferative activity. C1 [Miyake, Katsunori; Suzuki, Airi; Morita, Chihiro; Nakagawa-Goto, Kyoko] Kanazawa Univ, Coll Med Pharmaceut & Hlth Sci, Sch Pharmaceut Sci, Kanazawa, Ishikawa 9201192, Japan. [Goto, Masuo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung; Nakagawa-Goto, Kyoko] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Newman, David J.] NIH Special Volunteer, Wayne, PA 19087 USA. [O'Keefe, Barry R.] NCI Frederick, NCI, Nat Prod Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, 2 Yuh Der Rd, Taichung 40447, Taiwan. RP Nakagawa-Goto, K (reprint author), Kanazawa Univ, Coll Med Pharmaceut & Hlth Sci, Sch Pharmaceut Sci, Kanazawa, Ishikawa 9201192, Japan.; Nakagawa-Goto, K (reprint author), Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. EM kngoto@p.kanazawa-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI, Japan) [25293024]; NIH [CA177584]; National Cancer Institute, awarded FX This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI, Japan), awarded to K.N.G. (Grant Number 25293024). This work was also supported by NIH Grant CA177584 from the National Cancer Institute, awarded to K.H.L. We also thank the Biological Testing Branch, DTP, DCTD, NCI, for performing the NCI 60-cell cytotoxicity assay and the Natural Products Support Group, Leidos Biomedical Inc., for plant extraction. NR 15 TC 1 Z9 1 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD NOV PY 2016 VL 79 IS 11 BP 2883 EP 2889 DI 10.1021/acs.jnatprod.6b00645 PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA EL1VX UT WOS:000394410600014 PM 27797192 ER PT J AU Hibbett, D Abarenkov, K Koljalg, U Opik, M Chai, B Cole, J Wang, Q Crous, P Robert, V Helgason, T Herr, JR Kirk, P Lueschow, S O'Donnell, K Nilsson, RH Oono, R Schoch, C Smyth, C Walker, DM Porras-Alfaro, A Taylor, JW Geiser, DM AF Hibbett, David Abarenkov, Kessy Koljalg, Urmas Opik, Maarja Chai, Benli Cole, James Wang, Qiong Crous, Pedro Robert, Vincent Helgason, Thorunn Herr, Joshua R. Kirk, Paul Lueschow, Shiloh O'Donnell, Kerry Nilsson, R. Henrik Oono, Ryoko Schoch, Conrad Smyth, Christopher Walker, Donald M. Porras-Alfaro, Andrea Taylor, John W. Geiser, David M. TI Sequence-based classification and identification of Fungi SO MYCOLOGIA LA English DT Review DE biodiversity informatics; metagenomics; molecular ecology; nomenclature; systematics; taxonomy ID INTERNAL TRANSCRIBED SPACER; RIBOSOMAL DATABASE PROJECT; ARBUSCULAR MYCORRHIZAL FUNGI; OPERATIONAL TAXONOMIC UNITS; SPECIES LIVING TREE; RNA GENE DATABASE; AD-HOC-COMMITTEE; LARGE-SUBUNIT; MOLECULAR-IDENTIFICATION; ENVIRONMENTAL SEQUENCES AB Fungal taxonomy and ecology have been revolutionized by the application of molecular methods and both have increasing connections to genomics and functional biology. However, data streams from traditional specimen- and culture-based systematics are not yet fully integrated with those from metagenomic and metatranscriptomic studies, which limits understanding of the taxonomic diversity and metabolic properties of fungal communities. This article reviews current resources, needs, and opportunities for sequence-based classification and identification (SBCI) in fungi as well as related efforts in prokaryotes. To realize the full potential of fungal SBCI it will be necessary to make advances in multiple areas. Improvements in sequencing methods, including long-read and single-cell technologies, will empower fungal molecular ecologists to look beyond ITS and current shotgun metagenomics approaches. Data quality and accessibility will be enhanced by attention to data and metadata standards and rigorous enforcement of policies for deposition of data and workflows. Taxonomic communities will need to develop best practices for molecular characterization in their focal clades, while also contributing to globally useful datasets including ITS. Changes to nomenclatural rules are needed to enable valid publication of sequence-based taxon descriptions. Finally, cultural shifts are necessary to promote adoption of SBCI and to accord professional credit to individuals who contribute to community resources. C1 [Hibbett, David] Clark Univ, Dept Biol, Worcester, MA 01610 USA. [Abarenkov, Kessy; Koljalg, Urmas; Opik, Maarja] Univ Tartu, Inst Ecol & Earth Sci, 40 Lai St, EE-51005 Tartu, Estonia. [Chai, Benli; Cole, James; Wang, Qiong] Michigan State Univ, Dept Plant Soil & Microbial Sci, Plant & Soil Sci Bldg,1066 Bogue St,Room 540, E Lansing, MI 48824 USA. [Crous, Pedro; Robert, Vincent] Cent Bur Schimmelcultures Fungal Biodivers Ctr CB, NL-3508 AD Utrecht, Netherlands. [Helgason, Thorunn] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England. [Herr, Joshua R.] Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68503 USA. [Herr, Joshua R.] Univ Nebraska, Ctr Plant Sci Innovat, Lincoln, NE 68503 USA. [Kirk, Paul] Royal Bot Gardens, Biodivers Informat & Spatial Anal, Richmond TW9 3AF, Surrey, England. [Lueschow, Shiloh; O'Donnell, Kerry] NCAUR ARS USDA, 1815 N Univ St, Peoria, IL 61604 USA. [Nilsson, R. Henrik] Univ Gothenburg, Dept Biol & Environm Sci, S-40530 Gothenburg, Sweden. [Oono, Ryoko] Univ Calif Santa Barbara, Dept Ecol Evolut & Marine Biol, Santa Barbara, CA 93106 USA. [Schoch, Conrad] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Smyth, Christopher; Geiser, David M.] Penn State Univ, Dept Plant Pathol & Environm Microbiol, 121 Buckhout Lab, University Pk, PA 16802 USA. [Walker, Donald M.] Tennessee Technol Univ, Dept Biol, 1100 N Dixie Ave, Cookeville, TN 38505 USA. [Porras-Alfaro, Andrea] Western Illinois Univ, Dept Biol Sci, Waggoner Hall 372,1 Univ Circle, Macomb, IL 61455 USA. [Taylor, John W.] Univ Calif Berkeley, Dept Plant & Microbial Biol, 111 Koshland Hall, Berkeley, CA 94720 USA. RP Hibbett, D (reprint author), Clark Univ, Dept Biol, Worcester, MA 01610 USA. EM dhibbett@clarku.edu FU US National Science Foundation [DEB 1424740]; Intramural Research Program of the National Institutes of Health, National Library of Medicine; Estonian Research Council [IUT20-28]; European Regional Development Fund (Centre of Excellence EcolChange); NSF [DEB-1208719] FX Preparation of this article was initiated in a 2 d workshop on SBCI in Fungi that was held at the Kellogg Center of Michigan State University, East Lansing, Michigan, 12-13 Jun 2014 (Herr et al. 2015), which was supported by US National Science Foundation award No. DEB 1424740 to DG, AP-A, DSH, and JWT. A related symposium on "Sequence-based identification in Fungi" was held on 11 Jun 2014 at the annual meeting of the Mycological Society of America, and a Special Interest Group session on "Classifying, naming and communicating sequence based species" took place at the International Mycological Congress, 5 Aug 2014, Bangkok, Thailand. The authors thank Sam Kovaka, who performed the query of GenBank for species names (FIG. 2, SUPPLEMENTARY INFORMATION), P. Brandon Matheny, and two anonymous reviewers for helpful comments. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the Victorian government or the US Department of Agriculture. USDA is an equal opportunity provider and employer. CLS acknowledges support from the Intramural Research Program of the National Institutes of Health, National Library of Medicine. MO acknowledges support from the Estonian Research Council (grant No. IUT20-28) and European Regional Development Fund (Centre of Excellence EcolChange). DSH acknowledges support of NSF award No. DEB-1208719. NR 142 TC 0 Z9 0 U1 10 U2 10 PU ALLEN PRESS INC PI LAWRENCE PA 810 E 10TH ST, LAWRENCE, KS 66044 USA SN 0027-5514 EI 1557-2536 J9 MYCOLOGIA JI Mycologia PD NOV-DEC PY 2016 VL 108 IS 6 BP 1049 EP 1068 DI 10.3852/16-130 PG 20 WC Mycology SC Mycology GA EJ5PA UT WOS:000393269000001 ER PT J AU Brosse, A Korobeinikova, A Gottesman, S Guillier, M AF Brosse, Anais Korobeinikova, Anna Gottesman, Susan Guillier, Maude TI Unexpected properties of sRNA promoters allow feedback control via regulation of a two-component system SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI K-12; HISTIDINE KINASE ENVZ; GENE-EXPRESSION; OUTER-MEMBRANE; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; NEGATIVE REGULATION; BIOFILM FORMATION; FEEDFORWARD LOOP; DNA RECOGNITION AB Two-component systems (TCS) and small regulatory RNAs (sRNAs) are both widespread regulators of gene expression in bacteria. TCS are in most cases transcriptional regulators. A large class of sRNAs act as post-transcriptional regulators of gene expression that modulate the translation and/or stability of target-mRNAs. Many connections have been recently unraveled between these two types of regulators, resulting in mixed regulatory circuits with poorly characterized properties. This study focuses on the negative feedback circuit that exists between the EnvZ-OmpR TCS and the OmrA/B sRNAs. We have shown that OmpR directly activates transcription from the omrA and omrB promoters, allowing production of OmrA/B sRNAs that target multiple mRNAs, including the ompR-envZ mRNA. This control of ompR-envZ by the Omr sRNAs does not affect the amount of phosphorylated OmpR, i.e. the presumably active form of the regulator. Accordingly, expression of robust OmpR targets, such as the ompC or ompF porin genes, is not affected by OmrA/B. However, we find that several OmpR targets, including OmrA/B themselves, are sensitive to changing total OmpR levels. As a result, OmrA/B limit their own synthesis. These findings unravel an additional layer of control in the expression of some OmpR targets and suggest the existence of differential regulation within the OmpR regulon. C1 [Brosse, Anais; Korobeinikova, Anna; Guillier, Maude] Univ Paris Diderot, CNRS, UMR8261, Sorbonne Paris Cite,Inst Biol Physicochim, F-75005 Paris, France. [Gottesman, Susan] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Guillier, M (reprint author), Univ Paris Diderot, CNRS, UMR8261, Sorbonne Paris Cite,Inst Biol Physicochim, F-75005 Paris, France. EM maude.guillier@ibpc.fr FU CNRS; ANR [ANR-2010-JCJC-130801, ANR-14-CE10-0004-01]; 'Initiative d'Excellence' program from the French State ['DYNAMO'] [ANR-11-LABX-0011]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX CNRS, ANR [ANR-2010-JCJC-130801 and ANR-14-CE10-0004-01 to M.G.]; 'Initiative d'Excellence' program from the French State ['DYNAMO', ANR-11-LABX-0011]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funding for open access charge: ANR (french national research agency) [ANR-14-CE10-0004-01]. NR 70 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2016 VL 44 IS 20 BP 9650 EP 9666 DI 10.1093/nar/gkw642 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK3HR UT WOS:000393817800018 PM 27439713 ER PT J AU Kim, SH Trinh, AT Larsen, MC Mastrocola, AS Jefcoate, CR Bushel, PR Tibbetts, RS AF Kim, Sang Hwa Trinh, Anthony T. Larsen, Michele Campaigne Mastrocola, Adam S. Jefcoate, Colin R. Bushel, Pierre R. Tibbetts, Randal S. TI Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EXPRESSION MICROARRAY DATA; GENOME-WIDE ANALYSIS; NUCLEAR FACTOR CREB; TRANSCRIPTION FACTOR; GENE-EXPRESSION; MULTISITE PHOSPHORYLATION; ATAXIA-TELANGIECTASIA; UNSTRUCTURED REGION; PROTEIN CBP; CAMP AB cAMP response element binding protein (CREB) is a key regulator of glucose metabolism and synaptic plasticity that is canonically regulated through recruitment of transcriptional coactivators. Here we show that phosphorylation of CREB on a conserved cluster of Ser residues (the ATM/CK cluster) by the DNA damage-activated protein kinase ataxia-telangiectasia-mutated (ATM) and casein kinase1 (CK1) and casein kinase2 (CK2) positively and negatively regulates CREB-mediated transcription in a signal dependent manner. In response to genotoxic stress, phosphorylation of the ATM/CK cluster inhibited CREB-mediated gene expression, DNA binding activity and chromatin occupancy proportional to the number of modified Ser residues. Paradoxically, substoichiometric, ATM-independent, phosphorylation of the ATM/CK cluster potentiated bursts in CREB-mediated transcription by promoting recruitment of the CREB coactivator, cAMP-regulated transcriptional coactivators (CRTC2). Livers from mice expressing a non-phosphorylatable CREB allele failed to attenuate gluconeogenic genes in response to DNA damage or fully activate the same genes in response to glucagon. We propose that phosphorylation-dependent regulation of DNA binding activity evolved as a tunable mechanism to control CREB transcriptional output and promote metabolic homeostasis in response to rapidly changing environmental conditions. C1 [Kim, Sang Hwa; Trinh, Anthony T.; Mastrocola, Adam S.; Tibbetts, Randal S.] Univ Wisconsin, Dept Human Oncol, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Larsen, Michele Campaigne; Jefcoate, Colin R.] Univ Wisconsin, Dept Cell & Regenerat Biol, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Bushel, Pierre R.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Tibbetts, RS (reprint author), Univ Wisconsin, Dept Human Oncol, Sch Med & Publ Hlth, Madison, WI 53705 USA. EM rstibbetts@wisc.edu FU National Cancer Institute [R01CA180765-01]; National Institute for Neurological Disorders and Stroke [1R21NS090313-01A1]; National Institute of Diabetes and Digestive and Kidney diseases [R01DK090249]; Intramural Research Program of the National Institutes of Health [NIH]; National Institute of Environmental Health Sciences [NIEHS] FX National Cancer Institute [R01CA180765-01 to R.S.T.]; National Institute for Neurological Disorders and Stroke [1R21NS090313-01A1 to R.S.T.]; National Institute of Diabetes and Digestive and Kidney diseases [R01DK090249 to C.R.J.]; Intramural Research Program of the National Institutes of Health [NIH]; National Institute of Environmental Health Sciences [NIEHS]. Funding for open access charge: National Cancer Institute [R01CA180765-01]. NR 49 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2016 VL 44 IS 20 BP 9667 EP 9680 DI 10.1093/nar/gkw643 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK3HR UT WOS:000393817800019 PM 27431323 ER PT J AU Hao, CX Gely-Pernot, A Kervarrec, C Boudjema, M Becker, E Khil, P Tevosian, S Jegou, B Smagulova, F AF Hao, Chunxiang Gely-Pernot, Aurore Kervarrec, Christine Boudjema, Melissa Becker, Emmanuelle Khil, Pavel Tevosian, Sergei Jegou, Bernard Smagulova, Fatima TI Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EPIGENETIC TRANSGENERATIONAL INHERITANCE; EMBRYONIC STEM-CELLS; MOUSE SPERMATOZOA; NUCLEAR RECEPTORS; GENE-EXPRESSION; NONCODING RNAS; MESSENGER-RNA; ORAL-EXPOSURE; GERM-CELLS; MALE-RATS AB The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generationmales. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations. C1 [Hao, Chunxiang; Gely-Pernot, Aurore; Kervarrec, Christine; Boudjema, Melissa; Becker, Emmanuelle; Jegou, Bernard; Smagulova, Fatima] INSERM, IRSET, U1085, 9 Ave Prof Leon Bernard, F-35000 Rennes, France. [Jegou, Bernard] EHESP, 2 Ave Prof Leon Bernard, F-35000 Rennes, France. [Gely-Pernot, Aurore] NIH, Clin Ctr, Bethesda, MD 20892 USA. [Tevosian, Sergei] Univ Florida, Dept Physiol Sci, Box 100144,1333 Ctr Dr, Gainesville, FL 32610 USA. RP Smagulova, F (reprint author), INSERM, IRSET, U1085, 9 Ave Prof Leon Bernard, F-35000 Rennes, France. EM fatima.smagulova@inserm.fr FU Chair of Excellence program from the European University of Brittany [11-IRSET]; Atip-Avenir program from INSERM [R13139NS]; China Scholarship Council Fellowship; Atip-Avenir Fellowship for young researchers; ATIP-Avenir INSERM [R13139NS] FX Chair of Excellence program from the European University of Brittany [11-IRSET] (to F.S.); Atip-Avenir program from INSERM [R13139NS] (to F.S.); China Scholarship Council Fellowship (to C.H.); Atip-Avenir Fellowship for young researchers (to A.G.P.). Funding for open access charge: ATIP-Avenir 2013 INSERM [R13139NS]. NR 132 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2016 VL 44 IS 20 BP 9784 EP 9802 DI 10.1093/nar/gkw840 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK3HR UT WOS:000393817800028 PM 27655631 ER PT J AU Sztuba-Solinska, J Diaz, L Kumar, MR Kolb, G Wiley, MR Jozwick, L Kuhn, JH Palacios, G Radoshitzky, SR Le Grice, SFJ Johnson, RF AF Sztuba-Solinska, Joanna Diaz, Larissa Kumar, Mia R. Kolb, Gaelle Wiley, Michael R. Jozwick, Lucas Kuhn, Jens H. Palacios, Gustavo Radoshitzky, Sheli R. Le Grice, Stuart F. J. Johnson, Reed F. TI A small stem-loop structure of the Ebola virus trailer is essential for replication and interacts with heat-shock protein A8 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SELECTIVE 2'-HYDROXYL ACYLATION; RNA SECONDARY STRUCTURES; SINGLE NUCLEOTIDE RESOLUTION; PRIMER EXTENSION SHAPE; 3' UNTRANSLATED REGION; TRACT-BINDING-PROTEIN; MESSENGER-RNA; MARBURG-VIRUS; HOST PROTEIN; HIGH-THROUGHPUT AB Ebola virus (EBOV) is a single-stranded negative-sense RNA virus belonging to the Filoviridae family. The leader and trailer non-coding regions of the EBOV genome likely regulate its transcription, replication, and progeny genome packaging. We investigated the cis-acting RNA signals involved in RNA-RNA and RNA-protein interactions that regulate replication of eGFP-encoding EBOV minigenomic RNA and identified heat shock cognate protein family A (HSC70) member 8 (HSPA8) as an EBOV trailer-interacting host protein. Mutational analysis of the trailer HSPA8 binding motif revealed that this interaction is essential for EBOV minigenome replication. Selective 2'-hydroxyl acylation analyzed by primer extension analysis of the secondary structure of the EBOVminigenomic RNA indicates formation of a small stem-loop composed of the HSPA8 motif, a 3'-stem-loop (nucleotides 1868-1890) that is similar to a previously identified structure in the replicative intermediate (RI) RNA and a panhandle domain involving a trailer-to-leader interaction. Results ofminigenome assays and an EBOV reverse genetic system rescue support a role for both the panhandle domain and HSPA8 motif 1 in virus replication. C1 [Sztuba-Solinska, Joanna; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, Basic Res Lab, NIH, Frederick, MD 21702 USA. [Diaz, Larissa; Kumar, Mia R.; Kolb, Gaelle; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. [Wiley, Michael R.; Jozwick, Lucas; Palacios, Gustavo; Radoshitzky, Sheli R.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, Basic Res Lab, NIH, Frederick, MD 21702 USA.; Johnson, RF (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. EM legrices@mail.nih.gov; johnsonreed@mail.nih.gov OI Kuhn, Jens H./0000-0002-7800-6045; Palacios, Gustavo/0000-0001-5062-1938 FU NIAID Division of Intramural Research; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Battelle Memorial Institute's prime contract; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; The Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) of the Defense Threat Reduction Agency (DTRA) [1323839, CB3849]; Defense Threat Reduction Agency [CB10217] FX This work was supported by the NIAID Division of Intramural Research. S.L.G. and J.S.-S. were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is: J.H.K. an employee of Tunnell Government Services, Inc. S.R.R was supported by The Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) of the Defense Threat Reduction Agency (DTRA) (proposal #1323839 and CCAR# CB3849). Portions of this work performed by S.R.R. and L.J. were funded by the Defense Threat Reduction Agency, CB10217. NR 68 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2016 VL 44 IS 20 BP 9831 EP 9846 DI 10.1093/nar/gkw825 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK3HR UT WOS:000393817800031 PM 27651462 ER PT J AU Kellner, CH Husain, MM Knapp, RG McCall, WV Petrides, G Rudorfer, MV Young, RC Sampson, S McClintock, SM Mueller, M Prudic, J Greenberg, RM Weiner, RD Bailine, SH Rosenquist, PB Raza, A Kaliora, S Latoussakis, V Tobias, KG Briggs, MC Liebman, LS Geduldig, ET Teklehaimanot, AA Lisanby, SH AF Kellner, Charles H. Husain, Mustafa M. Knapp, Rebecca G. McCall, W. Vaughn Petrides, Georgios Rudorfer, Matthew V. Young, Robert C. Sampson, Shirlene McClintock, Shawn M. Mueller, Martina Prudic, Joan Greenberg, Robert M. Weiner, Richard D. Bailine, Samuel H. Rosenquist, Peter B. Raza, Ahmad Kaliora, Styliani Latoussakis, Vassilios Tobias, Kristen G. Briggs, Mimi C. Liebman, Lauren S. Geduldig, Emma T. Teklehaimanot, Abeba A. Lisanby, Sarah H. CA CORE PRIDE Work Grp TI Right Unilateral Ultrabrief Pulse ECT in Geriatric Depression: Phase 1 of the PRIDE Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID TREATMENT-RESISTANT DEPRESSION; ELECTROCONVULSIVE-THERAPY; MAJOR DEPRESSION; DOUBLE-BLIND; ELECTRODE PLACEMENT; CONTROLLED-TRIAL; RATING SCALE; PHARMACOTHERAPY; ANTIDEPRESSANT; EFFICACY AB Objective: The Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy of right unilateral ultra brief pulse electroconvulsive therapy (ECT) combined with venlafaxine for the treatment of geriatric depression. Method: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, combined with open-label venlafaxine at seven academic medical centers. In phase 2 (reported separately), patients who had remitted were randomly assigned to receive pharmacotherapy (venlafaxine plus lithium) or pharmacotherapy plus continuation ECT. In phase 1, depressed patients received high-dose ECT (at six times the seizure threshold) three times per week. Venlafaxine was started during the first week of treatment and continued throughout the study. The primary outcome measure was remission, assessed with the 24-item Hamilton Depression Rating Scale (HAM-D), which was administered three times per week. Secondary outcome measures were post-ECT reorientation and safety. Paired t tests were used to estimate and evaluate the significance of change from baseline in HAM-D scores. Results: Of 240 patients who entered phase 1 of the study, 172 completed it. Overall, 61.7% (148/240) of all patients met remission criteria, 10.0% (24/240) did not remit, and 28.3% (68/240) dropped out; 70% (169/240) met response criteria. Among those who remitted, the mean decrease in HAM-D score was 24.7 points (95% CI=23.4, 25.9), with a mean final score of 6.2 (SD-2.5) and an average change from baseline of 79%. The mean number of ECT treatments to remission was 7.3 (SD=3.1). Conclusions: Right unilateral ultrabrief pulse ECT, combined with venlafaxine, is a rapidly acting and highly effective treatment option for depressed geriatric patients, with excellent safety and tolerability. These data add to the evidence base supporting the efficacy of ECT to treat severe depression in elderly patients. C1 [Kellner, Charles H.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. Columbia Univ, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NYU, Dept Psychiat & Behav Hlth Sci, Lutheran Med Ctr, New York, NY USA. Med Univ South Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC USA. Zucker Hillside Hosp North Shore LIJ Hlth Syst, Dept Psychiat, New York, NY USA. Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX USA. New York Presbyterian Weill Cornell Med Ctr, Dept Psychiat, New York, NY USA. New York Presbyterian Weill Cornell Med Ctr, Dept Psychiat, White Plains, NY USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. Augusta Univ, Dept Psychiat & Hlth Behav, Med Coll Georgia, Augusta, GA USA. Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Kellner, CH (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM charles.kellner@mssm.edu FU NIMH [U01MH055495, U01MH081362, U01MH086127, U01MH086130, U01MH08612005, U01MH084241, U01MH086122]; Alkermes; Assurex; Avanir; Cyberonics; Brainsway; MagStim; NARSAD; National Institute of Neurological Disorders and Stroke; National Institute on Aging; NeoSync; Neuronetics; NIDA; NIMH; Stanley Foundation; St. Jude Medical (Advanced Neuromodulation Systems); American Foundation for the Prevention of Suicide and NIMH; Amgen; AstraZeneca; Corcept; Eli Lilly; Proteus; St. Jude Medical; Sunovion; Brain and Behavior Research Foundation; Stanley Medical Research Foundation; Nexstim; NIH FX Supported by NIMH grants U01MH055495, U01MH081362, U01MH086127, U01MH086127, U01MH086130, U01MH08612005, U01MH084241, and U01MH086122.; Dr. Kellner receives honoraria from UpToDate, Psychiatric Times, and Northwell Health and royalties from Cambridge University Press. Dr. Husain has received grant support from Alkermes, Assurex, Avanir, Cyberonics, Brainsway, MagStim, NARSAD, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, NeoSync, Neuronetics, NIDA, NIMH, the Stanley Foundation, and St. Jude Medical (Advanced Neuromodulation Systems). Dr. McCall has served as a scientific adviser for Multiple Energy Technologies, and he has received research support from the American Foundation for the Prevention of Suicide and NIMH, royalties from Wolters Kluwer, and honoraria from Anthem, Inc., CME Outfitters, and Global Medical Education. Dr. Petrides has received research support from Amgen, AstraZeneca, Corcept, Eli Lilly, Proteus, St. Jude Medical, and Sunovion, and he has served on an advisory panel for Corcept. Dr. Young is a consultant to NIH and has received research support from NIMH. Dr. McClintock has received research support from NIMH and a teaching honorarium from TMS Education Solutions; he is a member of the editorial board of the Journal of ECT. Dr. Lisanby has received grant support from the Brain and Behavior Research Foundation, the Stanley Medical Research Foundation, Neosync, Nexstim, NIH, and Brainsway; this work was performed while Dr. Lisanby was at Duke University School of Medicine. The other authors report no financial relationships with commercial interests. NR 36 TC 6 Z9 6 U1 2 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2016 VL 173 IS 11 BP 1101 EP 1109 DI 10.1176/appi.ajp.201615081101 PG 9 WC Psychiatry SC Psychiatry GA EA2LE UT WOS:000386423000009 ER PT J AU Kellner, CH Husain, MM Knapp, RG McCall, WV Petrides, G Rudorfer, MV Young, RC Sampson, S McClintock, SM Mueller, M Prudic, J Greenberg, RM Weiner, RD Bailine, SH Rosenquist, PB Raza, A Kaliora, S Latoussakis, V Tobias, KG Briggs, MC Liebman, LS Geduldig, ET Teklehaimanot, AA Dooley, M Lisanby, SH AF Kellner, Charles H. Husain, Mustafa M. Knapp, Rebecca G. McCall, W. Vaughn Petrides, Georgios Rudorfer, Matthew V. Young, Robert C. Sampson, Shirlene McClintock, Shawn M. Mueller, Martina Prudic, Joan Greenberg, Robert M. Weiner, Richard D. Bailine, Samuel H. Rosenquist, Peter B. Raza, Ahmad Kaliora, Styliani Latoussakis, Vassilios Tobias, Kristen G. Briggs, Mimi C. Liebman, Lauren S. Geduldig, Emma T. Teklehaimanot, Abeba A. Dooley, Mary Lisanby, Sarah H. CA CORE PRIDE Work Grp TI A Novel Strategy for Continuation ECT in Geriatric Depression: Phase 2 of the PRIDE Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RATING-SCALE; ELECTROCONVULSIVE-THERAPY; INTERVIEW; MINI AB Objective: The randomized phase (phase 2) of the Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy and tolerability of continuation ECT plus medication compared with medication alone in depressed geriatric patients after a successful course of ECT (phase 1). Method: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, augmented with venlafaxine. Phase 2 compared two randomized treatment arms: a medication only arm (venlafaxine plus lithium, over 24 weeks) and an ECT plus medication arm (four continuation ECTtreatments over1 month, plus additional ECT as needed, using the Symptom-Titrated, Algorithm-Based Longitudinal ECT [STABLE] algorithm, while continuing yenlafaxine plus lithium). The intent-to-treat sample comprised 120 remitters from phase 1. The primary efficacy outcome measure was score on the 24-item Hamilton Depression Rating Scale (HAM-D), and the secondary efficacy outcome was score on the Clinical Global Impressions severity scale (CGI-S). Tolerability as measured by neurocognitive performance (reported elsewhere) was assessed using an extensive test battery; global cognitive functioning as assessed by the Mini-Mental State Examination (MMSE) is reported here. Longitudinal mixed-effects repeated-measures modeling was used to compare ECT plus medication and medication alone for efficacy and global cognitive function outcomes. Results: At 24 weeks, the ECT plus medication group had statistically significantly lower HAM-D scores than the medication only group. The difference in adjusted mean HAM-D scores at study end was 4.2 (95% CI = 1.6, 6.9). Significantly more patients in the ECT plus medication group were rated "not ill at all" on the CGI-S compared with the medication only group. There was no statistically significant difference between groups in MMSE score. Conclusions: Additional ECT after remission (here operationalized as four continuation ECT treatments followed by further ECT only as needed) was beneficial in sustaining mood improvement for most patients. C1 [Kellner, Charles H.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. Columbia Univ, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NYU, Lutheran Med Ctr, Dept Psychiat & Behav Hlth Sci, New York, NY USA. Med Univ South Carolina, Coll Med, Dept Publ Hlth Sci, Charleston, SC USA. Zucker Hillside Hosp Northwell Hlth Syst, Dept Psychiat, New York, NY USA. Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX USA. New York Presbyterian Weill Cornell Med Ctr, Dept Psychiat, New York, NY USA. New York Presbyterian Weill Cornell Med Ctr, Dept Psychiat, White Plains, NY USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. Augusta Univ, Med Coll Georgia, Dept Psychiat & Hlth Behav, Augusta, GA USA. Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Kellner, CH (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM charles.kellner@mssm.edu OI Greenberg, Robert/0000-0001-7078-8970 FU NIMH [U01MH055495, U01MH081362, U01MH086127, U01MH086130, U01MH08612005, U01MH084241, U01MH086122]; Alkermes; Assurex; Avanir; Cyberonics; Brainsway; MagStim; NARSAD; National Institute of Neurological Disorders and Stroke; National Institute on Aging; NeoSync; Neuronetics; NIDA; NIMH; Stanley Foundation; St. Jude Medical (Advanced Neuromodulation Systems); American Foundation for the Prevention of Suicide; Amgen; AstraZeneca; Corcept; Eli Lilly; Proteus; St. Jude Medical; Sunovion; Brain and Behavior Research Foundation; Stanley Medical Research Foundation; Nexstim; NIH FX Supported by NIMH grants U01MH055495, U01MH081362, U01MH086127, U01MH086127, U01MH086130, U01MH08612005, U01MH084241, and U01MH086122.; Dr. Kellner receives honoraria from UpToDate, Psychiatnc Times, and Northwell Health and royalties from Cambridge University Press. Dr. Husain has received grant support from Alkermes, Assurex, Avanir, Cyberonics, Brainsway, MagStim, NARSAD, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, NeoSync, Neuronetics, NIDA, NIMH, the Stanley Foundation, and St. Jude Medical (Advanced Neuromodulation Systems). Dr. McCall has served as a scientific adviser for Multiple Energy Technologies, and he has received research support from the American Foundation for the Prevention of Suicide and NIMH, royalties from Wolters Kluwer, and honoraria from Anthem, Inc., CME Outfitters, and Global Medical Education. Dr. Petrides has received research support from Amgen, AstraZeneca, Corcept, Eli Lilly, Proteus, St. Jude Medical, and Sunovion, and he has served on an advisory panel for Corcept. Dr. Young is a consultant to NIH and has received research support from NIMH. Dr McClintock has received research support from NIMH and a teaching honorarium from TMS Education Solutions; he is a member of the editorial board of the Journal of ECT. Dr. Lisanby has received grant support from the Brain and Behavior Research Foundation, the Stanley Medical Research Foundation, Neosync, Nexstim, NIH, and Brainsway; this work was performed while Dr. Lisanby was at Duke University School of Medicine. The other authors report no financial relationships with commercial interests. NR 16 TC 5 Z9 5 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2016 VL 173 IS 11 BP 1110 EP 1118 DI 10.1176/appi.ajp.2016.16010118 PG 9 WC Psychiatry SC Psychiatry GA EA2LE UT WOS:000386423000010 ER PT J AU Loucks, EB Huang, YT Agha, G Chu, S Eaton, CB Gilman, SE Buka, SL Kelsey, KT AF Loucks, Eric B. Huang, Yen-Tsung Agha, Golareh Chu, Su Eaton, Charles B. Gilman, Stephen E. Buka, Stephen L. Kelsey, Karl T. TI Epigenetic Mediators Between Childhood Socioeconomic Disadvantage and Mid-Life Body Mass Index: The New England Family Study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE DNA methylation; epigenetics; adiposity; body mass index; socioeconomic disadvantage; socioeconomic status ID EARLY-LIFE ORIGINS; EPIGENOME-WIDE ASSOCIATION; WNT SIGNALING PATHWAY; DNA METHYLATION DATA; ADIPOSE-TISSUE; STRESS REACTIVITY; PERIPHERAL-BLOOD; GENE-EXPRESSION; OBESITY; CORTISOL AB Objective: Childhood socioeconomic disadvantage is associated with adulthood obesity risk; however, epigenetic mechanisms are poorly understood. This work's objective was to evaluate whether associations of childhood socioeconomic disadvantage with adulthood body mass index (BMI) are mediated by DNA methylation. Methods: Participants were 141 men and women from the New England Family Study, prospectively followed prenatally through a mean age of 47 years. Epigenomewide DNA methylation was evaluated in peripheral blood and adipose tissue obtained at adulthood, using the Infinium HumanMethylation450K BeadChip. Childhood socioeconomic status (SES) at age 7 years was assessed directly from parents' reports. Offspring adiposity was directly assessed using BMI at a mean age of 47 years. Associations of SES, DNA methylation, and BMI were estimated using least square estimators. Statistical mediation analyses were performed using joint significance test and bootstrapping. Results: Of CpG sites significant at the 25% false discovery rate level in epigenomewide methylation BMI analyses, 91 sites in men and 71 sites in women were additionally significant for SES-methylation associations (p < .001) in adipose tissue. Many involved genes biologically relevant for development of obesity, including fatty acid synthase, transmembrane protein 88, signal transducer and activator of transcription 3, and neuritin 1. There was no evidence of epigenetic mediation in peripheral blood leukocytes. Conclusions: DNA methylation at specific genes may be mediators of associations between childhood socioeconomic disadvantage and mid-life BMI in adipose tissue. Findings motivate continued efforts to study if and how childhood socioeconomic disadvantage is biologically embedded at the level of the epigenome in regions etiologically relevant for adiposity. C1 [Loucks, Eric B.; Huang, Yen-Tsung; Chu, Su; Eaton, Charles B.; Buka, Stephen L.; Kelsey, Karl T.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St, Providence, RI 02912 USA. [Agha, Golareh] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Eaton, Charles B.] Brown Univ, Warren Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Loucks, EB (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St, Providence, RI 02912 USA. EM eric.loucks@brown.edu FU NIH/NIA [RC2AG036666, R01AG048825]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Funding for this study was provided by NIH/NIA grants RC2AG036666 and R01AG048825, and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors report no conflicts of interest. NR 74 TC 2 Z9 2 U1 6 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 NOV-DEC PY 2016 VL 78 IS 9 BP 1053 EP 1065 DI 10.1097/PSY.0000000000000411 PG 13 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA EE5LR UT WOS:000389649600009 PM 27768648 ER PT J AU Li, H Zhu, YT Burnside, ES Drukker, K Hoadley, KA Fan, C Conzen, SD Whitman, GJ Sutton, EJ Net, JM Ganott, M Huang, E Morris, EA Perou, CM Ji, Y Giger, ML AF Li, Hui Zhu, Yitan Burnside, Elizabeth S. Drukker, Karen Hoadley, Katherine A. Fan, Cheng Conzen, Suzanne D. Whitman, Gary J. Sutton, Elizabeth J. Net, Jose M. Ganott, Marie Huang, Erich Morris, Elizabeth A. Perou, Charles M. Ji, Yuan Giger, Maryellen L. TI MR Imaging Radiomics Signatures for Predicting the Risk of Breast Cancer Recurrence as Given by Research Versions of MammaPrint, Oncotype DX, and PAM50 Gene Assays SO RADIOLOGY LA English DT Article ID MAXIMUM-LIKELIHOOD-ESTIMATION; BINORMAL ROC CURVES; COMPUTERIZED ANALYSIS; PROGNOSTIC MARKERS; DCE-MRI; LESIONS; EXPRESSION; IMAGES; DIAGNOSIS; SUBTYPES AB Purpose: To investigate relationships between computer-extracted breast magnetic resonance (MR) imaging phenotypes with multigene assays of MammaPrint, Oncotype DX, and PAM50 to assess the role of radiomics in evaluating the risk of breast cancer recurrence. Materials and Methods: Analysis was conducted on an institutional review board-approved retrospective data set of 84 deidentified, multi-institutional breast MR examinations from the National Cancer Institute Cancer Imaging Archive, along with clinical, histopathologic, and genomic data from The Cancer Genome Atlas. The data set of biopsy-proven invasive breast cancers included 74 (88%) ductal, eight (10%) lobular, and two (2%) mixed cancers. Of these, 73 (87%) were estrogen receptor positive, 67 (80%) were progesterone receptor positive, and 19 (23%) were human epidermal growth factor receptor 2 positive. For each case, computerized radiomics of the MR images yielded computer-extracted tumor phenotypes of size, shape, margin morphology, enhancement texture, and kinetic assessment. Regression and receiver operating characteristic analysis were conducted to assess the predictive ability of the MR radiomics features relative to the multigene assay classifications. Results: Multiple linear regression analyses demonstrated significant associations (R-2 = 0.25-0.32, r = 0.5-0.56, P < .0001) between radiomics signatures and multigene assay recurrence scores. Important radiomics features included tumor size and enhancement texture, which indicated tumor heterogeneity. Use of radiomics in the task of distinguishing between good and poor prognosis yielded area under the receiver operating characteristic curve values of 0.88 (standard error, 0.05), 0.76 (standard error, 0.06), 0.68 (standard error, 0.08), and 0.55 (standard error, 0.09) for MammaPrint, Oncotype DX, PAM50 risk of relapse based on subtype, and PAM50 risk of relapse based on subtype and proliferation, respectively, with all but the latter showing statistical difference from chance. Conclusion: Quantitative breast MR imaging radiomics shows promise for image-based phenotyping in assessing the risk of breast cancer recurrence. (C) RSNA, 2016 C1 [Li, Hui; Drukker, Karen; Giger, Maryellen L.] Univ Chicago, Dept Radiol, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. [Ji, Yuan] Univ Chicago, Dept Publ Hlth Sci, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. [Zhu, Yitan; Ji, Yuan] NorthShore Univ HealthSystem, Program Computat Gen & Med, Evanston, IL 60201 USA. [Burnside, Elizabeth S.] Univ Wisconsin, Dept Biol, Madison, WI 53706 USA. [Hoadley, Katherine A.; Fan, Cheng; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Conzen, Suzanne D.] Univ Chicago, Dept Med, Sect Hematol & Oncol, Chicago, IL 60637 USA. [Whitman, Gary J.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Sutton, Elizabeth J.; Morris, Elizabeth A.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Net, Jose M.] Univ Miami, Sylvester Comprehens Canc Ctr, Dept Radiol, Miami, FL USA. [Ganott, Marie] Univ Pittsburgh, Med Ctr, Dept Radiol, Pittsburgh, PA USA. [Huang, Erich] NCI, Div Canc Treatment & Diag, Biometr Res Branch, Bethesda, MD USA. RP Giger, ML (reprint author), Univ Chicago, Dept Radiol, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. EM m-giger@uchicago.edu OI Perou, Charles/0000-0001-9827-2247 FU National Cancer Institute [U01-CA195564, P30-CA14599, P50-CA58223, U24-CA143848-05]; Breast Cancer Research Foundation grant; Univ of Chicago Pritzker School of Medicine Dean Bridge Fund FX Supported by the National Cancer Institute (U01-CA195564, P30-CA14599, P50-CA58223, and U24-CA143848-05); a Breast Cancer Research Foundation grant; and The Univ of Chicago Pritzker School of Medicine Dean Bridge Fund. NR 39 TC 0 Z9 0 U1 6 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2016 VL 281 IS 2 BP 382 EP 391 DI 10.1148/radiol.2016152110 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4PL UT WOS:000393199200006 PM 27144536 ER PT J AU Meehan, RS Chen, AP Doroshow, JH AF Meehan, Robert S. Chen, Alice P. Doroshow, James H. TI Role of adaptive randomization in developing novel therapies for patients with breast cancer SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID BRCA MUTATION CARRIERS; POLY(ADP-RIBOSE) POLYMERASE; CLINICAL-TRIALS; PARP INHIBITORS; PHASE-2 TRIAL; COMBINATION; CARBOPLATIN; OVARIAN; TUMORS C1 [Meehan, Robert S.; Chen, Alice P.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Rom 3A-44,Bldg 31,31 Ctr Dr, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Rom 3A-44,Bldg 31,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This project was funded with federal funds from the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services. NR 21 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD NOV PY 2016 VL 5 SU 6 BP S1119 EP S1122 DI 10.21037/tcr.2016.11.27 PG 4 WC Oncology SC Oncology GA EJ6KM UT WOS:000393328100023 ER PT J AU Rath, BH Camphausen, K Tofilon, PJ AF Rath, Barbara H. Camphausen, Kevin Tofilon, Philip J. TI Glioblastoma radiosensitization by pimozide SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID VALPROIC ACID; CELL-LINES; STEM-CELL; TARGET; INHIBITORS; TEMOZOLOMIDE; PHENOTYPE; RADIATION; THERAPY; TUMORS C1 [Rath, Barbara H.; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, 10 Ctr Dr,MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM philip.tofilon@nih.gov NR 24 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD NOV PY 2016 VL 5 SU 6 BP S1029 EP S1032 DI 10.21037/tcr.2016.11.17 PG 4 WC Oncology SC Oncology GA EJ6KM UT WOS:000393328100001 ER PT J AU Schmidt, KT Figg, WD AF Schmidt, Keith T. Figg, William D. TI The potential role of curcumin in prostate cancer: the importance of optimizing pharmacokinetics in clinical studies SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID ANDROGEN RECEPTOR; PHASE-II; DOCETAXEL; ANALOGS; NANOPARTICLES; PREDNISONE; ASC-J9(R); GROWTH; ENZALUTAMIDE; MITOXANTRONE C1 [Schmidt, Keith T.; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. NR 25 TC 0 Z9 0 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD NOV PY 2016 VL 5 SU 6 BP S1107 EP S1110 DI 10.21037/tcr.2016.11.04 PG 4 WC Oncology SC Oncology GA EJ6KM UT WOS:000393328100020 ER PT J AU Bektas, A Sen, R Ferrucci, L AF Bektas, Arsun Sen, Ranjan Ferrucci, Luigi TI Does a bit of alcohol turn off inflammation and improve health? SO AGE AND AGEING LA English DT Editorial Material ID C-REACTIVE PROTEIN; CONSUMPTION; MARKERS; FRAILTY; DISEASE; COHORT; WOMEN; DIET C1 [Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM ferruccilu@grc.nia.nih.gov NR 18 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD NOV PY 2016 VL 45 IS 6 BP 747 EP 748 DI 10.1093/ageing/afw146 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EI7RY UT WOS:000392702200003 PM 27555047 ER PT J AU Teras, LR DeSantis, CE Cerhan, JR Morton, LM Jemal, A Flowers, CR AF Teras, Lauren R. DeSantis, Carol E. Cerhan, James R. Morton, Lindsay M. Jemal, Ahmedin Flowers, Christopher R. TI 2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article DE chronic lymphocytic leukemia; epidemiology; Hodgkin disease; multiple myeloma; non-Hodgkin lymphoma ID NON-HODGKIN-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENOME-WIDE ASSOCIATION; UNITED-STATES; BURKITT-LYMPHOMA; RISK-FACTORS; DESCRIPTIVE EPIDEMIOLOGY; INCIDENCE PATTERNS; CIGARETTE-SMOKING AB Collectively, lymphoid neoplasms are the fourth most common cancer and the sixth leading cause of cancer death in the United States. The authors provide contemporary lymphoid neoplasm statistics by subtype based on the 2008 World Health Organization classifications, including the most current US incidence and survival data. Presented for the first time are estimates of the total numbers of US lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence and survival statistics. In 2016, 136,960 new lymphoid neoplasms are expected. Overall lymphoma incidence rates have declined in recent years, but trends vary by subtype. Precursor lymphoid neoplasm incidence rates increased from 2001 to 2012, particularly for B-cell neoplasms. Among the mature lymphoid neoplasms, the fastest increase was for plasma cell neoplasms. Rates also increased for mantle cell lymphoma (males), marginal zone lymphoma, hairy cell leukemia, and mycosis fungoides. Like incidence, survival for both mature T-cell lymphomas and mature B-cell lymphomas varied by subtype and by race. Patients with peripheral T-cell lymphomas had among the worst 5-year relative survival (36%-56%, depending on race/sex), while those with mycosis fungoides had among the best survival (79%-92%). For B-cell lymphomas, 5-year survival ranged from 83% to 91% for patients with marginal zone lymphoma and from 78% to 92% for those with hairy cell leukemia; but the rates were as low as 47% to 63% for patients with Burkitt lymphoma and 44% to 48% for those with plasma cell neoplasms. In general, black men had the lowest survival across lymphoid malignancy subtypes. These contemporary incidence and survival statistics are useful for developing management strategies for these cancers and can offer clues regarding their etiology. (C) 2016 American Cancer Society. C1 [Teras, Lauren R.] Amer Canc Soc, Hematol Canc Res, Epidemiol Res Program, 250 Williams St NW, Atlanta, GA 30303 USA. [DeSantis, Carol E.] Amer Canc Soc, Breast & Gynecol Canc Surveillance, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Morton, Lindsay M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Flowers, Christopher R.] Emory Univ, Winship Canc Inst, Dept Hematol & Oncol, Lymphoma Program, Atlanta, GA 30322 USA. RP Teras, LR (reprint author), Amer Canc Soc, Hematol Canc Res, Epidemiol Res Program, 250 Williams St NW, Atlanta, GA 30303 USA. EM lauren.teras@cancer.org RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU Spectrum; Celgene; Optum Rx; Seattle Genetics; Genentech/Biogen-Idec/Roche and Millennium/Takeda; Abbvie; Acerta; Gilead Sciences; Infinity Pharmaceuticals; Millennium/Takeda; Onyx Pharmaceuticals; National Cancer Institute/National Institutes of Health; Borroughs Wellcome Fund; V Foundation; Clinical Care Options; Educational Concepts; PRIME Oncology; Research to Practice FX Christopher R. Flowers reports consulting fees from Spectrum, Celgene, Optum Rx, and Seattle Genetics; unpaid consultancy work for Genentech/Biogen-Idec/Roche and Millennium/Takeda; institutional research funding/grants from Abbvie, Acerta, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Millennium/Takeda, Spectrum, Onyx Pharmaceuticals, the National Cancer Institute/National Institutes of Health, the Borroughs Wellcome Fund, and The V Foundation; and personal fees for developing educational presentations from Clinical Care Options, Educational Concepts, PRIME Oncology, and Research to Practice, all outside the submitted work. All remaining authors report no conflicts of interest. NR 70 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD NOV-DEC PY 2016 VL 66 IS 6 BP 443 EP 459 DI 10.3322/caac.21357 PG 17 WC Oncology SC Oncology GA EI8KR UT WOS:000392755800003 ER PT J AU Harada, T Nakamura, Y Sato, K Nagaya, T Choyke, PL Seto, Y Kobayashi, H AF Harada, Toshiko Nakamura, Yuko Sato, Kazuhide Nagaya, Tadanobu Choyke, Peter L. Seto, Yasuyuki Kobayashi, Hisataka TI Surgical tissue handling methods to optimize ex vivo fluorescence with the activatable optical probe -glutamyl hydroxymethyl rhodamine green SO Contrast Media & Molecular Imaging LA English DT Article DE optical navigation surgery; fluorescent probe; surgical specimen; -glutamyl transpeptidase; ovarian cancer ID ADAPTED BETA-GALACTOSIDASE; MOLECULAR PROBES; DRUG-RESISTANCE; OVARIAN-CANCER; TRANSPEPTIDASE; TRANSFERASE; EXPRESSION; TUMORS; PURIFICATION; CLONING AB Optical fluorescence imaging has been developed as an aid to intraoperative diagnosis to improve surgical and endoscopic procedures. Compared with other intraoperative imaging methods, it is lower in cost, has a high safety margin, is portable and easy to use. -glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) is a recently developed activatable fluorescence probe that emits strong fluorescence in the presence of the enzyme -glutamyl transpeptidase (GGT), which is overexpressed in many cancers, including ovarian cancer. Ex vivo testing is important for clinical approval of such probes. The diagnostic performance of gGlu-HMRG in fresh excised surgical specimens has been reported; however, details of tissue handling have not been optimized. In this study, we investigated four different tissue handling procedures to optimize imaging in excised tumor specimens. The fluorescence intensity time courses after the different tissue handling methods were compared. Additionally, the fluorescence positive areas were correlated with the presence of red fluorescent protein (RFP) in an RFP positive cell line as the standard of reference for cancer location. In the intact' groups, tumors yielded quick and homogeneous activation of gGlu-HMRG. In the rinse' and cut' groups, the fluorescence intensity of the tumor was a little lower than that in the intact group. In the pressed' groups, however, fluorescence intensity from gGlu-HMRG was lower over the entire time course, suggesting a decrease or relocation of excreted GGT. In conclusion, we demonstrate that the method of tissue handling prior to ex vivo imaging with the activatable probe gGlu-HMRG has a strong influence on the signal derived from the specimen. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Harada, Toshiko; Nakamura, Yuko; Sato, Kazuhide; Nagaya, Tadanobu; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Seto, Yasuyuki] Univ Tokyo, Grad Sch Med, Dept Stomach & Esophageal Surg, Tokyo 113, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov NR 25 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 EI 1555-4317 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD NOV-DEC PY 2016 VL 11 IS 6 BP 572 EP 578 DI 10.1002/cmmi.1705 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI8LJ UT WOS:000392757600015 PM 27444370 ER PT J AU Pletnev, VZ Pletneva, NV Efremov, RG Goryacheva, EA Artemyev, IV Arkhipova, SF Sarkisyan, KS Mishin, AS Lukyanov, KA Pletnev, SV AF Pletnev, V. Z. Pletneva, N. V. Efremov, R. G. Goryacheva, E. A. Artemyev, I. V. Arkhipova, S. F. Sarkisyan, K. S. Mishin, A. S. Lukyanov, K. A. Pletnev, S. V. TI Three-dimensional structure of a pH-dependent fluorescent protein WasCFP with a tryptophan based deprotonated chromophore SO RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY LA English DT Article DE crystal structure; green fluorescent protein WasCFP; Trp based chromophore; Trp anionic form ID GREEN; MODE; FRET AB WasCFP, a pH-dependent green fluorescent protein with a tryptophan-based chromophore (Thr65-Trp66-Gly67) in anionic state, was designed from a cyan precursor mCerulean. In this study, the three-dimensional structure of WasCFP has been determined by an X-ray method at pH 5.5, pH 8.0 and pH 10.0, with a resolution of 1.14, 1.25 and 1.5 , respectively. We show that changes in the acidity of the media are accompanied by a synchronous change of the side chain conformations of the residues in the near-chromophore environment. Subsequent changes in the local H-bond network interacting with the chromophore lead to considerable alterations in the protein spectral properties as a consequence of reversible processes of ionization-protonation of the Trp chromophore. These experimental results have been supported by quantum chemistry calculations. C1 [Pletnev, V. Z.; Pletneva, N. V.; Efremov, R. G.; Goryacheva, E. A.; Artemyev, I. V.; Arkhipova, S. F.; Sarkisyan, K. S.; Mishin, A. S.; Lukyanov, K. A.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Pletnev, S. V.] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. RP Pletnev, VZ (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. EM vzpletnev@gmail.com FU Molecular and Cellular Biology fund of the Russian Academy of Sciences; Russian Foundation for Basic Research grant [14-04-00004]; Russian Science Foundation [14-24-00118]; Russian Federation [MK-7495.2016.4]; US Department of Energy [W-31-109-Eng-38]; NIH National Cancer Institute [HHSN261200800001E] FX X-ray diffraction studies of WasCFP at different pH values were performed with financial support of the Molecular and Cellular Biology fund of the Russian Academy of Sciences, and Russian Foundation for Basic Research grant 14-04-00004. Determination of the WasCFP spatial structure at physiological pH was carried out within the framework of the graduate research program. Quantum chemical calculations were carried out with the support of the Russian Science Foundation (grant 14-24-00118). Work on protein purification was carried out with the support of a grant by the President of the Russian Federation (MK-7495.2016.4) with a partial use of the equipment at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences. X-ray experimental data were obtained on a station (22 ID) of the synchrotron center (APS; Argonne, United States). Work at the APS center was supported by the US Department of Energy under the contract W-31-109-Eng-38, and, in part, by the contract funded by the NIH National Cancer Institute HHSN261200800001E. NR 24 TC 0 Z9 0 U1 0 U2 0 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1068-1620 EI 1608-330X J9 RUSS J BIOORG CHEM+ JI Russ. J. Bioorg. Chem. PD NOV PY 2016 VL 42 IS 6 BP 612 EP 618 DI 10.1134/S1068162016050149 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA EJ2MO UT WOS:000393044600004 ER PT J AU Xu, XZ Li, R Chen, GZ Hoopes, SL Zeldin, DC Wang, DW AF Xu, Xizhen Li, Rui Chen, Guangzhi Hoopes, Samantha L. Zeldin, Darryl C. Wang, Dao Wen TI The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases SO ADVANCES IN NUTRITION LA English DT Review DE cytochrome P450 (CYP) epoxygenase; epoxyeicosatrienoic acid; soluble epoxide hydrolase; insulin resistance; lipid; obesity; type 2 diabetes ID HIGH-FAT DIET; ENDOPLASMIC-RETICULUM STRESS; REDUCES INSULIN-RESISTANCE; FRUCTOSE-TREATED RATS; INDUCED DIABETIC MICE; CARDIOVASCULAR-DISEASE; VASCULAR DYSFUNCTION; ENDOTHELIAL-CELLS; ADIPOSE-TISSUE; LIVER-DISEASE AB Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes. Future areas of research to address current deficiencies in the understanding of these enzymes and their eicosanoid metabolites in various aspects of metabolic diseases are also discussed. C1 [Xu, Xizhen; Li, Rui; Chen, Guangzhi; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan, Peoples R China. [Xu, Xizhen; Li, Rui; Chen, Guangzhi; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens, Wuhan, Peoples R China. [Hoopes, Samantha L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan, Peoples R China.; Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens, Wuhan, Peoples R China. EM dwwang@tjh.tjmu.edu.cn FU National Natural Science Foundation of China [81100085, 81471021, 91439203, 31130031]; Intramural Research Division of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034] FX Supported by grants from the National Natural Science Foundation of China (81100085, 81471021, 91439203, and 31130031). Also supported in part by the Intramural Research Division of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034). NR 67 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD NOV PY 2016 VL 7 IS 6 BP 1122 EP 1128 DI 10.3945/an.116.012245 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EI1ZE UT WOS:000392284700012 PM 28140329 ER PT J AU Pongpiachan, S AF Pongpiachan, Siwatt TI Incremental Lifetime Cancer Risk of PM2.5 Bound Polycyclic Aromatic Hydrocarbons (PAHs) Before and After the Wildland Fire Episode SO AEROSOL AND AIR QUALITY RESEARCH LA English DT Article DE Wildland fire; PAHs; Northern Thailand; PM2.5; Incremental lifetime cancer risk ID EQUIVALENCY FACTORS TEFS; VERTICAL-DISTRIBUTION; PARTICULATE MATTER; CHEMICAL CHARACTERISTICS; ATMOSPHERIC PARTICLES; SEASONAL-VARIATION; TRAFFIC EMISSIONS; SIZE DISTRIBUTION; DRY DEPOSITION; CENTRAL TAIWAN AB In Northern Thailand, wildland fire during cold period releases large amounts of smoke and fine particles into the atmosphere. The fine particles include several persistent organic compounds such as PAHs. In this study, PM2.5-bound PAH concentrations in the air of nine administrative provinces, namely Chiang-Mai, Chiang-Rai, Nan, Phayao, Mae Hong Son, Phrae, Lampang, Lamphun, Uttaradit (N Thailand) were determined during the wildland fire and non-wildland fire seasons. The monitoring strategy comprised two campaigns in each season. PM2.5 was collected using MiniVolTM portable air samplers (Airmetrics) with quartz fibre filters. Both PAHs and their B[a] P-Equivalent concentrations of other urban cities around the world were significantly higher than those of northern provinces for both seasons. The average cancer risks observed at nine administrative provinces were 8.525 x 10(-4) +/- 3.493 x 10(-3) and 2.558 x 10(-3) +/- 6.986 x 10(-3) for ingestion rate of 50 and 100 mg day(-1), respectively. The excess cancer risks of world cities for ingestion rate of 50 and 100 mg day-1 were much higher than those of Northern Thailand for 851 and 567 times in that order. Dust ingestion was exceedingly critical to non-dietary PAH exposure in comparison with PM2.5 inhalation. These results are in good agreement with those of previous studies, underlining the significance of indoor air quality on long-term adverse respiratory diseases in Asian cities. C1 [Pongpiachan, Siwatt] NIDA, NIDA Ctr Res & Dev Disaster Prevent & Management, Sch Social & Environm Dev, Bangkok 10240, Thailand. RP Pongpiachan, S (reprint author), NIDA, NIDA Ctr Res & Dev Disaster Prevent & Management, Sch Social & Environm Dev, Bangkok 10240, Thailand. EM pongpiajun@gmail.com FU National Institute of Development Administration (NIDA) Research Center FX This project was financed by National Institute of Development Administration (NIDA) Research Center. The author acknowledges Assist. Prof. Dr. Torpong Kreetachart from School of Energy and Environment (SEEN), University of Phayao for their contributions on laboratory works. The authors thank the kind support from Pollution Control Department, Ministry of Natural Resources and Environment for providing meteorological data. NR 79 TC 4 Z9 4 U1 8 U2 8 PU TAIWAN ASSOC AEROSOL RES-TAAR PI TAICHUNG COUNTY PA CHAOYANG UNIV TECH, DEPT ENV ENG & MGMT, PROD CTR AAQR, NO 168, JIFONG E RD, WUFONG TOWNSHIP, TAICHUNG COUNTY, 41349, TAIWAN SN 1680-8584 EI 2071-1409 J9 AEROSOL AIR QUAL RES JI Aerosol Air Qual. Res. PD NOV PY 2016 VL 16 IS 11 SI SI BP 2907 EP 2919 DI 10.4209/aaqr.2015.01.0011 PG 13 WC Environmental Sciences SC Environmental Sciences & Ecology GA EI2HI UT WOS:000392307100025 ER PT J AU Roberts, L Ratnapriya, R du Plessis, M Chaitankar, V Ramesar, RS Swaroop, A AF Roberts, Lisa Ratnapriya, Rinki du Plessis, Morne Chaitankar, Vijender Ramesar, Raj S. Swaroop, Anand TI Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE next generation sequencing; genetic testing; photoreceptor dysfunction; South Africa; vision loss; inherited blindness; retinal degeneration; clinical genetics ID RETINITIS-PIGMENTOSA; SOUTHERN AFRICA; MUTATIONS; GENE; REVEALS; DISCOVERY; VARIANTS; DYSTROPHY; FRAMEWORK; FAMILIES AB PURPOSE. A majority of genes associated with inherited retinal diseases (IRDs) have been identified in patients of European origin. Indigenous African populations exhibit rich genomic diversity, and evaluation of reported genetic mutations has yielded low returns so far. Our goal was to perform whole-exome sequencing (WES) to examine variants in known IRD genes in underrepresented African cohorts. METHODS. Whole-exome sequencing was performed on 56 samples from 16 families with diverse IRD phenotypes that had remained undiagnosed after screening for known mutations using genotyping-based microarrays (Asper Ophthalmics). Variants in reported IRD genes were identified using WES and validated by Sanger sequencing. Custom TaqMan assays were used to screen for identified mutations in 193 unrelated indigenous Africans with IRDs. RESULTS. A total of 3494 variants were identified in 217 known IRD genes, leading to the identification of seven different mutations (including six novel) in six genes (RHO, PRPF3, PRPF31, ABCA4, CERKL, and PDE6B) in six distinct families. TaqMan screening in additional probands revealed identical homozygous CERKL and PDE6B variants in four more patients. CONCLUSIONS. This is the first report of WES of patients with IRDs in indigenous African populations. Our study identified genetic defects in almost 40% of the families analyzed, significantly enhancing the molecular diagnosis of IRD in South Africa. Thus, WES of understudied cohorts seems to present an effective strategy for determining novel mutations in heterogeneous retinal diseases. C1 [Roberts, Lisa; du Plessis, Morne; Ramesar, Raj S.] Univ Cape Town, MRC Human Genet Res Unit, Inst Infect Dis & Mol Med IDM, Div Human Genet,Dept Pathol,Fac Hlth Sci, Cape Town, Western Cape, South Africa. [Ratnapriya, Rinki; Chaitankar, Vijender; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, MSC0610,6 Ctr St, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, MSC0610,6 Ctr St, Bethesda, MD 20892 USA.; Roberts, L (reprint author), Univ Cape Town, Inst Infect Dis & Mol Med, Fac Hlth Sci, N3-14,Level 3,Wernher & Beit North Bldg,Anzio Rd, ZA-7925 Cape Town, Western Cape, South Africa. EM lisa.roberts@uct.ac.za; swaroopa@nei.nih.gov FU Retina South Africa; Medical Research Council of South Africa; Intramural Research Program of the National Eye Institute [EY000546] FX Research in South Africa was funded by Retina South Africa and the Medical Research Council of South Africa. WES and data analysis were supported by the Intramural Research Program (EY000546) of the National Eye Institute and utilized computational resources of the National Institutes of Health High-Performance Computing Biowulf cluster (https://hpc.nih.gov). NR 52 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD NOV PY 2016 VL 57 IS 14 BP 6374 EP 6381 DI 10.1167/iovs.16-19785 PG 8 WC Ophthalmology SC Ophthalmology GA EI3HG UT WOS:000392380000063 PM 27898983 ER PT J AU Datiles, MB Hejtmancik, JF AF Datiles, Manuel B. Hejtmancik, J. Fielding TI Congenital Cataracts: Classification and Association With Anterior Segment Abnormalities SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Editorial Material C1 [Datiles, Manuel B.; Hejtmancik, J. Fielding] NEI, NIH, Bethesda, MD 20892 USA. RP Datiles, MB (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM datilesm@nei.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD NOV PY 2016 VL 57 IS 14 BP 6396 EP 6396 DI 10.1167/iovs.16-21074 PG 1 WC Ophthalmology SC Ophthalmology GA EI3HG UT WOS:000392380000066 PM 27898986 ER PT J AU Kosty, MP Hanley, A Chollette, V Bruinooge, SS Taplin, SH AF Kosty, Michael P. Hanley, Amy Chollette, Veronica Bruinooge, Suanna S. Taplin, Steven H. TI National Cancer Institute-American Society of Clinical Oncology Teams in Cancer Care Project SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Editorial Material ID JOB-SATISFACTION C1 [Kosty, Michael P.] Scripps Clin, 10666 N Torrey Pines Rd,MS 217, La Jolla, CA 92037 USA. Amer Soc Clin Oncol, Alexandria, VA USA. NCI, Bethesda, MD 20892 USA. RP Kosty, MP (reprint author), Scripps Clin, 10666 N Torrey Pines Rd,MS 217, La Jolla, CA 92037 USA. EM mkosty@scripps.edu FU Conquer Cancer Foundation Mission Endowment FX The production of this manuscript was funded by the Conquer Cancer Foundation Mission Endowment. We wish to acknowledge the team that made this project a success. A special thank you to the group of patient advocates who kept the process focused on the patient and shared their experiences as patients and caregivers. In addition to the authors, we thank Eduardo Salas, PhD (Rice University), Sallie Weaver, PhD, MHS (Johns Hopkins University School of Medicine), Amanda Vogel, PhD, MPH (National Cancer Institute [NCI]), Brad Hesse, PhD(NCI), and Roni Reiter-Palmon, PhD(University of Nebraska Omaha), for their thoughtful insights and commentary; Caroline Schenkel (ASCO) and Mary May Kozlik (ASCO) for administrative support; reviewers who devoted significant time to evaluate applications and provided valuable feedback on draft manuscripts; the membership of the ASCO Workforce Advisory Group, who guided the project from its inception to the publication of these papers; and the23 teams who participated in this project. A list of those who participated in the February workshop and provided feedback on the draft papers is below. Jacqui Adams, MD, PhD; Noel Arring, DNP, RN, OCN; Bijal Balasubramanian, MD, PhD; Dena Battle; Rebecca Block, PhD, MSW, LCSW; Katherine L. Byar, MSN, APN, BC, BMTCN; Beverly Canin; Julia Lee Close, MD; Hannah Klein Connolly, MA; Robert Cooper, MD; John Cox, DO, FASCO; Sarah D'Ambruoso, NP; Susan (Soosi) Day, PhD; Dusty Joy Donaldson, MA; Amy Driga, OTR, BScOT; TeMaya Eatmon; Lee Ellington, PhD; Iris C. Fineberg, PhD, MSW, OSW-C; David Gerber, MD; Tracy Gosselin, PhD, MSN; Deborah Diaz Granados, PhD; Lisa Greaves; Anne H. Gross, PhD, RN, FAAN; Lauren Hamel, PhD; Elizabeth Henry, MD; Dawn Hershman, MD, MS; Brad Hesse, PhD; Maribeth Hohenstein, RN, BSN; Rosa Holloway; Fleur Huang, MD, MPH; Anshu Jain, MD; Rebecca Johnson, MD; Joann Keyton, PhD; Nandita Khera, MD; Michael A. King, MHA; Elizabeth Lazzara, PhD; Lynne Lederman, PhD; Ryan Leib; Rebecca Lobb, ScD, MPH; Filipa Lynce, MD; Catherine Fiona Macpherson, PhD, RN; Debra L. Madden, BA; Larissa A. Meyer, MD, MPH; Burt Needles, MD; Ingrid M. Nembhard, PhD, MS; Phioanh Leia Nghiemphu, MD; Katia Noyes, PhD, MPH; Sharon Nyquist; Susan K. Parsons, MD; Todd Pickard, MMSc, PA-C; Diane Portman, MD; Ryan Ramaekers, MD; Roni Reiter-Palmon, PhD; Gladys Rodriguez, MD; Hector P. Rodriguez, PhD, MPH; Carole Seigel; Ayan Sen, MD, MSc, FAAEM, FAC; Nick Sevdalis, PhD; Jon Tilburt, MD; Manasi A. Tirodkar, MS, PhD; Anne Ramey Tonachel; Richard Tonachel; Dominique Tremblay; Julia Trosman, PhD, MBA; Shin-Ping Tu, MD, MPH, FACP; Amanda Vogel, PhD, MPH; Julie Vose, MD, MBA, FASCO; Julie Waldfogel, PharmD, CPE; Anne Walling, MD, PhD; Sallie Weaver, PhD; Christine B. Weldon, MBA; Erin Williams, BA, MBA; Stephanie F. Williams, MD; and Yu-NingWong, MD, MSCE. NR 14 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2016 VL 12 IS 11 BP 955 EP + DI 10.1200/JOP.2016.018127 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400001 PM 27756798 ER PT J AU Vogel, AL Hall, KL AF Vogel, Amanda L. Hall, Kara L. TI Creating the Conditions for Implementing Team Principles in Cancer Care SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Editorial Material C1 Leidos Biomed Res, Clin Monitoring Res Program, Frederick, MD USA. NCI, Bethesda, MD 20892 USA. RP Vogel, AL (reprint author), Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, 9609 Med Ctr Dr,Room 3W-270, Rockville, MD 20850 USA. EM Amanda.Vogel@fnlcr.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Conquer Cancer Foundation Mission Endowment FX This project has been funded in whole or in part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The production of this manuscript was funded by the Conquer Cancer Foundation Mission Endowment. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The opinions expressed here are those of the authors and cannot be construed to reflect the views of the National Cancer Institute or the US Federal Government. We thank Tracey Goldner of the Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, for her help with graphic design. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2016 VL 12 IS 11 BP 964 EP + DI 10.1200/JOP.2016.018218 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400002 PM 27858545 ER PT J AU Johnson, RH Macpherson, CF Smith, AW Block, RG Keyton, J AF Johnson, Rebecca H. Macpherson, Catherine Fiona Smith, Ashley W. Block, Rebecca G. Keyton, Joann TI Facilitating Teamwork in Adolescent and Young Adult Oncology SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID CANCER; CARE; HEALTH; BEHAVIORS; EMERGENCY; SURVIVORS; TEAMS; MODEL AB A case of a young adult patient in the days immediately after a cancer diagnosis illustrates the critical importance of three interrelated core coordinating mechanisms-closed-loop communication, shared mental models, and mutual trust-of teamwork in an adolescent and young adult multidisciplinary oncology team. The case illustrates both the opportunities to increase team member coordination and the problems that can occur when coordination breaks down. A model for teamwork is presented, which highlights the relationships among these coordinating mechanisms and demonstrates how balance among them works to optimize team function and patient care. Implications for clinical practice and research suggested by the case are presented. C1 MultiCare Hlth Syst, Mary Bridge Hosp, Tacoma, WA USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. NCI, Bethesda, MD 20892 USA. Crit Mass Young Adult Canc Alliance, Austin, TX USA. North Carolina State Univ, Raleigh, NC USA. RP Johnson, RH (reprint author), POB 5299,311 S L St, Tacoma, WA 98415 USA. EM beckyj100@gmail.com FU Amgen (Inst) FX Amgen (Inst) NR 47 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2016 VL 12 IS 11 BP 1067 EP + DI 10.1200/JOP.2016.013870 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400016 PM 27624944 ER PT J AU Jelsema, CM Peddada, SD AF Jelsema, Casey M. Peddada, Shyamal D. TI CLME: An R Package for Linear Mixed Effects Models under Inequality Constraints SO JOURNAL OF STATISTICAL SOFTWARE LA English DT Article DE distribution free; linear inequality constraints; linear fixed effects models; linear mixed effects models; order restricted inference; residual bootstrap; R ID LONGITUDINAL DATA; DOSE-RESPONSE; HEARING-LOSS; INFERENCE AB In many applications researchers are typically interested in testing for inequality constraints in the context of linear fixed effects and mixed effects models. Although there exists a large body of literature for performing statistical inference under inequality constraints, user friendly statistical software implementing such methods is lacking, especially in the context of linear fixed and mixed effects models. In this article we introduce CLME, a package in the R language that can be used for testing a broad collection of inequality constraints. It uses residual bootstrap based methodology which is reasonably robust to non-normality as well as heteroscedasticity. The package is illustrated using two data sets. The package also contains a graphical user interface built using the shiny package. C1 [Jelsema, Casey M.] West Virginia Univ, Dept Stat, Morgantown, WV 26506 USA. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC USA. RP Jelsema, CM (reprint author), West Virginia Univ, Dept Stat, Morgantown, WV 26506 USA. EM casey.jelsema@mail.wvu.edu; peddada@niehs.nih.gov FU Intramural Research Program of the NIH, NIEHS [Z01 ES101744] FX This research is supported (in part) by the Intramural Research Program of the NIH, NIEHS (Z01 ES101744). The authors thank the following individuals: Drs. Katie O'Brien, Keith Shockley, and Bahjat Qaqish for carefully reading the manuscript and making numerous suggestions which substantially improved the presentation; Dr. Michelle Cora for providing the data on Sprague-Dawley rats analyzed in Section 4.1; and the editors of the Journal of Statistical Software and the two anonymous reviewers for providing suggestions which improved this work. NR 24 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL STATISTICAL SOFTWARE PI LOS ANGELES PA UCLA DEPT STATISTICS, 8130 MATH SCIENCES BLDG, BOX 951554, LOS ANGELES, CA 90095-1554 USA SN 1548-7660 J9 J STAT SOFTW JI J. Stat. Softw. PD NOV PY 2016 VL 75 IS 1 DI 10.18637/jss.v075.i01 PG 32 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA EI7SO UT WOS:000392703800001 ER PT J AU Ahi, YS Zhang, S Thappeta, Y Denman, A Feizpour, A Gummuluru, S Reinhard, B Muriaux, D Fivash, MJ Rein, A AF Ahi, Yadvinder S. Zhang, Shu Thappeta, Yashna Denman, Audrey Feizpour, Amin Gummuluru, Suryaram Reinhard, Bjoern Muriaux, Delphine Fivash, Matthew J. Rein, Alan TI Functional Interplay Between Murine Leukemia Virus Glycogag, Serinc5, and Surface Glycoprotein Governs Virus Entry, with Opposite Effects on Gammaretroviral and Ebolavirus Glycoproteins SO MBIO LA English DT Article ID GLYCOSYLATED GAG PROTEIN; ENVELOPE GLYCOPROTEIN; REVERSE-TRANSCRIPTASE; UNGLYCOSYLATED GAG; HIV-1 INFECTIVITY; CRE RECOMBINASE; T-LYMPHOCYTES; MOUSE CELLS; RECEPTOR; GENE AB Gammaretroviruses, such as murine leukemia viruses (MLVs), encode, in addition to the canonical Gag, Pol, and Env proteins that will form progeny virus particles, a protein called "glycogag" (glycosylated Gag). MLV glycogag contains the entire Gag sequence plus an 88-residue N-terminal extension. It has recently been reported that glycogag, like the Nef protein of HIV-1, counteracts the antiviral effects of the cellular protein Serinc5. We have found, in agreement with prior work, that glycogag strongly enhances the infectivity of MLVs with some Env proteins but not those with others. In contrast, however, glycogag was detrimental to MLVs carrying Ebolavirus glycoprotein. Glycogag could be replaced, with respect to viral infectivity, by the unrelated S2 protein of equine infectious anemia virus. We devised an assay for viral entry in which virus particles deliver the Cre recombinase into cells, leading to the expression of a reporter. Data from this assay showed that both the positive and the negative effects of glycogag and S2 upon MLV infectivity are exerted at the level of virus entry. Moreover, transfection of the virus-producing cells with a Serinc5 expression plasmid reduced the infectivity and entry capability of MLV carrying xenotropic MLV Env, particularly in the absence of glycogag. Conversely, Serinc5 expression abrogated the negative effects of glycogag upon the infectivity and entry capability of MLV carrying Ebolavirus glycoprotein. As Serinc5 may influence cellular phospholipid metabolism, it seems possible that all of these effects on virus entry derive from changes in the lipid composition of viral membranes. IMPORTANCE Many murine leukemia viruses (MLVs) encode a protein called "glycogag." The function of glycogag is not fully understood, but it can assist HIV-1 replication in the absence of the HIV-1 protein Nef under some circumstances. In turn, Nef counteracts the cellular protein Serinc5. Glycogag enhances the infectivity of MLVs with some but not all MLV Env proteins (which mediate viral entry into the host cell upon binding to cell surface receptors). We now report that glycogag acts by enhancing viral entry and that, like Nef, glycogag antagonizes Serinc5. Surprisingly, the effects of glycogag and Serinc5 upon the entry and infectivity of MLV particles carrying an Ebolavirus glycoprotein are the opposite of those observed with the MLV Env proteins. The unrelated S2 protein of equine infectious anemia virus (EIAV) is functionally analogous to glycogag in our experiments. Thus, three retroviruses (HIV-1, MLV, and EIAV) have independently evolved accessory proteins that counteract Serinc5. C1 [Ahi, Yadvinder S.; Zhang, Shu; Thappeta, Yashna; Denman, Audrey; Rein, Alan] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Feizpour, Amin; Reinhard, Bjoern] Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. [Feizpour, Amin; Reinhard, Bjoern] Boston Univ, Photon Ctr, Boston, MA 02215 USA. [Gummuluru, Suryaram] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Muriaux, Delphine] CNRS, UMR 5236, Ctr Etud Agents & Pathogenes & Biotechnol Santes, Montpellier, France. [Fivash, Matthew J.] Natl Canc Inst Frederick, Data Management Serv, Frederick, MD USA. RP Rein, A (reprint author), NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. EM reina@mail.nih.gov FU CNRS; HHS | NIH | National Cancer Institute (NCI); HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [AI064099] FX This work, including the efforts of Delphine Muriaux, was funded by CNRS. This work, including the efforts of Yadvinder S. Ahi, Shu Zhang, Yashna Thappeta, Audrey Denman, Matthew Fivash, and Alan Rein, was funded by HHS | NIH | National Cancer Institute (NCI). This work, including the efforts of Amin Feizpour, Suryaram Gummuluru, and Bjoern Reinhard, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI064099). NR 71 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01985 DI 10.1128/mBio.01985-16 PG 14 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500043 ER PT J AU Bansal, A Ojo, KK Mu, J Maly, DJ Van Voorhis, WC Miller, LH AF Bansal, Abhisheka Ojo, Kayode K. Mu, Jianbing Maly, Dustin J. Van Voorhis, Wesley C. Miller, Louis H. TI Reduced Activity of Mutant Calcium-Dependent Protein Kinase 1 Is Compensated in Plasmodium falciparum through the Action of Protein Kinase G SO MBIO LA English DT Article ID MALARIA PARASITES; INHIBITORS; TOXOPLASMA; TRANSMISSION; TARGETS; POCKET; POTENT; IDENTIFICATION; ACTIVATION; EXPRESSION AB We used a sensitization approach that involves replacement of the gatekeeper residue in a protein kinase with one with a different side chain. The activity of the enzyme with a bulky gatekeeper residue, such as methionine, cannot be inhibited using bumped kinase inhibitors (BKIs). Here, we have used this approach to study Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1). The methionine gatekeeper substitution, T145M, although it led to a 47% reduction in transphosphorylation, was successfully introduced into the CDPK1 locus using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9. As methionine is a bulky residue, BKI 1294 had a 10-fold-greater effect in vitro on the wild-type enzyme than on the methionine mutant. However, in contrast to in vitro data with recombinant enzymes, BKI 1294 had a slightly greater inhibition of the growth of CDPK1 T145M parasites than the wild type. Moreover, the CDPK1 T145M parasites were more sensitive to the action of compound 2 (C2), a specific inhibitor of protein kinase G (PKG). These results suggest that a reduction in the activity of CDPK1 due to methionine substitution at the gatekeeper position is compensated through the direct action of PKG or of another kinase under the regulation of PKG. The transcript levels of CDPK5 and CDPK6 were significantly upregulated in the CDPK1 T145M parasites. The increase in CDPK6 or some other kinase may compensate for decrease in CDPK1 activity during invasion. This study suggests that targeting two kinases may be more effective in chemotherapy to treat malaria so as not to select for mutations in one of the enzymes. IMPORTANCE Protein kinases of Plasmodium falciparum are being actively pursued as drug targets to treat malaria. However, compensatory mechanisms may reverse the drug activity against a kinase. In this study, we show that replacement of the wildtype threonine gatekeeper residue with methionine reduces the transphosphorylation activity of CDPK1. Mutant parasites with methionine gatekeeper residue compensate the reduced activity of CDPK1 through the action of PKG possibly by upregulation of CDPK6 or some other kinase. This study highlights that targeting one enzyme may lead to changes in transcript expression of other kinases that compensate for its function and may select for mutants that are less dependent on the target enzyme activity. Thus, inhibiting two kinases is a better strategy to protect the antimalarial activity of each, similar to artemisinin combination therapy or malarone (atovaquone and proguanil). C1 [Bansal, Abhisheka; Mu, Jianbing; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ojo, Kayode K.; Van Voorhis, Wesley C.] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA USA. [Ojo, Kayode K.; Van Voorhis, Wesley C.] Univ Washington, Ctr Emerging & Re Emerging Infect Dis, Seattle, WA 98195 USA. [Maly, Dustin J.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Maly, Dustin J.] Univ Washington, Dept Chem, Seattle, WA 98195 USA. RP Bansal, A; Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM bansal.abhisheka@gmail.com; LMILLER@niaid.nih.gov FU HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI111341-01 R01AI089441-01]; HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R01HD080670]; United States Department of Agriculture (USDA) [2014-06183] FX This work, including the efforts of Wesley C. Van Voorhis, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI111341-01 R01AI089441-01). This work, including the efforts of Wesley C. Van Voorhis, was funded by HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (R01HD080670). This work, including the efforts of Wesley C. Van Voorhis, was funded by United States Department of Agriculture (USDA) (grant number no. 2014-06183). NR 44 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e02011 DI 10.1128/mBio.02011-16 PG 12 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500057 ER PT J AU Bennuru, S Cotton, JA Ribeiro, JMC Grote, A Harsha, B Holroyd, N Mhashilkar, A Molina, DM Randall, AZ Shandling, AD Unnasch, TR Ghedin, E Berriman, M Lustigman, S Nutman, TB AF Bennuru, Sasisekhar Cotton, James A. Ribeiro, Jose M. C. Grote, Alexandra Harsha, Bhavana Holroyd, Nancy Mhashilkar, Amruta Molina, Douglas M. Randall, Arlo Z. Shandling, Adam D. Unnasch, Thomas R. Ghedin, Elodie Berriman, Matthew Lustigman, Sara Nutman, Thomas B. TI Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont SO MBIO LA English DT Article ID PUTATIVELY IMMUNE INDIVIDUALS; NEGLECTED TROPICAL DISEASES; BRUGIA-MALAYI; CAENORHABDITIS-ELEGANS; RNA INTERFERENCE; GENE-EXPRESSION; CATHEPSIN-L; NEMATODE; LARVAL; IDENTIFICATION AB Onchocerciasis (river blindness) is a neglected tropical disease that has been successfully targeted by mass drug treatment programs in the Americas and small parts of Africa. Achieving the long-term goal of elimination of onchocerciasis, however, requires additional tools, including drugs, vaccines, and biomarkers of infection. Here, we describe the transcriptome and proteome profiles of the major vector and the human host stages (L1, L2, L3, molting L3, L4, adult male, and adult female) of Onchocerca volvulus along with the proteome of each parasitic stage and of its Wolbachia endosymbiont (wOv). In so doing, we have identified stage-specific pathways important to the parasite's adaptation to its human host during its early development. Further, we generated a protein array that, when screened with well-characterized human samples, identified novel diagnostic biomarkers of O. volvulus infection and new potential vaccine candidates. This immunomic approach not only demonstrates the power of this postgenomic discovery platform but also provides additional tools for onchocerciasis control programs. IMPORTANCE The global onchocerciasis (river blindness) elimination program will have to rely on the development of new tools (drugs, vaccines, biomarkers) to achieve its goals by 2025. As an adjunct to the completed genomic sequencing of O. volvulus, we used a comprehensive proteomic and transcriptomic profiling strategy to gain a comprehensive understanding of both the vector-derived and human host-derived parasite stages. In so doing, we have identified proteins and pathways that enable novel drug targeting studies and the discovery of novel vaccine candidates, as well as useful biomarkers of active infection. C1 [Bennuru, Sasisekhar; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Cotton, James A.; Harsha, Bhavana; Holroyd, Nancy; Berriman, Matthew] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Hinxton, Cambs, England. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Grote, Alexandra; Ghedin, Elodie] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Mhashilkar, Amruta; Unnasch, Thomas R.] Univ S Florida, Tampa, FL USA. [Molina, Douglas M.; Randall, Arlo Z.; Shandling, Adam D.] Antigen Discovery Inc, Irvine, CA USA. [Ghedin, Elodie] NYU, Coll Global Publ Hlth, New York, NY USA. [Lustigman, Sara] New York Blood Ctr, New York, NY 10021 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA.; Lustigman, S (reprint author), New York Blood Ctr, New York, NY 10021 USA. EM slustigman@nybloodcenter.org; tnutman@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) [1ZIAAI000512]; Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation); HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [AI126466, AI42328]; Wellcome Trust through Wellcome Trust Sanger Institute [098051]; New York Blood Center; Edna McConnell Clark Foundation FX This work, including the efforts of Sasisekhar Bennuru, Jose M. C. Ribeiro, and Thomas B. Nutman, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) (1ZIAAI000512). This work, including the efforts of Sasisekhar Bennuru, Jose M. C. Ribeiro, Sara Lustigman, and Thomas B. Nutman, was funded by Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation). This work, including the efforts of Elodie Ghedin and Alexandra Grote, was funded by in part by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI126466). This work, including the efforts of James A. Cotton, Bhavana Harsha, Nancy Holroyd, and Matthew Berriman, was funded by the Wellcome Trust through core funding of the Wellcome Trust Sanger Institute (098051).; This work, including the efforts of Sara Lustigman, was funded in part from the New York Blood Center, The Edna McConnell Clark Foundation, and by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI42328). NR 65 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e02028 DI 10.1128/mBio.02028-16 PG 11 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500045 ER PT J AU Chu, CY Stewart, PE Bestor, A Hansen, B Lin, T Gao, LH Norris, SJ Rosa, PA AF Chu, Chen-Yi Stewart, Philip E. Bestor, Aaron Hansen, Bryan Lin, Tao Gao, Lihui Norris, Steven J. Rosa, Patricia A. TI Function of the Borrelia burgdorferi FtsH Homolog Is Essential for Viability both In Vitro and In Vivo and Independent of HflK/C (vol 7, e00404-16, 2016) SO MBIO LA English DT Correction C1 [Chu, Chen-Yi; Stewart, Philip E.; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Lin, Tao; Gao, Lihui; Norris, Steven J.] UTHealth, McGovern Med Sch, Dept Pathol & Lab Med, Houston, TX USA. [Chu, Chen-Yi] Acad Mil Med Sci, Inst Dis Control & Prevent, Beijing, Peoples R China. RP Stewart, PE (reprint author), NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e02135-16 DI 10.1128/mBio.02135-16 PG 1 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500075 ER PT J AU He, SS Chandler, M Varani, AM Hickman, AB Dekker, JP Dyda, F AF He, Susu Chandler, Michael Varani, Alessandro M. Hickman, Alison B. Dekker, John P. Dyda, Fred TI Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids SO MBIO LA English DT Article ID INSERTION SEQUENCES; TARGET IMMUNITY; BACTERIOPHAGE MU; B-PROTEIN; TRANSPOSITION; RECOMBINATION; IDENTIFICATION; REPLICATION; DELETIONS; TN7 AB The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. IMPORTANCE The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as transposons and integrons have been strongly associated with the rapid spread of genes responsible for antibiotic resistance. Understanding the consequences of their actions allowed us to establish unambiguous evolutionary relationships between plasmids in the analysis set. C1 [He, Susu; Hickman, Alison B.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chandler, Michael] CNRS, Lab Microbiol & Genet Mol, Toulouse, France. [Varani, Alessandro M.] Univ Estadual Paulista, Dept Tecnol, Fac Ciencias Agr & Vet Jaboticabal, Sao Paulo, Brazil. [Dekker, John P.] NIH, Dept Lab Med, Ctr Clin, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov FU HHS | National Institutes of Health (NIH); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); HHS | NIH | NIH Clinical Center; Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases; NIH Clinical Center FX This work, including the efforts of Alison B. Hickman, was funded by HHS | National Institutes of Health (NIH). This work, including the efforts of Fred Dyda, was funded by HHS | National Institutes of Health (NIH). This work, including the efforts of Susu He, was funded by HHS | National Institutes of Health (NIH). This work, including the efforts of Alessandro M. Varani, was funded by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). This work, including the efforts of Michael Chandler, was funded by Centre National de la Recherche Scientifique (CNRS). This work, including the efforts of John P. Dekker, was funded by HHS | NIH | NIH Clinical Center.; This work was partially supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (S.H., A.B.H., and F.D.) and the NIH Clinical Center (J.P.D.). NR 32 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01987 DI 10.1128/mBio.01987-16 PG 11 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500050 ER PT J AU Hidano, S Randall, LM Dawson, L Dietrich, HK Konradt, C Klover, PJ John, B Harris, TH Fang, Q Turek, B Kobayashi, T Hennighausen, L Beiting, DP Koshy, AA Hunter, CA AF Hidano, Shinya Randall, Louise M. Dawson, Lucas Dietrich, Hans K. Konradt, Christoph Klover, Peter J. John, Beena Harris, Tajie H. Fang, Qun Turek, Bradley Kobayashi, Takashi Hennighausen, Lothar Beiting, Daniel P. Koshy, Anita A. Hunter, Christopher A. TI STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System SO MBIO LA English DT Article ID TOXOPLASMA-GONDII INFECTION; INDUCIBLE NITRIC-OXIDE; CHEMOKINE GENE-EXPRESSION; CHRONIC VIRAL-INFECTION; T-CELL EXHAUSTION; GAMMA-INTERFERON; IFN-GAMMA; TRANSGENIC MICE; DENDRITIC CELLS; HOST-RESISTANCE AB The local production of gamma interferon (IFN-gamma) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-gamma to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen. IMPORTANCE Astrocytes are the most numerous cell type in the brain, and they are activated in response to many types of neuroinflammation, but their function in the control of CNS-specific infection is unclear. The parasite Toxoplasma gondii is one of the few clinically relevant microorganisms that naturally infects astrocytes, and the studies presented here establish that the ability of astrocytes to inhibit parasite replication is essential for the local control of this opportunistic pathogen. Together, these studies establish a key role for astrocytes as effector cells and in the coordination of many aspects of the protective immune response that operates in the brain. C1 [Hidano, Shinya; Dawson, Lucas; Konradt, Christoph; John, Beena; Fang, Qun; Turek, Bradley; Beiting, Daniel P.; Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Randall, Louise M.] Univ Melbourne, Dept Med, Peter Doherty Inst, Parkville, Vic, Australia. [Dietrich, Hans K.; Koshy, Anita A.] Univ Arizona, Dept Neurol, Dept Immunobiol, Inst BIO5, Tucson, AZ USA. [Klover, Peter J.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Harris, Tajie H.] Univ Virginia, Dept Neurosci, Ctr Brain Immunol & Glia BIG, Charlottesville, VA USA. [Hidano, Shinya; Kobayashi, Takashi] Oita Univ, Fac Med, Dept Infect Dis Control, Oita, Japan. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. EM chunter@vet.upenn.edu FU Commonwealth of Pennsylvania; Fellowship from Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation; NIH [AI41158, 5R21EY021314, NS65116]; Deutsche Forschungsgemeinschaft; IRP of the NIDDK/NIH FX This work was supported by the Commonwealth of Pennsylvania, a Fellowship from Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation (S.H.), NIH grants AI41158 and 5R21EY021314 (C.A.H.), and the Deutsche Forschungsgemeinschaft (C.K.). L.H. and P.J.K. were supported by the IRP of the NIDDK/NIH, while A.A.K. was supported by NIH NS65116. NR 78 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01881-16 DI 10.1128/mBio.01881-16 PG 15 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500025 ER PT J AU Kauffman, RC Bhuiyan, TR Nakajima, R Mayo-Smith, LM Rashu, R Hoq, MR Chowdhury, F Khan, AI Rahman, A Bhaumik, SK Harris, L O'Neal, JT Trost, JF Alam, NH Jasinskas, A Dotsey, E Kelly, M Charles, RC Xu, P Kovac, P Calderwood, SB Ryan, ET Felgner, PL Qadri, F Wrammert, J Harrise, JB AF Kauffman, Robert C. Bhuiyan, Taufiqur R. Nakajima, Rie Mayo-Smith, Leslie M. Rashu, Rasheduzzaman Hoq, Mohammad Rubel Chowdhury, Fahima Khan, Ashraful Islam Rahman, Atiqur Bhaumik, Siddhartha K. Harris, Levelle O'Neal, Justin T. Trost, Jessica F. Alam, Nur Haq Jasinskas, Algis Dotsey, Emmanuel Kelly, Meagan Charles, Richelle C. Xu, Peng Kovac, Pavol Calderwood, Stephen B. Ryan, Edward T. Felgner, Phillip L. Qadri, Firdausi Wrammert, Jens Harrise, Jason B. TI Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells SO MBIO LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; DENGUE VIRUS-INFECTION; O1 EL-TOR; SALMONELLA-TYPHIMURIUM; HOUSEHOLD CONTACTS; IMMUNE-RESPONSES; TOXIN; BANGLADESH; LIPOPOLYSACCHARIDE; DYNAMICS AB We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera. IMPORTANCE Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with Vibrio cholerae. Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different V. cholerae serotypes and the likely impact of prior enterotoxigenic Escherichia coli exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts. C1 [Kauffman, Robert C.; Mayo-Smith, Leslie M.; Bhaumik, Siddhartha K.; Trost, Jessica F.; Wrammert, Jens] Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA. [Kauffman, Robert C.; Bhaumik, Siddhartha K.; Harris, Levelle; O'Neal, Justin T.; Trost, Jessica F.; Wrammert, Jens] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Bhuiyan, Taufiqur R.; Rashu, Rasheduzzaman; Hoq, Mohammad Rubel; Chowdhury, Fahima; Khan, Ashraful Islam; Rahman, Atiqur; Alam, Nur Haq; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Div Infect Dis, Dhaka, Bangladesh. [Nakajima, Rie; Jasinskas, Algis; Dotsey, Emmanuel; Felgner, Phillip L.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Rahman, Atiqur; Kelly, Meagan; Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.; Harrise, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Med Sch, Dept Med, Boston, MA USA. [Xu, Peng; Kovac, Pavol] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Ryan, Edward T.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Harrise, Jason B.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. RP Wrammert, J (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA.; Wrammert, J (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Harrise, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Harrise, JB (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM jwramme@emory.edu; jbharris@partners.org FU HHS | National Institutes of Health (NIH) [AI103055, AI099243, AI106878, AI058935, AI074492, TW005572] FX This work, including the efforts of Firdausi Qadri, Jens Wrammert, and Jason B. Harris, was funded by HHS | National Institutes of Health (NIH) (AI103055). This work, including the efforts of Firdausi Qadri and Jason B. Harris, was funded by HHS | National Institutes of Health (NIH) (AI099243). This work, including the efforts of Edward T Ryan and Firdausi Qadri, was funded by HHS | National Institutes of Health (NIH) (AI106878). This work, including the efforts of Edward T Ryan and Firdausi Qadri, was funded by HHS | National Institutes of Health (NIH) (AI058935). This work, including the efforts of Robert C. Kauffman, was funded by HHS | National Institutes of Health (NIH) (AI074492). This work, including the efforts of Taufiqur Bhuiyan, was funded by HHS | National Institutes of Health (NIH) (TW005572). NR 44 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e02021 DI 10.1128/mBio.02021-16 PG 11 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500066 ER PT J AU McKinney, CC Kim, MJ Chen, D McBride, AA AF McKinney, Caleb C. Kim, Min Jung Chen, Dan McBride, Alison A. TI Brd4 Activates Early Viral Transcription upon Human Papillomavirus 18 Infection of Primary Keratinocytes SO MBIO LA English DT Article ID BROMODOMAIN PROTEIN BRD4; E2 PROTEIN; DNA-REPLICATION; MITOTIC CHROMOSOMES; LIFE-CYCLE; REGULATORY REGION; CHROMATIN; TYPE-16; BINDING; PHOSPHORYLATION AB Human papillomaviruses (HPVs) replicate in the cutaneous and mucosal epithelia, and the infectious cycle is synchronous with the differentiation program of the host keratinocytes. The virus initially infects dividing cells in the lower layers of the epithelium, where it establishes a persistent infection. The viral genome is maintained as a low-copy-number, extrachromosomal element in these proliferating cells but switches to the late stage of the life cycle in differentiated cells. The cellular chromatin adaptor protein Brd4 is involved in several stages and processes of the viral life cycle. In concert with the viral transcriptional regulator E2, Brd4 can repress transcription from the early viral promoter. Brd4 and E2 form a complex with the viral genome that associates with host chromosomes to partition the viral genome in dividing cells; Brd4 also localizes to active sites of productive HPV DNA replication. However, because of the difficulties in producing HPV viral particles, the role of Brd4 in modulating viral transcription and replication at the initial stage of infection is unclear. In this study, we have used an HPV18 quasivirus-based genome delivery system to assess the role of Brd4 in the initial infectivity of primary human keratinocytes. We show that, upon infection of primary human keratinocytes with HPV18 quasivirus, Brd4 activates viral transcription and replication. Furthermore, this activation is independent of the functional interaction between Brd4 and the HPV18 E2 protein. IMPORTANCE HPVs lack encapsidated proteins and so rely exquisitely on host cellular factors to initiate their gene expression programs in newly infected cells. Brd4 is an important cellular chromatin adaptor molecule that normally activates host transcription initiation and elongation. In this study, we further optimize and utilize a quasivirus infection system to show that Brd4 activates HPV18 transcription at early stages of infection. HPVs are important human pathogens causing a wide range of cutaneous and tumorigenic morbidities. Therefore, specifically targeting this protein could provide a new target of therapeutic prevention of establishment of HPV infections. C1 [McKinney, Caleb C.; Kim, Min Jung; Chen, Dan; McBride, Alison A.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [McKinney, Caleb C.] Georgetown Univ, Biomed Grad Educ, Washington, DC USA. [Kim, Min Jung] Columbia Univ, Microbiol & Immunol, New York, NY USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM amcbride@nih.gov FU HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [ZIA AI000713] FX This work, including the efforts of Caleb C. McKinney, Min Jung Kim, Dan Chen, and Alison A. McBride, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (ZIA AI000713). NR 55 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01644 DI 10.1128/mBio.01644-16 PG 12 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500042 ER PT J AU Smith, EP Miller, CN Child, R Cundiff, JA Celli, J AF Smith, Erin P. Miller, Cheryl N. Child, Robert Cundiff, Jennifer A. Celli, Jean TI Postreplication Roles of the Brucella VirB Type IV Secretion System Uncovered via Conditional Expression of the VirB11 ATPase SO MBIO LA English DT Article ID INTRACELLULAR REPLICATION; ENDOPLASMIC-RETICULUM; CONTAINING VACUOLE; GENE-EXPRESSION; TRAFFICKING; MACROPHAGES; CELLS; IDENTIFICATION; PATHWAY; PROTEIN AB Brucella abortus, the bacterial agent of the worldwide zoonosis brucellosis, primarily infects host phagocytes, where it undergoes an intracellular cycle within a dedicated membrane-bound vacuole, the Brucella-containing vacuole (BCV). Initially of endosomal origin (eBCV), BCVs are remodeled into replication-permissive organelles (rBCV) derived from the host endoplasmic reticulum, a process that requires modulation of host secretory functions via delivery of effector proteins by the Brucella VirB type IV secretion system (T4SS). Following replication, rBCVs are converted into autophagic vacuoles (aBCVs) that facilitate bacterial egress and subsequent infections, arguing that the bacterium sequentially manipulates multiple cellular pathways to complete its cycle. The VirB T4SS is essential for rBCV biogenesis, as VirB-deficient mutants are stalled in eBCVs and cannot mediate rBCV biogenesis. This has precluded analysis of whether the VirB apparatus also drives subsequent stages of the Brucella intracellular cycle. To address this issue, we have generated a B. abortus strain in which VirB T4SS function is conditionally controlled via anhydrotetracycline (ATc)-dependent complementation of a deletion of the virB11 gene encoding the VirB11 ATPase. We show in murine bone marrow-derived macrophages (BMMs) that early VirB production is essential for optimal rBCV biogenesis and bacterial replication. Transient expression of virB11 prior to infection was sufficient to mediate normal rBCV biogenesis and bacterial replication but led to T4SS inactivation and decreased aBCV formation and bacterial release, indicating that these postreplication stages are also T4SS dependent. Hence, our findings support the hypothesis of additional, postreplication roles of type IV secretion in the Brucella intracellular cycle. IMPORTANCE Many intracellular bacterial pathogens encode specialized secretion systems that deliver effector proteins into host cells to mediate the multiple stages of their intracellular cycles. Because these intracellular events occur sequentially, classical genetic approaches cannot address the late roles that these apparatuses play, as secretion-deficient mutants cannot proceed past their initial defect. Here we have designed a functionally controllable VirB type IV secretion system (T4SS) in the bacterial pathogen Brucella abortus to decipher its temporal requirements during the bacterium's intracellular cycle in macrophages. By controlling production of the VirB11 ATPase, which energizes the T4SS, we show not only that this apparatus is required early to generate the Brucella replicative organelle but also that it contributes to completion of the bacterium's cycle and bacterial egress. Our findings expand upon the pathogenic functions of the Brucella VirB T4SS and illustrate targeting of secretion ATPases as a useful strategy to manipulate the activity of bacterial secretion systems. C1 [Smith, Erin P.; Miller, Cheryl N.; Cundiff, Jennifer A.; Celli, Jean] Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. [Child, Robert; Celli, Jean] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Child, Robert] Univ Montana, Missoula, MT 59812 USA. RP Celli, J (reprint author), Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA.; Celli, J (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jcelli@vetmed.wsu.edu FU HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) [AI112649]; HHS | NIH | National Institute of General Medical Sciences (NIGMS) [AI007025]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Jean Celli, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI112649). This work, including the efforts of Cheryl N. Miller, was funded by HHS | NIH | National Institute of General Medical Sciences (NIGMS) (AI007025). This work, including the efforts of Jean Celli, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 28 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01730 DI 10.1128/mBio.01730-16 PG 10 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500049 ER PT J AU Roongpiboonsopit, D Charidimou, A William, CM Lauer, A Falcone, GJ Martinez-Ramirez, S Biffi, A Ayres, A Vashkevich, A Awosika, OO Rosand, J Gurol, ME Silverman, SB Greenberg, SM Viswanathan, A AF Roongpiboonsopit, Duangnapa Charidimou, Andreas William, Christopher M. Lauer, Arne Falcone, Guido J. Martinez-Ramirez, Sergi Biffi, Alessandro Ayres, Alison Vashkevich, Anastasia Awosika, Oluwole O. Rosand, Jonathan Gurol, M. Edip Silverman, Scott B. Greenberg, Steven M. Viswanathan, Anand TI Cortical superficial siderosis predicts early recurrent lobar hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; PRIMARY INTRACEREBRAL HEMORRHAGE; TRANSIENT ISCHEMIC ATTACK; SUBARACHNOID HEMORRHAGE; APOLIPOPROTEIN-E; BLOOD-PRESSURE; WARNING SIGN; RISK; DISEASE AB Objective: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA). Methods: Participants were consecutive survivors (age >= 55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (<= 3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders. Results: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively). Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA. C1 [Roongpiboonsopit, Duangnapa; Charidimou, Andreas; Lauer, Arne; Falcone, Guido J.; Martinez-Ramirez, Sergi; Ayres, Alison; Vashkevich, Anastasia; Gurol, M. Edip; Silverman, Scott B.; Greenberg, Steven M.; Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Hemorrhag Stroke Res Program, Boston, MA 02115 USA. [Biffi, Alessandro] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Div Behav Neurol, Boston, MA USA. [Biffi, Alessandro] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Div Neuropsychiat, Boston, MA USA. [William, Christopher M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Neuropathol Serv, Boston, MA USA. [Falcone, Guido J.; Rosand, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Roongpiboonsopit, Duangnapa] Naresuan Univ, Fac Med, Dept Med, Phitsanulok, Thailand. [Awosika, Oluwole O.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Roongpiboonsopit, D (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Hemorrhag Stroke Res Program, Boston, MA 02115 USA.; Roongpiboonsopit, D (reprint author), Naresuan Univ, Fac Med, Dept Med, Phitsanulok, Thailand. EM duangnapar@nu.ac.th FU NIH [R01AG047975, R01AG026484, P50AG005134, K23AG028726, K23 NS083711, R01 NS070834] FX Supported by NIH (R01AG047975, R01AG026484, P50AG005134, K23AG028726, K23 NS083711, and R01 NS070834). NR 33 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 1 PY 2016 VL 87 IS 18 BP 1863 EP 1870 DI 10.1212/WNL.0000000000003281 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JG UT WOS:000392232600008 PM 27694268 ER PT J AU Bruce, BB Digre, KB McDermott, MP Schron, EB Wall, M AF Bruce, Beau B. Digre, Kathleen B. McDermott, Michael P. Schron, Eleanor B. Wall, Michael CA NORDIC Idiopathic Intracranial TI Quality of life at 6 months in the Idiopathic Intracranial Hypertension Treatment Trial SO NEUROLOGY LA English DT Article ID PSEUDOTUMOR CEREBRI; DIAGNOSIS AB Objective: To examine the changes in vision-specific and overall health-related quality of life (QOL) at 6 months in participants with idiopathic intracranial hypertension (IIH) and mild visual loss enrolled in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and to determine the signs and symptoms of IIH that mediate the effect of acetazolamide on QOL. Methods: We assessed QOL using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), the 10-Item NEI-VFQ-25 Neuro-Ophthalmic Supplement, and the 36-Item Short Form Health Survey (SF-36). We examined associations among changes in QOL measures over 6 months, treatment status, and changes in signs and symptoms using linear and structural equation models. Results: Among the 165 participants with IIH (86 randomized to acetazolamide, 79 to placebo), beneficial effects of acetazolamide were seen on all QOL scales evaluated, as well as on the Near Activities (5.60 points, p = 0.03), Social Functioning (3.85 points, p = 0.04), and Mental Health (9.82, p = 0.04) subscales of the NEI-VFQ-25. Positive acetazolamide-related effects on QOL appeared to be primarily mediated by improvements in visual field, neck pain, pulsatile tinnitus, and dizziness/vertigo that outweighed the side effects of acetazolamide. Conclusions: The marked reductions in baseline QOL seen among patients with mild visual loss from IIH are improved by treatment with acetazolamide. When combined with acetazolamide-associated improvements in visual field and other aspects of IIH, our findings with respect to QOL provide further support from the IIHTT in favor of acetazolamide to augment a dietary intervention in the treatment of IIH with mild visual loss (clinicaltrials.gov: NCT01003639). C1 [Bruce, Beau B.] Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA. [Bruce, Beau B.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Bruce, Beau B.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Digre, Kathleen B.] Univ Utah, Moran Eye Ctr, Dept Neurol, Salt Lake City, UT USA. [Digre, Kathleen B.] Univ Utah, Moran Eye Ctr, Dept Ophthalmol, Salt Lake City, UT USA. [McDermott, Michael P.] Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. [McDermott, Michael P.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14627 USA. [Schron, Eleanor B.] NEI, Div Extramural Res, Bethesda, MD 20892 USA. [Wall, Michael] Univ Iowa, Carver Coll Med, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. RP Bruce, BB (reprint author), Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA.; Bruce, BB (reprint author), Emory Univ, Dept Neurol, Atlanta, GA 30322 USA.; Bruce, BB (reprint author), Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. EM bbbruce@emory.edu FU NIH [1U10EY017281-01A1, 1U10EY017387-01A1]; ARRA [3U10EY017281-01A1S1, 1U10EY017387-01A1S1]; Research to Prevent Blindness, Inc., New York, NY; [3U10EY017281-01A1S2]; [K23EY019341] FX NIH 1U10EY017281-01A1 and 1U10EY017387-01A1; ARRA for NORDIC 3U10EY017281-01A1S1 and DCBC 1U10EY017387-01A1S1; supplements for NORDIC 3U10EY017281-01A1S2. Dr. Bruce was supported by K23EY019341 and by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, to the Department of Ophthalmology at Emory University. Dr. Digre was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City. NR 17 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 1 PY 2016 VL 87 IS 18 BP 1871 EP 1877 DI 10.1212/WNL.0000000000003280 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JG UT WOS:000392232600009 PM 27694262 ER PT J AU Naidoo, J Panday, H Jackson, S Grossman, SA AF Naidoo, Jarushka Panday, Hardik Jackson, Sadhana Grossman, Stuart A. TI Optimizing the Delivery of Antineoplastic Therapies to the Central Nervous System SO ONCOLOGY-NEW YORK LA English DT Article ID BLOOD-BRAIN-BARRIER; CONVECTION-ENHANCED DELIVERY; GUIDED FOCUSED ULTRASOUND; HIGH-GRADE GLIOMAS; NORMAL RAT-BRAIN; MALIGNANT GLIOMAS; DRUG-DELIVERY; INTRAARTERIAL CHEMOTHERAPY; GLIOBLASTOMA-MULTIFORME; RECURRENT GLIOBLASTOMA AB Despite signifi cant advances in the treatment of systemic cancers, progress in the treatment of primary brain tumors has been quite modest. In addition, an increasing proportion of patients with systemic cancers are presenting with brain-only metastases. These observations highlight the critical role that the blood-brain barrier plays in preventing antineoplastic therapies from reaching the central nervous system in therapeutic concentrations. This review describes the anatomy of the blood-brain barrier and currently available methods to quantify the entry of therapeutic compounds into the brain. It also summarizes data from a variety of approaches designed to improve drug delivery to the central nervous system. These include: 1) directly placing drugs inside the blood-brain barrier (polymeric implants, convection-enhanced delivery, and intraventricular administration), 2) modifying systemic chemotherapy (by using high-dose methotrexate and intra-arterial drug administration), 3) temporary disruption of the blood-brain barrier (via use of intra-arterial mannitol, focused ultrasound, or pharmacologic agents), and 4) designing drugs that can pass through the blood-brain barrier. Given that lymphocytes readily traverse the blood-brain barrier, immunotherapy represents a novel approach to cancer therapy that is of particular interest to practitioners in the field of neurooncology. The efficacy of vaccines and immune checkpoint inhibitors is currently being actively investigated in patients with primary and metastatic brain tumors, as well as leptomeningeal carcinomatosis. The challenge of delivering effective antineoplastic therapies to the central nervous system remains a primary obstacle to improving outcomes in patients with primary and metastatic brain tumors. C1 [Naidoo, Jarushka; Grossman, Stuart A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Panday, Hardik] All India Inst Med Sci, New Delhi, India. [Jackson, Sadhana] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. RP Grossman, SA (reprint author), Johns Hopkins Univ, Sch Med, 1550 Orleans St,Suite 1M-16, Baltimore, MD 21287 USA. EM grossman@jhmi.edu NR 51 TC 1 Z9 1 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2016 VL 30 IS 11 BP 953 EP 962 PG 10 WC Oncology SC Oncology GA EI0WC UT WOS:000392194900002 ER PT J AU D'Souza, G Anantharaman, D Gheit, T Abedi-Ardekani, B Beachler, DC Conway, DI Olshan, AF Wunsch, V Toporcov, TN Ahrens, W Wisniewski, K Merletti, F Boccia, S Tajara, EH Zevallos, JP Levi, JE Weissler, MC Wright, S Scelo, G Mazul, AL Tommasino, M Cadoni, G Brennan, P AF D'Souza, Gypsyamber Anantharaman, Devasena Gheit, Tarik Abedi-Ardekani, Behnoush Beachler, Daniel C. Conway, David I. Olshan, Andrew F. Wunsch-Filho, Victor Toporcov, Tatiana N. Ahrens, Wolfgang Wisniewski, Kathy Merletti, Franco Boccia, Stefania Tajara, Eloiza H. Zevallos, Jose P. Levi, Jose Eduardo Weissler, Mark C. Wright, Sylvia Scelo, Ghislaine Mazul, Angela L. Tommasino, Massimo Cadoni, Gabriella Brennan, Paul TI Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents SO ORAL ONCOLOGY LA English DT Article DE HPV; P16; Survival; HNSCC; Oral HPV; Non-OP; Prognostic; Risk factors; Brazil; Europe ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; OROPHARYNGEAL CANCER; PROGNOSTIC-SIGNIFICANCE; METAANALYSIS; PREVALENCE; P16(INK4A); BIOMARKERS; SMOKING; EXPRESSION AB Objectives: To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers. Methods: Data from 1362 head and neck SCC (HNSCC) diagnosed 2002-2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n = 388), U.S. (CHANCE study, n = 472), and Europe (ARCAGE study, n = 502). Tumors were centrally tested for p16(INK4a) and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models. Results: There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58 years and median follow-up of 3.1 years (IQR = 1.4-5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16(+)/HPV16(+)) compared to 333 HPV-unrelated (p16-and/or HPV16-) cases (HR = 0.25, 95% CI = 0.18-0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p <= 0.01) and after adjustment, remained significantly reduced (aHR = 0.34, 95% CI = 0.24-0.49). Among non-OP HNSCC, neither p16 (aHR = 0.83, 95% CI = 0.60-1.14), HPV16 DNA (aHR = 1.20, 95% CI = 0.89-1.63), or p16+/HPV16+ (aHR = 0.59, 95% CI = 0.32-1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction = 0.02). Conclusion: HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC. (C) 2016 Elsevier Ltd. All rights reserved. C1 [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Anantharaman, Devasena; Scelo, Ghislaine; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Gheit, Tarik; Tommasino, Massimo] Int Agcy Res Canc, Infect & Canc Biol Grp, Lyon, France. [Abedi-Ardekani, Behnoush] Int Agcy Res Canc, Genet Canc Susceptibil Grp, Lyon, France. [Beachler, Daniel C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Conway, David I.] Univ Glasgow, Sch Med Dent & Nursing, Glasgow, Lanark, Scotland. [Olshan, Andrew F.; Wisniewski, Kathy; Mazul, Angela L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Wunsch-Filho, Victor; Toporcov, Tatiana N.] Univ Sao Paulo, Sch Publ Hlth, Dept Epidemiol, Sao Paulo, Brazil. [Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, Bremen, Germany. [Merletti, Franco] Univ Turin, Dept Med Sci, Turin, Italy. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Fac Med, Inst Publ Hlth, Sect Hyg, Rome, Italy. [Tajara, Eloiza H.] Fac Med Sao Jose Rio Preto, Dept Mol Biol, Rome, Italy. [Zevallos, Jose P.; Weissler, Mark C.] Univ North Carolina Chapel Hill, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. [Levi, Jose Eduardo] Univ Sao Paulo, Inst Trop Med, Virol Lab, Sao Paulo, Brazil. [Wright, Sylvia] Queen Elizabeth Univ Hosp, Dept Pathol, Glasgow, Lanark, Scotland. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Fdn Policlin A Gemelli, Inst Otorhinolaryngol, Head & Neck Surg Dept, Rome, Italy. RP D'Souza, G (reprint author), Johns Hopkins Sch Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA.; Brennan, P (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM gdsouza2@jhu.edu; brennan@iarc.fr OI Ahrens, Wolfgang/0000-0003-3777-570X FU FAPESP; National Cancer Institute; European Framework Programs; French Health Ministry; Italian AIRC FX This work was support by FAPESP, National Cancer Institute, European Framework Programs, French Health Ministry, and Italian AIRC. NR 28 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD NOV PY 2016 VL 62 BP 20 EP 27 DI 10.1016/j.oraloncology.2016.09.005 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA EI6VL UT WOS:000392635300006 PM 27865368 ER PT J AU Alibhai, J Blanco, RA Barria, MA Piccardo, P Caughey, B Perry, VH Freeman, TC Manson, JC AF Alibhai, James Blanco, Richard A. Barria, Marcelo A. Piccardo, Pedro Caughey, Byron Perry, V. Hugh Freeman, Tom C. Manson, Jean C. TI Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration SO PLOS BIOLOGY LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; GENE-EXPRESSION PROFILES; ALZHEIMERS-DISEASE; MICROGLIAL ACTIVATION; IN-VIVO; SCRAPIE; MICE; PRP; ABSENCE; PROGRESSION AB Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread, and distribution are restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein (PrP) seeds were observed widespread throughout the brain, accumulating in all brain regions examined irrespective of neurodegeneration. Importantly, neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prioninfected brains: a novel homeostatic response in all regions and an innate immune response restricted to sites of neurodegeneration. Therefore, accumulation of misfolded prion protein alone does not define targeting of neurodegeneration, which instead results only when misfolded prion protein accompanies a specific innate immune response. C1 [Alibhai, James; Blanco, Richard A.; Piccardo, Pedro; Freeman, Tom C.; Manson, Jean C.] Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland. [Alibhai, James; Blanco, Richard A.; Piccardo, Pedro; Freeman, Tom C.; Manson, Jean C.] Univ Edinburgh, Royal Dick Sch Vet Studies, Edinburgh, Midlothian, Scotland. [Barria, Marcelo A.] Univ Edinburgh, Western Gen Hosp, Ctr Clin Brain Sci, Natl CJD Res & Surveillance Unit, Edinburgh, Midlothian, Scotland. [Caughey, Byron] NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. [Perry, V. Hugh] Univ Southampton, Ctr Biol Sci, Southampton, Hants, England. RP Manson, JC (reprint author), Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland.; Manson, JC (reprint author), Univ Edinburgh, Royal Dick Sch Vet Studies, Edinburgh, Midlothian, Scotland. EM jean.manson@roslin.ed.ac.uk FU Biotechnology and Biological Sciences Research Council (BBSRC) DTA studentship [BB/F01693X/1]; BBSRC Institute Strategic Grant [BB/J004332/1] FX This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC) DTA studentship (BB/F01693X/1) and BBSRC Institute Strategic Grant (BB/J004332/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 57 TC 1 Z9 1 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2016 VL 14 IS 11 AR e1002579 DI 10.1371/journal.pbio.1002579 PG 25 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EH9TH UT WOS:000392113500014 PM 27880767 ER PT J AU Happel, C Ramalingam, D Ziegelbauer, JM AF Happel, Christine Ramalingam, Dhivya Ziegelbauer, Joseph M. TI Virus-Mediated Alterations in miRNA Factors and Degradation of Viral miRNAs by MCPIP1 SO PLOS BIOLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; INFLAMMATORY-CYTOKINE EXPRESSION; BINDING PROTEIN AUF1; MESSENGER-RNA DECAY; KAPPA-B ACTIVATION; KAPOSIS-SARCOMA; CELL-LINES; MICRORNAS; INFECTION; REVEALS AB Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma, encodes 25 mature viral miRNAs. MCP-1-induced protein-1 (MCPIP1), a critical regulator of immune homeostasis, has been shown to suppress miRNA biosynthesis via cleavage of precursor miRNAs through its RNase domain. We demonstrate that MCPIP1 can directly cleave KSHV and EBV precursor miRNAs and that MCPIP1 expression is repressed following de novo KSHV infection. In addition, repression with siRNAs to MCPIP1 in KSHV-infected cells increased IL-6 and KSHV miRNA expression, supporting a role for MCPIP1 in IL-6 and KSHV miRNA regulation. We also provide evidence that KSHV miRNAs repress MCPIP1 expression by targeting the 3'UTR of MCPIP1. Conversely, expression of essential miRNA biogenesis components Dicer and TRBP is increased following latent KSHV infection. We propose that KSHV infection inhibits a negative regulator of miRNA biogenesis (MCPIP1) and up-regulates critical miRNA processing components to evade host mechanisms that inhibit expression of viral miRNAs. KSHV-mediated alterations in miRNA biogenesis represent a novel mechanism by which KSHV interacts with its host and a new mechanism for the regulation of viral miRNA expression. C1 [Happel, Christine; Ramalingam, Dhivya; 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 FU National Cancer Institute [1ZIABC011176]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX National Cancer Institute (grant number 1ZIABC011176).(Received by JZ) This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2016 VL 14 IS 11 AR e2000998 DI 10.1371/journal.pbio.2000998 PG 23 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EH9TH UT WOS:000392113500019 PM 27893764 ER PT J AU Zhang, XL Japee, S Safiullah, Z Mlynaryk, N Ungerleider, LG AF Zhang, Xilin Japee, Shruti Safiullah, Zaid Mlynaryk, Nicole Ungerleider, Leslie G. TI A Normalization Framework for Emotional Attention SO PLOS BIOLOGY LA English DT Article ID CONTRAST RESPONSE FUNCTIONS; HUMAN VISUAL-CORTEX; NEURAL MECHANISMS; DISTRACTOR SUPPRESSION; ORBITOFRONTAL CORTEX; SELECTIVE ATTENTION; PREFRONTAL NEURONS; EVOKED POTENTIALS; SPATIAL ATTENTION; COVERT ATTENTION AB The normalization model of attention proposes that attention can affect performance by response-or contrast-gain changes, depending on the size of the stimulus and attention field. Here, we manipulated the attention field by emotional valence, negative faces versus positive faces, while holding stimulus size constant in a spatial cueing task. We observed changes in the cueing effect consonant with changes in response gain for negative faces and contrast gain for positive faces. Neuroimaging experiments confirmed that subjects' attention fields were narrowed for negative faces and broadened for positive faces. Importantly, across subjects, the self-reported emotional strength of negative faces and positive faces correlated, respectively, both with response-and contrast-gain changes and with primary visual cortex (V1) narrowed and broadened attention fields. Effective connectivity analysis showed that the emotional valence-dependent attention field was closely associated with feedback from the dorsolateral prefrontal cortex (DLPFC) to V1. These findings indicate a crucial involvement of DLPFC in the normalization processes of emotional attention. C1 [Zhang, Xilin; Japee, Shruti; Safiullah, Zaid; Mlynaryk, Nicole; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Zhang, XL (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM xilin.zhang@nih.gov FU National Institute of Mental Health [NCT00001360] FX This work was supported by the National Institute of Mental Health Intramural Research Program (NCT00001360). URL: http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_1993-M-0170.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2016 VL 14 IS 11 AR e1002578 DI 10.1371/journal.pbio.1002578 PG 25 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EH9TH UT WOS:000392113500008 PM 27870851 ER PT J AU Livne, ZB Alon, S Vallone, D Bayleyen, Y Tovin, A Shainer, I Nisembaum, LG Aviram, I Smadja-Storz, S Fuentes, M Falcon, J Eisenberg, E Klein, DC Burgess, HA Foulkes, NS Gothilf, Y AF Livne, Zohar Ben-Moshe Alon, Shahar Vallone, Daniela Bayleyen, Yared Tovin, Adi Shainer, Inbal Nisembaum, Laura G. Aviram, Idit Smadja-Storz, Sima Fuentes, Michael Falcon, Jack Eisenberg, Eli Klein, David C. Burgess, Harold A. Foulkes, Nicholas S. Gothilf, Yoav TI Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior SO PLOS GENETICS LA English DT Article ID MOUSE PARS TUBERALIS; N-ACETYLTRANSFERASE ACTIVITY; PHOTOENDOCRINE TRANSDUCTION; PROTEASOMAL PROTEOLYSIS; MELATONIN PRODUCTION; LARVAL ZEBRAFISH; GENE-EXPRESSION; LIGHT; RHYTHMS; GLAND AB The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior. C1 [Livne, Zohar Ben-Moshe; Alon, Shahar; Tovin, Adi; Shainer, Inbal; Aviram, Idit; Smadja-Storz, Sima; Gothilf, Yoav] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, Tel Aviv, Israel. [Alon, Shahar; Eisenberg, Eli; Gothilf, Yoav] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Vallone, Daniela; Foulkes, Nicholas S.] Karlsruhe Inst Technol, Inst Toxicol & Genet, Eggenstein Leopoldshafen, Germany. [Bayleyen, Yared; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Behav Neurogenet, NIH, Bethesda, MD USA. [Nisembaum, Laura G.; Fuentes, Michael; Falcon, Jack] UPMC Univ Paris 06, Sorbonne Univ, Observ Oceanol, CNRS,Biol Integrat Organismes Marins, Banyuls Sur Mer, France. [Eisenberg, Eli] Tel Aviv Univ, Raymond & Beverly Sackler Sch Phys & Astron, Tel Aviv, Israel. [Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, NIH, Bethesda, MD USA. [Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Sci Directory, NIH, Bethesda, MD USA. RP Gothilf, Y (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, Tel Aviv, Israel.; Gothilf, Y (reprint author), Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. EM yoavg@tauex.tau.ac.il FU United States Israel Binational Science Foundation, Jerusalem, Israel [2013/433]; Israel Science Foundation, Jerusalem, Israel [1084/12, 443/16]; Helmholtz Association, Germany FX The United States Israel Binational Science Foundation (grant number 2013/433 to YG and HAB), Jerusalem, Israel; The Israel Science Foundation (grants number 1084/12 and 443/16 to YG), Jerusalem, Israel. The BioInterfaces in Technology and Medicine funding programme of the Helmholtz Association, Germany (to NSF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 0 Z9 0 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2016 VL 12 IS 11 AR e1006445 DI 10.1371/journal.pgen.1006445 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA EH9ZA UT WOS:000392129600042 ER PT J AU Zhang, Y Zhang, L Tang, XN Bhardwaj, SR Ji, JY Rong, YS AF Zhang, Yi Zhang, Liang Tang, Xiaona Bhardwaj, Shilpa R. Ji, Jingyun Rong, Yikang S. TI MTV, an ssDNA Protecting Complex Essential for Transposon-Based Telomere Maintenance in Drosophila SO PLOS GENETICS LA English DT Article ID HOMOLOGOUS RECOMBINATION; TARGETED MUTAGENESIS; PROTEIN; MELANOGASTER; GENE; HOAP; SPECIALIZATION; REPLICATION; RECRUITMENT; PATHWAYS AB Multiple complexes protect telomeres. In telomerase-maintained organisms, Shelterin related complexes occupy the duplex region while the CST and Tpp1-Pot1 complexes bind the single stranded overhang of telomeres. Drosophila uses a transposon-based mechanism for end protection. We showed that the HOAP-HipHop complex occupies the duplex region. Whether an ssDNA-binding complex exists is not known. Here we discover a novel protein, Tea, that is specifically enriched at telomeres to prevent telomere fusion. We also identify a complex consisting of Tea and two known capping proteins, Ver and Moi. The Moi-Tea-Ver (MTV) complex purified in vitro binds and protects ssDNA in a sequence-independent manner. Tea recruits Ver and Moi to telomeres, and point mutations disrupting MTV interaction in vitro result in telomere uncapping, consistent with these proteins functioning as a complex in vivo. MTV thus shares functional similarities with CST or TPP1-POT1 in protecting ssDNA, highlighting a conserved feature in end protecting mechanisms. C1 [Zhang, Yi; Ji, Jingyun; Rong, Yikang S.] Sun Yat Sen Univ, Sch Life Sci, Inst Entomol, State Key Lab Biocontrol, Guangzhou, Guangdong, Peoples R China. [Zhang, Yi; Zhang, Liang; Tang, Xiaona; Bhardwaj, Shilpa R.; Rong, Yikang S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Rong, YS (reprint author), Sun Yat Sen Univ, Sch Life Sci, Inst Entomol, State Key Lab Biocontrol, Guangzhou, Guangdong, Peoples R China.; Rong, YS (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM rongyik@mail.sysu.edu.cn FU National Cancer Institute, USA; NSFC of China [31371364] FX This work was supported by the intramural research program of the National Cancer Institute, USA and subsequently a grant from NSFC of China (Grant #31371364). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 1 Z9 1 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2016 VL 12 IS 11 AR e1006435 DI 10.1371/journal.pgen.1006435 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EH9ZA UT WOS:000392129600036 PM 27835648 ER PT J AU Baseler, L Scott, DP Saturday, G Horne, E Rosenke, R Thomas, T Meade-White, K Haddock, E Feldmann, H de Wit, E AF Baseler, Laura Scott, Dana P. Saturday, Greg Horne, Eva Rosenke, Rebecca Thomas, Tina Meade-White, Kimberly Haddock, Elaine Feldmann, Heinz de Wit, Emmie TI Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CLINICAL-FEATURES; MARGINAL ZONE; PIG-FARMERS; BANGLADESH; MALAYSIA; TRANSMISSION; ENCEPHALITIS; OUTBREAK; MACROPHAGES AB Background Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M) or Bangladesh (NiV-B). Methodology/Principal Findings Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi). Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi. Conclusions/Significance Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central nervous system pathology. C1 [Baseler, Laura; Horne, Eva; Thomas, Tina; Haddock, Elaine; Feldmann, Heinz; de Wit, Emmie] NIAID, Virol Lab, NIH, Hamilton, MT 59840 USA. [Baseler, Laura] Purdue Univ, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Scott, Dana P.; Saturday, Greg; Rosenke, Rebecca; Meade-White, Kimberly] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Baseler, Laura] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USA. RP de Wit, E (reprint author), NIAID, Virol Lab, NIH, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Institutes of Health Comparative Biomedical Scientist Training Program FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. LB was supported in part by the National Institutes of Health Comparative Biomedical Scientist Training Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2016 VL 10 IS 11 AR e0005120 DI 10.1371/journal.pntd.0005120 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EI0HR UT WOS:000392154400040 PM 27812087 ER PT J AU Traore, B Oliveira, F Faye, O Dicko, A Coulibaly, CA Sissoko, IM Sibiry, S Sogoba, N Sangare, MB Coulibaly, YI Traore, P Traore, SF Anderson, JM Keita, S Valenzuela, JG Kamhawi, S Doumbia, S AF Traore, Bourama Oliveira, Fabiano Faye, Ousmane Dicko, Adama Coulibaly, Cheick A. Sissoko, Ibrahim M. Sibiry, Samake Sogoba, Nafomon Sangare, Moussa Brema Coulibaly, Yaya I. Traore, Pierre Traore, Sekou F. Anderson, Jennifer M. Keita, Somita Valenzuela, Jesus G. Kamhawi, Shaden Doumbia, Seydou TI Prevalence of Cutaneous Leishmaniasis in Districts of High and Low Endemicity in Mali SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID THIES AREA SENEGAL; IMMUNE-RESPONSE; MAJOR INFECTION; SENSITIVITY; ECOLOGY; FOCUS AB Historically the western sahelian dry regions of Mali are known to be highly endemic for cutaneous leishmaniasis (CL) caused by Leishmania major, while cases are rarely reported from the Southern savanna forest of the country. Here, we report baseline prevalence of CL infection in 3 ecologically distinct districts of Mali (dry sahelian, north savanna and southern savanna forest areas). We screened 195 to 250 subjects from 50 to 60 randomly selected households in each of the 6 villages (four from the western sahelian district of Diema in Kayes region, one from the central district of Kolokani and one from the southern savanna district of Kolodieba, region of Sikasso). The screening consisted of: 1] A Leishmanin Skin Test (LST) for detection of exposure to Leishmania parasites; 2] clinical examination of suspected lesions, followed by validation with PCR and 3] finger prick blood sample to determine antibody levels to sand fly saliva. LST positivity was higher in the western district of Diema (49.9%) than in Kolokani (24.9%) and was much lower in Kolondieba (2.6%). LST positivity increased with age rising from 13.8% to 88% in Diema for age groups 2-5 years and 41-65 years, respectively. All eight PCR-confirmed L. major CL cases were diagnosed in subjects below 18 years of age and all were residents of the district of Diema. Exposure to sand fly bites, measured by anti-saliva antibody titers, was comparable in individuals living in all three districts. However, antibody titers were significantly higher in LST positive individuals (P<0.0001). In conclusion, CL transmission remains active in the western region of Mali where lesions were mainly prevalent among children under 18 years old. LST positivity correlated to higher levels of antibodies to sand fly salivary proteins, suggesting their potential as a risk marker for CL acquisition in Mali. C1 [Traore, Bourama; Coulibaly, Cheick A.; Sissoko, Ibrahim M.; Sibiry, Samake; Sogoba, Nafomon; Sangare, Moussa Brema; Coulibaly, Yaya I.; Traore, Sekou F.; Doumbia, Seydou] USTTB, Int Ctr Excellence Res ICER MALI, Bamako, Mali. [Oliveira, Fabiano; Anderson, Jennifer M.; Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, LMVR, NIH, Rockville, MD USA. [Faye, Ousmane; Dicko, Adama; Traore, Pierre; Keita, Somita] Ctr Natl Appui Lutte Malad CNAM, Bamako, Mali. RP Doumbia, S (reprint author), USTTB, Int Ctr Excellence Res ICER MALI, Bamako, Mali. EM sdoumbi@icermali.org FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [P50AI098505]; Division of Intramural Research Program of NIAID, National Institutes of Health, Bethesda, MD, USA FX This work was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number P50AI098505 (Tropical Medicine Research Center, TMRC) and the Division of Intramural Research Program of NIAID, National Institutes of Health, Bethesda, MD, USA. The views expressed in this manuscript are solely those of the authors and do not necessarily represent the officials views of the funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2016 VL 10 IS 11 AR e0005141 DI 10.1371/journal.pntd.0005141 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EI0HR UT WOS:000392154400048 PM 27898671 ER PT J AU Prodger, JL Gray, RH Shannon, B Shahabi, K Kong, XR Grabowski, K Kigozi, G Nalugoda, F Serwadda, D Wawer, MJ Reynolds, SJ Liu, CM Tobian, AAR Kaul, R AF Prodger, Jessica L. Gray, Ronald H. Shannon, Brett Shahabi, Kamnoosh Kong, Xiangrong Grabowski, Kate Kigozi, Godfrey Nalugoda, Fred Serwadda, David Wawer, Maria J. Reynolds, Steven J. Liu, Cindy M. Tobian, Aaron A. R. Kaul, Rupert TI Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ATTRACTANT ACTIVATION PROTEIN-1; BACTERIAL VAGINOSIS; TH17 CELLS; SEXUAL TRANSMISSION; HUMAN NEUTROPHILS; TYPE-2 INFECTION; DENDRITIC CELLS; EXPLANT TISSUE AB Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95% CI 1.04 +/- 6.40) and Monokine Induced by.-interferon (MIG aOR 2.72, 95% CI 1.15 +/- 8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man's female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95% CI 0.44 +/- 0.87), and continued to decline for at least two years (PRR 0.29, 95% CI 0.16 +/- 0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision. C1 [Prodger, Jessica L.; Gray, Ronald H.; Kong, Xiangrong; Grabowski, Kate; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gray, Ronald H.; Kigozi, Godfrey; Nalugoda, Fred; Serwadda, David; Wawer, Maria J.; Reynolds, Steven J.; Tobian, Aaron A. R.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Shannon, Brett; Shahabi, Kamnoosh; Kaul, Rupert] Univ Toronto, Dept Med, Toronto, ON, Canada. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Dept Infect Dis, Baltimore, MD USA. [Liu, Cindy M.] George Washington Univ, Dept Environm & Occupat Hlth, Washington, DC USA. [Liu, Cindy M.] Translat Genom Res Inst, Flagstaff, AZ USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Kaul, R (reprint author), Univ Toronto, Dept Med, Toronto, ON, Canada. EM rupert.kaul@utoronto.ca OI Prodger, Jessica/0000-0003-0805-4196 FU Bill and Melinda Gates Foundation [22006.03]; National Institutes of Health [R01AI087409-01A1, UO1AI51171, 1UO1AI075115-01A1]; Fogarty International Center [1D43TWO09578-01]; Canadian Institutes of Health Research [TMI-138656, 201302MFE-300992-230373]; NIH [1K23AI093152-01A1]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Bill and Melinda Gates Foundation, grant number 22006.03; National Institutes of Health, grant numbers R01AI087409-01A1, UO1AI51171 and 1UO1AI075115-01A1; Fogarty International Center, grant number 1D43TWO09578-01; Canadian Institutes of Health Research, grant number TMI-138656. JLP was supported by the Canadian Institutes of Health Research 201302MFE-300992-230373.AART was supported by the NIH 1K23AI093152-01A1. Partial support (SJR) was provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2016 VL 12 IS 11 AR e1006025 DI 10.1371/journal.ppat.1006025 PG 21 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0VO UT WOS:000392193200045 PM 27898732 ER PT J AU Tompkins, VS Sompallae, R Rosean, TR Walsh, S Acevedo, M Kovalchuk, AL Han, SS Jing, X Holman, C Rehg, JE Herms, S Sunderland, JS Morse, HC Janz, S AF Tompkins, V. S. Sompallae, R. Rosean, T. R. Walsh, S. Acevedo, M. Kovalchuk, A. L. Han, S-S Jing, X. Holman, C. Rehg, J. E. Herms, S. Sunderland, J. S. Morse, H. C. Janz, S. TI Transgenic mouse model of IgM(+) lymphoproliferative disease mimicking Waldenstrom macroglobulinemia SO BLOOD CANCER JOURNAL LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMAGENESIS; CYTIDINE DEAMINASE AID; MULTIPLE-MYELOMA; PLASMA-CELLS; TUMOR MICROENVIRONMENT; EXPRESSION PATTERNS; GENOMIC LANDSCAPE; CXCR4 MUTATIONS; PRE-B AB Waldenstrom macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM(+)) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the proinflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, E mu SV-BCL2-22 and H2-L-d-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2(+) IL6(+) AID(-) and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM(+) lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2(+) IL6(+) AID(-) model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM. C1 [Tompkins, V. S.; Sompallae, R.; Rosean, T. R.; Han, S-S; Jing, X.; Holman, C.; Janz, S.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa Inst Human Genet, Dept Pathol, Iowa City, IA 52242 USA. [Sompallae, R.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa Inst Human Genet, Bioinformat Div, Iowa City, IA USA. [Walsh, S.; Acevedo, M.; Sunderland, J. S.] Univ Iowa, Dept Radiol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Kovalchuk, A. L.; Morse, H. C.] NIAID, Immunogenet Lab, Virol & Cellular Immunol Sect, NIH, Rockville, MD 20852 USA. [Rehg, J. E.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Herms, S.] Int Waldenstroms Macroglobulinemia Fdn, Sarasota, FL USA. RP Janz, S (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pathol, 1030 Med Labs, Iowa City, IA 52242 USA. EM siegfried-janz@uiowa.edu FU IWMF [2010-1]; NCI [R01CA151354]; NIH [T32-HL07734, T32-AI007485]; ALSAC; Intramural Research Program of the NIH, NIAID; NCI Core Grant of The University of Iowa Holden Comprehensive Cancer Center [P30CA086862] FX The technical assistance of Ling Hu and veterinary care provided by staff of the UI CCOM transgenic mouse facility are gratefully acknowledged. We thank Drs Torgny Fredrickson and Alicia Olivier for their expert histopathological advice. This work was funded by IWMF research grant 2010-1 (SJ). Additional support was provided by NCI R01CA151354 (SJ), by NIH Training Grants T32-HL07734 (VST) and T32-AI007485 (TRR), by ALSAC (JER), by the Intramural Research Program of the NIH, NIAID (HCM and ALK) and by NCI Core Grant P30CA086862 in support of The University of Iowa Holden Comprehensive Cancer Center. NR 60 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2044-5385 J9 BLOOD CANCER J JI Blood Cancer J. PD NOV PY 2016 VL 6 AR e488 DI 10.1038/bcj.2016.95 PG 11 WC Oncology SC Oncology GA EH5IM UT WOS:000391806500001 PM 27813533 ER PT J AU Robinson, LM Morton, FB Gartner, MC Widness, J Paukner, A Essler, JL Brosnan, SF Weiss, A AF Robinson, Lauren M. Morton, F. Blake Gartner, Marieke C. Widness, Jane Paukner, Annika Essler, Jennifer L. Brosnan, Sarah F. Weiss, Alexander TI Divergent Personality Structures of Brown (Sapajus apella) and White-Faced Capuchins (Cebus capucinus) SO JOURNAL OF COMPARATIVE PSYCHOLOGY LA English DT Article DE capuchin; Cebus; New World primates; personality; Sapajus ID 5-FACTOR MODEL; CHIMPANZEE PERSONALITY; SOCIAL RELATIONSHIPS; ZOOLOGICAL PARKS; MONKEYS; UNIVERSAL; EVOLUTION; MACAQUES; ROTATION; TRAITS AB One way to gain insights into personality evolution is by comparing the personality structures of related species. We compared the personality structure of 240 wild white-faced capuchin monkeys to the personality structure of 100 captive brown capuchin monkeys. An ancillary goal was to test the degree to which different personality questionnaires yielded similar personality dimensions. Both species were rated on a common set of 26 antonym pairs. The brown capuchin monkeys were also rated on the 54-item Hominoid Personality Questionnaire. Our cross-species comparisons revealed 3 personality dimensions-Assertiveness, Openness, and Neuroticism-shared by brown and white-faced capuchins, suggesting that these dimensions were present in the common ancestor of these species. Our comparison of the dimensions derived from the antonym pairs and the Hominoid Personality Questionnaire revealed that three common dimensions were identified by both questionnaires. In addition, the dimension Attentiveness was only identified using the Hominoid Personality Questionnaire. These results indicate that major features of capuchin personality are conserved and that the structure of some traits, such as those related to focus, persistence, and attention, diverged. Further work is needed to identify the evolutionary bases that led to the conservation of some dimensions but not others. C1 [Robinson, Lauren M.; Weiss, Alexander] Univ Edinburgh, Dept Psychol, Sch Philosophy Psychol & Language Sci, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Robinson, Lauren M.] Univ Edinburgh, Jeanne Marchig Int Ctr Anim Welf Educ, Royal Dick Sch Vet Studies, Edinburgh EH8 9JZ, Midlothian, Scotland. [Robinson, Lauren M.; Morton, F. Blake; Weiss, Alexander] Scottish Primate Res Grp, Edinburgh, Midlothian, Scotland. [Morton, F. Blake] Franklin & Marshall Coll, Dept Psychol, Lancaster, PA 17604 USA. [Gartner, Marieke C.] Philadelphia Zoo, Philadelphia, PA USA. [Widness, Jane] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Paukner, Annika] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Bethesda, MD USA. [Essler, Jennifer L.] Med Univ Vienna, Univ Vet Med Vienna, Messerli Res Inst, Comparat Cognit, Vienna, Austria. [Essler, Jennifer L.] Univ Vienna, A-1010 Vienna, Austria. [Brosnan, Sarah F.] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. RP Robinson, LM (reprint author), Univ Edinburgh, Dept Psychol, Sch Philosophy Psychol & Language Sci, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM l.robinson@ed.ac.uk FU University of Stirling; Primate Society of Great Britain; Division of Intramural Research, NICHD [Z99 HD999999] FX First and foremost, we extend a very special thank you to all the raters across the sites that took the time to fill out the personality questionnaires for us and the directors of the centers for giving us permission to research their capuchins: Peter Judge, David Washburn, and Andy Whiten. We also thank Kelly Leverett and Lara Wood for their help coordinating our research and Joe Manson for supplying us with white capuchin component-loading matrices. Particular thanks go to the staff and students for support and assistance during data collection. We acknowledge the University of Stirling, Primate Society of Great Britain, and the Division of Intramural Research, NICHD Z99 HD999999, for providing funding. NR 43 TC 0 Z9 0 U1 4 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7036 EI 1939-2087 J9 J COMP PSYCHOL JI J. Comp. Psychol. PD NOV PY 2016 VL 130 IS 4 BP 305 EP 312 DI 10.1037/com0000037 PG 8 WC Behavioral Sciences; Psychology; Psychology, Multidisciplinary; Zoology SC Behavioral Sciences; Psychology; Zoology GA EC9XG UT WOS:000388497000001 PM 27841454 ER PT J AU Konig, G Pickard, FC Huang, J Simmonett, AC Tofoleanu, F Lee, J Dral, PO Prasad, S Jones, M Shao, YH Thiel, W Brooks, BR AF Koenig, Gerhard Pickard, Frank C. Huang, Jing Simmonett, Andrew C. Tofoleanu, Florentina Lee, Juyong Dral, Pavlo O. Prasad, Samarjeet Jones, Michael Shao, Yihan Thiel, Walter Brooks, Bernard R. TI Calculating distribution coefficients based on multi-scale free energy simulations: an evaluation of MM and QM/MM explicit solvent simulations of water-cyclohexane transfer in the SAMPL5 challenge SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Distribution coefficient; Partition coefficient; Water; Cyclohexane; Multi-scale free energy simulations; Explicit solvent ID SOLVATION FREE-ENERGIES; HYDRATION FREE-ENERGIES; QUANTUM-MECHANICAL CALCULATIONS; BENNETT REWEIGHTING SCHEMES; DENSITY-FUNCTIONAL THEORY; ACCEPTANCE RATIO METHOD; SEMIEMPIRICAL METHODS; BLIND PREDICTION; PERTURBATION METHOD; BINDING AFFINITIES AB One of the central aspects of biomolecular recognition is the hydrophobic effect, which is experimentally evaluated by measuring the distribution coefficients of compounds between polar and apolar phases. We use our predictions of the distribution coefficients between water and cyclohexane from the SAMPL5 challenge to estimate the hydrophobicity of different explicit solvent simulation techniques. Based on molecular dynamics trajectories with the CHARMM General Force Field, we compare pure molecular mechanics (MM) with quantum-mechanical (QM) calculations based on QM/MM schemes that treat the solvent at the MM level. We perform QM/MM with both density functional theory (BLYP) and semi-empirical methods (OM1, OM2, OM3, PM3). The calculations also serve to test the sensitivity of partition coefficients to solute polarizability as well as the interplay of the quantum-mechanical region with the fixed-charge molecular mechanics environment. Our results indicate that QM/MM with both BLYP and OM2 outperforms pure MM. However, this observation is limited to a subset of cases where convergence of the free energy can be achieved. C1 [Koenig, Gerhard; Pickard, Frank C.; Huang, Jing; Simmonett, Andrew C.; Tofoleanu, Florentina; Lee, Juyong; Prasad, Samarjeet; Jones, Michael; Shao, Yihan; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Koenig, Gerhard; Dral, Pavlo O.; Thiel, Walter] Max Planck Inst Kohlenforsch, D-45470 Mulheim, Germany. RP Konig, G (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA.; Konig, G (reprint author), Max Planck Inst Kohlenforsch, D-45470 Mulheim, Germany. EM gkoenig@mpi-muelheim.mpg.de RI Thiel, Walter/A-5677-2016; Huang, Jing/G-5320-2011; Dral, Pavlo/A-6089-2016; OI Thiel, Walter/0000-0001-6780-0350; Huang, Jing/0000-0001-9639-2907; Dral, Pavlo/0000-0002-2975-9876; Lee, Juyong/0000-0003-1174-4358 FU National Heart, Lung and Blood Institute of the National Institutes of Health; European Research Council within an ERC Advanced Grant (OMSQC) FX The authors would like to thank Tim Miller, Richard Venable and John Legato for technical assistance. We would also like to thank Richard Pastor and Richard Venable for very helpful discussions concerning the nature of the apolar phase, especially in octanol. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute of the National Institutes of Health and utilized the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. (http://www.lobos.nih.gov and http://hpc.nih.gov). The research leading to these results has also received funding from the European Research Council within an ERC Advanced Grant (OMSQC). NR 112 TC 2 Z9 2 U1 9 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD NOV PY 2016 VL 30 IS 11 SI SI BP 989 EP 1006 DI 10.1007/s10822-016-9936-x PN 1 PG 18 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA EH0MU UT WOS:000391459000006 PM 27577746 ER PT J AU Pickard, FC Konig, G Tofoleanu, F Lee, J Simmonett, AC Shao, YH Ponder, JW Brooks, BR AF Pickard, Frank C. Koenig, Gerhard Tofoleanu, Florentina Lee, Juyong Simmonett, Andrew C. Shao, Yihan Ponder, Jay W. Brooks, Bernard R. TI Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pK (a) corrections SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Free energy; Partition coefficients; Distribution coefficients; Non-Boltzmann Bennett; Implicit solvent; SAMPL5; pK(a); Protomer; Tautomer ID FREE-ENERGY CALCULATIONS; MOLECULAR-DYNAMICS SIMULATIONS; BENNETT REWEIGHTING SCHEMES; HYDRATION FREE-ENERGIES; SOLVATION FREE-ENERGIES; DENSITY FUNCTIONALS; PK(A) CALCULATIONS; CONTINUUM MODEL; DRUG DISCOVERY; QM/MM APPROACH AB The computation of distribution coefficients between polar and apolar phases requires both an accurate characterization of transfer free energies between phases and proper accounting of ionization and protomerization. We present a protocol for accurately predicting partition coefficients between two immiscible phases, and then apply it to 53 drug-like molecules in the SAMPL5 blind prediction challenge. Our results combine implicit solvent QM calculations with classical MD simulations using the non-Boltzmann Bennett free energy estimator. The OLYP/DZP/SMD method yields predictions that have a small deviation from experiment (RMSD = 2.3 D units), relative to other participants in the challenge. Our free energy corrections based on QM protomer and calculations increase the correlation between predicted and experimental distribution coefficients, for all methods used. Unfortunately, these corrections are overly hydrophilic, and fail to account for additional effects such as aggregation, water dragging and the presence of polar impurities in the apolar phase. We show that, although expensive, QM-NBB free energy calculations offer an accurate and robust method that is superior to standard MM and QM techniques alone. C1 [Pickard, Frank C.; Koenig, Gerhard; Tofoleanu, Florentina; Lee, Juyong; Simmonett, Andrew C.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. [Koenig, Gerhard] Max Planck Inst Kohlenforsch, D-45470 Mulheim, Germany. [Shao, Yihan] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. [Ponder, Jay W.] Washington Univ, Dept Chem, St Louis, MO 63130 USA. RP Pickard, FC (reprint author), NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. EM frank.pickard@nih.gov OI Pickard, Frank/0000-0002-9608-3466 FU National Heart, Lung and Blood Institute of the National Institutes of Health FX This work was supported by the intramural research program of the National Heart, Lung and Blood Institute of the National Institutes of Health and utilized the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. (http://www.lobos.nih.gov and http://biowulf.nih.gov) NR 80 TC 2 Z9 2 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD NOV PY 2016 VL 30 IS 11 SI SI BP 1087 EP 1100 DI 10.1007/s10822-016-9955-7 PN 1 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA EH0MU UT WOS:000391459000014 PM 27646286 ER PT J AU Jones, MR Brooks, BR Wilson, AK AF Jones, Michael R. Brooks, Bernard R. Wilson, Angela K. TI Partition coefficients for the SAMPL5 challenge using transfer free energies SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE SAMPL; Distribution coefficient; Partition coefficient; Water; Cyclohexane; SMD; B3PW91; DFT; Solvation ID CONSISTENT BASIS-SETS; DENSITY-FUNCTIONAL THEORY; SOLVATION FREE-ENERGIES; CORRELATED MOLECULAR CALCULATIONS; GAUSSIAN-BASIS SETS; HYDRATION FREE-ENERGIES; WATER CLUSTERS; NONCOVALENT INTERACTIONS; THERMOCHEMICAL KINETICS; BLIND PREDICTION AB SAMPL challenges (Mobley et al. in J Comput Aided Mol Des 28:135-150, 2014; Skillman in J Comput Aided Mol Des 26:473-474, 2012; Geballe in J Comput Aided Mol Des 24:259-279, 2010; Guthrie in J Phys Chem B 113:4501-4507, 2009) provide excellent opportunities to assess theoretical approaches on new data sets with a goal of gaining greater insight towards protein and ligand modeling. In the SAMPL5 experiment, cyclohexane-water partition coefficients were determined using a vertical solvation scheme in conjunction with the SMD continuum solvent model. Several DFT functionals partnered with correlation consistent basis sets were evaluated for the prediction of the partition coefficients. The approach chosen for the competition, a B3PW91 vertical solvation scheme, yields a mean absolute deviation of 1.9 logP units and performs well at estimating the correct hydrophilicity and hydrophobicity for the full SAMPL5 molecule set. C1 [Jones, Michael R.; Wilson, Angela K.] Michigan State Univ, Dept Chem, 578 S Shaw Ln, E Lansing, MI 48824 USA. [Jones, Michael R.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. RP Wilson, AK (reprint author), Michigan State Univ, Dept Chem, 578 S Shaw Ln, E Lansing, MI 48824 USA. EM wilson@chemistry.msu.edu FU Intramural Research Program of the NIH, NHLBI FX This research was supported in part by the Intramural Research Program of the NIH, NHLBI. During the beginning of the SAMPL5 competition, AKW and MRJ were at the University of North Texas, where the calculations were done. Thus, the authors gratefully acknowledge Research Computing Services at the University of North Texas for computational resources. The authors thank Frank C. Pickard IV and Yihan Shao for their comments on the manuscript. NR 57 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD NOV PY 2016 VL 30 IS 11 SI SI BP 1129 EP 1138 DI 10.1007/s10822-016-9964-6 PN 1 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA EH0MU UT WOS:000391459000017 PM 27646287 ER PT J AU McMahon, B Aflaki, E Sidransky, E AF McMahon, Benjamin Aflaki, Elma Sidransky, Ellen TI Chaperoning glucocerebrosidase: a therapeutic strategy for both Gaucher disease and Parkinsonism SO NEURAL REGENERATION RESEARCH LA English DT Editorial Material ID ALPHA-SYNUCLEIN; NEURONS C1 [McMahon, Benjamin; Aflaki, Elma; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. NR 13 TC 0 Z9 0 U1 1 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1673-5374 EI 1876-7958 J9 NEURAL REGEN RES JI Neural Regen. Res. PD NOV PY 2016 VL 11 IS 11 BP 1760 EP 1761 DI 10.4103/1673-5374.194717 PG 2 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA EH2DW UT WOS:000391578600018 PM 28123414 ER PT J AU Goey, AKL Sissung, TM Peer, CJ Figg, WD AF Goey, Andrew K. L. Sissung, Tristan M. Peer, Cody J. Figg, William D. TI Pharmacogenomics and histone deacetylase inhibitors SO PHARMACOGENOMICS LA English DT Review DE belinostat; HDAC inhibitors; panobinostat; pharmacogenomics; romidepsin; UGT1A1; valproic acid; vorinostat ID GLUCURONOSYLTRANSFERASE 1A1 PROMOTER; VALPROIC ACID PHARMACOKINETICS; IRINOTECAN-INDUCED NEUTROPENIA; CHINESE EPILEPSY PATIENTS; UGT1A1-ASTERISK-28 GENOTYPE; PANOBINOSTAT LBH589; FUNCTIONAL IMPACT; GLUCURONIDATION; POLYMORPHISMS; UGT2B7 AB The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping. C1 [Goey, Andrew K. L.; Sissung, Tristan M.; Peer, Cody J.; Figg, William D.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov NR 48 TC 0 Z9 0 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD NOV PY 2016 VL 17 IS 16 BP 1807 EP 1815 DI 10.2217/pgs-2016-0113 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH6EL UT WOS:000391865500008 PM 27767376 ER PT J AU Podolanczukt, AJ Oelsner, EC Barr, RG Hoffman, EA Armstrong, HF Austin, JHM Basner, RC Bartels, MN Christie, JD Enright, PL Gochuico, BR Stukovsky, KH Kaufman, JD Nath, PH Newell, JD Palmer, SM Rabinowitz, D Raghu, G Sell, JL Sieren, J Sonavane, SK Tracy, RP Watts, JR Williams, K Kawut, SM Lederer, DJ AF Podolanczukt, Anna J. Oelsner, Elizabeth C. Barr, R. Graham Hoffman, Eric A. Armstrong, Hilary F. Austin, John H. M. Basner, Robert C. Bartels, Matthew N. Christie, Jason D. Enright, Paul L. Gochuico, Bernadette R. Stukovsky, Karen Hinckley Kaufman, Joel D. Nath, P. Hrudaya Newell, John D., Jr. Palmer, Scott M. Rabinowitz, Dan Raghu, Ganesh Sell, Jessica L. Sieren, Jered Sonavane, Sushil K. Tracy, Russell P. Watts, Jubal R. Williams, Kayleen Kawut, Steven M. Lederer, David J. TI High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; INTERSTITIAL LUNG ABNORMALITIES; C-REACTIVE PROTEIN; AIR-FLOW OBSTRUCTION; ATHEROSCLEROSIS MESA; CARDIAC CT; DISEASE; EMPHYSEMA; INTERLEUKIN-6; ASSOCIATION AB Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3-11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8-13.0), lower forced vital capacity (FVC) (mean adjusted difference -82 mL, 95% CI -119--44), lower 6-min walk distance (mean adjusted difference -40 m, 95% CI -1--80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43-2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39-1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. C1 [Podolanczukt, Anna J.; Oelsner, Elizabeth C.; Barr, R. Graham; Basner, Robert C.; Sell, Jessica L.; Lederer, David J.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Barr, R. Graham; Armstrong, Hilary F.; Lederer, David J.] Columbia Univ, Med Ctr, Dept Epidemiol, New York, NY USA. [Hoffman, Eric A.; Newell, John D., Jr.] Univ Iowa, Dept Radiol, Carver Coll Med, Iowa City, IA 52242 USA. [Hoffman, Eric A.; Newell, John D., Jr.] Univ Iowa, Dept Med, Carver Coll Med, Iowa City, IA 52242 USA. [Hoffman, Eric A.; Newell, John D., Jr.] Univ Iowa, Dept Biomed Engn, Carver Coll Med, Iowa City, IA 52242 USA. [Austin, John H. M.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Bartels, Matthew N.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Rehabil Med, Bronx, NY 10467 USA. [Christie, Jason D.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Christie, Jason D.] Univ Penn, Ctr Translat Lung Biol, Philadelphia, PA 19104 USA. [Enright, Paul L.] Univ Arizona, Dept Epidemiol, Tucson, AZ USA. [Gochuico, Bernadette R.] NHGRI, Bethesda, MD 20892 USA. [Stukovsky, Karen Hinckley] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kaufman, Joel D.; Raghu, Ganesh; Williams, Kayleen] Univ Washington, Dept Med, Seattle, WA USA. [Nath, P. Hrudaya; Sonavane, Sushil K.; Watts, Jubal R.] Univ Alabama, Dept Radiol, South Birmingham, AL USA. [Palmer, Scott M.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Rabinowitz, Dan] Columbia Univ, Dept Stat, New York, NY USA. [Sieren, Jered] VIDA Diagnost Inc, Coralville, IA USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. [Kawut, Steven M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. Columbia Univ, Med Ctr, Med & Epidemiol, New York, NY 10032 USA. RP Lederer, DJ (reprint author), Columbia Univ, Med Ctr, Med & Epidemiol, 161 Ft Washington Ave,Room 3-321A, New York, NY 10032 USA. EM davidlederer@columbia.edu OI Kaufman, Joel/0000-0003-4174-9037; Watts, Jubal/0000-0002-9006-1637 FU National Heart, Lung, and Blood Institute [R01 HL103676, R01 HL077612, R01 HL114626, RC1-100543, R01-HL093081, 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, T32 HL105323]; NCRR/NCATS [UL1-TR-000040, UL1-RR-025005]; Pulmonary Fibrosis Foundation; FundRef FX This research was supported by grants and contracts R01 HL103676, R01 HL077612, R01 HL114626, RC1-100543 and R01-HL093081, 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, and T32 HL105323 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR/NCATS. This project was funded in part by the Pulmonary Fibrosis Foundation. Funding information for this manuscript has been deposited with FundRef. NR 55 TC 3 Z9 3 U1 0 U2 0 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 NOV PY 2016 VL 48 IS 5 BP 1442 EP 1452 DI 10.1183/13993003.00129-2016 PG 11 WC Respiratory System SC Respiratory System GA EG3VW UT WOS:000390973800023 PM 27471206 ER PT J AU Lamb, AE Biesecker, BB Umstead, KL Muratori, M Biesecker, LG Erby, LH AF Lamb, Amanda E. Biesecker, Barbara B. Umstead, Kendall L. Muratori, Michelle Biesecker, Leslie G. Erby, Lori H. TI Family functioning mediates adaptation in caregivers of individuals with Rett syndrome SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Adaptation; Family functioning; Rett syndrome; Coping; Self-efficacy; Caregiver; Neurodevelopmental disorder ID AUTISM SPECTRUM DISORDER; SICKLE-CELL-DISEASE; PSYCHOLOGICAL ADJUSTMENT; CYSTIC-FIBROSIS; SELF-EFFICACY; MENTAL-HEALTH; CHILDREN; MOTHERS; STRESS; PARENTS AB Objective: The objective of this study was to investigate factors related to family functioning and adaptation in caregivers of individuals with Rett syndrome (RS). Methods: A cross-sectional quantitative survey explored the relationships between demographics, parental self-efficacy, coping methods, family functioning and adaptation. A forward-backward, step-wise model selection procedure was used to evaluate variables associated with both family functioning and adaptation. Analyses also explored family functioning as a mediator of the relationship between other variables and adaptation. Results: Bivariate analyses (N = 400) revealed that greater parental self-efficacy, a greater proportion of problem-focused coping, and a lesser proportion of emotion-focused coping were associated with more effective family functioning. In addition, these key variables were significantly associated with greater adaptation, as was family functioning, while controlling for confounders. Finally, regression analyses suggest family functioning as a mediator of the relationships between three variables (parental self-efficacy, problem-focused coping, and emotion-focused coping) with adaptation. Conclusion: This study demonstrates the potentially predictive roles of expectations and coping methods and the mediator role of family functioning in adaptation among caregivers of individuals with RS, a chronic developmental disorder. Practice implications: A potential target for intervention is strengthening of caregiver competence in the parenting role to enhance caregiver adaptation. Published by Elsevier Ireland Ltd. C1 [Lamb, Amanda E.; Biesecker, Barbara B.; Umstead, Kendall L.; Erby, Lori H.] NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Rm B1B36, Bethesda, MD 20814 USA. [Lamb, Amanda E.; Biesecker, Barbara B.; Muratori, Michelle; Erby, Lori H.] Johns Hopkins Bloomberg Sch Publ Hlth, Hlth Behav & Soc, Baltimore, MD 21205 USA. [Biesecker, Barbara B.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20814 USA. [Biesecker, Barbara B.; Muratori, Michelle] Johns Hopkins Ctr Talented Youth, Baltimore, MD USA. RP Biesecker, BB (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Rm B1B36, Bethesda, MD 20814 USA. EM barbarab@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 39 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD NOV PY 2016 VL 99 IS 11 BP 1873 EP 1879 DI 10.1016/j.pec.2016.06.018 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA EG7JC UT WOS:000391222100018 PM 27373960 ER PT J AU Singhal, A Simmons, M Lu, ZY AF Singhal, Ayush Simmons, Michael Lu, Zhiyong TI Text Mining Genotype-Phenotype Relationships from Biomedical Literature for Database Curation and Precision Medicine SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MANUAL CURATION; GENETIC-VARIANTS; MUTATION; DISEASE; IMPACT; IDENTIFICATION; NORMALIZATION; EXTRACTION; SEQUENCES; GENOMES AB The practice of precision medicine will ultimately require databases of genes and mutations for healthcare providers to reference in order to understand the clinical implications of each patient's genetic makeup. Although the highest quality databases require manual curation, text mining tools can facilitate the curation process, increasing accuracy, coverage, and productivity. However, to date there are no available text mining tools that offer high-accuracy performance for extracting such triplets from biomedical literature. In this paper we propose a high-performance machine learning approach to automate the extraction of disease-gene-variant triplets from biomedical literature. Our approach is unique because we identify the genes and protein products associated with each mutation from not just the local text content, but from a global context as well (from the Internet and from all literature in PubMed). Our approach also incorporates protein sequence validation and disease association using a novel text-mining-based machine learning approach. We extract disease-gene-variant triplets from all abstracts in PubMed related to a set of ten important diseases (breast cancer, prostate cancer, pancreatic cancer, lung cancer, acute myeloid leukemia, Alzheimer's disease, hemochromatosis, age-related macular degeneration (AMD), diabetes mellitus, and cystic fibrosis). We then evaluate our approach in two ways: (1) a direct comparison with the state of the art using benchmark datasets; (2) a validation study comparing the results of our approach with entries in a popular human-curated database (UniProt) for each of the previously mentioned diseases. In the benchmark comparison, our full approach achieves a 28% improvement in F-1-measure (from 0.62 to 0.79) over the state-of-the-art results. For the validation study with UniProt Knowledgebase (KB), we present a thorough analysis of the results and errors. Across all diseases, our approach returned 272 triplets (disease-gene-variant) that overlapped with entries in UniProt and 5,384 triplets without overlap in UniProt. Analysis of the overlapping triplets and of a stratified sample of the nonoverlapping triplets revealed accuracies of 93% and 80% for the respective categories (cumulative accuracy, 77%). We conclude that our process represents an important and broadly applicable improvement to the state of the art for curation of disease-gene-variant relationships. C1 [Singhal, Ayush; Simmons, Michael; Lu, Zhiyong] NIH, NCBI, NLM, Bldg 10, Bethesda, MD 20892 USA. RP Lu, ZY (reprint author), NIH, NCBI, NLM, Bldg 10, Bethesda, MD 20892 USA. EM zhiyong.lu@nih.gov OI singhal, ayush/0000-0002-2378-3795 FU NIH Intramural Research Program; National Library of Medicine; NIH Medical Research Scholars Program; NIH FX This research was supported by the NIH Intramural Research Program, National Library of Medicine and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the Howard Hughes Medical Institute, the American Association for Dental Research, the Colgate-Palmolive Company, and other private donors. No funds from the Doris Duke Charitable Foundation were used to support research that used animals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD NOV PY 2016 VL 12 IS 11 AR e1005017 DI 10.1371/journal.pcbi.1005017 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EG7MC UT WOS:000391230900002 PM 27902695 ER PT J AU Rid, A Johansson, MA Leung, G Valantine, H Burchard, EG Oh, SS Zimmerman, C AF Rid, Annette Johansson, Michael A. Leung, Gabriel Valantine, Hannah Burchard, Esteban G. Oh, Sam S. Zimmerman, Cathy CA PLOS Med Editors TI Towards Equity in Health: Researchers Take Stock SO PLOS MEDICINE LA English DT Editorial Material ID DIVERSITY C1 Publ Lib Sci, San Francisco, CA USA. [PLOS Med Editors] Publ Lib Sci, Cambridge, England. [Rid, Annette] Kings Coll London, Dept Global Hlth & Social Med, London, England. [Johansson, Michael A.] Ctr Dis Control & Prevent, Div Vector Borne Dis, San Juan, PR USA. [Johansson, Michael A.] TH Chan Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA USA. [Leung, Gabriel] Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Valantine, Hannah] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Valantine, Hannah] NHLBI, Lab Genome Transplantat, NIH, Bldg 10, Bethesda, MD 20892 USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Burchard, Esteban G.; Oh, Sam S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Zimmerman, Cathy] London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England. RP Rid, A (reprint author), Kings Coll London, Dept Global Hlth & Social Med, London, England. NR 27 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD NOV PY 2016 VL 13 IS 11 AR e1002186 DI 10.1371/journal.pmed.1002186 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EG7NE UT WOS:000391233800022 ER PT J AU Gonzalez, FJ Jiang, CT Patterson, AD AF Gonzalez, Frank J. Jiang, Changtao Patterson, Andrew D. TI An Intestinal Microbiota-Farnesoid X Receptor Axis Modulates Metabolic Disease SO GASTROENTEROLOGY LA English DT Review DE Bile Acids; Farnesoid X Receptor; Metabolic Disease; Ceramides ID FATTY LIVER-DISEASE; PLACEBO-CONTROLLED TRIAL; BILE-ACID RECEPTORS; GROWTH-FACTOR 19; NUCLEAR RECEPTOR; GUT MICROBIOTA; INSULIN-RESISTANCE; ENTEROHEPATIC CIRCULATION; HEPATOCELLULAR-CARCINOMA; DIABETES-MELLITUS AB The gut microbiota is associated with metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease, as shown by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was owing to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-b-muricholic acid (MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD induced obesity, insulin resistance, and nonalcoholic fatty liver disease, thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist, glycine-b-MCA (Gly-MCA), which is resistant to BSH, was developed, which, when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decrease in adverse metabolic phenotype by tempol, antibiotics, and Gly-MCA was caused by decreased serum ceramides. Mice lacking FXR in the intestine also have lower serum ceramide levels, and are resistant to HFD-induced metabolic disease, and this was reversed by injection of C16:0 ceramide. In mouse ileum, because of the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered they are repressed, which likely accounts for the decrease in serum ceramides. These studies show that ceramides produced in the ileum under control of FXR influence metabolic diseases. C1 [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jiang, Changtao] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100191, Peoples R China. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Jiang, CT (reprint author), Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100191, Peoples R China. EM gonzalef@mail.nih.gov; jiangchangtao@bjmu.edu.cn FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Environmental Health Sciences [ES022186]; National Natural Science Foundation of China [81522007, 81470554] FX This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (F.J.G.); the National Institutes of Environmental Health Sciences (ES022186 to A.D.P.); and by the National Natural Science Foundation of China (81522007 and 81470554 to C.J.). NR 137 TC 4 Z9 4 U1 11 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2016 VL 151 IS 5 BP 845 EP 859 DI 10.1053/j.gastro.2016.08.057 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OM UT WOS:000390954600025 PM 27639801 ER PT J AU Bosetti, F Galis, ZS Bynoe, MS Charette, M Cipolla, MJ del Zoppo, GJ Gould, D Hatsukami, TS Jones, TLZ Koenig, JI Lutty, GA Maric-Bilkan, C Stevens, T Tolunay, HE Koroshetz, W AF Bosetti, Francesca Galis, Zorina S. Bynoe, Margaret S. Charette, Marc Cipolla, Marilyn J. del Zoppo, Gregory J. Gould, Douglas Hatsukami, Thomas S. Jones, Teresa L. Z. Koenig, James I. Lutty, Gerard A. Maric-Bilkan, Christine Stevens, Troy Tolunay, H. Eser Koroshetz, Walter CA Small Blood Vessels Big Hlth TI "Small Blood Vessels: Big Health Problems?": Scientific Recommendations of the National Institutes of Health Workshop SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE endothelium; hypertension; imaging; ischemia; microcirculation; remodeling ID VASCULAR COGNITIVE IMPAIRMENT; PHENOTYPIC HETEROGENEITY; HYPERTENSION MECHANISMS; COLLATERAL CIRCULATION; RANDOMIZED-TRIALS; VITAMIN-E; DISEASE; BRAIN; STROKE; DEMENTIA C1 [Bosetti, Francesca; Koenig, James I.; Koroshetz, Walter] NINDS, NIH, 6001 Execut Blvd,Rm 2115, Bethesda, MD 20892 USA. [Jones, Teresa L. Z.] NIDDK, NIH, Bethesda, MD 20892 USA. [Galis, Zorina S.; Charette, Marc; Maric-Bilkan, Christine; Tolunay, H. Eser] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bynoe, Margaret S.] Cornell Univ, Ithaca, NY USA. [Cipolla, Marilyn J.] Univ Vermont, Burlington, VT USA. [del Zoppo, Gregory J.; Hatsukami, Thomas S.] Univ Washington, Seattle, WA 98195 USA. [Gould, Douglas] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lutty, Gerard A.] Johns Hopkins Univ, Baltimore, MD USA. [Stevens, Troy] Univ S Alabama, Mobile, AL USA. RP Bosetti, F (reprint author), NINDS, NIH, 6001 Execut Blvd,Rm 2115, Bethesda, MD 20892 USA. EM frances@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute; National Eye Institute; National Institutes of Health Office of Disease Prevention; Office of Research on Women's Health; Microcirculatory Society FX The workshop was supported by National Institute of Neurological Disorders and Stroke, National Heart, Lung and Blood Institute, National Eye Institute, National Institutes of Health Office of Disease Prevention, and Office of Research on Women's Health. The dMicrocirculatory Society sponsored 6 Travel Awards to support the attendance of trainees and junior faculty members. NR 73 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD NOV PY 2016 VL 5 IS 11 AR e004389 DI 10.1161/JAHA.116.004389 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EG1IU UT WOS:000390786600044 ER PT J AU Hayes, SR Vargas, AJ AF Hayes, Shelby R. Vargas, Ashley J. TI PROBIOTICS FOR THE PREVENTION OF PEDIATRIC ANTIBIOTIC-ASSOCIATED DIARRHEA SO EXPLORE-THE JOURNAL OF SCIENCE AND HEALING LA English DT Article ID CLOSTRIDIUM-DIFFICILE INFECTIONS; TRIALS C1 [Hayes, Shelby R.; Vargas, Ashley J.] NCI, 6100 Execut Bldv, Rockville, MD 20852 USA. RP Vargas, AJ (reprint author), NCI, 6100 Execut Bldv, Rockville, MD 20852 USA. EM ashley.vargas@nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 18 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-8307 EI 1878-7541 J9 EXPLORE-NY JI Explore-J Sci. Heal. PD NOV-DEC PY 2016 VL 12 IS 6 BP 463 EP 466 PG 4 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA EF8YW UT WOS:000390618900014 PM 27688016 ER PT J AU Shisler, S Eiden, RD Molnar, DS Schuetze, P Coles, CD Huestis, M Colder, CR AF Shisler, Shannon Eiden, Rina D. Molnar, Danielle S. Schuetze, Pamela Coles, Claire D. Huestis, Marilyn Colder, Craig R. TI Effects of fetal tobacco exposure on focused attention in infancy SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Prenatal tobacco exposure; Focused attention; Behavioral reactivity; Infants ID EMOTION REGULATION; PRENATAL SMOKING; VISUAL-ATTENTION; NORMATIVE DATA; RELIABILITY; EXPLORATION; METABOLITES; MECONIUM; ADHD AB This study examined the association between fetal tobacco exposure (FTE) and focused attention at 9 months of child age, and the role of child sex and infant behavioral reactivity as potential moderators of this association. Data were obtained from 203 mothers and their infants (105 fetally exposed and 98 non-exposed) on infant focused attention and behavioral reactivity to a frustration task. FTE was ascertained via nicotine metabolites in infant meconium, reflecting primarily third trimester fetal exposure. Results demonstrated a main effect of FTE on focused attention, such that exposed infants exhibited lower levels of focused attention than non-exposed infants. Behavioral reactivity, but not infant sex, moderated the relationship between FTE and focused attention, such that exposed infants who were highly reactive to frustration had the lowest levels of focused attention. Results suggest that smoking interventions, even in the third trimester, may have a positive impact on attentional outcomes for infants. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shisler, Shannon; Eiden, Rina D.; Molnar, Danielle S.] SUNY Buffalo, Res Inst Addict, 1021 Main St, Buffalo, NY 14203 USA. [Schuetze, Pamela] SUNY Coll Buffalo, Dept Psychol, 1300 Elmwood Ave, Buffalo, NY 14222 USA. [Coles, Claire D.] Emory Univ, Psychiat & Behav Sci, Pediat, 201 Dowman Dr, Atlanta, GA 30322 USA. [Huestis, Marilyn] NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, Suite 200,Room 05A-721,251 Bayview Blvd, Baltimore, MD 21224 USA. [Colder, Craig R.] SUNY Buffalo, Dept Psychol, 227 Pk Hall, Buffalo, NY 14260 USA. RP Shisler, S (reprint author), SUNY Buffalo, Res Inst Addict, 1021 Main St, Buffalo, NY 14203 USA. EM sshisler@ria.buffalo.edu; eiden@ria.buffalo.edu; dmolnar@ria.buffalo.edu; schuetp@buffalostate.edu; ccoles@emory.edu; marilyn.huestis@gmail.com; ccolder@buffalo.edu FU National Institute on Drug Abuse [R01DA019632] FX The authors thank the families who participated in this study and the research staff responsible for data collection. Special thanks to Dr. Amol Lele for collaboration on data collection at Women and Children's Hospital of Buffalo. The study was supported by Award #R01DA019632 from the National Institute on Drug Abuse. NR 41 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 EI 1879-0453 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD NOV PY 2016 VL 45 BP 1 EP 10 DI 10.1016/j.infbeh.2016.07.008 PN A PG 10 WC Psychology, Developmental SC Psychology GA EG1XJ UT WOS:000390827400001 PM 27543942 ER PT J AU Johns, LE Ferguson, KK Meeker, JD AF Johns, Lauren E. Ferguson, Kelly K. Meeker, John D. TI Relationships Between Urinary Phthalate Metabolite and Bisphenol A Concentrations and Vitamin D Levels in US Adults: National Health and Nutrition Examination Survey (NHANES), 2005-2010 SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ENDOCRINE DISRUPTING CHEMICALS; EXPOSURE; POPULATION; EXPRESSION; ENZYMES; MODELS; SYSTEM; GENES; WOMEN; MEN AB Context: Recent research suggests that environmental exposure to endocrine-disrupting chemicals may alter circulating 25-hydroxyvitamin D [25(OH)D] levels in humans. To date, no studies have assessed the associations between phthalates and bisphenol A (BPA) and total 25(OH)D in the U.S. general population. Objective: To explore relationships between urinary concentrations of 11 phthalate metabolites and BPA and serum total 25(OH)D in a representative sample of U.S. adults. Design: A cross-sectional study. Setting: U.S. National Health and Nutrition Examination Survey, 2005-2010. Patients or Other Participants: U.S. general adult population (aged ce20 years). Interventions: None Main Outcome Measures: Serum total 25(OH)D measured by liquid chromatography-tandem mass spectrometry. Results: Metabolites of di(2-ethylhexyl) phthalate (DEHP) were consistently inversely associated with total 25(OH)D in the overall study population and in gender-stratified models. In the overall population, we detected a significant inverse relationship for the molar sum of DEHP metabolites (IDEHP), where an interquartile range increase in IDEHP was associated with a 1.90% decrease (95% confidence interval [CI], -3.64, -0.17) in total 25(OH)D. A positive association was detected for monoethyl phthalate. For BPA, we found a statistically significant inverse relationship in women, but not in men. In women, an interquartile range increase in urinary BPA was associated with a 3.71% decrease (95% CI, -6.41, -1.02) in total 25(OH)D. Conclusions: Overall, our results provide suggestive evidence that environmental exposure to phthalates and BPA may alter circulating levels of total 25(OH)D in adults. Future human and animal studies are required to resolvethe direction, temporality, and impact of these relationships. C1 [Johns, Lauren E.; Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Ferguson, Kelly K.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Meeker, JD (reprint author), Dept Environm Hlth Sci, 1835 SPH 1,1415 Washington Hts, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI Ferguson, Kelly/0000-0001-8467-3250 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; National Institute of Environmental Health Sciences, National Institutes of Health [R01ES018872, P42ES017198, P50ES026049, P01ES0228544, T32ES007062] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Funding was also provided by the National Institute of Environmental Health Sciences, National Institutes of Health (Grants R01ES018872, P42ES017198, P50ES026049, P01ES0228544, and T32ES007062). NR 43 TC 2 Z9 2 U1 6 U2 6 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 NOV PY 2016 VL 101 IS 11 BP 4062 EP 4069 DI 10.1210/jc.2016-2134 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600022 PM 27648964 ER PT J AU Song, IS Han, K Park, YM Ji, S Jun, SH Ryu, JJ Park, JB AF Song, In-Seok Han, Kyungdo Park, Yong-Moon Ji, Suk Jun, Sang Ho Ryu, Jae-Jun Park, Jun-Beom TI Severe Periodontitis Is Associated with Insulin Resistance in Non-abdominal Obese Adults SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NUTRITION EXAMINATION SURVEY; NORMAL GLUCOSE-TOLERANCE; KOREA NATIONAL-HEALTH; BETA-CELL FUNCTION; METABOLICALLY OBESE; DIABETES-MELLITUS; DISEASE; POPULATION; RISK; INFECTIONS AB Context: We hypothesized that insulin resistance, even with normal body weight (body mass index or waist circumference), can aggravate periodontitis severity. Objective: We investigated the associations between diabetes, insulin resistance, and severe periodontitis. Design: Among 29 235 total participants, 5690 subjects aged > 30 y who had periodontal disease with community periodontal index (CPI) of 3 or 4 were selected for this study. Participants: Data were derived from the 2008-2010 Korea National Health and Nutrition Examination Survey. Results: Patients diagnosed with type 2 diabetes were more likely to have severe periodontitis (CPI 4) compared with patients with normal glucose tolerance or impaired fasting glucose (P.001). Subjects with severe periodontitis had significantly higher prevalence of abdominal obesity, serum triglycerides, and insulin resistance (P values of .012, <.001, and.003, respectively). The odds ratios (ORs) for prevalence of severe periodontitis were significantly increased from normal glucose tolerance and impaired fasting glucose (OR = 1.32; 95% confidence interval, 1.06-1.64) to type 2 diabetes (OR = 1.5; 95% CI, 1.11-2.02), after adjusting for potential confounders (P for trend =.003). The prevalence of severe periodontitis increased significantly with increasing insulin resistance (P for trend =.04) in nondiabetic individuals. Furthermore, insulin-resistant individuals with normal waist circumference showed significantly higher odds of severe periodontitis (OR = 1.47; 95% CI, 1.16-1.87) than did insulin sensitive individuals with normal waist circumference. Conclusions: Non-abdominally obese subjects with insulin resistance were more likely to have severe periodontitis. Insulin resistance can be considered an independent riskfactor of periodontal disease in normal weight population defined by abdominal obesity. C1 [Song, In-Seok; Jun, Sang Ho] Korea Univ, Anam Hosp, Dept Oral & Maxillofacial Surg, Seoul 02841, South Korea. [Han, Kyungdo] Catholic Univ Korea, Coll Med, Dept Biostat, Seoul 06591, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Ji, Suk] Ajou Univ Hosp, Dept Periodontol, Suwon 16499, South Korea. [Ryu, Jae-Jun] Korea Univ, Anam Hosp, Dept Prosthodont, 73 Inchon Ro, Seoul 02841, South Korea. [Park, Jun-Beom] Catholic Univ Korea, Coll Med, Dept Periodont, Seoul 06591, South Korea. RP Ryu, JJ (reprint author), Korea Univ, Anam Hosp, Dept Prosthodont, 73 Inchon Ro, Seoul 02841, South Korea.; Park, JB (reprint author), Catholic Univ Korea, Coll Med, Seoul St Marys Hosp, Dept Periodont, 222 Banpo Daero, Seoul 06591, South Korea. EM koprosth@unitel.co.kr; jbassoonis@yahoo.co.kr NR 40 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 4251 EP 4259 DI 10.1210/jc.2016-2061 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600045 PM 27598510 ER PT J AU Chaker, L Baumgartner, C den Elzen, WPJ Collet, TH Ikram, MA Blum, MR Dehghan, A Drechsler, C Luben, RN Portegies, MLP Lervasi, G Medici, M Stott, DJ Dullaart, RP Ford, I Bremner, A Newman, AB Wanner, C Sgarbi, JA Dorr, M Longstreth, WT Psaty, BM Ferrucci, L Maciel, RMB Westendorp, RG Jukema, JW Ceresini, G Imaizumi, M Hofman, A Bakker, SJL Franklyn, JA Khaw, KT Bauer, DC Walsh, JP Razvi, S Gussekloo, J Volzke, H Franco, OH Cappola, AR Rodondi, N Peeters, RP AF Chaker, Layal Baumgartner, Christine den Elzen, Wendy P. J. Collet, Tinh-Hai Ikram, M. Arfan Blum, Manuel R. Dehghan, Abbas Drechsler, Christiane Luben, Robert N. Portegies, Marileen L. P. Lervasi, Giorgio Medici, Marco Stott, David J. Dullaart, Robin P. Ford, Ian Bremner, Alexandra Newman, Anne B. Wanner, Christoph Sgarbi, Jose A. Dorr, Marcus Longstreth, W. T., Jr. Psaty, Bruce M. Ferrucci, Luigi Maciel, Rui M. B. Westendorp, Rudi G. Jukema, J. Wouter Ceresini, Graziano Imaizumi, Misa Hofman, Albert Bakker, Stephan J. L. Franklyn, Jayne A. Khaw, Kay-Tee Bauer, Douglas C. Walsh, John P. Razvi, Salman Gussekloo, Jacobijn Volzke, Henry Franco, Oscar H. Cappola, Anne R. Rodondi, Nicolas Peeters, Robin P. CA Thyroid Studies Collaboration TI Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ISCHEMIC-HEART-DISEASE; SERVICES TASK-FORCE; SUBCLINICAL HYPOTHYROIDISM; CARDIOVASCULAR RISK; SERUM THYROTROPIN; MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; OLDER-ADULTS; ALL-CAUSE; DYSFUNCTION AB Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. Design and Setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T-4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. Conclusion: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function. C1 [Chaker, Layal; Medici, Marco; Peeters, Robin P.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Chaker, Layal; Medici, Marco; Peeters, Robin P.] Erasmus Filed Ctr, Rotterdam Thyroid Ctr, NL-3000 CA Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Filed Ctr, Dept Radiol & Neurol, NL-3000 CA Rotterdam, Netherlands. [Baumgartner, Christine; Blum, Manuel R.; Rodondi, Nicolas] Univ Bern, Bern Univ Hosp, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. [Collet, Tinh-Hai] Univ Lausanne Hosp, Serv Endocrinol Diabet & Metab, CH-1011 Lausanne, Switzerland. [den Elzen, Wendy P. J.] Leiden Univ, Med Ctr, Dept Clin Chem & Lab Med, NL-2300 RC Leiden, Netherlands. [Gussekloo, Jacobijn] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2300 RC Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Razvi, Salman] Gateshead Hlth Fdn Natl Hlth Serv Mast, Dept Endocrinol, Gateshead SE18 4QH, England. [Walsh, John P.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Walsh, John P.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia. [Bremner, Alexandra] Univ Western Australia, Sch Populat Hlth, Crawley, WA 6009, Australia. [Lervasi, Giorgio] Natl Council Res Inst ot Clin Physiol, I-56124 Pisa, Italy. [Ford, Ian] Univ Glasgow, Fac Med, Robertson Ctr Biostat, Glasgow G12 8TA, Lanark, Scotland. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Dullaart, Robin P.; Bakker, Stephan J. L.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 AB Groningen, Netherlands. [Drechsler, Christiane; Wanner, Christoph] Univ Hosp Wurzburg, Div Nephrol, Dept Med, D-97070 Wurzburg, Germany. [Drechsler, Christiane; Wanner, Christoph] Comprehens Heart Failure Ctr, D-97070 Wurzburg, Germany. [Imaizumi, Misa] Radiat Eftects Res Fdn, Dept Clin Studies, Nagasaki 8508555, Japan. [Ceresini, Graziano] Univ Parma, Dept Clin & Expt Med, I-143100 Parma, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21225 USA. [Volzke, Henry] German Ctr Cardiovasc Res, Clin Epidemiol Res, Study Hlth Pomerania, Inst Community Med,Univ Med, D-17187 Greifswald, Germany. [Dorr, Marcus] German Ctr Cardiovasc Res, Dept Internal Med, D-17187 Greifswald, Germany. [Dorr, Marcus] German Ctr Cardiovasc Res, Univ Med, D-17187 Greifswald, Germany. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98108 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98108 USA. [Longstreth, W. T., Jr.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98108 USA. [Longstreth, W. T., Jr.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98108 USA. [Longstreth, W. T., Jr.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98108 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Maciel, Rui M. B.; Franklyn, Jayne A.] Univ Fed Sao Paulo, Dept Med, Div Endocrinol, BR-05150890 Sao Paulo, Brazil. [Sgarbi, Jose A.] Fau Med Marilia, Div Endocrinol, Marilia, Brazil. [Luben, Robert N.; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, NL-3508 GA Utrecht, Netherlands. [Franklyn, Jayne A.] Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England. [Westendorp, Rudi G.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, DK-2400 Copenhagen, Denmark. [Westendorp, Rudi G.] Univ Copenhagen, Fac Hlth & Med Sci, Ctr Hlth Ageing, DK-2400 Copenhagen, Denmark. RP Peeters, RP (reprint author), Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam Thyroid Ctr, Room NA28-18,POB 2040, NL-3000 CA Rotterdam, Netherlands.; Peeters, RP (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam Thyroid Ctr, Room NA28-18,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM r.peeters@erasmusmc.nl OI Blum, Manuel/0000-0003-4638-775X; Collet, Tinh-Hai/0000-0002-3243-1222 FU Erasmus Medical Center MRACE grant; ZonMW TOP grant [91212044]; Genzyme B.V.; Swiss National Science Foundation [PBLAP3-145870, P3SMP3-155318, SNSF 320030-138267, 320030-150025]; Loll LifeCor; Johnson Johnson; National Institute on Aging [R01AG032317, K24AG042765, AG023629, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Heart, Lung, and Blood Institute [HHSN268 201200036C, HHSN268200800007C, N01HC55222, N01HC 85079, N01HC85080, N01HC85081, N01HC85082, N01HC8 5083, N01HC285086, HL080295]; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging; Research Network of Community Medicine of the University Medicine Greifswald; German Research Foundation [DFG Vo 955/12-2]; Japanese Ministry of Health, Labor, and Welfare; US Department of Energy; Radiation Effects Research Foundation [A3-13]; Sao Paulo State Research Foundation (Fundacao de Amaparo a Pesquisa do Estado de Sao Paulo) [6/59737-9]; Dutch Kidney Foundation [E.033]; University Medical Center Groningen; Dutch Heart Foundation [2001-005]; National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences; National Institutes of Health Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG04 2139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128] FX R.P.P. and L.C. are supported by an Erasmus Medical Center MRACE grant and a ZonMW TOP grant (Grant 91212044). R.P.P. has received lecture and consultancy-fees from Genzyme B.V. T.-H.C.'s research is supported by Grants PBLAP3-145870 and P3SMP3-155318 from the Swiss National Science Foundation. B.M.P. serves on a DSMB for a clinical trial of a device funded by the manufacturer (Loll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The Thyroid Studies Collaboration is supported by Grants SNSF 320030-138267 and 320030-150025 from the Swiss National Science Foundation (to N.R.).r Cohort-related funding included the Cardiovascular Health Study supported by Grants R01AG032317 and K24AG042765 from the National Institute on Aging; Contracts HHSN268 201200036C, HHSN268200800007C, N01HC55222, N01HC 85079, N01HC85080, N01HC85081, N01HC85082, N01HC8 5083, and N01HC285086 and Grant HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by Grant AG023629 from the National Institute on Aging. A full list of the principal Cardiovascular Health Study investigators and institutions can be found at chs-nhlbi.org.r The Health ABC Study was supported by National Institute on Aging Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging Grant R01-AG028050; and National Institute of Nursing Research Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.r The Study of Health in Pomerania analyses were funded by the Research Network of Community Medicine of the University Medicine Greifswald (www.community-medicine.de) and the German Research Foundation Grant DFG Vo 955/12-2.r The Radiation Effects Research Foundation (Hiroshima and Nagasaki, Japan) is a public interest foundation supported by the Japanese Ministry of Health, Labor, and Welfare and the US Department of Energy. This publication was supported by Radiation Effects Research Foundation Research Protocol Grant A3-13.r The Brazilian Thyroid Study was supported by an unrestricted grant from the Sao Paulo State Research Foundation (Fundacao de Amaparo a Pesquisa do Estado de Sao Paulo) Grant 6/59737-9 (to R.M.B.M.).r The Dutch Kidney Foundation supported the infrastructure of the PREVEND program from 1997 to 2003 (Grant E.033). The University Medical Center Groningen supported the infrastructure from 2003 to 2006. Dade Behring, Ausam, Roche, and Abbott financed laboratory equipment and reagents by which various laboratory determinations could be performed. The Dutch Heart Foundation supported studies on lipid metabolism (Grant 2001-005).r The Osteoporotic Fractures in Men Study is supported by the National Institutes of Health. The following institutes provide support: the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and National Institutes of Health Roadmap for Medical Research under the following grants: U01 AG027810, U01 AG042124, U01 AG04 2139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. NR 59 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 4270 EP 4282 DI 10.1210/jc.2016-2255 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600047 PM 27603906 ER PT J AU Shmeeda, H Amitay, Y Gorin, J Tzemach, D Mak, L Stern, ST Barenholz, Y Gabizon, A AF Shmeeda, Hilary Amitay, Yasmine Gorin, Jenny Tzemach, Dina Mak, Lidia Stern, Stephan T. Barenholz, Yechezkel Gabizon, Alberto TI Coencapsulation of alendronate and doxorubicin in pegylated liposomes: a novel formulation for chemoimmunotherapy of cancer SO JOURNAL OF DRUG TARGETING LA English DT Article DE Alendronate; chemoimmunotherapy; coencapsulation; pegylated liposomes ID LIPID-BASED PRODRUG; DELTA T-CELLS; ZOLEDRONIC ACID; BREAST-CANCER; IN-VIVO; TUMOR-GROWTH; MITOMYCIN-C; BISPHOSPHONATES; THERAPY; ACTIVATION AB We developed a pegylated liposome formulation of a dissociable salt of a nitrogen-containing bisphosphonate, alendronate (Ald), coencapsulated with the anthracycline, doxorubicin (Dox), a commonly used chemotherapeutic agent. Liposome-encapsulated ammonium Ald generates a gradient driving Dox into liposomes, forming a salt that holds both drugs in the liposome water phase. The resulting formulation (PLAD) allows for a high-loading efficiency of Dox, comparable to that of clinically approved pegylated liposomal doxorubicin sulfate (PLD) and is very stable in plasma stability assays. Cytotoxicity tests indicate greater potency for PLAD compared to PLD. This appears to be related to a synergistic effect of the coencapsulated Ald and Dox. PLAD and PLD differed in in vitro monocyte-induced IL-1 release (greater for PLAD) and complement activation (greater for PLD). A molar ratio Ald/Dox of approximate to 1:1 seems to provide an optimal compromise between loading efficiency of Dox, circulation time and in vivo toxicity of PLAD. In mice, the circulation half-life and tumor uptake of PLAD were comparable to PLD. In the M109R and 4T1 tumor models in immunocompetent mice, PLAD was superior to PLD in the growth inhibition of subcutaneous tumor implants. This new formulation appears to be a promising tool to exploit the antitumor effects of aminobisphosphonates in synergy with chemotherapy. C1 [Shmeeda, Hilary; Amitay, Yasmine; Gorin, Jenny; Tzemach, Dina; Mak, Lidia; Gabizon, Alberto] Shaare Zedek Med Ctr, Jerusalem, Israel. [Amitay, Yasmine; Barenholz, Yechezkel; Gabizon, Alberto] Hebrew Univ Jerusalem, Sch Med, Jerusalem, Israel. [Stern, Stephan T.] NCL, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Gabizon, A (reprint author), Shaare Zedek Med Ctr, Inst Oncol, POB 3235, IL-91031 Jerusalem, Israel. EM alberto.gabizon@gmail.com RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU Israel Cancer Research Fund; Janssen Pharmaceuticals FX This work was supported by grants from the Israel Cancer Research Fund, and Janssen Pharmaceuticals. NR 42 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1061-186X EI 1029-2330 J9 J DRUG TARGET JI J. Drug Target. PD NOV PY 2016 VL 24 IS 9 SI SI BP 878 EP 889 DI 10.1080/1061186X.2016.1191081 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EF8RA UT WOS:000390595600015 PM 27187807 ER PT J AU Kendall, GM Miles, JCH Rees, D Wakeford, R Bunch, KJ Vincent, TJ Little, MP AF Kendall, Gerald M. Miles, Jon C. H. Rees, David Wakeford, Richard Bunch, Kathryn J. Vincent, Tim J. Little, Mark P. TI Variation with socioeconomic status of indoor radon levels in Great Britain: The less affluent have less radon SO JOURNAL OF ENVIRONMENTAL RADIOACTIVITY LA English DT Article DE Radon; Socioeconomic status; Deprivation; Epidemiology ID CHILDHOOD LEUKEMIA; RESIDENTIAL RADON; LUNG-CANCER; UNITED-STATES; COLLABORATIVE ANALYSIS; INDIVIDUAL DATA; RISK; RADIATION; EXPOSURE; INDICATORS AB We demonstrate a strong correlation between domestic radon levels and socio-economic status (SES) in Great Britain, so that radon levels in homes of people with lower SES are, on average, only about two thirds of those of the more affluent. This trend is apparent using small area measures of SES and also using individual social classes. The reasons for these differences are not known with certainty, but may be connected with greater underpressure in warmer and better-sealed dwellings. There is also a variation of indoor radon levels with the design of the house (detached, terraced, etc.). In part this is probably an effect of SES, but it appears to have other causes as well. Data from other countries are also reviewed, and broadly similar effects seen in the United States for SES, and in other European countries for detached vs other types of housing. Because of correlations with smoking, this tendency for the lower SES groups to experience lower radon levels may underlie the negative association between radon levels and lung cancer rates in a well-known ecological study based on US Counties. Those conducting epidemiological studies of radon should be alert for this effect and control adequately for SES. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kendall, Gerald M.] Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Miles, Jon C. H.; Rees, David] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Didcot OX11 0RQ, Oxon, England. [Wakeford, Richard] Univ Manchester, Inst Populat Hlth, Ctr Occupat & Environm Hlth, Ellen Wilkinson Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. [Bunch, Kathryn J.] Univ Oxford, Natl Perinatal Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Vincent, Tim J.] Univ Oxford, Formerly Childhood Canc Res Grp, New Richards Bldg,Old Rd 12, Oxford OX3 7LF, England. [Little, Mark P.] NCI, Radiat Epidemiol Branch, DHHS, NIH,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kendall, GM (reprint author), Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. EM Gerald.Kendall@ceu.ox.ac.uk OI Wakeford, Richard/0000-0002-2934-0987 FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics; Children with Cancer UK [HTRVVKO] FX The Childhood Cancer Research Group investigators were supported by Children with Cancer UK under grant number HTRVVKO. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors are grateful for the detailed and helpful comments of the three referees. RW does consultancy work, including for the UK Compensation Scheme for Radiation-linked Diseases. The authors declare that they otherwise have no actual or potential competing financial interests. NR 58 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0265-931X EI 1879-1700 J9 J ENVIRON RADIOACTIV JI J. Environ. Radioact. PD NOV PY 2016 VL 164 BP 84 EP 90 DI 10.1016/j.jenvrad.2016.07.001 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA EF7KF UT WOS:000390507800010 PM 27442258 ER PT J AU Chernyayskiy, P Kendall, GM Wakeford, R Little, MP AF Chernyayskiy, P. Kendall, G. M. Wakeford, R. Little, M. P. TI Spatial prediction of naturally occurring gamma radiation in Great Britain SO JOURNAL OF ENVIRONMENTAL RADIOACTIVITY LA English DT Article DE Natural gamma radiation; Kriging; Variogram; Multi-resolution Gaussian process; Childhood cancer; Ordinary least squares ID CHILDHOOD LEUKEMIA INCIDENCE; BACKGROUND-RADIATION; IONIZING-RADIATION; TERRESTRIAL; EXPOSURE; MODELS; RADON AB Gamma radiation from natural sources is an important component of background radiation, and correlates with childhood leukaemia risk in Great Britain. The geographic variation of indoor gamma radiation dose-rates in Great Britain is explored using various geo-statistical methods. A multi-resolution Gaussian-process model using radial basis functions with 2, 4, or 8 components, is fitted via maximum likelihood, and a non-spatial model is also used, fitted by ordinary least squares. Because of the dataset size (N = 10,199), four other parametric spatial models are fitted by variogram-fitting. A randomly selected 70:30 split is used for fitting:validation. The models are evaluated based on their predictive performance as measured by Mean Absolute Error, Mean Squared Error, as well as Pearson correlation and rank-correlation between predicted and actual dose-rates. Each of the four parametric models (Matern, Gaussian, Bessel, Spherical) fitted the empirical variogram well, and yielded similar predictions at >50 km separation, although with more substantial differences in predicted variograms at <50 km. The multi-resolution Gaussian-process model with 8 components had the best predictive accuracy among the models considered. The Spherical, Bessel, Matern, Gaussian and ordinary least squares models had progressively worse predictive performance, the ordinary least squares model being particularly poor in this respect. Published by Elsevier Ltd. C1 [Chernyayskiy, P.; Little, M. P.] NCI, Radiat Epidemiol Branch, DHHS, NIH,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kendall, G. M.] Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Wakeford, R.] Univ Manchester, Inst Populat Hlth, Ctr Occupat & Environm Hlth, Ellen Wilkinson Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. RP Little, MP (reprint author), NCI, Room 7E546,9609 Med Ctr Dr, Rockville, MD 20892 USA. EM pavel.chernyayskiy@nih.gov; gerald.kendall@ceu.ox.ac.uk; richard.wakeford@gmail.com; mark.little@nih.gov OI Wakeford, Richard/0000-0002-2934-0987; Little, Mark/0000-0003-0980-7567; Kendall, Gerald/0000-0002-9561-1837 FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics; Children with Cancer (UK) [HTRVVK0] FX We are very grateful to for the detailed comments of the referee and to Dr Jill Simpson of the University of York and to the other UKCCS investigators for making available the indoor gamma-ray dose-rate measurements made for the United Kingdom Childhood Cancer Study and for advice on the interpretation of the data. We are also very grateful to Mr JD Appleton for advice on geological matters generally and in particular for suggesting geological classification schemes. We are grateful to Drs Phil Gilvin, Luke Hager and Rick Tanner at Public Health England (PHE) for advice on the dosimetry of the National Survey and the UKCCS, and to Dr Simon Bouffler and other colleagues at PHE for allowing the use of the National Survey data and for advice on its interpretation. We are grateful to Tim Vincent for help with the census data. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The work of GMK was supported by Children with Cancer (UK) under grant number HTRVVK0. NR 30 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0265-931X EI 1879-1700 J9 J ENVIRON RADIOACTIV JI J. Environ. Radioact. PD NOV PY 2016 VL 164 BP 300 EP 311 DI 10.1016/j.jenvrad.2016.07.029 PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA EF7KF UT WOS:000390507800035 PM 27544074 ER PT J AU Papamichael, D Renfro, LA Matthaiou, C Yothers, G Saltz, L Guthrie, KA Van Cutsem, E Schmoll, HJ Labianca, R Andre, T O'Connell, M Alberts, SR Haller, DG Kountourakis, P Sargent, DJ AF Papamichael, Demetris Renfro, Lindsay A. Matthaiou, Christiana Yothers, Greg Saltz, Leonard Guthrie, Katherine A. Van Cutsem, Eric Schmoll, Hans-Joachim Labianca, Roberto Andre, Thierry O'Connell, Michael Alberts, Steven R. Haller, Daniel G. Kountourakis, Panteleimon Sargent, Daniel J. CA Adjuvant Colon Cancer Endpoints TI Validity of Adjuvant! Online in older patients with stage III colon cancer based on 2967 patients from the ACCENT database SO JOURNAL OF GERIATRIC ONCOLOGY LA English DT Article DE Colorectal; Older; Adjuvant; ACCENT ID PHASE-III; RANDOMIZED-TRIAL; POOLED ANALYSIS; FLUOROURACIL; LEUCOVORIN; OXALIPLATIN; SURVIVAL; CHEMOTHERAPY; LEVAMISOLE; IRINOTECAN AB Background: Adjuvant! Online is a tool used for clinical decision making in patients with early stage colon cancer. As details of the tool's construction are not published, the ability of Adjuvant! Online to accurately predict outcomes for older patients (age 70+) with node positive colon cancer receiving adjuvant chemotherapy is unclear. Methods: Individual data from older patients with stage III colon cancer who enrolled into multiple trials within the ACCENT database were entered into the Adjuvant! Online program to obtain predicted probabilities of 5-year overall survival (OS) and recurrence-free survival (RFS). Median predictions were compared with known rates. As co-morbidities were not known for ACCENT patients, but required for calculator entry, patients were assumed to have either "minor" or "average for age" co-morbidities. Results: 2967 older patients from 10 randomized studies were included. When "minor" co-morbidities were assumed, the median predicted 5-year OS rate of 64% nearly matched the actual rate of 65%; when "average for age" co-morbidities were assumed, the median prediction dropped to 58%, outside the CI for the actual rate. On the other hand, assuming "minor" co-morbidities gave a median 5-year RFS prediction of 62%, outside the 95% CI for the actual rate of 58%, while assuming "average for age" co-morbidities yielded a better median prediction of 57%. Conclusion: Adjuvant! Online is reasonably accurate overall for predicting outcomes in older trial patients with stage III colon cancer, though accuracy may differ between 5-year RFS and 5-year OS predictions when a fixed degree of co-morbidities is assumed. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Papamichael, Demetris; Matthaiou, Christiana; Kountourakis, Panteleimon] BO Cyprus Oncol Ctr, Nicosia, Cyprus. [Renfro, Lindsay A.; Alberts, Steven R.; Sargent, Daniel J.] Mayo Clin, Rochester, MN USA. [Yothers, Greg; O'Connell, Michael] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Saltz, Leonard] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Guthrie, Katherine A.] SWOG Southwest Oncol Grp, Ctr Stat, Seattle, WA USA. [Van Cutsem, Eric] Univ Hosp Gasthuisberg, Gasthuisberg, Belgium. [Schmoll, Hans-Joachim] Martin Luther Univ Halle Wittenberg, Berlin, Germany. [Labianca, Roberto; Andre, Thierry] Hop St Antoine, Paris, France. [Sargent, Daniel J.] Univ Penn, Abrarnson Canc Ctr, Philadelphia, PA 19104 USA. RP Papamichael, D (reprint author), Bank Cyprus Oncol Ctr, Dept Med Oncol, 32 Acropoleos Ave, CY-2006 Nicosia, Cyprus. EM demetris.papamichael@bococ.org.cy FU National Cancer Institute at the National Institutes of Health [CA 25224] FX This work was supported by the National Cancer Institute at the National Institutes of Health [grant number CA 25224]. NR 21 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1879-4068 EI 1879-4076 J9 J GERIATR ONCOL JI J. Geriatr. Oncol. PD NOV PY 2016 VL 7 IS 6 BP 422 EP 429 DI 10.1016/j.jgo.2016.07.002 PG 8 WC Oncology; Geriatrics & Gerontology SC Oncology; Geriatrics & Gerontology GA EF9GS UT WOS:000390639300003 PM 27468630 ER PT J AU Xu, C Hu, S Chen, XY AF Xu, Can Hu, Shuo Chen, Xiaoyuan TI Artificial cells: from basic science to applications SO MATERIALS TODAY LA English DT Article ID MEMBRANE-COATED NANOPARTICLES; RED-BLOOD-CELLS; GIANT VESICLES; SYNTHETIC BIOLOGY; SEMIPERMEABLE MICROCAPSULES; ESCHERICHIA-COLI; GENE-EXPRESSION; DRUG-DELIVERY; MINIMAL CELL; SELF-REPRODUCTION AB Artificial cells have attracted much attention as substitutes for natural cells. There are many different forms of artificial cells with many different definitions. They can be integral biological cell imitators with cell-like structures and exhibit some of the key characteristics of living cells. Alternatively, they can be engineered materials that only mimic some of the properties of cells, such as surface characteristics, shapes, morphology, or a few specific functions. These artificial cells can have applications in many fields from medicine to environment, and may be useful in constructing the theory of the origin of life. However, even the simplest unicellular organisms are extremely complex and synthesis of living artificial cells from inanimate components seems very daunting. Nevertheless, recent progress in the formulation of artificial cells ranging from simple protocells and synthetic cells to cell-mimic particles, suggests that the construction of living life is now not an unrealistic goal. This review aims to provide a comprehensive summary of the latest developments in the construction and application of artificial cells, as well as highlight the current problems, limitations, challenges and opportunities in this field. C1 [Xu, Can; Hu, Shuo] Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China. [Xu, Can; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Hu, S (reprint author), Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. EM hushuo_xy@163.com; shawn.chen@nih.gov NR 152 TC 0 Z9 0 U1 25 U2 25 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1369-7021 EI 1873-4103 J9 MATER TODAY JI Mater. Today PD NOV PY 2016 VL 19 IS 9 BP 516 EP 532 DI 10.1016/j.mattod.2016.02.020 PG 17 WC Materials Science, Multidisciplinary SC Materials Science GA EF8XA UT WOS:000390614100013 PM 28077925 ER PT J AU Ouadani, H Ben-Mustapha, I Ben-Ali, M Largueche, B Jovanic, T Garcia, S Arcangioli, B Elloumi-Zghal, H Fathallah, D Hachicha, M Masmoudi, H Rougeon, F Barbouche, MR AF Ouadani, Hanen Ben-Mustapha, Imen Ben-ali, Meriem Largueche, Beya Jovanic, Tihana Garcia, Sylvie Arcangioli, Benoit Elloumi-Zghal, Houda Fathallah, Dahmani Hachicha, Mongia Masmoudi, Hatem Rougeon, Francois Barbouche, Mohamed-Ridha TI Activation induced cytidine deaminase mutant (AID-His130Pro) from Hyper IgM 2 patient retained mutagenic activity on SHM artificial substrate SO MOLECULAR IMMUNOLOGY LA English DT Article DE Activation induced cytidine deaminase; Class switch recombination; Somatic hypermutation; AID mutagenic activity; Cofactors; Hyper IgM 2 ID CLASS-SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; SYNDROME TYPE-2; AID; DNA; GENE; EXPRESSION; MUTATION; REGION; DIVERSIFICATION AB Activation induced cytidine deaminase (AID) is an essential enzyme for class switch recombination (CSR) and somatic hypermutation (SHM) during secondary immune response. Mutations in the AICDA gene are responsible for Hyper IgM 2 syndrome where both CSR and SHM or only CSR are affected. Indeed, triggering either of the two mechanisms requires the DNA deamination activity of AID. Besides, different domains of AID may be differentially involved in CSR and SHM through their interaction with specific cofactors. Herein, we studied the AID-induced SHM activity of the AID-His130Pro mutant identified in a patient with Hyper IgM 2 syndrome. AID mutagenic activity was monitored by the reversion of nonsense mutations of the EGFP gene assessed by flow cytometry. We found that the His130Pro mutation, which affects CSR, preserves AID mutagenic activity. Indeed, the His130 residue is located in a putative specific CSR region in the APOBEC-like domain, known to involve CSR specific cofactors that probably play a major role in AID physiological activities. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ouadani, Hanen; Ben-Mustapha, Imen; Ben-ali, Meriem; Largueche, Beya; Elloumi-Zghal, Houda; Fathallah, Dahmani; Barbouche, Mohamed-Ridha] Inst Pasteur Tunis, Lab Transmiss Control & Immunobiol Infect LR11IPT, 13 Pl Pasteur BP74, Tunis 1002, Tunisia. [Ouadani, Hanen; Ben-Mustapha, Imen; Ben-ali, Meriem; Barbouche, Mohamed-Ridha] Univ Tunis El Manar, Tunis, Tunisia. [Jovanic, Tihana; Rougeon, Francois] Inst Pasteur Paris, Biochem & Genet Dev Unit URA CNRS 2581, Paris, France. [Garcia, Sylvie] Inst Pasteur Paris, Lab Lymphocyte Populat Biol, Paris, France. [Arcangioli, Benoit] Inst Pasteur Paris, Lab Dynam Genome, Paris, France. [Hachicha, Mongia] Hedi Chaker Hosp, Dept Pediat, Sfax, Tunisia. [Masmoudi, Hatem] Habib Bourguiba Hosp, Immunol Lab, Sfax, Tunisia. [Jovanic, Tihana] Howard Huges Med Inst, Janelia Res Campus, Ashburn, VA USA. [Elloumi-Zghal, Houda] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fathallah, Dahmani] Arabian Gulf Univ, Coll Postgrad Studies, Manama, Bahrain. RP Barbouche, MR (reprint author), Inst Pasteur Tunis, Lab Transmiss Control & Immunobiol Infect LR11IPT, 13 Pl Pasteur BP74, Tunis 1002, Tunisia. EM ridha.barbouche@pasteur.rns.tn FU Ministry of Health (Tunisia) FX This work was supported by the Ministry of Health (Tunisia). NR 47 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD NOV PY 2016 VL 79 BP 77 EP 82 DI 10.1016/j.molimm.2016.09.025 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA EG0JL UT WOS:000390718500009 PM 27716525 ER PT J AU Smith-Vikos, T Liu, ZY Parsons, C Gorospe, M Ferrucci, L Gill, TM Slack, FJ AF Smith-Vikos, Thalyana Liu, Zuyun Parsons, Christine Gorospe, Myriam Ferrucci, Luigi Gill, Thomas M. Slack, Frank J. TI A serum miRNA profile of human longevity: findings from the Baltimore Longitudinal Study of Aging (BLSA) SO AGING-US LA English DT Article DE miRNA; aging; long-lived; short-lived; biomarker; longitudinal study ID POLY(ADP-RIBOSE) POLYMERASE-ACTIVITY; AGE-RELATED DISEASES; CIRCULATING MICRORNAS; BIOMARKERS; CANCER; CENTENARIANS; BLOOD; EXPRESSION; PROGNOSIS; DIAGNOSIS AB In C. elegans, miRNAs are genetic biomarkers of aging. Similarly, multiple miRNAs are differentially expressed between younger and older persons, suggesting that miRNA-regulated biological mechanisms affecting aging are evolutionarily conserved. Previous human studies have not considered participants' lifespans, a key factor in identifying biomarkers of aging. Using PCR arrays, we measured miRNA levels from serum samples obtained longitudinally at ages 50, 55, and 60 from 16 non-Hispanic males who had documented lifespans from 58 to 92. Numerous miRNAs showed significant changes in expression levels. At age 50, 24 miRNAs were significantly upregulated, and 73 were significantly downregulated in the long-lived subgroup (76-92 years) as compared with the short-lived subgroup (58-75 years). In long-lived participants, the most upregulated was miR-373-5p, while the most downregulated was miR-15b-5p. Longitudinally, significant Pearson correlations were observed between lifespan and expression of nine miRNAs (p value<0.05). Six of these nine miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) were also significantly up- or downregulated when comparing long-lived and short-lived participants. Twenty-four validated targets of these miRNAs encoded aging-associated proteins, including PARP1, IGF1R, and IGF2R. We propose that the expression profiles of the six miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, and 1225-3p) may be useful biomarkers of aging. C1 [Smith-Vikos, Thalyana; Slack, Frank J.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. [Liu, Zuyun; Gill, Thomas M.] Yale Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Parsons, Christine] Bowdoin Coll, Brunswick, ME 04011 USA. [Gorospe, Myriam; Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Slack, Frank J.] Harvard Med Sch, Dept Pathol, Beth Israel Deaconess Med Ctr, Inst RNA Med, Boston, MA 02215 USA. [Smith-Vikos, Thalyana] Columbia Univ, Grad Sch Arts & Sci, New York, NY 10027 USA. RP Slack, FJ (reprint author), Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.; Slack, FJ (reprint author), Harvard Med Sch, Dept Pathol, Beth Israel Deaconess Med Ctr, Inst RNA Med, Boston, MA 02215 USA. EM fslack@bidmc.harvard.edu FU NIH [AG033921]; Claude D. Pepper Older Americans Independence Center [P30AG021342]; Academic Leadership Award from the National Institute on Aging [K07AG3587] FX This research was supported by a grant to Dr. Slack from the NIH (AG033921) and by the Claude D. Pepper Older Americans Independence Center (P30AG021342). Dr. Gill is the recipient of an Academic Leadership Award (K07AG3587) from the National Institute on Aging. NR 43 TC 1 Z9 1 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2016 VL 8 IS 11 BP 2971 EP 2987 DI 10.18632/aging.101106 PG 17 WC Cell Biology SC Cell Biology GA EF4PA UT WOS:000390311900028 PM 27824314 ER PT J AU Gong, Y Shao, Z Fu, ZJ Edin, ML Sun, Y Liegl, RG Wang, ZX Liu, CH Burnim, SB Meng, SS Lih, FB SanGiovanni, JP Zeldin, DC Hellstrom, A Smith, LEH AF Gong, Yan Shao, Zhuo Fu, Zhongjie Edin, Matthew L. Sun, Ye Liegl, Raffael G. Wang, Zhongxiao Liu, Chi-Hsiu Burnim, Samuel B. Meng, Steven S. Lih, Fred B. SanGiovanni, John Paul Zeldin, Darryl C. Hellstrom, Ann Smith, Lois E. H. TI Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis SO EBIOMEDICINE LA English DT Article DE Fenofibrate; Choroidal neovascularization; Retinopathy; Retinal neovascularization; Cytochrome P450 epoxygenase 2C; Omega-3 long-chain polyunsaturated fatty acids ID POLYUNSATURATED FATTY-ACIDS; ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED CONTROLLED-TRIAL; OXYGEN-INDUCED RETINOPATHY; DIABETIC-RETINOPATHY; PPAR-ALPHA; CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; MOUSE; METABOLITES AB Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)alpha agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP) 2C with higher affinity than to PPAR alpha. CYP2C metabolizes omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). While omega-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both omega-3 and omega-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C omega-3 LCPUFA (and omega-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPAR alpha-/-mice and augmented omega-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic.-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPAR alpha. Fenofibrate augmented the overall protective effects of omega-3 LCPUFAs on neovascular eye diseases. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://reativecommons.org/licenses/by-nc-nd/4.0/). C1 [Gong, Yan; Shao, Zhuo; Fu, Zhongjie; Sun, Ye; Liegl, Raffael G.; Wang, Zhongxiao; Liu, Chi-Hsiu; Burnim, Samuel B.; Meng, Steven S.; Smith, Lois E. H.] Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 01248 USA. [Edin, Matthew L.; Lih, Fred B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [SanGiovanni, John Paul] NIAAA, Sect Nutrit Neurosci, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD 20892 USA. [Hellstrom, Ann] Univ Gothenburg, Sahlgrenska Acad, Dept Ophthalmol, S-40530 Gothenburg, Sweden. RP Smith, LEH (reprint author), 300 Longwood Ave, Boston, MA 02115 USA. EM lois.smith@childrens.harvard.edu FU NEI NIH HHS [R24 EY024864]; NICHD NIH HHS [U54 HD090255] NR 61 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD NOV PY 2016 VL 13 BP 201 EP 211 DI 10.1016/j.ebiom.2016.09.025 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EG0EU UT WOS:000390704800035 PM 27720395 ER PT J AU Gonzalez, NL O'Brien, KM D'Aloisio, AA Sandler, DP Weinberg, CR AF Gonzalez, Nicole L. O'Brien, Katie M. D'Aloisio, Aimee A. Sandler, Dale P. Weinberg, Clarice R. TI Douching, Talc Use, and Risk of Ovarian Cancer SO EPIDEMIOLOGY LA English DT Article ID EXPOSURE; WOMEN; METAANALYSIS; PHTHALATE; HEALTH; STATES; CELL AB Background: Douching was recently reported to be associated with elevated levels of urinary metabolites of endocrine disrupting phthalates, but there is no literature on douching in relation to ovarian cancer. Numerous case-control studies of genital talc use have reported an increased risk of ovarian cancer, but prospective cohort studies have not uniformly confirmed this association. Behavioral correlation between talc use and douching could produce confounding. Methods: The Sister Study (2003-2009) enrolled and followed 50,884 women in the US and Puerto Rico who had a sister diagnosed with breast cancer. At baseline, participants were asked about douching and talc use during the previous 12 months. During follow-up (median of 6.6 years), 154 participants reported a diagnosis of ovarian cancer. We computed adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer risk using the Cox proportional hazards model. Results: There was little association between baseline perineal talc use and subsequent ovarian cancer (HR: 0.73, CI: 0.44, 1.2). Douching was more common among talc users (odds ratio: 2.1, CI: 2.0, 2.3), and douching at baseline was associated with increased subsequent risk of ovarian cancer (HR: 1.8, CI: 1.2, 2.8). Conclusions: Douching but not talc use was associated with increased risk of ovarian cancer in the Sister Study. C1 [Gonzalez, Nicole L.; O'Brien, Katie M.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [D'Aloisio, Aimee A.] Social & Sci Syst Inc, Durham, NC USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov OI O'Brien, Katie/0000-0002-1931-1349; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES044005] FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Project Z01-ES044005 to DPS). NR 26 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2016 VL 27 IS 6 BP 797 EP 802 DI 10.1097/EDE.0000000000000528 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3UZ UT WOS:000390251500007 PM 27327020 ER PT J AU Radin, RG Mikkelsen, EM Rothman, KJ Hatch, EE Sorensen, HT Riis, AH Kuohung, W Wise, LA AF Radin, Rose G. Mikkelsen, Ellen M. Rothman, Kenneth J. Hatch, Elizabeth E. Sorensen, Henrik T. Riis, Anders H. Kuohung, Wendy Wise, Lauren A. TI Cesarean Delivery and Subsequent Fecundability SO EPIDEMIOLOGY LA English DT Article ID PRIMARY-MODE; LIVE BIRTH; 1ST BIRTH; SECTION; FERTILITY; PREGNANCY; COHORT; REGISTER; IMPACT; WOMEN AB Background: Studies have shown that cesarean delivery is associated with fewer subsequent births relative to vaginal delivery, but it is unclear whether confounding by pregnancy intention or indication for surgery explained these results. We evaluated the association between cesarean delivery and subsequent fecundability among 910 primiparous women after singleton live birth. Methods: In a cohort of Danish women planning pregnancy (2007-2012), obstetrical history was obtained via registry linkage; time-to-pregnancy and covariate data were collected via questionnaire. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were adjusted for potential confounders. Results: Relative to spontaneous vaginal delivery, emergency cesarean delivery with cephalic presentation showed little association with fecundability (FR = 1.0, 95% CI = 0.83, 1.3), but cesarean delivery with breech presentation (FR = 0.72, 95% CI = 0.53, 0.97) and planned cesarean delivery with cephalic presentation (FR = 0.51, 95% CI = 0.25, 1.0) were associated with reduced fecundability. Conclusions: The cesarean-fecundability association varied by previous fetal presentation and emergency status. C1 [Radin, Rose G.; Rothman, Kenneth J.; Hatch, Elizabeth E.; Wise, Lauren A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. [Radin, Rose G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Mikkelsen, Ellen M.; Sorensen, Henrik T.; Riis, Anders H.] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. [Rothman, Kenneth J.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Kuohung, Wendy] Boston Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA 02118 USA. RP Radin, RG (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. EM radin@bu.edu FU National Institutes of Health (NIH) [R21-HD050264]; Danish Medical Research Council [271-07-0338]; NIH [T32-HD052458]; NIH Intramural Research Program FX This study was supported by the National Institutes of Health (NIH) (R21-HD050264) and the Danish Medical Research Council (271-07-0338). Rose Radin was supported by NIH Training Grant T32-HD052458 and by the NIH Intramural Research Program. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 40 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2016 VL 27 IS 6 BP 889 EP 893 DI 10.1097/EDE.0000000000000553 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3UZ UT WOS:000390251500019 PM 27571458 ER PT J AU Turkbey, B Choyke, PL AF Turkbey, Baris Choyke, Peter L. TI Prostate cancer imaging: a special focus issue from Future Oncology SO FUTURE ONCOLOGY LA English DT Editorial Material DE imaging; multi-parametric MRI; prostate cancer C1 [Turkbey, Baris; Choyke, Peter L.] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. EM ismail.turkbey@nih.gov NR 9 TC 0 Z9 0 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD NOV PY 2016 VL 12 IS 21 BP 2389 EP 2391 DI 10.2217/fon-2016-0396 PG 3 WC Oncology SC Oncology GA DZ8PG UT WOS:000386132500001 PM 27734724 ER PT J AU Watson, MJ George, AK Maruf, M Frye, TP Muthigi, A Kongnyuy, M Valayil, SG Pinto, PA AF Watson, Matthew J. George, Arvin K. Maruf, Mahir Frye, Thomas P. Muthigi, Akhil Kongnyuy, Michael Valayil, Subin G. Pinto, Peter A. TI Risk stratification of prostate cancer: integrating multiparametric MRI, nomograms and biomarkers SO FUTURE ONCOLOGY LA English DT Review DE biomarkers; multiparametric MRI; nomograms; prostate; prostate cancer ID SEMINAL-VESICLE INVASION; PREDICTING EXTRACAPSULAR EXTENSION; RESONANCE-ULTRASOUND FUSION; IMAGE-GUIDED BIOPSY; PELVIC LYMPH-NODES; RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; ACTIVE SURVEILLANCE; PARTIN TABLES; PATHOLOGICAL STAGE AB Accurate risk stratification of prostate cancer is achieved with a number of existing tools to ensure the identification of at-risk patients, characterization of disease aggressiveness, prediction of cancer burden and extrapolation of treatment outcomes for appropriate management of the disease. Statistical tables and nomograms using classic clinicopathological variables have long been the standard of care. However, the introduction of multiparametric MRI, along with fusion-guided targeted prostate biopsy and novel biomarkers, are being assimilated into clinical practice. The majority of studies to date present the outcomes of each in isolation. The current review offers a critical and objective assessment regarding the integration of multiparametric MRI and fusion-guided prostate biopsy with novel biomarkers and predictive nomograms in contemporary clinical practice. C1 [Watson, Matthew J.; George, Arvin K.; Maruf, Mahir; Frye, Thomas P.; Muthigi, Akhil; Kongnyuy, Michael; Valayil, Subin G.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Center for Interventional Oncology; NIH FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr and Mrs Joel S Marcus and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 123 TC 2 Z9 2 U1 3 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD NOV PY 2016 VL 12 IS 21 BP 2417 EP 2430 DI 10.2217/fon-2016-0178 PG 14 WC Oncology SC Oncology GA DZ8PG UT WOS:000386132500005 PM 27400645 ER PT J AU Mertan, FV Lindenberg, L Choyke, PL Turkbey, B AF Mertan, Francesca V. Lindenberg, Liza Choyke, Peter L. Turkbey, Baris TI PET imaging of recurrent and metastatic prostate cancer with novel tracers SO FUTURE ONCOLOGY LA English DT Review DE biochemical recurrence; PET; prostate cancer ID GA-68-LABELED PSMA LIGAND; POSITRON-EMISSION-TOMOGRAPHY; FATTY-ACID SYNTHASE; C-11-CHOLINE PET/CT; BONE METASTASES; BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; MEMBRANE ANTIGEN; ANTI-1-AMINO-3-F-18-FLUOROCYCLOBUTANE-1-CARBOXYLIC ACID; F-18-FLUOROCHOLINE PET/CT AB Early detection of recurrent prostate cancer (PCa) is of paramount importance to deliver prompt and accurate therapy reducing the chance of progression to metastatic disease. However, current imaging modalities such as conventional computed tomography, MRI and PET scanning do not provide sufficient sensitivity, especially at lower prostate-specific antigen values. Moreover, biological characterization of PCa has become increasingly important to provide patient-specific therapy and current imaging poorly characterizes disease aggressiveness. The current uprise of novel PET tracers in recurrent and metastatic PCa shows promising, yet variable sensitivities and specificities in detection, indicating the need for further studies. In this review, we highlight current and new PET tracers that have been developed to improve the detection of recurrent and metastatic PCa. C1 [Mertan, Francesca V.; Lindenberg, Liza; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 82 TC 1 Z9 1 U1 3 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD NOV PY 2016 VL 12 IS 21 BP 2463 EP 2477 DI 10.2217/fon-2016-0270 PG 15 WC Oncology SC Oncology GA DZ8PG UT WOS:000386132500008 PM 27527923 ER PT J AU Switzer, GE Bruce, J Kiefer, DM Kobusingye, H Drexler, R Besser, RM Confer, DL Horowitz, MM King, RJ Shaw, BE van Walraven, SM Wiener, L Packman, W Varni, JW Pulsipher, MA AF Switzer, Galen E. Bruce, Jessica Kiefer, Deidre M. Kobusingye, Hati Drexler, Rebecca Besser, RaeAnne M. Confer, Dennis L. Horowitz, Mary M. King, Roberta J. Shaw, Bronwen E. van Walraven, Suzanna M. Wiener, Lori Packman, Wendy Varni, James W. Pulsipher, Michael A. TI Health-Related Quality of Life among Pediatric Hematopoietic Stem Cell Donors SO JOURNAL OF PEDIATRICS LA English DT Article ID BONE-MARROW DONATION; SIBLING DONOR; THE-LITERATURE; EXPERIENCE; TRANSPLANTATION; PEDSQL(TM)-4.0; RELIABILITY; VALIDITY; HARVEST; SAFETY AB Objectives To examine health-related quality of life (HRQoL) among sibling pediatric hematopoietic stem cell donors from predonation through 1 year postdonation, to compare donor-reported HRQoL scores with proxy-reports by parents/guardians and those of healthy norms, and to identify predonation factors (including donor age) potentially associated with postdonation HRQoL, to better understand the physical and psychosocial effects of pediatric hematopoietic stem cell donation. Study design A random sample of 105 pediatric donors from US centers and a parent/guardian were interviewed by telephone predonation and 4 weeks and 1 year postdonation. The interview included sociodemographic, psychosocial, and HRQoL items. A sample of healthy controls matched to donors by age, gender, and race/ethnicity was generated. Results Key findings included (1) approximately 20% of donors at each time point had very poor HRQoL; (2) child self-reported HRQoL was significantly lower than parent proxy-reported HRQoL at all 3 time points and significantly lower than that of norms at predonation and 4 weeks postdonation; and (3) younger children were at particular risk of poor HRQoL. Conclusions Additional research to identify the specific sources of poorer HRQoL among at-risk donors (eg, the donation experience vs having a chronically ill sibling) and the reasons that parents may be overestimating HRQoL in their donor children is critical and should lead to interventions and policy changes that ensure positive experiences for these minor donors. C1 [Switzer, Galen E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Switzer, Galen E.; Bruce, Jessica] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Switzer, Galen E.] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA USA. [Switzer, Galen E.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Kiefer, Deidre M.; Kobusingye, Hati; Drexler, Rebecca; Besser, RaeAnne M.; Confer, Dennis L.; King, Roberta J.] Natl Marrow Donor Program Be Match, Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Horowitz, Mary M.; Shaw, Bronwen E.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [van Walraven, Suzanna M.] Sanquin Blood Supply, Dept Donor Serv, Amsterdam, Netherlands. [van Walraven, Suzanna M.] Leiden Univ, Med Ctr, Dept Pediat Stem Cell Transplantat, Willem Alexander Childrens Hosp, Leiden, Netherlands. [Wiener, Lori] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Packman, Wendy] Palo Alto Univ, Dept Psychol, Palo Alto, CA USA. [Varni, James W.] Texas A&M Univ, Dept Pediat, College Stn, TX USA. [Varni, James W.] Texas A&M Univ, Ctr Hlth Syst & Design, Dept Landscape Architecture & Urban Planning, College Stn, TX USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Div Hematol Oncol & Bone Marrow Transplantat, Los Angeles, CA 90027 USA. RP Switzer, GE (reprint author), Univ Pittsburgh, 3501 Forbes Ave,Oxford Bldg,Suite 410, Pittsburgh, PA 15213 USA. EM SwitzerGE@upmc.edu FU National Heart, Lung, and Blood Institute [R01 HL085707]; Mapi Research Trust FX Supported by the National Heart, Lung, and Blood Institute (R01 HL085707). J.V. holds the copyright and the trademark for the Pediatric Quality of Life Inventory and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory. The other authors declare no conflicts of interest. NR 27 TC 1 Z9 1 U1 4 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2016 VL 178 BP 164 EP + DI 10.1016/j.jpeds.2016.07.009 PG 8 WC Pediatrics SC Pediatrics GA EF0ON UT WOS:000390025400031 PM 27522440 ER PT J AU Sindhar, S Lugo, M Levin, MD Danback, JR Brink, BD Yu, E Dietzen, DJ Clark, AL Purgert, CA Waxler, JL Elder, RW Pober, BR Kozel, BA AF Sindhar, Sampat Lugo, Michael Levin, Mark D. Danback, Joshua R. Brink, Benjamin D. Yu, Eric Dietzen, Dennis J. Clark, Amy L. Purgert, Carolyn A. Waxler, Jessica L. Elder, Robert W. Pober, Barbara R. Kozel, Beth A. TI Hypercalcemia in Patients with Williams-Beuren Syndrome SO JOURNAL OF PEDIATRICS LA English DT Article ID INFANTILE HYPERCALCEMIA; VITAMIN-D; CALCIUM; PAMIDRONATE; CHROMOSOME-7; MANAGEMENT; DIAGNOSIS; DELETIONS; INFUSION; ADULTS AB Objective To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome ( WBS) through a multicenter retrospective study. Study design Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. Results On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. Conclusions Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis. C1 [Sindhar, Sampat; Lugo, Michael; Danback, Joshua R.; Dietzen, Dennis J.; Clark, Amy L.; Purgert, Carolyn A.; Kozel, Beth A.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Levin, Mark D.; Kozel, Beth A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Brink, Benjamin D.; Yu, Eric; Pober, Barbara R.] Quinnipiac Univ, Frank H Netter Sch Med, North Haven, CT USA. [Waxler, Jessica L.; Pober, Barbara R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Elder, Robert W.] Yale Univ, Sch Med, Dept Pediat, Sect Cardiol, New Haven, CT 06510 USA. [Elder, Robert W.] Yale Univ, Sch Med, Dept Internal Med, Sect Cardiol, New Haven, CT 06510 USA. [Pober, Barbara R.] Harvard Med Sch, Boston, MA USA. RP Kozel, BA (reprint author), NHLBI, Bldg 10,8N-110, Bethesda, MD 20892 USA. EM beth.kozel@nih.gov FU Children's Discovery Institute (Washington University School of Medicine/St. Louis Children's Hospital) [CH-FR-2011-169]; Division of Intramural Research of the National Heart, Lung, and Blood Institute; National Institutes of Health [T32HD043010, T35DK074375] FX Funded by the Children's Discovery Institute (CH-FR-2011-169 at Washington University School of Medicine/St. Louis Children's Hospital [to B.K.]) and the Division of Intramural Research of the National Heart, Lung, and Blood Institute. A.C. is supported by the National Institutes of Health (T32HD043010). S.S. was supported by the National Institutes of Health (T35DK074375). The authors declare no conflicts of interest. NR 35 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2016 VL 178 BP 254 EP + DI 10.1016/j.jpeds.2016.08.027 PG 11 WC Pediatrics SC Pediatrics GA EF0ON UT WOS:000390025400045 PM 27574996 ER PT J AU Tamburro, RF Jenkins, TL Kochanek, PM AF Tamburro, Robert F. Jenkins, Tammara L. Kochanek, Patrick M. TI Strategic Planning for Research in Pediatric Critical Care SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE mortality; multiple organ dysfunction syndrome; pediatric critical care medicine; pediatrics; research ID ORGAN DYSFUNCTION SYNDROME; INTENSIVE-CARE; MORTALITY; CHILDREN AB Objective: To summarize the scientific priorities and potential future research directions for pediatric critical care research discussed by a panel of experts at the inaugural Strategic Planning Conference of the Pediatric Trauma and Critical Illness Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Data Sources: Expert opinion expressed during the Strategic Planning Conference. Study Selection: Not applicable. Data Extraction: Chaired by an experienced expert from the field, issues relevant to the conduct of pediatric critical care research were discussed and debated by the invited participants. Data Synthesis: Common themes and suggested priorities were identified and coalesced. Conclusions: Of the many pathophysiologic conditions discussed, the multiple organ dysfunction syndrome emerged as a topic in need of more study that is most relevant to the field. Additionally, the experts offered that the interrelationship and impact of critical illness on child development and family functioning are important research priorities. Consequently, long-term outcomes research was encouraged. The expert group also suggested that multidisciplinary conferences are needed to help identify key knowledge gaps to advance and direct research in the field. The Pediatric Critical Care and Trauma Scientist Development National K12 Program and the Collaborative Pediatric Critical Care Research Network were recognized as successful and important programs supported by the branch. The development of core data resources including biorepositories with robust phenotypic data using common data elements was also suggested to foster data sharing among investigators and to enhance disease diagnosis and discovery. Multicenter clinical trials and innovative study designs to address understudied and poorly understood conditions were considered important for field advancement. Finally, the growth of the pediatric critical care research workforce was offered as a priority that could be spawned in many ways including by expanded transdisciplinary and multiprofessional collaboration and diversity representation. C1 [Tamburro, Robert F.; Jenkins, Tammara L.] Eunice Kennedy Shover Natl Inst Child Hlth & Huma, Pediat Trauma & Crit Illness Branch, NIH, Bethesda, MD 20892 USA. [Kochanek, Patrick M.] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Dept Crit Care Med, Pittsburgh, PA USA. [Kochanek, Patrick M.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Safar Ctr Resuscitat Res, Pittsburgh, PA 15261 USA. [Kochanek, Patrick M.] Univ Pittsburgh, Sch Med, Dept Pediat, Safar Ctr Resuscitat Res, Pittsburgh, PA 15261 USA. [Kochanek, Patrick M.] Univ Pittsburgh, Sch Med, Dept Bioengn, Safar Ctr Resuscitat Res, Pittsburgh, PA USA. [Kochanek, Patrick M.] Univ Pittsburgh, Sch Med, Dept Clin & Translat Sci, Safar Ctr Resuscitat Res, Pittsburgh, PA USA. RP Tamburro, RF (reprint author), Eunice Kennedy Shover Natl Inst Child Hlth & Huma, Pediat Trauma & Crit Illness Branch, NIH, Bethesda, MD 20892 USA. EM robert.tamburro@nih.gov FU Springer Publishing; National Institutes of Health; U.S. Army FX Dr. Tamburro received funding from Springer Publishing and other (the calfactant used in a multicenter trial of calfactant in acute lung injury in pediatric hematopoietic stem cell transplant patients was provided free of charge) and disclosed government work. Dr. Jenkins disclosed government work. Dr. Kochanek received support for article research from the National Institutes of Health and U.S. Army. NR 16 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD NOV PY 2016 VL 17 IS 11 BP E539 EP E542 DI 10.1097/PCC.0000000000000946 PG 4 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA EF2ES UT WOS:000390138100007 PM 27679964 ER PT J AU Guy, GP Berkowitz, Z Ekwueme, DU Rim, SH Yabroff, KR AF Guy, Gery P., Jr. Berkowitz, Zahava Ekwueme, Donatus U. Rim, Sun Hee Yabroff, K. Robin TI Annual Economic Burden of Productivity Losses Among Adult Survivors of Childhood Cancers SO PEDIATRICS LA English DT Article ID HEALTH-INSURANCE COVERAGE; AFFORDABLE CARE ACT; UNITED-STATES; COHORT; AGREEMENT; OUTCOMES AB BACKGROUND AND OBJECTIVES: Although adult survivors of childhood cancers have poorer health and greater health limitations than other adults, substantial gaps remain in understanding the economic consequences of surviving childhood cancer. Therefore, we estimated the economic burden of productivity losses among adult survivors of childhood cancers. METHODS: We examined health status, functional limitations, and productivity loss among adult survivors of childhood cancers (n = 239) diagnosed at = 14 years of age compared with adults without a history of cancer (n = 304 265) by using the 2004-2014 National Health Interview Survey. We estimated economic burden using the productivity loss from health-related unemployment, missed work days, missed household productivity, and multivariable regression models controlling for age, sex, race/ethnicity, education, comorbidities, and survey year. RESULTS: Childhood cancer survivorship is associated with a substantial economic burden. Adult survivors of childhood cancers are more likely to be in poorer health, need assistance with personal care and routine needs, have work limitations, be unable to work because of health, miss more days of work, and have greater household productivity loss compared with adults without a history of cancer (all P < .05). The annual productivity loss for adult survivors of childhood cancer is $8169 per person compared with $3083 per person for individuals without a history of cancer. CONCLUSIONS: These findings underscore the importance of efforts to reduce the health and economic burden among adult survivors of childhood cancer. In addition, this study highlights the potential productivity losses that could be avoided during adulthood from the prevention of childhood cancer in the United States. C1 [Guy, Gery P., Jr.; Berkowitz, Zahava; Ekwueme, Donatus U.; Rim, Sun Hee] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA USA. [Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Guy, GP (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Hwy NE,MS F-76, Chamblee, GA 30341 USA. EM irm2@cdc.gov FU US Government FX All authors are federal government employees, and the preparation of the manuscript was entirely funded by the US Government. NR 34 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2016 VL 138 SU 1 BP S15 EP S21 DI 10.1542/peds.2015-4268D PG 7 WC Pediatrics SC Pediatrics GA EE2LA UT WOS:000389414300003 PM 27940973 ER PT J AU Troisi, R Hatch, EE Titus, L AF Troisi, Rebecca Hatch, Elizabeth E. Titus, Linda TI The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy SO PEDIATRICS LA English DT Article ID EXPOSED IN-UTERO; CANCER RISK; WOMEN; DES; ADENOCARCINOMA; VAGINA AB Although the basic tenet of medicine is "First, do no harm," history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself. In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population's level of risk, the morbidity and/or mortality associated with the disease, and the intervention's efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness. Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for " routine C1 [Troisi, Rebecca] NCI, Epidemiol & Biostat Program, Div Epidemiol & Genet, NIH,US Dept HHS, Rockville, MD USA. [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Titus, Linda] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Titus, Linda] Hood Ctr Children & Families, Lebanon, NH USA. RP Troisi, R (reprint author), NCI, Epidemiol & Biostat Program, Off Director, Div Epidemiol & Genet, 9609-7E578,9609 Med Ctr Dr, Rockville, MD 20850 USA. EM troisir@mail.nih.gov FU National Institutes of Health (NIH) FX Dr. Troisi is an intramural investigator at the National Institutes of Health. The research upon which this editorial is based was performed using intramural research funds. Funded by the National Institutes of Health (NIH). NR 12 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2016 VL 138 SU 1 BP S42 EP S44 DI 10.1542/peds.2015-4268G PG 3 WC Pediatrics SC Pediatrics GA EE2LA UT WOS:000389414300006 PM 27940976 ER PT J AU Talbot, JN Geffert, LM Jorvig, JE Goldstein, RI Nielsen, CL Wolters, NE Amos, ME Munro, CA Dallman, E Mereu, M Tanda, G Katz, JL Indarte, M Madura, JD Choi, H Leak, RK Surratt, CK AF Talbot, Jeffery N. Geffert, Laura M. Jorvig, Jessica E. Goldstein, Ruben I. Nielsen, Cienna L. Wolters, Nicholas E. Amos, Mary Ellen Munro, Caitlin A. Dallman, Elizabeth Mereu, Maddalena Tanda, Gianluigi Katz, Jonathan L. Indarte, Martin Madura, Jeffry D. Choi, Hailey Leak, Rehana K. Surratt, Christopher K. TI Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Virtual screen; Monoamine transporter; Ro-25-6981; Ketamine; Serotonin selective reuptake inhibitor; Antidepressant ID FORCED SWIM TEST; RESISTANT MAJOR DEPRESSION; D-ASPARTATE ANTAGONIST; BINDING-SITE; NEUROTRANSMITTER TRANSPORTERS; SEROTONIN TRANSPORTER; SUBSTRATE-BINDING; NR2B SUBUNIT; KETAMINE; DOPAMINE AB Rational design of lead compounds targeting monoamine transporters (MATS) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecule library for high DAT affinity drug-like compounds. One hit, coded "MI-4", inhibited human dopamine, norepinephrine, and serotonin transporters invitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21 day, 10 mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10 mg/kg, bid) in the novelty-induced hypophagia test, which requires chronic treatment to produce antidepressant-like effects. MI-4 (10 mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social avoidance test following 10 days of social defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold. (C) 2016 Elsevier Inc. All rights reserved. C1 [Talbot, Jeffery N.; Jorvig, Jessica E.; Goldstein, Ruben I.] Roseman Univ Hlth Sci, Coll Pharm, Res Ctr Subst Abuse & Depress, 11 Sunset Way, Henderson, NV 89014 USA. [Geffert, Laura M.; Choi, Hailey; Leak, Rehana K.; Surratt, Christopher K.] Duquesne Univ, Mylan Sch Pharm, Div Pharmaceut Sci, 600 Forbes Ave, Pittsburgh, PA 15282 USA. [Nielsen, Cienna L.] Touro Univ Nevada, Dept Basic Sci, 874 Amer Pacific Dr, Henderson, NV 89014 USA. [Wolters, Nicholas E.; Amos, Mary Ellen; Munro, Caitlin A.; Dallman, Elizabeth] Ohio Northern Univ, Raabe Coll Pharm, 525 S Main St, Ada, OH 45810 USA. [Mereu, Maddalena; Tanda, Gianluigi; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Indarte, Martin] Phusis Therapeut Inc, 3210 Mertyfield Row, San Diego, CA 92121 USA. [Madura, Jeffry D.] Duquesne Univ, Ctr Computat Sci, Dept Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. [Madura, Jeffry D.] Duquesne Univ, Ctr Computat Sci, Dept Biochem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. RP Talbot, JN (reprint author), Roseman Univ Hlth Sci, Coll Pharm, Res Ctr Subst Abuse & Depress, 11 Sunset Way, Henderson, NV 89014 USA.; Surratt, CK (reprint author), Duquesne Univ, 437 Mellon Hall,600 Forbes Ave, Pittsburgh, PA 15219 USA. EM jtalbot@roseman.edu; surratt@duq.edu RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU NIDA [R01DA026530, R01DA027806]; U.S. Department of Education [P116Z050331, P116Z080180]; Bower Bennett Bennett Foundation; Intramural Research Program of the National Institute on Drug Abuse FX The authors declare no conflicts of interest regarding the work described herein. This work was supported by NIDA grants R01DA026530 and R01DA027806, U.S. Department of Education grants P116Z050331 and P116Z080180, the Bower Bennett Bennett Foundation, and the Intramural Research Program of the National Institute on Drug Abuse. NR 62 TC 0 Z9 0 U1 2 U2 2 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 NOV-DEC PY 2016 VL 150 BP 22 EP 30 DI 10.1016/j.pbb.2016.08.007 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EF1KU UT WOS:000390084500004 PM 27569602 ER PT J AU Bouchelouche, K Turkbey, B Choyke, PL AF Bouchelouche, Kirsten Turkbey, Baris Choyke, Peter L. TI PSMA PET and Radionuclide Therapy in Prostate Cancer SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; MONOCLONAL-ANTIBODY J591; LYMPH-NODE DISSECTION; PSA DOUBLING TIME; MEMBRANE ANTIGEN-EXPRESSION; OF-THE-LITERATURE; PHASE-I TRIAL; RADICAL PROSTATECTOMY; HIGH-RISK; BIOCHEMICAL RECURRENCE AB Prostate cancer (PCa) is the most common malignancy in men and a major cause of cancer death. Accurate imaging plays an important role in diagnosis, staging, restaging, detection of biochemical recurrence, and for therapy of patients with PCa. Because no effective treatment is available for advanced PCa, there is an urgent need to develop new and more effective therapeutic strategies. To optimize treatment outcome, especially in high-risk patients with PCa, therapy for PCa is moving rapidly toward personalization. Medical imaging, including positron emission tomography (PET)/computed tomography (CD, plays an important role in personalized medicine in oncology. In the recent years, much focus has been on prostate specific membrane antigen (PSMA) as a promising target for imaging and therapy with radionuclides, as it is upregulated in most PCa. In the prostate, one potential role for PSMA PET imaging is to help guide focal therapy. Several studies have shown great potential of PSMA PET/CT for initial staging, lymph node staging, and detection of recurrence of PCa, even at very low prostate-specific antigen values after primary therapy. Furthermore, studies have shown that PSMA PET/CT has a higher detection rate than choline PET/CT. Radiolabeled PSMA ligands for therapy show promise in several studies with metastatic PCa and is an area of active investigation. The "image and treat" strategy, with radiolabeled PSMA ligands, has the potential to improve the treatment outcome of patients with PCa and is paving the way for precision medicine in PCa. The aim of this review is to give an overview of recent advancement in PSMA PET and radionuclide therapy for PCa. Published by Elsevier Inc. C1 [Bouchelouche, Kirsten] Aarhus Univ Hosp, Dept Nucl Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus, Denmark. [Bouchelouche, Kirsten] Aarhus Univ Hosp, PET Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus, Denmark. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bouchelouche, K (reprint author), Aarhus Univ Hosp, Dept Nucl Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus, Denmark.; Bouchelouche, K (reprint author), Aarhus Univ Hosp, PET Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus, Denmark. EM kirsbouc@rm.dk FU Intramural Program of the National Cancer Institute FX Peter Choyke and Baris Turkbey received support from the Intramural Program of the National Cancer Institute. NR 111 TC 1 Z9 1 U1 2 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 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD NOV PY 2016 VL 46 IS 6 BP 522 EP 535 DI 10.1053/j.semnuclmed.2016.07.006 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF1IX UT WOS:000390079600008 PM 27825432 ER PT J AU Lindenberg, L Ahlman, M Turkbey, B Mena, E Choyke, P AF Lindenberg, Liza Ahlman, Mark Turkbey, Baris Mena, Esther Choyke, Peter TI Advancement of MR and PET/MR in Prostate Cancer SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID SEMINAL-VESICLE INVASION; PLANAR BONE-SCINTIGRAPHY; INTEGRATED WHOLE-BODY; FUSION-GUIDED BIOPSY; EXTRACAPSULAR EXTENSION; INITIAL-EXPERIENCE; CHOLINE-PET/CT; METASTASES; METAANALYSIS; DIAGNOSIS AB Multiparametric magnetic resonance (mpMRI) imaging has assumed a larger role in the diagnosis and management of prostate cancer. The current method of detecting prostate cancer relies on blind systematic biopsy, guided only by transrectal ultrasound that generally directs the needle biopsy to sextants of the prostate rather than specific lesions. MpMRI is playing an increasing role in the detection of primary cancer as it can visualize cancers and direct biopsies. However, even mpMRI is inherently nonspecific and numerous biopsies performed under MR guidance prove to be negative. Positron emission tomography (PET) has the potential to improve the sensitivity and specificity for prostate cancer in combination with mpMRI. Prostate-specific membrane antigen is a widely expressed tumor antigen in prostate cancer for which multiple PET ligands, labeled with Ga-68 and F-18, are being developed. However, the low spatial resolution of PET mandates that it be combined with a higher resolution imaging modality, which typically has been computed tomography (CD. However, MRI is not only better at localizing lesions in the prostate and prostatic bed, but it is also more sensitive than CT for early bone marrow changes in bone metastases caused by prostate cancer. Prostate-specific membrane antigen based PET agents show promise in the early detection of recurrent and metastatic disease. Recent developments in hybrid imaging now allow PET/MRI to be performed simultaneously on a single scanner allowing one-to-one correspondence between the PET activity and MRI findings. This offers the opportunity for both high sensitivity and specificity with excellent anatomic location and could allow for more targeted biopsies and treatments. Here, we review the current status of PET/MRI for prostate cancer. (C) 2016 Published by Elsevier Inc. C1 [Lindenberg, Liza; Turkbey, Baris; Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ahlman, Mark] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Mena, Esther] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. RP Choyke, P (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Rm B3B69F,10 Ctr Dr, Bethesda, MD 20892 USA. EM pchoyke@nih.gov NR 49 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD NOV PY 2016 VL 46 IS 6 BP 536 EP 543 DI 10.10536/j.semnuclmed.2016.07.001 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF1IX UT WOS:000390079600009 PM 27825433 ER PT J AU Wright, TE Terplan, M Ondersma, SJ Boyce, C Yonkers, K Chang, G Creanga, AA AF Wright, Tricia E. Terplan, Mishka Ondersma, Steven J. Boyce, Cheryl Yonkers, Kimberly Chang, Grace Creanga, Andreea A. TI The role of screening, brief intervention, and referral to treatment in the perinatal period SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE alcohol; brief intervention; opioid use; pregnancy; referral to treatment; screening; substance use disorders; tobacco ID ILLICIT DRUG-USE; SUBSTANCE-USE; ALCOHOL-USE; PREGNANT-WOMEN; RANDOMIZED-TRIAL; MECONIUM ANALYSIS; POSTPARTUM WOMEN; CLINICAL CARE; UNITED-STATES; ABUSE AB Substance use during pregnancy is at least as common as many of the medical conditions screened for and managed during pregnancy. While harmful and costly, it is often ignored or managed poorly. Screening, brief intervention, and referral to treatment is an evidence-based approach to manage substance use. In September 2012, the US Centers for Disease Control and Prevention convened an Expert Meeting on Perinatal Illicit Drug Abuse to help address key issues around drug use in pregnancy in the United States. This article reflects the formal conclusions of the expert panel that discussed the use of screening, brief intervention, and referral to treatment during pregnancy. Screening for substance use during pregnancy should be universal. It allows stratification of women into zones of risk given their pattern of use. Low-risk women should receive brief advice, those classified as moderate risk should receive a brief intervention, whereas those who are high risk need referral to specialty care. A brief intervention is a patient-centered form of counseling using the principles of motivational interviewing. Screening, brief intervention, and referral to treatment has the potential to reduce the burden of substance use in pregnancy and should be integrated into prenatal care. C1 [Wright, Tricia E.] Univ Hawaii, John A Burns Sch Med, Dept Obstet Gynecol & Womens Hlth, Honolulu, HI 96822 USA. [Wright, Tricia E.] Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. [Terplan, Mishka] Behav Hlth Syst, Baltimore, MD USA. [Ondersma, Steven J.] Wayne State Univ, Merrill Palmer Skillman Inst, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Ondersma, Steven J.] Wayne State Univ, Merrill Palmer Skillman Inst, Dept Obstet & Gynecol, Detroit, MI USA. [Boyce, Cheryl] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Yonkers, Kimberly] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Yonkers, Kimberly] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. [Yonkers, Kimberly] Yale Univ, Sch Med, Sch Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Chang, Grace] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Chang, Grace] Boston Healthcare Syst, Dept Vet Affairs, Dept Psychiat, Brockton, MA USA. [Creanga, Andreea A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Creanga, Andreea A.] Johns Hopkins Bloomberg Sch Publ Hlth, Int Ctr Maternal & Newborn Hlth, Baltimore, MD USA. [Creanga, Andreea A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Wright, TE (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Obstet Gynecol & Womens Hlth, Honolulu, HI 96822 USA.; Wright, TE (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. EM tewright@hawaii.edu NR 65 TC 3 Z9 3 U1 4 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 NOV PY 2016 VL 215 IS 5 BP 539 EP 547 DI 10.1016/j.ajog.2016.06.038 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RK UT WOS:000389513700002 PM 27373599 ER PT J AU Bernard, MA AF Bernard, M. A. TI THE STATE OF NIA BUDGET AND PLANNING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Bernard, M. A.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 471 EP 471 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002215 ER PT J AU Bernard, MA AF Bernard, M. A. TI A CONVERSATION WITH NIA SENIOR LEADERSHIP SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Bernard, M. A.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 471 EP 471 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002216 ER PT J AU Ma, J Jacques, PF Hwang, SJ Troy, LM McKeown, NM Chu, AY Fox, CS AF Ma, Jiantao Jacques, Paul F. Hwang, Shih-Jen Troy, Lisa M. McKeown, Nicola M. Chu, Audrey Y. Fox, Caroline S. TI Dietary Guideline Adherence Index and Kidney Measures in the Framingham Heart Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Dietary Guidelines for Americans Adherence Index (DGAI); meat and legumes; dairy products; estimated glomerular filtration rate (eGFR); incident low eGFR; rapid eGFR decline; renal function; kidney disease progression; modifiable risk factor; diet; Framingham Heart Study Offspring Cohort; albuminuria; urinary albumin-creatinine ratio (UACR) ID FOOD-FREQUENCY QUESTIONNAIRE; CARDIOVASCULAR-DISEASE; RENAL-FUNCTION; FUNCTION DECLINE; SWEETENED SODA; PROTEIN-INTAKE; RISK-FACTOR; ASSOCIATIONS; REPRODUCIBILITY; ALBUMINURIA AB Background: No observational studies have directly considered dietary guidelines when examining the prospective association between dietary intake and kidney measures. Study Design: Prospective cohort study. Setting & Participants: We examined participants who attended examinations 7 (1998-2001) and 8 (2005-2008) in the Framingham Offspring Cohort. Predictors: Individual components of Dietary Guidelines for Americans Adherence Index (DGAI) that reflect adherence to key dietary recommendations based on the 2005 guideline. Outcomes & Measures: The primary outcome was incident low estimated glomerular filtration rate (eGFR) at follow-up after exclusion of prevalent low eGFR at baseline. Low eGFR was defined as serum creatinine-based eGFR <60 mL/min/1.73 m(2). Results: Among 1,822 participants (mean age, 59.4 years; 54.6% women), 181 incident cases of low eGFR were identified. After adjustment for potential confounders, compared to optimal adherence to meat and legume recommendations, low adherence was associated with higher odds of incident low eGFR (P for trend = 0.01); ORs in the lowest and intermediate adherence categories were 2.98 (95% CI, 1.13-7.92) and 1.65 (95% CI, 1.02-2.66), respectively. Low adherence to dairy product recommendations was also associated with higher odds of incident low eGFR compared to optimal adherence (P for trend = 0.03); ORs in the lowest and intermediate adherence categories were 1.98 (95% CI, 1.03-3.82) and 1.59 (95% CI, 0.81-3.11), respectively. In addition, low adherence to meat and legume recommendations was associated with rapid eGFR decline (P for trend = 0.01), and low adherence to dairy product recommendations was associated with rapid eGFR decline (P for trend = 0.01) and incident albuminuria (P for trend = 0.03). Limitations: The DGAI was developed based on the 2005 Dietary Guidelines for Americans. Conclusions: Better adherence to dietary recommendations for both meat and legumes and dairy products was associated with lower risk for developing adverse kidney measures. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. C1 [Ma, Jiantao; Hwang, Shih-Jen; Chu, Audrey Y.; Fox, Caroline S.] NHLBI, Framingham Heart Study & Populat Sci Branch, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. [Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [Troy, Lisa M.] Univ Massachusetts, Dept Nutr, Amherst, MA 01003 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study & Populat Sci Branch, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NHLBI Framingham Heart Study [N01-HC-25195] FX This work was conducted in part using resources and data from the Framingham Heart Study of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) and Boston University School of Medicine. This work was supported by the NHLBI Framingham Heart Study (N01-HC-25195). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the NIH, or the US Department of Health and Human Services. NR 30 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2016 VL 68 IS 5 BP 703 EP 715 DI 10.1053/j.ajkd.2016.04.015 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA EE3QT UT WOS:000389511300010 PM 27261331 ER PT J AU Melamed, N Pittini, A Hiersch, L Yogev, Y Korzeniewski, SJ Romero, R Barrett, J AF Melamed, Nir Pittini, Alex Hiersch, Liran Yogev, Yariv Korzeniewski, Steven J. Romero, Roberto Barrett, Jon TI Do serial measurements of cervical length improve the prediction of preterm birth in asymptomatic women with twin gestations? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE biomarker; cervical ripening; cervical shortening; cervix; labor; longitudinal study; prediction; pregnancy; prematurity; preterm labor; screening; ultrasound ID RESPIRATORY-DISTRESS-SYNDROME; PARTICIPANT DATA METAANALYSIS; TRANSVAGINAL SONOGRAPHIC MEASUREMENT; ANTEPARTUM CORTICOSTEROID TREATMENT; VAGINAL MICRONIZED PROGESTERONE; RANDOMIZED CONTROLLED-TRIAL; MULTIPLE PREGNANCY PROTWIN; PLURALITY-DEPENDENT RISK; FETAL FIBRONECTIN; PROSPECTIVE MULTICENTER AB BACKGROUND: Cervical length at midtrimester is a powerful predictor of preterm birth in twin gestations. However, given the fact that, in some cases, cervical shortening may become evident only later during the second trimester, it seems reasonable that serial monitoring of cervical length may improve the detection of preterm birth in women with twins. However, data in support of such a practice are limited and conflicting. The contradictory results may be related to the fact that in most of these studies, the analysis of the predictive value of serial measurements of cervical length was limited to data derived from only two sequential measurements of cervical length, while data on the predictive value of multiple (>2) measurements are scarce. OBJECTIVE: We sought to determine whether serial measurements of cervical length can improve the prediction of preterm birth in asymptomatic women with twin gestations compared with a single measurement of cervical length at midgestation. STUDY DESIGN: This was a retrospective cohort study of women with twin pregnancies followed up in a tertiary medical center from 2012 through 2014. All participants underwent routine measurement of cervical length at midgestation and every 2-3 weeks thereafter until 2832 weeks. For each patient, cervical length was determined at the following time periods: 18+0 to 21+6 weeks (period 1, routine exam), 22+0 to 24+6 weeks (period 2), 25+0 to 27+6 weeks (period 3), and 28+0 to 32+0 weeks (period 4). Measurements of cervical length at periods 2-4 were analyzed in the form of either absolute length (in millimeters) or percent shortening relative to cervical length at period 1. The performance of a stepwise algorithm that incorporated serial measurements of cervical length for the prediction of preterm birth was compared to that achieved with a single measurement of cervical length at period 1. RESULTS: Overall, 441 women with twin pregnancies who were eligible for the study underwent a total of 2374 cervical length measurements. The association of a short cervix (<10th percentile) with preterm birth at <32 weeks persisted in each of the 4 periods of gestation [ odds ratio (95% confidence interval): 7.2 (3.1-16.5), 15.3 (6.4-36.7), 10.3 (4.4-24.3), and 23.1(8.3-64.1), respectively]. Compared with a single measurement of cervical length at midgestation (period 1), a stepwise algorithm integrating serial cervical length measurements from all 4 successive gestational age periods resulted in a significant increase in the area under the receiver operating characteristic curve (0.917 vs 0.613, P < .001). Similarly, when a target false-positive rate of 5% was used, the same stepwise algorithm was associated with a higher detection rate (69% vs 28%, P< .001), higher positive likelihood ratio (14.54 vs 5.12), and lower negative likelihood ratio (0.32 vs 0.76) for preterm birth at < 32 weeks compared with a single measurement of cervical length at period 1. CONCLUSION: Integration of serial measurements of cervical length using a stepwise algorithm in asymptomatic women with twin gestations can improve the detection of women at risk of preterm birth. Prospective studies are needed to validate these findings, and to investigate whether improved risk assessment performance is sufficient to offset the additional costs associated with serial cervical length measurements. C1 [Melamed, Nir; Pittini, Alex; Barrett, Jon] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Toronto, ON, Canada. [Hiersch, Liran; Yogev, Yariv] Tel Aviv Sourasky Med Ctr, Lis Hosp Women, Dept Obstet & Gynecol, Tel Aviv, Israel. [Korzeniewski, Steven J.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Korzeniewski, Steven J.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Korzeniewski, Steven J.; Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. RP Melamed, N (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Toronto, ON, Canada. EM nir.melamed@sunnybrook.ca FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH); Department of Health and Human Services; NICHD/NIH [HSN27520130000] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services and, in part, with federal funds from NICHD/NIH under contract no. HSN27520130000. NR 134 TC 0 Z9 0 U1 2 U2 2 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 NOV PY 2016 VL 215 IS 5 AR 616.e1-14 DI 10.1016/j.ajog.2016.06.034 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RK UT WOS:000389513700024 PM 27365003 ER PT J AU Scheraga, RG Thompson, C Tulapurkar, ME Nagarsekar, AC Cowan, M Potla, R Sun, JF Cai, RM Logun, C Shelhamer, J Todd, NW Singh, IS Luzina, IG Atamas, SP Hasday, JD AF Scheraga, Rachel G. Thompson, Christopher Tulapurkar, Mohan E. Nagarsekar, Ashish C. Cowan, Mark Potla, Ratnakar Sun, Junfeng Cai, Rongman Logun, Carolea Shelhamer, James Todd, Nevins W. Singh, Ishwar S. Luzina, Irina G. Atamas, Sergei P. Hasday, Jeffrey D. TI Activation of heat shock response augments fibroblast growth factor-1 expression in wounded lung epithelium SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE fibroblast growth factor-1; heat shock factor-1; epithelial wound healing; idiopathic pulmonary fibrosis; heat shock ID IDIOPATHIC PULMONARY-FIBROSIS; FACTOR MESSENGER-RNA; KAPPA-B-ALPHA; ACUTE EXACERBATION; PROTEIN INDUCTION; CELL-MIGRATION; A549 CELLS; HYPERTHERMIA; MECHANISMS; APOPTOSIS AB We previously showed that coincident exposure to heat shock (HS; 42 degrees C for 2 h) and TNF-alpha synergistically induces apoptosis in mouse lung epithelium. We extended this work by analyzing HS effects on human lung epithelial responses to clinically relevant injury. Cotreatment with TNF-alpha and HS induced little caspase-3 and poly(ADP-ribose) polymerase cleavage in human small airway epithelial cells, A549 cells, and BEAS2B cells. Scratch wound closure rates almost doubled when A549 and BEAS2B cells and air-liquid interface cultures of human bronchial epithelial cells were heat shocked immediately after wounding. Microarray, qRT-PCR, and immunoblotting showed fibroblast growth factor 1 (FGF1) to be synergistically induced by HS and wounding. Enhanced FGF1 expression in HS/wounded A549 was blocked by inhibitors of p38 MAPK (SB203580) or HS factor (HSF)-1 (KNK-437) and in HSF1 knockout BEAS2B cells. PCR demonstrated FGF1 to be expressed from the two most distal promoters in wounded/HS cells. Wound closure in HS A549 and BEAS2B cells was reduced by FGF receptor-1/3 inhibition (SU-5402) or FGF1 depletion. Exogenous FGF1 accelerated A549 wound closure in the absence but not presence of HS. In the presence of exogenous FGF1, HS slowed wound closure, suggesting that it increases FGF1 expression but impairs FGF1-stimulated wound closure. Frozen sections from normal and idiopathic pulmonary fibrosis (IPF) lung were analyzed for FGF1 and HSP70 by immunofluorescence confocal microscopy and qRT-PCR. FGF1 and HSP70 mRNA levels were 7.5 and 5.9-fold higher in IPF than normal lung, and the proteins colocalized to fibroblastic foci in IPF lung. We conclude that HS signaling may have an important impact on gene expression contributing to lung injury, healing, and fibrosis. C1 [Scheraga, Rachel G.; Tulapurkar, Mohan E.; Nagarsekar, Ashish C.; Cowan, Mark; Potla, Ratnakar; Todd, Nevins W.; Singh, Ishwar S.; Hasday, Jeffrey D.] Univ Maryland, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Luzina, Irina G.; Atamas, Sergei P.] Univ Maryland, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21201 USA. [Cowan, Mark; Todd, Nevins W.; Singh, Ishwar S.; Luzina, Irina G.; Atamas, Sergei P.; Hasday, Jeffrey D.] Baltimore Vet Affairs Med Care Syst, Med & Res Serv, Baltimore, MD USA. [Thompson, Christopher] Loyola Univ Maryland, Dept Biol, Baltimore, MD USA. [Scheraga, Rachel G.; Sun, Junfeng; Cai, Rongman; Logun, Carolea; Shelhamer, James] NHLBI, Crit Care Sect, Bldg 10, Bethesda, MD 20892 USA. RP Hasday, JD (reprint author), Univ Maryland, Sch Med, Hlth Sci Facil 2, Rm S347,20 Penn St, Baltimore, MD 21201 USA. EM jhasday@umaryland.edu FU NIH [R01HL69057]; VA Merit Review grant [IBX002143A] FX This work was supported by NIH grant R01HL69057 and VA Merit Review grant IBX002143A. NR 76 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD NOV 1 PY 2016 VL 311 IS 5 BP L941 EP L955 DI 10.1152/ajplung.00262.2016 PG 15 WC Physiology; Respiratory System SC Physiology; Respiratory System GA EE5IS UT WOS:000389640700012 PM 27638903 ER PT J AU Bologna, M Paparella, G Fabbrini, A Leodori, G Rocchi, L Hallett, M Berardelli, A AF Bologna, Matteo Paparella, Giulia Fabbrini, Andrea Leodori, Giorgio Rocchi, Lorenzo Hallett, Mark Berardelli, Alfredo TI Effects of cerebellar theta-burst stimulation on arm and neck movement kinematics in patients with focal dystonia SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Transcranial magnetic stimulation; Dystonia; Cerebellum; Motor control ID TRANSCRANIAL MAGNETIC STIMULATION; TOXIN TYPE-A; CERVICAL DYSTONIA; WRITERS CRAMP; MOTOR CORTEX; HAND DYSTONIA; BASAL GANGLIA; EXCITABILITY; CIRCUITS; CONNECTIVITY AB Objective: To investigate the cerebellar inhibitory influence on the primary motor cortex in patients with focal dystonia using a cerebellar continuous theta-burst stimulation protocol (cTBS) and to evaluate any relationship with movement abnormalities. Methods: Thirteen patients with focal hand dystonia, 13 patients with cervical dystonia and 13 healthy subjects underwent two sessions: (i) cTBS over the cerebellar hemisphere (real cTBS) and (ii) cTBS over the neck muscles (sham cTBS). The effects of cerebellar cTBS were quantified as excitability changes in the contralateral primary motor cortex, as well as possible changes in arm and neck movements in patients. Results: Real cerebellar cTBS reduced the excitability in the contralateral primary motor cortex in healthy subjects and in patients with cervical dystonia, though not in patients with focal hand dystonia. There was no correlation between changes in primary motor cortex excitability and arm and neck movement kinematics in patients. There were no changes in clinical scores or in kinematic measures, after either real or sham cerebellar cTBS in patients. Conclusions: The reduced cerebellar inhibitory modulation of primary motor cortex excitability in focal dystonia may be related to the body areas affected by dystonia as opposed to being a widespread pathophysiological abnormality. Significance: The present study yields information on the differential role played by the cerebellum in the pathophysiology of different focal dystonias. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Bologna, Matteo; Paparella, Giulia; Fabbrini, Andrea; Leodori, Giorgio; Rocchi, Lorenzo; Berardelli, Alfredo] Sapienza Univ Rome, Dept Neurol & Psychiat, Rome, Italy. [Bologna, Matteo; Berardelli, Alfredo] Neuromed Inst IRCCS, Pozzilli, IS, Italy. [Hallett, Mark] NINDS, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Berardelli, A (reprint author), Sapienza Univ Rome, Dept Neurol & Psychiat, Neuromed Inst, Viale Univ 30, I-00185 Rome, Italy. EM alfredo.berardelli@uniroma1.it FU Office of Rare Diseases Research at the National Center for Advancing Translational Sciences (NCATS) [U54 TR01456]; National Institute of Neurological Disorders and Stroke (NINDS) from the NIH [U54 NS065701]; NINDS Intramural Program FX This study was funded in part by grants to the Dystonia Coalition from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences (NCATS U54 TR01456) and the National Institute of Neurological Disorders and Stroke (NINDS U54 NS065701) from the NIH. Dr. Hallett is supported by the NINDS Intramural Program. NR 54 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD NOV PY 2016 VL 127 IS 11 BP 3472 EP 3479 DI 10.1016/j.clinph.2016.09.008 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EE3QO UT WOS:000389510200009 PM 27721106 ER PT J AU Coble, MD Buckleton, J Butler, JM Egeland, T Fimmers, R Gill, P Gusmao, L Guttman, B Krawczak, M Morling, N Parson, W Pinto, N Schneider, PM Sherry, ST Willuweit, S Prinz, M AF Coble, M. D. Buckleton, J. Butler, J. M. Egeland, T. Fimmers, R. Gill, P. Gusmao, L. Guttman, B. Krawczak, M. Morling, N. Parson, W. Pinto, N. Schneider, P. M. Sherry, S. T. Willuweit, S. Prinz, M. TI DNA Commission of the International Society for Forensic Genetics: Recommendations on the validation of software programs performing biostatistical calculations for forensic genetics applications SO FORENSIC SCIENCE INTERNATIONAL-GENETICS LA English DT Article DE Biostatistical software; Software validation; Validation and verification; Forensic genetics; Software training and testing ID LIKELIHOOD RATIOS; DROP-OUT; PROFILES; PROPOSITIONS; PATERNITY; MIXTURE; MODELS AB The use of biostatistical software programs to assist in data interpretation and calculate likelihood ratios is essential to forensic geneticists and part of the daily case work flow for both kinship and DNA identification laboratories. Previous recommendations issued by the DNA Commission of the International Society for Forensic Genetics (ISFG) covered the application of bio-statistical evaluations for STR typing results in identification and kinship cases, and this is now being expanded to provide best practices regarding validation and verification of the software required for these calculations. With larger multiplexes, more complex mixtures, and increasing requests for extended family testing, laboratories are relying more than ever on specific software solutions and sufficient validation, training and extensive documentation are of upmost importance. Here, we present recommendations for the minimum requirements to validate bio-statistical software to be used in forensic genetics. We distinguish between developmental validation and the responsibilities of the software developer or provider, and the internal validation studies to be performed by the end user. Recommendations for the software provider address, for example, the documentation of the underlying models used by the software, validation data expectations, version control, implementation and training support, as well as continuity and user notifications. For the internal validations the recommendations include: creating a validation plan, requirements for the range of samples to be tested, Standard Operating Procedure development, and internal laboratory training and education. To ensure that all laboratories have access to a wide range of samples for validation and training purposes the ISFG DNA commission encourages collaborative studies and public repositories of STR typing results. Published by Elsevier Ireland Ltd. C1 [Coble, M. D.] Natl Inst Stand & Technol, Appl Genet Grp, 100 Bur Dr MS 8314, Gaithersburg, MD 20899 USA. [Buckleton, J.] ESR, Private Bag 92021, Auckland 1142, New Zealand. [Buckleton, J.] Natl Inst Stand & Technol, Stat Engn Div Guest Researcher, Gaithersburg, MD 20899 USA. [Butler, J. M.] Natl Inst Stand & Technol, Special Programs Off, Gaithersburg, MD 20899 USA. [Egeland, T.] Norwegian Univ Life Sci, Oslo, Norway. [Fimmers, R.] Univ Bonn, Inst Med Stat Informat & Epidemiol, Bonn, Germany. [Gill, P.] Norwegian Inst Publ Hlth, Oslo, Norway. [Gill, P.] Univ Oslo, Oslo, Norway. [Gusmao, L.] State Univ Rio de Janeiro UERJ, Rio De Janeiro, Brazil. [Gusmao, L.; Pinto, N.] Univ Porto, Inst Mol Pathol & Immunol, IPATIMUP, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Gusmao, L.; Pinto, N.] Univ Porto, Inst Invest & Inovacao Saude, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Guttman, B.] Natl Inst Stand & Technol, Software & Syst Div, Gaithersburg, MD 20899 USA. [Krawczak, M.] Christian Albrechts Univ Kiel, Inst Med Informat & Stat, Kiel, Germany. [Morling, N.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Forens Med, Sect Forens Genet, DK-1168 Copenhagen, Denmark. [Parson, W.] Med Univ Innsbruck, Inst Legal Med, Innsbruck, Austria. [Parson, W.] Penn State Univ, Forens Sci Program, University Pk, PA 16802 USA. [Pinto, N.] Univ Porto, Inst Res & Innovat Hlth I3S, Oporto, Portugal. [Pinto, N.] Univ Porto, Ctr Math, Oporto, Portugal. [Schneider, P. M.] Univ Cologne, Fac Med, Inst Legal Med, Cologne, Germany. [Sherry, S. T.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Willuweit, S.] Charite, Inst Legal Med & Forens Sci, Dept Forens Genet, Berlin, Germany. [Prinz, M.] John Jay Coll Criminal Justice, New York, NY USA. RP Coble, MD (reprint author), Natl Inst Stand & Technol, Appl Genet Grp, 100 Bur Dr MS 8314, Gaithersburg, MD 20899 USA. EM mcoble@nist.gov RI Gusmao, Leonor/B-3122-2013; Krawczak, Michael/A-8964-2010 OI Gusmao, Leonor/0000-0003-0432-6481; Krawczak, Michael/0000-0003-2603-1502 NR 34 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1872-4973 EI 1878-0326 J9 FORENSIC SCI INT-GEN JI Forensic Sci. Int.-Genet. PD NOV PY 2016 VL 25 BP 191 EP 197 DI 10.1016/j.fsigen.2016.09.002 PG 7 WC Genetics & Heredity; Medicine, Legal SC Genetics & Heredity; Legal Medicine GA EE3YX UT WOS:000389539600033 PM 27643465 ER PT J AU Quang, T Schwarz, RA Dawsey, SM Tan, MC Patel, K Yu, XY Wang, GQ Zhang, F Xu, H Anandasabapathy, S Richards-Kortum, R AF Quang, Timothy Schwarz, Richard A. Dawsey, Sanford M. Tan, Mimi C. Patel, Kalpesh Yu, Xinying Wang, Guiqi Zhang, Fan Xu, Hong Anandasabapathy, Sharmila Richards-Kortum, Rebecca TI A tablet-interfaced high-resolution microendoscope with automated image interpretation for real-time evaluation of esophageal squamous cell neoplasia SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID LOW-COST; CARCINOMA; CANCER; EPIDEMIOLOGY; DIAGNOSIS; DYSPLASIA; REGION; TRIAL; CHINA; RISK AB Background and Aims: In recent years high-resolution microendoscopy (HRME) has shown potential to improve screening for esophageal squamous cell neoplasia. Furthering its utility in a clinical setting, especially in lower-resource settings, could be accomplished by reducing the size and cost of the system as well as incorporating the ability of real-time, objective feedback. This article describes a tablet-interfaced HRME with fully automated, real-time image analysis. Methods: The performance of the tablet-interfaced HRME was assessed by acquiring images from the oral mucosa in a normal volunteer. An automated, real-time analysis algorithm was developed and evaluated using training, test, and validation images from a previous in vivo study of 177 patients referred for screening or surveillance endoscopy in China. The algorithm was then implemented in a tablet HRME that was used to obtain and analyze images from esophageal tissue in 3 patients. Images were displayed alongside the probability that the imaged region was neoplastic. Results: The tablet-interfaced HRME demonstrated comparable imaging performance at a lower cost compared with first-generation laptop-interfaced HRME systems. In a post-hoc quantitative analysis, the algorithm identified neoplasia with a sensitivity and specificity of 95% and 91%, respectively, in the validation set compared with 84% and 95% achieved in the original study. Conclusions: The tablet-based HRME is a low-cost tool that provides quantitative diagnostic information to the endoscopist in real time. This could be especially beneficial in lower-resource settings for operators with less experience interpreting HRME images. C1 [Quang, Timothy; Schwarz, Richard A.; Richards-Kortum, Rebecca] Rice Univ, Dept Bioengn, 6500 Main St, Houston, TX 77030 USA. [Dawsey, Sanford M.] NCI, Dept Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Tan, Mimi C.; Patel, Kalpesh; Anandasabapathy, Sharmila] Baylor Coll Med, Dept Gastroenterol, Houston, TX 77030 USA. [Yu, Xinying; Wang, Guiqi] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Endoscopy, Beijing, Peoples R China. [Zhang, Fan; Xu, Hong] Jilin Univ, Hosp 1, Dept Gastrointestinal Med, Changchun, Jilin, Peoples R China. RP Quang, T (reprint author), Rice Univ, Dept Bioengn, 6500 Main St, Houston, TX 77030 USA. FU Remicalm; National Cancer Institute of the National Institutes of Health [R01CA181275] FX The following authors disclosed financial relationships relevant to this publication: R. Richards-Kortum: Licensing fees recipient for IP licensed from the University of Texas from Remicalm. All other authors disclosed no financial relationships relevant to this publication. Research support for this study was provided by the National Cancer Institute of the National Institutes of Health under Award Number R01CA181275. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 17 TC 2 Z9 2 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD NOV PY 2016 VL 84 IS 5 BP 834 EP 841 DI 10.1016/j.gie.2016.03.1472 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE4AK UT WOS:000389543800015 PM 27036635 ER PT J AU Lin, J Kelley-Moore, J AF Lin, J. Kelley-Moore, J. TI NEW DIMENSIONS OF INEQUALITY: INTER-INDIVIDUAL VARIABILITY IN FUNCTIONAL LIMITATIONS BY RACE/GENDER SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lin, J.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Kelley-Moore, J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 22 EP 22 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000087 ER PT J AU Agha, G Joehanes, R Levy, D Baccarelli, A AF Agha, G. Joehanes, R. Levy, D. Baccarelli, A. TI DNA METHYLATION IS ASSOCIATED WITH INCIDENT CARDIOVASCULAR DISEASE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Agha, G.; Baccarelli, A.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Joehanes, R.] Hebrew SeniorLife, Boston, MA USA. [Levy, D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 35 EP 35 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000136 ER PT J AU Levine, ME Hosgood, HD Chen, B Absher, D Assimes, T Horvath, S AF Levine, M. E. Hosgood, H. D. Chen, B. Absher, D. Assimes, T. Horvath, S. TI DNA METHYLATION AGE OF BLOOD PREDICTS ONSET OF LUNG CANCER IN THE WOMEN'S HEALTH INITIATIVE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Levine, M. E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Chen, B.] NIA, Bethesda, MD 20892 USA. [Absher, D.] Hudson Alpha Inst Biotechnol, Huntsville, AL USA. [Assimes, T.] Standford Univ, Sch Med, Stanford, CA USA. [Horvath, S.] David Geffen Sch Med, Los Angeles, CA USA. [Hosgood, H. D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 35 EP 36 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000137 ER PT J AU Murabito, JM Rong, J Lunetta, K Tanriverdi, K Freedman, J Levy, D Larson, MG AF Murabito, J. M. Rong, J. Lunetta, K. Tanriverdi, K. Freedman, J. Levy, D. Larson, M. G. TI RELATIONS BETWEEN MICRORNA EXPRESSION IN BLOOD AND HAND GRIP STRENGTH IN A COMMUNITY SAMPLE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Murabito, J. M.] Boston Univ, Sch Med, Gen Internal Med Sect, Med, Framingham, MA USA. [Rong, J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Lunetta, K.; Larson, M. G.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Tanriverdi, K.; Freedman, J.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Levy, D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 36 EP 36 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000138 ER PT J AU Koehly, L AF Koehly, L. TI IT'S INTER-PERSONAL: FAMILY RELATIONSHIPS, GENETIC RISK, AND CAREGIVING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Koehly, L.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 39 EP 39 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000147 ER PT J AU Smith, C Morgan, L Evans, MK Zonderman, AB AF Smith, C. Morgan, L. Evans, M. K. Zonderman, A. B. TI LIFETIME USE OF ILLICIT DRUGS IN AN URBAN SAMPLE OF MIDDLE-AGED ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Smith, C.; Morgan, L.] UMBC, Baltimore, MD USA. [Evans, M. K.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 79 EP 80 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000288 ER PT J AU Sutphin, GL Backer, G Sheehan, S Murabito, JM Johnson, A Korstanje, R AF Sutphin, G. L. Backer, G. Sheehan, S. Murabito, J. M. Johnson, A. Korstanje, R. TI KYNURENINE PATHWAY GENES INFLUENCE AGING THROUGH MULTIPLE DISTINCT MOLECULAR MECHANISMS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Sutphin, G. L.; Backer, G.; Sheehan, S.; Korstanje, R.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Murabito, J. M.] Boston Univ, Sch Med, Sect Gen Med, Boston, MA 02118 USA. [Murabito, J. M.; Johnson, A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Johnson, A.] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 110 EP 111 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000398 ER PT J AU Elliott, C AF Elliott, C. TI NATIONAL INSTITUTE ON AGING - DIVISION OF NEUROSCIENCE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Elliott, C.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000487 ER PT J AU Hill, C Elliott, C AF Hill, C. Elliott, C. TI HEALTH DISPARITIES RESEARCH WITH THE NATIONAL INSTITUTE ON AGING (NIA) SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Hill, C.; Elliott, C.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000486 ER PT J AU Joseph, L AF Joseph, L. TI GERIATRICS AND CLINICAL GERONTOLOGY'S APPROACHES FOR ADDRESSING HEALTH DISPARITIES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Joseph, L.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000488 ER PT J AU Nielsen, L AF Nielsen, L. TI HEALTH DISPARITIES RESEARCH AND PRIORITIES IN THE NIA DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Nielsen, L.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000489 ER PT J AU Sierra, F AF Sierra, F. TI HEALTH DISPARITIES RESEARCH AT NIA'S DIVISION OF AGING BIOLOGY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Sierra, F.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000490 ER PT J AU Salimi, S Shardell, M Huang, Y Gruber-Baldini, A Miller, R Guralnik, J Orwig, D Magaziner, J AF Salimi, S. Shardell, M. Huang, Y. Gruber-Baldini, A. Miller, R. Guralnik, J. Orwig, D. Magaziner, J. TI TNFAR-1 AND FRAILTY IN MEN AND WOMEN AFTER HIP FRACTURE: FINDINGS FROM THE BALTIMORE HIP STUDIES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Salimi, S.; Shardell, M.; Gruber-Baldini, A.; Guralnik, J.; Orwig, D.; Magaziner, J.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Salimi, S.; Shardell, M.] NIA, NIH, Baltimore, MD 21224 USA. [Huang, Y.] Univ Maryland, Dept Math & Stat, Baltimore, MD 21201 USA. [Miller, R.] Novartis Inst Biomed Res, Cambridge, MA USA. [Miller, R.] Novartis Inst Biomed Res, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 177 EP 177 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000649 ER PT J AU Kane, AE Mitchell, S Mach, J Huizer-Pajkos, A Cogger, V Le Couteur, D De Cabo, R Hilmer, S AF Kane, A. E. Mitchell, S. Mach, J. Huizer-Pajkos, A. Cogger, V. Le Couteur, D. De Cabo, R. Hilmer, S. TI ACETAMINOPHEN HEPATOTOXICITY IN MICE: EFFECT OF AGE, FRAILTY AND EXPOSURE TYPE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Kane, A. E.; Mach, J.; Huizer-Pajkos, A.; Hilmer, S.] Kolling Inst, St Leonards, NSW, Australia. [Kane, A. E.; Mach, J.; Cogger, V.; Le Couteur, D.; Hilmer, S.] Univ Sydney, Sydney, NSW, Australia. [Kane, A. E.; Mach, J.; Huizer-Pajkos, A.; Hilmer, S.] Royal North Shore Hosp, St Leonards, NSW, Australia. [Mitchell, S.; De Cabo, R.] NIA, Baltimore, MD 21224 USA. [Cogger, V.; Le Couteur, D.] ANZAC Res Inst, Concord, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 180 EP 180 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585000658 ER PT J AU Strotmeyer, ES Boudreau, RM Minion, SC Cauley, JA Donohue, JM Harris, TB Newman, AB Waters, TM AF Strotmeyer, E. S. Boudreau, R. M. Minion, S. C. Cauley, J. A. Donohue, J. M. Harris, T. B. Newman, A. B. Waters, T. M. TI SENSORY NERVE IMPAIRMENT IS ASSOCIATED WITH HIGHER TOTAL MEDICARE COSTS: THE HEALTH ABC STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Strotmeyer, E. S.; Boudreau, R. M.; Minion, S. C.; Cauley, J. A.; Donohue, J. M.; Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Waters, T. M.] Univ Tennessee, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 216 EP 217 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001043 ER PT J AU ChilesShaffer, N Simonsick, E Studenski, S AF ChilesShaffer, N. Simonsick, E. Studenski, S. TI FAT MASS PREDICTS GAIT SPEED DECLINE EXCEPT IN THOSE OVER 80 SO GERONTOLOGIST LA English DT Meeting Abstract C1 [ChilesShaffer, N.; Simonsick, E.; Studenski, S.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 218 EP 219 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001052 ER PT J AU Ko, S Jerome, G Simonsick, EM Studenski, S Hausdorff, JM Ferrucci, L AF Ko, S. Jerome, G. Simonsick, E. M. Studenski, S. Hausdorff, J. M. Ferrucci, L. TI DUAL-TASK-WALK PERFORMANCE AND USUAL GAIT PATTERNS IN HEALTHY OLDER ADULTS RESULTS FROM THE BLSA SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Ko, S.] Chonnam Natl Univ, Yeosu, South Korea. [Jerome, G.] Towson Univ, Towson, MD USA. [Simonsick, E. M.; Studenski, S.; Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. [Hausdorff, J. M.] Tel Aviv Sourasky Med Ctr, Dept Neurol, Tel Aviv, Israel. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 218 EP 218 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001051 ER PT J AU Tian, Q Resnick, SM Bilgel, M Wong, DF Ferrucci, L Studenski, S AF Tian, Q. Resnick, S. M. Bilgel, M. Wong, D. F. Ferrucci, L. Studenski, S. TI beta-AMYLOID BURDEN PREDICTS LOWER EXTREMITY PERFORMANCE DECLINE IN COGNITIVELY NORMAL OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tian, Q.; Resnick, S. M.; Bilgel, M.; Ferrucci, L.; Studenski, S.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Wong, D. F.] Johns Hopkins Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 218 EP 218 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001050 ER PT J AU Simonsick, EM Meier, H ChilesShaffer, N Studenski, S Ferrucci, L AF Simonsick, E. M. Meier, H. ChilesShaffer, N. Studenski, S. Ferrucci, L. TI CORE BODY TEMPERATURE AS A BIOMARKER OF ENERGETIC EFFICIENCY AND MOBILITY PERFORMANCE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Simonsick, E. M.; ChilesShaffer, N.; Studenski, S.; Ferrucci, L.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Meier, H.] NIEHS, Durham, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 219 EP 219 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001053 ER PT J AU Schrack, J Simonsick, E Studenski, S Ferrucci, L AF Schrack, J. Simonsick, E. Studenski, S. Ferrucci, L. TI DECLINING WALKING EFFICIENCY PREDICTS GREATER PERCEIVED FATIGABILITY WITH AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Schrack, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Simonsick, E.; Studenski, S.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 240 EP 241 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001141 ER PT J AU Santanasto, AJ Newman, AB Strotmeyer, ES Caserotti, P Harris, TB Simonsick, E Glynn, NW AF Santanasto, A. J. Newman, A. B. Strotmeyer, E. S. Caserotti, P. Harris, T. B. Simonsick, E. Glynn, N. W. TI RELATIONSHIP BETWEEN FAT MASS AND FATIGABILITY IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Santanasto, A. J.; Newman, A. B.; Strotmeyer, E. S.; Glynn, N. W.] Univ Pittsburgh, Pittsburgh, PA USA. [Caserotti, P.] Univ Southern Denmark, Odense, Denmark. [Harris, T. B.; Simonsick, E.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 241 EP 241 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001143 ER PT J AU Simonsick, EM Jerome, G Nicklas, B Schrack, J Studenski, S Ferrucci, L AF Simonsick, E. M. Jerome, G. Nicklas, B. Schrack, J. Studenski, S. Ferrucci, L. TI THE WEIGHTINESS OF FATIGABILITY: FINDINGS FROM THE BALTIMORE LONGITUDINAL STUDY OF AGING (BLSA) SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Simonsick, E. M.; Studenski, S.; Ferrucci, L.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Jerome, G.] Towson Univ, Towson, MD USA. [Nicklas, B.] Wake Forest Univ, Wake Forest, NC USA. [Schrack, J.] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 241 EP 241 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001144 ER PT J AU ChilesShaffer, N Thorpe, R Simonsick, E Studenski, S AF ChilesShaffer, N. Thorpe, R. Simonsick, E. Studenski, S. TI BODY COMPOSITION DOES NOT EXPLAIN THE RELATIONSHIP BETWEEN RACE AND PHYSICAL PERFORMANCE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [ChilesShaffer, N.; Simonsick, E.; Studenski, S.] NIA, Baltimore, MD 21224 USA. [Thorpe, R.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 242 EP 242 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001149 ER PT J AU Espeland, M Crimmins, E Grossardt, B Harris, TB Kritchevsky, S Rocca, W Temprosa, M Barzilai, N AF Espeland, M. Crimmins, E. Grossardt, B. Harris, T. B. Kritchevsky, S. Rocca, W. Temprosa, M. Barzilai, N. TI BENCHMARKS FOR DESIGNING CLINICAL TRIALS WITH MULTIPLE MORBIDITY OUTCOMES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Espeland, M.; Kritchevsky, S.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Crimmins, E.] Univ Southern Calif, Los Angeles, CA USA. [Grossardt, B.; Rocca, W.] Mayo Clin, Rochester, MN USA. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Temprosa, M.] George Washington Univ, Rockville, MD USA. [Barzilai, N.] Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 251 EP 252 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001185 ER PT J AU Mueller, M Bures, R Gee, NR AF Mueller, M. Bures, R. Gee, N. R. TI HUMAN-ANIMAL INTERACTION AND HEALTHY AGING: FINDINGS FROM THE 2012 HEALTH AND RETIREMENT STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Gee, N. R.] WALTHAM, Melton Mobray, England. [Mueller, M.] Tufts Univ, North Grafton, MA USA. [Bures, R.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 261 EP 261 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001230 ER PT J AU Gross, A McAdams-DeMarco, M Xue, Q Carlson, M Simonsick, EM Bandeen-Roche, KJ Walston, J AF Gross, A. McAdams-DeMarco, M. Xue, Q. Carlson, M. Simonsick, E. M. Bandeen-Roche, K. J. Walston, J. TI BIOLOGICAL MARKERS OF PHYSIOLOGIC DYSREGULATION AS MEASURES OF FRAILTY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Gross, A.; McAdams-DeMarco, M.; Carlson, M.; Bandeen-Roche, K. J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Xue, Q.; Walston, J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 285 EP 286 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001330 ER PT J AU Rosso, AL Winger, ME Cauley, JA Harris, TB Schwartz, A Waters, TM Yaffe, K Strotmeyer, ES AF Rosso, A. L. Winger, M. E. Cauley, J. A. Harris, T. B. Schwartz, A. Waters, T. M. Yaffe, K. Strotmeyer, E. S. TI COGNITIVE FUNCTION AND RISK OF FALL-RELATED FRACTURE AND NON-FRACTURE INJURIES IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Rosso, A. L.; Winger, M. E.; Cauley, J. A.; Strotmeyer, E. S.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Waters, T. M.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Yaffe, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 316 EP 316 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001458 ER PT J AU Tian, Q Resnick, SM Ferrucci, L Studenski, S AF Tian, Q. Resnick, S. M. Ferrucci, L. Studenski, S. TI THE TEMPORAL SEQUENCE OF COGNITION AND MOBILITY IN AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tian, Q.; Resnick, S. M.; Ferrucci, L.; Studenski, S.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 337 EP 337 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001534 ER PT J AU Kane, AE Huizer-Pajkos, A Mach, J Howlett, SE Mitchell, S de Cabo, R Le Couteur, D Hilmer, S AF Kane, A. E. Huizer-Pajkos, A. Mach, J. Howlett, S. E. Mitchell, S. de Cabo, R. Le Couteur, D. Hilmer, S. TI A COMPARISON OF TWO MOUSE FRAILTY ASSESSMENT TOOLS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Kane, A. E.; Huizer-Pajkos, A.; Mach, J.; Hilmer, S.] Kolling Inst, St Leonards, NSW, Australia. [Kane, A. E.; Mach, J.; Le Couteur, D.; Hilmer, S.] Univ Sydney, Sydney, NSW, Australia. [Kane, A. E.; Huizer-Pajkos, A.; Mach, J.; Hilmer, S.] Royal North Shore Hosp, St Leonards, NSW, Australia. [Howlett, S. E.] Dalhousie Univ, Halifax, NS, Canada. [Mitchell, S.; de Cabo, R.] NIA, Baltimore, MD 21224 USA. [Le Couteur, D.] Concord Hosp, Concord, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 348 EP 349 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585001572 ER PT J AU Sardina, A Gamaldo, A Andel, R Evans, M Zonderman, AB AF Sardina, A. Gamaldo, A. Andel, R. Evans, M. Zonderman, A. B. TI PAIN AND PHYSICAL FUNCTION IN A RACIALLY AND SOCIOECONOMICALLY DIVERSE SAMPLE OF MIDDLE-AGED ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Sardina, A.; Gamaldo, A.; Andel, R.] Univ S Florida, Tampa, FL USA. [Gamaldo, A.; Evans, M.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 418 EP 418 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002012 ER PT J AU Shardell, M Bandinelli, S Colpo, M Ferrucci, L AF Shardell, M. Bandinelli, S. Colpo, M. Ferrucci, L. TI LONGITUDINAL 25-HYDROXYVITAMIN D AND DEPRESSIVE SYMPTOMS WITH STRUCTURAL MODELS: THE INCHIANTI STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Shardell, M.; Ferrucci, L.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Bandinelli, S.; Colpo, M.] LHTC, Local Hlth Unit, Tuscany Ctr, Geriatr Unit, Florence, Italy. [Colpo, M.] Univ Firenze, Dept Stat Informat & Applicat, Florence, Italy. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 438 EP 438 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002084 ER PT J AU Wilkinson, M Luo, S Gabriel, KP Tanaka, T Simonsick, E Day, R AF Wilkinson, M. Luo, S. Gabriel, K. Pettee Tanaka, T. Simonsick, E. Day, R. TI A HOMOCYSTEINE METABOLISM BASED DIET PATTERN AND PHYSICAL FUNCTION IN OLDER ADULTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Wilkinson, M.; Luo, S.; Day, R.] UTHlth Sch Publ Hlth Houston, Houston, TX USA. [Tanaka, T.; Simonsick, E.] NIA, Baltimore, MD 21224 USA. [Gabriel, K. Pettee] UTHlth Sch Publ Hlth Austin, Austin Reg Campus, Austin, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 455 EP 455 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002152 ER PT J AU Schrack, J Leroux, A Fleg, J Simonsick, E Zipunnikov, V Studenski, S Ferrucci, L Crainiceanu, C AF Schrack, J. Leroux, A. Fleg, J. Simonsick, E. Zipunnikov, V. Studenski, S. Ferrucci, L. Crainiceanu, C. TI GETTING TO THE HEART OF THE MATTER: USING HEART RATE TO DEFINE PHYSICAL ACTIVITY INTENSITY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Schrack, J.; Leroux, A.; Zipunnikov, V.; Crainiceanu, C.] Johns Hopkins Bloomberg Sch Publ Hlth, Epidemiol, Baltimore, MD USA. [Fleg, J.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Simonsick, E.; Studenski, S.; Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 469 EP 470 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002209 ER PT J AU Ashida, S Marcum, CS Koehly, L AF Ashida, S. Marcum, C. S. Koehly, L. TI SOCIAL INTERACTION CHARACTERISTICS ASSOCIATED WITH PERCEPTIONS OF UNMET EXPECTATIONS IN CAREGIVING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Ashida, S.] Univ Iowa, Coll Publ Hlth, Community & Behav Hlth, Iowa City, IA USA. [Marcum, C. S.; Koehly, L.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 493 EP 494 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002309 ER PT J AU Das, S Roberts, S Ravussin, E Holloszy, J Hadley, E Romashkan, S Kraus, W AF Das, S. Roberts, S. Ravussin, E. Holloszy, J. Hadley, E. Romashkan, S. Kraus, W. TI FINDINGS FROM A TWO-YEAR RANDOMIZED CONTROLLED TRIAL OF HUMAN CALORIC RESTRICTION SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Das, S.; Roberts, S.] Tufts Univ, Energy Metab, Jean Mayer USDA, HNRCA, Boston, MA 02111 USA. [Ravussin, E.] PBRC, Baton Rouge, LA USA. [Holloszy, J.] Washington Univ, St Louis, MO USA. [Hadley, E.; Romashkan, S.] NIA, NIH, Bethesda, MD 20892 USA. [Kraus, W.] Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 497 EP 497 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002324 ER PT J AU Sheets, DJ Beach, C Hundza, S Mitz, A MacDonald, S Asche, C Gali, B AF Sheets, D. J. Beach, C. Hundza, S. Mitz, A. MacDonald, S. Asche, C. Gali, B. TI CAREGIVER PERCEPTIONS OF TECHNOLOGIES TO SUPPORT COMMUNITY-DWELLING OLDER ADULTS WITH DEMENTIA SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Sheets, D. J.; Hundza, S.; MacDonald, S.; Asche, C.; Gali, B.] Univ Victoria, Sch Nursing, Victoria, BC, Canada. [Beach, C.] Canadian Inst Hlth Informat, Victoria, BC, Canada. [Mitz, A.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 526 EP 526 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002446 ER PT J AU Quinones, A Markwardt, S Rostant, OS Vasquez, E Thielke, S Botoseneanu, A AF Quinones, A. Markwardt, S. Rostant, O. S. Vasquez, E. Thielke, S. Botoseneanu, A. TI MULTIMORBIDITY COMBINATION ASSOCIATIONS WITH PROSPECTIVE DISABILITY IN THE NHATS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Quinones, A.; Markwardt, S.] Oregon Hlth & Sci Univ, Sch Publ Hlth, Portland, OR 97201 USA. [Rostant, O. S.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Vasquez, E.] SUNY Albany, Albany, NY 12222 USA. [Thielke, S.] Puget Sound VA Med Ctr, Seattle, WA USA. [Thielke, S.] Univ Washington, Seattle, WA 98195 USA. [Botoseneanu, A.] Univ Michigan, Dearborn, MI 48128 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 529 EP 529 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002457 ER PT J AU Armstrong, N Gross, A Andrews, R Varma, V Xue, Q Carlson, M AF Armstrong, N. Gross, A. Andrews, R. Varma, V. Xue, Q. Carlson, M. TI ASSOCIATION BETWEEN TRIAL-LEVEL CHANGE IN STROOP TEST AND MOBILITY: BALTIMORE EXPERIENCE CORPS TRIAL SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Armstrong, N.; Gross, A.; Andrews, R.; Xue, Q.; Carlson, M.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Varma, V.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 541 EP 541 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002496 ER PT J AU Tian, Q Resnick, SM Landman, BA Ferrucci, L Studenski, S AF Tian, Q. Resnick, S. M. Landman, B. A. Ferrucci, L. Studenski, S. TI AGE-RELATED WHITE MATTER MICROSTRUCTURAL CHANGES AND GAIT DECLINE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tian, Q.; Resnick, S. M.; Ferrucci, L.; Studenski, S.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Landman, B. A.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 560 EP 560 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002561 ER PT J AU Marcum, CS Koehly, L AF Marcum, C. S. Koehly, L. TI THE EFFECT OF AGE AND MULTIPLEXITY ON HEALTH DISCUSSION NETWORKS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Marcum, C. S.; Koehly, L.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 590 EP 590 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002677 ER PT J AU Onken, L AF Onken, L. TI NEW FEDERAL MODELS AND FUNDING INITIATIVES TO ENCOURAGE TRANSLATIONAL AND IMPLEMENTATION RESEARCH SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Onken, L.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 608 EP 609 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585002754 ER PT J AU Mair, C Zweiacher, H Waldstein, S Lehning, A Evans, M Zonderman, AB AF Mair, C. Zweiacher, H. Waldstein, S. Lehning, A. Evans, M. Zonderman, A. B. TI SOCIAL ENVIRONMENT AND SOCIAL SUPPORT IN BALTIMORE CITY: AN EXPLORATION OF NEIGHBORHOOD CONTEXTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Mair, C.; Zweiacher, H.; Waldstein, S.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Evans, M.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. [Lehning, A.] Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 714 EP 714 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585003372 ER PT J AU Wright, RS Waldstein, S Gerassimakis, C Sprung, M Moody, DLB Taylor, A Evans, MK Zonderman, AB AF Wright, R. S. Waldstein, S. Gerassimakis, C. Sprung, M. Moody, D. L. Beatty Taylor, A. Evans, M. K. Zonderman, A. B. TI PREDICTORS OF NEUROCOGNITIVE PERFORMANCE AMONG AFRICAN AMERICANS ENROLLED IN THE HANDLS STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Wright, R. S.; Gerassimakis, C.] Univ Delaware, Sch Nursing, Newark, DE USA. [Waldstein, S.; Moody, D. L. Beatty; Taylor, A.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Sprung, M.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Evans, M. K.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 733 EP 734 PG 2 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585003446 ER PT J AU Moody, DLB Waldstein, S Al-Najjar, E Evans, MK Zonderman, AB AF Moody, D. L. Beatty Waldstein, S. Al-Najjar, E. Evans, M. K. Zonderman, A. B. TI SOCIAL PATTERNING OF MULTIPLE FORMS OF DISCRIMINATION IN AFRICAN AMERICAN ADULTS IN THE HANDLS STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Moody, D. L. Beatty; Waldstein, S.; Al-Najjar, E.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. [Evans, M. K.; Zonderman, A. B.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 BP 734 EP 734 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585003448 ER PT J AU Lines, L Cohen, J Halpern, MT Lines, L Kent, E Smith, AW Halpern, MT AF Lines, L. Cohen, J. Halpern, M. T. Lines, L. Kent, E. Smith, A. Wilder Halpern, M. T. TI Experiences of Care Among Dually Eligible Beneficiaries With and Without Cancer: SEER-CAHPS, 2007-2013 SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lines, L.; Cohen, J.; Halpern, M. T.] RTI Int, Qual Measurement & Hlth Policy, Waltham, MA USA. [Lines, L.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Kent, E.; Smith, A. Wilder] NCI, Rockville, MD USA. [Halpern, M. T.] Temple Univ, Philadelphia, PA 19122 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585003606 ER PT J AU Wahl, D Cogger, V Solon-Biet, S Le Couteur, D de Cabo, R Simpson, S AF Wahl, D. Cogger, V. Solon-Biet, S. Le Couteur, D. de Cabo, R. Simpson, S. TI Is a Low-Protein, High-Carbohydrate Diet an Essential Key to Brain Health? SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Wahl, D.; Cogger, V.; Solon-Biet, S.; Le Couteur, D.] Charles Perkins Ctr, ANZAC Res Inst, Pyrmont, NSW, Australia. [de Cabo, R.] NIA, NIH, Baltimore, MD 21224 USA. [Simpson, S.] Charles Perkins Ctr, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2016 VL 56 SU 3 PG 1 WC Gerontology SC Geriatrics & Gerontology GA ED1DT UT WOS:000388585003571 ER PT J AU Le Gall, C Laurent, J Vince, N Lizee, A Agrawal, A Walencik, A Rettman, P Gagne, K Retiere, C Hollenbach, J Cesbron, A Limou, S Gourraud, PA AF Le Gall, Caroline Laurent, Julie Vince, Nicolas Lizee, Antoine Agrawal, Alisha Walencik, Alexandre Rettman, Pauline Gagne, Katia Retiere, Christelle Hollenbach, Jill Cesbron, Anne Limou, Sophie Gourraud, Pierre-Antoine TI Multidimensional reduction of multicentric cohort heterogeneity: An alternative method to increase statistical power and robustness SO HUMAN IMMUNOLOGY LA English DT Article DE Multidimensional reduction; Multiple correspondence analyses; Multicentric cohort; Heterogeneity; Hematopoietic stem cell transplantation ID CLINICAL-TRIALS; TRANSPLANTATION; DESIGN; MODELS AB Modern clinical research takes advantage of multicentric cohorts to increase sample size and gain in statistical power. However, combining individuals from different recruitment centers provides heterogeneity in the dataset that needs to be accounted for to obtain robust results. Sophisticated statistical multivariate models adjusting for center effect can be implemented, but they can become unstable and can be complex to interpret with the increasing number of covariates to consider. Here, we present a multidimensional reduction technique to identify heterogeneity in a French multicentric cohort of hematopoietic stem cell transplantations and characterize a homogeneous subgroup prior to performing simple statistical univariate analyses. The exclusion of outliers allowed the identification of two genetic factors associated with post-transplantation overall survival. We therefore provide proof-of-concept that a sample size reduction method can efficiently account for heterogeneity and center effect in multicentric cohorts while increasing statistical power and robustness for discovery of new association signals. (C) 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Le Gall, Caroline; Laurent, Julie; Gourraud, Pierre-Antoine] Methodomics, Toulouse, France. [Vince, Nicolas] Leidos Biomed Res Inc, Frederick Natl Lab, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Vince, Nicolas] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Lizee, Antoine; Agrawal, Alisha; Hollenbach, Jill; Gourraud, Pierre-Antoine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Walencik, Alexandre; Rettman, Pauline; Gagne, Katia; Retiere, Christelle; Cesbron, Anne; Gourraud, Pierre-Antoine] Etab Francais Sang, Nantes, France. [Walencik, Alexandre] Hosp Nantes, Inserm Unit 1064, Nantes, France. [Walencik, Alexandre] Univ Nantes, Inserm Unit 1064, Nantes, France. [Limou, Sophie] NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program,NIH,Leidos Biomed Res Inc,Frede, Frederick, MD 21701 USA. RP Gourraud, PA (reprint author), CHU Nantes, ATIP Avenir Team Translat Immunogen Transplantat, CRTI, UMR Inserm 1064, 30 Bd Jean Monnet 1er Etage, F-44093 Nantes 1, France. EM pierre-antoine.gourraud@univ-nantes.fr OI Lizee, Antoine/0000-0002-1073-3190 NR 16 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 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD NOV PY 2016 VL 77 IS 11 SI SI BP 1024 EP 1029 DI 10.1016/j.humimm.2016.05.013 PG 6 WC Immunology SC Immunology GA EE4II UT WOS:000389565100004 PM 27262455 ER PT J AU Ding, XR Zhao, N Yang, GZ Pettigrew, RI Lo, B Miao, F Li, Y Liu, J Zhang, YT AF Ding, Xiao-Rong Zhao, Ni Yang, Guang-Zhong Pettigrew, Roderic I. Lo, Benny Miao, Fen Li, Ye Liu, Jing Zhang, Yuan-Ting TI Continuous Blood Pressure Measurement From Invasive to Unobtrusive: Celebration of 200th Birth Anniversary of Carl Ludwig SO IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS LA English DT Article DE Carl ludwig; continuous; cuffless blood pressure (BP); kymograph; unobtrusive ID PULSE TRANSIT-TIME; CUFF-LESS; TRACKING CAPABILITIES; CLINICAL-EVALUATION; HEALTH INFORMATICS; ARRIVAL-TIME; SENSOR; WAVE; ACCURACY; DEVICE AB The year 2016 marks the 200th birth anniversary of Carl Friedrich Wilhelm Ludwig (1816-1895). As one of the most remarkable scientists, Ludwig invented the kymograph, which for the first time enabled the recording of continuous blood pressure (BP), opening the door to the modern study of physiology. Almost a century later, intra-arterial BP monitoring through an arterial line has been used clinically. Subsequently, arterial tonometry and volume clamp method were developed and applied in continuous BP measurement in a noninvasive way. In the last two decades, additional efforts have been made to transform the method of unobtrusive continuous BP monitoring without the use of a cuff. This review summarizes the key milestones in continuous BP measurement; that is, kymograph, intra-arterial BP monitoring, arterial tonometry, volume clamp method, and cuffless BP technologies. Our emphasis is on recent studies of unobtrusive BP measurements as well as on challenges and future directions. C1 [Ding, Xiao-Rong; Zhao, Ni; Liu, Jing; Zhang, Yuan-Ting] Chinese Univ Hong Kong, Dept Elect Engn, Hong Kong, Hong Kong, Peoples R China. [Yang, Guang-Zhong; Lo, Benny] Imperial Coll London, Hamlyn Ctr, London SW7 2AZ, England. [Pettigrew, Roderic I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Miao, Fen; Li, Ye] Chinese Acad Sci, Shenzhen Inst Adv Technol, Dept Biomed & Hlth Engn, Shenzhen 518055, Peoples R China. [Miao, Fen; Li, Ye; Zhang, Yuan-Ting] Chinese Acad Sci, Shenzhen Inst Adv Technol, Key Lab Hlth Informat, Shenzhen 518055, Peoples R China. RP Zhang, YT (reprint author), Chinese Univ Hong Kong, Dept Elect Engn, Hong Kong, Hong Kong, Peoples R China.; Zhang, YT (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, Key Lab Hlth Informat, Shenzhen 518055, Peoples R China. EM xrding@ee.cuhk.edu.hk; nzhao@ee.cuhk.edu.hk; g.z.yang@imperial.ac.uk; rpettig@mail.nih.gov; benny.lo@imperial.ac.uk; fen.miao@siat.ac.cn; ye.li@siat.ac.cn; jingliu@ee.cuhk.edu.hk; ytzhang@ee.cuhk.edu.hk FU Innovation and Technology Fund from the Innovation and Technology Commission of Hong Kong [ITS/275/15FP] FX The work was supported in part by the Innovation and Technology Fund (Ref. ITS/275/15FP) from the Innovation and Technology Commission of Hong Kong. NR 112 TC 0 Z9 0 U1 8 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2194 J9 IEEE J BIOMED HEALTH JI IEEE J. Biomed. Health Inform. PD NOV PY 2016 VL 20 IS 6 BP 1455 EP 1465 DI 10.1109/JBHI.2016.2620995 PG 11 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA EE8AN UT WOS:000389846700001 PM 28113184 ER PT J AU Guo, P Banerjee, K Stanley, RJ Long, R Antani, S Thoma, G Zuna, R Frazier, SR Moss, RH Stoecker, WV AF Guo, Peng Banerjee, Koyel Stanley, R. Joe Long, Rodney Antani, Sameer Thoma, George Zuna, Rosemary Frazier, Shelliane R. Moss, Randy H. Stoecker, William V. TI Nuclei-Based Features for Uterine Cervical Cancer Histology Image Analysis With Fusion-Based Classification SO IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS LA English DT Article DE Cervical cancer; cervical intraepithelial neoplasia (CIN); fusion-based classification; image processing; linear discriminant analysis (LDA); support vector machine (SVM) ID INTRAEPITHELIAL NEOPLASIA CIN; SELECTION AB Cervical cancer, which has been affecting women worldwide as the second most common cancer, can be cured if detected early and treated well. Routinely, expert pathologists visually examine histology slides for cervix tissue abnormality assessment. In previous research, we investigated an automated, localized, fusion-based approach for classifying squamous epithelium into Normal, CIN1, CIN2, and CIN3 grades of cervical intraepithelial neoplasia (CIN) based on image analysis of 61 digitized histology images. This paper introduces novel acellular and atypical cell concentration features computed from vertical segment partitions of the epithelium region within digitized histology images to quantize the relative increase in nuclei numbers as the CIN grade increases. Based on the CIN grade assessments from two expert pathologists, image-based epithelium classification is investigated with voting fusion of vertical segments using support vector machine and linear discriminant analysis approaches. Leaveone-out is used for the training and testing for CIN classification, achieving an exact grade labeling accuracy as high as 88.5%. C1 [Guo, Peng; Banerjee, Koyel; Stanley, R. Joe; Moss, Randy H.] Missouri Univ Sci & Technol, Dept Elect & Comp Engn, Rolla, MO 65409 USA. [Long, Rodney; Antani, Sameer; Thoma, George] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, DHHS, Bethesda, MD 20894 USA. [Zuna, Rosemary] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73117 USA. [Frazier, Shelliane R.] Univ Missouri, Dept Surg Pathol, Hosp & Clin, Columbia, MO 65202 USA. [Stoecker, William V.] Stoecker & Associates, Rolla, MO 65401 USA. RP Guo, P (reprint author), Missouri Univ Sci & Technol, Dept Elect & Comp Engn, Rolla, MO 65409 USA. EM kbnm6@mst.edu; stanleyj@mst.edu; long@nlm.nih.gov; antani@nlm.nih.gov; gthoma@mail.nih.gov; rosemary-zuna@ouhsc.edu; FrazierSR@health.missouri.edu; rhm@mst.edu; wvs@mst.edu FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; Lister Hill National Center for Biomedical Communications FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, the National Library of Medicine, and the Lister Hill National Center for Biomedical Communications. NR 28 TC 0 Z9 0 U1 1 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2194 J9 IEEE J BIOMED HEALTH JI IEEE J. Biomed. Health Inform. PD NOV PY 2016 VL 20 IS 6 BP 1595 EP 1607 DI 10.1109/JBHI.2015.2483318 PG 13 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA EE8AN UT WOS:000389846700015 PM 26529792 ER PT J AU Bacon, SL Czajkowski, SM Lavoie, KL Freedland, KE AF Bacon, S. L. Czajkowski, S. M. Lavoie, K. L. Freedland, K. E. TI THE INTERNATIONAL BEHAVIOURAL TRIALS NETWORK (IBTN): AN INTERNATIONAL EFFORT TO IMPROVE THE RIGOR AND IMPACT OF BEHAVIORAL CLINICAL TRIALS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Bacon, S. L.; Lavoie, K. L.] Hop Sacre Coeur Montreal, Montreal Behav Med Ctr, Montreal, PQ, Canada. [Bacon, S. L.] Concordia Univ, Dept Exercise Sci, Montreal, PQ, Canada. [Czajkowski, S. M.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Betheseda, MD USA. [Lavoie, K. L.] Univ Quebec Montreal, Dept Psychol, Montreal, PQ, Canada. [Freedland, K. E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S163 BP S53 EP S54 PG 2 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400174 ER PT J AU Czajkowski, SM Naar, S Powell, LH Bacon, SL AF Czajkowski, S. M. Naar, S. Powell, L. H. Bacon, S. L. TI NEW APPROACHES TO OBESITY PREVENTION AND TREATMENT: FINDINGS FROM THE OBESITY-RELATED BEHAVIORAL INTERVENTION TRIALS (ORBIT) CONSORTIUM SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, S. M.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Naar, S.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Powell, L. H.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. [Bacon, S. L.] Hop Sacre Coeur Montreal, Montreal Behav Med Ctr, Montreal, PQ, Canada. [Bacon, S. L.] Concordia Univ, Dept Exercise Sci, Montreal, PQ, Canada. EM Simon.bacon@concordia.ca NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S380 BP S124 EP S124 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400393 ER PT J AU Czajkowski, SM AF Czajkowski, S. M. CA Obesity-Related Behavioral TI THE OBESITY-RELATED BEHAVIORAL INTERVENTION TRIALS (ORBIT) CONSORTIUM: DEVELOPING NEW WAYS TO PREVENT AND TREAT OBESITY SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, S. M.; Obesity-Related Behavioral] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. EM Susan.Czajkowski@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S382 BP S124 EP S124 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400394 ER PT J AU Czajkowski, SM Powell, LH Naar, S AF Czajkowski, S. M. Powell, L. H. Naar, S. CA Obesity-Related Behav Intervention TI DESIGNING MORE EFFECTIVE BEHAVIORAL TREATMENTS FOR CHRONIC DISEASES: THE ORBIT MODEL FOR BEHAVIORAL INTERVENTION DEVELOPMENT SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, S. M.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Betheseda, MD USA. [Powell, L. H.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. [Naar, S.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S165 BP S54 EP S54 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400176 ER PT J AU Green, P Colditz, G van der Leeden, M Emery, J Suls, J AF Green, P. Colditz, G. van der Leeden, M. Emery, J. Suls, J. TI CANCER IN THE CONTEXT OF COMORBIDITY AND MULTIMORBIDITY: PERSPECTIVES FROM BEHAVIOURAL MEDICINE SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Green, P.; Suls, J.] NCI, Bethesda, MD USA. [Colditz, G.] Washington Univ, Sch Med, St Louis, MO USA. [van der Leeden, M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Emery, J.] Univ Melbourne, Melbourne, Vic, Australia. EM paige.green@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S097 BP S32 EP S33 PG 2 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400108 ER PT J AU Kaufmann, PG Freedland, KE Powell, LH AF Kaufmann, Peter G. Freedland, Kenneth E. Powell, Lynda H. TI ADVANCED CONCEPTS IN HIGH QUALITY RANDOMISED CLINICAL TRIALS - PART 2 SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufmann, Peter G.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD USA. [Freedland, Kenneth E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Powell, Lynda H.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA 9 BP S2 EP S2 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400010 ER PT J AU Kaufmann, PG Freedland, KE Powell, LH AF Kaufmann, Peter G. Freedland, Kenneth E. Powell, Lynda H. TI ADVANCED CONCEPTS IN HIGH QUALITY RANDOMIZED CLINICAL TRIALS - PART 1 SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufmann, Peter G.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD USA. [Freedland, Kenneth E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Powell, Lynda H.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA 3 BP S1 EP S1 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400005 ER PT J AU McGregor, LM Wilson, C Myers, RE Klein, W Flight, I von Wagner, C AF McGregor, L. M. Wilson, C. Myers, R. E. Klein, W. Flight, I. von Wagner, C. TI COLORECTAL CANCER SCREENING: HOW TO ENGAGE INVITEES AND KEEP THEM COMING BACK FOR MORE SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [McGregor, L. M.; von Wagner, C.] UCL, Dept Epidemiol & Publ Hlth, CR UK Hlth Behav Res Ctr, London, England. [Wilson, C.; Flight, I.] Flinders Univ S Australia, Flinders Ctr Innovat Canc, Adelaide, SA, Australia. [Wilson, C.; Flight, I.] Canc Council South Australia, Adelaide, SA, Australia. [Myers, R. E.] Thomas Jefferson Univ, Dept Med Oncol, Div Populat Sci, Philadelphia, PA 19107 USA. [Klein, W.] NCI, NIH, DHHS, 9609 Med Ctr Dr,Room 3E140,MSC 9761, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S397 BP S129 EP S129 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400409 ER PT J AU Sheeran, P Rothman, A Abraham, C Klein, W AF Sheeran, Paschal Rothman, Alexander Abraham, Charles Klein, William TI UNDERSTANDING WHAT WORKS IN INTERVENTIONS DESIGNED TO CHANGE HEALTH BEHAVIOUR: NEW APPROACHES TO LINKING THEORY RESEARCH DESIGN, AND EVIDENCE SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Sheeran, Paschal] Univ N Carolina, Chapel Hill, NC USA. [Rothman, Alexander] Univ Minnesota, Minneapolis, MN 55455 USA. [Abraham, Charles] Univ Exeter, Psychol Appl Hlth, Sch Med, Exeter, Devon, England. [Klein, William] NCI, Bethesda, MD 20892 USA. EM psheeran@email.unc.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA S669 BP S216 EP S217 PG 2 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400679 ER PT J AU Waller, J Haddrell, J Chorley, A Ferrer, R Marlow, L AF Waller, J. Haddrell, J. Chorley, A. Ferrer, R. Marlow, L. TI USING THE PRECAUTION ADOPTION PROCESS MODEL TO UNDERSTAND NON-PARTICIPATION IN CERVICAL SCREENING SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Waller, J.; Haddrell, J.; Chorley, A.; Marlow, L.] UCL, Dept Epidemiol & Publ Hlth, Hlth Behav Res Ctr, London, England. [Ferrer, R.] NCI, Behav Res Programme, Div Canc Control & Populat Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD NOV PY 2016 VL 23 SU 1 MA P548 BP S177 EP S177 PG 1 WC Psychology, Clinical SC Psychology GA ED6CV UT WOS:000388943400558 ER PT J AU Houghton, LC Ganmaa, D Rosenberg, PS Davaalkham, D Stanczyk, FZ Hoover, RN Troisi, R AF Houghton, Lauren C. Ganmaa, Davaasambuu Rosenberg, Philip S. Davaalkham, Dambadarjaa Stanczyk, Frank Z. Hoover, Robert N. Troisi, Rebecca TI Associations of Breast Cancer Risk Factors with Premenopausal Sex Hormones in Women with Very Low Breast Cancer Risk SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE breast cancer; sex steroids; estrogen; progesterone; testosterone; urban migration; Mongolia ID LIFE-STYLE; BODY; ESTROGENS; AMERICAN; MONGOLIA; STEROIDS AB Breast cancer incidence rates are low but rising in urban Mongolia. We collected reproductive and lifestyle factor information and measured anthropometrics and serum sex steroid concentrations among 314 premenopausal women living in Ulaanbaatar, Mongolia. Mean differences in hormone concentrations by these factors were calculated using age-adjusted quadratic regression splines. Estrone and estradiol in college-educated women were, respectively, 18.2% (p = 0.03) and 23.6% (p = 0.03) lower than in high-school-educated women. Progesterone concentrations appeared 55.8% lower (p = 0.10) in women residing in modern housing compared with women living in traditional housing (gers), although this finding was not statistically significant. Testosterone concentrations were positively associated with adiposity and central fat distribution; 17.1% difference (p = 0.001) for highest vs. lowest quarter for body mass index and 15.1% difference (p = 0.005) for waist-to-height ratio. Estrogens were higher in the follicular phase of women who breastfed each child for shorter durations. A distinct hormonal profile was associated with an urban lifestyle in premenopausal, Mongol women. In particular, heavier, more-educated women living in urban dwellings had higher testosterone and lower estrogen and progesterone levels. Higher breast cancer incidence in urban compared with rural women suggest that the hormonal profile associated with a more traditional lifestyle may be protective among Mongol women. C1 [Houghton, Lauren C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Ganmaa, Davaasambuu] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Ganmaa, Davaasambuu] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Harvard Med Sch, Boston, MA 02115 USA. [Rosenberg, Philip S.; Hoover, Robert N.; Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Davaalkham, Dambadarjaa] Hlth Sci Univ Mongolia, Ulaanbaatar 210648, Mongol Peo Rep. [Stanczyk, Frank Z.] Univ Southern Calif, Keck Sch Med, Div Reprod Endocrinol & Infertil, Los Angeles, CA 90033 USA. RP Troisi, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM lh2746@columbia.edu; gdavaasa@hsph.harvard.edu; rosenbep@exchange.nih.gov; davaalham@yahoo.com; fstanczyk@att.net; hooverr@mail.nih.gov; troisir@mail.nih.gov FU Intramural Division of the National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Division of the National Cancer Institute at the National Institutes of Health. NR 27 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD NOV PY 2016 VL 13 IS 11 AR 1066 DI 10.3390/ijerph13111066 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE4KR UT WOS:000389571300025 ER PT J AU Reznik, SE Gardner, EL Ashby, CR AF Reznik, Sandra E. Gardner, Eliot L. Ashby, Charles R., Jr. TI Cannabidiol: a potential treatment for post Ebola syndrome? SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; Cannabidiol; Post Ebola Syndrome; Phytocannabinoids ID VIRUS DISEASE; SIERRA-LEONE; CANNABINOIDS; SURVIVORS; SEQUELAE AB Patients recovered from Ebola virus infection may experience short-and long-term physical, neuropsychological and social sequelae, including arthralgia, musculoskeletal pain, ophthalmic inflammation, auditory problems, fatigue, confusion, insomnia, short-term memory impairment, anxiety, depression and anorexia, all lasting from two weeks to more than two years. Currently there are no treatments for post Ebola sequelae. We hypothesize that cannabidiol (CBD) may attenuate some of these post Ebola sequelae, several of which have been postulated to result from inflammation and/or an autoimmune response. CBD has anti-inflammatory actions in various animal models. Clinical studies have shown that oral administration of CBD, compared to placebo, significantly reduces anxiety, has antinociceptive and anticonvulsant actions, and may be therapeutic for insomnia. Overall, CBD has a number of pharmacological effects that may significantly improve the mental and somatic health of patients suffering from post Ebola sequelae. In humans, CBD, at therapeutic doses, does not: 1) elicit dependence or tolerance; 2) significantly alter heart rate or blood pressure; 3) affect gastrointestinal transit; 4) produce significant cognitive or psychomotor impairments. Mild sedation and nausea are the most commonly reported adverse effects associated with CBD. CBD, based on its pharmacological effects and favorable safety profile, should be considered as a treatment for individuals with post Ebola sequelae. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. C1 [Reznik, Sandra E.; Ashby, Charles R., Jr.] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY USA. [Reznik, Sandra E.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pathol, 111 E 210th St, Bronx, NY 10467 USA. [Reznik, Sandra E.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, 111 E 210th St, Bronx, NY 10467 USA. [Gardner, Eliot L.] NIDA, NIH, Neuropsychopharmacol Sect, Mol Targets & Medicat Discovery Branch,Intramural, Bethesda, MD 20892 USA. RP Ashby, CR (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY USA. EM cnsratdoc@optonline.net NR 19 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD NOV PY 2016 VL 52 BP 74 EP 76 DI 10.1016/j.ijid.2016.09.020 PG 3 WC Infectious Diseases SC Infectious Diseases GA EE3RZ UT WOS:000389516600015 PM 27686726 ER PT J AU Magnus, MC Karlstad, O Midtun, O Haberg, SE Tunheim, G Parr, CL Nafstad, P London, SJ Nilsen, RM Ueland, PM Nystad, W AF Magnus, Maria C. Karlstad, Oystein Midtun, Oivind Haberg, Siri E. Tunheim, Gro Parr, Christine L. Nafstad, Per London, Stephanie J. Nilsen, Roy M. Ueland, Per M. Nystad, Wenche TI Maternal plasma total neopterin and kynurenine/tryptophan levels during pregnancy in relation to asthma development in the offspring SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; kynurenine; neopterin; pregnancy; tryptophan ID INDOLEAMINE 2,3-DIOXYGENASE; TRYPTOPHAN CATABOLISM; URINARY NEOPTERIN; INTERFERON-GAMMA; NORWEGIAN MOTHER; VITAMIN STATUS; IMMUNE-SYSTEM; CHILD COHORT; DISEASE; ACTIVATION AB Background: Neopterin levels and kynurenine/tryptophan ratios (KTRs) increase with IFN-gamma stimulation, indicating T(H)1 immunity, and thus might be inversely associated with asthma. Objective: We sought to examine the association of maternal neopterin levels and KTRs during pregnancy with asthma in the offspring. Methods: We analyzed the associations of maternal plasma total neopterin levels and KTRs in midpregnancy with asthma at age 7 years among 2883 children in the Norwegian Mother and Child Cohort Study. Asthma was classified either based on registered dispensed asthma medications in the Norwegian Prescription Database or maternal report. We calculated adjusted relative risks using log-binomial regression. Results: The median gestational week of blood sampling was 18 weeks (interquartile range, 17-19 weeks). The risk of dispensed asthma medications at age 7 years was highest among children of mothers in the highest quartile of neopterin levels, whereas the risk was similar in the 3 lowest quartiles. The adjusted relative risk of dispensed asthma medications was 1.66 (95% CI, 1.16-2.38) when comparing children of mothers in the highest quartile with those in the 3 lowest quartiles. A similar association was observed for maternal report of asthma at age 7 years. When we evaluated allergic versus nonallergic asthma, neopterin levels tended to be associated with nonallergic asthma. Maternal KTR was not associated with asthma development. Conclusions: Our findings indicate that high maternal levels of neopterin, a marker of cellular immune activation, during pregnancy were positively associated with asthma in offspring. Experimental studies would be needed to further elucidate underlying mechanisms. C1 [Magnus, Maria C.; Karlstad, Oystein; Haberg, Siri E.; Parr, Christine L.; Nafstad, Per; Nystad, Wenche] Norwegian Inst Publ Hlth, Div Mental & Phys Hlth, Oslo, Norway. [Tunheim, Gro] Norwegian Inst Publ Hlth, Div Infect Control & Environm Hlth, Oslo, Norway. [Midtun, Oivind] Bevital AS, Bergen, Norway. [Nafstad, Per] Univ Oslo, Fac Med, Dept Community Med, Bergen, Norway. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Nilsen, Roy M.] Haukeland Hosp, Clin Res Ctr, Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, Lab Clin Biochem, Bergen, Norway. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, Bergen, Norway. RP Magnus, MC (reprint author), Norwegian Inst Publ Hlth, Dept Chron Dis, POB 4404 Nydalen, Oslo, Norway. EM Maria.Christine.Magnus@fhi.no OI Karlstad, Oystein/0000-0003-1204-787X; London, Stephanie/0000-0003-4911-5290 FU National Institute of Health (National Institute of Environmental Health Sciences) [N01-ES-75558]; National Institute of Health (National Institute of Neurological Disorders and Stroke) [UO1 NS 047537-01, UO1 NS 047537-06A1]; Norwegian Research Council/FUGE [151918/S10]; Norwegian Research Council [221919]; Division of Intramural Research at the National Institute of Environmental Health Sciences FX Data collection in the Norwegian Mother and Child Cohort Study is supported by National Institutes of Health (National Institute of Environmental Health Sciences contract no. N01-ES-75558, National Institute of Neurological Disorders and Stroke grants UO1 NS 047537-01 and UO1 NS 047537-06A1) and the Norwegian Research Council/FUGE (grant no. 151918/S10). This work was supported by the Norwegian Research Council (grant no. 221919 to W.N.). The work is also supported by the Division of Intramural Research at the National Institute of Environmental Health Sciences (to S.J.L.). NR 35 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2016 VL 138 IS 5 BP 1319 EP + DI 10.1016/j.jaci.2016.02.032 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA EE4AA UT WOS:000389542700010 PM 27221136 ER PT J AU Jacobino, SR Nederend, M Hennus, M Houben, ML Ngwuta, JO Viveen, M Coenjaerts, FEJ Hack, CE van Neerven, RJJ Graham, BS Bont, L Leusen, JHW AF Jacobino, Shamir R. Nederend, Maaike Hennus, Marije Houben, Michiel L. Ngwuta, Joan O. Viveen, Marco Coenjaerts, Frank E. J. Hack, C. Erik van Neerven, R. J. Joost Graham, Barney S. Bont, Louis Leusen, Jeanette H. W. TI Human amniotic fluid antibodies protect the neonate against respiratory syncytial virus infection SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID RSV; IMMUNITY; CHILDREN; INFANTS C1 [Jacobino, Shamir R.; Nederend, Maaike; Hennus, Marije; Hack, C. Erik; Bont, Louis; Leusen, Jeanette H. W.] UMC Utrecht, Lab Translat Immunol, Utrecht, Netherlands. [Hennus, Marije; Bont, Louis] Wilhelmina Childrens Hosp, Dept Pediat, Utrecht, Netherlands. [Ngwuta, Joan O.; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Viveen, Marco; Coenjaerts, Frank E. J.] UMC Utrecht, Med Microbiol, Utrecht, Netherlands. [van Neerven, R. J. Joost] Wageningen Univ, Cell Biol & Immunol, Wageningen, Netherlands. RP Leusen, JHW (reprint author), UMC Utrecht, Lab Translat Immunol, Utrecht, Netherlands. EM jleusen@umcutrecht.nl OI Leusen, Jeanette/0000-0003-4982-6914 NR 9 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2016 VL 138 IS 5 BP 1477 EP + DI 10.1016/j.jaci.2016.06.001 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA EE4AA UT WOS:000389542700038 PM 27448445 ER PT J AU Kamoun, C Morsheimer, M Sullivan, KE Holland, SM Rundles, CC Bunin, N Heimall, JR AF Kamoun, Camilia Morsheimer, Megan Sullivan, Kathleen E. Holland, Steven M. Rundles, Charlotte Cunningham Bunin, Nancy Heimall, Jennifer R. TI Successful unrelated cord blood transplant for complete IFN-gamma receptor 2 deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID STEM-CELL TRANSPLANTATION; CHILD; SUSCEPTIBILITY C1 [Kamoun, Camilia] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Morsheimer, Megan; Sullivan, Kathleen E.; Heimall, Jennifer R.] Childrens Hosp Philadelphia, Dept Pediat, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rundles, Charlotte Cunningham] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bunin, Nancy] Childrens Hosp Philadelphia, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. RP Heimall, JR (reprint author), Childrens Hosp Philadelphia, Dept Pediat, Div Allergy & Immunol, Philadelphia, PA 19104 USA. EM heimallj@email.chop.edu NR 9 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2016 VL 138 IS 5 BP 1489 EP + DI 10.1016/j.jaci.2016.06.017 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA EE4AA UT WOS:000389542700042 PM 27522156 ER PT J AU Wang, YG Hwangpo, T Martin, MP Vince, N Qi, Y Reynolds, RJ Absher, D Gao, XJ Ballinger, CA Burrows, PD Atkinson, TP Brown, EE Elgavish, A Liu, CR Carrington, M Schroeder, HW AF Wang, Yuge Hwangpo, Tracy Martin, Maureen P. Vince, Nicolas Qi, Ying Reynolds, Richard J. Absher, Devin Gao, Xiaojiang Ballinger, Carol A. Burrows, Peter D. Atkinson, T. Prescott Brown, Elizabeth E. Elgavish, Ada Liu, Cunren Carrington, Mary Schroeder, Harry W. TI Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID SUSCEPTIBILITY; HLA; RECOGNITION; ARTHRITIS; GENES C1 [Wang, Yuge; Burrows, Peter D.; Schroeder, Harry W.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Wang, Yuge; Hwangpo, Tracy; Reynolds, Richard J.; Ballinger, Carol A.; Elgavish, Ada; Liu, Cunren; Schroeder, Harry W.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Martin, Maureen P.; Qi, Ying; Gao, Xiaojiang; Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Vince, Nicolas; Carrington, Mary] MIT & Harvard, Ragon Inst MGH, Cambridge, MA USA. [Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Atkinson, T. Prescott] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Brown, Elizabeth E.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. RP Schroeder, HW (reprint author), Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. EM hschroeder@uabmc.edu FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; NCRR NIH HHS [M01 RR000032]; NIAID NIH HHS [R21 AI079741, T32 AI007051, U01 AI090902]; NIAMS NIH HHS [K01 AR060848] NR 9 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2016 VL 138 IS 5 BP 1495 EP 1498 DI 10.1016/j.jaci.2016.07.011 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA EE4AA UT WOS:000389542700045 PM 27665490 ER PT J AU Thomsen, IP Smith, MA Holland, SM Creech, CB AF Thomsen, Isaac P. Smith, Meaghan A. Holland, Steven M. Creech, C. Buddy TI A Comprehensive Approach to the Management of Children and Adults with Chronic Granulomatous Disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Chronic granulomatous disease; Multidisciplinary care; IFN-gamma ID STEM-CELL TRANSPLANTATION; MANIFESTATIONS; INFECTIONS; FEATURES; CARRIERS; THERAPY; COLITIS AB Chronic granulomatous disease (CGD), a disease characterized by inadequate neutrophil killing of microbial pathogens, affects 4 to 5 per million live births. For many decades following its description, CGD was a fatal disease in childhood. With the development of effective preventive therapies and the early recognition of infectious complications, 90% of children with CGD now survive into adulthood. The management of CGD in adults includes unique challenges and potential disease manifestations. In this article, the authors discuss the current approach to the management of CGD in both children and adults. This includes a focus on the importance of a comprehensive multidisciplinary approach in the care of CGD and its potential complications. In addition, a novel approach to improving education about CGD, and subsequently improving adherence to preventive therapies, is discussed. (C) 2016 American Academy of Allergy, Asthma & Immunology. C1 [Thomsen, Isaac P.; Smith, Meaghan A.; Creech, C. Buddy] Vanderbilt Univ, Sch Med, Dept Pediat, Div Pediat Infect Dis,Vanderbilt Vaccine Res Prog, Nashville, TN 37212 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Thomsen, IP (reprint author), D-7235 MCN,1161 21st Ave South, Nashville, TN 37232 USA. EM isaac.thomsen@vanderbilt.edu FU Horizon Pharma, plc. FX This work was supported in part by an educational grant from Horizon Pharma, plc. NR 32 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD NOV-DEC PY 2016 VL 4 IS 6 BP 1082 EP 1088 DI 10.1016/j.jaip.2016.03.021 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA EE4ZA UT WOS:000389613300007 PM 27178966 ER PT J AU Freeman, AF Shah, NN Parta, M Su, HC Brofferio, A Gradus-Pizlo, I Butty, S Hughes, TE Kleiner, DE Avila, D Heller, T Kong, HH Holland, SM Hickstein, DD AF Freeman, Alexandra F. Shah, Nirali N. Parta, Mark Su, Helen C. Brofferio, Alessandra Gradus-Pizlo, Irma Butty, Sabah Hughes, Thomas E. Kleiner, David E. Avila, Daniele Heller, Theo Kong, Heidi H. Holland, Steven M. Hickstein, Dennis D. TI Haploidentical related donor hematopoietic stem cell transplantation with post-transplantation cyclophos phamide for DOCK8 deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter C1 [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bldg 10,Room 12C103,9000 Rockville Pike, Bethesda, MD 20892 USA. [Shah, Nirali N.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Parta, Mark] Leidos Biomedical Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus Frederick, Frederick, MD USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Brofferio, Alessandra] NHLBI, Cardiovasc Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gradus-Pizlo, Irma; Butty, Sabah] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hughes, Thomas E.] NIH, Clin Ctr Pharm Dept, Bldg 10, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Lab Pathol Branch, NIH, Bethesda, MD 20892 USA. [Avila, Daniele; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Kong, Heidi H.] NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bldg 10,Room 12C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD NOV-DEC PY 2016 VL 4 IS 6 BP 1239 EP + DI 10.1016/j.jaip.2016.06.028 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA EE4ZA UT WOS:000389613300031 PM 27641484 ER PT J AU Torre, P Hoffman, HJ Springer, G Cox, C Young, MA Margolick, JB Plankey, M AF Torre, Peter, III Hoffman, Howard J. Springer, Gayle Cox, Christopher Young, Mary A. Margolick, Joseph B. Plankey, Michael TI Speech audiometry findings from HIV plus and HIV- adults in the MACS and WIHS longitudinal cohort studies SO JOURNAL OF COMMUNICATION DISORDERS LA English DT Article DE HIV; Speech audiometry; Adults ID MULTICENTER AIDS COHORT; WOMENS INTERAGENCY HIV; HEARING-LOSS; SERONEGATIVE MEN; MANIFESTATIONS; HIV/AIDS AB The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV +, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air-and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40 dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0 to 25 dB hearing level (HL) with one category as >= 30 dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV adults had a similar percentages of word recognition scores <90%, a lower percentage of HIV- adults had 90-99%, but HIV adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio PRI= 1.45, p = 0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication. (C) 2016 Elsevier Inc. All rights reserved. C1 [Torre, Peter, III] San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr,SLHS 244, San Diego, CA 92182 USA. [Hoffman, Howard J.] NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Springer, Gayle; Cox, Christopher] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Young, Mary A.; Plankey, Michael] Georgetown Univ, Med Ctr, Div Infect Dis, Dept Med, Washington, DC 20007 USA. [Margolick, Joseph B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Torre, P (reprint author), San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr,SLHS 244, San Diego, CA 92182 USA. EM ptorre@mail.sdsu.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID), NIH [U01 AI-035042-18, U01 AI-034994-17]; NIAID [U01-AI-34994]; National Cancer Institute [U01-AI-35042]; ICTR [UL1-RR025005]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH [U01-HD-32632] FX This research was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) via interagency agreement with the National Institute of Allergy and Infectious Diseases (NIAID), NIH for Cooperative Agreements U01 AI-035042-18 (MACS) and U01 AI-034994-17 (WIHS). Support of the Baltimore-Washington, DC MACS site was provided by the NIAID, with additional supplemental funding from the National Cancer Institute (U01-AI-35042) and ICTR (UL1-RR025005). Support of the Metropolitan Washington, DC WIHS site was provided by the NIAID (U01-AI-34994) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH (U01-HD-32632). NR 16 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 0021-9924 EI 1873-7994 J9 J COMMUN DISORD JI J. Commun. Disord. PD NOV-DEC PY 2016 VL 64 BP 103 EP 109 DI 10.1016/j.jcomdis.2016.07.004 PG 7 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EE4IQ UT WOS:000389565900008 PM 27477593 ER PT J AU Bottomley, A Pe, M Sloan, J Basch, E Bonnetain, F Calvert, M Campbell, A Cleeland, C Cocks, K Collette, L Dueck, AC Devlin, N Flechtner, HH Gotay, C Greimel, E Griebsch, I Groenvold, M Hamel, JF King, M Kluetz, PG Koller, M Malone, DC Martinelli, F Mitchell, SA Moinpour, CM Musoro, J O'Connor, D Oliver, K Piault-Louis, E Piccart, M Pimentel, FL Quinten, C Reijneveld, JC Schurmann, C Smith, AW Soltys, KM Taphoorn, MJB Velikova, G Coens, C AF Bottomley, Andrew Pe, Madeline Sloan, Jeff Basch, Ethan Bonnetain, Franck Calvert, Melanie Campbell, Alicyn Cleeland, Charles Cocks, Kim Collette, Laurence Dueck, Amylou C. Devlin, Nancy Flechtner, Hans-Henning Gotay, Carolyn Greimel, Eva Griebsch, Ingolf Groenvold, Mogens Hamel, Jean-Francois King, Madeleine Kluetz, Paul G. Koller, Michael Malone, Daniel C. Martinelli, Francesca Mitchell, Sandra A. Moinpour, Carol M. Musoro, Jammbe O'Connor, Daniel Oliver, Kathy Piault-Louis, Elisabeth Piccart, Martine Pimentel, Francisco L. Quinten, Chantal Reijneveld, Jaap C. Schuermann, Christoph Smith, Ashley Wilder Soltys, Katherine M. Taphoorn, Martin J. B. Velikova, Galina Coens, Corneel CA Setting Int Stand Analyzing TI Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards SO LANCET ONCOLOGY LA English DT Article ID EVEROLIMUS PLUS EXEMESTANE; BREAST-CANCER AB Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes data in cancer randomised trials. This Personal View discusses the reasons why this project was initiated, the rationale for the planned work, and the expected benefits to cancer research, patient and provider decision making, care delivery, and policy making. C1 [Bottomley, Andrew; Pe, Madeline; Collette, Laurence; Martinelli, Francesca; Musoro, Jammbe; Coens, Corneel] EORTC Headquarters, 83-11 Ave E Mounier, B-1200 Brussels, Belgium. [Sloan, Jeff] Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Bonnetain, Franck] Univ Hosp Besancon, Methodol & Qual Life Unit Canc, INSERM, U1098, Besancon, France. [Calvert, Melanie] Univ Birmingham, Coll Med & Dent Sci, Inst Appl Hlth Res, Ctr Patient Reported Outcomes Res, Birmingham, W Midlands, England. [Campbell, Alicyn; Piault-Louis, Elisabeth] Genentech Inc, San Francisco, CA USA. [Cleeland, Charles] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Cocks, Kim] Adelphi Values, Bollington, Cheshire, England. [Dueck, Amylou C.] Mayo Clin, Alliance Stat & Data Ctr, Scottsdale, AZ USA. [Devlin, Nancy] Off Hlth Econ, London, England. [Flechtner, Hans-Henning] Univ Magdeburg, Clin Child & Adolescent Psychiat & Psychotherapy, Magdeburg, Germany. [Gotay, Carolyn] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Greimel, Eva] Med Univ Graz, Obstet & Gynecol, Graz, Austria. [Griebsch, Ingolf] Boehringer Ingelheim GmbH & Co KG, Frankfurt, Germany. [Groenvold, Mogens] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Groenvold, Mogens] Univ Copenhagen, Bispebjerg Hosp, Copenhagen, Denmark. [Hamel, Jean-Francois] Univ Hosp Angers UNAM, Methodol & Biostat Dept, Angers, France. [King, Madeleine] Univ Sydney, Sch Psychol, Sydney, NSW, Australia. [King, Madeleine] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia. [Kluetz, Paul G.] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Koller, Michael] Univ Hosp Regensburg, Ctr Clin Studies, Regensburg, Germany. [Malone, Daniel C.] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Mitchell, Sandra A.; Smith, Ashley Wilder] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [O'Connor, Daniel] Med & Healthcare Prod Regulatory Agcy, London, England. [Oliver, Kathy] Int Brain Tumour Alliance, Tadworth, Surrey, England. [Piccart, Martine] Inst Jules Bordet, Internal Med Oncol, Brussels, Belgium. [Pimentel, Francisco L.] Univ Aveiro, Hlth Sci, Aveiro, Portugal. [Pimentel, Francisco L.] Lenitudes Med Ctr & Res, Santa Maria Feira, Portugal. [Quinten, Chantal] European Ctr Dis Prevent & Control, Surveillance & Response Support Unit, Epidemiol Methods Sect, Stockholm, Sweden. [Reijneveld, Jaap C.] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Reijneveld, Jaap C.] Vrije Univ Amsterdam Med Ctr, Brain Tumor Ctr, Amsterdam, Netherlands. [Schuermann, Christoph] Inst Qual & Efficiency Hlth Care, Cologne, Germany. [Soltys, Katherine M.] Hlth Canada, Ottawa, ON, Canada. [Taphoorn, Martin J. B.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Taphoorn, Martin J. B.] Med Ctr Haaglanden, The Hague, Netherlands. [Velikova, Galina] Univ Leeds, St Jamess Hosp, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. RP Bottomley, A (reprint author), EORTC Headquarters, 83-11 Ave E Mounier, B-1200 Brussels, Belgium. EM andrew.bottomley@eortc.be OI Pimentel, Francisco Luis/0000-0001-5993-5132 FU Boehringer Ingelheim GmbH; EORTC Cancer Research Fund; Fonds Cancer (FOCA) from Belgium FX EORTC received an unrestricted education grant from Boehringer Ingelheim GmbH to initiate this work and additional financial support was provided by the EORTC Cancer Research Fund and Fonds Cancer (FOCA) from Belgium. Andrew Bottomley confirms final responsibility for the decision to submit for publication. This publication reflects the views of the individual authors and should not be construed to represent official views or policies of the US Food and Drug Administration, US National Cancer Institute, Medicines and Healthcare products Regulatory Agency, or Health Canada. NR 26 TC 1 Z9 1 U1 2 U2 2 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 NOV PY 2016 VL 17 IS 11 BP E510 EP E514 DI 10.1016/S1470-2045(16)30510-1 PG 5 WC Oncology SC Oncology GA EE3YF UT WOS:000389537600021 PM 27769798 ER PT J AU Lau, MWL Ferre-D'Amare, AR AF Lau, Matthew W. L. Ferre-D'Amare, Adrian R. TI Many Activities, One Structure: Functional Plasticity of Ribozyme Folds SO MOLECULES LA English DT Review DE ribozyme; in vitro selection; fitness landscape ID GLMS RIBOZYME; INTERVENING SEQUENCE; NUCLEOTIDE SYNTHESIS; RNA; SELECTION; BINDING; TETRAHYMENA; RIBOSWITCH; PROTEIN; GLUCOSAMINE-6-PHOSPHATE AB Catalytic RNAs, or ribozymes, are involved in a number of essential biological processes, such as replication of RNA genomes and mobile genetic elements, RNA splicing, translation, and RNA degradation. The function of ribozymes requires the formation of active sites decorated with RNA functional groups within defined three-dimensional (3D) structures. The genotype (sequence) of RNAs ultimately determines what 3D structures they adopt (as a function of their environmental conditions). These 3D structures, in turn, give rise to biochemical activity, which can further elaborate them by catalytic rearrangements or association with other molecules. The fitness landscape of a non-periodic linear polymer, such as RNA, relates its primary structure to a phenotype. Two major challenges in the analysis of ribozymes is to map all possible genotypes to their corresponding catalytic activity (that is, to determine their fitness landscape experimentally), and to understand whether their genotypes and three-dimensional structures can support multiple different catalytic functions. Recently, the combined results of experiments that employ in vitro evolution methods, high-throughput sequencing and crystallographic structure determination have hinted at answers to these two questions: while the fitness landscape of ribozymes is rugged, meaning that their catalytic activity cannot be optimized by a smooth trajectory in sequence space, once an RNA achieves a stable three-dimensional fold, it can be endowed with distinctly different biochemical activities through small changes in genotype. This functional plasticity of highly structured RNAs may be particularly advantageous for the adaptation of organisms to drastic changes in selective pressure, or for the development of new biotechnological tools. C1 [Lau, Matthew W. L.; Ferre-D'Amare, Adrian R.] NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM matt.wl.lau@gmail.com; adrian.ferre@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health FX We thank J.N. Pitt for discussions. This work was supported in part by the intramural program of the National Heart, Lung and Blood Institute, National Institutes of Health. M.W.L. was a Croucher Foundation Post-doctoral Fellow. NR 40 TC 1 Z9 1 U1 8 U2 8 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD NOV PY 2016 VL 21 IS 11 AR 1570 DI 10.3390/molecules21111570 PG 8 WC Chemistry, Organic SC Chemistry GA EE9AO UT WOS:000389918200150 ER PT J AU Lizardo, MM Morrow, JJ Miller, TE Hong, ES Ren, L Mendoza, A Halsey, CH Scacheri, PC Helman, LJ Khanna, C AF Lizardo, Michael M. Morrow, James J. Miller, Tyler E. Hong, Ellen S. Ren, Ling Mendoza, Arnulfo Halsey, Charles H. Scacheri, Peter C. Helman, Lee J. Khanna, Chand TI Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression SO NEOPLASIA LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; BREAST-CANCER; TUMOR; GRP78; OSTEOSARCOMA; RESISTANCE; APOPTOSIS; IDENTIFICATION; MECHANISM; CHAPERONE AB Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies. C1 [Lizardo, Michael M.; Hong, Ellen S.; Mendoza, Arnulfo; Helman, Lee J.; Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morrow, James J.; Miller, Tyler E.; Scacheri, Peter C.] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA. [Morrow, James J.; Miller, Tyler E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Ren, Ling] NCI, Comparat Oncol Program, NIH, Bethesda, MD 20892 USA. [Halsey, Charles H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Khanna, Chand] Ethos Discovery, Washington, DC 20009 USA. [Khanna, Chand] Ethos Vet Hlth, Wolburn, MA 01801 USA. RP Khanna, C (reprint author), Ethos Discovery, Washington, DC 20009 USA.; Khanna, C (reprint author), Ethos Vet Hlth, Wolburn, MA 01801 USA. EM ckhanna@animalci.com FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research, Pediatric Oncology Branch; National Institutes of Health [15335, T32GM007250]; National Institutes of Health/National Cancer Institute [F30 CA186633, CA183510]; [RO1CA160356] FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, Pediatric Oncology Branch. M.M.L. was supported by National Institutes of Health Intramural Visiting Fellow Program(award 15335), J.J.M. and T.E.M. were funded by National Institutes of Health T32GM007250. J.J.M. and T.E.M. were also funded by National Institutes of Health/National Cancer Institute F30 CA186633 and CA183510, respectively. P.C.S. received grant support RO1CA160356. NR 36 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 1476-5586 J9 NEOPLASIA JI Neoplasia PD NOV PY 2016 VL 18 IS 11 BP 699 EP 710 DI 10.1016/j.neo.2016.09.001 PG 12 WC Oncology SC Oncology GA EE3TC UT WOS:000389520300006 PM 27973325 ER PT J AU Yee, LM Sandoval, G Bailit, J Reddy, UM Wapner, RJ Varner, MW Caritis, SN Prasad, M Tita, ATN Saade, G Sorokin, Y Rouse, DJ Blackwell, SC Tolosa, JE AF Yee, Lynn M. Sandoval, Grecio Bailit, Jennifer Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Caritis, Steve N. Prasad, Mona Tita, Alan T. N. Saade, George Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst TI Maternal and Neonatal Outcomes With Early Compared With Delayed Pushing Among Nulliparous Women SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CONTINUOUS EPIDURAL ANALGESIA; PERINATAL OUTCOMES; 2ND-STAGE; LABOR; DURATION; MANAGEMENT; MIDWIFERY; TRIAL; CARE AB OBJECTIVE: To describe factors associated with delayed pushing and evaluate the relationship between delayed pushing and perinatal outcomes in nulliparous women with singleton term gestations. METHODS: This was a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Assessment of Perinatal Excellence cohort of 115,502 women and their neonates born in 25 U.S. hospitals from 2008 to 2011. Nulliparous women with singleton, cephalic, nonanomalous term births who achieved 10-cm cervical dilation were included. Women in whom pushing was delayed by 60 minutes or greater (delayed group) were compared with those who initiated pushing within 30 minutes (early group). Multivariable regression analyses were used to assess the independent association of delayed pushing with mode of delivery, length of the second stage, and other maternal and perinatal outcomes (significance defined as P<.05). RESULTS: Of 21,034 women in the primary analysis sample, pushing was delayed in 18.4% (n=3,870). Women who were older, privately insured, or non-Hispanic white as well as those who had induction or augmentation of labor, diabetes, or epidural analgesia were more likely to have delayed pushing. Delayed pushing was more common when the second stage began during daytime hours or in hospitals with dedicated 24-hour obstetric anesthesia, although differences were small. After adjusting for differences in baseline and labor characteristics including center, women in the delayed group had longer mean durations of the second stage (191 compared with 84 minutes, P<.001) and of active pushing (86 compared with 76 minutes, P<.001). Delayed pushing was associated with greater rates of cesarean delivery (11.2% compared with 5.1%; adjusted odds ratio [OR] 1.86, 95% confidence interval [CI] 1.63-2.12), operative vaginal delivery (adjusted OR 1.26, 95% CI 1.14-1.40), postpartum hemorrhage (adjusted OR 1.43, 95% CI 1.05-1.95), and blood transfusion (adjusted OR 1.51, 95% CI 1.04-2.17). Delayed pushing was not associated with increased odds of adverse neonatal outcomes compared with early pushing. CONCLUSION: In this large birth cohort, delayed pushing was associated with longer second stage duration, increased odds of cesarean delivery, and increased odds of postpartum hemorrhage, but was not associated with neonatal morbidity. C1 Northwestern Univ, Dept Obstet, Chicago, IL 60611 USA. Northwestern Univ, Dept Gynecol, Chicago, IL 60611 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Columbia Univ, New York, NY USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama Birmingham, Birmingham, AL USA. Wayne State Univ, Detroit, MI USA. Brown Univ, Providence, RI 02912 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Yee, LM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, 250 E Super St,5-2191, Chicago, IL 60611 USA. EM lynn.yee@northwestern.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources [UL1 RR024989, 5UL1 RR025764] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (UL1 RR024989, 5UL1 RR025764). NR 19 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2016 VL 128 IS 5 BP 1039 EP 1047 DI 10.1097/AOG.0000000000001683 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE0GA UT WOS:000389251000020 PM 27741203 ER PT J AU Domalpally, A Danis, R Agorn, E Blodi, B Clemons, T Chew, E AF Domalpally, Amitha Danis, Ronald Agorn, Elvira Blodi, Barbara Clemons, Traci Chew, Emily CA Age-Related Eye Dis Study Res Grp TI Evaluation of Geographic Atrophy from Color Photographs and Fundus Autofluorescence Images Age-Related Eye Disease Study 2 Report Number 11 SO OPHTHALMOLOGY LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; VISUAL-ACUITY LOSS; MACULAR DEGENERATION; NATURAL-HISTORY; CLINICAL-TRIALS; PROGRESSION; OPHTHALMOSCOPE; ENLARGEMENT; PATTERNS; RATES AB Purpose: To compare measurements of area of geographic atrophy (GA) and change in GA area from color photographs and fundus autofluorescence (FAF) images. Design: The Age-Related Eye Disease Study 2 (AREDS2) was a prospective multicenter randomized clinical trial evaluating progression of dry age-related macular degeneration (AMD) using color photographs at annual visits over a 5-year study period. The FAF images were acquired in a subset of participants who joined the FAF ancillary study at any of the annual visits over the study period. Participants: The AREDS2 FAF ancillary study included 8070 corresponding color and FAF visits of 2202 participants with variable follow-up. Methods: Corresponding color and FAF images were independently evaluated at a central reading center for GA area measurement, lesion growth, and involvement of the macula center. Main Outcome Measures: Presence, area, growth rate of GA, and involvement of center of macula from color and FAF images. Results: Hypoautofluorescence was visible in 2048 visits (25.4%). Agreement for the presence of GA between the 2 modalities had a kappa of 0.79, with 23% of visits with hypoautofluorescence not presenting with GA on color photographs. Percentage agreement for GA presence ranged from 43% at baseline to 81% at year 5 with improving agreement over time. The mean difference in GA area between the 2 modalities was 0.5 mm(2), with larger areas on FAF. Growth rate of GA was 1.45 mm(2) from color photographs and 1.43 mm2 from FAF images. The center of the macula was involved in 51% of color photographs and 56% with FAF images. Conclusions: Geographic atrophy may be detected earlier by the use of FAF images, but over the course of the study, the 2 modalities become comparable. Progression of GA area is comparable between color photographs and FAF images, but evaluating involvement of the center of the macula may differ, probably because of macular pigmentation blocking autofluorescence. (C) 2016 by the American Academy of Ophthalmology. C1 [Domalpally, Amitha; Danis, Ronald; Blodi, Barbara] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. [Clemons, Traci] EMMES Corp, Rockville, MD USA. [Agorn, Elvira; Chew, Emily] NEI, Bethesda, MD 20892 USA. RP Domalpally, A (reprint author), Univ Wisconsin, Fundus Photograph Reading Ctr, Dept Ophthalmol & Visual Sci, 2828 Marshall Court,Suite 200, Madison, WI 53705 USA. EM adomalpally@rc.ophth.wisc.edu OI Domalpally, Amitha/0000-0002-8145-9619 FU National Eye Institute [HHS-N-260-2005-00007-C]; Research to Prevent Blindness FX The author(s) have made the following disclosure(s): A.D., R.D., E.A., B.B., E.C. and T.C.: Grant National Eye Institute grant no. HHS-N-260-2005-00007-C (TEC). Supported in part by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison (A.D., R.D., and B.B.). NR 35 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2016 VL 123 IS 11 BP 2401 EP 2407 DI 10.1016/j.ophtha.2016.06.025 PG 7 WC Ophthalmology SC Ophthalmology GA EE3QK UT WOS:000389509500025 PM 27448832 ER PT J AU Colin, VM Auperin, A Pillon, M Burke, A Anderson, J Barkausk, D Wheatley, K Delgado, R Alexander, S Uyttebroeck, A Bollard, C Zsiros, J Csoka, M Goma, G Tulard, A Patte, C Gross, T AF Colin, V. Minard Auperin, A. Pillon, M. Burke, A. Anderson, J. Barkausk, D. Wheatley, K. Delgado, R. Alexander, S. Uyttebroeck, A. Bollard, C. Zsiros, J. Csoka, M. Goma, G. Tulard, A. Patte, C. Gross, T. TI Results of the Randomized Intergroup Trial Inter-B-NHL RITUX 2010 for Children/Adolescents with High-Risk B-Cell Non Hodgkin Lymphoma (B-NHL) and Mature Acute Leukemia (B-AL) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Colin, V. Minard; Auperin, A.; Goma, G.; Tulard, A.; Patte, C.] Gustave Roussy, Paediat, Villejuif, France. [Pillon, M.] Univ Padua, Clin Oncoematol Paediat, Padua, Italy. [Burke, A.] Addenbrookes NHS Trust, Childrens Serv, Cambridge, England. [Anderson, J.] Merck Res Labs, Oncol, N Wales, PA USA. [Barkausk, D.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Biostat Div, Los Angeles, CA USA. [Wheatley, K.] Sch Canc Sci, Canc Res UK Clin Trials Unit, Birmingham, W Midlands, England. [Delgado, R.] Dept Pediat, Valencia, Spain. [Alexander, S.] Hosp Sick Child, Div Haematol Oncol, Toronto, ON, Canada. [Uyttebroeck, A.] Univ Hosp Leuven, Dept Paediat Haematooncol, Leuven, Belgium. [Bollard, C.] Main Hosp, Allergy & Immunol, Washington, DC USA. [Zsiros, J.] Univ Amsterdam, Emma Childrens Hosp, Dept Paediat Oncol, Amsterdam, Netherlands. [Csoka, M.] Semmelweis Univ, Dept Paediat 2, Budapest, Hungary. [Gross, T.] NCI, NIH, DHHS, Ctr Global Hlth, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 SU 3 MA O-104 BP S31 EP S31 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DY0XF UT WOS:000384818800439 ER EF