FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Alvarez, Y Tuen, M Shen, GM Nawaz, F Arthos, J Wolff, MJ Poles, MA Hioe, CE AF Alvarez, Yelina Tuen, Michael Shen, Guomiao Nawaz, Fatima Arthos, James Wolff, Martin J. Poles, Michael A. Hioe, Catarina E. TI Preferential HIV Infection of CCR6(+) Th17 Cells Is Associated with Higher Levels of Virus Receptor Expression and Lack of CCR5 Ligands SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE-DERIVED MACROPHAGES; PERIPHERAL-BLOOD; TYPE-1 INFECTION; IN-VITRO; PHYTOHEMAGGLUTININ STIMULATION; HOMING RECEPTOR; LYMPHOID-TISSUE; LYMPHOCYTES AB Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6(+) CD4(+) T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1 beta (IL-1 beta) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6(+) and Th17-depleted CCR6(+) CD4 T cell cultures and noted that Th17-enriched CCR6(+) cells expressed higher levels of alpha 4 beta 7 and bound HIV envelope in an alpha 4 beta 7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6(-) cells. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1 beta (CCL4), increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV. C1 [Alvarez, Yelina; Tuen, Michael; Shen, Guomiao; Hioe, Catarina E.] Dept Vet Affairs New York Harbor Healthcare Syst, VA Res Serv, New York, NY USA. [Alvarez, Yelina; Tuen, Michael; Shen, Guomiao; Hioe, Catarina E.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Nawaz, Fatima] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Nawaz, Fatima; Arthos, James] NYU, Sch Med, Sackler Inst Grad Biomed Sci, New York, NY USA. [Wolff, Martin J.; Poles, Michael A.] NYU, Sch Med, Dept Med, Div Gastroenterol, New York, NY USA. RP Hioe, CE (reprint author), Dept Vet Affairs New York Harbor Healthcare Syst, VA Res Serv, Manhattan Campus, New York, NY USA. EM catarina.hioe@nyumc.org OI Wolff, Martin/0000-0003-4391-2395; Poles, Michael/0000-0002-7993-6156 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; Department of Veterans Affairs Merit Review Award and Research Career Scientist Award; NIH [F31 AI085958, R01 AI-084807] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, the Department of Veterans Affairs Merit Review Award and Research Career Scientist Award (C.E.H.), and NIH grants F31 AI085958 (Y.A.) and R01 AI-084807 (C.E.H.). NR 46 TC 35 Z9 36 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2013 VL 87 IS 19 BP 10843 EP 10854 DI 10.1128/JVI.01838-13 PG 12 WC Virology SC Virology GA 214WV UT WOS:000324169200038 PM 23903844 ER PT J AU Min, JY Santos, C Fitch, A Twaddle, A Toyoda, Y DePasse, JV Ghedin, E Subbarao, K AF Min, Ji-Young Santos, Celia Fitch, Adam Twaddle, Alan Toyoda, Yoshiko DePasse, Jay V. Ghedin, Elodie Subbarao, Kanta TI Mammalian Adaptation in the PB2 Gene of Avian H5N1 Influenza Virus SO JOURNAL OF VIROLOGY LA English DT Article ID A VIRUSES; VIRULENCE; MICE AB The substitution of glutamic acid (E) for lysine (K) at position 627 of the PB2 protein of avian H5N1 viruses has been identified as a virulence and host range determinant for infection of mammals. Here, we report that the E-to-K host-adaptive mutation in the PB2 gene appeared from day 4 and 5 along the respiratory tracts of mice and was complete by day 6 postinoculation. This mutation correlated with efficient replication of the virus in mice. C1 [Min, Ji-Young; Santos, Celia; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Fitch, Adam; Twaddle, Alan; Toyoda, Yoshiko; DePasse, Jay V.; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM elg21@pitt.edu; ksubbarao@niaid.nih.gov OI Twaddle, Alan/0000-0001-9293-7607 FU NIAID, NIH; National Institute of General Medical Science, NIH [U54GM088491] FX This research was supported in part by the Intramural Research Program of the NIAID, NIH (K.S. and J.-Y.M.), and in part by the National Institute of General Medical Science, NIH, under award number U54GM088491 (E.G., J.V.D., and Y.T.). NR 19 TC 7 Z9 7 U1 1 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2013 VL 87 IS 19 BP 10884 EP 10888 DI 10.1128/JVI.01016-13 PG 5 WC Virology SC Virology GA 214WV UT WOS:000324169200041 PM 23864613 ER PT J AU Shi, M Holmes, EC Brar, MS Leung, FCC AF Shi, Mang Holmes, Edward C. Brar, Manreetpal Singh Leung, Frederick Chi-Ching TI Recombination Is Associated with an Outbreak of Novel Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Viruses in China SO JOURNAL OF VIROLOGY LA English DT Article AB In 2009 to 2010, there was a marked increase in the number of infections with highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) in China. Through phylogenetic analysis, we show that viruses from this outbreak originated from a single recombination event, illustrating the potential importance of this process for disease emergence. C1 [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Brar, Manreetpal Singh; Leung, Frederick Chi-Ching] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. [Leung, Frederick Chi-Ching] Nanjing Agr Univ, Bioinformat Ctr, Nanjing, Jiangsu, Peoples R China. RP Shi, M (reprint author), Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. EM rotund_zheda@hotmail.com OI Holmes, Edward/0000-0001-9596-3552 FU Research Grant Council of the Hong Kong Government [GRF770612]; HKU Strategic Research Theme of Infection and Immunology; International Postgraduate Research Scholarship from the University of Sydney; NHMRC Australia Fellowship; Bioinformatics Center, Nanjing Agricultural University FX This work was partly supported by grants from the Research Grant Council of the Hong Kong Government (GRF770612), HKU Strategic Research Theme of Infection and Immunology, and Bioinformatics Center, Nanjing Agricultural University, to F.C.-C.L. Mang Shi is supported by an International Postgraduate Research Scholarship from the University of Sydney, while E.C.H. is supported by an NHMRC Australia Fellowship. NR 13 TC 21 Z9 26 U1 1 U2 19 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2013 VL 87 IS 19 BP 10904 EP 10907 DI 10.1128/JVI.01270-13 PG 4 WC Virology SC Virology GA 214WV UT WOS:000324169200045 PM 23885071 ER PT J AU Kruse, AC Weiss, DR Rossi, M Hu, JX Hu, K Eitel, K Gmeiner, P Wess, J Kobilka, BK Shoichet, BK AF Kruse, Andrew C. Weiss, Dahlia R. Rossi, Mario Hu, Jianxin Hu, Kelly Eitel, Katrin Gmeiner, Peter Wess, Juergen Kobilka, Brian K. Shoichet, Brian K. TI Muscarinic Receptors as Model Targets and Antitargets for Structure-Based Ligand Discovery SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ACETYLCHOLINE-RECEPTORS; CRYSTAL-STRUCTURE; BETA(2)-ADRENERGIC RECEPTOR; ALLOSTERIC MODULATORS; ALZHEIMERS-DISEASE; DRUG-DISCOVERY; HOMOLOGY MODEL; CNS DISORDERS; BINDING-SITE AB G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M-2 and M-3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M-2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar K-i values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M-2 and M-3 receptors, we selected molecules predicted by docking to bind to the M-3 and but not the M-2 receptor. Of 16 molecules tested, 8 bound to the M-3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M-3 receptor without measurable M-2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse beta-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology. C1 [Kruse, Andrew C.; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Weiss, Dahlia R.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA. [Shoichet, Brian K.] Univ Toronto, Fac Pharm, Toronto, ON, Canada. [Rossi, Mario; Hu, Jianxin; Hu, Kelly; Wess, Juergen] NIDDK, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. [Eitel, Katrin; Gmeiner, Peter] Univ Erlangen Nurnberg, Dept Chem & Pharm, D-91054 Erlangen, Germany. RP Kobilka, BK (reprint author), Stanford Univ, 157 Beckman Ctr,279 Campus Dr, Stanford, CA 94305 USA. EM kobilka@stanford.edu; bshoichet@gmail.com RI Gmeiner, Peter/N-5275-2015 FU National Science Foundation [CHE-1223785]; National Institutes of Health [P01 GM106990, R01 GM71896, R01 NS028471, F32 GM093580]; Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases]; Mathers Charitable Foundation; Bavaria California Technology Center FX This work was supported by the National Science Foundation [Grant CHE-1223785]; and the National Institutes of Health [Grant P01 GM106990] and [Grants R01 GM71896 (to B. K. S.), R01 NS028471 (to B. K. K.), and F32 GM093580 (to D. R. W.)]. Support was also provided by the Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases] (to J.W.); the Mathers Charitable Foundation (to BKK); Bavaria California Technology Center (to M. R., J.H., K. H., P. G., and K. E.); and the National Science Foundation (Graduate Research Fellowship to A.C.K.). NR 48 TC 30 Z9 30 U1 1 U2 18 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2013 VL 84 IS 4 BP 528 EP 540 DI 10.1124/mol.113.087551 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 216YN UT WOS:000324322900005 PM 23887926 ER PT J AU Bianchini, MA Pontual, MAB Bez, L Benfatti, CAM Boabaid, F Somerman, MJ Magini, RS AF Bianchini, Marco Aurelio Pontual, Marco Antonio B. Bez, Leonardo Benfatti, Cesar Augusto M. Boabaid, Fernanda Somerman, Martha J. Magini, Ricardo S. TI The use of bovine screws to promote bone formation using a tibia model in dogs SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID VERTICAL RIDGE AUGMENTATION; PARTIALLY EDENTULOUS PATIENTS; OSSEOINTEGRATED IMPLANTS; MEMBRANE; REGENERATION; GRAFTS; MATRIX AB The objective of this study was to evaluate the use of a unique resorbable bovine bone screw to stimulate bone formation. Bovine bone screws were inserted in the tibia of beagle dogs. Each animal received 8 screws, divided into groups A (screws + no membranes), B (screws + titanium reinforced membranes), and C (bone defects treated with autogenous bone grafts). Animals were killed at 2, 4, and 6 months. New bone was measured with a periodontal probe and reported an average of 7.4 mm in vertical bone gain for group B, 3.6 mm for group A, and 1.7 mm for group C. Submission to Kruskal-Wallis test showed statistical differences among groups (P < .05). Histologic examination revealed an intimate contact between the newly formed bone and the resorbing bone screws. We conclude that bovine bone screws provide an environment for new bone formation and thus may provide an alternative therapy for enhancing bone formation vertically, including for regenerative procedures as well as before implant therapy. C1 [Bianchini, Marco Aurelio; Bez, Leonardo; Benfatti, Cesar Augusto M.; Boabaid, Fernanda; Magini, Ricardo S.] Univ Fed Santa Catarina, Dept Periodontol, BR-88040970 Florianopolis, SC, Brazil. [Somerman, Martha J.] NIAMSD, NIH, Bethesda, MD USA. RP Boabaid, F (reprint author), Univ Fed Santa Catarina, Ctr Hlth Sci, Ctr Study & Res Dent Implants, Campus Univ, BR-88040970 Florianopolis, SC, Brazil. EM feboabaid_1999@yahoo.com FU Intramural NIH HHS [ZIA AR041196-01] NR 26 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD OCT PY 2013 VL 116 IS 4 BP E215 EP E220 DI 10.1016/j.oooo.2011.12.018 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 215XP UT WOS:000324244700001 PM 23058228 ER PT J AU Zhao, GX Jin, ZM Wang, YL Allewell, NM Tuchman, M Shi, DS AF Zhao, Gengxiang Jin, Zhongmin Wang, Yanli Allewell, Norma M. Tuchman, Mendel Shi, Dashuang TI Structure and function of Escherichia coli RimK, an ATP-grasp fold, l-glutamyl ligase enzyme SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE RimK enzyme; ATP-grasp fold; post-translational modification of ribosomal protein; poly--glutamate synthetase; folypolyglutamate synthetase ID GLUTATHIONE; DISCOVERY; SYNTHASE AB We report herein the crystal structure of Escherichia coli RimK at a resolution of 2.85 angstrom, an enzyme that catalyzes the post-translational addition of up to 15 C-terminal glutamate residues to ribosomal protein S6. The structure belongs to the ATP-grasp superfamily and is organized as a tetramer, consistent with gel filtration analysis. Each subunit consists of three distinct structural domains and the active site is located in the cleft between these domains. The catalytic reaction appears to occur at the junction between the three domains as ATP binds between the B and C domains, and other substrates bind nearby.Proteins 2013; 81:1847-1854. (c) 2013 Wiley Periodicals, Inc. C1 [Zhao, Gengxiang; Tuchman, Mendel; Shi, Dashuang] George Washington Univ, Childrens Natl Med Ctr, Dept Integrat Syst Biol, Med Genet Res Ctr, Washington, DC 20010 USA. [Jin, Zhongmin] Argonne Natl Lab, Adv Photon Source, Southeast Reg Collaborat Access Team, Argonne, IL 60439 USA. [Wang, Yanli] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Allewell, Norma M.] Univ Maryland, Dept Cell Biol & Mol Genet, Coll Comp Math & Nat Sci, College Pk, MD 20742 USA. [Allewell, Norma M.] Univ Maryland, Dept Chem & Biochem, Coll Comp Math & Nat Sci, College Pk, MD 20742 USA. [Shi, Dashuang] Gannan Normal Univ, Key Lab Organo Pharmaceut Chem, Ganzhou 341000, Jiangxi, Peoples R China. RP Shi, DS (reprint author), George Washington Univ, Childrens Natl Med Ctr, Dept Integrat Syst Biol, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM dshi@cnmcresearch.org FU U. S. Department of Energy, Office of Science and Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH, the National Library of Medicine FX Grant sponsor: The U. S. Department of Energy, Office of Science and Office of Basic Energy Sciences; Grant number: W-31-109-Eng-38; Grant sponsor: Intramural Research Program of the NIH, the National Library of Medicine. NR 17 TC 5 Z9 6 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 J9 PROTEINS JI Proteins PD OCT PY 2013 VL 81 IS 10 BP 1847 EP 1854 DI 10.1002/prot.24311 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 214FA UT WOS:000324115400014 PM 23609986 ER PT J AU Shmulewitz, D Wall, MM Aharonovich, E Spivak, B Weizman, A Frisch, A Grant, BF Hasin, D AF Shmulewitz, D. Wall, M. M. Aharonovich, E. Spivak, B. Weizman, A. Frisch, A. Grant, B. F. Hasin, D. TI Validity of proposed DSM-5 diagnostic criteria for nicotine use disorder: results from 734 Israeli lifetime smokers SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Cigarettes; DSM-5; Israel; nicotine dependence; nicotine use disorders; receiver operating characteristic curve analysis; smoking; validity ID NATIONAL EPIDEMIOLOGIC SURVEY; RECENT RUSSIAN IMMIGRANTS; ALCOHOL-USE DISORDERS; TOBACCO DEPENDENCE; DRUG-DEPENDENCE; SMOKING-CESSATION; POPULATION-SAMPLE; UNITED-STATES; ABUSE; IV AB Background. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes aligning nicotine use disorder (NUD) criteria with those for other substances, by including the current DSM fourth edition (DSM-IV) nicotine dependence (ND) criteria, three abuse criteria (neglect roles, hazardous use, interpersonal problems) and craving. Although NUD criteria indicate one latent trait, evidence is lacking on: (1) validity of each criterion; (2) validity of the criteria as a set; (3) comparative validity between DSM-5 NUD and DSM-IV ND criterion sets; and (4) NUD prevalence. Method. Nicotine criteria (DSM-IV ND, abuse and craving) and external validators (e. g. smoking soon after awakening, number of cigarettes per day) were assessed with a structured interview in 734 lifetime smokers from an Israeli household sample. Regression analysis evaluated the association between validators and each criterion. Receiver operating characteristic analysis assessed the association of the validators with the DSM-5 NUD set (number of criteria endorsed) and tested whether DSM-5 or DSM-IV provided the most discriminating criterion set. Changes in prevalence were examined. Results. Each DSM-5 NUD criterion was significantly associated with the validators, with strength of associations similar across the criteria. As a set, DSM-5 criteria were significantly associated with the validators, were significantly more discriminating than DSM-IV ND criteria, and led to increased prevalence of binary NUD (two or more criteria) over ND. Conclusions. All findings address previous concerns about the DSM-IV nicotine diagnosis and its criteria and support the proposed changes for DSM-5 NUD, which should result in improved diagnosis of nicotine disorders. C1 [Shmulewitz, D.; Wall, M. M.; Aharonovich, E.; Hasin, D.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Shmulewitz, D.; Wall, M. M.; Aharonovich, E.; Hasin, D.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Wall, M. M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Spivak, B.; Weizman, A.; Frisch, A.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Weizman, A.; Frisch, A.] Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Weizman, A.] Geha Mental Hlth Ctr, Res Unit, Petah Tiqwa, Israel. [Grant, B. F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD USA. [Hasin, D.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Hasin, D (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institutes of Health [R01AA013654, R01DA018652, K05AA014223, K23DA016743]; New York State Psychiatric Institute FX This research was funded by National Institutes of Health grants no. R01AA013654, R01DA018652 and K05AA014223 (to D. H.) and no. K23DA016743 (to E. A.), and by the New York State Psychiatric Institute (to D. H.). None of the authors or researchers has any connection with the tobacco, alcohol, pharmaceutical or gaming industries or any body substantially funded by one of these organizations. We acknowledge the helpful consultations of Rachel Bar-Hamburger, Ph.D., Rina Meyer and Zalman Shoval in collecting the data in Israel. NR 60 TC 5 Z9 5 U1 2 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD OCT PY 2013 VL 43 IS 10 BP 2179 EP 2190 DI 10.1017/S0033291712002954 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 213AC UT WOS:000324024100017 PM 23312475 ER PT J AU Kunos, G Volkow, ND AF Kunos, George Volkow, Nora D. TI Preface to the special issue of psychopharmacology: 10 years of the Jacob P. Waletzky Award SO PSYCHOPHARMACOLOGY LA English DT Editorial Material C1 [Kunos, George] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Bethesda, MD 20892 USA. EM George.Kunos@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2013 VL 229 IS 3 SI SI BP 383 EP 384 DI 10.1007/s00213-013-3225-3 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214PG UT WOS:000324145500001 ER PT J AU Mereu, M Bonci, A Newman, AH Tanda, G AF Mereu, Maddalena Bonci, Antonello Newman, Amy Hauck Tanda, Gianluigi TI The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders SO PSYCHOPHARMACOLOGY LA English DT Review DE ADHD; Addiction; Cocaine; Cognition; Dopamine; Drug abuse; Methamphetamine; Modafinil; Psychostimulant ID PLACEBO-CONTROLLED TRIAL; PROMOTING DRUG MODAFINIL; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MELANIN-CONCENTRATING HORMONE; METHAMPHETAMINE-DEPENDENT INDIVIDUALS; DEFICIT HYPERACTIVITY DISORDER; AMINOBUTYRIC-ACID OUTFLOW; DOPAMINE UPTAKE INHIBITOR; IMPROVES WORKING-MEMORY; CENTRAL-NERVOUS-SYSTEM AB Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations. C1 [Mereu, Maddalena; Newman, Amy Hauck; Tanda, Gianluigi] NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Bonci, Antonello] NIDA, Synapt Plast Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Tanda, G (reprint author), NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, NIH,DHHS, 251 Bayview Blvd,NIDA Suite 200, Baltimore, MD 21224 USA. EM gtanda@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009 OI Tanda, Gianluigi/0000-0001-9526-9878 FU NIDA Intramural Research Program, NIH/DHHS FX This study was funded by the NIDA Intramural Research Program, NIH/DHHS. NR 204 TC 35 Z9 36 U1 5 U2 56 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2013 VL 229 IS 3 SI SI BP 415 EP 434 DI 10.1007/s00213-013-3232-4 PG 20 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214PG UT WOS:000324145500004 PM 23934211 ER PT J AU Bossert, JM Marchant, NJ Calu, DJ Shaham, Y AF Bossert, Jennifer M. Marchant, Nathan J. Calu, Donna J. Shaham, Yavin TI The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research SO PSYCHOPHARMACOLOGY LA English DT Review DE Context; Craving; Cue; Extinction; Drug priming; Drug self-administration; Reconsolidation; Reinstatement; Relapse; Review; Stress ID COCAINE-SEEKING BEHAVIOR; STRESS-INDUCED REINSTATEMENT; CUE-INDUCED REINSTATEMENT; VENTRAL TEGMENTAL AREA; CONTEXT-INDUCED REINSTATEMENT; MEDIAL PREFRONTAL CORTEX; CORTICOTROPIN-RELEASING-FACTOR; NUCLEUS-ACCUMBENS CORE; MEMORY RECONSOLIDATION PROCESSES; HYPOTHALAMIC HYPOCRETIN SYSTEM AB Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. In this review, we first summarize recent (2009-present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model. Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving. C1 [Bossert, Jennifer M.; Marchant, Nathan J.; Calu, Donna J.; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. RP Bossert, JM (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. EM jennifer.bossert@nih.gov; yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Marchant, Nathan/0000-0001-8269-0532; Calu, Donna/0000-0003-2377-9494 FU National Institute on Drug Abuse FX This research was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. We thank Robyn St. Laurent for editorial corrections. The review is dedicated to the Waletzky family. NR 250 TC 121 Z9 121 U1 2 U2 48 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2013 VL 229 IS 3 SI SI BP 453 EP 476 DI 10.1007/s00213-013-3120-y PG 24 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214PG UT WOS:000324145500006 PM 23685858 ER PT J AU Wied, HM Jones, JL Cooch, NK Berg, BA Schoenbaum, G AF Wied, Heather M. Jones, Joshua L. Cooch, Nisha K. Berg, Benjamin A. Schoenbaum, Geoffrey TI Disruption of model-based behavior and learning by cocaine self-administration in rats SO PSYCHOPHARMACOLOGY LA English DT Review DE Addiction; Cocaine; Orbitofrontal; Sensory preconditioning; Blocking ID MEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL-CORTEX; INCENTIVE-SENSITIZATION; REINFORCER DEVALUATION; AMPHETAMINE EXPOSURE; MONETARY REWARD; WORKING-MEMORY; DRUG-ADDICTION; LESIONS; DYSFUNCTION AB Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control. C1 [Wied, Heather M.; Jones, Joshua L.; Cooch, Nisha K.; Berg, Benjamin A.; Schoenbaum, Geoffrey] NIDA, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Wied, Heather M.; Jones, Joshua L.; Cooch, Nisha K.; Schoenbaum, Geoffrey] Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. RP Schoenbaum, G (reprint author), NIDA, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov FU Intramural Research Program; National Institute on Drug Abuse [F30-DA033100, F32-DA031517] FX This work was supported by the Intramural Research Program (G. S.) and grants from the National Institute on Drug Abuse (H. M. W. F30-DA033100, J.L.J. F32-DA031517). The opinions expressed in this article are the authors' own and do not reflect the view of the NIH/DHHS. NR 54 TC 3 Z9 3 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2013 VL 229 IS 3 SI SI BP 493 EP 501 DI 10.1007/s00213-013-3222-6 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214PG UT WOS:000324145500009 PM 23949256 ER PT J AU Holmes, A Spanagel, R Krystal, JH AF Holmes, Andrew Spanagel, Rainer Krystal, John H. TI Glutamatergic targets for new alcohol medications SO PSYCHOPHARMACOLOGY LA English DT Review DE Ethanol; Craving; NMDA; GluN2A; GluN2B; mGluR2/3; mGluR5; Memantine; Addiction; Glycine ID METHYL-D-ASPARTATE; CUE-INDUCED REINSTATEMENT; RANDOMIZED CONTROLLED-TRIAL; MGLUR5 ANTAGONIST MPEP; CONDITIONED PLACE PREFERENCE; REDUCES ETHANOL-CONSUMPTION; PREFERRING P RATS; CULTURED HIPPOCAMPAL-NEURONS; HANDLING-INDUCED CONVULSIONS; VENTRAL TEGMENTAL AREA AB An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol's intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism. We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-d-aspartate (NMDA) receptor and specific NMDA subunits, the glycine(B) site on the NMDA receptors (NMDAR), l-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters. Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycine(B) site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol. Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism. C1 [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Spanagel, Rainer] Heidelberg Univ, Inst Psychopharmacol, Cent Inst Mental Hlth, Med Fac Mannheim, Heidelberg, Germany. [Krystal, John H.] Yale Univ, Sch Med, Dept Psychiat, NIAAA Ctr Translat Neurosci Alcoholism, New Haven, CT USA. RP Holmes, A (reprint author), 5625 Fishers Lane Room 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov FU NIAAA intramural research program; Bundesministerium fur Bildung und Forschung (NGFN Plus) [01GS08152]; Deutsche Forschungsgemeinschaft (DFG) [SFB 636 (B1)]; Reinhart-Koselleck Award [SP 383/5-1]; MWK in Baden-Wurttemberg; U.S. National Institute on Alcohol Abuse and Alcoholism [2P50AA012870]; National Center on Advancing Translational Science (CTSA) [UL1 RR024139]; U.S. Department of Veterans Affairs through VA National Center for PTSD; Yale-New Haven Hospital FX AH is supported by the NIAAA intramural research program. RS is supported by the Bundesministerium fur Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, see under Spanagel et al., 2010 and www.ngfn-alkohol.de), the Deutsche Forschungsgemeinschaft (DFG): SFB 636 (B1) and Reinhart-Koselleck Award SP 383/5-1, and the MWK in Baden-Wurttemberg. JHK is supported by the U.S. National Institute on Alcohol Abuse and Alcoholism (2P50AA012870), the National Center on Advancing Translational Science (CTSA Grant Number UL1 RR024139), the U.S. Department of Veterans Affairs through its support for the VA National Center for PTSD, and Yale-New Haven Hospital. NR 213 TC 52 Z9 52 U1 4 U2 41 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2013 VL 229 IS 3 SI SI BP 539 EP 554 DI 10.1007/s00213-013-3226-2 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214PG UT WOS:000324145500013 PM 23995381 ER PT J AU Yong, KJ Milenic, DE Baidoo, KE Kim, YS Brechbiel, MW AF Yong, Kwon J. Milenic, Diane E. Baidoo, Kwamena E. Kim, Young-Seung Brechbiel, Martin W. TI Gene expression profiling upon Pb-212-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model SO CANCER MEDICINE LA English DT Article DE Pb-212-TCMC-trastuzumab; disseminated intraperitoneal disease; gene expression AB Recent studies have demonstrated that therapy with Pb-212-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of Pb-212-TCMC- trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to Pb-212-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to Pb-212-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45 alpha, GADD45 gamma, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45 alpha, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by Pb-212-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by Pb-212-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by Pb-212-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using alpha-particle emitters. C1 [Yong, Kwon J.; Milenic, Diane E.; Baidoo, Kwamena E.; Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr MSC 1002,Room B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; AREVA Med LLC FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and AREVA Med LLC. NR 26 TC 7 Z9 8 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2013 VL 2 IS 5 BP 646 EP 653 DI 10.1002/cam4.132 PG 8 WC Oncology SC Oncology GA V36KL UT WOS:000209210900006 PM 24403230 ER PT J AU Morrison, BL Mullendore, ME Stockwin, LH Borgel, S Hollingshead, MG Newton, DL AF Morrison, Bethanie L. Mullendore, Michael E. Stockwin, Luke H. Borgel, Suzanne Hollingshead, Melinda G. Newton, Dianne L. TI Oxyphenisatin acetate (NSC 59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrine TNF alpha-mediated apoptosis SO CANCER MEDICINE LA English DT Article DE Autophagy; breast cancer; oxyphenisatin; protein synthesis; TNF alpha AB Oxyphenisatin (3,3-bis(4-hydroxyphenyl)-1H-indol-2-one) and several structurally related molecules have been shown to have in vitro and in vivo antiproliferative activity. This study aims to confirm and extend mechanistic studies by focusing on oxyphenisatin acetate (OXY, NSC 59687), the pro-drug of oxyphenisatin. Results confirm that OXY inhibits the growth of the breast cancer cell lines MCF7, T47D, HS578T, and MDA-MB-468. This effect is associated with selective inhibition of translation accompanied by rapid phosphorylation of the nutrient sensing eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinases, GCN2 and PERK. This effect was paralleled by activation of AMP-activated protein kinase (AMPK) combined with reduced phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6K and 4E-BP1. Microarray analysis highlighted activation of pathways involved in apoptosis induction, autophagy, RNA/protein metabolism, starvation responses, and solute transport. Pathway inhibitor combination studies suggested a role for AMPK/mTOR signaling, de novo transcription and translation, reactive oxygen species (ROS)/glutathione metabolism, calcium homeostasis and plasma membrane Na+/K+/Ca2+ transport in activity. Further examination confirmed that OXY treatment was associated with autophagy, mitochondrial dysfunction, and ROS generation. Additionally, treatment was associated with activation of both intrinsic and extrinsic apoptotic pathways. In the estrogen receptor (ER) positive MCF7 and T47D cells, OXY induced TNF alpha expression and TNFR1 degradation, indicating autocrine receptor-mediated apoptosis in these lines. Lastly, in an MCF7 xenograft model, OXY delivered intraperitoneally inhibited tumor growth, accompanied by phosphorylation of eIF2 alpha and degradation of TNFR1. These data suggest that OXY induces a multifaceted cell starvation response, which ultimately induces programmed cell death. C1 [Morrison, Bethanie L.; Mullendore, Michael E.; Stockwin, Luke H.; Newton, Dianne L.] SAIC Frederick Inc, Drug Mech Grp, Biol Testing Branch, Dev Therapeut Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Borgel, Suzanne] SAIC Frederick Inc, In Vivo Preclin Support Grp, Biol Testing Branch, Dev Therapeut Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Hollingshead, Melinda G.] Frederick Natl Lab Canc Res, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Newton, DL (reprint author), SAIC Frederick, Frederick Natl Lab Canc Res, Drug Mech Grp, Dev Therapeut Program, Bldg 320 Rm 9, Frederick, MD 21702 USA. EM newtondianne@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200 800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute 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. HHSN261200 800001E. 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 Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 52 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2013 VL 2 IS 5 BP 687 EP 700 DI 10.1002/cam4.107 PG 14 WC Oncology SC Oncology GA V36KL UT WOS:000209210900010 PM 24403234 ER PT J AU Olshan, AF Kuo, TM Meyer, AM Nielsen, ME Purdue, MP Rathmell, WK AF Olshan, Andrew F. Kuo, Tzy-Mey Meyer, Anne-Marie Nielsen, Matthew E. Purdue, Mark P. Rathmell, W. Kimryn TI Racial difference in histologic subtype of renal cell carcinoma SO CANCER MEDICINE LA English DT Article DE Epidemiology; histological type; incidence; race; renal cell carcinoma AB In the United States, renal cell carcinoma (RCC) has rapidly increased in incidence for over two decades. The most common histologic subtypes of RCC, clear cell, papillary, and chromophobe have distinct genetic and clinical characteristics; however, epidemiologic features of these subtypes have not been well characterized, particularly regarding any associations between race, disease subtypes, and recent incidence trends. Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we examined differences in the age-adjusted incidence rates and trends of RCC subtypes, including analysis focusing on racial differences. Incidence rates increased over time (2001-2009) for all three subtypes. However, the proportion of white cases with clear cell histology was higher than among blacks (50% vs. 31%, respectively), whereas black cases were more likely than white cases to have papillary RCC (23% vs. 9%, respectively). Moreover, papillary RCC incidence increased more rapidly for blacks than whites (P < 0.01) over this period. We also observed that increased incidence of papillary histology among blacks is not limited to the smallest size strata. We observed racial differences in proportionate incidence of RCC subtypes, which appear to be increasing over time; this novel finding motivates further etiologic, clinical, molecular, and genetic studies. C1 [Olshan, Andrew F.; Kuo, Tzy-Mey; Meyer, Anne-Marie; Nielsen, Matthew E.; Rathmell, W. Kimryn] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Olshan, AF (reprint author), Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, 2301B McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM andy_olshan@unc.edu RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Integrated Cancer Information and Surveillance System; UNC Lineberger Comprehensive Cancer Center; University Cancer Research Fund via the state of North Carolina FX This work was supported by the Integrated Cancer Information and Surveillance System, UNC Lineberger Comprehensive Cancer Center, with funding provided by the University Cancer Research Fund via the state of North Carolina. NR 39 TC 15 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2013 VL 2 IS 5 BP 744 EP 749 DI 10.1002/cam4.110 PG 6 WC Oncology SC Oncology GA V36KL UT WOS:000209210900016 PM 24403240 ER PT J AU Kim, MK Chakka, S Caplen, N Annunziata, C AF Kim, Marianne K. Chakka, Sirisha Caplen, Natasha Annunziata, Christina TI An unbiased functional screen identifies kinases essential to ovarian cancer cell survival SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract C1 [Kim, Marianne K.; Chakka, Sirisha; Caplen, Natasha; Annunziata, Christina] NCI, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 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 OCT 1 PY 2013 VL 19 SU S MA B25 DI 10.1158/1078-0432.OVCA13-B25 PG 1 WC Oncology SC Oncology GA V40RQ UT WOS:000209496100091 ER PT J AU Vigliotti, M Lum, E Banerjee, N Cutter, N Wrzeszczynski, KO Khan, S Kamalakaran, S Levine, DA Dimitrova, N Lucito, R AF Vigliotti, Michele Lum, Elena Banerjee, Nilanjana Cutter, Noelle Wrzeszczynski, Kazimierz O. Khan, Sohail Kamalakaran, Sitharthan Levine, Douglas A. Dimitrova, Nevenka Lucito, Robert TI Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract C1 [Vigliotti, Michele; Lum, Elena] Cold Spring Harbor Labs, Woodbury, NY USA. [Banerjee, Nilanjana; Kamalakaran, Sitharthan; Dimitrova, Nevenka] Philips Inc, Briarcliff Manor, NY USA. [Cutter, Noelle] Molloy Coll, Rockville Ctr, NY USA. [Wrzeszczynski, Kazimierz O.] NCI, Bethesda, MD 20892 USA. [Khan, Sohail] Long Isl Jewish, Lake Success, NY USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lucito, Robert] Hofstra North Shore LIJ Sch Med, Hempstead, NY USA. NR 0 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 OCT 1 PY 2013 VL 19 SU S MA A46 DI 10.1158/1078-0432.OVCA13-A46 PG 1 WC Oncology SC Oncology GA V40RQ UT WOS:000209496100040 ER PT J AU Wardell, JR Grive, KJ Hodgkinson, KM Binder, AK Seymour, KA Lovasco, LA Korach, KS Vanderhyden, BC Freiman, RN AF Wardell, Jennifer R. Grive, Kathryn J. Hodgkinson, Kendra M. Binder, April K. Seymour, Kimberly A. Lovasco, Lindsay A. Korach, Ken S. Vanderhyden, Barbara C. Freiman, Richard N. TI Estrogen-responsiveness of the TFIID subunit TAF4B and its potential function in ovarian cancer, epigenetic regulation and meiotic DNA repair SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract C1 [Wardell, Jennifer R.; Freiman, Richard N.] Brown Univ, Pathobiol Grad Program, Providence, RI 02912 USA. [Grive, Kathryn J.; Seymour, Kimberly A.; Lovasco, Lindsay A.; Freiman, Richard N.] Brown Univ, Dept Mol & Cellular Biol, Providence, RI 02912 USA. [Hodgkinson, Kendra M.; Vanderhyden, Barbara C.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1N 6N5, Canada. [Hodgkinson, Kendra M.; Vanderhyden, Barbara C.] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON K1N 6N5, Canada. [Binder, April K.; Korach, Ken S.] NIEHS, Lab Reprod & Dev Toxicol, Berkeley, CA USA. NR 0 TC 0 Z9 0 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 OCT 1 PY 2013 VL 19 SU S MA A81 DI 10.1158/1078-0432.OVCA13-A81 PG 1 WC Oncology SC Oncology GA V40RQ UT WOS:000209496100067 ER PT J AU Alfahad, TB Nath, A AF Alfahad, Tariq B. Nath, Avindra TI Update on HIV-Associated Neurocognitive Disorders SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Human immunodeficiency virus; HIV-associated neurocognitive disorders; Compartmentalization; Antiretroviral; Latency AB Neurocognitive disorders are a feared complication of HIV infection, especially in the post-antiretroviral era as patients are living longer. These disorders are challenging in terms of diagnosis and treatment. The clinical syndrome has evolved, driven in part by comorbidities such as aging, drug abuse, psychiatric illnesses, and a metabolic syndrome associated with the use of antiretroviral drugs. Additionally some individuals may develop a fulminant immune reconstitution syndrome. Hence, treatment of these patients needs to be individualized. The focus of research in the HIV field has recently switched towards elimination of the HIV reservoir as a means of combating long-term HIV complications. However, these approaches may be suitable for limited populations and might not be applicable once the HIV reservoir has been established in the brain. Further, all clinical trials using neuroprotective or anti-inflammatory drugs for treatment of HIV-associated neurocognitive disorders have been unsuccessful. Hence, neurological complications of HIV infection are the biggest challenge facing HIV researchers, and there is a critical need to develop new diagnostics and approaches for treatment of these disorders. C1 [Alfahad, Tariq B.; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, 10 Ctr Dr,Bldg 10-7-4647, Bethesda, MD 20892 USA. EM tariq.alfahad@nih.gov; natha@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003130-02] NR 64 TC 26 Z9 27 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD OCT PY 2013 VL 13 IS 10 AR 387 DI 10.1007/s11910-013-0387-7 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V40DI UT WOS:000209458900009 PM 23954972 ER PT J AU Di Bonaventura, MM Ubaldi, M Rice, K Massi, M Ciccocioppo, R Cifani, C AF Di Bonaventura, M. Micioni Ubaldi, M. Rice, K. Massi, M. Ciccocioppo, R. Cifani, C. TI Selective antagonism at CRF1 receptor as a novel pharmacological treatment for binge-type eating disorders SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Di Bonaventura, M. Micioni; Ubaldi, M.; Massi, M.; Ciccocioppo, R.; Cifani, C.] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, MC, Italy. [Rice, K.] NIDA, NIH, Chem Biol Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2013 VL 23 SU 2 MA P.1.h.028 BP S259 EP S259 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40HR UT WOS:000209470200290 ER PT J AU Kashkin, V Shekunova, E Bagrov, Y Bagrov, A AF Kashkin, V. Shekunova, E. Bagrov, Y. Bagrov, A. TI Spironolactone suppresses ethanol-seeking behavior and relapse in rats SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Kashkin, V.; Shekunova, E.] Pavlov State Med Univ, Dept Psychopharmacol, St Petersburg, Russia. [Bagrov, Y.] Sechenov Inst Evolutionary Physiol & Biochem, Labs Membrane Barrier Funct & Pharmacol, St Petersburg, Russia. [Bagrov, A.] NIA, NIH, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2013 VL 23 SU 2 MA P.6.a.003 BP S553 EP S554 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40HR UT WOS:000209470200766 ER PT J AU Richmond, BJ AF Richmond, B. J. TI Neural mechanisms of reinforcement learning: a computational approach SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Richmond, B. J.] NIMH, NIH, US Dept HHS, Neuropsychol Lab, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2013 VL 23 SU 2 MA S.08.02 BP S123 EP S123 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40HR UT WOS:000209470200040 ER PT J AU Puch, IC Wang, D Sun, J Solomon, SB Kanias, T Remy, K Feng, J Popovsky, MA Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Puch, I. Cortes Wang, D. Sun, J. Solomon, S. B. Kanias, T. Remy, K. Feng, J. Popovsky, M. A. Gladwin, M. T. Kim-Shapiro, D. B. Klein, H. G. Natanson, C. TI WASHING OLDER UNITS OF BLOOD REDUCES PLASMA IRON DURING TRANSFUSION AND IMPROVES OUTCOMES SO INTENSIVE CARE MEDICINE LA English DT Meeting Abstract CT ESICM 26th Annual Congress CY OCT 05-09, 2013 CL Paris, FRANCE SP ESICM C1 [Puch, I. Cortes; Wang, D.; Sun, J.; Solomon, S. B.; Remy, K.; Feng, J.; Natanson, C.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kanias, T.; Gladwin, M. T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Popovsky, M. A.] Haemonet Corp, Braintree, Essex, England. [Gladwin, M. T.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Klein, H. G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD OCT PY 2013 VL 39 SU 2 MA 0600 BP S384 EP S384 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA AP9WI UT WOS:000342431600599 ER PT J AU Puch, IC Wang, D Sun, J Solomon, SB Kanias, T Remy, K Feng, J Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Puch, I. Cortes Wang, D. Sun, J. Solomon, S. B. Kanias, T. Remy, K. Feng, J. Gladwin, M. T. Kim-Shapiro, D. B. Klein, H. G. Natanson, C. TI INCREASING S. AUREUS CHALLENGE REDUCES PLASMA IRON AFTER TRANSFUSION WITH OLDER STORED BLOOD BUT WORSENS MORTALITY AND LUNG INJURY SO INTENSIVE CARE MEDICINE LA English DT Meeting Abstract CT ESICM 26th Annual Congress CY OCT 05-09, 2013 CL Paris, FRANCE SP ESICM C1 [Puch, I. Cortes; Wang, D.; Sun, J.; Solomon, S. B.; Remy, K.; Feng, J.; Natanson, C.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kanias, T.; Gladwin, M. T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Gladwin, M. T.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Klein, H. G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD OCT PY 2013 VL 39 SU 2 MA 0600 BP S384 EP S384 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA AP9WI UT WOS:000342431600598 ER PT J AU Kozmin, SG Stepchenkova, EI Schaaper, RM AF Kozmin, Stanislav G. Stepchenkova, Elena I. Schaaper, Roel M. TI TusA (YhhP) and IscS are required for molybdenum cofactor-dependent base-analog detoxification SO MICROBIOLOGYOPEN LA English DT Article DE 6-N-hydroxylaminopurine (HAP) sensitivity; chlorate resistance; IscS cysteine desulfurase; molybdenum cofactor (Moco) biosynthesis; TusA sulfur-carrier protein ID REDUCING COMPONENT MARC; CONTAINING ENZYME MARC; ESCHERICHIA-COLI K-12; SALMONELLA-TYPHIMURIUM; BIOSYNTHESIS; SULFUR; PROTEIN; 6-N-HYDROXYLAMINOPURINE; RESISTANCE; IDENTIFICATION AB Lack of molybdenum cofactor (Moco) in Escherichia coli leads to hypersensitivity to the mutagenic and toxic effects of N-hydroxylated base analogs, such as 6-N-hydroxylaminopurine (HAP). This phenotype is due to the loss of two Moco-dependent activities, YcbX and YiiM, that are capable of reducing HAP to adenine. Here, we describe two novel HAP-sensitive mutants containing a defect in iscS or tusA (yhhP) gene. IscS is a major L-cysteine desulfurase involved in iron-sulfur cluster synthesis, thiamine synthesis, and tRNA thiomodification. TusA is a small sulfur-carrier protein that interacts with IscS. We show that both IscS and TusA operate within the Moco-dependent pathway. Like other Moco-deficient strains, tusA and iscS mutants are HAP sensitive and resistant to chlorate under anaerobic conditions. The base-analog sensitivity of iscS or tusA strains could be suppressed by supplying exogenous L-cysteine or sulfide or by an increase in endogenous sulfur donors (cysB constitutive mutant). The data suggest that iscS and tusA mutants have a defect in the mobilization of sulfur required for active YcbX/YiiM proteins as well as nitrate reductase, presumably due to lack of functional Moco. Overall, our data imply a novel and indispensable role of the IscS/TusA complex in the activity of several molybdoenzymes. C1 [Kozmin, Stanislav G.; Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Stepchenkova, Elena I.] St Petersburg State Univ, Dept Genet & Biotechnol, St Petersburg 199034, Russia. [Stepchenkova, Elena I.] RAS, Inst Gen Genet, St Petersburg Branch, St Petersburg 199034, Russia. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov RI Stepchenkova, Elena/F-9931-2014 OI Stepchenkova, Elena/0000-0002-5854-8701 FU Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) [ES050170] FX This work was supported by project ES050170 of the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS). NR 48 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-8827 J9 MICROBIOLOGYOPEN JI MicrobiologyOpen PD OCT PY 2013 VL 2 IS 5 BP 743 EP 755 DI 10.1002/mbo3.108 PG 13 WC Microbiology SC Microbiology GA AP8TK UT WOS:000342351700003 PM 23894086 ER PT J AU Sato, M Kadota, M Tang, BW Yang, YA Shan, MG Weng, J Welsh, M Nagano, Y Michalowski, A Yang, H Clifford, R Lee, M Wakefield, L AF Sato, Misako Kadota, Mitsutaka Tang, Binwu Yang, Yu-an Shan, Mengge Weng, Jia Welsh, Michael Nagano, Yoshiko Michalowski, Aleksandra Yang, Howard Clifford, Robert Lee, Maxwell Wakefield, Lalage TI Dissecting out the tumor suppressor aspect of TGF-beta in breast cancer using integrated genomics SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract C1 [Sato, Misako; Kadota, Mitsutaka; Tang, Binwu; Yang, Yu-an; Shan, Mengge; Weng, Jia; Welsh, Michael; Nagano, Yoshiko; Michalowski, Aleksandra; Yang, Howard; Clifford, Robert; Lee, Maxwell; Wakefield, Lalage] NCI, Bethesda, MD 20892 USA. NR 0 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 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD OCT PY 2013 VL 11 SU 10 MA B029 DI 10.1158/1557-3125.ADVBC-B029 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA V40OL UT WOS:000209487800102 ER PT J AU Sequeira, GR Vanzulli, SI May, M Rojas, P Lamb, CA Molinolo, A Lanari, C AF Sequeira, Gonzalo R. Vanzulli, Silvia I. May, Maria Rojas, Paola Lamb, Caroline A. Molinolo, Alfredo Lanari, Claudia TI Antiprogestins induce tumor vessels remodeling and increase the effects of albumin-bound paclitaxel or doxorubicin-pegylated liposomes in PR-A (+) but not in PR-B (+) T47D xenografts SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract C1 [Sequeira, Gonzalo R.; May, Maria; Rojas, Paola; Lamb, Caroline A.; Lanari, Claudia] IByME, Caba, Argentina. [Vanzulli, Silvia I.] Acad Med, Caba, Argentina. [Molinolo, Alfredo] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD OCT PY 2013 VL 11 SU 10 MA B126 DI 10.1158/1557-3125.ADVBC-B126 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA V40OL UT WOS:000209487800154 ER PT J AU Atkinson, TM Li, YL Mitchell, SA Dueck, AC Mendoza, TR Bennett, AV Rogak, L Castro, K Reeve, BB Basch, E AF Atkinson, Thomas M. Li, Yuelin Mitchell, Sandra A. Dueck, Amylou C. Mendoza, Tito R. Bennett, Antonia V. Rogak, Lauren Castro, Kathleen Reeve, Bryce B. Basch, Ethan TI Concordance between clinician-rated adverse symptom events and patient grading using the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE): application of a Bayesian graded item response model SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Atkinson, Thomas M.; Li, Yuelin; Rogak, Lauren] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mitchell, Sandra A.; Castro, Kathleen] NCI, Rockville, MD USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bennett, Antonia V.; Reeve, Bryce B.; Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2013 VL 22 SU 1 MA 103.4 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QX UT WOS:000209359000042 ER PT J AU Bennett, AV Dueck, AC Mitchell, SA Mendoza, TR Reeve, BB Castro, K Denicoff, A Rogak, L Clauser, SB Basch, E AF Bennett, Antonia V. Dueck, Amylou C. Mitchell, Sandra A. Mendoza, Tito R. Reeve, Bryce B. Castro, Kathleen Denicoff, Andrea Rogak, Lauren Clauser, Steven B. Basch, Ethan TI Mode equivalence and acceptability of web-, interactive voice response system-, and paper-based administration of us national cancer institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Bennett, Antonia V.; Reeve, Bryce B.; Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Mitchell, Sandra A.; Clauser, Steven B.] NCI, Rockville, MD USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Castro, Kathleen] NCI, Bethesda, MD 20892 USA. [Denicoff, Andrea] NCI, NIH, Potomac, MD USA. [Rogak, Lauren] Mem Sloan Kettering Canc Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2013 VL 22 SU 1 MA 304.1 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QX UT WOS:000209359000113 ER PT J AU Evensen, C Keller, S Arora, NK Garfinkel, S Yost, KJ Frentzel, E AF Evensen, Christian Keller, San Arora, Neeraj K. Garfinkel, Steven Yost, Kathleen J. Frentzel, Elizabeth TI Measuring cancer care quality: psychometric properties of an instrument for assessing patient experience with cancer care SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Evensen, Christian; Keller, San; Garfinkel, Steven; Frentzel, Elizabeth] Amer Inst Res, Chapel Hill, NC USA. [Arora, Neeraj K.] NCI, Bethesda, MD 20892 USA. [Yost, Kathleen J.] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2013 VL 22 SU 1 MA 205.3 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QX UT WOS:000209359000071 ER PT J AU Kent, EE Ambs, A Mitchell, SA Clauser, SB Smith, AW Hays, RD AF Kent, Erin E. Ambs, Anita Mitchell, Sandra A. Clauser, Steven B. Smith, Ashley Wilder Hays, Ronald D. TI Patient-reported outcomes in Medicare beneficiaries with less common cancers: population-based surveillance using the SEER-MHOS data linkage SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Kent, Erin E.; Smith, Ashley Wilder] NCI, Bethesda, MD 20892 USA. [Ambs, Anita; Mitchell, Sandra A.; Clauser, Steven B.] NCI, Rockville, MD USA. [Hays, Ronald D.] RAND Corp, Santa Monica, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2013 VL 22 SU 1 MA 302.5 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QX UT WOS:000209359000107 ER PT J AU Wood, WA Deal, AM Mitchell, SA Basch, E Bennett, AV Shatten, C Kim, YH Whitley, JS Reeve, BB AF Wood, William A. Deal, Allison M. Mitchell, Sandra A. Basch, Ethan Bennett, Antonia V. Shatten, Charlotte Kim, Yoon Hie Whitley, Julia S. Reeve, Bryce B. TI Feasibility and value of daily symptom reporting in patients undergoing hematopoietic cell transplantation SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Wood, William A.; Deal, Allison M.; Basch, Ethan; Bennett, Antonia V.; Shatten, Charlotte; Whitley, Julia S.; Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC USA. [Mitchell, Sandra A.] NCI, Rockville, MD USA. [Kim, Yoon Hie] E Carolina Univ, Greenville, NC 27858 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2013 VL 22 SU 1 MA 2082 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QX UT WOS:000209359000301 ER PT J AU Eggert, T McGlynn, KA Duffy, A Manns, MP Greten, TF Altekruse, SF AF Eggert, Tobias McGlynn, Katherine A. Duffy, Austin Manns, Michael P. Greten, Tim F. Altekruse, Sean F. TI Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database SO UNITED EUROPEAN GASTROENTEROLOGY JOURNAL LA English DT Article DE Liver cancer; epidemiology; fibrolamellar AB Objective: Epidemiological and clinical information on fibrolamellar hepatocellular carcinoma (fHCC) is scarce. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis with the aim of collecting information to better understand the biology and clinical aspects of this rare disease. Design: Incidence trends, race-and age-specific rates, tumor size, first course surgery and five-year relative survival of 191 US cases (SEER) diagnosed with fHCC during 2000-2010 were compared to cases with hepatocellular carcinoma (HCC), HCC-not otherwise specified (HCC-NOS) and other HCC-types. Results: While HCC-NOS incidence rates increased by 5.2% annually from 2000-2008 (p < 0.05) before leveling, the 1.3% change in fHCC incidence was not statistically significant. The rates of fHCC were similar across ethnic groups while HCC-NOS incidence rates were higher among non-whites. Although 16% of fHCC patients had primary tumors <= 5 cm compared to 37% of HCC-NOS cases five-year survival was better among fHCC (34%) than HCC-NOS cases (16%). Fibrolamellar HCC cases of 0-39 years of age were more likely to receive radiofrequency ablation, transplant or resection than HCC-NOS cases of that age. Survival was similar among fibrolamellar and HCC-NOS cases receiving surgery. Conclusion: In this largest case series, fibrolamellar and HCC-NOS age-and race-specific incidence rates and time trends differed. Despite larger tumor size than HCC-NOS cases fibrolamellar cases received surgery more often and had better survival rates. Differences in co-morbidity may influence treatment. Studies of fHCC biology, including by age, are recommended. C1 [Eggert, Tobias; Duffy, Austin; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Eggert, Tobias; Manns, Michael P.] Sch Med, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Greten, TF (reprint author), NCI, Bldg 10 Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU NIH, National Cancer Institute, National Cancer Institute FX Intramural Research Program of the NIH, National Cancer Institute, National Cancer Institute contracts with SEER registries. NR 20 TC 22 Z9 22 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2050-6406 EI 2050-6414 J9 UNITED EUR GASTROENT JI United European Gastroenterol. J. PD OCT PY 2013 VL 1 IS 5 BP 351 EP 357 DI 10.1177/2050640613501507 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V36GF UT WOS:000209200300007 PM 24917983 ER PT J AU Cao, SF Mao, X Liu, DL Buck, M AF Cao, Shufen Mao, Xi'an Liu, Deli Buck, Matthias TI Backbone assignment and secondary structure of Rnd1, an unusual Rho family small GTPase SO BIOMOLECULAR NMR ASSIGNMENTS LA English DT Article DE Rnd1; GTPase; NMR assignment; Signal transduction ID SWITCH-I MUTANT; RECEPTOR PLEXIN-B1; ONCOGENIC MUTANT; N-15 RESONANCES; BINDING-SITE; PC12 CELLS; PDZ-RHOGEF; R-RAS; PROTEIN; RAC1 AB Rho GTPases have attracted considerable interest as signaling molecules due to their variety of functional roles in cells. Rnd1 is a relatively recently discovered Rho GTPase with no enzymatic activity against its bound GTP nucleotide, setting it apart from other family members. Research has revealed a critical role for Rnd1 not only in neurite outgrowth, dendrite development, axon guidance, but also in gastric cancer and in endothelial cells during inflammation. Structural information is crucial for understanding the mechanism that forms the basis for protein-protein interactions and functions, but until recently there were no reports of NMR studies directly on the Rnd1 protein. In this paper we report assignments for the majority of Rnd1 NMR resonances based on 2D and 3D NMR spectra. Rnd1 assignment was a challenging task, however, despite optimization strategies that have facilitated NMR studies of the protein (Cao and Buck in Small GTPase 2:295-304, 2012). Besides common triple-resonance experiments, 3D HNCA, 3D HN(CO)CA, 3D HNCO which are usually employed for sequence assignment, 3D NOESY experiments and specific labeling of 13 kinds of amino acids were also utilized to gain as many H-1(N), C-13, and N-15 resonances assignments as possible. For 170 cross peaks observed out of 183 possible mainchain N-H correlations in the H-1-N-15 TROSY spectrum, backbone assignment was finally completed for 127 resonances. The secondary structure was then defined by chemical shifts and TALOS+ based on the assignments. The overall structure in solution compares well with that of Rnd1 in a crystal, except for two short segments, residues 77-83 and residues 127-131. Given that some features are shared among Rho GTPases, Rnd1 assignments are also compared with two other family members, Cdc42 and Rac1. The overall level of Rnd1 assignment is lower than for Cdc42 and Rac1, consistent with its lower stability and possibly increased internal dynamics. However, while the Rnd1 switch II region remained un-assigned, the switch I region could be more fully assigned compared to Cdc42 and Rac1. The NMR assignment and structure analysis reported here provides a robust basis for future study of the binding between Rnd1 and other proteins, as well as for further studies of the molecular function of this unusual GTPase. C1 [Cao, Shufen; Liu, Deli] Cent China Normal Univ, Coll Life Sci, Wuhan 430079, Hubei, Peoples R China. [Cao, Shufen; Buck, Matthias] Case Western Reserve Univ, Dept Physiol & Biophys, Sch Med, Cleveland, OH 44106 USA. [Mao, Xi'an; Buck, Matthias] Case Western Reserve Univ, Dept Pharmacol, Sch Med, Cleveland, OH 44106 USA. [Buck, Matthias] Case Western Reserve Univ, Dept Neurosci, Sch Med, Cleveland, OH 44106 USA. [Buck, Matthias] Case Western Reserve Univ, NCI Case Comprehens Canc Ctr, Sch Med, Cleveland, OH 44106 USA. RP Cao, SF (reprint author), Case Western Reserve Univ, Dept Physiol & Biophys, Sch Med, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM sfcao1982@gmail.com; matthias.buck@case.edu RI Cao, Shufen/I-1515-2014; Buck, Matthias/B-2106-2017 OI Buck, Matthias/0000-0002-2958-0403 FU National Institutes of Health [1R01GM73071, 1R01GM092851]; China Scholarship Council FX We thank Dr. Hyeong Ju Lee for help with NMR experiments and for critical discussion, Drs. Yanwu Yang and Jianmin Liu for suggestions on processing of the NMR spectra and Prasanta K. Hota, Soon Kim for additional help. We thank Dr. Declan Doyle, formerly of the Structural genomics consortium for providing the plasmid of Rnd1. The work of M.B. is supported by the National Institutes of Health grants 1R01GM73071, which included an ARRA supplement and later by 1R01GM092851. Predoctoral student Shufen Cao is supported by the non-profit institution China Scholarship Council. NR 48 TC 0 Z9 0 U1 0 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1874-2718 J9 BIOMOL NMR ASSIGN JI Biomol. NMR Assign. PD OCT PY 2013 VL 7 IS 2 BP 121 EP 128 DI 10.1007/s12104-012-9391-0 PG 8 WC Biophysics; Spectroscopy SC Biophysics; Spectroscopy GA 209FO UT WOS:000323740300002 PM 22618864 ER PT J AU Martins, L Rodrigues, TL Ribeiro, MM Saito, MT Giorgetti, APO Casati, MZ Sallum, EA Foster, BL Somerman, MJ Nociti, FH AF Martins, Luciane Rodrigues, Thaisangela L. Ribeiro, Mariana Martins Saito, Miki Taketomi Oliveira Giorgetti, Ana Paula Casati, Marcio Z. Sallum, Enilson A. Foster, Brian L. Somerman, Martha J. Nociti, Francisco H., Jr. TI Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype SO BONE LA English DT Article DE Hypophosphatasia; Odontohypophosphatasia; Tissue non-specific alkaline phosphatase; ALPL; Collagen-binding site; Compound heterozygous mutations ID NONSPECIFIC ALKALINE-PHOSPHATASE; SWISS-MODEL WORKSPACE; PROTEIN-STRUCTURE; PERINATAL HYPOPHOSPHATASIA; LETHAL HYPOPHOSPHATASIA; STRUCTURAL EVIDENCE; MISSENSE MUTATIONS; MINERALIZATION; DEGRADATION; FORMS AB Hypopbosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in ALPL, encoding tissue non-specific alkaline phosphatase (TNAP). Here, we report the molecular findings from monozygotic twins, clinically diagnosed with tooth-specific odontohypophosphatasia (odonto-HPP). Sequencing of ALPL identified two genetic alterations in the probands, including a heterozygous missense mutation c.454C>T, leading to change of arginine 152 to cysteine (p.R152C), and a novel heterozygous gene deletion c.1318_1320delAAC, leading to the loss of an asparagine residue at codon 440 (p.N440de1). Clinical identification of low serum TNAP activity, dental abnormalities, and pedigree data strongly suggests a genotype-phenotype correlation between p.N440del and odonto-HPP in this family. Computational analysis of the p.N440del protein structure revealed an alteration in the tertiary structure affecting the collagen-binding site (loop 422-452), which could potentially impair the mineralization process. Nevertheless, the probands (compound heterozygous: p.[N440de1];[R152C]) feature early-onset and severe odonto-HPP phenotype, whereas the father (p.[N440del];[=]) has only moderate symptoms, suggesting p.R152C may contribute or predispose to a more severe dental phenotype in combination with the deletion. These results assist in defining the genotype-phenotype associations for odonto-HPP, and further identify the collagen-binding site as a region of potential structural importance for TNAP function in the biomineralization. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Martins, Luciane; Rodrigues, Thaisangela L.; Saito, Miki Taketomi; Oliveira Giorgetti, Ana Paula; Casati, Marcio Z.; Sallum, Enilson A.; Nociti, Francisco H., Jr.] Univ Campinas UNICAMP, Dept Prosthodont & Periodont, Div Periodont, Piracicaba Dent Sch, Piracicaba, SP, Brazil. [Ribeiro, Mariana Martins] Univ Campinas UNICAMP, Dept Morphol, Piracicaba Dent Sch, Piracicaba, SP, Brazil. [Foster, Brian L.; Somerman, Martha J.; Nociti, Francisco H., Jr.] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Natl Inst Hlth NIH, Bethesda, MD USA. RP Nociti, FH (reprint author), Piracicaba Dent Sch, Dept Prosthodont & Periodont, Div Periodont, Av Limeira 901, BR-13414903 Piracicaba, SP, Brazil. EM nociti@fop.unicamp.br RI Rodrigues, Thaisangela/C-2293-2014; Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015; Martins, Luciane/C-9010-2016; Sallum, Enilson/G-2097-2016; casati, marcio /G-7475-2012 OI Foster, Brian/0000-0003-3444-0576; Martins, Luciane/0000-0003-3635-7928; FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Sao Paulo State Research Foundation (FAPESP, Brazil) [07/08192-5, 08/00534-7]; Coordination for the Improvement of the Higher Level Personnel (CAPES) [02426/09-9]; National Council for Scientific and Technological Development (CNPq) [553386/200875]; National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) [DE15109]; NIH [5R03TW007590-03] FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. A portion of this research was performed while MJS and BLF were affiliated with the University of Washington School of Dentistry, Seattle, WA, USA. The present study was supported by the Sao Paulo State Research Foundation (FAPESP, Brazil, grant #07/08192-5 and 08/00534-7), Coordination for the Improvement of the Higher Level Personnel (CAPES): 02426/09-9, National Council for Scientific and Technological Development (CNPq): 553386/200875, National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) DE15109, and NIH Fogarty International Research Collaboration Award (FIRCA) grant 5R03TW007590-03. NR 44 TC 2 Z9 3 U1 2 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 OCT PY 2013 VL 56 IS 2 BP 390 EP 397 DI 10.1016/j.bone.2013.06.010 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 210VX UT WOS:000323864000023 PM 23791648 ER PT J AU Ziats, MN Rennert, OM AF Ziats, Mark N. Rennert, Owen M. TI The Cerebellum in Autism: Pathogenic or an Anatomical Beacon? SO CEREBELLUM LA English DT Letter ID HUMAN BRAIN; TRANSCRIPTOME; EXPRESSION C1 [Ziats, Mark N.; Rennert, Owen M.] NICHHD, Lab Clin & Dev Genom, NIH, Bethesda, MD 20814 USA. [Ziats, Mark N.] Baylor Coll Med MSTP, Houston, TX USA. [Ziats, Mark N.] NIH Univ Cambridge Biomed Scholars Program, Cambridge, England. RP Ziats, MN (reprint author), NICHHD, Lab Clin & Dev Genom, NIH, 49 Convent Dr,Bldg 49,Room 2C08, Bethesda, MD 20814 USA. EM ziatsm@mail.nih.gov; rennerto@mail.nih.gov FU Intramural NIH HHS [ZIA HD008822-07] NR 17 TC 4 Z9 4 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 J9 CEREBELLUM JI Cerebellum PD OCT PY 2013 VL 12 IS 5 BP 776 EP 777 DI 10.1007/s12311-013-0483-x PG 2 WC Neurosciences SC Neurosciences & Neurology GA 210PB UT WOS:000323845100018 PM 23605119 ER PT J AU Franceschini, N Haack, K Goring, HHH Voruganti, VS Laston, S Almasy, L Lee, ET Best, LG Fabsitz, RR North, KE MacCluer, JW Meigs, JB Pankow, JS Cole, SA AF Franceschini, N. Haack, K. Goering, H. H. H. Voruganti, V. S. Laston, S. Almasy, L. Lee, E. T. Best, L. G. Fabsitz, R. R. North, K. E. MacCluer, J. W. Meigs, J. B. Pankow, J. S. Cole, S. A. TI Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study SO DIABETOLOGIA LA English DT Article DE Heritability; Impaired fasting glucose; Single nucleotide polymorphisms; Type 2 diabetes ID IMPAIRED GLUCOSE-TOLERANCE; TYPE-2 DIABETES-MELLITUS; NUTRITION EXAMINATION SURVEY; GENOME-WIDE ASSOCIATION; FASTING GLUCOSE; INSULIN-RESISTANCE; LIFE-STYLE; NATURAL-HISTORY; NATIONAL-HEALTH; PIMA-INDIANS AB Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration. Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h(2)) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies. We noted high h(2) for diabetes progression (h(2) = 0.65 +/- 0.16, p = 2.7 x 10(-6)) but little contribution of genetic factors to transitory IFG (h(2) = 0.09 +/- 0.10, p = 0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies. Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure. C1 [Franceschini, N.; North, K. E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Haack, K.; Goering, H. H. H.; Voruganti, V. S.; Laston, S.; Almasy, L.; MacCluer, J. W.; Meigs, J. B.; Cole, S. A.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Lee, E. T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Best, L. G.] Missouri Breaks Ind Res, Timber Lake, SD USA. [Fabsitz, R. R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [Meigs, J. B.] Harvard Univ, Sch Med, Boston, MA USA. [Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Pankow, J. S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 306 CB 8050, Chapel Hill, NC 27599 USA. EM noraf@unc.edu FU NHLBI [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521]; NIDDK [K24 DK080140] FX The SHS is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654 and U01 HL65521. J. B. Meigs is supported in part by NIDDK K24 DK080140. None of the authors have any disclosures to report. NR 49 TC 3 Z9 3 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2013 VL 56 IS 10 BP 2194 EP 2202 DI 10.1007/s00125-013-2988-8 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213MY UT WOS:000324062800013 PM 23851660 ER PT J AU Moore, CM Kasivisvanathan, V Eggener, S Emberton, M Futterer, JJ Gill, IS Grubb, RL Hadaschik, B Klotz, L Margolis, DJA Marks, LS Melamed, J Oto, A Palmer, SL Pinto, P Puech, P Punwani, S Rosenkrantz, AB Schoots, IG Simon, R Taneja, SS Turkbey, B Ukimura, O van der Meulen, J Villers, A Watanabe, Y AF Moore, Caroline M. Kasivisvanathan, Veeru Eggener, Scott Emberton, Mark Futterer, Jurgen J. Gill, Inderbir S. Grubb, Robert L., III Hadaschik, Boris Klotz, Laurence Margolis, Daniel J. A. Marks, Leonard S. Melamed, Jonathan Oto, Aytekin Palmer, Suzanne L. Pinto, Peter Puech, Philippe Punwani, Shonit Rosenkrantz, Andrew B. Schoots, Ivo G. Simon, Richard Taneja, Samir S. Turkbey, Baris Ukimura, Osamu van der Meulen, Jan Villers, Arnauld Watanabe, Yuji CA START Consortium TI Standards of Reporting for MRI-targeted Biopsy Studies (START) of the Prostate: Recommendations from an International Working Group SO EUROPEAN UROLOGY LA English DT Article DE Diagnosis; Magnetic resonance imaging; Prostate cancer ID CANCER-DETECTION; FUSION AB Background: A systematic literature review of magnetic resonance imaging (MRI)-targeted prostate biopsy demonstrates poor adherence to the Standards for the Reporting of Diagnostic Accuracy (STARD) recommendations for the full and transparent reporting of diagnostic studies. Objective: To define and recommend Standards of Reporting for MRI-targeted Biopsy Studies (START). Design, setting, and participants: Each member of a panel of 23 experts in urology, radiology, histopathology, and methodology used the RAND/UCLA appropriateness methodology to score a 258-statement premeeting questionnaire. The collated responses were presented at a face-to-face meeting, and each statement was rescored after group discussion. Outcome measurements and statistical analysis: Measures of agreement and consensus were calculated for each statement. The most important statements, based on group median score, the degree of group consensus, and the content of the group discussion, were used to create a checklist of reporting criteria (the START checklist). Results and limitations: The strongest recommendations were to report histologic results of standard and targeted cores separately using Gleason score and maximum cancer core length. A table comparing detection rates of clinically significant and clinically insignificant disease by targeted and standard approaches should also be used. It was recommended to report the recruitment criteria for MRI-targeted biopsy, prior biopsy status of the population, a brief description of the MRI sequences, MRI reporting method, radiologist experience, and image registration technique. There was uncertainty about which histologic criteria constitute clinically significant cancer when the prostate is sampled using MRI-targeted biopsy, and it was agreed that a new definition of clinical significance in this setting needed to be derived in future studies. Conclusions: Use of the START checklist would improve the quality of reporting in MRI-targeted biopsy studies and facilitate a comparison between standard and MRI-targeted approaches. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Moore, Caroline M.; Kasivisvanathan, Veeru; Emberton, Mark] UCL, Div Surg & Intervent Sci, London W1W 7EJ, England. [Eggener, Scott] Univ Chicago, Urol Sect, Chicago, IL 60637 USA. [Futterer, Jurgen J.] Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6525 ED Nijmegen, Netherlands. [Gill, Inderbir S.; Ukimura, Osamu] Univ South Calif, Keck Sch Med, Dept Urol, USC Inst Urol, Los Angeles, CA USA. [Grubb, Robert L., III] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Hadaschik, Boris] Univ Heidelberg Hosp, Dept Urol, Heidelberg, Germany. [Klotz, Laurence] Sunnybrook Med Ctr, Dept Urol, Toronto, ON, Canada. [Margolis, Daniel J. A.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Marks, Leonard S.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Melamed, Jonathan] NYU, Langone Med Ctr, Dept Histopathol, New York, NY USA. [Oto, Aytekin] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Palmer, Suzanne L.] Univ So Calif, Keck Sch Med, Dept Radiol, Los Angeles, CA 90033 USA. [Pinto, Peter] NIH, Dept Urol, Bethesda, MD 20892 USA. [Puech, Philippe] Univ Lille Nord France, Dept Radiol, CHU Lille, Inserm,U703, Lille, France. [Punwani, Shonit] UCL, Dept Imaging, London W1W 7EJ, England. [Rosenkrantz, Andrew B.] NYU, Dept Radiol, Langone Med Ctr, New York, NY 10016 USA. [Schoots, Ivo G.] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Simon, Richard] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Taneja, Samir S.] NYU, Langone Med Ctr, Dept Urol, New York, NY USA. [Turkbey, Baris] NCI, Mol Imaging Programme, NIH, Bethesda, MD 20892 USA. [van der Meulen, Jan] London Sch Hyg & Trop Med, Dept Hlth Serv Res & Policy, London WC1, England. [Villers, Arnauld] Univ Lille Nord France, CHU Lille, Dept Urol, Lille, France. [Watanabe, Yuji] Kurashiki Cent Hosp, Dept Radiol, Kurashiki, Okayama, Japan. RP Moore, CM (reprint author), UCL, Div Surg & Intervent Sci, Charles Bell House,67-73 Riding House St, London W1W 7EJ, England. EM carolinemoore@doctors.org.uk RI futterer, jurgen/A-1455-2014; Arnauld, VILLERS/K-6629-2016; OI Arnauld, VILLERS/0000-0002-6298-7758; Melamed, Jonathan/0000-0003-2844-7990 FU Pelican Foundation (UK); Peter Michael Foundation (USA); National Cancer Institute [R01CA158627] FX The Pelican Foundation (UK) and the Peter Michael Foundation (USA) supported the meeting, both in terms of administrative support and support of the costs of overnight accommodation and catering costs. Each participating institution covered the travel costs. The meeting was hosted by Samir Taneja at the New York University Langone Medical Centre, New York, USA on 25 October 2012. The work of Drs. Marks and Margolis was supported by Award Number R01CA158627 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 17 TC 130 Z9 130 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD OCT PY 2013 VL 64 IS 4 BP 544 EP 552 DI 10.1016/j.eururo.2013.03.030 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 211VQ UT WOS:000323939900012 PM 23537686 ER PT J AU Aris, JP Alvers, AL Ferraiuolo, RA Fishwick, LK Hanvivatpong, A Hu, D Kirlew, C Leonard, MT Losin, KJ Marraffini, M Seo, AY Swanberg, V Westcott, JL Wood, MS Leeuwenburgh, C Dunn, WA AF Aris, John P. Alvers, Ashley L. Ferraiuolo, Roy A. Fishwick, Laura K. Hanvivatpong, Amanda Hu, Doreen Kirlew, Christine Leonard, Michael T. Losin, Kyle J. Marraffini, Michelle Seo, Arnold Y. Swanberg, Veronica Westcott, Jennifer L. Wood, Michael S. Leeuwenburgh, Christiaan Dunn, William A., Jr. TI Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Aging; Autophagy; Calorie restriction; Leucine; Respiration; Saccharomyces cerevisiae ID LIFE-SPAN EXTENSION; SACCHAROMYCES-CEREVISIAE; CAENORHABDITIS-ELEGANS; MOLECULAR-MECHANISM; PROTEIN-SYNTHESIS; C-ELEGANS; MITOCHONDRIAL; MAINTENANCE; DNA; DYSFUNCTION AB We have previously shown that autophagy is required for chronological longevity in the budding yeast Saccharomyces cerevisiae. Here we examine the requirements for autophagy during extension of chronological life span (CLS) by calorie restriction (CR). We find that autophagy is upregulated by two CR interventions that extend CLS: water wash CR and low glucose CR. Autophagy is required for full extension of CLS during water wash CR under all growth conditions tested. In contrast, autophagy was not uniformly required for full extension of CLS during low glucose CR, depending on the atg allele and strain genetic background. Leucine status influenced CLS during CR. Eliminating the leucine requirement in yeast strains or adding supplemental leucine to growth media extended CLS during CR. In addition, we observed that both water wash and low glucose CR promote mitochondrial respiration proficiency during aging of autophagy-deficient yeast. In general, the extension of CLS by water wash or low glucose CR was inversely related to respiration deficiency in autophagy-deficient cells. Also, autophagy is required for full extension of CLS under non-CR conditions in buffered media, suggesting that extension of CLS during CR is not solely due to reduced medium acidity. Thus, our findings show that autophagy is: (1) induced by CR, (2) required for full extension of CLS by CR in most cases (depending on atg allele, strain, and leucine availability) and, (3) promotes mitochondrial respiration proficiency during aging under CR conditions. (C) 2013 Elsevier Inc. All rights reserved. C1 [Aris, John P.; Ferraiuolo, Roy A.; Fishwick, Laura K.; Hanvivatpong, Amanda; Hu, Doreen; Kirlew, Christine; Leonard, Michael T.; Losin, Kyle J.; Marraffini, Michelle; Swanberg, Veronica; Westcott, Jennifer L.; Wood, Michael S.; Dunn, William A., Jr.] Univ Florida, Hlth Sci Ctr, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Seo, Arnold Y.; Leeuwenburgh, Christiaan] Univ Florida, Hlth Sci Ctr, Dept Aging & Geriatr Res, Gainesville, FL 32610 USA. [Alvers, Ashley L.] Duke Univ, Med Ctr, Dev Biol Program, Durham, NC 27710 USA. [Seo, Arnold Y.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Aris, JP (reprint author), Univ Florida, Hlth Sci Ctr, Dept Anat & Cell Biol, 1600 SW Archer Rd, Gainesville, FL 32610 USA. EM johnaris@ufl.edu OI Aris, John/0000-0002-6475-064X FU AHA [0615256B]; NIH [AG023719, AG17994, AG21042]; University of Florida Honors Program FX This study has been supported over a span of (too) many years by an AHA predoctoral fellowship 0615256B to AYS and NIH grants AG023719 to JPA and AG17994 and AG21042 to CL. We thank Joshua Cohen and Maximilian Lang for technical assistance. We gratefully acknowledge the programmatic support of undergraduate research by the University of Florida Honors Program. NR 70 TC 16 Z9 18 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD OCT PY 2013 VL 48 IS 10 BP 1107 EP 1119 DI 10.1016/j.exger.2013.01.006 PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 213AZ UT WOS:000324026600017 PM 23337777 ER PT J AU Urbanski, HF Mattison, JA Roth, GS Ingram, DK AF Urbanski, Henryk F. Mattison, Julie A. Roth, George S. Ingram, Donald K. TI Dehydroepiandrosterone sulfate (DHEAS) as an endocrine marker of aging in calorie restriction studies SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE Adrenal gland; Biomarker; Cortisol; DHEAS; Rhesus macaque ID AGE-RELATED DECLINE; RHESUS-MONKEYS; DIETARY RESTRICTION; IDENTIFYING BIOMARKERS; NUTRITIONAL-STATUS; OXIDATIVE STRESS; BLOOD-CHEMISTRY; LIFE-SPAN; LONGEVITY; PRIMATE AB The adrenal steroid, dehydroepiandrosterone sulfate (DHEAS), is generally regarded as being a reliable endocrine marker of aging, because in humans and nonhuman primates its circulating concentrations are very high during young adulthood, and the concentrations then decline markedly during aging. Despite promising results from early studies, we were recently surprised to find that caloric restriction (CR) did little to prevent or delay the decline of DHEAS concentrations in old rhesus macaques. Here we summarize the use of circulating DHEAS concentrations as a biomarker of aging in CR studies and suggest reasons for its limited value. Although DHEAS can reliably predict aging in animals maintained on a standard diet, dietary manipulations may affect liver enzymes involved in the metabolism of steroid hormones. Consequently, in CR studies the reliability of using DHEAS as a biomarker of aging may be compromised. (C) 2013 Elsevier Inc. All rights reserved. C1 [Urbanski, Henryk F.] Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Urbanski, Henryk F.] Oregon Hlth & Sci Univ, Div Reprod & Dev Sci, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Urbanski, Henryk F.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Urbanski, Henryk F.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. [Mattison, Julie A.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Roth, George S.] GeroScience Inc, Pylesville, MD 21132 USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Urbanski, HF (reprint author), Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. EM urbanski@ohsu.edu FU National Institutes of Health (NIH) [AG-019914, AG-036670, OD-011092]; Intramural Research Program of the National Institute on Aging, NIH FX This work was supported by National Institutes of Health (NIH) grants AG-019914, AG-036670 and OD-011092. Support was also provided in part by the Intramural Research Program of the National Institute on Aging, NIH. NR 47 TC 3 Z9 3 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD OCT PY 2013 VL 48 IS 10 BP 1136 EP 1139 DI 10.1016/j.exger.2013.01.001 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 213AZ UT WOS:000324026600020 PM 23318475 ER PT J AU Vucic, S Ziemann, U Eisen, A Hallett, M Kiernan, MC AF Vucic, Steve Ziemann, Ulf Eisen, Andrew Hallett, Mark Kiernan, Matthew C. TI Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Review DE ALS; EMG ID MOTOR-NEURON DISEASE; INTERVAL INTRACORTICAL INHIBITION; AXONAL EXCITABILITY PROPERTIES; FRONTOTEMPORAL LOBAR DEGENERATION; THRESHOLD TRACKING TECHNIQUES; PROGRESSIVE MUSCULAR-ATROPHY; GLUTAMATE TRANSPORTER EAAT2; CORTICAL SILENT PERIOD; D90A SOD1 ALS; BRAIN-STIMULATION AB Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS. C1 [Vucic, Steve] Univ Sydney, Sydney Med Sch Westmead, Sydney, NSW 2045, Australia. [Vucic, Steve; Kiernan, Matthew C.] Neurosci Res Australia, Sydney, NSW, Australia. [Ziemann, Ulf] Univ Tubingen, Dept Neurol & Stroke, Hertie Inst Clin Brain Res, Tubingen, Germany. [Eisen, Andrew] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada. [Hallett, Mark] NINDS, Human Control Sect, NIH, Bethesda, MD 20892 USA. [Kiernan, Matthew C.] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia. RP Vucic, S (reprint author), Univ Sydney, Sydney Med Sch Westmead, Darcy & Hawkesbury Rd, Sydney, NSW 2045, Australia. EM s.vucic@neura.edu.au RI Kiernan, Matthew/E-4460-2011 FU Motor Neuron Disease Research Institute of Australia (MNDRIA); Sylvia and Charles Viertel Charitable Foundation; Ramaciotti Foundation; National Health and Medical Research Council of Australia [510233, 1024915] FX Support from the Motor Neuron Disease Research Institute of Australia (MNDRIA), Sylvia and Charles Viertel Charitable Foundation Clinical Investigator grant, Ramaciotti Foundation and National Health and Medical Research Council of Australia (Project grant numbers 510233 and 1024915) is gratefully acknowledged. NR 196 TC 59 Z9 61 U1 1 U2 22 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2013 VL 84 IS 10 BP 1161 EP 1170 DI 10.1136/jnnp-2012-304019 PG 10 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 209SH UT WOS:000323779800021 PM 23264687 ER PT J AU Li, L Lu, XK Dean, J AF Li, Lei Lu, Xukun Dean, Jurrien TI The maternal to zygotic transition in mammals SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Maternal to zygotic transition (MZT); Mouse fertilization; Gamete recognition; DNA methylation; Histone modification; Zygotic genome activation (ZGA); Maternal effect genes; Subcortical maternal complex (SCMC) ID PREIMPLANTATION MOUSE EMBRYO; ZONA-PELLUCIDA GLYCOPROTEIN; SPERM-EGG INTERACTION; BECKWITH-WIEDEMANN-SYNDROME; O-LINKED OLIGOSACCHARIDES; RNA DIFFERENTIAL DISPLAY; FERTILIZATION IN-VITRO; GOLDEN-HAMSTER EGGS; GENE-EXPRESSION; DNA METHYLATION AB Prior to activation of the embryonic genome, the initiating events of mammalian development are under maternal control and include fertilization, the block to polyspermy and processing sperm DNA. Following gamete union, the transcriptionally inert sperm DNA is repackaged into the male pronucleus which fuses with the female pronucleus to form a 1-cell zygote. Embryonic transcription begins during the maternal to zygotic transfer of control in directing development. This transition occurs at species-specific times after one or several rounds of blastomere cleavage and is essential for normal development. However, even after activation of the embryonic genome, successful development relies on stored maternal components without which embryos fail to progress beyond initial cell divisions. Better understanding of the molecular basis of maternal to zygotic transition including fertilization, the activation of the embryonic genome and cleavage-stage development will provide insight into early human development that should translate into clinical applications for regenerative medicine and assisted reproductive technologies. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Li, Lei; Lu, Xukun] Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Div Mol Embryon Dev, Beijing 100101, Peoples R China. [Lu, Xukun] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. [Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Li, L (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Div Mol Embryon Dev, Beijing 100101, Peoples R China. EM lil@ioz.ac.cn; jurriend@helix.nih.gov OI Li, Lei/0000-0001-5478-5681 FU National Basic Research Program of China [2012CB944401, 2011CB944501]; National Natural Science Foundation of China [30971655, 31171382]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01010103]; Hundred Talents Program of Chinese Academy of Sciences; Intramural Research Program of the National Institutes of Health, NIDDK FX We thank Professor Giuseppe Familiari for the scanning electron microscopy images of the mouse and human zonae pellucidae as well as our scientific colleagues for the many discussions that helped shape this review. This work is supported by the National Basic Research Program of China (2012CB944401, 2011CB944501), the National Natural Science Foundation of China (30971655, 31171382), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01010103), the Hundred Talents Program of Chinese Academy of Sciences and the Intramural Research Program of the National Institutes of Health, NIDDK. NR 230 TC 44 Z9 49 U1 3 U2 79 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2013 VL 34 IS 5 SI SI BP 919 EP 938 DI 10.1016/j.mam.2013.01.003 PG 20 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 207HD UT WOS:000323588600003 PM 23352575 ER PT J AU Zhang, S Lin, HY Kong, SB Wang, SM Wang, HM Wang, HB Armant, DR AF Zhang, Shuang Lin, Haiyan Kong, Shuangbo Wang, Shumin Wang, Hongmei Wang, Haibin Armant, D. Randall TI Physiological and molecular determinants of embryo implantation SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Blastocyst activation; Uterine receptivity; Blastocyst attachment; Embryo implantation; Decidualization ID LEUKEMIA INHIBITORY FACTOR; ENDOMETRIAL STROMAL CELLS; REGULATORY T-CELLS; IN-VITRO FERTILIZATION; ESTROGEN-RECEPTOR-ALPHA; EPIDERMAL-GROWTH-FACTOR; NATURAL-KILLER-CELLS; FEMALE REPRODUCTIVE-TRACT; BINDING-PROTEIN-BETA; PERIIMPLANTATION MOUSE UTERUS AB Embryo implantation involves the intimate interaction between an implantation-competent blastocyst and a receptive uterus, which occurs in a limited time period known as the window of implantation. Emerging evidence shows that defects originating during embryo implantation induce ripple effects with adverse consequences on later gestation events, highlighting the significance of this event for pregnancy success. Although a multitude of cellular events and molecular pathways involved in embryo-uterine crosstalk during implantation have been identified through gene expression studies and genetically engineered mouse models, a comprehensive understanding of the nature of embryo implantation is still missing. This review focuses on recent progress with particular attention to physiological and molecular determinants of blastocyst activation, uterine receptivity, blastocyst attachment and uterine decidualization. A better understanding of underlying mechanisms governing embryo implantation should generate new strategies to rectify implantation failure and improve pregnancy rates in women. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Zhang, Shuang; Lin, Haiyan; Kong, Shuangbo; Wang, Shumin; Wang, Hongmei; Wang, Haibin] Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing 100101, Peoples R China. [Zhang, Shuang; Kong, Shuangbo] Chinese Acad Sci, Grad Sch, Beijing 100039, Peoples R China. [Armant, D. Randall] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Wang, HB (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, 1 Beichen West Rd, Beijing 100101, Peoples R China. EM hbwang@ioz.ac.cn; D.Armant@wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU National Basic Research Program of China [2011CB944400]; National Natural Science Foundation [30825015, 81130009]; Beijing Natural Science Foundation [5091002]; National Institutes of Health [HD071408]; Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Work incorporated in this article was partially supported by the National Basic Research Program of China (2011CB944400), the National Natural Science Foundation (30825015, 81130009), Beijing Natural Science Foundation (5091002), the National Institutes of Health (HD071408) and the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. We apologize for unintended omission of any relevant references. NR 672 TC 81 Z9 86 U1 8 U2 91 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 EI 1872-9452 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD OCT PY 2013 VL 34 IS 5 SI SI BP 939 EP 980 DI 10.1016/j.mam.2012.12.011 PG 42 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 207HD UT WOS:000323588600004 PM 23290997 ER PT J AU Krasnova, IN Chiflikyan, M Justinova, Z McCoy, MT Ladenheim, B Jayanthi, S Quintero, C Brannock, C Barnes, C Adair, JE Lehrmann, E Kobeissy, FH Gold, MS Becker, KG Goldberg, SR Cadet, JL AF Krasnova, Irina N. Chiflikyan, Margarit Justinova, Zuzana McCoy, Michael T. Ladenheim, Bruce Jayanthi, Subramaniam Quintero, Cynthia Brannock, Christie Barnes, Chanel Adair, Jordan E. Lehrmann, Elin Kobeissy, Firas H. Gold, Mark S. Becker, Kevin G. Goldberg, Steven R. Cadet, Jean Lud TI CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Methamphetamine; Self-administration; Dorsal striatum; Delta FosB; BDNF; pCREB ID MESOLIMBIC DOPAMINE SYSTEM; C-FOS GENE; NEUROTROPHIC FACTOR; MESSENGER-RNA; DELTA-FOSB; NUCLEUS-ACCUMBENS; STRUCTURAL PLASTICITY; PREFRONTAL CORTEX; COCAINE SEEKING; DORSAL STRIATUM AB Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1 mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2 h, 24 h, or 1 month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in Delta FosB, BDNF and TrkB protein levels, with increases after 2 and 24 h, but decreases after 1 month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2 h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity. Published by Elsevier Inc. C1 [Krasnova, Irina N.; Chiflikyan, Margarit; McCoy, Michael T.; Ladenheim, Bruce; Jayanthi, Subramaniam; Quintero, Cynthia; Brannock, Christie; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Justinova, Zuzana; Barnes, Chanel; Adair, Jordan E.; Goldberg, Steven R.] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Lehrmann, Elin; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Kobeissy, Firas H.; Gold, Mark S.] Univ Florida, Dept Psychiat, Ctr Neuroprote & Biomarkers Res, McKnight Brain Inst, Gainesville, FL 32611 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011; kobeissy, firas/E-7042-2017; OI Justinova, Zuzana/0000-0001-5793-7484; kobeissy, firas/0000-0002-5008-6944; Lehrmann, Elin/0000-0002-9869-9475; Becker, Kevin/0000-0002-6794-6656 FU NIDA, NIH; DHHS FX This work is supported by Intramural Research Program of NIDA, NIH, and DHHS. NR 87 TC 35 Z9 37 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2013 VL 58 BP 132 EP 143 DI 10.1016/j.nbd.2013.05.009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 207GC UT WOS:000323585900016 PM 23726845 ER PT J AU Quiroga-Varela, A Walters, JR Brazhnik, E Marin, C Obeso, JA AF Quiroga-Varela, A. Walters, J. R. Brazhnik, E. Marin, C. Obeso, J. A. TI What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity SO NEUROBIOLOGY OF DISEASE LA English DT Review DE Basal ganglia; Oscillatory activity; Parkinson's disease; Beta oscillations ID EXTERNAL GLOBUS-PALLIDUS; BETA FREQUENCY SYNCHRONIZATION; LEVODOPA-INDUCED DYSKINESIAS; PRIMATE SUBTHALAMIC NUCLEUS; LOCAL-FIELD POTENTIALS; SUBSTANTIA-NIGRA; CEREBRAL-CORTEX; MPTP MODEL; NIGROSTRIATAL SYSTEM; DOPAMINE DEPLETION AB One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state. (C) 2013 Elsevier Inc. All rights reserved. C1 [Obeso, J. A.] Univ Navarra, Dept Neurol & Neurosci Area, Clin Univ, E-31080 Pamplona, Spain. [Obeso, J. A.] Univ Navarra, Sch Med, E-31080 Pamplona, Spain. [Quiroga-Varela, A.; Obeso, J. A.] Univ Navarra, CIMA, E-31080 Pamplona, Spain. [Quiroga-Varela, A.; Marin, C.; Obeso, J. A.] Ctr Invest Redes Enfermedades Neurodegenerat CIBE, Madrid, Spain. [Walters, J. R.; Brazhnik, E.] Natl Inst Neurol Disorders & Stroke, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD USA. [Marin, C.] IDIBAPS, Lab Neurol Expt, Barcelona, Spain. RP Obeso, JA (reprint author), CIMA Neurociencias, Ave Pio 12 55, Pamplona 31008, Spain. EM jobeso@unav.es FU Intramural NIH HHS [Z01 NS002139-33] NR 91 TC 20 Z9 20 U1 2 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2013 VL 58 BP 242 EP 248 DI 10.1016/j.nbd.2013.05.010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 207GC UT WOS:000323585900028 PM 23727447 ER PT J AU Phillips, KA Epstein, DH Preston, KL AF Phillips, Karran A. Epstein, David H. Preston, Kenzie L. TI Daily temporal patterns of heroin and cocaine use and craving: Relationship with business hours regardless of actual employment status SO ADDICTIVE BEHAVIORS LA English DT Article DE Ecological Momentary Assessment; Cocaine; Heroin; Craving/use; Business hours ID DAILY-LIFE AB Real-time monitoring of behavior using Ecological Momentary Assessment (EMA) has provided detailed data about daily temporal patterns of craving and use in cigarette smokers. We have collected similar data from a sample of cocaine and heroin users. Here we analyzed it in the context of its relationship with a societal construct of daily temporal organization: 9-to-5 business hours. In a 28-week prospective study, 112 methadone-maintained polydrug-abusing individuals initiated an electronic-diary entry and provided data each time they used cocaine, heroin, or both during weeks 4 to 28. EMA data were collected for 10,781 person-days and included: 663 cocaine-craving events, 710 cocaine-use events, 288 heroin-craving events, 66 heroin-use events, 630 craving-both-drugs events, and 282 use-of-both-drugs events. At baseline, 34% of the participants reported full-time employment in the preceding 3-year period. Most participants' current employment status fluctuated throughout the study. In a generalized linear mixed model (SAS Proc Glimmix), cocaine use varied by time of day relative to business hours (p < 0.0001) and there was a significant interaction between Day of the Week and Time Relative to Business Hours (p < 0.002) regardless of current work status. Cocaine craving also varied by time of day relative to business hours (p < 0.0001), however, there was no significant interaction between Day of the Week and Time Relative to Business Hours (p = .57). Heroin craving and use were mostly reported during business hours, but data were sparse. Cocaine craving is most frequent during business hours while cocaine use is more frequent after business hours. Cocaine use during business hours, but not craving, seems suppressed on most weekdays, but not weekends, suggesting that societal conventions reflected in business hours influence drug-use patterns even in individuals whose daily schedules are not necessarily dictated by employment during conventional business hours. Published by Elsevier Ltd. C1 [Phillips, Karran A.; Epstein, David H.; Preston, Kenzie L.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Phillips, KA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,BRC Bldg,Suite 200, Baltimore, MD 21224 USA. EM phillipsk@nida.nih.gov; depstein@intra.nida.nih.gov; kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU National Institute on Drug Abuse (NIDA), National Institutes of Health; NIH Genes, Environment and Health Initiative [Z01-000499] FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health and the NIH Genes, Environment and Health Initiative Z01-000499. NR 12 TC 2 Z9 2 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD OCT PY 2013 VL 38 IS 10 BP 2485 EP 2491 DI 10.1016/j.addbeh.2013.05.010 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 204JQ UT WOS:000323362000004 PM 23770647 ER PT J AU Murray, KW Haynie, DL Howard, DE Cheng, TL Simons-Morton, B AF Murray, Kantahyanee W. Haynie, Denise L. Howard, Donna E. Cheng, Tina L. Simons-Morton, Bruce TI Adolescent Reports of Aggression as Predictors of Perceived Parenting Behaviors and Expectations SO FAMILY RELATIONS LA English DT Article DE parenting; adolescent at risk behavior; urban populations; African American related ID AFRICAN-AMERICAN FAMILIES; PSYCHOLOGICAL CONTROL; RECIPROCAL INFLUENCES; COMMUNITY VIOLENCE; YOUNG ADOLESCENTS; NEIGHBORHOOD DISADVANTAGE; TRANSACTIONAL MODEL; ANTISOCIAL-BEHAVIOR; MULTIPLE IMPUTATION; CONDUCT PROBLEMS AB This study examined the associations between adolescent self-report of aggression and adolescents' perceptions of parenting practices in a sample of African American early adolescents living in low-income, urban communities. Sixth graders (N=209) completed questionnaires about their aggressive behaviors and perceptions of caregivers' parenting practices at two time points during the school year. Path model findings reveal that adolescent-reported aggression at Time 1 predicted higher levels of perceived parent psychological control and perceived parent expectations for aggressive solutions to conflicts at Time 2. Findings suggest that early adolescent aggression elicits negative parenting behaviors at a subsequent time point. C1 [Murray, Kantahyanee W.] Univ Maryland, Sch Social Work, Ruth H Young Ctr Families & Children, Baltimore, MD 21201 USA. [Haynie, Denise L.; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Howard, Donna E.] Univ Maryland, Dept Publ & Community Hlth, Sch Publ Hlth, College Pk, MD 20742 USA. [Cheng, Tina L.] Johns Hopkins Univ, Sch Med, Div Gen Pediat & Adolescent Med, Baltimore, MD 21287 USA. RP Murray, KW (reprint author), Univ Maryland, Sch Social Work, Ruth H Young Ctr Families & Children, 525 West Redwood St, Baltimore, MD 21201 USA. EM kmurray@ssw.umaryland.edu OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU Intramural NIH HHS [Z99 HD999999] NR 75 TC 3 Z9 3 U1 6 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0197-6664 J9 FAM RELAT JI Fam. Relat. PD OCT PY 2013 VL 62 IS 4 BP 637 EP 648 DI 10.1111/fare.12025 PG 12 WC Family Studies; Social Work SC Family Studies; Social Work GA 205IN UT WOS:000323437600009 PM 27087729 ER PT J AU Capes-Davis, A Alston-Roberts, C Kerrigan, L Reid, YA Barrett, T Burnett, EC Cooper, JR Freshney, RI Healy, L Kohara, A Korch, C Masters, JRW Nakamura, Y Nims, RW Storts, DR Dirks, WG MacLeod, RAF Drexler, HG AF Capes-Davis, Amanda Alston-Roberts, Christine Kerrigan, Liz Reid, Yvonne A. Barrett, Tanya Burnett, Edward C. Cooper, Jim R. Freshney, R. Ian Healy, Lyn Kohara, Arihiro Korch, Christopher Masters, John R. W. Nakamura, Yukio Nims, Raymond W. Storts, Douglas R. Dirks, Wilhelm G. MacLeod, Roderick A. F. Drexler, Hans G. TI Beware imposters: MA-1, a novel MALT lymphoma cell line, is misidentified and corresponds to Pfeiffer, a diffuse large B-cell lymphoma cell line SO GENES CHROMOSOMES & CANCER LA English DT Letter C1 [Capes-Davis, Amanda] CellBank Australia, Childrens Med Res Inst, Westmead, NSW, Australia. [Alston-Roberts, Christine; Kerrigan, Liz; Reid, Yvonne A.] ATCC, Manassas, VA USA. [Barrett, Tanya] NIH, NCBI, NLB, Bethesda, MD 20892 USA. [Burnett, Edward C.; Cooper, Jim R.] Culture Collect Publ Hlth England, Porton Down, England. [Freshney, R. Ian] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Healy, Lyn] Natl Inst Biol Stand & Controls, UK Stem Cell Bank, Potters Bar, Herts, England. [Kohara, Arihiro] JCRB, Natl Inst Biomed Innovat, Osaka, Japan. [Korch, Christopher] Univ Colorado, DNA Sequencing & Anal Core, Aurora, CO USA. [Masters, John R. W.] UCL, Prostate Canc Res Ctr, London, England. [Nakamura, Yukio] RIKEN BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki, Japan. [Nims, Raymond W.] RMC Pharmaceut Solut, Longmont, CO USA. [Storts, Douglas R.] Promega Corp, Madison, WI USA. [Dirks, Wilhelm G.; MacLeod, Roderick A. F.; Drexler, Hans G.] German Collect Microorganisms & Cell Cultures, Leibniz Inst DSMZ, Braunschweig, Germany. RP Capes-Davis, A (reprint author), CellBank Australia, Childrens Med Res Inst, Locked Bag 23, Wentworthville, NSW 2145, Australia. EM acapdav@gmail.com RI Nakamura, Yukio/A-5263-2016; OI Capes-Davis, Amanda/0000-0003-4184-6339 NR 9 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD OCT PY 2013 VL 52 IS 10 BP 986 EP 988 DI 10.1002/gcc.22094 PG 3 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 205FY UT WOS:000323429700012 PM 23907998 ER PT J AU Muessel, MJ Harry, GJ Armstrong, DL Storey, NM AF Muessel, Michelle J. Harry, G. Jean Armstrong, David L. Storey, Nina M. TI SDF-1 and LPA modulate microglia potassium channels through rho gtpases to regulate cell morphology SO GLIA LA English DT Article DE microglia; Rho GTPases; PI3-kinase; potassium channel ID KIR2.1 CHANNELS; K+ CHANNELS; FILAMIN-A; ACTIVATION; MIGRATION; RECEPTOR; RAC; EXPRESSION; MEMBRANE; POLARITY AB Microglia are the resident immune cells of the brain, which are important therapeutic targets for regulating the inflammatory responses particularly neurodegeneration in the aging human brain. The activation, chemotaxis and migration of microglia are regulated through G-protein coupled receptors by chemokines such as stromal cell-derived factor (SDF)-1 and bioactive lysophospholipids such as lysophosphatidic acid (LPA). Potassium channels play important roles in microglial function and cell fate decisions; however, the regulation of microglial potassium channels has not been fully elucidated. Here we show reciprocal action of SDF-1 and LPA, on potassium currents through Kir2.1 channels in primary murine microglia. The potassium channel modulation is mediated by the same small GTPases, Rac and Rho that regulate the actin cytoskeleton. SDF-1 rapidly increased the Kir2.1 current amplitude and cell spreading. These effects were mimicked by dialysing the cells with constitutively active Rac1 protein, and they were blocked by inhibiting the phosphatidylinositol 3-kinase (PI3K) with wortmannin. In contrast, LPA and constitutively active RhoA decreased the Kir2.1 currents and stimulated cell contraction. Thus, SDF-1 and LPA regulate both the actin cytoskeleton and the Kir2.1 potassium channels through the same Rho GTPase signaling pathways. The inhibition of Kir2.1 with chloroethylclonidine produced cell contraction independently of chemokine action. This suggests that potassium channels are essential for the morphological phenotype and functioning of microglia. In conclusion, the small GTPases, Rac and Rho, modulate Kir2.1 channels and block of Kir2.1 channels causes changes in microglia morphology. GLIA 2013;61:1620-1628 C1 [Muessel, Michelle J.; Armstrong, David L.; Storey, Nina M.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Muessel, Michelle J.] Univ Leicester, Dept Infect Immun & Inflammat, Leicester LE1 9HN, Leics, England. [Harry, G. Jean] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Storey, Nina M.] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. RP Storey, NM (reprint author), Univ Leicester, Dept Cell Physiol & Pharmacol, Coll Med Biol Sci & Psychol, Maurice Shock Med Sci Bldg,Univ Rd,POB 138, Leicester LE1 9HN, Leics, England. EM ns140@le.ac.uk FU NIH Intramural Research Program at the National Institute of Environmental Health Sciences, NIH, DHHS FX Grant sponsor: This work was supported by the NIH Intramural Research Program at the National Institute of Environmental Health Sciences, NIH, DHHS. NR 48 TC 8 Z9 9 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2013 VL 61 IS 10 BP 1620 EP 1628 DI 10.1002/glia.22543 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 205NU UT WOS:000323451900005 PM 23893870 ER PT J AU Spiegel, AM Koh, MT Vogt, NM Rapp, PR Gallagher, M AF Spiegel, Amy M. Koh, Ming Teng Vogt, Nicholas M. Rapp, Peter R. Gallagher, Michela TI Hilar interneuron vulnerability distinguishes aged rats with memory impairment SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE hippocampus; interneuron; somatostatin; neuropeptide Y; stereology; levetiracetam ID SPATIAL-LEARNING IMPAIRMENT; ALZHEIMERS-DISEASE; DENTATE GYRUS; NEUROPEPTIDE-Y; NEURON NUMBER; COGNITIVE IMPAIRMENT; PATTERN SEPARATION; PLACE CELLS; HIPPOCAMPUS; SOMATOSTATIN AB Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment. J. Comp. Neurol. 521:3508-3523, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Spiegel, Amy M.; Koh, Ming Teng; Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Vogt, Nicholas M.] Swarthmore Coll, Dept Psychol, Swarthmore, PA 19081 USA. [Rapp, Peter R.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. RP Gallagher, M (reprint author), Johns Hopkins Univ, Dept Psychol & Brain Sci, 3400 N Charles St, Baltimore, MD 21218 USA. EM michela@jhu.edu FU National Institute on Aging [P01AG009973-18]; Intramural Research Program of the National Institute on Aging FX Grant sponsor: National Institute on Aging; Grant number: P01AG009973-18 (to M. G.); Grant sponsor: Intramural Research Program of the National Institute on Aging.. NR 50 TC 27 Z9 27 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD OCT PY 2013 VL 521 IS 15 BP 3508 EP 3523 DI 10.1002/cne.23367 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 204QT UT WOS:000323383800010 PM 23749483 ER PT J AU Hamada, N Ito, H Iwamoto, I Mizuno, M Morishita, R Inaguma, Y Kawamoto, S Tabata, H Nagata, K AF Hamada, Nanako Ito, Hidenori Iwamoto, Ikuko Mizuno, Makoto Morishita, Rika Inaguma, Yutaka Kawamoto, Sachiyo Tabata, Hidenori Nagata, Koh-ichi TI Biochemical and morphological characterization of A2BP1 in neuronal tissue SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE A2BP1; antibody; cerebral cortex; neuron ID CELL BIOLOGICAL CHARACTERIZATION; MULTIDOMAIN ADAPTER PROTEIN; MAMMALIAN SEPTIN; BINDING PARTNER; IDENTIFICATION; COMPLEX; ASSOCIATION; HOMOLOGS; GENE AB A2BP1 is considered to regulate alternative splicing of important neuronal transcripts and has been implicated in a variety of neurological and developmental disorders. A2BP1 was found in neuronal cells and was analyzed biochemically and morphologically. In this study, we prepared a specific antibody against A2BP1, anti-A2BP1, and carried out protein expression and localization analyses of A2BP1 in rat and mouse tissues. By Western blotting, A2BP1 showed tissue-dependent expression profiles and was expressed in a developmental-stage-dependent manner in the brain. A2BP1 was detected at high levels in neocortex and cerebellum in the rat brain. Immunohistochemical analyses demonstrated that A2BP1 was highly expressed in differentiated neurons but not in mitotically active progenitor cells in the cerebral cortex during developmental stages. In cortical neurons, A2BP1 had accumulated mainly in the nucleus and diffusely distributed in the cell body and dendrites. In differentiated primary cultured rat hippocampal neurons, although A2BP1 was enriched in the nucleus and diffusely distributed in the cytoplasm, it was found in a punctate distribution adjacent to synapses. The results suggest that in neuronal tissues A2BP1 plays important roles, which are regulated in a spatiotemporal manner. (c) 2013 Wiley Periodicals, Inc. C1 [Hamada, Nanako; Ito, Hidenori; Iwamoto, Ikuko; Mizuno, Makoto; Morishita, Rika; Inaguma, Yutaka; Tabata, Hidenori; Nagata, Koh-ichi] Aichi Human Serv Ctr, Inst Dev Res, Kasugai, Aichi 4800392, Japan. [Kawamoto, Sachiyo] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Nagata, K (reprint author), Aichi Human Serv Ctr, Inst Dev Res, Dept Mol Neurobiol, 713-8 Kamiya, Kasugai, Aichi 4800392, Japan. EM knagata@inst-hsc.jp FU Ministry of Education, Science, Technology, Sports and Culture of Japan; Takeda Science Foundation; Novartis Foundation Grants from The Japan Science Society FX Contract grant sponsor: Ministry of Education, Science, Technology, Sports and Culture of Japan; Contract grant sponsor: Takeda Science Foundation; Contract grant sponsor: Novartis Foundation Grants from The Japan Science Society. NR 26 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD OCT PY 2013 VL 91 IS 10 BP 1303 EP 1311 DI 10.1002/jnr.23266 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 204UE UT WOS:000323394400005 PM 23918472 ER PT J AU Badralmaa, Y Natarajan, V AF Badralmaa, Yunden Natarajan, Ven TI Impact of the DNA extraction method on 2-LTR DNA circle recovery from HIV-1 infected cells SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE 2-LTR; HIV; Episome; Mitochondrial DNA; Retrovirus; PCR ID ACTIVE ANTIRETROVIRAL THERAPY; VIRUS TYPE-1 REPLICATION; TERMINAL REPEAT CIRCLES; CIRCULAR VIRAL-DNA; MITOCHONDRIAL-DNA; HIV-1 INFECTION; IN-VIVO; RALTEGRAVIR INTENSIFICATION; NONDIVIDING CELLS; COPY NUMBER AB Detection of episomal 2-LTR DNA circles is used as a marker for the ongoing virus replication in patients infected with HIV-1, and efficient extraction of episomal DNA is critical for accurate estimation of the 2-LTR circles. The impact of different methods of DNA extraction on the recovery of 2-LTR circles was compared using mitochondrial DNA extracted as an internal control. The bacterial plasmid DNA isolation method extracted less than 10% of cellular DNA, 40% of mitochondrial DNA and 12-20% of the input 2-LTR DNA. The total DNA isolation method recovered about 70% of mitochondrial DNA and 45% of the input 2-LTR DNA. The total nucleic acid isolation method recovered 90% of mitochondrial DNA and 60% of the input 2-LTR DNA. Similar results were obtained when the DNA was extracted from HIV-1 infected cells. Plasmid DNA isolation could not distinguish between 12 and 25 copies of 2-LTR DNA per million cells, whereas the total nucleic acid isolation showed a consistent and statistically significant difference between 12 and 25 copies. In conclusion, the total nucleic acid isolation method is more efficient than the plasmid DNA isolation method in recovering mitochondrial DNA and 2-LTR DNA circles from HIV-1 infected cells. (c) 2013 Elsevier B.V. All rights reserved. C1 [Badralmaa, Yunden; Natarajan, Ven] SAIC Frederick Inc, Mol Cell Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Natarajan, V (reprint author), SAIC Frederick Inc, Mol Cell Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM vnatarajan@mail.nih.gov FU National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the National Institute of Allergy and Infectious Diseases. 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. We thank Drs Yamashita and Emerman for providing 2-LTR plasmid, Heather Marshall for DNA from HIV-1 infected cells, Dr. Robin Dewar for critical evaluation of the manuscript and Drs Ishaq and Lin for suggestions on the manuscript. The following reagent was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: MT-2 from Dr. Douglas Richman. NR 36 TC 9 Z9 9 U1 0 U2 50 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD OCT PY 2013 VL 193 IS 1 BP 184 EP 189 DI 10.1016/j.jviromet.2013.06.014 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 204JR UT WOS:000323362100030 PM 23773807 ER PT J AU Kamato, D Burch, ML Piva, TJ Rezaei, HB Rostam, MA Xu, SW Zheng, WH Little, PJ Osman, N AF Kamato, Danielle Burch, Micah L. Piva, Terrence J. Rezaei, Hossein Babaahmadi Rostam, Muhamad Ashraf Xu, Suowen Zheng, Wenhua Little, Peter J. Osman, Narin TI Transforming growth factor-beta signalling: Role and consequences of Smad linker region phosphorylation SO CELLULAR SIGNALLING LA English DT Review DE Transforming growth factor-beta; Smads; Phosphorylation; Cell signalling; Serine/threonine kinases ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; VASCULAR SMOOTH-MUSCLE; PROTEIN-KINASE PATHWAYS; FAMILY MEDIATOR SMAD1; TGF-BETA; NITRIC-OXIDE; CROSS-TALK; RECEPTOR KINASE; MAP KINASE; MH1 DOMAIN AB Transforming growth factor-beta (TGF-beta) is a secreted homodimeric protein that plays an important role in regulating various cellular responses including cell proliferation and differentiation, extracellular matrix production, embryonic development and apoptosis. Disruption of the TGF-beta signalling pathway is associated with diverse disease states including cancer, renal and cardiac fibrosis and atherosclerosis. At the cell surface TGF-beta complex consists of two type I and two type II transmembrane receptors (T beta RI and T beta RII respectively) which have serine/threonine kinase activity. Upon TGF-beta engagement Tr3RII phosphorylates T beta RI which in turn phosphorylates Smad2/3 on two serine residues at their C-terminus which enables binding to Smad4 to form heteromeric Smad complexes that enter the nucleus to initiate gene transcription including for extracellular matrix proteins. TGF-beta signalling is also known to activate other serine/threonine kinase signalling that results in the phosphorylation of the linker region of Smad2. The Smad linker region is defined as the domain which lies between the MHI and MH2 domains of a Smad protein. Serine/threonine kinases that are known to phosphorylate the Smad linker region include mitogen-activated protein kinases, extracellular-signal regulated kinase, Jun N-terminal kinase and p38 kinase, the tyrosine kinase Src, phosphatidylinositol 3'-kinase, cyclin-dependent kinases, rho-associated protein kinase, calcium calmodulin-dependent kinase and glycogen synthase kinase-3. This review will cover the role of Smad linker region phosphorylation downstream of TGF-beta signalling in vascular cells. Key factors including the identification of the kinases that phosphorylate individual Smad residues, the upstream agents that activate these kinases, the cellular location of the phosphorylation event and the importance of the linker region in regulation and expression of genes induced by TGF-beta are covered. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kamato, Danielle; Burch, Micah L.; Rezaei, Hossein Babaahmadi; Rostam, Muhamad Ashraf; Little, Peter J.; Osman, Narin] RMIT Univ, Sch Med Sci, Discipline Pharm, Bundoora, Vic 3083, Australia. [Kamato, Danielle; Burch, Micah L.; Rezaei, Hossein Babaahmadi; Rostam, Muhamad Ashraf; Little, Peter J.; Osman, Narin] RMIT Univ, Diabet Complicat Grp, Hlth Innovat Res Inst, Bundoora, Vic 3083, Australia. [Piva, Terrence J.] RMIT Univ, Discipline Cell Biol & Anat, Sch Med Sci, Bundoora, Vic 3083, Australia. [Piva, Terrence J.] RMIT Univ, Hlth Innovat Res Inst, Bundoora, Vic 3083, Australia. [Rezaei, Hossein Babaahmadi] Ahvaz Jundishapur Univ Med Sci, Dept Clin Biochem, Ahwaz, Iran. [Xu, Suowen] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD USA. [Zheng, Wenhua] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Little, Peter J.; Osman, Narin] Monash Univ, Dept Med, Cent & Eastern Clin Sch, Melbourne, Vic 3004, Australia. [Little, Peter J.; Osman, Narin] Monash Univ, Dept Immunol, Cent & Eastern Clin Sch, Melbourne, Vic 3004, Australia. RP Osman, N (reprint author), RMIT Univ, Sch Med Sci, Dep Head Diabet Complicat Grp, POB 71, Bundoora, Vic 3083, Australia. EM danielle.kamato@rmit.edu.au; micah.burch@rmit.edu.au; teriy.piva@rmit.edu.au; hbabaahmadi@gmail.com; muhamad.rostam@rmit.edu.au; suo-wen.xu@nih.gov; whzheng123@gmail.com; peter.little@rmit.edu.au; narin.osman@rmit.edu.au RI Little, Peter/F-9865-2015; OI Little, Peter/0000-0002-0335-3835; Rostam, Muhamad Ashraf/0000-0001-9217-8305; Osman, Narin/0000-0002-6738-6513 FU National Heart Foundation of Australia [G10M5211]; Diabetes Australia Research Trust; National Natural Science Fund of China [30670652, 30711120565, 30970935]; Science and Technology Project of Guangdong Province [201113050200005, 20098060700008]; Health Innovations Research Institute at RMIT University FX This study was supported by a National Heart Foundation of Australia grant-in-aid (PJL) G10M5211 and Diabetes Australia Research Trust grants (PJL and NO). This work was also supported by funding from the National Natural Science Fund of China (no. 30670652; no. 30711120565; no. 30970935) and the Science and Technology Project of Guangdong Province (no. 201113050200005; no. 20098060700008) (WZ). HBR was supported for his 6 months in the Little laboratory by a scholarship from the Health Innovations Research Institute at RMIT University. NR 95 TC 69 Z9 77 U1 2 U2 47 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2013 VL 25 IS 10 BP 2017 EP 2024 DI 10.1016/j.cellsig.2013.06.001 PG 8 WC Cell Biology SC Cell Biology GA 198SX UT WOS:000322943700009 PM 23770288 ER PT J AU Jacob, KD Noren Hooten, N Tadokoro, T Lohani, A Barnes, J Evans, MK AF Jacob, Kimberly D. Noren Hooten, Nicole Tadokoro, Takashi Lohani, Althaf Barnes, Janice Evans, Michele K. TI Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE 8-Oxoguanine-DNA glycosylase; DNA damage; DNA repair; Oxidative stress; 8-Oxoguanine; Base excision repair; Alzheimer's disease; Free radicals ID HUMAN 8-OXOGUANINE-DNA GLYCOSYLASE; INCREASED OXIDATIVE DAMAGE; MILD COGNITIVE IMPAIRMENT; BASE EXCISION-REPAIR; AP LYASE ACTIVITY; MITOCHONDRIAL-DNA; BIOCHEMICAL EXPLORATION; MISSENSE MUTATIONS; HUMAN BRAIN; PROTEIN AB Brain tissues from Alzheimer's disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8-oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, whereas the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1(-/-) cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein-binding activities that could be related to the increase in oxidative damage to DNA found in AD brains. Published by Elsevier Inc. C1 [Jacob, Kimberly D.; Noren Hooten, Nicole; Lohani, Althaf; Barnes, Janice; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Tadokoro, Takashi] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov FU NIH, National Institute on Aging FX We thank Dr. Deborah Croteau (Laboratory of Molecular Gerontology, NIA) for helpful discussions and technical assistance with the EMSA and for critically reading the manuscript. We thank Dr. Alan Zonderman for assistance in the statistical analysis of the EMSA data and Dr. David Wilson III for technical advice and assistance. We appreciate the helpful discussions and technical assistance of Dr. Jeff Hill, Dr. Hansen Du, and Dr. Mahdu Lal Nag and the excellent review comments provided by Dr. Sebastian Fugmann. We also thank Dr. Yie Liu for the generous gift of the wild-type and OGG1-/- primary MEFs. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 51 TC 11 Z9 13 U1 1 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT PY 2013 VL 63 SI SI BP 115 EP 125 DI 10.1016/j.freeradbiomed.2013.05.010 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 200TV UT WOS:000323094700010 PM 23684897 ER PT J AU Tang, WB Bentley, AR Kritchevsky, SB Harris, TB Newman, AB Bauer, DC Meibohm, B Cassano, PA AF Tang, Wenbo Bentley, Amy R. Kritchevsky, Stephen B. Harris, Tamara B. Newman, Anne B. Bauer, Douglas C. Meibohm, Bernd Cassano, Patricia A. CA Hlth ABC Study TI Genetic variation in antioxidant enzymes, cigarette smoking, and longitudinal change in lung function SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Antioxidant enzymes; Cigarette smoking; Gene-by-environment interaction; Genetic association; Longitudinal change; Lung function; Oxidative stress; Free radicals ID OBSTRUCTIVE PULMONARY-DISEASE; FORCED EXPIRATORY VOLUME; VITAMIN-C INTAKE; GENERAL-POPULATION; OXIDATIVE STRESS; GLOBAL BURDEN; COPD; POLYMORPHISMS; DECLINE; ASSOCIATION AB Antioxidant enzymes play an important role in the defense against oxidative stress in the lung and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Sequence variation in genes encoding antioxidant enzymes may alter susceptibility to COPD by affecting longitudinal change in lung function in adults. We genotyped 384 sequence variants in 56 candidate genes in 1281 African American and 1794 European American elderly adults in the Health, Aging, and Body Composition study. Single-marker associations and gene-by-smoking interactions with rate of change in FEV1 and FEV1/FVC were evaluated using linear mixed-effects models, stratified by race/ethnicity. In European Americans, rs17883901 in GCLC was statistically significantly associated with rate of change in FEV1/FVC; the recessive genotype (TT) was associated with a 0.9% per year steeper decline (P = 4.50 x 10(-5)). Statistically significant gene-by-smoking interactions were observed for variants in two genes in European Americans: the minor allele of rs2297765 in mGST3 attenuated the accelerated decline in FEV1/FVC in smokers by 0.45% per year (P = 1.13 x 10(-4)); for participants with greater baseline smoking pack-years, the minor allele of rs2073192 in IDH3B was associated with an accelerated decline in FEV1/FVC (P = 2.10 x 10(-4)). For both genes, nominally significant interactions (P < 0.01) were observed at the gene level in African Americans (P = 0.007 and 4.60 x 10(-4), respectively). Nominally significant evidence of association was observed for variants in SOD3 and GLRX2 in multiple analyses. This study identifies two novel genes associated with longitudinal lung function phenotypes in both African and European Americans and confirms a prior finding for GCLC. These findings suggest novel mechanisms and molecular targets for future research and advance the understanding of genetic determinants of lung function and COPD risk. (C) 2013 Elsevier Inc. All rights reserved. C1 [Tang, Wenbo; Bentley, Amy R.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Bentley, Amy R.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27106 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Ctr Aging & Populat Hlth, Pittsburgh, PA 15260 USA. [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. [Meibohm, Bernd] Univ Tennessee, Memphis, TN 38103 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY 10065 USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM pac6@cornell.edu RI Newman, Anne B./C-6408-2013; OI Newman, Anne B./0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIH [R01HL071022]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C]; Johns Hopkins University under U.S. Federal Government [N01HV48195]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported by NIH R01HL071022 (P.A.C.) and by NIA Contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, Contract HHSN268200782096C. Genotyping services specific to this study were Provided by the Johns Hopkins University under U.S. Federal Government Contract N01HV48195. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (A.R.B.). The Health ABC study was approved by Institutional Review Boards at the University of Pittsburgh (Pittsburgh, PA, USA) and the University of Tennessee (Memphis, TN, USA), and participants provided written informed consent for the study. The Institutional Review Board at Cornell University (Ithaca, NY, USA) approved the current study. NR 47 TC 6 Z9 6 U1 1 U2 75 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT PY 2013 VL 63 SI SI BP 304 EP 312 DI 10.1016/j.freeradbiomed.2013.05.016 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 200TV UT WOS:000323094700029 PM 23688726 ER PT J AU Towner, RA Smith, N Saunders, D Lupu, F Silasi-Mansat, R West, M Ramirez, DC Gomez-Mejiba, SE Bonini, MG Mason, RP Ehrenshaft, M Hensley, K AF Towner, Rheal A. Smith, Nataliya Saunders, Debra Lupu, Florea Silasi-Mansat, Robert West, Melinda Ramirez, Dario C. Gomez-Mejiba, Sandra E. Bonini, Marcelo G. Mason, Ronald P. Ehrenshaft, Marilyn Hensley, Kenneth TI In vivo detection of free radicals using molecular MRI and immuno-spin trapping in a mouse model for amyotrophic lateral sclerosis SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE In vivo; Immuno-spin trapping; Molecular magnetic resonance imaging; Amyotrophic lateral sclerosis; Free radicals; DMPO; Gd-DTPA-albumin-anti-DMPO-biotin probe; Anti-DMPO probe ID SUPEROXIDE-DISMUTASE GENE; HYDROGEN-PEROXIDE; OXIDATIVE DAMAGE; TRANSGENIC MICE; GROWTH-FACTOR; FATTY-ACIDS; PROTEIN; ALS; CORD; STRESS AB Free radicals associated with oxidative stress play a major role in amyotrophic lateral sclerosis (ALS). By combining immuno-spin trapping and molecular magnetic resonance imaging, in vivo trapped radical adducts were detected in the spinal cords of SOD1(G93A)-transgenic (Tg) mice, a model for ALS. For this study, the nitrone spin trap DMPO (5,5-dimethyl-1-pyrroline N-oxide) was administered (ip) over 5 days before administration (iv) of an anti-DMPO probe (anti-DMPO antibody covalently bound to an albumin-gadolinium-diethylenetriamine pentaacetic acid-biotin MRI contrast agent) to trap free radicals. MRI was used to detect the presence of the anti-DMPO radical adducts by a significant sustained increase in MR signal intensities (p < 0.05) or anti-DMPO probe concentrations measured from T-1 relaxations (p < 0.01). The biotin moiety of the anti-DMPO probe was targeted with fluorescence-labeled streptavidin to locate the probe in excised tissues. Negative controls included either Tg ALS mice initially administered saline rather than DMPO followed by the anti-DMPO probe or non-Tg mice initially administered DMPO and then the anti-DMPO probe. The anti-DMPO probe was found to bind to neurons via colocalization fluorescence microscopy. DMPO adducts were also confirmed in diseased/nondiseased tissues from animals administered DMPO. Apparent diffusion coefficients from diffusion-weighted images of spinal cords from Tg mice were significantly elevated (p < 0.001) compared to wild-type controls. This is the first report regarding the detection of in vivo trapped radical adducts in an ALS model. This novel, noninvasive, in vivo diagnostic method can be applied to investigate the involvement of free radical mechanisms in ALS rodent models. (C) 2013 Elsevier Inc. All rights reserved. C1 [Towner, Rheal A.; Smith, Nataliya; Saunders, Debra] Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. [Lupu, Florea; Silasi-Mansat, Robert; West, Melinda] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Ramirez, Dario C.; Gomez-Mejiba, Sandra E.] Natl Univ San Luis, CONICET, Inst Multidisciplinario Invest Biol San Luis, Lab Expt Med & Therapeut, RA-5700 San Luis, Argentina. [Bonini, Marcelo G.] Univ Illinois, Dept Med, Chicago, IL 60612 USA. [Bonini, Marcelo G.] Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. [Mason, Ronald P.; Ehrenshaft, Marilyn] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Hensley, Kenneth] Univ Toledo, Dept Pathol, Toledo, OH 43614 USA. RP Towner, RA (reprint author), Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM Rheal-Towner@omrf.org RI D'Avila, Joana/L-8970-2013; RAMIREZ, DARIO/K-3312-2013; OI RAMIREZ, DARIO/0000-0001-6725-3326; Silasi, Robert/0000-0001-9590-6160 FU Oklahoma Medical Research Foundation; National Institute of Environmental Health Sciences; Muscular Dystrophy Association; Judith and Jean Pape Adams Charitable Foundation FX Funding was obtained from the Oklahoma Medical Research Foundation (R.A.T.), the National Institute of Environmental Health Sciences (R.P.M.), the Muscular Dystrophy Association (K.H.), and the Judith and Jean Pape Adams Charitable Foundation (K.H.). We thank Dr. Yasvir Tesiram (currently at the University of Queensland, Brisbane, QLD, Australia), for assistance in optimization of the DWI pulse sequence, and Mr. Haitham Abd El-Moaty (currently at Texas Southern University), for assisting in data acquisition for the DWI study. NR 56 TC 11 Z9 11 U1 1 U2 41 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT PY 2013 VL 63 SI SI BP 351 EP 360 DI 10.1016/j.freeradbiomed.2013.05.026 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 200TV UT WOS:000323094700034 PM 23722162 ER PT J AU Zhang, XX Ito, Y Liang, JR Su, Q Zhang, YM Liu, JL Sun, WJ AF Zhang, Xinxin Ito, Yoichiro Liang, Jinru Su, Qi Zhang, Yongmin Liu, Jianli Sun, Wenji TI Preparative isolation and purification of five steroid saponins from Dioscorea zingiberensis CHWright by counter-current chromatography coupled with evaporative light scattering detector SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Dioscorea zingiberensis CH Wright; Counter-current chromatography; Evaporative light scattering detector; Steroid saponins; Traditional Chinese medicine ID PERFORMANCE LIQUID-CHROMATOGRAPHY; HYDRODYNAMIC BEHAVIOR; SOLVENT SYSTEMS; SEPARATION; PHASE; DIOSGENIN; COLUMNS; WRIGHT AB A counter-current chromatography (CCC) method was successfully applied to separate and purify steroid saponins from the traditional Chinese medicine Dioscorea zingiberensis C.H.Wright for the first time. Ethyl acetate-n-butanol-methanol-water (4:1:2:4, v/v) was used as the two-phase solvent system, and evaporative light scattering detector (ELSD) was used as the detector in this method. The method separated in a single run the following five steroid saponins: 26-O-beta-D-glucopyranosyl-(25R)-furost-5-en-3 beta, 22 zeta, 26-triol-3-O-[beta-D-glucopyranosyl-(1 -> 3)-beta-D-glucopyranol-(1 -> 4)-alpha-L-rhamnopyranosyl-(1 -> 2)]-beta-D-glucopyranoside (Compound A); 26-O-beta-D-glucopyranosyl-(25R)-furost-5-en-3 beta, 22 zeta, 26-triol-3-O-[beta-D-glucopyranosyl(1 -> 3)-alpha-L-rhamnopyranosyl(1 -> 2)]-beta-D-glucopyranoside (Compound B); 26-O-beta-D-glucopyranosyl-(25R)-furost-5-en-3 beta, 22 zeta, 26-triol-3-O-[alpha-L-rhamnopyranosyl(1 -> 4)]-beta-D-glucopyranoside (Compound C); 26-O-beta-D-glucopyranosyl-(25R)-furost-5, 20(22)-diene-3 beta, 26-diol-3-O-{alpha-L-rhamnopyranosyl-(1 -> 4)-[beta-D-glucopytanosyl-(1 -> 3)-beta-D-glucopyranosyl-(1 -> 2)]}-beta-D-glucopyranoside (Compound D); and 26-O-beta-D-glucopyranosyl-(25R)-furost-5, 20(22)-diene-3 beta, 26-diol-3-O-[beta-D-glucopyranosyl(1 -> 4)-alpha-L-rhamnopyranosyl(1 -> 2)]-beta-D-glucopyranoside (Compound E). Their structural identification of the five steroid saponins was performed by means of ESI-MS, and C-13 NMR. (C) 2013 Published by Elsevier B.V. C1 [Zhang, Xinxin; Liang, Jinru; Su, Qi; Liu, Jianli; Sun, Wenji] NW Univ Xian, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Zhang, Yongmin] Univ Paris 06, Inst Parisien Chim Mol, F-75252 Paris 05, France. RP Liu, JL (reprint author), NW Univ Xian, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM guoxiaolizhang@163.com; stevelily@163.com FU Intramural NIH HHS [Z99 HL999999] NR 29 TC 7 Z9 9 U1 1 U2 47 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD OCT PY 2013 VL 84 BP 117 EP 123 DI 10.1016/j.jpba.2013.02.005 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 196DE UT WOS:000322752800017 PM 23831486 ER PT J AU Beaton, EA Schmidt, LA Schulkin, J Hall, GB AF Beaton, Elliott A. Schmidt, Louis A. Schulkin, Jay Hall, Geoffrey B. TI Repeated measurement of salivary cortisol within and across days among shy young adults SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Allostatic load; Hypothalamic adrenal (HPA) axis; Repeated measures; Salivary cortisol; Shyness; Social anxiety; Social phobia; Young adults ID PERSONALLY FAMILIAR FACES; BEHAVIORAL-INHIBITION; SOCIAL PHOBIA; ALLOSTATIC LOAD; CHILDREN; SHYNESS; STRESS; RESPONSES; SOCIABILITY; HYPOCORTISOLISM AB Temperamental shyness emerges early in childhood and remains relatively stable throughout development and has been associated with high and low levels of the stress hormone cortisol. Studies examining the relation between shyness and cortisol have been limited because they have traditionally collected only one measure of cortisol on a single day in the laboratory, restricting the reliability and diurnal profile of the measure in the participant's everyday environment. We collected 15 saliva samples across three separate days (i.e., upon waking, +60 min post-waking, +8 h post-waking, +10 h post-waking, and bedtime) in a sample of healthy young adults selected for high and low shyness in order to characterize a portion of the diurnal cortisol rhythm. Overall, shy individuals demonstrated relatively lower cortisol across the day and across multiple mornings than non-shy adults. Higher self-reported social anxiety across multiple measures was also related to lower total cortisol levels across all participants. The present study replicates and extends our previous findings of low salivary cortisol measured in the laboratory in shy adults to repeated measurement in their everyday environments. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Beaton, Elliott A.; Hall, Geoffrey B.] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8S 4K1, Canada. [Beaton, Elliott A.] Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. [Beaton, Elliott A.; Schmidt, Louis A.; Hall, Geoffrey B.] McMaster Univ, Dept Psychol Neurosci & Behav, Hamilton, ON L8S 4K1, Canada. [Schmidt, Louis A.; Hall, Geoffrey B.] McMaster Univ, MINDS, Hamilton, ON L8S 4K1, Canada. [Schulkin, Jay] NIMH, Behav Endocrinol Sect, NIH, Bethesda, MD 20892 USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Dept Neurosci, Washington, DC USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Ctr Brain Basis Cognit, Washington, DC USA. RP Beaton, EA (reprint author), McMaster Univ, Dept Psychol Neurosci & Behav, 1280 Main St W, Hamilton, ON L8S 4K1, Canada. EM ebeaton@uno.edu; schmidtl@mcmaster.ca OI Beaton, Elliott/0000-0001-7631-4637 NR 39 TC 3 Z9 3 U1 2 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD OCT PY 2013 VL 55 IS 6 BP 705 EP 710 DI 10.1016/j.paid.2013.05.024 PG 6 WC Psychology, Social SC Psychology GA 199TY UT WOS:000323019600015 ER PT J AU Chan, YS Wong, JH Fang, EF Pan, WL Ng, TB AF Chan, Yau Sang Wong, Jack Ho Fang, Evandro Fei Pan, Wenliang Tzi Bun Ng TI A Hemagglutinin from Northeast Red Beans with Immunomodulatory Activity and Anti-proliferative and Apoptosis-inducing Activities Toward Tumor Cells SO PROTEIN AND PEPTIDE LETTERS LA English DT Article DE Bean; hemagglutinin; isolation; immunomodulatory; anti-proliferative; apoptosis-inducing ID ANTI-HIV-1 REVERSE-TRANSCRIPTASE; C-TYPE LECTINS; PHASEOLUS-VULGARIS; IN-VITRO; PHYSICOCHEMICAL CHARACTERIZATION; ANTITUMOR-ACTIVITY; INTERFERON-GAMMA; NECROSIS-FACTOR; BINDING LECTIN; PURIFICATION AB A 64-kDa hemagglutinin from a Phaseolus vulgaris cultivar, the northeast red bean, was purified by a protocol composed of three chromatographic steps involving affinity chromatography on Affi-gel blue gel, cation exchange chromatography on SP-Sepharose and FPLC-gel filtration on Superdex 75. The purified hemagglutinin appeared as a single 32-kDa band in SDS-PAGE indicating its dimeric nature. The N-terminal amino acid sequence of the hemagglutinin resembled the sequences of lectins and hemagglutinins from a number of Phaseolus species. The hemagglutinin manifested moderate thermostability and pH stability. It retained full activity up to 65 degrees C and in the pH range 2 - 12. It did not interact with simple sugars such as glucose, mannose and galactose. The hemagglutinin exerted immunostimulatory effects by upregulating the expression of cytokines like interferon-gamma and tumor necrosis factor-alpha. It also exhibited antiproliferative activity on a number of tumor cells including MCF7 (breast cancer), HepG2 (liver cancer), CNE1 and CNE2 (nasopharyngeal cancer) cells, with stronger activity toward MCF7 and CNE1 cells. The hemagglutinin induced phophatidylserine externalization, mitochondrial depolarization and DNA condensation in MCF7 cells, indicating initiation of apoptosis. However, at high hemagglutinin concentrations, severe damage to the MCF7 cells was detected. C1 [Chan, Yau Sang; Wong, Jack Ho; Pan, Wenliang; Tzi Bun Ng] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Fang, Evandro Fei] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Ng, TB (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM b021770@mailserv.cuhk.edu.hk FU Intramural NIH HHS [Z01 AG000723-01] NR 53 TC 3 Z9 3 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD OCT PY 2013 VL 20 IS 10 BP 1159 EP 1169 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 200BS UT WOS:000323042100011 PM 23514011 ER PT J AU Barchi, JJ AF Barchi, Joseph J., Jr. TI Mucin-Type Glycopeptide Structure in Solution: Past, Present, and Future SO BIOPOLYMERS LA English DT Review DE mucins; O-linked glycans; NMR; conformation; serine; threonine ID INTERSTITIAL CYSTITIS PATIENTS; ANTIPROLIFERATIVE FACTOR APF; O-LINKED GLYCOSYLATION; NUCLEAR MAGNETIC-RESONANCE; BLADDER EPITHELIAL-CELLS; HUMAN GLYCOPHORIN-AM; NMR-SPECTROSCOPY; ADHESION DOMAIN; HUMAN CD2; PARACELLULAR PERMEABILITY AB Mucins are very high molecular weight glycoproteins that form a "mucus" barrier at the surface of epithelial cells. They are heavily glycosylated with O-linked glycans that are involved in myriad cellular functions, including protection from external changes in pH, ion flux and reactive oxygen species. Aberrations in mucin expression and their glycan constitution have been associated with many disease states including gastritis, pulmonary disorders and cancer. High resolution structural information on mucins is lacking due to their complexity, in particular their large size and the many variants of O-linked glycans produced in their biosynthesis. This review discusses the structures of glycopeptides that contain "mucin-type" glycosylation, and concentrates primarily on data obtained by NMR spectroscopy. The effect of the glycan on the peptide backbone, the features that have shown to be common to this type of glycosylation and the differences of glycosylation at serine and threonine residues are the major topics of discussion. Published 2013 Wiley Periodicals, Inc. C1 NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM barchij@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 NR 90 TC 6 Z9 6 U1 0 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD OCT PY 2013 VL 99 IS 10 SI SI BP 713 EP 723 DI 10.1002/bip.22313 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 190DO UT WOS:000322318900007 PM 23765378 ER PT J AU Bewley, CA Shahzad-ul-Hussan, S AF Bewley, Carole A. Shahzad-ul-Hussan, Syed TI Characterizing Carbohydrate-Protein Interactions by Nuclear Magnetic Resonance Spectroscopy SO BIOPOLYMERS LA English DT Review DE glycan binding; complex-type glycan; oligomannose; multivalent ID HIV-INACTIVATING PROTEIN; TRANSFER DIFFERENCE NMR; CYANOVIRIN-N; STRUCTURAL BASIS; NOD FACTORS; STD NMR; DC-SIGN; BINDING; LIGAND; POTENT AB Interactions between proteins and soluble carbohydrates and/or surface displayed glycans are central to countless recognition, attachment and signaling events in biology. The physical chemical features associated with these binding events vary considerably, depending on the biological system of interest. For example, carbohydrate-protein interactions can be stoichiometric or multivalent, the protein receptors can be monomeric or oligomeric, and the specificity of recognition can be highly stringent or rather promiscuous. Equilibrium dissociation constants for carbohydrate binding are known to vary from micromolar to millimolar, with weak interactions being far more prevalent; and individual carbohydrate-binding sites can be truly symmetrical or merely homologous, and hence, the affinities of individual sites within a single protein can vary, as can the order of binding. Several factors, including the weak affinities with which glycans bind their protein receptors, the dynamic nature of the glycans themselves, and the nonequivalent interactions among oligomeric carbohydrate receptors, have made nuclear magnetic resonance (NMR) an especially powerful tool for studying and defining carbohydrate-protein interactions. Here, we describe those NMR approaches that have proven to be the most robust in characterizing these systems, and explain what type of information can (or cannot) be obtained from each. Our goal is to provide the reader the information necessary for selecting the correct experiment or sets of experiments to characterize their carbohydrate-protein interaction of interest. Published (C) 2013 Wiley Periodicals, Inc. C1 [Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Shahzad-ul-Hussan, Syed] NIAID, Struct Virol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov; hussans@niaid.nih.gov FU National Institutes of Health (NIDDK); National Institutes of Health (NIAID) FX Contract grant sponsor: Intramural Research Program of the National Institutes of Health (NIDDK and NIAID) NR 58 TC 7 Z9 7 U1 0 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD OCT PY 2013 VL 99 IS 10 SI SI BP 796 EP 806 DI 10.1002/bip.22329 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 190DO UT WOS:000322318900014 PM 23784792 ER PT J AU Thambisetty, M Beason-Held, LL An, Y Kraut, M Metter, J Egan, J Ferrucci, L O'Brien, R Resnick, SM AF Thambisetty, Madhav Beason-Held, Lori L. An, Yang Kraut, Michael Metter, Jeffrey Egan, Josephine Ferrucci, Luigi O'Brien, Richard Resnick, Susan M. TI Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging SO NEUROBIOLOGY OF AGING LA English DT Article DE Insulin resistance; Impaired glucose tolerance; Brain function; PET; Cerebral blood flow; Alzheimer's; Aging ID CEREBRAL-BLOOD-FLOW; INSULIN-RESISTANCE; ALZHEIMERS-DISEASE; COGNITIVE DECLINE; OLDER-ADULTS; POPULATION; DEMENTIA; RISK; METABOLISM; BLSA AB We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial O-15-water positron emission tomography scans (age at first scan, 69.6 +/- 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 +/- 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals. Published by Elsevier Inc. C1 [Thambisetty, Madhav] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Beason-Held, Lori L.; An, Yang; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Kraut, Michael] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Metter, Jeffrey; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Egan, Josephine] NIA, Lab Clin Investigat, NIH, Baltimore, MD 21224 USA. [O'Brien, Richard] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Thambisetty, M (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov FU Intramural Research Program, National Institute on Aging, National Institutes of Health [N01-AG-3-2124] FX We are grateful to the BLSA participants and neuroimaging staff for their dedication to these studies and the staff of the Johns Hopkins University PET facility for their assistance. This work was supported in part by research and development contract N01-AG-3-2124 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 23 TC 9 Z9 9 U1 0 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2013 VL 34 IS 10 BP 2271 EP 2276 DI 10.1016/j.neurobiolaging.2013.03.025 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 187JM UT WOS:000322113800004 PM 23608110 ER PT J AU Ma, WX Cojocaru, R Gotoh, N Gieser, L Villasmil, R Cogliati, T Swaroop, A Wong, WT AF Ma, Wenxin Cojocaru, Radu Gotoh, Norimoto Gieser, Linn Villasmil, Rafael Cogliati, Tiziana Swaroop, Anand Wong, Wai T. TI Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Microglia; Retina; Microarray; Gene expression; Complement; Activation; Angiogenesis; Neurotrophic factors; Senescence ID 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; AGE-RELATED ALTERATIONS; COMPLEMENT FACTOR B; MACULAR DEGENERATION; IN-VIVO; DIABETIC-RETINOPATHY; PHOSPHOLIPASE A(2); VISUAL IMPAIRMENT; UNITED-STATES; RECIPROCAL REGULATION AB Microglia, the resident immune cells of the central nervous system (CNS), are thought to contribute to the pathogenesis of age-related neurodegenerative disorders. It has been hypothesized that microglia undergo age-related changes in gene expression patterns that give rise to pathogenic phenotypes. We compared the gene expression profiles in microglia isolated ex vivo from the retinas of mice ranging from early adulthood to late senescence. We discovered that microglial gene expression demonstrated progressive change with increasing age, and involved genes that regulate microglial supportive functions and immune activation. Molecular pathways involving immune function and regulation, angiogenesis, and neurotrophin signaling demonstrated age-related change. In particular, expression levels of complement genes, C3 and CFB, previously associated with age-related macular degeneration (AMD), increased with aging, suggesting that senescent microglia may contribute to complement dysregulation during disease pathogenesis. Taken together, senescent microglia demonstrate age-related gene expression changes capable of altering their constitutive support functions and regulation of their activation status in ways relating to neuroinflammation and neurodegeneration in the CNS. Published by Elsevier Inc. C1 [Ma, Wenxin; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Cojocaru, Radu; Gotoh, Norimoto; Gieser, Linn; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Villasmil, Rafael] NEI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017; OI Wong, Wai/0000-0003-0681-4016; Swaroop, Anand/0000-0002-1975-1141 FU NEI Intramural; National Eye Institute Intramural Research Program; American Health Assistance Foundation (AHAF); program of the American Health Assistance Foundation FX This study was supported by the NEI Intramural by the National Eye Institute Intramural Research Program and a grant from the American Health Assistance Foundation (AHAF). Acknowledgement is made to the donors of ADR, a program of the American Health Assistance Foundation, for support of this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The data in this manuscript is published or submitted elsewhere, and has been approved by all contributing authors. Procedures involving animals here have been previously approved by institutional review boards. NR 108 TC 21 Z9 21 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2013 VL 34 IS 10 BP 2310 EP 2321 DI 10.1016/j.neurobiolaging.2013.03.022 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 187JM UT WOS:000322113800010 PM 23608111 ER PT J AU Wennerberg, E Sarhan, D Carlsten, M Kaminskyy, VO D'Arcy, P Zhivotovsky, B Childs, R Lundqvist, A AF Wennerberg, Erik Sarhan, Dhifaf Carlsten, Mattias Kaminskyy, Vitaliy O. D'Arcy, Padraig Zhivotovsky, Boris Childs, Richard Lundqvist, Andreas TI Doxorubicin sensitizes human tumor cells to NK cell- and T-cell-mediated killing by augmented TRAIL receptor signaling SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE doxorubicin; adoptive cell therapy; natural killer cells; tumor-infiltrating lymphocytes ID NATURAL-KILLER-CELLS; APOPTOSIS-INDUCING LIGAND; AGONISTIC MONOCLONAL-ANTIBODY; PHASE-I; METASTATIC MELANOMA; ACTIVATING RECEPTORS; CYTOLYTIC ACTIVITY; ADOPTIVE TRANSFER; BREAST-CARCINOMA; CANCER-CELLS AB Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p<0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p<0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p<0.05) or T cells (p<0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p<0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer. What's new? Doxorubicin is widely deployed against a variety of cancers. This study asked whether doxorubicin could make tumor cells more vulnerable to death at the hands of immune cells. The authors treated tumor cell lines with the drug, then unleashed NK and T-cells on them. The immune cells were better able to destroy the pre-treated cells, thanks to a boost to the TRAIL-signaling pathway. Thus a combination therapy, using doxorubicin to prep the tumors for assault by adoptively transferred NK cells and T cells, could improve existing treatment methods. C1 [Wennerberg, Erik; Sarhan, Dhifaf; D'Arcy, Padraig; Lundqvist, Andreas] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Carlsten, Mattias; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kaminskyy, Vitaliy O.; Zhivotovsky, Boris] Karolinska Inst, Inst Environm Med, Div Toxicol, S-17176 Stockholm, Sweden. RP Lundqvist, A (reprint author), Karolinska Inst, Dept Oncol Pathol, R8 01, S-17176 Stockholm, Sweden. EM andreas.lundqvist@ki.se OI D'Arcy, Padraig/0000-0001-6671-7600; Sarhan, Dhifaf/0000-0003-0196-4496; Zhivotovsky, Boris/0000-0002-2238-3482; Lundqvist, Andreas/0000-0002-9709-2970; Carlsten, Mattias/0000-0001-9815-0012; Wennerberg, Erik/0000-0001-7689-5988; Kaminskyy, Vitaliy/0000-0002-8151-5270 FU Swedish Research Council; Swedish Cancer Society; European Research Council Society; Karolinska Institutet; Jeanssons Stiftelser; Ake Wibergs Stiftelse; Magnus Bergvalls Stiftelse; Fredrik och Ingrid Thurings Stiftelse; Stiftelsen Clas Groschinskys Minnesfond; Swedish Society of Medicine FX Grant sponsor: Swedish Research Council, Swedish Cancer Society, European Research Council Society, Karolinska Institutet, Jeanssons Stiftelser, Ake Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Fredrik och Ingrid Thurings Stiftelse, Stiftelsen Clas Groschinskys Minnesfond, Swedish Society of Medicine NR 49 TC 16 Z9 18 U1 3 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2013 VL 133 IS 7 BP 1643 EP 1652 DI 10.1002/ijc.28163 PG 10 WC Oncology SC Oncology GA 182RR UT WOS:000321762200013 PM 23504627 ER PT J AU Castro, FA Koshiol, J Hsing, AW Devesa, SS AF Castro, Felipe A. Koshiol, Jill Hsing, Ann W. Devesa, Susan S. TI Biliary tract cancer incidence in the United StatesDemographic and temporal variations by anatomic site SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE biliary tract cancer; gallbladder cancer; extrahepatic bile duct cancer; ampulla of Vater cancer; Klatskin tumors; incidence ID EXTRAHEPATIC BILE-DUCT; GALLBLADDER CANCER; RISK-FACTORS; METABOLIC SYNDROME; 5 CONTINENTS; EPIDEMIOLOGY; TRENDS; CHOLANGIOCARCINOMA; CHOLECYSTECTOMY; RATES AB We evaluated incidence patterns of biliary tract cancers (gallbladder, extrahepatic bile duct, ampulla of Vater and not otherwise specified) to provide potential insight into the etiology of these cancers. Data were obtained from the population-based Surveillance, Epidemiology and End Results program. Rates for cases diagnosed during 1992-2009 were calculated by racial/ethnic, gender and age groups. Temporal trends during 1974-2009 and annual percentage changes (APC) during 1992-2009 were estimated. Age-adjusted rates by site were higher among American Indian/Alaska Natives, Hispanics (white) and Asian/Pacific Islanders (Asian/PI) and lower among whites and blacks. Gallbladder cancer was more common among women in all ethnic groups (female-to-male incidence rate ratio [IRR] ranged from 1.24 to 2.86), but bile duct and ampulla of Vater cancers were more common among men (female-to-male IRR 0.57 to 0.82). Gallbladder cancer rates declined among all racial/ethnic and gender groups except blacks (APC -0.4% to -3.9%). In contrast, extrahepatic bile duct cancer rates rose significantly in most female racial/ethnic groups; the APCs among whites were 0.8 among females and 1.3 among males, both significant. Rates for ampulla of Vater cancer decreased among Asian/PI females (APC -2.7%) but remained stable for the other groups. In addition to confirming that biliary tract cancer incidence patterns differ by gender and site and that the gallbladder cancer incidence rates have been declining, our study provides novel evidence that extrahepatic bile duct cancer rates are rising. These observations may help guide future etiologic studies. What's new? Cancers of the biliary tract are rare but often fatal, and the risk factors for them are not well known. Analysis of data from the U.S. Surveillance, Epidemiology, and End Results (SEER) program revealed elevated rates of biliary tract cancers among American Indian/Alaska Natives, Hispanics, and Asian/Pacific Islanders compared with blacks and whites. Gallbladder cancer rates declined among most ethnic groups, whereas extrahepatic bile duct cancer rates rose, especially among women. These observations suggest that these cancers may differ in their etiology and provide clues for further research. C1 [Castro, Felipe A.; Koshiol, Jill; Hsing, Ann W.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. RP Castro, FA (reprint author), 6120 Execut Blvd,EPS 7057, Rockville, MD 20852 USA. EM felipe.castro@nih.gov RI Castro, Felipe/N-4241-2013 FU National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA FX Grant sponsor: Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA. NR 49 TC 23 Z9 23 U1 2 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2013 VL 133 IS 7 BP 1664 EP 1671 DI 10.1002/ijc.28161 PG 8 WC Oncology SC Oncology GA 182RR UT WOS:000321762200015 PM 23504585 ER PT J AU Witze, ES Connacher, MK Houel, S Schwartz, MP Morphew, MK Reid, L Sacks, DB Anseth, KS Ahn, NG AF Witze, Eric S. Connacher, Mary Katherine Houel, Stephane Schwartz, Michael P. Morphew, Mary K. Reid, Leah Sacks, David B. Anseth, Kristi S. Ahn, Natalie G. TI Wnt5a Directs Polarized Calcium Gradients by Recruiting Cortical Endoplasmic Reticulum to the Cell Trailing Edge SO DEVELOPMENTAL CELL LA English DT Article ID MIGRATION; ADHESION; ACTIVATION; MEMBRANE; MELANOMA; INVASION; PROTEIN; TRANSPORT; MOVEMENT; BINDING AB Wnt5a directs the assembly of the Wnt-receptor-actin-myosin-polarity (WRAMP) structure, which integrates cell-adhesion receptors with F-actin and myosin to form a microfilament array associated with multivesicular bodies (MVBs). The WRAMP structure is polarized to the cell posterior, where it directs tail-end membrane retraction, driving forward translocation of the cell body. Here we define constituents of the WRAMP proteome, including regulators of microfilament and microtubule dynamics, protein interactions, and enzymatic activity. IQGAP1, a scaffold for F-actin nucleation and crosslinking, is necessary for WRAMP structure formation, potentially bridging microfilaments and MVBs. Vesicle coat proteins, including coatomer-I subunits, localize to and are required for the WRAMP structure. Electron microscopy and live imaging demonstrate movement of the ER to the WRAMP structure and plasma membrane, followed by elevation of intracellular Ca2+. Thus, Wnt5a controls directional movement by recruiting cortical ER to mobilize a rear-directed, localized Ca2+ signal, activating actomyosin contraction and adhesion disassembly for membrane retraction. C1 [Witze, Eric S.; Connacher, Mary Katherine; Houel, Stephane; Reid, Leah; Ahn, Natalie G.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Houel, Stephane; Schwartz, Michael P.; Anseth, Kristi S.; Ahn, Natalie G.] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. [Schwartz, Michael P.; Anseth, Kristi S.] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. [Morphew, Mary K.; Sacks, David B.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Anseth, Kristi S.; Ahn, Natalie G.] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Morphew, Mary K.; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Ahn, NG (reprint author), Univ Colorado, Dept Chem & Biochem, Campus Box 215, Boulder, CO 80309 USA. EM natalie.ahn@colorado.edu RI Schwartz, Michael/B-3417-2008; Schwartz, Mike/O-7963-2016 OI Schwartz, Michael/0000-0003-3785-6606; Schwartz, Mike/0000-0003-3785-6606 FU NIH [F32-CA112847, R01-CA118972, P41-RR000592] FX We are indebted to Amy Palmer and William Old for many helpful discussions, Robert Rogers for assistance with 3D cell culture, Kevin Dean for assistance with light microscopy, and Andreas Hoenger for access to the Boulder Laboratory for 3D Electron Microscopy, a National Research Resource. This work was supported by NIH grants F32-CA112847 (E.S.W.), R01-CA118972 (N.G.A.), and P41-RR000592 (to Andreas Hoenger). NR 58 TC 22 Z9 23 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD SEP 30 PY 2013 VL 26 IS 6 BP 645 EP 657 DI 10.1016/j.devcel.2013.08.019 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 243GO UT WOS:000326305100013 PM 24091015 ER PT J AU Mbulaiteye, SM AF Mbulaiteye, Sam M. TI Burkitt Lymphoma: beyond discoveries SO INFECTIOUS AGENTS AND CANCER LA English DT Editorial Material ID EPSTEIN-BARR-VIRUS; AFRICAN CHILDREN; UNITED-STATES; MALIGNANT LYMPHOMA; CHEMOTHERAPY; PATTERNS; ETIOLOGY; TUMOR; US AB First described in 1958 in Uganda, Burkitt lymphoma (BL) attracted interest worldwide following reports of its uneven geographic distribution and rapidly fatal clinical course. Both suggested infectious etiology and curability. Seminal discoveries followed in quick succession. Viral etiology - due to Epstein-Barr virus (EBV) - was confirmed. Chromosomal translocations, involving cellular MYC, a protooncogene, were discovered, shown to be a hallmark of BL, and central to the genetic basis of cancer. Cure of BL using combination chemotherapy was demonstrated. Unfortunately, civil disturbance in Africa disrupted BL research and blunted its impact on education and oncology care in Africa. Important questions went unanswered. The risk of BL due to malaria or EBV was not quantified. Efforts to answer whether BL could be prevented - by preventing malaria or early EBV infection - were abandoned. The mechanism of malaria in BL is unknown. In Africa, BL remains mostly fatal and diagnosis is still made clinically. Unprecedented advances in molecular, genomics and proteomic technologies, promising to unlock mysteries of cancers, have re-awakened interest in BL. With return of stability to Africa, the unanswered questions about BL are re-attracting global interest. This interest now includes exploiting the knowledge gained about genetics, proteomics, and bioinformatics to enable the development of targeted less toxic treatment for BL; and simpler methods to diagnose BL with high accuracy and sensitivity. The articles in the Burkitt Lymphoma (BL): Beyond Discoveries in Infectious Agents and Cancer highlight BL as priority. Authors explore etiology, pathology, pathogenesis of BL, and whether knowledge gained in the studies of BL can catalyze sustainable cancer services in one of the world's poorest served regions. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS,Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. RP Mbulaiteye, SM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS,Infect & Immunoepidemiol Branch, 9609 Med Ctr Dr,Rm 6E118 MSC 9704, Bethesda, MD 20892 USA. EM mbulaits@mail.nih.gov NR 37 TC 5 Z9 5 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD SEP 30 PY 2013 VL 8 AR UNSP 35 DI 10.1186/1750-9378-8-35 PG 4 WC Oncology; Immunology SC Oncology; Immunology GA 241LK UT WOS:000326168200001 PM 24079372 ER PT J AU Huang, JH Lv, G Min, YF Yang, L Lin, PC AF Huang, Jianhua Lv, Gang Min, Yongfen Yang, Li Lin, P. Charles TI Intravenous administration of Gr-1+CD11b+myeloid cells increases neovascularization and improves cardiac function after heart infarction SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Gr-1+CD11b+myeloid cells; Angiogenesis; Vasculogenesis; Heart infarction; Cell therapy ID TUMOR ANGIOGENESIS; INHIBITION; DISEASE; GROWTH; MODEL C1 [Huang, Jianhua; Lv, Gang] Liaoning Med Univ, Affiliated Hosp 1, Key Lab Med Tissue Engn Liaoning Prov, Jinzhou 121000, Liaoning, Peoples R China. [Huang, Jianhua; Min, Yongfen; Yang, Li; Lin, P. Charles] Vanderbilt Univ, Sch Med, Dept Radiat Oncol, Nashville, TN 37232 USA. [Min, Yongfen; Yang, Li; Lin, P. Charles] Natl Canc Inst Frederick, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Huang, Jianhua] Liaoning Med Univ, Affiliated Hosp 1, Dept Surg Lab, Jinzhou 121000, Liaoning, Peoples R China. RP Huang, JH (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Key Lab Med Tissue Engn Liaoning Prov, Renmin St 5-2, Jinzhou 121000, Liaoning, Peoples R China. EM hjhdr@hotmail.com FU NCI NIH HHS [R01 CA108856, CA108856] NR 9 TC 1 Z9 1 U1 0 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 SEP 30 PY 2013 VL 168 IS 2 BP 1702 EP 1705 DI 10.1016/j.ijcard.2013.03.069 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 231JN UT WOS:000325412800247 PM 23601210 ER PT J AU Yu, BB AF Yu, Binbing TI Predicting county-level cancer incidence rates and counts in the USA SO STATISTICS IN MEDICINE LA English DT Article DE cancer incidence; SEER; spatial correlation; ZIP model; joinpoint model ID CURRENT CALENDAR YEAR; JOINPOINT REGRESSION; MORTALITY COUNTS; UNITED-STATES; SURVIVAL-DATA; MODELS; STATISTICS; TRENDS AB Many countries, including the USA, publish predicted numbers of cancer incidence and death in current and future years for the whole country. These predictions provide important information on the cancer burden for cancer control planners, policymakers and the general public. Based on evidence from several empirical studies, the joinpoint (segmented-line linear regression) model (JPM) has been adopted by the American Cancer Society to estimate the number of new cancer cases in the USA and in individual states since 2007. Recently, cancer incidence in smaller geographic regions such as counties, and local policy makers are increasingly interested with Federal Information Processing Standard code regions. The natural extension is to directly apply the JPM to county-level cancer incidence data. The direct application has several drawbacks and its performance has not been evaluated. To address the concerns, we developed a spatial random-effects JPM for county-level cancer incidence data. The proposed model was used to predict both cancer incidence rates and counts at the county level. The standard JPM and the proposed method were compared through a validation study. The proposed method outperformed the standard JPM for almost all cancer sites, especially for moderate or rare cancer sites and for counties with small population sizes. As an application, we predicted county-level prostate cancer incidence rates and counts for the year 2011 in Connecticut. Published 2013. This article is a US Government work and is in the public domain in the USA. C1 NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. EM whybb@yahoo.com FU National Institute on Aging [ZIC AG001120-03] FX The research was supported in part by the Intramural Research Program of the National Institute on Aging (project number: ZIC AG001120-03). The author would like to thank two anonymous referees for their insightful comments and Ms. Caroline Phillips for her conscientious editorial help and suggestions. NR 30 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2013 VL 32 IS 22 BP 3911 EP 3925 DI 10.1002/sim.5833 PG 15 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 216YV UT WOS:000324324000010 PM 23670947 ER PT J AU Lerit, DA Rusan, NM AF Lerit, Dorothy A. Rusan, Nasser M. TI PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DROSOPHILA-NEUROBLASTS; PERICENTRIOLAR MATERIAL; SPINDLE ORIENTATION; CENTRIOLE; PROTEIN; DRIVE; MORPHOGENESIS; ASSOCIATION; RECRUITMENT; ASYMMETRY AB Centrosomes determine the mitotic axis of asymmetrically dividing stem cells. Several studies have shown that the centrosomes of the Drosophila melanogaster central brain neural stem cells are themselves asymmetric, organizing varying levels of pericentriolar material and microtubules. This asymmetry produces one active and one inactive centrosome during interphase. We identify pericentrin-like protein (PLP) as a negative regulator of centrosome maturation and activity. We show that PLP is enriched on the inactive interphase centrosome, where it blocks recruitment of the master regulator of centrosome maturation, Polo kinase. Furthermore, we find that ectopic Centrobin expression influenced PLP levels on the basal centrosome, suggesting it may normally function to regulate PLP. Finally, we conclude that, although asymmetric centrosome maturation is not required for asymmetric cell division, it is required for proper centrosome segregation to the two daughter cells. C1 [Lerit, Dorothy A.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Rusan, NM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU division of intramural research at the National Institutes of Health/National Heart, Lung, and Blood Institute [1ZIAHL006126]; Lenfant Biomedical Postdoctoral Fellowship FX This work was supported by the division of intramural research at the National Institutes of Health/National Heart, Lung, and Blood Institute (1ZIAHL006126) and a Lenfant Biomedical Postdoctoral Fellowship awarded to D.A. Lerit. NR 30 TC 22 Z9 22 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 30 PY 2013 VL 202 IS 7 BP 1013 EP 1022 DI 10.1083/jcb.201303141 PG 10 WC Cell Biology SC Cell Biology GA 227VQ UT WOS:000325144000005 PM 24081489 ER PT J AU Nugent, AC Davis, RM Zarate, CA Drevets, WC AF Nugent, Allison Carol Davis, Rebecca Marie Zarate, Carlos Alberto, Jr. Drevets, Wayne Curtis TI Reduced thalamic volumes in major depressive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Depression; Magnetic resonance imaging; Morphometry ID VOXEL-BASED MORPHOMETRY; MAGNETIC-RESONANCE; MOOD DISORDERS; UNIPOLAR DEPRESSION; BASAL GANGLIA; HIPPOCAMPAL; ABNORMALITIES; MRI; NUCLEI; CONNECTIVITY AB Altered function in the limbic-cortical-striatial-pallidal-thalamic (LCSPT) circuit has been implicated in the pathophysiology of major depressive disorder (MDD). This study evaluated volumetric differences in subcortical volumes between depressed subjects with MDD (N=142), subjects with MDD in remission (N=72), and healthy controls (N=169). Participants underwent magnetic resonance imaging (MRI) scanning, and subcortical volumes were extracted using FMRIB's Integrated Registration and Segmentation Tool (FIRST), University of Oxford, UK. The depressed MDD subjects exhibited significantly smaller volumes in the bilateral thalamus and hippocampus compared to control subjects, and the differences in the bilateral thalamus remained significant after controlling for total intracranial volume. In a smaller subset of healthy controls and depressed MDD subjects matched to the remitted MDD subjects, significant differences in volume were observed across groups in the bilateral thalamus, as well as the right lateralized caudate, hippocampus, and pallidum; these were primarily accounted for by differences between the depressed MDD subjects versus both the remitted and healthy subjects, though none of these changes remained significant after controlling for total intracranial volume (TIV). Volumetric reductions in the thalamus and hippocampus may contribute to dysfunction within subcortical-cortical networks, consistent with previous evidence of metabolic and hemodynamic abnormalities in these regions in MDD. Published by Elsevier Ireland Ltd. C1 [Nugent, Allison Carol; Zarate, Carlos Alberto, Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Davis, Rebecca Marie] Pacific Sci & Engn, San Diego, CA USA. [Drevets, Wayne Curtis] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne Curtis] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. [Drevets, Wayne Curtis] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Nugent, AC (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr MSC 1030, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This research was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). This study used the high-performance computational capabilities of the Helix Systems at the National Institutes of Health, Bethesda, MD (http://helix.nih.gov). Ioline Henter provided excellent editorial assistance. NR 46 TC 10 Z9 10 U1 0 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD SEP 30 PY 2013 VL 213 IS 3 BP 179 EP 185 DI 10.1016/j.pscychresns.2013.05.004 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 211TV UT WOS:000323934800001 PM 23850106 ER PT J AU Henry, ME Lauriat, TL Lowen, SB Churchill, JH Hodgkinson, CA Goldman, D Renshaw, PF AF Henry, Michael E. Lauriat, Tara L. Lowen, Steven B. Churchill, Jeffrey H. Hodgkinson, Colin A. Goldman, David Renshaw, Perry F. TI Effects of citalopram and escitalopram on fMRI response to affective stimuli in healthy volunteers selected by serotonin transporter genotype SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Functional magnetic resonance imaging; Pharmaco-fMRI; Antidepressant; Imaging genetics; Affective stimulus ID EMOTIONAL FACIAL EXPRESSIONS; MAJOR DEPRESSION; HUMAN AMYGDALA; FUNCTIONAL CONNECTIVITY; MOOD STATE; METAANALYSIS; FACES; BRAIN; GENE; ACTIVATION AB This study was designed to assess whether functional magnetic resonance imaging (fMRI) following antidepressant administration (pharmaco-fMRI) is sufficiently sensitive to detect differences in patterns of activation between enantiomers of the same compound. Healthy adult males (n = 11) participated in a randomized, double-blind, cross-over trial with three medication periods during which they received citalopram (racemic mixture), escitalopram (S-citalopram alone), or placebo for 2 weeks. All participants had high expression serotonin transporter genotypes. An fMRI scan that included passive viewing of overt and covert affective faces and affective words was performed after each medication period. Activation in response to overt faces was greater following escitalopram than following citalopram in the right insula, thalamus, and putamen when the faces were compared with a fixation stimulus. For the rapid covert presentation, a greater response was observed in the left middle temporal gyrus in the happy versus fearful contrast following escitalopram than following citalopram. Thus, the combination of genomics and fMRI was successful in discriminating between two very similar drugs. However, the pattern of activation observed suggests that further studies are indicated to understand how to optimally combine the two techniques. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Henry, Michael E.; Lauriat, Tara L.; Churchill, Jeffrey H.] St Elizabeths Med Ctr, Dept Psychiat, Boston, MA 02135 USA. [Henry, Michael E.; Lauriat, Tara L.; Lowen, Steven B.] McLean Hosp, McLean Imaging Ctr, Belmont, MA 02478 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Renshaw, Perry F.] Univ Utah, Inst Brain, Salt Lake City, UT 84112 USA. RP Henry, ME (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bipolar Clin & Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM mhenry14@partners.org RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Lauriat, Tara/0000-0003-0729-9386 FU Forest Research Institute FX The study was funded by Forest Research Institute as an Investigator-Initiated Trial awarded to MEH. Escitalopram was supplied by Forest and metabolite assays were performed in their analytical laboratory. We thank Hanady Gouta, Athari Alyazidi, and Sophia Shrand for assistance with subject screenings; Ayu Tesfaye for investigational pharmacy services; Cherisse Ferrier for serotonin transporter genotyping; and Bonnie Adams for performing magnetic resonance scans. This study was presented at the 2012 NCDEU meeting in Phoenix, AZ. NR 45 TC 3 Z9 3 U1 4 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD SEP 30 PY 2013 VL 213 IS 3 BP 217 EP 224 DI 10.1016/j.pscychresns.2013.05.008 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 211TV UT WOS:000323934800006 PM 23845563 ER PT J AU Imholte, GC Sauteraud, R Korber, B Bailer, RT Turk, ET Shen, XY Tomaras, GD Mascola, JR Koup, RA Montefiori, DC Gottardo, R AF Imholte, Greg C. Sauteraud, Renan Korber, Bette Bailer, Robert T. Turk, Ellen T. Shen, Xiaoying Tomaras, Georgia D. Mascola, John R. Koup, Richard A. Montefiori, David C. Gottardo, Raphael TI A computational framework for the analysis of peptide microarray antibody binding data with application to HIV vaccine profiling SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Peptide microarrays; Antibodies; Normalization; Positivity calls; Software; Visualization ID FALSE DISCOVERY RATES; ARRAY DATA; CHIP-CHIP; NORMALIZATION; RESPONSES; VARIANCE; EPITOPES; EFFICACY AB We present an integrated analytical method for analyzing peptide microarray antibody binding data, from normalization through subject-specific positivity calls and data integration and visualization. Current techniques for the normalization of such data sets do not account for nonspecific binding activity. A novel normalization technique based on peptide sequence information quickly and effectively reduced systematic biases. We also employed a sliding mean window technique that borrows strength from peptides sharing similar sequences, resulting in reduced signal variability. A smoothed signal aided in the detection of weak antibody binding hotspots. A new principled FDR method of setting positivity thresholds struck a balance between sensitivity and specificity. In addition, we demonstrate the utility and importance of using baseline control measurements when making subject-specific positivity calls. Data sets from two human clinical trials of candidate HIV-1 vaccines were used to validate the effectiveness of our overall computational framework. (C) 2013 Elsevier B.V. All rights reserved. C1 [Imholte, Greg C.; Sauteraud, Renan; Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Imholte, Greg C.; Gottardo, Raphael] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Bailer, Robert T.; Turk, Ellen T.; Mascola, John R.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Korber, Bette] Santa Fe Inst, Santa Fe, NM 87501 USA. [Shen, Xiaoying; Tomaras, Georgia D.; Montefiori, David C.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. RP Gottardo, R (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave North,M2-C200,POB 19024, Seattle, WA 98109 USA. EM gimholte@uw.edu; rgottard@fhcrc.org RI Tomaras, Georgia/J-5041-2016; OI Korber, Bette/0000-0002-2026-5757 FU Bill and Melinda Gates Foundation VISC (Vaccine Immunology Statistical Center) [OPP38744, OPP1032317]; National Institute of Health [U01 AI068635-01] FX The authors thank the participants, investigators, and sponsors of the RV144 Thai trial, including the U.S. Military HIV Research Program (MHRP); U.S. Army Medical Research and Materiel Command; NIAID; U.S. and Thai Components, Armed Forces Research Institute of Medical Science; Ministry of Public Health, Thailand; Mahidol University; Sanofi Pasteur; and Global Solutions for Infectious Diseases. We acknowledge the support from the Bill and Melinda Gates Foundation VISC (Vaccine Immunology Statistical Center) [grant numbers OPP38744, OPP1032317] and the National Institute of Health funded HIV Vaccine Trials Network [grant number U01 AI068635-01]. Finally, we are grateful to JPT for their help and technical assistance. NR 29 TC 8 Z9 8 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD SEP 30 PY 2013 VL 395 IS 1-2 BP 1 EP 13 DI 10.1016/j.jim.2013.06.001 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 212WC UT WOS:000324012500001 PM 23770318 ER PT J AU Berezhkovskii, AM Szabo, A AF Berezhkovskii, Alexander M. Szabo, Attila TI Effect of ligand diffusion on occupancy fluctuations of cell-surface receptors SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID BOUNDARY-CONDITIONS; HOMOGENIZATION; KINETICS; FLUORESCENCE; RELAXATION; BINDING AB The role of diffusion in the kinetics of reversible ligand binding to receptors on a cell surface or to a macromolecule with multiple binding sites is considered. A formalism is developed that is based on a Markovian master equation for the distribution function of the number of occupied receptors containing rate constants that depend on the ligand diffusivity. The formalism is used to derive (1) a nonlinear rate equation for the mean number of occupied receptors and (2) an analytical expression for the relaxation time that characterizes the decay of equilibrium fluctuations of the occupancy of the receptors. The relaxation time is shown to depend on the ligand diffusivity and concentration, the number of receptors, the cell radius, and intrinsic association/dissociation rate constants. This result is then used to estimate the accuracy of the ligand concentration measurements by the cell, which, according to the Berg-Purcell model, is related to fluctuations in the receptor occupancy, averaged over a finite interval of time. Specifically, a simple expression (which is exact in the framework of our formalism) is derived for the variance in the measured ligand concentration in the limit of long averaging times. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 FU National Institutes of Health (NIH), Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology, and National Institute of Diabetes and Digestive and Kidney Diseases. We are grateful to Irina Gopich for her suggestions. NR 16 TC 16 Z9 16 U1 0 U2 11 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 28 PY 2013 VL 139 IS 12 AR 121910 DI 10.1063/1.4816105 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 231DA UT WOS:000325392000013 PM 24089722 ER PT J AU Muthukumar, M Nossal, R AF Muthukumar, M. Nossal, Ralph TI Micellization model for the polymerization of clathrin baskets SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID COATED VESICLES; MEDIATED ENDOCYTOSIS; MECHANISM; MEMBRANE; CAGE; MICROSCOPY; TRISKELION; REVEALS; PROTEIN; MITOSIS AB A thermodynamic model is used to investigate the conditions under which clathrin triskelions form polyhedral baskets. The analysis, which is similar to classical methods used to study micelle formation, relates clathrin basket energetics to system parameters linked to triskelial rigidity, the natural curvature of an isolated triskelion, and interactions between triskelial legs in the assembled polyhedra. Mathematical theory predicts that a minimal ("critical") clathrin concentration, C-C, needs to be surpassed in order for basket polymerization to occur, and indicates how C-C, and the amount of polymerized material, depend on the chosen parameters. Analytical expressions are obtained to indicate how changes in the parameters affect the sizes of the polyhedra which arise when the total clathrin concentration exceeds C-C. A continuum analytic approximation then is used to produce numerical results that illustrate the derived dependences. (C) 2013 AIP Publishing LLC. C1 [Muthukumar, M.] Univ Massachusetts, Dept Polymer Sci & Engn, Dept Phys, Amherst, MA 01003 USA. [Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Nossal, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM nossalr@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health (NIH) [R01HG002776-10]; National Science Foundation (NSF) [1105029]; Air Force Office of Scientific Research (AFOSR) [FA9550-10-1-0159]; Materials Research Science and Engineering Center at the University of Massachusetts, Amherst FX This work was supported in part by intramural research funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Acknowledgement is also made to the National Institutes of Health (NIH Grant No. R01HG002776-10), National Science Foundation (NSF Grant No. 1105029), Air Force Office of Scientific Research (AFOSR Grant No. FA9550-10-1-0159), and the Materials Research Science and Engineering Center at the University of Massachusetts, Amherst. NR 47 TC 4 Z9 4 U1 0 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 28 PY 2013 VL 139 IS 12 AR 121928 DI 10.1063/1.4816634 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 231DA UT WOS:000325392000031 PM 24089740 ER PT J AU Viswakarma, N Jia, YZ Bai, L Gao, Q Lin, BL Zhang, XH Misra, P Rana, A Jain, S Gonzalez, FJ Zhu, YJ Thimmapaya, B Reddy, JK AF Viswakarma, Navin Jia, Yuzhi Bai, Liang Gao, Qian Lin, Bingliang Zhang, Xiaohong Misra, Parimal Rana, Ajay Jain, Sanjay Gonzalez, Frank J. Zhu, Yi-Jun Thimmapaya, Bayar Reddy, Janardan K. TI The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; RECEPTOR-BINDING PROTEIN; RNA-POLYMERASE-II; PEROXISOME-PROLIFERATOR; MOUSE-LIVER; TRANSCRIPTIONAL COACTIVATOR; (PPAR)-BINDING PROTEIN; HEPATIC STEATOSIS; TRAP220 COMPONENT; NUCLEAR RECEPTORS AB Mediator, a large multisubunit protein complex, plays a pivotal role in gene transcription by linking gene-specific transcription factors with the preinitiation complex and RNA polymerase II. In the liver, the key subunit of the Mediator complex, Med1, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. Conditional knock-out of Med1 in the liver showed that hepatocytes lacking Med1 did not regenerate following either partial hepatectomy or treatment with certain nuclear receptor activators and failed to give rise to tumors when challenged with carcinogens. We now report that the adenovirally driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control, and liver-specific genes, indicating that Med1 alone is necessary and sufficient for liver cell proliferation. Importantly, we demonstrate that AMP-activated protein kinase (AMPK), an important cellular energy sensor, interacts with, and directly phosphorylates, Med1 in vitro at serine 656, serine 756, and serine 796. AMPK also phosphorylates Med1 in vivo in mouse liver and in cultured primary hepatocytes and HEK293 and HeLa cells. In addition, we demonstrate that PPAR alpha activators increase AMPK-mediated Med1 phosphorylation in vivo. Inhibition of AMPK by compound C decreased hepatocyte proliferation induced by Med1 and also by the PPAR alpha activators fenofibrate and Wy-14,643. Co-treatment with compound C attenuated PPAR alpha activator-inducible fatty acid beta-oxidation in liver. Our results suggest that Med1 phosphorylation by its association with AMPK regulates liver cell proliferation and fatty acid oxidation, most likely as a downstream effector of PPAR alpha and AMPK. C1 [Viswakarma, Navin; Jia, Yuzhi; Bai, Liang; Gao, Qian; Lin, Bingliang; Zhang, Xiaohong; Zhu, Yi-Jun; Reddy, Janardan K.] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Misra, Parimal] Dr Reddys Inst Life Sci, Hyderabad 500046, Andhra Pradesh, India. [Rana, Ajay] Loyola Univ Chicago, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA. [Jain, Sanjay] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Thimmapaya, Bayar] Northwestern Univ, Feinberg Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. RP Reddy, JK (reprint author), 303 E Chicago Ave, Chicago, IL 60611 USA. EM jkreddy@northwestern.edu FU National Institutes of Health Cancer Center [NIH CA06600553] FX We thank Dr. Samuel G. Mackintosh (Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock) for his generous help with LC-MS/MS studies. We express our appreciation to Dr. Aurore Vluggens for her participation in the early phases of this work. We also thank Rahil Hasan, Sandeep Bharadwaj, and Izer Martinez for their participation in this work as summer students and Dr. Nadereh Zafri for helpful discussions on microarray studies. The genomic core facility used in this study was supported by National Institutes of Health Cancer Center Support Grant NIH CA06600553. NR 72 TC 6 Z9 6 U1 0 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 SEP 27 PY 2013 VL 288 IS 39 BP 27898 EP 27911 DI 10.1074/jbc.M113.486696 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302OB UT WOS:000330612800018 PM 23943624 ER PT J AU Bharti, SK Sommers, JA George, F Kuper, J Hamon, F Shin-ya, K Teulade-Fichou, MP Kisker, C Brosh, RM AF Bharti, Sanjay Kumar Sommers, Joshua A. George, Fourbears Kuper, Jochen Hamon, Florian Shin-ya, Kazuo Teulade-Fichou, Marie-Paule Kisker, Caroline Brosh, Robert M., Jr. TI Specialization among Iron-Sulfur Cluster Helicases to Resolve G-quadruplex DNA Structures That Threaten Genomic Stability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANEMIA GROUP J; BIOCHEMICAL-CHARACTERIZATION; SACCHAROMYCES-CEREVISIAE; SMALL-MOLECULE; FANCJ; REPLICATION; GENE; TELOMERES; BACH1; TELOMESTATIN AB G-quadruplex (G4) DNA, an alternate structure formed by Hoogsteen hydrogen bonds between guanines in G-rich sequences, threatens genomic stability by perturbing normal DNA transactions including replication, repair, and transcription. A variety of G4 topologies (intra- and intermolecular) can form in vitro, but the molecular architecture and cellular factors influencing G4 land-scape in vivo are not clear. Helicases that unwind structured DNA molecules are emerging as an important class of G4-resolving enzymes. The BRCA1-associated FANCJ helicase is among those helicases able to unwind G4 DNA in vitro, and FANCJ mutations are associated with breast cancer and linked to Fanconi anemia. FANCJ belongs to a conserved iron-sulfur (Fe S) cluster family of helicases important for genomic stability including XPD (nucleotide excision repair), DDX11 (sister chromatid cohesion), and RTEL (telomere metabolism), genetically linked to xeroderma pigmentosum/Cockayne syndrome, Warsaw breakage syndrome, and dyskeratosis congenita, respectively. To elucidate the role of FANCJ in genomic stability, its molecular functions in G4 metabolism were examined. FANCJ efficiently unwound in a kinetic and ATPase-dependent manner entropically favored unimolecular G4 DNA, whereas other Fe-S helicases tested did not. The G4-specific ligands Phen-DC3 or Phen-DC6 inhibited FANCJ helicase on unimolecular G4 similar to 1000-fold better than bi- or tetramolecular G4 DNA. The G4 ligand telomestatin induced DNA damage inhuman cells deficient in FANCJ but not DDX11 or XPD. These findings suggest FANCJ is a specialized Fe-S cluster helicase that preserves chromosomal stability by unwinding unimolecular G4 DNA likely to form in transiently unwound single-stranded genomic regions. C1 [Bharti, Sanjay Kumar; Sommers, Joshua A.; George, Fourbears; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Kuper, Jochen; Kisker, Caroline] Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg, Germany. [Hamon, Florian; Teulade-Fichou, Marie-Paule] Univ Paris 11, CNRS, UMR 176, Inst Curie, F-91405 Orsay, France. [Shin-ya, Kazuo] Natl Inst Adv Ind Sci & Technol, Biomed Informat Res Ctr, Koto Ku, Tokyo 1350064, Japan. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health, NIA; Fanconi Anemia Research Fund; Deutsche Forschungsgemeinschaft [Forschungszentrum FZ82] FX This work was supported by the Intramural Research program of the National Institutes of Health, NIA. This work was also supported by the Fanconi Anemia Research Fund (to R. M. B.) and through the Deutsche Forschungsgemeinschaft (Forschungszentrum FZ82; to C.K.). NR 43 TC 30 Z9 30 U1 2 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 SEP 27 PY 2013 VL 288 IS 39 BP 28217 EP 28229 DI 10.1074/jbc.M113.496463 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302OB UT WOS:000330612800044 PM 23935105 ER PT J AU Nakagawa, T Ge, Q Pawlosky, R Wynn, RM Veech, RL Uyeda, K AF Nakagawa, Tsutomu Ge, Qiang Pawlosky, Robert Wynn, R. Max Veech, Richard L. Uyeda, Kosaku TI Metabolite Regulation of Nucleo-cytosolic Trafficking of Carbohydrate Response Element-binding Protein (ChREBP) ROLE OF KETONE BODIES SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR; SUBCELLULAR-LOCALIZATION; XYLULOSE 5-PHOSPHATE; RAT-LIVER; GLUCOSE; KINASE; GENE; PHOSPHORYLATION; LIPOGENESIS; DEFICIENCY AB The carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in converting excess carbohydrate to storage fat in liver. In response to changing glucose levels, ChREBP activity is regulated by nucleo-cytoplasmic shuttling of ChREBP via interactions with 14-3-3 proteins and importins. The nuclear/cytosol trafficking is regulated partly by phosphorylation/dephosphorylation of serine 196 mediated by cAMP-dependent protein kinase and protein phosphatase. Weshow here that protein-free extracts of starved and high fat-fed livers contain metabolites that activate interaction of ChREBP center dot 14-3-3 and inhibit the ChREBP/importin alpha interaction, resulting in cytosolic localization. These metabolites were identified as beta-hydroxybutyrate and acetoacetate. Nuclear localization of GFP-ChREBP is rapidly inhibited in hepatocytes incubated in beta-hydroxybutyrate or fatty acids, and the observed inhibition is closely correlated with the production of ketone bodies. These observations show that ketone bodies play an important role in the regulation of ChREBP activity by restricting ChREBP localization to the cytoplasm, thus inhibiting fat synthesis during periods of ketosis. C1 Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Uyeda, Kosaku] Dallas Vet Affairs Med Ctr, Dallas, TX 75216 USA. [Pawlosky, Robert; Veech, Richard L.] NIAAA, Bethesda, MD 20892 USA. RP Uyeda, K (reprint author), Dallas Vet Affairs Med Ctr, Dallas, TX 75216 USA. EM Kosaku.Uyeda@utsouthwestern.edu FU National Institutes of Health [DK06394804]; Veterans Affairs Merit Review; Welch Grant FX This work was supported, in whole or in part, by National Institutes of Health Grant DK06394804. This work was also supported by Veterans Affairs Merit Review and a Welch Grant. NR 25 TC 14 Z9 15 U1 1 U2 7 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 SEP 27 PY 2013 VL 288 IS 39 BP 28358 EP 28367 DI 10.1074/jbc.M113.498550 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302OB UT WOS:000330612800064 PM 23918932 ER PT J AU Nakano, S Ikebe, E Tsukamoto, Y Wang, Y Matsumoto, T Mitsui, T Yahiro, T Inoue, K Kawazato, H Yasuda, A Ito, K Yokoyama, S Takahashi, N Hori, M Shimada, T Moriyama, M Kubota, T Ono, K Fujibuchi, W Jeang, KT Iha, H Nishizono, A AF Nakano, Satoko Ikebe, Emi Tsukamoto, Yoshiyuki Wang, Yan Matsumoto, Takashi Mitsui, Takahiro Yahiro, Takaaki Inoue, Kunimitsu Kawazato, Hiroaki Yasuda, Aiko Ito, Kanako Yokoyama, Shigeo Takahashi, Naohiko Hori, Mitsuo Shimada, Tatsuo Moriyama, Masatsugu Kubota, Toshiaki Ono, Katsushige Fujibuchi, Wataru Jeang, Kuan-Teh Iha, Hidekatsu Nishizono, Akira TI Commensal Microbiota Contributes to Chronic Endocarditis in TAX1BP1 Deficient Mice SO PLOS ONE LA English DT Article ID NF-KAPPA-B; T-CELL LEUKEMIA; VIRUS TYPE-I; RESEMBLING RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; A20 TNFAIP3; TAX PROTEIN; HTLV-1 TAX; TNF-ALPHA; INFLAMMATION AB Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-kappa B by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3), CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-kappa B alpha reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced 'germ free' status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named 'pseudo-infective endocarditis' were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction. C1 [Nakano, Satoko; Ikebe, Emi; Matsumoto, Takashi; Mitsui, Takahiro; Yahiro, Takaaki; Inoue, Kunimitsu; Iha, Hidekatsu; Nishizono, Akira] Oita Univ, Fac Med, Dept Microbiol, Oita 87011, Japan. [Nakano, Satoko; Kubota, Toshiaki] Oita Univ, Fac Med, Dept Ophthalmol, Oita 87011, Japan. [Tsukamoto, Yoshiyuki; Moriyama, Masatsugu] Oita Univ, Fac Med, Dept Mol Pathol, Oita 87011, Japan. [Wang, Yan; Ono, Katsushige] Oita Univ, Fac Med, Dept Pathophysiol, Oita 87011, Japan. [Kawazato, Hiroaki; Yasuda, Aiko] Oita Univ, Fac Med, Res Promot Inst, Oita 87011, Japan. [Ito, Kanako] Oita Univ, Fac Med, Dept Internal Med 2, Oita 87011, Japan. [Yokoyama, Shigeo] Oita Univ, Fac Med, Dept Diagnost Pathol, Oita 87011, Japan. [Takahashi, Naohiko] Oita Univ, Fac Med, Dept Lab Examinat & Diagnost, Oita 87011, Japan. [Hori, Mitsuo] Ibaragi Prefectural Cent Hosp, Div Hematol, Kasama, Ibaraki, Japan. [Shimada, Tatsuo] Oita Univ, Sch Nursing, Dept Hlth Sci, Oita 87011, Japan. [Fujibuchi, Wataru] Kyoto Univ, Dept Cell Growth & Differentiat, Ctr iPS Cell Res & Applicat, Kyoto, Japan. [Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Iha, H (reprint author), Oita Univ, Fac Med, Dept Microbiol, Oita 87011, Japan. EM hiha@oita-u.ac.jp OI Iha, Hidekatsu/0000-0002-0999-5636 FU Ministry of Education, Culture, Sports, Science, and Technology; Okinawa Science and Technology Promotion Center (OSTPC); Miyazaki Prefectural Industrial Support Foundation; Hita Tenryosui Co. Ltd. FX This study is supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology; Okinawa Science and Technology Promotion Center (OSTPC); Miyazaki Prefectural Industrial Support Foundation. E. I. is a research fellow of the OSTPC and was a recipient of the Hita Tenryosui Research Scholarship from Hita Tenryosui Co. Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 3 Z9 3 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 27 PY 2013 VL 8 IS 9 AR UNSP e73205 DI 10.1371/journal.pone.0073205 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228WY UT WOS:000325223900012 PM 24086273 ER PT J AU Taliani, S Pugliesi, I Barresi, E Salerno, S Marchand, C Agama, K Simorini, F La Motta, C Marini, AM Di Leva, FS Marinelli, L Cosconati, S Novellino, E Pommier, Y Di Santo, R Da Settimo, F AF Taliani, Sabrina Pugliesi, Isabella Barresi, Elisabetta Salerno, Silvia Marchand, Christophe Agama, Keli Simorini, Francesca La Motta, Concettina Marini, Anna Maria Di Leva, Francesco Saverio Marinelli, Luciana Cosconati, Sandro Novellino, Ettore Pommier, Yves Di Santo, Roberto Da Settimo, Federico TI Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: A Suitable Scaffold for the Development of Noncamptothecin Topoisomerase I (Top1) Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL ANTITUMOR AGENTS; ANTIPROLIFERATIVE ACTIVITY; MJ-III-65 NSC-706744; FORCE-FIELD; DNA-BINDING; CAMPTOTHECIN; DESOLVATION AB In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top I poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol. C1 [Taliani, Sabrina; Pugliesi, Isabella; Barresi, Elisabetta; Salerno, Silvia; Simorini, Francesca; La Motta, Concettina; Marini, Anna Maria; Da Settimo, Federico] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy. [Di Santo, Roberto] Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Marchand, Christophe; Agama, Keli; Pommier, Yves] NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Di Leva, Francesco Saverio] IIT, Dept Drug Discovery & Dev, I-16163 Genoa, Italy. [Cosconati, Sandro] Univ Naples 2, DiSTABiF, I-81100 Caserta, Italy. [Marinelli, Luciana; Novellino, Ettore] Univ Naples Federico II, Dept Pharm, I-80131 Naples, Italy. RP Taliani, S (reprint author), Univ Pisa, Dept Pharm, Via Bonanno 6, I-56126 Pisa, Italy. EM sabrina.taliani@farm.unipi.it RI Da Settimo, Federico/M-1451-2015; La Motta, Concettina/M-3821-2015; OI Da Settimo, Federico/0000-0002-7897-7917; Cosconati, Sandro/0000-0002-8900-0968; Marinelli, Luciana/0000-0002-4084-8044; La Motta, Concettina/0000-0002-0194-5431; Barresi, Elisabetta/0000-0002-9814-7195; TALIANI, SABRINA/0000-0001-8675-939X; Marini, Anna Maria/0000-0001-8664-375X; Di Santo, Roberto/0000-0002-4279-7666; Salerno, Silvia/0000-0002-6072-4698 FU University of Pisa; "Sapienza" University of Rome; Center for Cancer Research, Intramural Program of the NCI, NIH FX This work was financially supported by University of Pisa, "Sapienza" University of Rome, and the Center for Cancer Research, Intramural Program of the NCI, NIH. NR 21 TC 11 Z9 11 U1 0 U2 14 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 SEP 26 PY 2013 VL 56 IS 18 BP 7458 EP 7462 DI 10.1021/jm400932c PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295DV UT WOS:000330097700026 PM 23987476 ER PT J AU Coletta, A Castelli, S Chillemi, G Sanna, N Cushman, M Pommier, Y Desideri, A AF Coletta, Andrea Castelli, Silvia Chillemi, Giovanni Sanna, Nico Cushman, Mark Pommier, Yves Desideri, Alessandro TI Solvent Dependency of the UV-Vis Spectrum of Indenoisoquinolines: Role of Keto-Oxygens as Polarity Interaction Probes SO PLOS ONE LA English DT Article ID TOPOISOMERASE-I INHIBITORS; TOPOTECAN ANTICANCER DRUG; DNA COVALENT COMPLEX; CLEAVAGE COMPLEX; AQUEOUS-SOLUTION; NORINDENOISOQUINOLINE; RESISTANCE; MECHANISM; DENSITY; BINDING AB Indenoisoquinolines are the most promising non-campthotecins topoisomerase IB inhibitors. We present an integrated experimental/computational investigation of the UV-Vis spectra of the IQNs parental compound (NSC314622) and two of its derivatives (NSC724998 and NSC725776) currently undergoing Phase I clinical trials. In all the three compounds a similar dependence of the relative absorption intensities at 270 nm and 290 nm on solvent polarity is found. The keto-oxygens in positions 5 and 11 of the molecular scaffold of the molecule are the principal chromophores involved in this dependence. Protic interactions on these sites are also found to give rise to absorptions at wavelength <250 nm observed in water solution, due to the stabilization of highly polarized tautomers of the molecule. These results suggest that the keto-oxygens are important polarizable groups that can act as useful interactors with the molecular receptor, providing at the same time an useful fingerprint for the monitoring of the drug binding to topoisomerase IB. C1 [Coletta, Andrea; Castelli, Silvia; Desideri, Alessandro] Univ Roma Tor Vergata, Dipartimento Biol, I-00173 Rome, Italy. [Chillemi, Giovanni; Sanna, Nico] Consorzio Interuniv Applicaz Supercalcolo Univ &, Rome, Italy. [Cushman, Mark] Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Desideri, A (reprint author), Univ Roma Tor Vergata, Dipartimento Biol, I-00173 Rome, Italy. EM desideri@uniroma2.it RI Chillemi, Giovanni/E-5201-2010; Coletta, Andrea/H-9856-2012; SANNA, Nico/R-8799-2016 OI Chillemi, Giovanni/0000-0003-3901-6926; Coletta, Andrea/0000-0003-4032-394X; SANNA, Nico/0000-0002-1947-7939 FU Associazione Italiana per la Ricerca sul Cancro Research Project [IG-10121]; National Institutes of Health Research Grant [UO1 CA89566]; CASPUR/CINECA [std11-434]; National Cancer Institute Intramural Program, Center for Cancer Research FX Funding from Associazione Italiana per la Ricerca sul Cancro Research Project IG-10121; National Institutes of Health Research Grant UO1 CA89566; CASPUR/CINECA std11-434, "Characterization of anticancer drug selectively targeting human topoisomerase IB by ab-initio calculations"; and National Cancer Institute Intramural Program, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 1 Z9 1 U1 2 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 SEP 26 PY 2013 VL 8 IS 9 AR e73881 DI 10.1371/journal.pone.0073881 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228VP UT WOS:000325220000004 PM 24086299 ER PT J AU Gottardo, R Bailer, RT Korber, BT Gnanakaran, S Phillips, J Shen, XY Tomaras, GD Turk, E Imholte, G Eckler, L Wenschuh, H Zerweck, J Greene, K Gao, HM Berman, PW Francis, D Sinangil, F Lee, C Nitayaphan, S Rerks-Ngarm, S Kaewkungwal, J Pitisuttithum, P Tartaglia, J Robb, ML Michael, NL Kim, JH Zolla-Pazner, S Haynes, BF Mascola, JR Self, S Gilbert, P Montefiori, DC AF Gottardo, Raphael Bailer, Robert T. Korber, Bette T. Gnanakaran, S. Phillips, Joshua Shen, Xiaoying Tomaras, Georgia D. Turk, Ellen Imholte, Gregory Eckler, Larry Wenschuh, Holger Zerweck, Johannes Greene, Kelli Gao, Hongmei Berman, Phillip W. Francis, Donald Sinangil, Faruk Lee, Carter Nitayaphan, Sorachai Rerks-Ngarm, Supachai Kaewkungwal, Jaranit Pitisuttithum, Punnee Tartaglia, James Robb, Merlin L. Michael, Nelson L. Kim, Jerome H. Zolla-Pazner, Susan Haynes, Barton F. Mascola, John R. Self, Steve Gilbert, Peter Montefiori, David C. TI Plasma IgG to Linear Epitopes in the V2 and V3 Regions of HIV-1 gp120 Correlate with a Reduced Risk of Infection in the RV144 Vaccine Efficacy Trial SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; DEPENDENT CELLULAR CYTOTOXICITY; RECOMBINANT GLYCOPROTEIN-120 VACCINE; CD4 BINDING-SITE; ENVELOPE PROTEIN; NEUTRALIZING ANTIBODIES; CONFORMATIONAL EPITOPE; TRANSMEMBRANE PROTEIN; BROAD NEUTRALIZATION AB Neutralizing and non-neutralizing antibodies to linear epitopes on HIV-1 envelope glycoproteins have potential to mediate antiviral effector functions that could be beneficial to vaccine-induced protection. Here, plasma IgG responses were assessed in three HIV-1 gp120 vaccine efficacy trials (RV144, Vax003, Vax004) and in HIV-1-infected individuals by using arrays of overlapping peptides spanning the entire consensus gp160 of all major genetic subtypes and circulating recombinant forms (CRFs) of the virus. In RV144, where 31.2% efficacy against HIV-1 infection was seen, dominant responses targeted the C1, V2, V3 and C5 regions of gp120. An analysis of RV144 case-control samples showed that IgG to V2 CRF01_AE significantly inversely correlated with infection risk (OR=0.54, p=0.0042), as did the response to other V2 subtypes (OR=0.60-0.63, p=0.016-0.025). The response to V3 CRF01_AE also inversely correlated with infection risk but only in vaccine recipients who had lower levels of other antibodies, especially Env-specific plasma IgA (OR=0.49, p=0.007) and neutralizing antibodies (OR=0.5, p=0.008). Responses to C1 and C5 showed no significant correlation with infection risk. In Vax003 and Vax004, where no significant protection was seen, serum IgG responses targeted the same epitopes as in RV144 with the exception of an additional C1 reactivity in Vax003 and infrequent V2 reactivity in Vax004. In HIV-1 infected subjects, dominant responses targeted the V3 and C5 regions of gp120, as well as the immunodominant domain, heptad repeat 1 (HR-1) and membrane proximal external region (MPER) of gp41. These results highlight the presence of several dominant linear B cell epitopes on the HIV-1 envelope glycoproteins. They also generate the hypothesis that IgG to linear epitopes in the V2 and V3 regions of gp120 are part of a complex interplay of immune responses that contributed to protection in RV144. C1 [Gottardo, Raphael; Imholte, Gregory; Self, Steve; Gilbert, Peter] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Bailer, Robert T.; Turk, Ellen; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Korber, Bette T.; Gnanakaran, S.; Phillips, Joshua] Los Alamos Natl Lab, Los Alamos, NM USA. [Shen, Xiaoying; Tomaras, Georgia D.; Greene, Kelli; Gao, Hongmei; Haynes, Barton F.; Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Eckler, Larry; Wenschuh, Holger; Zerweck, Johannes] JPT Peptide Technol GmbH, Berlin, Germany. [Berman, Phillip W.] Univ Calif Santa Cruz, Baskin Sch Engn, Santa Cruz, CA 95064 USA. [Francis, Donald; Sinangil, Faruk; Lee, Carter] Global Solut Infect Dis, San Francisco, CA USA. [Nitayaphan, Sorachai] US Army Med Component, Dept Retrovirol, AFRIMS, Bangkok, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Kaewkungwal, Jaranit] Mahidol Univ, Fac Trop Med, Ctr Excellence Biomed & Publ Hlth Informat BIOPHI, Bangkok, Thailand. [Pitisuttithum, Punnee] Mahidol Univ, Vaccine Trial Ctr, Bangkok 10700, Thailand. [Pitisuttithum, Punnee] Mahidol Univ, Dept Clin Trop Med, Bangkok 10700, Thailand. [Tartaglia, James] Sanofi Pasteur, Dept Res & Dev, Swiftwater, PA USA. [Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Zolla-Pazner, Susan] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. [Zolla-Pazner, Susan] NYU, Sch Med, New York, NY USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. EM david.montefiori@duke.edu RI Tomaras, Georgia/J-5041-2016; OI Gnanakaran, S/0000-0002-9368-3044; Korber, Bette/0000-0002-2026-5757 FU Bill & Melinda Gates Foundation [38619]; U.S. Army Medical Research and Material Command (USAMRMC) [Y1-AI-2642-12]; National Institutes of Allergy and Infectious Diseases [Y1-AI-2642-12]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [Y1-AI-2642-12]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense (DOD) [W81XWH-07-2-0067]; New York University School of Medicine [692526] FX This study was funded in part by a grant from the Bill & Melinda Gates Foundation (#38619) to DCM as part of the Collaboration for AIDS Vaccine Discovery (www.cavd.org), and by an Interagency Agreement Y1-AI-2642-12 between U.S. Army Medical Research and Material Command (USAMRMC), the National Institutes of Allergy and Infectious Diseases, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD) and New York University School of Medicine (Contract No. 692526). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 81 Z9 82 U1 0 U2 12 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 SEP 26 PY 2013 VL 8 IS 9 AR e75665 DI 10.1371/journal.pone.0075665 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228VP UT WOS:000325220000034 PM 24086607 ER PT J AU Zhang, P Nakatsukasa, H Tu, E Kasagi, S Cui, KR Ishikawa, M Konkel, JE Maruyama, T Wei, G Abbatiello, B Wang, ZQ Zhao, KJ Chen, WJ AF Zhang, Pin Nakatsukasa, Hiroko Tu, Eric Kasagi, Shimpei Cui, Kairong Ishikawa, Masaki Konkel, Joanne E. Maruyama, Takashi Wei, Gang Abbatiello, Brittany Wang, Zhao-Qi Zhao, Keji Chen, WanJun TI PARP-1 regulates expression of TGF-beta receptors in T cells SO BLOOD LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE GENE; ADP-RIBOSE POLYMERASE; FOXP3 EXPRESSION; DENDRITIC CELLS; RETINOIC-ACID; T(H)17 CELLS; MICE LACKING; DIFFERENTIATION; TRANSCRIPTION; MECHANISMS AB Transforming growth factor-beta (TGF-beta) receptors (T beta Rs) are essential components for TGF-beta signal transduction in T cells, yet the mechanisms by which the receptors are regulated remain poorly understood. We show here that Poly(ADP-ribose) polymerase-1 (PARP-1) regulates TGF-beta receptor I (T beta RI) and II (T beta RII) expression in CD4(+) T cells and subsequently affects Smad2/3-mediated TGF-beta signal transduction. Inhibition of PARP-1 led to the upregulation of both T beta RI and T beta RII, yet the underlying molecular mechanisms were distinct. PARP-1 selectively bound to the promoter of T beta RII, whereas the enzymatic activity of PARP-1 was responsible for the inhibition of T beta RI expression. Importantly, inhibition of PARP-1 also enhanced expression of T beta Rs in human CD4(+) T cells. Thus, PARP-1 regulates T beta R expression and TGF-beta signaling in T cells. C1 [Zhang, Pin; Nakatsukasa, Hiroko; Tu, Eric; Kasagi, Shimpei; Konkel, Joanne E.; Maruyama, Takashi; Abbatiello, Brittany; Chen, WanJun] NIDCR, Mucosal Immunol Sect, OPCB, NIH, Bethesda, MD 20892 USA. [Cui, Kairong; Wei, Gang; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Ishikawa, Masaki] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Wang, Zhao-Qi] Univ Jena, Leibniz Inst Age Res, Fritz Lipmann Inst, Fac Biol Pharm, Jena, Germany. RP Chen, WJ (reprint author), NIDCR, Mucosal Immunol Sect, OPCB, NIH, Bldg 30,Room 304, Bethesda, MD 20892 USA. EM wchen@dir.nidcr.nih.gov RI MaruYama, Takashi/N-5994-2014 FU Intramural Research Program of the National Institute of Dental and Craniofacial Research (National Institutes of Health) FX This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (National Institutes of Health). NR 41 TC 13 Z9 13 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 26 PY 2013 VL 122 IS 13 BP 2224 EP 2232 DI 10.1182/blood-2013-05-503250 PG 9 WC Hematology SC Hematology GA 229MN UT WOS:000325269900014 PM 23940283 ER PT J AU Orru, V Steri, M Sole, G Sidore, C Virdis, F Dei, M Lai, S Zoledziewska, M Busonero, F Mulas, A Floris, M Mentzen, WI Urru, SAM Olla, S Marongiu, M Piras, MG Lobina, M Maschio, A Pitzalis, M Urru, MF Marcelli, M Cusano, R Deidda, F Serra, V Oppo, M Pilu, R Reinier, F Berutti, R Pireddu, L Zara, I Porcu, E Kwong, A Brennan, C Tarrier, B Lyons, R Kang, HM Uzzau, S Atzeni, R Valentini, M Firinu, D Leoni, L Rotta, G Naitza, S Angius, A Congia, M Whalen, MB Jones, CM Schlessinger, D Abecasis, GR Fiorillo, E Sanna, S Cucca, F AF Orru, Valeria Steri, Maristella Sole, Gabriella Sidore, Carlo Virdis, Francesca Dei, Mariano Lai, Sandra Zoledziewska, Magdalena Busonero, Fabio Mulas, Antonella Floris, Matteo Mentzen, Wieslawa I. Urru, Silvana A. M. Olla, Stefania Marongiu, Michele Piras, Maria G. Lobina, Monia Maschio, Andrea Pitzalis, Maristella Urru, Maria F. Marcelli, Marco Cusano, Roberto Deidda, Francesca Serra, Valentina Oppo, Manuela Pilu, Rosella Reinier, Frederic Berutti, Riccardo Pireddu, Luca Zara, Ilenia Porcu, Eleonora Kwong, Alan Brennan, Christine Tarrier, Brendan Lyons, Robert Kang, Hyun M. Uzzau, Sergio Atzeni, Rossano Valentini, Maria Firinu, Davide Leoni, Lidia Rotta, Gianluca Naitza, Silvia Angius, Andrea Congia, Mauro Whalen, Michael B. Jones, Chris M. Schlessinger, David Abecasis, Goncalo R. Fiorillo, Edoardo Sanna, Serena Cucca, Francesco TI Genetic Variants Regulating Immune Cell Levels in Health and Disease SO CELL LA English DT Article ID GENOME-WIDE ASSOCIATION; CD4 T-CELLS; SUSCEPTIBILITY LOCI; MULTIPLE-SCLEROSIS; DIABETES-MELLITUS; HUMAN IMMUNOLOGY; DENDRITIC CELLS; SELF-TOLERANCE; POPULATION; EXPRESSION AB The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self'' result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. Wefirst estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing similar to 8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease. C1 [Orru, Valeria; Steri, Maristella; Sole, Gabriella; Sidore, Carlo; Virdis, Francesca; Dei, Mariano; Lai, Sandra; Zoledziewska, Magdalena; Busonero, Fabio; Mulas, Antonella; Mentzen, Wieslawa I.; Olla, Stefania; Marongiu, Michele; Piras, Maria G.; Lobina, Monia; Maschio, Andrea; Pitzalis, Maristella; Cusano, Roberto; Deidda, Francesca; Serra, Valentina; Pilu, Rosella; Porcu, Eleonora; Naitza, Silvia; Angius, Andrea; Whalen, Michael B.; Fiorillo, Edoardo; Sanna, Serena; Cucca, Francesco] CNR, IRGB, I-09042 Monserrato, Italy. [Sidore, Carlo; Maschio, Andrea; Kwong, Alan; Kang, Hyun M.; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sidore, Carlo; Mulas, Antonella; Lobina, Monia; Serra, Valentina; Berutti, Riccardo; Porcu, Eleonora; Uzzau, Sergio; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Floris, Matteo; Urru, Silvana A. M.; Urru, Maria F.; Marcelli, Marco; Cusano, Roberto; Deidda, Francesca; Oppo, Manuela; Pilu, Rosella; Reinier, Frederic; Berutti, Riccardo; Pireddu, Luca; Zara, Ilenia; Atzeni, Rossano; Valentini, Maria; Leoni, Lidia; Angius, Andrea; Jones, Chris M.] CRS4, I-09010 Cagliari, Italy. [Pireddu, Luca] Univ Cagliari, I-09010 Cagliari, Italy. [Uzzau, Sergio] Porto Conte Ric Srl, Lab Prote, I-07041 Tramariglio, Alghero, Italy. [Firinu, Davide] Univ Cagliari, Dipartimento Allergol & Immunol, I-09124 Cagliari, Italy. [Rotta, Gianluca] BD Biosci Italia, I-20090 Milan, Italy. [Congia, Mauro] Univ Cagliari, Dipartimento Sci Biomed & Biotecnol, I-09124 Cagliari, Italy. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Brennan, Christine; Tarrier, Brendan; Lyons, Robert] Univ Michigan, Sch Med, Sequencing Core, Ann Arbor, MI 48109 USA. RP Fiorillo, E (reprint author), CNR, IRGB, I-09042 Monserrato, Italy. EM edoardo.fiorillo@irgb.cnr.it; serena.sanna@irgb.cnr.it; francesco.cucca@irgb.cnr.it RI Angius, Andrea/B-8966-2015; Angius, Andrea/P-9549-2015; Naitza, Silvia/D-5620-2017; Sole, Gabriella/I-4820-2013; OI Angius, Andrea/0000-0003-2596-6461; Congia, Mauro/0000-0003-1688-304X; Sole, Gabriella/0000-0001-5292-5038; Mulas, Antonella/0000-0002-6856-1483; Orro, Valeria/0000-0002-6047-4625; Angius, Andrea/0000-0001-9372-1162; Pireddu, Luca/0000-0002-4663-5613; Steri, Anna Maristella/0000-0001-5869-3872 FU Intramural Research Program of the NIH, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]; Italian grants [FISM 2011/R/13]; Farmaci e Reti Biotecnologiche di Qualita [FaReBio2011]; MIUR/CNR; National Human Genome Research Institute [HG005581, HG005552, HG007022] FX This work is dedicated to the memory of Professor Antonio Cao, mentor and leader, who passed away while this manuscript was in preparation. We thank all of the volunteers who generously participated in this study and made this research possible. We thank John Todd and Marcella Devoto for critical revisions of the manuscript, Manuela Sironi and Rachele Cagliani for advice on balancing selection tests, Luiz Pereira for web server implementation, and Manuela Uda for her previous leadership on the ProgeNIA/SardiNIA study. This research was supported, in part, by the Intramural Research Program of the NIH, National Institute on Aging, with contracts N01-AG-1-2109 and HHSN271201100005C; by Italian grants FISM 2011/R/13 "Approccio razionale per la ricerca di composti per la cura della sclerosi multipla basato sull'analisi dei target biologici individuati dagli studi di associazione sull'intero genoma in Sardegna'' and FaReBio2011 "Farmaci e Reti Biotecnologiche di Qualita` ''; by funds MIUR/CNR for rare diseases and molecular screening, PNR- CNR Aging Program 2012-2014, Giovani Ricercatori 2007 (D. lgs 502/92) from the Italian Ministry of Health to F.C.; and by National Human Genome Research Institute grants HG005581, HG005552, and HG007022 to G.R.A. NR 45 TC 72 Z9 73 U1 0 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 26 PY 2013 VL 155 IS 1 BP 242 EP 256 DI 10.1016/j.cell.2013.08.041 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 224UX UT WOS:000324916700023 ER PT J AU Major, EO Frohman, E Douek, D AF Major, Eugene O. Frohman, Elliot Douek, Daniel TI More on JC Viremia in Natalizumab-Treated Patients with Multiple Sclerosis REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB Ivacaftor, an oral potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, has been shown to be efficacious in patients heterozygous for the G551D mutation in CFTR. This letter describes the effect of ivacaftor in a patient homozygous for this mutation.To the Editor: Recent studies provide support for the usefulness of the oral potentiator ivacaftor in patients with cystic fibrosis who are heterozygous for the G551D mutation.(1) The possibility of an increased response in persons who are homozygous for the mutation is unknown because of its low prevalence. Ivacaftor potentiates the open-channel probability of the G551D-cystic fibrosis transmembrane conductance regulator (CFTR) protein.(1) The most common cystic fibrosis mutation, F508del, results in little or no CFTR reaching the cell surface, whereas with the G551D-CFTR mutation, there are potentially normal levels of nonfunctional CFTR channels at the cell surface.(2) Therefore, we postulate ... C1 [Major, Eugene O.] NINDS, Bethesda, MD 20892 USA. [Frohman, Elliot] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Douek, Daniel] NIAID, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 2 TC 5 Z9 5 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 26 PY 2013 VL 369 IS 13 BP 1280 EP 1280 DI 10.1056/NEJMc1213681 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 224LT UT WOS:000324888200030 PM 24066761 ER PT J AU Yildiz, Y Hoffmann, P vom Dahl, S Breiden, B Sandhoff, R Niederau, C Horwitz, M Karlsson, S Filocamo, M Elstein, D Beck, M Sandhoff, K Mengel, E Gonzalez, MC Nothen, MM Sidransky, E Zimran, A Mattheisen, M AF Yildiz, Yildiz Hoffmann, Per vom Dahl, Stefan Breiden, Bernadette Sandhoff, Roger Niederau, Claus Horwitz, Mia Karlsson, Stefan Filocamo, Mirella Elstein, Deborah Beck, Michael Sandhoff, Konrad Mengel, Eugen Gonzalez, Maria C. Noethen, Markus M. Sidransky, Ellen Zimran, Ari Mattheisen, Manuel TI Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article ID ACID BETA-GLUCOSIDASE; GLUCOCEREBROSIDASE GENE; MUTATION; POPULATION; EXPRESSION; PROFILE; MODEL AB Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single-and multi-marker association with GD. Results: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. Conclusions: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD. C1 [Yildiz, Yildiz; Gonzalez, Maria C.] Univ Clin Bonn, Dept Internal Med 1, Bonn, Germany. [Yildiz, Yildiz] Landeskrankenhaus Bregenz, Dept Internal Med, Bregenz, Austria. [Hoffmann, Per; Noethen, Markus M.] Univ Clin Bonn, Inst Human Genet, Bonn, Germany. [Hoffmann, Per; Noethen, Markus M.; Mattheisen, Manuel] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [vom Dahl, Stefan] St Franziskus Hosp Koln, Dept Internal Med, Cologne, Germany. [Breiden, Bernadette; Sandhoff, Konrad] Univ Bonn, Kekule Inst Chem & Biochem, Life & Med Sci Inst LIMES, Bonn, Germany. [Sandhoff, Roger] German Canc Res Ctr, Lipid Pathobiochem Grp, Heidelberg, Germany. [Sandhoff, Roger] Tech Univ Appl Sci Mannheim, Dept Instrumental Analyt & Bioanalyt, Mannheim, Germany. [Niederau, Claus] St Josef Hosp Oberhausen, Dept Internal Med, Oberhausen, Germany. [Horwitz, Mia] Tel Aviv Univ, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. [Karlsson, Stefan] Lund Univ, Fac Med, Lund, Sweden. [Filocamo, Mirella] G Gaslini Inst Children, Ctr Diagnost Genet & Biochim Malattie Metab, Genoa, Italy. [Elstein, Deborah; Zimran, Ari] Shaare Zedek Med Ctr, Jerusalem, Israel. [Beck, Michael; Mengel, Eugen] Johannes Gutenberg Univ Mainz, Dept Paediat, D-55122 Mainz, Germany. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, Bonn, Germany. [Mattheisen, Manuel] Univ Aarhus, Dept Biomed, DK-8000 Aarhus C, Denmark. RP Yildiz, Y (reprint author), Univ Clin Bonn, Dept Internal Med 1, Bonn, Germany. EM yildiz.yildiz@lkhb.at; mm@hum-gen.au.dk RI Breiden, Bernadette/F-2422-2014; Mattheisen, Manuel/B-4949-2012; OI Breiden, Bernadette/0000-0002-4838-4109; Mattheisen, Manuel/0000-0002-8442-493X; Nothen, Markus/0000-0002-8770-2464 FU Deutsche Forschungsgemeinschaft [SFB 645]; (G. Gaslini Institute) - Telethon Network of Genetic Biobanks [GTB07001] FX We are grateful to all of the patients who contributed to this study and would like to thank Samira Boussettaoui for her great technical help. We are greatful to Britta Brugger, Heidelberg, Germany, who enabled us to use the tandem mass spectrometer. This work was supported by the Deutsche Forschungsgemeinschaft grant SFB 645. We would like to thank the G. Gaslini Institute for providing samples from the "Cell Line and DNA Biobank from Patients affected by Genetic Diseases" (G. Gaslini Institute) - Telethon Network of Genetic Biobanks (Project No. GTB07001). NR 31 TC 11 Z9 12 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD SEP 26 PY 2013 VL 8 AR 151 DI 10.1186/1750-1172-8-151 PG 8 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 230JZ UT WOS:000325336300001 PM 24070122 ER PT J AU Muniyappa, R Yavuz, S AF Muniyappa, Ranganath Yavuz, Sahzene TI Metabolic actions of angiotensin II and insulin: A microvascular endothelial balancing act SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Nitric oxide; Insulin resistance; Endothelial dysfunction; Angiotensin II ID NITRIC-OXIDE SYNTHASE; SPONTANEOUSLY HYPERTENSIVE-RATS; MUSCLE GLUCOSE-UPTAKE; HUMAN SKELETAL-MUSCLE; TYPE-2 RECEPTOR; BLOOD-FLOW; IN-VIVO; CARDIOVASCULAR-DISEASE; CAPILLARY RECRUITMENT; ALDOSTERONE SYSTEM AB Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1 -dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT(2) receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT(1) receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT(1) receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT(1), and AT(2) receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature. Published by Elsevier Ireland Ltd. C1 [Muniyappa, Ranganath; Yavuz, Sahzene] NIDDK, Clin Endocrine Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Muniyappa, R (reprint author), NIDDK, Clin Endocrine Sect, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5-3671, Bethesda, MD 20892 USA. EM muniyapr@mail.nih.gov FU NIDDK, NIH FX This work was supported by the Intramural Research Program, NIDDK, NIH. NR 137 TC 9 Z9 10 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 25 PY 2013 VL 378 IS 1-2 SI SI BP 59 EP 69 DI 10.1016/j.mce.2012.05.017 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242CC UT WOS:000326214000008 PM 22684034 ER PT J AU Fesinmeyer, MD Meigs, JB North, KE Schumacher, FR Buzkova, P Franceschini, N Haessler, J Goodloe, R Spencer, KL Voruganti, VS Howard, BV Jackson, R Kolonel, LN Liu, SM Manson, JE Monroe, KR Mukamal, K Dilks, HH Pendergrass, SA Nato, A Wan, P Wilkens, LR Le Marchand, L Ambite, JL Buyske, S Florez, JC Crawford, DC Hindorff, LA Haiman, CA Peters, U Pankow, JS AF Fesinmeyer, Megan D. Meigs, James B. North, Kari E. Schumacher, Fredrick R. Buzkova, Petra Franceschini, Nora Haessler, Jeffrey Goodloe, Robert Spencer, Kylee L. Voruganti, Venkata Saroja Howard, Barbara V. Jackson, Rebecca Kolonel, Laurence N. Liu, Simin Manson, JoAnn E. Monroe, Kristine R. Mukamal, Kenneth Dilks, Holli H. Pendergrass, Sarah A. Nato, Andrew Wan, Peggy Wilkens, Lynne R. Le Marchand, Loic Ambite, Jose Luis Buyske, Steven Florez, Jose C. Crawford, Dana C. Hindorff, Lucia A. Haiman, Christopher A. Peters, Ulrike Pankow, James S. TI Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study SO BMC MEDICAL GENETICS LA English DT Article ID CARDIOVASCULAR-DISEASE; PLASMA-GLUCOSE; RESISTANCE; DESIGN; LOCI; RISK; POLYMORPHISM; TOLERANCE AB Background: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U. S. Methods: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. Results: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 x 10(-15)), versus 3/9 in AA (p=0.03 to 6 x 10(-5)), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. Conclusions: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium. C1 [Fesinmeyer, Megan D.; Haessler, Jeffrey; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Div Gen Med, Boston, MA USA. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [North, Kari E.; Franceschini, Nora] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Schumacher, Fredrick R.; Monroe, Kristine R.; Wan, Peggy; Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Goodloe, Robert; Spencer, Kylee L.; Dilks, Holli H.; Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Voruganti, Venkata Saroja] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Howard, Barbara V.] Georgetown Univ, MedStar Res Inst, Hyattsville, MD USA. [Jackson, Rebecca] Ohio State Med Ctr, Dept Internal Med, Columbus, OH USA. [Kolonel, Laurence N.; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Liu, Simin] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Mukamal, Kenneth] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Pendergrass, Sarah A.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Nato, Andrew; Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Pankow, JS (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. EM pankow@umn.edu RI Liu, Simin/I-3689-2014; Nato, Alejandro/J-3880-2016; OI Liu, Simin/0000-0003-2098-3844; Nato, Alejandro/0000-0002-8745-9046; Buyske, Steven/0000-0001-8539-5416 FU NHGRI PAGE program [U01HG004798-01, U01HG004802, U01HG004790, U01HG004803]; NHGRI PAGE program (NHGRI ARRA supplement); Johns Hopkins University from NHLBI [N01-HV-48195]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, 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, HL080295]; National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058]; NHLBI [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521] FX The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)" is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). Genotyping services for select NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from NHLBI. The study participants derive from the National Health and Nutrition Examination Surveys (NHANES), and these studies are supported by the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.; The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758).; Funding support for the " Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Long%20List.pdf. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01HG004803 and its NHGRI ARRA supplement). The following studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022. The Cardiovascular Health Study (CHS) is supported by contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging (NIA). The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service.; Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. NR 27 TC 6 Z9 6 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 25 PY 2013 VL 14 AR 98 DI 10.1186/1471-2350-14-98 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 236JQ UT WOS:000325792300001 PM 24063630 ER PT J AU Fong, JH Murphy, TD Pruitt, KD AF Fong, Jessica H. Murphy, Terence D. Pruitt, Kim D. TI Comparison of RefSeq protein-coding regions in human and vertebrate genomes SO BMC GENOMICS LA English DT Article DE Genome annotation; RefSeq proteins; Protein quality assessment; Splice orthologs ID IDENTIFICATION; ANNOTATION; SEQUENCES; SEARCH AB Background: Advances in high-throughput sequencing technology have yielded a large number of publicly available vertebrate genomes, many of which are selected for inclusion in NCBI's RefSeq project and subsequently processed by NCBI's eukaryotic annotation pipeline. Genome annotation results are affected by differences in available support evidence and may be impacted by annotation pipeline software changes over time. The RefSeq project has not previously assessed annotation trends across organisms or over time. To address this deficiency, we have developed a comparative protocol which integrates analysis of annotated protein-coding regions across a data set of vertebrate orthologs in genomic sequence coordinates, protein sequences, and protein features. Results: We assessed an ortholog dataset that includes 34 annotated vertebrate RefSeq genomes including human. We confirm that RefSeq protein-coding gene annotations in mammals exhibit considerable similarity. Over 50% of the orthologous protein-coding genes in 20 organisms are supported at the level of splicing conservation with at least three selected reference genomes. Approximately 7,500 ortholog sets include at least half of the analyzed organisms, show highly similar sequence and conserved splicing, and may serve as a minimal set of mammalian "core proteins" for initial assessment of new mammalian genomes. Additionally, 80% of the proteins analyzed pass a suite of tests to detect proteins that lack splicing conservation and have unusual sequence or domain annotation. We use these tests to define an annotation quality metric that is based directly on the annotated proteins thus operates independently of other quality metrics such as availability of transcripts or assembly quality measures. Results are available on the RefSeq FTP site [ftp://ftp.ncbi.nlm.nih.gov/refseq/supplemental/ProtCore/SM1.txt]. Conclusions: Our multi-factored analysis demonstrates a high level of consistency in RefSeq protein representation among vertebrates. We find that the majority of the RefSeq vertebrate proteins for which we have calculated orthology are good as measured by these metrics. The process flow described provides specific information on the scope and degree of conservation for the analyzed protein sequences and annotations and will be used to enrich the quality of RefSeq records by identifying targets for further improvement in the computational annotation pipeline, and by flagging specific genes for manual curation. C1 [Fong, Jessica H.; Murphy, Terence D.; Pruitt, Kim D.] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), US Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM pruitt@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We would like to acknowledge technical support provided by Andrei Shkeda and Olga Ermolaeva. NR 28 TC 7 Z9 7 U1 0 U2 3 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 SEP 25 PY 2013 VL 14 AR 654 DI 10.1186/1471-2164-14-654 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 227CD UT WOS:000325084700001 PM 24063302 ER PT J AU Bowling, CB Sharma, P Fox, CS O'Hare, AM Muntner, P AF Bowling, C. Barrett Sharma, Pradeep Fox, Caroline S. O'Hare, Ann M. Muntner, Paul TI Prevalence of Reduced Estimated Glomerular Filtration Rate Among the Oldest Old From 1988-1994 Through 2005-2010 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CHRONIC KIDNEY-DISEASE; AGE C1 [Bowling, C. Barrett] Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Atlanta, GA 30033 USA. [Sharma, Pradeep; Muntner, Paul] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [O'Hare, Ann M.] VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA USA. RP Bowling, CB (reprint author), Atlanta Vet Affairs Med Ctr, 1670 Clairmont Rd 11B, Decatur, GA 30033 USA. EM cbbowli@emory.edu FU CSRD VA [IK2 CX000856]; NHLBI NIH HHS [Y1-HC-8039]; NIA NIH HHS [R03 AG042336, R03AG042336-01] NR 6 TC 12 Z9 12 U1 0 U2 1 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 SEP 25 PY 2013 VL 310 IS 12 BP 1284 EP 1286 DI 10.1001/jama.2013.252441 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 222SO UT WOS:000324751800026 PM 24065016 ER PT J AU Shin, YW Demidzic, M Jo, HJ Long, ZY Medlock, C Dydak, U Goddard, AW AF Shin, Yong-Wook Demidzic, Mario Jo, Hang Joon Long, Zaiyang Medlock, Carla Dydak, Ulrike Goddard, Andrew W. TI Increased resting-state functional connectivity between the anterior cingulate cortex and the precuneus in panic disorder: Resting-state connectivity in panic disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Default mode network; Anterior cingulate cortex; Gamma-aminobutyric acid; Panic disorder ID ANXIETY SENSITIVITY; DEFAULT-MODE; BRAIN; STIMULATION; NETWORK; FMRI; RESPONSES; DISEASE; SCALE AB Background: The structural and functional abnormalities of the anterior cingulate cortex (ACC) have been reported in panic disorder (PD). Patients with PD have shown decreased gamma-aminobutyric acid (GABA) concentration in the ACC. The GABA concentration in the ACC was found to be associated with default mode network (DMN) activity in normal human subjects. Therefore, it was hypothesized that the DMN would show abnormal activity in PD. Methods: We identified and compared the functional connectivity maps with seed region of interest (ROI) located in the perigenual area of ACC between the 11 patients with panic disorder and age- and sex-matched normal control subjects. Combining magnetic resonance spectroscopy (MRS) and resting HMI, we investigated the correlation between the GABA concentration in the seed ROI and the index of Functional connectivity between ACC and the area showing group differences. Results: The patients with PD showed increased functional connectivity between ACC and precuneus compared to control subjects. The functional connectivity between the ACC and the precuneus negatively correlated with the GABA concentration of the ACC. Limitations: The relatively small sample size and seed based analysis with the selection of a single ROI limits the generalizability of the result. Conclusions: Increased functional connectivity in the two medial nodes of the resting-state default mode network, the ACC and the precuneus, might play an important role in the pathophysiology of panic disorder. The treatment aimed to normalize the functional connectivity between ACC and precuneus might have clinical benefits in PD. (C) 2013 Elsevier B.V. All rights reserved. C1 [Shin, Yong-Wook] Univ Ulsan, Sch Med, Dept Psychiat, Seoul 138736, South Korea. [Demidzic, Mario; Goddard, Andrew W.] Indiana Univ, Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA. [Demidzic, Mario] Indiana Univ, Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Jo, Hang Joon] NIMH, NIH, Bethesda, MD 20892 USA. [Long, Zaiyang; Dydak, Ulrike] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Medlock, Carla; Goddard, Andrew W.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. RP Goddard, AW (reprint author), Indiana Univ, Sch Med, Dept Psychiat, GH 2800,355W 16th St, Indianapolis, IN 46202 USA. EM agoddard@iupui.edu RI JO, HANG JOON/D-1775-2011; OI JO, HANG JOON/0000-0002-9180-3831; Shin, Yong-Wook/0000-0002-0360-6118 FU Collaborative Research Grant by the Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources [RR 02576] FX This work was supported by a Collaborative Research Grant by the Indiana Clinical and Translational Sciences Institute, funded in part by grant # RR 02576 from the National Institutes of Health, National Center for Research Resources. NR 34 TC 10 Z9 12 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD SEP 25 PY 2013 VL 150 IS 3 BP 1091 EP 1095 DI 10.1016/j.jad.2013.04.026 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 213ER UT WOS:000324038000053 PM 23688914 ER PT J AU Lu, J Bushel, PR AF Lu, Jun Bushel, Pierre R. TI Dynamic expression of 3 ' UTRs revealed by Poisson hidden Markov modeling of RNA-Seq: Implications in gene expression profiling SO GENE LA English DT Article DE Untranslated region; Alternative polyadenylation; Microarray ID GENOME BROWSER DATABASE; ALTERNATIVE POLYADENYLATION; MESSENGER-RNA; UNTRANSLATED REGIONS; END FORMATION; TRANSCRIPTS; CELLS; MECHANISMS; SEQUENCES; CANCER AB RNA sequencing (RNA-Seq) allows for the identification of novel exon-exon junctions and quantification of gene expression levels. We show that from RNA-Seq data one may also detect utilization of alternative polyadenylation (APA) in 3' untranslated regions (3' UTRs) known to play a critical role in the regulation of mRNA stability, cellular localization and translation efficiency. Given the dynamic nature of APA, it is desirable to examine the APA on a sample by sample basis. We used a Poisson hidden Markov model (PHMM) of RNA-Seq data to identify potential APA in human liver and brain cortex tissues leading to shortened 3' UTRs. Over three hundred transcripts with shortened 3' UTRs were detected with sensitivity >75% and specificity >60%. Tissue-specific 3' UTR shortening was observed for 32 genes with a q-value <= 0.1. When compared to alternative isoforms detected by Cufflinks or MISO, our PHMM method agreed on over 100 transcripts with shortened 3' UTRs. Given the increasing usage of RNA-Seq for gene expression profiling, using PHMM to investigate sample-specific 3' UTR shortening could be an added benefit from this emerging technology. Published by Elsevier B.V. C1 [Lu, Jun; Bushel, Pierre R.] NIEHS, Microarray & Genome Informat Grp, Res Triangle Pk, NC 27709 USA. [Lu, Jun] SPA Int Inc, Res Triangle Pk, NC 27709 USA. [Bushel, Pierre R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Bushel, PR (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM jason.lu@omicsoft.com; bushel@niehs.nih.gov FU National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04] FX We thank Mercedes Arana and Weichun Huang for their critical review of the manuscript. We also thank Ingmar Visser for helping with model fitting using the depmixS4 R package. This research was supported, in part by, the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04]. NR 51 TC 6 Z9 6 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD SEP 25 PY 2013 VL 527 IS 2 BP 616 EP 623 DI 10.1016/j.gene.2013.06.052 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 210YW UT WOS:000323872300028 PM 23845781 ER PT J AU Dangkulwanich, M Ishibashi, T Liu, SX Kireeva, ML Lubkowska, L Kashlev, M Bustamante, CJ AF Dangkulwanich, Manchuta Ishibashi, Toyotaka Liu, Shixin Kireeva, Maria L. Lubkowska, Lucyna Kashlev, Mikhail Bustamante, Carlos J. TI Complete dissection of transcription elongation reveals slow translocation of RNA polymerase II in a linear ratchet mechanism SO ELIFE LA English DT Article ID STRUCTURAL BASIS; ESCHERICHIA-COLI; SINGLE-MOLECULE; TRIGGER LOOP; NUCLEOSIDE TRIPHOSPHATES; ALLOSTERIC BINDING; DNA TRANSLOCATION; DYNAMICS; FIDELITY; BARRIER AB During transcription elongation, RNA polymerase has been assumed to attain equilibrium between pre- and post-translocated states rapidly relative to the subsequent catalysis. Under this assumption, recent single-molecule studies proposed a branched Brownian ratchet mechanism that necessitates a putative secondary nucleotide binding site on the enzyme. By challenging individual yeast RNA polymerase II with a nucleosomal barrier, we separately measured the forward and reverse translocation rates. Surprisingly, we found that the forward translocation rate is comparable to the catalysis rate. This finding reveals a linear, non-branched ratchet mechanism for the nucleotide addition cycle in which translocation is one of the rate-limiting steps. We further determined all the major on- and off-pathway kinetic parameters in the elongation cycle. The resulting translocation energy landscape shows that the off-pathway states are favored thermodynamically but not kinetically over the on-pathway states, conferring the enzyme its propensity to pause and furnishing the physical basis for transcriptional regulation. C1 [Dangkulwanich, Manchuta; Ishibashi, Toyotaka; Liu, Shixin; Bustamante, Carlos J.] Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. [Dangkulwanich, Manchuta; Bustamante, Carlos J.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Ishibashi, Toyotaka; Bustamante, Carlos J.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Liu, Shixin; Bustamante, Carlos J.] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Phys, Berkeley, CA 94720 USA. [Kireeva, Maria L.; Lubkowska, Lucyna; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Bustamante, Carlos J.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Bustamante, Carlos J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. RP Bustamante, CJ (reprint author), Univ Calif Berkeley, Jason L Choy Lab Single Mol Biophys, Berkeley, CA 94720 USA. EM carlos@alice.berkeley.edu OI Ishibashi, Toyotaka/0000-0001-8015-2319 FU National Institutes of Health [R01-GM032543]; Department of Energy [DE-AC02-05CH11231]; Howard Hughes Medical Institute FX National Institutes of Health R01-GM032543 Carlos J Bustamante; Department of Energy DE-AC02-05CH11231 Carlos J Bustamante; Howard Hughes Medical Institute Carlos J Bustamante NR 73 TC 32 Z9 32 U1 1 U2 14 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 24 PY 2013 VL 2 AR e00971 DI 10.7554/eLife.00971 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274SY UT WOS:000328627700003 PM 24066225 ER PT J AU Larson, DR Fritzsch, C Sun, L Meng, XH Lawrence, DS Singer, RH AF Larson, Daniel R. Fritzsch, Christoph Sun, Liang Meng, Xiuhau Lawrence, David S. Singer, Robert H. TI Direct observation of frequency modulated transcription in single cells using light activation SO ELIFE LA English DT Article ID EUKARYOTIC GENE-EXPRESSION; LIVING MAMMALIAN-CELLS; REAL-TIME ANALYSIS; GLUCOCORTICOID-RECEPTOR; PROTEIN EXPRESSION; RAPID EXCHANGE; BUDDING YEAST; IN-SITU; KINETICS; PROMOTER AB Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus. C1 [Larson, Daniel R.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fritzsch, Christoph] Johannes Gutenberg Univ Mainz, Inst Mol Biol, D-55122 Mainz, Germany. [Sun, Liang; Lawrence, David S.] Univ N Carolina, Dept Chem, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Sun, Liang; Lawrence, David S.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Meng, Xiuhau; Singer, Robert H.] Albert Einstein Coll Med, Dept Anat & Struct Biol, New York, NY USA. [Singer, Robert H.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, New York, NY USA. RP Larson, DR (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dan.larson@nih.gov RI Larson, Daniel/B-9829-2008 OI Larson, Daniel/0000-0001-9253-3055 FU National Institutes of Health [GM 86217]; National Cancer Institute Intramural Research Program of the NIH FX National Institutes of Health GM 86217 Robert H Singer; National Cancer Institute Intramural Research Program of the NIH Daniel R Larson NR 66 TC 30 Z9 31 U1 2 U2 14 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 24 PY 2013 VL 2 AR e00750 DI 10.7554/eLife.00750 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274SY UT WOS:000328627700001 PM 24069527 ER PT J AU Dunn, BK AF Dunn, Barbara K. TI Phase 3 Trials in Breast Cancer Prevention: Focus on Estrogen-Targeting Agents, Selective Estrogen Receptor Modulators and Aromatase Inhibitors SO PROGRESS IN CHEMISTRY LA English DT Article DE breast cancer prevention; selective estrogen receptor modulators; aromatase inhibitors; phase III clinical trials; risk models ID RANDOMIZED CLINICAL-TRIAL; SURGICAL ADJUVANT BREAST; LOW-DOSE TAMOXIFEN; BOWEL PROJECT P-1; POSTMENOPAUSAL WOMEN; FOLLOW-UP; CHEMOPREVENTION TRIAL; COMBINATION TRIAL; HEALTHY WOMEN; ATAC ARIMIDEX AB Worldwide, breast cancer is the most common cancer in women, with 1.38 million breast cancer diagnoses cases estimated for 2008, accounting for 23% of all cancers in women. Breast cancer has the highest mortality rate of all cancers among women worldwide. Although technological advances in early detection and treatment have made inroads into these rates, breast cancer associated mortality remains high. Hence, interest has emerged in exploring approaches to preventing this disease and developing risk models to identify women most likely to benefit from preventive interventions. The current chapter addresses breast cancer risk-reducing agents that have progressed in their development to testing in phase III clinical trials or in some cases to formal approval for a breast cancer risk reduction indication. The discussion here concentrates on agents targeting estrogen receptor (ER)-positive breast cancers, specifically selective ER modulators (SERMs) and aromatase inhibitors (AIs). The large phase III clinical trials assessing efficacy of these agents in breast cancer prevention are the focus, as these represent the gold standard in clinical testing and serve as the basis for approval of these anti-estrogens for risk reduction of breast cancer among high-risk women. C1 NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Dunn, BK (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. EM dunnb@mail.nih.gov NR 75 TC 1 Z9 1 U1 0 U2 5 PU CHINESE ACAD SCIENCES PI BEIJING PA NO. 33 BEISIHUANXILU, ZHONGGUANCUN, BEIJING 100080, PEOPLES R CHINA SN 1005-281X J9 PROG CHEM JI Prog. Chem. PD SEP 24 PY 2013 VL 25 IS 9 SI SI BP 1429 EP 1449 PG 21 WC Chemistry, Multidisciplinary SC Chemistry GA 244TD UT WOS:000326412200004 ER PT J AU Vasu, S Bandettini, WP Hsu, LY Kellman, P Leung, S Mancini, C Shanbhag, SM Wilson, J Booker, OJ Arai, AE AF Vasu, Sujethra Bandettini, W. Patricia Hsu, Li-Yueh Kellman, Peter Leung, Steve Mancini, Christine Shanbhag, Sujata M. Wilson, Joel Booker, Oscar Julian Arai, Andrew E. TI Regadenoson and adenosine are equivalent vasodilators and are superior than dipyridamole- a study of first pass quantitative perfusion cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Regadenoson; Dipyridamole; Adenosine; Quantitative myocardial perfusion; Magnetic resonance imaging ID CORONARY-ARTERY-DISEASE; EMISSION COMPUTED-TOMOGRAPHY; PLACEBO-CONTROLLED TRIAL; A(2A) RECEPTOR AGONIST; MYOCARDIAL-PERFUSION; DOBUTAMINE STRESS; CONSCIOUS DOGS; INPUT FUNCTION; DOUBLE-BLIND; MULTICENTER AB Background: Regadenoson, dipyridamole and adenosine are commonly used vasodilators in myocardial perfusion imaging for the detection of obstructive coronary artery disease. There are few comparative studies of the vasodilator properties of regadenoson, adenosine and dipyridamole in humans. The specific aim of this study was to determine the relative potency of these three vasodilators by quantifying stress and rest myocardial perfusion in humans using cardiovascular magnetic resonance (CMR). Methods: Fifteen healthy normal volunteers, with Framingham score less than 1% underwent vasodilator stress testing with regadenoson (400 mu g bolus), dipyridamole (0.56 mg/kg) and adenosine (140 mu g/kg/min) on separate days. Rest perfusion imaging was performed initially. Twenty minutes later, stress imaging was performed at peak vasodilation, i.e. 70 seconds after regadenoson, 4 minutes after dipyridamole infusion and between 3-4 minutes of the adenosine infusion. Myocardial blood flow (MBF) in ml/min/g and myocardial perfusion reserve (MPR) were quantified using a fully quantitative model constrained deconvolution. Results: Regadenoson produced higher stress MBF than dipyridamole and adenosine (3.58 +/- 0.58 vs. 2.81 +/- 0.67 vs. 2.78 +/- 0.61 ml/min/g, p = 0.0009 and p = 0.0008 respectively). Regadenoson had a much higher heart rate response than adenosine and dipyridamole respectively (95 +/- 11 vs. 76 +/- 13 vs. 86 +/- 12 beats/minute) When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8 +/- 6 vs. 36.6 +/- 4 mu l/sec/g, p = NS), but differences between regadenoson and dipyridamole persisted (37.8 +/- 6 vs. 32.6 +/- 5 mu l/sec/g, p = 0.03). The unadjusted MPR was higher with regadenoson (3.11 +/- 0.63) when compared with adenosine (2.7 +/- 0.61, p = 0.02) and when compared with dipyridamole (2.61 +/- 0.57, p = 0.04). Similar to stress MBF, these differences in MPR between regadenoson and adenosine were abolished when adjusted for heart rate (2.04 +/- 0.34 vs. 2.12 +/- 0.27, p = NS), but persisted between regadenoson and dipyridamole (2.04 +/- 0.34 vs. 1.77 +/- 0.33, p = 0.07) and between adenosine and dipyridamole (2.12 +/- 0.27 vs. 1.77 +/- 0.33, p = 0.01). Conclusions: Based on fully quantitative perfusion using CMR, regadenoson and adenosine have similar vasodilator efficacy and are superior to dipyridamole. C1 [Vasu, Sujethra] Wake Forest Univ, Bowman Gray Sch Med, Cardiol Sect, Winston Salem, NC USA. [Bandettini, W. Patricia; Hsu, Li-Yueh; Kellman, Peter; Leung, Steve; Mancini, Christine; Shanbhag, Sujata M.; Wilson, Joel; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Booker, Oscar Julian] Univ Alabama Birmingham, Dept Cardiol, Birmingham, AL USA. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM araia@nih.gov RI Leung, Steve/E-5624-2011 OI Leung, Steve/0000-0003-2832-2258 FU National Heart, Lung, and Blood Institute, NIH, USA [1 Z01 HL004607-08 CE] FX This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH, USA (1 Z01 HL004607-08 CE). Relationship with Industry Policy: Dr. Arai is a principal investigator on a US government Cooperative Research And Development Agreement (CRADA) with Siemens Medical Solutions (HL-CR-05-004). NR 32 TC 19 Z9 20 U1 1 U2 6 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 SEP 24 PY 2013 VL 15 AR 85 DI 10.1186/1532-429X-15-85 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 245LJ UT WOS:000326464900001 PM 24063278 ER PT J AU Zarelli, VE Dawid, IB AF Zarelli, Valeria E. Dawid, Igor B. TI The BTB-Containing Protein Kctd15 Is SUMOylated In Vivo SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR AP-2; NEURAL CREST FORMATION; SUMO MODIFICATION; MOTIF; REPRESSION; MODIFIER; GENE; PHOSPHORYLATION; DIFFERENTIATION; DESUMOYLATION AB Potassium Channel Tetramerization Domain containing 15 (Kctd15) has a role in regulating the neural crest (NC) domain in the embryo. Kctd15 inhibits NC induction by antagonizing Wnt signaling and by interaction with the transcription factor AP2a activation domain blocking its activity. Here we demonstrate that Kctd15 is SUMOylated by SUMO1 and SUMO2/3. Kctd15 contains a classical SUMO interacting motif, psi KxE, at the C-terminal end, and variants of the motif within the molecule. Kctd15 SUMOylation occurs exclusively in the C-terminal motif. Inability to be SUMOylated did not affect Kctd15's subcellular localization, or its ability to repress AP-2 transcriptional activity and to inhibit NC formation in zebrafish embryos. In contrast, a fusion of Kctd15 and SUMO had little effectiveness in AP-2 inhibition and in blocking of NC formation. These data suggest that the non-SUMOylated form of Kctd15 functions in NC development. C1 [Zarelli, Valeria E.; Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. EM idawid@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. 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 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 24 PY 2013 VL 8 IS 9 AR e75016 DI 10.1371/journal.pone.0075016 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 226HG UT WOS:000325025200019 PM 24086424 ER PT J AU Campbell, CT Llewellyn, SR Damberg, T Morgan, IL Robert-Guroff, M Gildersleeve, JC AF Campbell, Christopher T. Llewellyn, Sean R. Damberg, Thorsten Morgan, Ian L. Robert-Guroff, Marjorie Gildersleeve, Jeffrey C. TI High-Throughput Profiling of Anti-Glycan Humoral Responses to SIV Vaccination and Challenge SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; O-LINKED CARBOHYDRATE; CELL-INDEPENDENT ANTIGENS; SITE-SPECIFIC ANALYSIS; RHESUS MACAQUES; SERUM ANTIBODIES; HIV-INFECTION; NEUTRALIZATION EPITOPE; ENVELOPE GLYCOPROTEIN; SIVMAC251 CHALLENGE AB Recent progress toward an HIV vaccine highlights both the potential of vaccines to end the AIDS pandemic and the need to boost efficacy by incorporating additional vaccine strategies. Although many aspects of the immune response can contribute to vaccine efficacy, the key factors have not been defined fully yet. A particular area that may yield new insights is anti-glycan immune responses, such as those against the glycan shield that HIV uses to evade the immune system. In this study, we used glycan microarray technology to evaluate anti-glycan antibody responses induced by SIV vaccination and infection in a non-human primate model of HIV infection. This comprehensive profiling of circulating anti-glycan antibodies found changes in anti-glycan antibody levels after both vaccination with the Ad5hr-SIV vaccine and SIV infection. Notably, SIV infection produced generalized declines in anti-glycan IgM antibodies in a number of animals. Additionally, some infected animals generated antibodies to the Tn antigen, which is a cryptic tumor-associated antigen exposed by premature termination of O-linked glycans; however, the Ad5hr-SIV vaccine did not induce anti-Tn IgG antibodies. Overall, this study demonstrates the potential contributions that glycan microarrays can make for HIV vaccine development. C1 [Campbell, Christopher T.; Llewellyn, Sean R.; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, NIH, Frederick, MD 21701 USA. [Damberg, Thorsten; Morgan, Ian L.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM gildersj@mail.nih.gov; guroffm@mail.nih.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU NCI, NIH; Pharmacology Research Training (PRAT) program of the NIGMS FX This research was supported by the intramural research program of the NCI, NIH. C. T. C. received fellowship funding from the Pharmacology Research Training (PRAT) program of the NIGMS. There were no external funding sources for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 6 Z9 6 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2013 VL 8 IS 9 AR e75302 DI 10.1371/journal.pone.0075302 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 246EK UT WOS:000326520200096 PM 24086502 ER PT J AU Chen, PF Zhang, J Zhan, Y Su, JJ Du, YR Xu, GL Shi, YF Siebenlist, U Zhang, XR AF Chen, Pengfei Zhang, Jun Zhan, Yu Su, Juanjuan Du, Yarui Xu, Guoliang Shi, Yufang Siebenlist, Ulrich Zhang, Xiaoren TI Established Thymic Epithelial Progenitor/Stem Cell-Like Cell Lines Differentiate into Mature Thymic Epithelial Cells and Support T Cell Development SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; AUTOIMMUNE REGULATOR; NEGATIVE SELECTION; SELF-TOLERANCE; AIRE; MICROENVIRONMENT; THYMOCYTES; IDENTIFICATION; PROLIFERATION; MAINTENANCE AB Common thymic epithelial progenitor/stem cells (TEPCs) differentiate into cortical and medullary thymic epithelial cells (TECs), which are required for the development and selection of thymocytes. Mature TEC lines have been widely established. However, the establishment of TEPC lines is rarely reported. Here we describe the establishment of thymic epithelial stomal cell lines, named TSCs, from fetal thymus. TSCs express some of the markers present on tissue progenitor/stem cells such as Sca-1. Gene expression profiling verifies the thymic identity of TSCs. RANK stimulation of these cells induces expression of autoimmune regulator (Aire) and Aire-dependent tissue-restricted antigens (TRAs) in TSCs in vitro. TSCs could be differentiated into medullary thymic epithelial cell-like cells with exogenously expressed NF-kappa B subunits ReIB and p52. Importantly, upon transplantation under the kidney capsules of nude mice, TSCs are able to differentiate into mature TEC-like cells that can support some limited development of T cells in vivo. These findings suggest that the TSC lines we established bear some characteristics of TEPC cells and are able to differentiate into functional TEC-like cells in vitro and in vivo. The cloned TEPC-like cell lines may provide useful tools to study the differentiation of mature TEC cells from precursors. C1 [Chen, Pengfei; Zhan, Yu; Su, Juanjuan; Shi, Yufang; Zhang, Xiaoren] Chinese Acad Sci, Key Lab Stem Cell Biol, Inst Hlth Sci, Shanghai, Peoples R China. [Chen, Pengfei; Zhan, Yu; Su, Juanjuan; Shi, Yufang; Zhang, Xiaoren] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200030, Peoples R China. [Zhang, Jun] Bengbu Med Coll, Affiliated Hosp 1, Dept Transfus, Bengbu, Anhui, Peoples R China. [Du, Yarui; Xu, Guoliang] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, XR (reprint author), Chinese Acad Sci, Key Lab Stem Cell Biol, Inst Hlth Sci, Shanghai, Peoples R China. EM xrzhang@sibs.ac.cn FU National Basic Research program [2011CB946102]; National Natural Science Foundation of China [90919017, 30972695, 31270937]; Chinese Academy of Sciences [KSCX1-YW-22]; National Key Programs on Infectious Disease [2008ZX10002-014]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by grants from the National Basic Research program (2011CB946102), the National Natural Science Foundation of China (90919017, 30972695 and 31270937), Knowledge Innovation Project of Chinese Academy of Sciences (KSCX1-YW-22), National Key Programs on Infectious Disease (2008ZX10002-014) and with support from the Intramural Research Program of the 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 39 TC 0 Z9 0 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2013 VL 8 IS 9 AR UNSP e75222 DI 10.1371/journal.pone.0075222 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 246EK UT WOS:000326520200090 PM 24086471 ER PT J AU Hanauske-Abel, HM Saxena, D Palumbo, PE Hanauske, AR Luchessi, AD Cambiaghi, TD Hoque, M Spino, M Gandolfi, DD Heller, DS Singh, S Park, MH Cracchiolo, BM Tricta, F Connelly, J Popowicz, AM Cone, RA Holland, B Pe'ery, T Mathews, MB AF Hanauske-Abel, Hartmut M. Saxena, Deepti Palumbo, Paul E. Hanauske, Axel-Rainer Luchessi, Augusto D. Cambiaghi, Tavane D. Hoque, Mainul Spino, Michael Gandolfi, Darlene D'Alliessi Heller, Debra S. Singh, Sukhwinder Park, Myung Hee Cracchiolo, Bernadette M. Tricta, Fernando Connelly, John Popowicz, Anthony M. Cone, Richard A. Holland, Bart Pe'ery, Tsafi Mathews, Michael B. TI Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INITIATION-FACTOR 5A; ACTIVE ANTIRETROVIRAL THERAPY; INTRACELLULAR LABILE IRON; CD4(+) T-CELLS; BLOOD MONONUCLEAR-CELLS; TYPE-1 TAT PROTEIN; GENE-EXPRESSION; IN-VITRO; MOTEXAFIN GADOLINIUM AB HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients. C1 [Hanauske-Abel, Hartmut M.; Luchessi, Augusto D.; Cambiaghi, Tavane D.; Hoque, Mainul; Pe'ery, Tsafi; Mathews, Michael B.] Rutgers State Univ, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07102 USA. [Hanauske-Abel, Hartmut M.; Saxena, Deepti; Palumbo, Paul E.] Rutgers State Univ, New Jersey Med Sch, Dept Pediat, Newark, NJ 07102 USA. [Hanauske-Abel, Hartmut M.; Cracchiolo, Bernadette M.] Rutgers State Univ, Dept Obstet Gynecol & Womens Hlth, New Jersey Med Sch, Newark, NJ 07102 USA. [Hanauske, Axel-Rainer] Asklepios Clin St George, Ctr Oncol, Hamburg, Germany. [Hanauske, Axel-Rainer] Asklepios Clin St George, Med Clin 3, Hamburg, Germany. [Spino, Michael] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada. [Spino, Michael; Tricta, Fernando; Connelly, John] ApoPharma Inc, Toronto, ON, Canada. [Gandolfi, Darlene D'Alliessi] Manhattanville Coll, Dept Chem, Purchase, NY USA. [Heller, Debra S.; Singh, Sukhwinder] Rutgers State Univ, New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ 07102 USA. [Park, Myung Hee] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. [Popowicz, Anthony M.] Rockefeller Univ, Dept Informat Technol, New York, NY 10021 USA. [Cone, Richard A.] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA. [Holland, Bart] Rutgers State Univ, Dept Prevent Med & Community Hlth, New Jersey Med Sch, Newark, NJ 07102 USA. [Pe'ery, Tsafi] Rutgers State Univ, Dept Med, New Jersey Med Sch, Newark, NJ 07102 USA. RP Hanauske-Abel, HM (reprint author), Rutgers State Univ, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07102 USA. EM hanaushm@njms.rutgers.edu; mathews@njms.rutgers.edu FU Foundation of UMDNJ; National Institutes of Health [HD-1457, AI034552, AI060403]; National Institutes of Health (NIH-NIDCR); State of New Jersey, through its Commission on Cancer Research [05-2405-CCR-EO]; Pediatric AIDS Clinical Trials Group, the National Institutes of Health; DAIDS [202PVCL05]; Foundation IND Synergen; The State of SApoundo Paulo Research Foundation (FAPESP) [08/50355-1, 04/040181-6] FX This work was supported by a grant from the Foundation of UMDNJ to MBM and HMHA. The BIRCWH (Building Interdisciplinary Research Careers in Women's Health) Program of the National Institutes of Health (HD-1457), in which HMHA was a Scholar, supported this study. MBM and TP were funded by the National Institutes of Health (AI034552 and AI060403). MHP and ECW were supported by the Intramural Research Program of the National Institutes of Health (NIH-NIDCR); BMC by the State of New Jersey, through its Commission on Cancer Research (05-2405-CCR-EO); PEP by the Pediatric AIDS Clinical Trials Group, the National Institutes of Health, and DAIDS (202PVCL05); and ARH by the Foundation IND Synergen. ADL and TDC were recipients of grants (08/50355-1 and 04/040181-6) from The State of SA o pound Paulo Research Foundation (FAPESP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 218 TC 4 Z9 4 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2013 VL 8 IS 9 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 246EK UT WOS:000326520200030 ER PT J AU Ioerger, TR O'Malley, T Liao, R Guinn, KM Hickey, MJ Mohaideen, N Murphy, KC Boshoff, HIM Mizrahi, V Rubin, EJ Sassetti, CM Barry, CE Sherman, DR Parish, T Sacchettini, JC AF Ioerger, Thomas R. O'Malley, Theresa Liao, Reiling Guinn, Kristine M. Hickey, Mark J. Mohaideen, Nilofar Murphy, Kenan C. Boshoff, Helena I. M. Mizrahi, Valerie Rubin, Eric J. Sassetti, Christopher M. Barry, Clifton E., III Sherman, David R. Parish, Tanya Sacchettini, James C. TI Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosis SO PLOS ONE LA English DT Article ID TRANSFER-RNA-SYNTHETASE; EFFLUX PUMP; MYCOLIC ACIDS; ATP SYNTHASE; ETHIONAMIDE; INHIBITORS; DISCOVERY; GROWTH; ACTIVATION; PROTEIN AB Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis, especially given the increase of resistance worldwide to first-and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery. C1 [Ioerger, Thomas R.] Texas A&M Univ, Dept Comp Sci & Engn, College Stn, TX USA. [O'Malley, Theresa; Parish, Tanya] Infect Dis Res Inst, Seattle, WA USA. [Liao, Reiling; Hickey, Mark J.; Sherman, David R.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Guinn, Kristine M.; Rubin, Eric J.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Mohaideen, Nilofar; Sacchettini, James C.] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. [Murphy, Kenan C.; Sassetti, Christopher M.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, Lab Clin Infect Dis, TB Res Sect, Bethesda, MD 20892 USA. [Mizrahi, Valerie] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Sassetti, Christopher M.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Sacchettini, JC (reprint author), Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. EM jim.sacchettini@gmail.com RI Barry, III, Clifton/H-3839-2012; OI Rubin, Eric/0000-0001-5120-962X FU Bill & Melinda Gates Foundation; Paul G. Allen Family Foundation; NIH [U01GM094568]; Robert A. Welch Foundation [A-0015]; NIAID, NIH FX This work was funded by grants from the Bill & Melinda Gates Foundation, the Paul G. Allen Family Foundation (to DRS), NIH grant U01GM094568 (JCS, EJR, TRI), grant A-0015 from the Robert A. Welch Foundation (JCS), and the intramural research program of NIAID, NIH (to CEB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 53 Z9 54 U1 11 U2 43 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 SEP 23 PY 2013 VL 8 IS 9 AR e75245 DI 10.1371/journal.pone.0075245 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 246EK UT WOS:000326520200093 PM 24086479 ER PT J AU Ross, OA Soto-Ortolaza, AI Heckman, MG Verbeeck, C Serie, DJ Rayaprolu, S Rich, SS Nalls, MA Singleton, A Guerreiro, R Kinsella, E Wszolek, ZK Brott, TG Brown, RD Worrall, BB Meschia, JF AF Ross, Owen A. Soto-Ortolaza, Alexandra I. Heckman, Michael G. Verbeeck, Christophe Serie, Daniel J. Rayaprolu, Sruti Rich, Stephen S. Nalls, Michael A. Singleton, Andrew Guerreiro, Rita Kinsella, Emma Wszolek, Zbigniew K. Brott, Thomas G. Brown, Robert D., Jr. Worrall, Bradford B. Meschia, James F. TI NOTCH3 Variants and Risk of Ischemic Stroke SO PLOS ONE LA English DT Article ID SMALL-VESSEL-DISEASE; CADASIL; MUTATION; PATIENT; ARTERIOPATHY; DEMENTIA; INFARCTS; BRAIN; GENE AB Background: Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved. Methods: All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS). Results: Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p. R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p. R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series. Conclusion: Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study. C1 [Ross, Owen A.; Soto-Ortolaza, Alexandra I.; Verbeeck, Christophe; Rayaprolu, Sruti] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Heckman, Michael G.; Serie, Daniel J.] Mayo Clin, Biostat Sect, Jacksonville, FL 32224 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Nalls, Michael A.; Singleton, Andrew; Guerreiro, Rita; Kinsella, Emma] Natl Inst Hlth, Natl Inst Aging, Neurogenet Lab, Bethesda, MD USA. [Guerreiro, Rita] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Guerreiro, Rita] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Guerreiro, Rita] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Kinsella, Emma] Cardiff Univ, Sch Med, Cardiff, Wales. [Wszolek, Zbigniew K.; Brott, Thomas G.; Meschia, James F.] Mayo Clin, Coll Med, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. RP Ross, OA (reprint author), Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. EM ross.owen@mayo.edu RI Singleton, Andrew/C-3010-2009; Guerreiro, Rita/A-1327-2011 FU James and Ester King Foundation New Investigator Award from the Department of Health, Florida State; American Heart Association (AHA); Myron and Jane Hanley Award in Stroke Research; National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS39987]; Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine; NINDS [R01 NS42733]; National Institutes of Health (NIH) /NINDS [P50 NS072187]; Mayo Clinic Center for Regenerative Medicine; Dystonia Medical Research Foundation; Intramural Research Program of the National Institute on Aging, NIH, Department of Health and Human Services [Z01 AG000950-06]; UK Motor Neurone Disease Association [6057]; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; UCL/Institute of Neurology; University of Sheffield; MRC Protein Phosphorylation Unit at the University of Dundee; Alzheimer's Research UK FX OAR is a recipient of a James and Ester King Foundation New Investigator Award from the Department of Health, Florida State. OAR is also funded by the American Heart Association (AHA) and the Myron and Jane Hanley Award in Stroke Research. The Siblings with Ischemic Stroke Study was funded by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) (R01 NS39987; JFM, PI) and by a Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine. The Ischemic Stroke Genetics Study (ISGS) was funded by a grant from the NINDS (R01 NS42733). ZKW is partially supported by the National Institutes of Health (NIH) /NINDS P50 NS072187, Mayo Clinic Center for Regenerative Medicine, and Dystonia Medical Research Foundation. This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Department of Health and Human Services, project number Z01 AG000950-06; the UK Motor Neurone Disease Association grant 6057 to John Hardy and Richard Orrell and Alzheimer's Research UK funding to John Hardy. This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee and a fellowship from Alzheimer's Research UK to Dr. Guerreiro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 12 Z9 13 U1 1 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 SEP 23 PY 2013 VL 8 IS 9 AR UNSP e75035 DI 10.1371/journal.pone.0075035 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 246EK UT WOS:000326520200074 PM 24086431 ER PT J AU Roche, J Ying, JF Maltsev, AS Bax, A AF Roche, Julien Ying, Jinfa Maltsev, Alexander S. Bax, Ad TI Impact of Hydrostatic Pressure on an Intrinsically Disordered Protein: A High-Pressure NMR Study of alpha-Synuclein SO CHEMBIOCHEM LA English DT Article DE N-15 relaxation; intrinsically disordered proteins; nonuniform sampling; random coils; triple resonance ID RESIDUAL DIPOLAR COUPLINGS; N-15 CHEMICAL-SHIFTS; X-RAY-SCATTERING; UNFOLDED PROTEINS; SECONDARY STRUCTURE; HYDRATION SHELL; HYDROGEN-BONDS; DYNAMICS; BACKBONE; TEMPERATURE AB The impact of pressure on the backbone N-15, H-1 and C-13 chemical shifts in N-terminally acetylated alpha-synuclein has been evaluated over a pressure range 1-2500 bar. Even while the chemical shifts fall very close to random coil values, as expected for an intrinsically disordered protein, substantial deviations in the pressure dependence of the chemical shifts are seen relative to those in short model peptides. In particular, the nonlinear pressure response of the H-1(N) chemical shifts, which commonly is associated with the presence of low-lying "excited states", is much larger in alpha-synuclein than in model peptides. The linear pressure response of H-1(N) chemical shift, commonly linked to H-bond length change, correlates well with those in short model peptides, and is found to be anticorrelated with its temperature dependence. The pressure dependence of C-13 chemical shifts shows remarkably large variations, even when accounting for residue type, and do not point to a clear shift in population between different regions of the Ramachandran map. However, a nearly universal decrease in (3)J(HN-H alpha) by 0.22 +/- 0.05 Hz suggests a slight increase in population of the polyproline II region at 2500 bar. The first six residues of N-terminally acetylated synuclein show a transient of approximately 15% population of alpha-helix, which slightly diminishes at 2500 bar. The backbone dynamics of the protein is not visibly affected beyond the effect of slight increase in water viscosity at 2500 bar. C1 [Roche, Julien; Ying, Jinfa; Maltsev, Alexander S.; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Roche, Julien/O-3204-2013 OI Roche, Julien/0000-0003-3892-0200 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, NIH. The authors thank James Baber for technical assistance. NR 55 TC 15 Z9 16 U1 3 U2 45 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 23 PY 2013 VL 14 IS 14 BP 1754 EP 1761 DI 10.1002/cbic.201300244 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 237ER UT WOS:000325851800010 PM 23813793 ER PT J AU Melamed, S Wyatt, LS Kastenmayer, RJ Moss, B AF Melamed, Sharon Wyatt, Linda S. Kastenmayer, Robin J. Moss, Bernard TI Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants SO VACCINE LA English DT Article DE Attenuated live vaccines; Recombinant vaccinia virus; Virus vectors; Virus pathogenesis ID CELL-LINES; SMALLPOX VACCINE; GENOMIC SEQUENCE; INFLUENZA-VIRUS; MVA STRAIN; PROPAGATION; VIRULENCE; IMMUNITY; NYVAC; MICE AB Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture, (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production. Published by Elsevier Ltd. C1 [Melamed, Sharon; Wyatt, Linda S.; Kastenmayer, Robin J.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@niaid.nih.gov FU Intramural Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX We thank Jeffrey Americo and Catherine Cotter for excellent technical assistance and Patricia Earl for advice. This work was supported by the Intramural Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health. NR 44 TC 7 Z9 7 U1 0 U2 2 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 SEP 23 PY 2013 VL 31 IS 41 BP 4569 EP 4577 DI 10.1016/j.vaccine.2013.07.057 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 239FP UT WOS:000326008300016 PM 23928462 ER PT J AU Kugler, DG Mittelstadt, PR Ashwell, JD Sher, A Jankovic, D AF Kugler, David G. Mittelstadt, Paul R. Ashwell, Jonathan D. Sher, Alan Jankovic, Dragana TI CD4(+) T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IMMUNE-RESPONSE; CUTTING EDGE; IFN-GAMMA; TNF-ALPHA; GONDII; RECEPTOR; IL-12; LYMPHOCYTES; ACTIVATION; MECHANISM AB Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GR(lck-Cre)) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GR(lck-Cre) mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-gamma and TNF production in vivo. Unexpectedly, these CD4(+) T lymphocytes also overexpressed IL-10. Importantly, CD4(+) T cell depletion in wild-type or GR(lck-Cre) mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG(-/-) animals, adoptive transfer of CD4(+) T lymphocytes was required for GC induction. These findings establish a novel IL-10-independent immunomodulatory circuit in which CD4(+) T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival. C1 [Kugler, David G.; Sher, Alan; Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mittelstadt, Paul R.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kugler, David G.] Johns Hopkins Univ, Natl Inst Hlth Grad Partnership Program, NIH, Bethesda, MD 20892 USA. RP Jankovic, D (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ASher@niaid.nih.gov; DJankovic@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Intramural AIDS Research Fellowship FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part by an Intramural AIDS Research Fellowship (to D.G. Kugler). NR 30 TC 12 Z9 12 U1 2 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 23 PY 2013 VL 210 IS 10 BP 1919 EP 1927 DI 10.1084/jem.20122300 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 223NR UT WOS:000324813000004 PM 23980098 ER PT J AU Klebanoff, CA Spencer, SP Torabi-Parizi, P Grainger, JR Roychoudhuri, R Ji, Y Sukumar, M Muranski, P Scott, CD Hall, JA Ferreyra, GA Leonardi, AJ Borman, ZA Wang, JS Palmer, DC Wilhelm, C Cai, RM Sun, JF Napoli, JL Danner, RL Gattinoni, L Belkaid, Y Restifo, NP AF Klebanoff, Christopher A. Spencer, Sean P. Torabi-Parizi, Parizad Grainger, John R. Roychoudhuri, Rahul Ji, Yun Sukumar, Madhusudhanan Muranski, Pawel Scott, Christopher D. Hall, Jason A. Ferreyra, Gabriela A. Leonardi, Anthony J. Borman, Zachary A. Wang, Jinshan Palmer, Douglas C. Wilhelm, Christoph Cai, Rongman Sun, Junfeng Napoli, Joseph L. Danner, Robert L. Gattinoni, Luca Belkaid, Yasmine Restifo, Nicholas P. TI Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CD8(+) T-CELLS; IN-VIVO; VITAMIN-A; ANTIGEN PRESENTATION; SIGNALING CONTROLS; MYELOID CELLS; STEADY-STATE; B-CELLS; DIFFERENTIATION; EXPRESSION AB Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8 alpha(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8 alpha(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8 alpha(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8 alpha(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b-(C)D8 alpha(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation. C1 [Klebanoff, Christopher A.] NCI, Clin Investigator Dev Program, NIH, Bethesda, MD 20892 USA. [Ji, Yun; Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Klebanoff, Christopher A.; Roychoudhuri, Rahul; Ji, Yun; Sukumar, Madhusudhanan; Muranski, Pawel; Scott, Christopher D.; Leonardi, Anthony J.; Borman, Zachary A.; Palmer, Douglas C.; Gattinoni, Luca; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Spencer, Sean P.; Grainger, John R.; Hall, Jason A.; Wilhelm, Christoph; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Spencer, Sean P.; Hall, Jason A.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Ferreyra, Gabriela A.; Cai, Rongman; Sun, Junfeng; Danner, Robert L.] NIH, Funct Genom & Prote Facil, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad; Ferreyra, Gabriela A.; Cai, Rongman; Sun, Junfeng; Danner, Robert L.] NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Jinshan; Napoli, Joseph L.] Univ Calif Berkeley, Program Metab Biol Nutr Sci & Toxicol, Berkeley, CA 94720 USA. RP Klebanoff, CA (reprint author), NCI, Clin Investigator Dev Program, NIH, Bethesda, MD 20892 USA. EM klebanoc@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Palmer, Douglas/B-9454-2008; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Palmer, Douglas/0000-0001-5018-5734; Roychoudhuri, Rahul/0000-0002-5392-1853; Restifo, Nicholas P./0000-0003-4229-4580; Grainger, John/0000-0002-4052-5923 FU Intramural Research Program of the National Cancer Institute; Center for Cancer Research of the US NIH; NIH Office of Dietary Supplements; NIH grant [F30 DK094708-02]; Human Frontiers Science Program FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US NIH, the NIH Office of Dietary Supplements (S.P. Spencer, J.R. Grainger, and J.A. Hall), NIH grant F30 DK094708-02 (to S.P. Spencer), and the Human Frontiers Science Program (C. Wilhelm). NR 68 TC 44 Z9 44 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 23 PY 2013 VL 210 IS 10 BP 1961 EP 1976 DI 10.1084/jem.20122508 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 223NR UT WOS:000324813000008 PM 23999499 ER PT J AU O'Brien, TJ Kidd, RS Richard, CAH Ha, NH Witcher, P Tran, LV Barbour, A Tuck, M McIntosh, SD Douglas, JN Harralson, AF AF O'Brien, Travis J. Kidd, Robert S. Richard, Craig A. H. Ha, Ngoc-Han Witcher, Preston Tran, Linda V. Barbour, April Tuck, Matthew McIntosh, Samantha D. Douglas, Jacqueline N. Harralson, Arthur F. TI First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele SO CLINICA CHIMICA ACTA LA English DT Article DE Warfarin; CYP2C9; CYP2C9*12; rs9332239 ID VKORC1 GENE POLYMORPHISMS; AFRICAN-AMERICANS; ANTICOAGULANT RESPONSE; CYP2C9; GENOTYPE; ASSOCIATION; POPULATION; HAPLOTYPES; DISCOVERY; CYP4F2 AB Background: Warfarin is the most frequently prescribed anticoagulant in North America and Europe. It is administered as a racemate, but S-warfarin is principally responsible for its anticoagulant activity. Cytochrome P450 (CYP) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin. Numerous variant alleles of CYP2C9 have been identified. The CYP2C9*12 (rs9332239) allele harbors a P489S substitution in CYP2C9 which has been shown to result in a 40% decline in catalytic activity in vitro. Cases: Four Caucasian patients with a low mean weekly warfarin dose (MWWD) were genotyped for CYP2C9, VKORC1 and APOE variant alleles. None of the four patients carried the common CYP2C9 variant alleles (*2, *3, *5, *6, *7, *8, *9, *11, *13) despite a relatively low MWWD (23.4 +/- 7.94 mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2 +/- 12.65 mg). Given that CYP2C9*12 confers decreased in vitro activity to the enzyme, we investigated whether these patients carried this allele. All four patients were CYP2C9*12 CT heterozygotes. Individual comparisons with patients possessing the same VKORC1 and APOE genotypes also demonstrated lower dose requirements in the patients that possessed CYP2C9*12 allele. Conclusions: There are no reports of the clinical impact of rs9332239 on CYP2C9 substrates. This is the first report of patients with the rare CYP2C9*12 genotype and lower warfarin dose requirements. (c) 2013 Elsevier B.V. All rights reserved. C1 [O'Brien, Travis J.; Tran, Linda V.; Harralson, Arthur F.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Kidd, Robert S.; Richard, Craig A. H.; Witcher, Preston; Harralson, Arthur F.] Shenandoah Univ, Bernard J Dunn Sch Pharm, Winchester, VA USA. [Ha, Ngoc-Han] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Barbour, April; Tuck, Matthew; Douglas, Jacqueline N.] George Washington Univ, Dept Med, Washington, DC USA. [Tuck, Matthew; McIntosh, Samantha D.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Tuck, Matthew; McIntosh, Samantha D.] Vet Affairs Med Ctr, Washington, DC 20422 USA. RP Harralson, AF (reprint author), George Washington Univ, Bernard J Dunn Sch Pharm, Virginia Sci & Technol Campus,45085 Univ Dr,202S, Ashburn, VA 20147 USA. EM Aharrals@su.edu FU National Collaboration On Aging; Professional Practice Plan of the Shenandoah University FX This study was supported by National Collaboration On Aging and the Professional Practice Plan of the Shenandoah University. Due to space limitations, the authors would like to apologize for the valuable studies that were not included in this manuscript. NR 30 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD SEP 23 PY 2013 VL 424 BP 73 EP 75 DI 10.1016/j.cca.2013.05.008 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 226NH UT WOS:000325042600013 PM 23688605 ER PT J AU Jia, JP Parikh, H Xiao, WM Hoskins, JW Pflicke, H Liu, XL Collins, I Zhou, WY Wang, ZM Powell, J Thorgeirsson, SS Rudloff, U Petersen, GM Amundadottir, LT AF Jia, Jinping Parikh, Hemang Xiao, Wenming Hoskins, Jason W. Pflicke, Holger Liu, Xuelu Collins, Irene Zhou, Weiyin Wang, Zhaoming Powell, John Thorgeirsson, Snorri S. Rudloff, Udo Petersen, Gloria M. Amundadottir, Laufey T. TI An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer SO BMC MEDICAL GENOMICS LA English DT Article DE Pancreatic cancer; Transcriptome; Epigenome; Sequencing; ALDH1A3 ID REAL-TIME PCR; STEM-CELLS; ALDEHYDE DEHYDROGENASE; DUCTAL ADENOCARCINOMA; HUMAN GENOME; ASSOCIATION; EXPRESSION; MARKER; PROMOTERS; MICRORNAS AB Background: Pancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities. Methods: To begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas. Results: By RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues. Conclusions: As aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells. C1 [Jia, Jinping; Parikh, Hemang; Hoskins, Jason W.; Collins, Irene; Amundadottir, Laufey T.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming; Liu, Xuelu; Powell, John] NIH, Div Computat Biosci, Ctr Informat Technol, Bioinformat & Mol Anal Sect, Bethesda, MD 20892 USA. [Pflicke, Holger; Rudloff, Udo] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, Xuelu] SRA Int, Fairfax, VA 22033 USA. [Zhou, Weiyin; Wang, Zhaoming] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. RP Amundadottir, LT (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM amundadottirl@mail.nih.gov RI Hoskins, Jason/F-5672-2012; Amundadottir, Laufey/L-7656-2016 OI Hoskins, Jason/0000-0001-6944-1996; Amundadottir, Laufey/0000-0003-1859-8971 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) [HHSN2612 00800001E] FX We thank staff at the National Cancer Institute's Center for Cancer Research Sequencing Facility (Gaithersburg, MD) for performing Next Generation sequencing and staff at the National Cancer Institute's Cancer Genomics Research Laboratory (CGR) for performing genotyping. We are grateful to Michele Guescini, Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Urbino, Italy, for assistance with the analysis of real-time qPCR data. This study was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) under Contract No. HHSN2612 00800001E. 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 51 TC 10 Z9 11 U1 1 U2 8 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 SEP 22 PY 2013 VL 6 AR UNSP 33 DI 10.1186/1755-8794-6-33 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 235EP UT WOS:000325699500001 PM 24053169 ER PT J AU Karargyris, A Koulaouzidis, A AF Karargyris, Alexandros Koulaouzidis, Anastasios TI Capsule-odometer: A concept to improve accurate lesion localisation SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Capsule endoscopy; Odometer; Localisation; Hardware; Software AB In order to improve lesion localisation in small-bowel capsule endoscopy, a modified capsule design has been proposed incorporating localisation and - in theory stabilization capabilities. The proposed design consists of a capsule fitted with protruding wheels attached to a spring-mechanism. This would act as a miniature odometer, leading to more accurate lesion localization information in relation to the onset of the investigation (spring expansion e.g., pyloric opening). Furthermore, this capsule could allow stabilization of the recorded video as any erratic, non-forward movement through the gut is minimised. Three-dimensional (3-D) printing technology was used to build a capsule prototype. Thereafter, miniature wheels were also 3-D printed and mounted on a spring which was attached to conventional capsule endoscopes for the purpose of this proof-of-concept experiment. In vitro and ex vivo experiments with porcine small-bowel are presented herein. Further experiments have been scheduled. (C) 2013 Baishideng. All rights reserved. C1 [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20814 USA. [Koulaouzidis, Anastasios] Royal Infirm Edinburgh NHS Trust, Endoscopy Unit, Ctr Liver & Digest Disorders, Edinburgh EH16 4SA, Midlothian, Scotland. RP Koulaouzidis, A (reprint author), Royal Infirm Edinburgh NHS Trust, Endoscopy Unit, Ctr Liver & Digest Disorders, 51 Little France Crescent,Old Dalkeith Rd, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com FU SynMed(C) UK; Dr Falk Pharma, United kingdom FX Supported by SynMed (c) UK related to this work; Dr. Koulaouzidis A has also received lecture honoraria from Dr Falk Pharma, United kingdom NR 14 TC 12 Z9 12 U1 0 U2 8 PU BAISHIDENG PUBL GRP CO LTD PI WANCHAI PA ROOM 1701, 17-F, HENAN BUILDING, NO. 90, JAFFE RD, WANCHAI, HONG KONG 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD SEP 21 PY 2013 VL 19 IS 35 BP 5943 EP 5946 DI 10.3748/wjg.v19.i35.5943 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 224SL UT WOS:000324909300025 PM 24124345 ER PT J AU Martin-Marcos, P Nanda, J Luna, RE Wagner, G Lorsch, JR Hinnebusch, AG AF Martin-Marcos, Pilar Nanda, Jagpreet Luna, Rafael E. Wagner, Gerhard Lorsch, Jon R. Hinnebusch, Alan G. TI beta-Hairpin Loop of Eukaryotic Initiation Factor 1 (eIF1) Mediates 40 S Ribosome Binding to Regulate Initiator tRNA(Met) Recruitment and Accuracy of AUG Selection in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID START CODON SELECTION; TRANSLATION INITIATION; SACCHAROMYCES-CEREVISIAE; PREINITIATION COMPLEX; SUBUNIT; RECOGNITION; YEAST; PROTEIN; FIDELITY; POSITION AB Recognition of the translation initiation codon is thought to require dissociation of eIF1 from the 40 S ribosomal subunit, enabling irreversible GTP hydrolysis (P-i release) by the eIF2.GTP.Met-tRNAi ternary complex (TC), rearrangement of the 40 S subunit to a closed conformation incompatible with scanning, and stable binding of Met-tRNA(i) to the P site. The crystal structure of a Tetrahymena 40 S.eIF1 complex revealed several basic amino acids in eIF1 contacting 18 S rRNA, and we tested the prediction that their counterparts in yeast eIF1 are required to prevent premature eIF1 dissociation from scanning ribosomes at non-AUG triplets. Supporting this idea, substituting Lys-60 in helix alpha 1, or either Lys-37 or Arg-33 in beta-hairpin loop-1, impairs binding of yeast eIF1 to 40 S.eIF1A complexes in vitro, and it confers increased initiation at UUG codons (Sui(-) phenotype) or lethality, in a manner suppressed by overexpressing the mutant proteins or by an eIF1A mutation (17-21) known to impede eIF1 dissociation in vitro. The eIF1 Sui(-) mutations also derepress translation of GCN4 mRNA, indicating impaired ternary complex loading, and this Gcd(-) phenotype is likewise suppressed by eIF1 overexpression or the 17-21 mutation. These findings indicate that direct contacts of eIF1 with 18 S rRNA seen in the Tetrahymena 40 S.eIF1 complex are crucial in yeast to stabilize the open conformation of the 40 S subunit and are required for rapid TC loading and ribosomal scanning and to impede rearrangement to the closed complex at non-AUG codons. Finally, we implicate the unstructured N-terminal tail of eIF1 in blocking rearrangement to the closed conformation in the scanning preinitiation complex. C1 [Martin-Marcos, Pilar; Hinnebusch, Alan G.] Eunice K Shriver NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Nanda, Jagpreet; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Luna, Rafael E.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu; ahinnebusch@nih.gov FU National Institutes of Health [GM62128, CA068262]; Intramural Research Program FX This work was supported, in whole or in part, by National Institutes of Health Grants GM62128 (to J. R. L.) and CA068262 (to G. W.) and by the Intramural Research Program (to P. M. M. and A. G. H.). NR 27 TC 12 Z9 12 U1 0 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 SEP 20 PY 2013 VL 288 IS 38 BP 27546 EP 27562 DI 10.1074/jbc.M113.498642 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IG UT WOS:000330597300050 PM 23893413 ER PT J AU Hsieh, ML James, TD Knipling, L Waddell, MB White, S Hinton, DM AF Hsieh, Meng-Lun James, Tamara D. Knipling, Leslie Waddell, M. Brett White, Stephen Hinton, Deborah M. TI Architecture of the Bacteriophage T4 Activator MotA/Promoter DNA Interaction during Sigma Appropriation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLI RNA-POLYMERASE; MOTA TRANSCRIPTION FACTOR; ASIA PROTEIN; MIDDLE PROMOTER; CRYSTAL-STRUCTURE; OPEN COMPLEXES; REGION 4; BINDING; SUBUNIT; DOMAIN AB Gene expression can be regulated through factors that direct RNA polymerase to the correct promoter sequence at the correct time. Bacteriophage T4 controls its development in this way using phage proteins that interact with host RNA polymerase. Using a process called sigma appropriation, the T4 co-activator AsiA structurally remodels the sigma(70) subunit of host RNA polymerase, while a T4 activator, MotA, engages the C terminus of sigma(70) and binds to a DNA promoter element, the MotA box. Structures for the N-terminal (NTD) and C-terminal (CTD) domains of MotA are available, but no structure exists for MotA with or without DNA. We report the first molecular map of the MotA/DNA interaction within the sigma-appropriated complex, which we obtained by using the cleaving reagent, iron bromoacetamidobenzyl-EDTA (FeBABE). We conjugated surface-exposed, single cysteines in MotA with FeBABE and performed cleavage reactions in the context of stable transcription complexes. The DNA cleavage sites were analyzed using ICM Molsoft software and three-dimensional physical models of MotA(NTD), MotA(CTD), and the DNA to investigate shape complementarity between the protein and the DNA and to position MotA on the DNA. We found that the unusual "double wing" motif present within MotA(CTD) resides in the major groove of the MotA box. In addition, we have used surface plasmon resonance to show that MotA alone is in a very dynamic equilibrium with the MotA element. Our results demonstrate the utility of fine resolution FeBABE mapping to determine the architecture of protein-DNA complexes that have been recalcitrant to traditional structure analyses. C1 [Hsieh, Meng-Lun; James, Tamara D.; Knipling, Leslie; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [James, Tamara D.] NYU, Struct Biol Program, Sackler Inst, Langone Med Ctr, New York, NY 10016 USA. [Waddell, M. Brett] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [White, Stephen] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA. RP Hinton, DM (reprint author), NIH, Bldg 8,Rm 2A-13, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU National Institutes of Health [GM066934]; Cancer Center Core Grant [CA21765]; NIDDK; American Lebanese Syrian Associated Charities (ALSAC) FX This work was supported, in whole or in part, by National Institutes of Health Grant GM066934 (to S. W.), Cancer Center Core Grant CA21765, and by the Intramural Research Program of the NIDDK. This work was also supported by the American Lebanese Syrian Associated Charities (ALSAC; to S. W.) NR 56 TC 3 Z9 3 U1 1 U2 5 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 SEP 20 PY 2013 VL 288 IS 38 BP 27607 EP 27618 DI 10.1074/jbc.M113.475434 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IG UT WOS:000330597300055 PM 23902794 ER PT J AU Doroshow, JH AF Doroshow, James H. TI Timely Completion of Scientifically Rigorous Cancer Clinical Trials: An Unfulfilled Priority SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SPONSORED TRIALS; PARTICIPATION; INHIBITION; EXPERIENCE; PATIENT; KINASE; TUMORS C1 NCI, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 43 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2013 VL 31 IS 27 BP 3312 EP + DI 10.1200/JCO.2013.51.3192 PG 4 WC Oncology SC Oncology GA 301NH UT WOS:000330538500005 PM 23960175 ER PT J AU Morton, LM Dores, GM Curtis, RE Lynch, CF Stovall, M Hall, P Gilbert, ES Hodgson, DC Storm, HH Johannesen, TB Smith, SA Weathers, RE Andersson, M Fossa, SD Hauptmann, M Holowaty, EJ Joensuu, H Kaijser, M Kleinerman, RA Langmark, F Pukkala, E Vaalavirta, L van den Belt-Dusebout, AW Fraumeni, JF Travis, LB Aleman, BM van Leeuwen, FE AF Morton, Lindsay M. Dores, Graca M. Curtis, Rochelle E. Lynch, Charles F. Stovall, Marilyn Hall, Per Gilbert, Ethel S. Hodgson, David C. Storm, Hans H. Johannesen, Tom Borge Smith, Susan A. Weathers, Rita E. Andersson, Michael Fossa, Sophie D. Hauptmann, Michael Holowaty, Eric J. Joensuu, Heikki Kaijser, Magnus Kleinerman, Ruth A. Langmark, Froydis Pukkala, Eero Vaalavirta, Leila van den Belt-Dusebout, Alexandra W. Fraumeni, Joseph F., Jr. Travis, Lois B. Aleman, Berthe M. van Leeuwen, Flora E. TI Stomach Cancer Risk After Treatment for Hodgkin Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LONG-TERM SURVIVORS; CHILDHOOD-CANCER; 2ND MALIGNANCY; GASTROINTESTINAL CANCER; 5-YEAR SURVIVORS; SUBSEQUENT NEOPLASMS; FOLLOW-UP; DISEASE; RADIATION; CHEMOTHERAPY AB Purpose Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. Patients and Methods We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. Results Stomach cancer risk increased with increasing radiation dose to the stomach (P-trend <.001) and with increasing number of AA-containing chemotherapy cycles (P-trend =.02). Patients who received both radiation to the stomach >= 25 Gy and high-dose procarbazine (>= 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (P-interaction <.001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach >= 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. Conclusion Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly. (C) 2013 by American Society of Clinical Oncology C1 [Morton, Lindsay M.; Dores, Graca M.; Curtis, Rochelle E.; Gilbert, Ethel S.; Kleinerman, Ruth A.; Fraumeni, Joseph F., Jr.] NCI, Bethesda, MD 20892 USA. [Dores, Graca M.] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. [Lynch, Charles F.] Univ Iowa, Iowa City, IA USA. [Stovall, Marilyn; Smith, Susan A.; Weathers, Rita E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hall, Per; Kaijser, Magnus] Karolinska Inst, Stockholm, Sweden. [Hodgson, David C.; Holowaty, Eric J.] Univ Toronto, Toronto, ON, Canada. [Storm, Hans H.] Danish Canc Soc, Copenhagen, Denmark. [Andersson, Michael] Copenhagen Univ Hosp, Copenhagen, Denmark. [Johannesen, Tom Borge; Langmark, Froydis] Canc Registry Norway, Oslo, Norway. [Fossa, Sophie D.] Oslo Univ Hosp, Oslo, Norway. [Fossa, Sophie D.] Univ Oslo, Oslo, Norway. [Hauptmann, Michael; van den Belt-Dusebout, Alexandra W.; Aleman, Berthe M.; van Leeuwen, Flora E.] Netherlands Canc Inst, Amsterdam, Netherlands. [Joensuu, Heikki; Vaalavirta, Leila] Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. [Pukkala, Eero] Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, FIN-00170 Helsinki, Finland. [Travis, Lois B.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Morton, LM (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,Rm 7E-454,MSC 9778, Bethesda, MD 20892 USA. EM mortonli@mail.nih.gov RI Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Storm, Hans/0000-0001-7223-8198; Kleinerman, Ruth/0000-0001-7415-2478; Joensuu, Heikki/0000-0003-0281-2507 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; National Cancer Institute [N01-CP-31157, N01-CP-31019, N01-CP-31154, N01-CP-31003, N01-CP-31156, N01-CP-31155, N02-CP-55503, N02-CP-31136]; Lance Armstrong Foundation; Dutch Cancer Society [NKI 04-3068] FX Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and National Cancer Institute Contract No. N01-CP-31157 to Cancer Care Ontario, Toronto, Canada; Danish Cancer Society, Copenhagen, Denmark (Contract No. N01-CP-31019); Finnish Cancer Registry, Helsinki, Finland (Contract No. N01-CP-31154); Information Management Services, Silver Spring, MD (Contract No. N01-CP-31003); Karolinska Institute, Stockholm, Sweden (Contract No. N01-CP-31156); University of Iowa, Iowa City, IA (Contract No. N01-CP-31155); University of Texas MD Anderson Cancer Center, Houston, TX (Contract No. N02-CP-55503); and Westat, Rockville, MD (Contract No. N02-CP-31136). The Dutch study also was supported by the Lance Armstrong Foundation and Contract No. NKI 04-3068 from the Dutch Cancer Society. NR 41 TC 31 Z9 31 U1 0 U2 5 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 SEP 20 PY 2013 VL 31 IS 27 BP 3369 EP + DI 10.1200/JCO.2013.50.6832 PG 10 WC Oncology SC Oncology GA 301NH UT WOS:000330538500013 PM 23980092 ER PT J AU Kanduluru, AK Banerjee, P Beutler, JA Fuchs, PL AF Kanduluru, Ananda Kumar Banerjee, Prabal Beutler, John A. Fuchs, Philip L. TI A Convergent Total Synthesis of the Potent Cephalostatin/Ritterazine Hybrid-25-epi Ritterostatin G(N)1(N) SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID EFFICIENT PROTOCOL; HECOGENIN ACETATE; HEMISPHERE; SUPPORT; UNIT; FUNCTIONALIZATION; CEPHALOSTATIN-1 AB The convergent synthesis of 25-epi ritterostatin G(N)1(N) is described for the first time, starting from hecogenin acetate (HA). Stereoselective dihydroxylation employing the chiral ligand (DHQ)(2)PHAL was used as the key step to introduce the C25 epi-stereocenter on the north 1 segment. The title compound was obtained through a coupling reaction between the C3-keto-azide (cstat North 1) and North G. C1 [Kanduluru, Ananda Kumar; Banerjee, Prabal; Fuchs, Philip L.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Kanduluru, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM kanduluruak@yahoo.com; pfuchs@purdue.edu OI Kanduluru, Ananda Kumar/0000-0003-2669-8665 FU NIH [CA 60548]; NIH, National Cancer Institute, Center for Cancer Research FX This research work was supported by the NIH (CA 60548) and in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. We sincerely acknowledge Dr. Douglas Lantrip for technical support from the lab and Dr. Hui Cao for his initial experiments on north 1 synthesis and thank Dr. Karl Wood and Arlene Rothwell of Purdue University for mass spectral data. NR 26 TC 5 Z9 5 U1 1 U2 16 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 SEP 20 PY 2013 VL 78 IS 18 BP 9085 EP 9092 DI 10.1021/jo401171q PG 8 WC Chemistry, Organic SC Chemistry GA 296BG UT WOS:000330159500015 PM 23899273 ER PT J AU Bright, MA Davis, K Babb, S Bunnelh, R Rodes, R Alexander, R Coln, C Zhang, L Beistk, D Mitchko, J McAfee, T AF Bright, Mary Anne Davis, Kevin Babb, Stephen Bunnelh, Rebecca Rodes, Robert Alexander, Robert Coln, Caryn Zhang, Lei Beistk, Diane Mitchko, Jane McAfee, Timothy TI Impact of a National Tobacco Education Campaign on Weekly Numbers of Quitline Calls and Website Visitors - United States, March 4-June 23, 2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID SMOKING-CESSATION C1 [Bright, Mary Anne] NCI, Bethesda, MD 20892 USA. [Davis, Kevin] RTI Int, Res Triangle Pk, NC USA. [Babb, Stephen; Bunnelh, Rebecca; Rodes, Robert; Alexander, Robert; Coln, Caryn; Zhang, Lei; Beistk, Diane; Mitchko, Jane; McAfee, Timothy] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Babb, S (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM sbabb@cdc.gov NR 9 TC 11 Z9 11 U1 0 U2 0 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD SEP 20 PY 2013 VL 62 IS 37 BP 763 EP 767 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 239WR UT WOS:000326057200003 ER PT J AU Lalmansingh, AS Arora, K DeMarco, RA Hager, GL Nagaich, AK AF Lalmansingh, Avin S. Arora, Kamalpreet DeMarco, Richard A. Hager, Gordon L. Nagaich, Akhilesh K. TI High-Throughput RNA FISH Analysis by Imaging Flow Cytometry Reveals That Pioneer Factor Foxa1 Reduces Transcriptional Stochasticity SO PLOS ONE LA English DT Article ID TUMOR VIRUS PROMOTER; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; NATURAL PROMOTER; CHROMATIN; BINDING; MODES AB Genes are regulated at the single-cell level. Here, we performed RNA FISH of thousands of cells by flow cytometry (flow-RNA FISH) to gain insight into transcriptional variability between individual cells. These experiments utilized the murine adenocarcinoma 3134 cell line with 200 copies of the MMTV-Ras reporter integrated at a single genomic locus. The MMTV array contains approximately 800-1200 binding sites for the glucocorticoid receptor (GR) and 600 binding sites for the pioneer factor Foxa1. Hormone activation of endogenous GR by dexamethasone treatment resulted in highly variable changes in the RNA FISH intensity (25-300 pixel intensity units) and size (1.25-15 mu m), indicative of probabilistic or stochastic mechanisms governing GR and cofactor activation of the MMTV promoter. Exogenous expression of the pioneer factor Foxa1 increased the FISH signal intensity and size as expected for a chromatin remodeler that enhances transcriptional competence through increased chromatin accessibility. In addition, specific analysis of Foxa1-enriched cell sub-populations showed that low and high Foxa1 levels substantially lowered the cell-to-cell variability in the FISH intensity as determined by a noise calculation termed the % coefficient of variation. These results suggest that an additional function of the pioneer factor Foxa1 may be to decrease transcriptional noise. C1 [Lalmansingh, Avin S.; Arora, Kamalpreet; Nagaich, Akhilesh K.] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [DeMarco, Richard A.] EMD Millipore Corp, Amnis, Seattle, WA USA. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Nagaich, AK (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM akhilesh.nagaich@fda.hhs.gov FU United States Food and Drug Administration (FDA) within the Center for Drug Evaluation and Research (CDER); United States Department of Energy; FDA FX This work was supported by the United States Food and Drug Administration (FDA) within the Center for Drug Evaluation and Research (CDER). This project was supported in part by an appointment to the Research Participation Program at CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the United States Department of Energy and FDA [to A.S.L.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 2 Z9 2 U1 0 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 SEP 20 PY 2013 VL 8 IS 9 AR e76043 DI 10.1371/journal.pone.0076043 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222YC UT WOS:000324768000097 PM 24073287 ER PT J AU Shen, M Zhang, YQ Saba, N Austin, CP Wiestner, A Auld, DS AF Shen, Min Zhang, Yaqin Saba, Nakhle Austin, Christopher P. Wiestner, Adrian Auld, Douglas S. TI Identification of Therapeutic Candidates for Chronic Lymphocytic Leukemia from a Library of Approved Drugs SO PLOS ONE LA English DT Article ID BIOLOGICAL-ACTIVITIES; UNTREATED PATIENTS; INITIAL THERAPY; FLUDARABINE; CYCLOPHOSPHAMIDE; DISEASE; TRIAL; PLICAMYCIN; PREGABALIN; RITUXIMAB AB Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and patients are left with limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL ("consensus" drugs) with five of these showing low or no activity on lymphocytes from a majority of normal donors, suggesting some degree of specificity for the leukemic cells. To our knowledge, this is the first study to screen a drug library against primary CLL cells to identify candidate agents for anti-cancer therapy. The results presented here offer possibilities for the development of novel drug candidates for therapeutic uses to treat CLL and other diseases. C1 [Shen, Min; Zhang, Yaqin; Austin, Christopher P.; Auld, Douglas S.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Saba, Nakhle; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. RP Shen, M (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. EM shenmin@mail.nih.gov; douglas.auld@novartis.com FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 50 TC 7 Z9 7 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2013 VL 8 IS 9 AR e75252 DI 10.1371/journal.pone.0075252 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222YC UT WOS:000324768000066 PM 24073257 ER PT J AU Shoghi, KI Xu, JB Su, Y He, J Rowland, D Yan, Y Garbow, JR Tu, ZD Jones, LA Higashikubo, R Wheeler, KT Lubet, RA Mach, RH You, M AF Shoghi, Kooresh I. Xu, Jinbin Su, Yi He, June Rowland, Douglas Yan, Ying Garbow, Joel R. Tu, Zhude Jones, Lynne A. Higashikubo, Ryuji Wheeler, Kenneth T. Lubet, Ronald A. Mach, Robert H. You, Ming TI Quantitative Receptor-Based Imaging of Tumor Proliferation with the Sigma-2 Ligand [F-18]ISO-1 SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MAMMARY-CANCER MODEL; BREAST-CANCER; PERFORMANCE EVALUATION; ENDOCRINE THERAPY; CELLS-INVITRO; SOLID TUMORS; IN-VIVO; FDG PET; EXPRESSION AB The sigma-2 receptor is expressed in higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells, thus providing an attractive target for imaging the proliferative status (i.e., P:Q ratio) of solid tumors. Here we evaluate the utility of the sigma-2 receptor ligand 2-(2-[F-18]fluoroethoxy)-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-5-methyl-benzamide, [F-18]ISO-1, in two different rodent models of breast cancer. In the first study, small animal Positron Emission Tomography (PET) imaging studies were conducted with [F-18]ISO-1 and (18)FDG in xenografts of mouse mammary tumor 66 and tracer uptake was correlated with the in vivo P: Q ratio determined by flow cytometric measures of BrdU-labeled tumor cells. The second model utilized a chemically-induced (N-methyl-N-nitrosourea [MNU]) model of rat mammary carcinoma to correlate measures of [F-18]ISO-1 and FDG uptake with MR-based volumetric measures of tumor growth. In addition, [F-18]ISO-1 and FDG were used to assess the response of MNU-induced tumors to bexarotene and Vorozole therapy. In the mouse mammary 66 tumors, a strong linear correlation was observed between the [F-18]ISO-1 tumor: background ratio and the proliferative status (P: Q ratio) of the tumor (R = 0.87). Similarly, measures of [F-18]ISO-1 uptake in MNU-induced tumors significantly correlated (R = 0.68, P<0.003) with changes in tumor volume between consecutive MR imaging sessions. Our data suggest that PET studies of [F-18]ISO-1 provide a measure of both the proliferative status and tumor growth rate, which would be valuable in designing an appropriate treatment strategy. C1 [Shoghi, Kooresh I.; Xu, Jinbin; Su, Yi; Garbow, Joel R.; Tu, Zhude; Jones, Lynne A.; Mach, Robert H.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Shoghi, Kooresh I.] Washington Univ, Sch Med, Dept Biomed Engn, St Louis, MO USA. [He, June; Yan, Ying; Higashikubo, Ryuji; You, Ming] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Mach, Robert H.] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. [Mach, Robert H.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Shoghi, Kooresh I.; Mach, Robert H.] Washington Univ, Sch Med, Div Biol & Biomed Sci, St Louis, MO USA. [Rowland, Douglas] Univ Calif Davis, Ctr Mol & Genom Imaging, Davis, CA 95616 USA. [Wheeler, Kenneth T.] Wake Forest Univ, Hlth Sci Ctr, Dept Radiol, Winston Salem, NC 27109 USA. [Lubet, Ronald A.] NIH, Bethesda, MD 20892 USA. [You, Ming] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [You, Ming] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. RP Shoghi, KI (reprint author), Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. EM shoghik@wustl.edu RI Rowland, Douglas/F-3104-2014; Shoghi, Kooresh/H-7398-2014; OI Rowland, Douglas/0000-0001-8059-6905; Shoghi, Kooresh/0000-0003-3204-457X; Jones, Lynne/0000-0003-0235-9538 FU NIH/NCI [N01-CN-43308]; Siteman Cancer Center [P30CA091842]; NIH [CA102869] FX Funding provided by NIH/NCI contract N01-CN-43308, Siteman Cancer Center support grant P30CA091842, NIH grant CA102869 (www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 20 Z9 20 U1 1 U2 15 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 SEP 20 PY 2013 VL 8 IS 9 AR e74188 DI 10.1371/journal.pone.0074188 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222YC UT WOS:000324768000011 PM 24073202 ER PT J AU Seder, RA Chang, LJ Enama, ME Zephir, KL Sarwar, UN Gordon, IJ Holman, LA James, ER Billingsley, PF Gunasekera, A Richman, A Chakravarty, S Manoj, A Velmurugan, S Li, ML Ruben, AJ Li, T Eappen, AG Stafford, RE Plummer, SH Hendel, CS Novik, L Costner, PJM Mendoza, FH Saunders, JG Nason, MC Richardson, JH Murphy, J Davidson, SA Richie, TL Sedegah, M Sutamihardja, A Fahle, GA Lyke, KE Laurens, MB Roederer, M Tewari, K Epstein, JE Sim, BKL Ledgerwood, JE Graham, BS Hoffman, SL AF Seder, Robert A. Chang, Lee-Jah Enama, Mary E. Zephir, Kathryn L. Sarwar, Uzma N. Gordon, Ingelise J. Holman, LaSonji A. James, Eric R. Billingsley, Peter F. Gunasekera, Anusha Richman, Adam Chakravarty, Sumana Manoj, Anita Velmurugan, Soundarapandian Li, MingLin Ruben, Adam J. Li, Tao Eappen, Abraham G. Stafford, Richard E. Plummer, Sarah H. Hendel, Cynthia S. Novik, Laura Costner, Pamela J. M. Mendoza, Floreliz H. Saunders, Jamie G. Nason, Martha C. Richardson, Jason H. Murphy, Jittawadee Davidson, Silas A. Richie, Thomas L. Sedegah, Martha Sutamihardja, Awalludin Fahle, Gary A. Lyke, Kirsten E. Laurens, Matthew B. Roederer, Mario Tewari, Kavita Epstein, Judith E. Sim, B. Kim Lee Ledgerwood, Julie E. Graham, Barney S. Hoffman, Stephen L. CA VRC 312 Study Team TI Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine SO SCIENCE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; CIRCUMSPOROZOITE PROTEIN VACCINE; CD8+ T-CELLS; LIVER STAGES; IMMUNITY; MICE; ANTIBODIES; EFFICACY; TRIAL AB Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine-composed of attenuated, aseptic, purified, cryopreserved PfSPZ-was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 x 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards. C1 [Seder, Robert A.; Chang, Lee-Jah; Enama, Mary E.; Zephir, Kathryn L.; Sarwar, Uzma N.; Gordon, Ingelise J.; Holman, LaSonji A.; Plummer, Sarah H.; Hendel, Cynthia S.; Novik, Laura; Costner, Pamela J. M.; Mendoza, Floreliz H.; Saunders, Jamie G.; Roederer, Mario; Tewari, Kavita; Ledgerwood, Julie E.; Graham, Barney S.] NIAID, VRC, NIH, Rockville, MD 20852 USA. [James, Eric R.; Billingsley, Peter F.; Gunasekera, Anusha; Richman, Adam; Chakravarty, Sumana; Manoj, Anita; Velmurugan, Soundarapandian; Ruben, Adam J.; Li, Tao; Eappen, Abraham G.; Stafford, Richard E.; Sim, B. Kim Lee; Hoffman, Stephen L.] Sanaria, Rockville, MD 20850 USA. [Li, MingLin; Stafford, Richard E.; Sim, B. Kim Lee; Hoffman, Stephen L.] Prot Potential, Rockville, MD 20850 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, Div Clin Res, NIH, Rockville, MD 20852 USA. [Richardson, Jason H.; Murphy, Jittawadee; Davidson, Silas A.] Walter Reed Army Inst Res, Entomol Branch, Silver Spring, MD 20910 USA. [Richie, Thomas L.; Sedegah, Martha; Sutamihardja, Awalludin; Epstein, Judith E.] Naval Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD 20910 USA. [Fahle, Gary A.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Lyke, Kirsten E.; Laurens, Matthew B.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Laurens, Matthew B.] Howard Hughes Med Inst, Baltimore, MD 21201 USA. RP Seder, RA (reprint author), NIAID, VRC, NIH, Rockville, MD 20852 USA. EM rseder@mail.nih.gov RI Laurens, Matthew/E-7293-2013; OI Laurens, Matthew/0000-0003-3874-581X; Richie, Thomas/0000-0002-2946-5456 FU National Institute of Allergy and Infectious Diseases (NIAID) [4R44AI055229-08, 3R44AI055229-06S1, 5R44AI058499-05, N01-AI-40096]; Howard Hughes Medical Institute; [6000.RADI.F.A0309] FX The data presented in this manuscript are tabulated in the main figures and the supplementary materials. The clinical trial was funded and supported by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research Program. Production and characterization of the vaccine were supported in part by NIAID Small Business Innovation Research grants 4R44AI055229-08, 3R44AI055229-06S1, and 5R44AI058499-05. Preclinical toxicology and biodistribution studies were supported in part by NIAID preclinical service contract N01-AI-40096. Molecular diagnosis was supported by the Howard Hughes Medical Institute. A materials transfer agreement will be required for the use of recombinant PfMSP-1 and PfEBA-175, HC-04 cells, and 2A10 monoclonal antibody. A number of patents on PfSPZ have been issued, allowed, or filed in the United States and internationally. The U.S. patents include S. L. Hoffman et al., U.S. Patent 7,229,627 (2007) (there is a divisional of this patent with claims directed to aseptic adult Anopheles-species mosquitoes and aseptic Plasmodium-species sporozoites, USSN 11/726,622); S. L. Hoffman et al., U.S. Patent Pub. US2005/0208078 (2005); and B. K. L. Sim, S. L. Hoffman, M. Li, R. E. Stafford, U.S. Patent Pub U.S. 2010/0183680 (2010). There is also a patent on HC-04 cells [J. Prachumsri et al., U.S. Patent 7015036 (2006)]. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency or collaborators. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, Department of Defense, or the U.S. government. This work was supported by work unit number 6000.RADI.F.A0309. The study protocol was approved by the Naval Medical Research Center Institutional Review Board in compliance with all applicable federal regulations governing the protection of human subjects. J.E.E., T.L.R., J.H.R., J.M., and S.A.D. are military service members. This work was prepared as part of their official duties. Title 17 U.S.C. 101 defines a US. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the Departments of the Army, Navy, or Defense. The authors thank the vaccine trial participants for their contribution and commitment to vaccine research. We acknowledge the contributions of our NIH Clinical Center and NIAID colleagues, especially A. S. Fauci for thoughtful advice and review of the manuscript; J. Stein, J. Pierson, R. Eckes, P. Driscoll, L. Ediger, and the nursing staff of the 5NW, SCSU, 5SE-S, and 5SE-N units; our VRC colleagues, especially B. Flynn, A. Mittelman, M. Young, C. Artis, R. Hicks, and T. Abram; the EMMES Corporation; R. Thompson, F. Beams, M. Garley, A. Hoffman, and D. Dolberg of Sanaria for administrative, operations, and legal support and T. Luke for insight and inspiration; the NIAID Institutional Review Board; the NIAID Office of Communications and Government Relations; the NIH Clinical Center Investigational New Drug Pharmacy; and the NIH Clinical Center Patient Recruitment and Public Liaison Office. We appreciate the expert reviews of the Safety Monitoring Committee (A. Durbin, K. Kester, and A. Cross) and the assistance from the U.S.; Military Malaria Vaccine Program, the Walter Reed Army Institute of Research Entomology Branch, and the Naval Medical Research Center, especially A. Reyes, Y. Alcorta, G. Banania, C. Fedders, M. Dowler, T. Savransky, D. Patel, C. Brando, and K. Kobylinski. NR 36 TC 232 Z9 234 U1 8 U2 89 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 20 PY 2013 VL 341 IS 6152 BP 1359 EP 1365 DI 10.1126/science.1241800 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 220PK UT WOS:000324597200037 PM 23929949 ER PT J AU Gray, RR Tanaka, Y Takebe, Y Magiorkinis, G Buskell, Z Seeff, L Alter, HJ Pybus, OG AF Gray, Rebecca R. Tanaka, Yasuhito Takebe, Yutaka Magiorkinis, Gkikas Buskell, Zelma Seeff, Leonard Alter, Harvey J. Pybus, Oliver G. TI Evolutionary analysis of hepatitis C virus gene sequences from 1953 SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE molecular epidemiology; phylogenetics ID NON-B-HEPATITIS; HEPATOCELLULAR-CARCINOMA; MOLECULAR SEQUENCES; MAXIMUM-LIKELIHOOD; UNITED-STATES; NON-A; EPIDEMIC; INFECTION; POPULATION; DIVERSITY AB Reconstructing the transmission history of infectious diseases in the absence of medical or epidemiological records often relies on the evolutionary analysis of pathogen genetic sequences. The precision of evolutionary estimates of epidemic history can be increased by the inclusion of sequences derived from 'archived' samples that are genetically distinct from contemporary strains. Historical sequences are especially valuable for viral pathogens that circulated for many years before being formally identified, including HIV and the hepatitis C virus (HCV). However, surprisingly few HCV isolates sampled before discovery of the virus in 1989 are currently available. Here, we report and analyse two HCV subgenomic sequences obtained from infected individuals in 1953, which represent the oldest genetic evidence of HCV infection. The pair-wise genetic diversity between the two sequences indicates a substantial period of HCV transmission prior to the 1950s, and their inclusion in evolutionary analyses provides new estimates of the common ancestor of HCV in the USA. To explore and validate the evolutionary information provided by these sequences, we used a new phylogenetic molecular clock method to estimate the date of sampling of the archived strains, plus the dates of four more contemporary reference genomes. Despite the short fragments available, we conclude that the archived sequences are consistent with a proposed sampling date of 1953, although statistical uncertainty is large. Our cross-validation analyses suggest that the bias and low statistical power observed here likely arise from a combination of high evolutionary rate heterogeneity and an unstructured, star-like phylogeny. We expect that attempts to date other historical viruses under similar circumstances will meet similar problems. C1 [Gray, Rebecca R.; Magiorkinis, Gkikas; Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Mizuho Ku, Nagoya, Aichi, Japan. [Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Liver Unit, Mizuho Ku, Nagoya, Aichi, Japan. [Takebe, Yutaka] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo 1628640, Japan. [Buskell, Zelma] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Seeff, Leonard] Hill Grp, Bethesda, MD USA. [Alter, Harvey J.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Gray, RR (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM rebecca.gray@zoo.ox.ac.uk; oliver.pybus@zoo.ox.ac.uk OI Pybus, Oliver/0000-0002-8797-2667 FU UK Medical Research Council; Marie Curie Actions FX R.R.G. was supported by the UK Medical Research Council. G.M. was supported by Marie Curie Actions. NR 31 TC 11 Z9 11 U1 0 U2 4 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD SEP 19 PY 2013 VL 368 IS 1626 AR 20130168 DI 10.1098/rstb.2013.0168 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AA6QE UT WOS:000331222100013 PM 23938759 ER PT J AU Gardner, JM Metzger, TC McMahon, EJ Au-Yeung, BB Krawisz, AK Lu, W Price, JD Johannes, KP Satpathy, AT Murphy, KM Tarbell, KV Weiss, A Anderson, MS AF Gardner, James M. Metzger, Todd C. McMahon, Eileen J. Au-Yeung, Byron B. Krawisz, Anna K. Lu, Wen Price, Jeffrey D. Johannes, Kellsey P. Satpathy, Ansuman T. Murphy, Kenneth M. Tarbell, Kristin V. Weiss, Arthur Anderson, Mark S. TI Extrathymic Aire-Expressing Cells Are a Distinct Bone Marrow-Derived Population that Induce Functional Inactivation of CD4(+) T Cells SO IMMUNITY LA English DT Article ID THYMIC EPITHELIAL-CELLS; NONOBESE DIABETIC MICE; DENDRITIC CELLS; ANTIGEN PRESENTATION; LYMPH-NODES; PERIPHERAL TOLERANCE; STEADY-STATE; SELF; GENE; PROTEIN AB The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its role is best understood in the thymus, where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)(hi), CD80(lo), CD86(lo), epithelial cell adhesion molecule (EpCAM)(hi), CD45(lo) bone marrow-derived peripheral antigen-presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4(+) T cells through a mechanism that does not require regulatory T cells (Treg) and is resistant to innate inflammatory stimuli. Together, these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs. C1 [Gardner, James M.; Metzger, Todd C.; McMahon, Eileen J.; Krawisz, Anna K.; Lu, Wen; Johannes, Kellsey P.; Anderson, Mark S.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Gardner, James M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [McMahon, Eileen J.] Westmont Coll, Dept Biol, Santa Barbara, CA 93108 USA. [Au-Yeung, Byron B.] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthrit, Dept Microbiol & Immunol, Howard Hughes Med Inst,Dept Med, San Francisco, CA 94143 USA. [Price, Jeffrey D.] Natl Inst Diabet & Digest & Kidney Dis, Immune Tolerance Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Satpathy, Ansuman T.; Murphy, Kenneth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Anderson, MS (reprint author), Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. EM manderson@diabetes.ucsf.edu OI Tarbell, Kristin/0000-0003-3738-379X; Au-Yeung, Byron/0000-0002-6446-9102 FU Helmsley Charitable Trust; American Diabetes Association; UCSF Medical Scientist Training Program; UCSF Department of Surgery; National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Network for Pancreatic Organ Donors with Diabetes (nPOD); Juvenile Diabetes Research Foundation International (JDRF) FX We thank M. Cheng for critical reading of the manuscript; J. Esensten, J. Bluestone, Q. Tang, H. van Santen, P. Peterson, H. Scott, E. Unanue, D. Mathis, and C. Benoist for reagents and mice, and N. Killeen and the UCSF Transgenic Core for help generating transgenic mice. This work was supported by the US National Institutes of Health AI035297 (M. S. A), DK59958 and DK063720 for core support, the Helmsley Charitable Trust (M. S. A, T. C. M), the American Diabetes Association (J. M. G.), the UCSF Medical Scientist Training Program (J. M. G.), the UCSF Department of Surgery (J. M. G.), and the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (J. D. P. and K. V. T.). This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation International (JDRF). Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/our-partners.php. NR 34 TC 40 Z9 42 U1 0 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 SEP 19 PY 2013 VL 39 IS 3 BP 560 EP 572 DI 10.1016/j.immuni.2013.08.005 PG 13 WC Immunology SC Immunology GA AA2UM UT WOS:000330949600018 PM 23993652 ER PT J AU Jakubzick, C Gautier, EL Gibbings, SL Sojka, DK Schlitzer, A Johnson, TE Ivanov, S Duan, QN Bala, S Condon, T van Rooijen, N Grainger, JR Belkaid, Y Ma'ayan, A Riches, DWH Yokoyama, WM Ginhoux, F Henson, PM Randolph, GJ AF Jakubzick, Claudia Gautier, Emmanuel L. Gibbings, Sophie L. Sojka, Dorothy K. Schlitzer, Andreas Johnson, Theodore E. Ivanov, Stoyan Duan, Qiaonan Bala, Shashi Condon, Tracy van Rooijen, Nico Grainger, John R. Belkaid, Yasmine Ma'ayan, Avi Riches, David W. H. Yokoyama, Wayne M. Ginhoux, Florent Henson, Peter M. Randolph, Gwendalyn J. TI Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes SO IMMUNITY LA English DT Article ID GENE-EXPRESSION PROFILES; DENDRITIC CELL-MIGRATION; BLOOD MONOCYTES; CD8(+) T; MACROPHAGES; INFECTION; SUBSETS; RESPONSES; REVEALS; PROLIFERATION AB It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C(+) monocytes constitutively trafficked into skin, lung, and lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default. C1 [Jakubzick, Claudia; Gibbings, Sophie L.; Riches, David W. H.; Henson, Peter M.] Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA. [Jakubzick, Claudia; Johnson, Theodore E.; Condon, Tracy; Riches, David W. H.; Henson, Peter M.] Univ Colorado, Integrated Dept Immunol, Denver, CO 80206 USA. [Jakubzick, Claudia; Randolph, Gwendalyn J.] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. [Gautier, Emmanuel L.; Ivanov, Stoyan; Bala, Shashi; Randolph, Gwendalyn J.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Sojka, Dorothy K.; Yokoyama, Wayne M.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Yokoyama, Wayne M.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. [Schlitzer, Andreas; Ginhoux, Florent] ASTAR, Singapore Immunol Network, Singapore SIgN, Singapore 138648, Singapore. [Duan, Qiaonan; Ma'ayan, Avi] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [van Rooijen, Nico] Free Univ Med Ctr, Dept Mol Cell Biol, NL-1007 Amsterdam, Netherlands. [Grainger, John R.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Randolph, GJ (reprint author), Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. EM grandolph@path.wustl.edu RI Schlitzer, Andreas/R-2237-2016; Gautier, Emmanuel L./E-2259-2017; OI Schlitzer, Andreas/0000-0001-7662-3712; Gautier, Emmanuel L./0000-0003-2976-7566; Ivanov, Stoyan/0000-0002-0527-2297; Grainger, John/0000-0002-4052-5923 FU National Institutes of Health [AI049653]; U.S. Department of Defense [DOD W81XWH-07-1-0550-Mason]; AHA [10POST4160140]; Training in Cancer Biology grant [T32CA009547]; Singapore Immunology Network core grant; Washington University Digestive Diseases Research Core Center (DDRCC) [DK052574]; [NHLBI-HL81151]; [NHLBI-HL115334]; [R24 AI072073] FX We thank C. Benoist and the Immunological Genome Consortium (Immgen) for their roles in the gene expression analysis. We thank J. Faith and J. Gordon for gnotobiotic mice, R. Schreiber for anti-IFN-gamma mAb H22, L. Yang for technical assistance and advice with parabiosis, and D. Homann for assistance and reagents used in chemokine staining. This work was supported by National Institutes of Health grant AI049653 to G. J. R. with a Primary Caregiver's Supplement to C. J. C. J. and P. M. H. were supported by NHLBI-HL81151 and NHLBI-HL115334. D. W. H. R. and T. C. were supported by the U.S. Department of Defense grant DOD W81XWH-07-1-0550-Mason. E. L. G. was funded in part by the AHA (10POST4160140). D. K. S. is supported by Training in Cancer Biology grant T32CA009547. A. S. and F. G. were supported by a Singapore Immunology Network core grant. The Immunological Genome project is funded by R24 AI072073 to C. Benoist. Funding related to the use of gnotobiotic mice was through Washington University Digestive Diseases Research Core Center (DDRCC) grant DK052574. NR 35 TC 165 Z9 166 U1 2 U2 20 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 SEP 19 PY 2013 VL 39 IS 3 BP 599 EP 610 DI 10.1016/j.immuni.2013.08.007 PG 12 WC Immunology SC Immunology GA AA2UM UT WOS:000330949600021 PM 24012416 ER PT J AU Barrott, JJ Hughes, PF Osada, T Yang, XY Hartman, ZC Loiselle, DR Spector, NL Neckers, L Rajaram, N Hu, FY Ramanujam, N Vaidyanathan, G Zalutsky, MR Lyerly, HK Haystead, TA AF Barrott, Jared J. Hughes, Philip F. Osada, Takuya Yang, Xiao-Yi Hartman, Zachary C. Loiselle, David R. Spector, Neil L. Neckers, Len Rajaram, Narasimhan Hu, Fangyao Ramanujam, Nimmi Vaidyanathan, Ganesan Zalutsky, Michael R. Lyerly, H. Kim Haystead, Timothy A. TI Optical and Radioiodinated Tethered Hsp90 Inhibitors Reveal Selective Internalization of Ectopic Hsp90 in Malignant Breast Tumor Cells SO CHEMISTRY & BIOLOGY LA English DT Article ID SHOCK-PROTEIN 90; MOLECULAR CHAPERONE HSP90; CANCER; HSP90-ALPHA; SECRETION; MOTILITY; COMPLEX; CONFORMATION; METASTASIS; ACTIVATION AB Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethylene-glycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging. C1 [Barrott, Jared J.; Hughes, Philip F.; Loiselle, David R.; Haystead, Timothy A.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Osada, Takuya; Yang, Xiao-Yi; Hartman, Zachary C.; Lyerly, H. Kim] Duke Univ, Dept Surg, Durham, NC 27710 USA. [Spector, Neil L.] Duke Univ, Dept Med, Durham, NC 27710 USA. [Rajaram, Narasimhan; Hu, Fangyao; Ramanujam, Nimmi] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. [Vaidyanathan, Ganesan; Zalutsky, Michael R.] Duke Univ, Dept Radiol, Durham, NC 27710 USA. [Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Haystead, TA (reprint author), Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. EM hayst001@dm.duke.edu RI Lyerly, Herbert/B-6528-2014; Rajaram, Narasimhan/A-2249-2010 OI Lyerly, Herbert/0000-0002-0063-4770; Rajaram, Narasimhan/0000-0003-1224-8567 FU NIH [1R01-AI089526-01, 1R01AI090644-01]; Department of Defense Transformative Vision Award FX This work was funded by NIH grants 1R01-AI089526-01 and 1R01AI090644-01 to T.A.J.H. and a Department of Defense Transformative Vision Award to T.A.J.H., N.L.S., and H.K.L. There is a patent-pending application by P.F.H. and T.A.H. for several of the small-molecule inhibitors listed in this work. Reagents are available upon request. NR 47 TC 12 Z9 12 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD SEP 19 PY 2013 VL 20 IS 9 BP 1187 EP 1197 DI 10.1016/j.chembiol.2013.08.004 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 298MT UT WOS:000330328700014 PM 24035283 ER PT J AU Bona, M Nowak, E Miller, JT Ogendi, B Nowotny, M Le Grice, SFJ AF Bona, Marion Nowak, Elzbieta Miller, Jennifer T. Ogendi, Brian Nowotny, Marcin Le Grice, Stuart F. J. TI Ty3 reverse transcriptase complexed with an RNA/DNA hybrid shows structural and functional asymmetry SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Miller, Jennifer T.; Ogendi, Brian; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Bona, Marion] SAIC Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S37 EP S37 AR P109 PG 1 WC Virology SC Virology GA 240LY UT WOS:000326099100114 ER PT J AU Corona, A Meleddu, R Esposito, F Distinto, S Bianco, G Maccioni, E Le Grice, SSF Tramontano, E AF Corona, Angela Meleddu, Rita Esposito, Francesca Distinto, Simona Bianco, Giulia Maccioni, Elias Le Grice, Stuart S. F. Tramontano, Enzo TI Site directed mutagenesis studies on HIV-1 reverse transcriptase (RT) shed light on the mechanism of action of a new Ribonuclease H/DNA polymerase RT dual inhibitor SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Corona, Angela; Meleddu, Rita; Esposito, Francesca; Distinto, Simona; Bianco, Giulia; Maccioni, Elias; Tramontano, Enzo] Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy. [Le Grice, Stuart S. F.] NCI, Frederick, MD 21701 USA. RI Corona, Angela/G-7327-2014; Maccioni, Elias/I-8719-2014; Tramontano, Enzo/B-4919-2012; Esposito, Francesca/I-8879-2012 OI Corona, Angela/0000-0002-6630-8636; Tramontano, Enzo/0000-0002-4849-0980; Esposito, Francesca/0000-0001-9725-7977 NR 2 TC 0 Z9 0 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S15 EP S16 AR P18 PG 2 WC Virology SC Virology GA 240LY UT WOS:000326099100050 ER PT J AU Kenyon, J Prestwood, L Le Grice, S Lever, A AF Kenyon, Julia Prestwood, Liam Le Grice, Stuart Lever, Andrew TI A novel method to examine individual RNA structures within a mixed population reveals insights into the HIV-1 RNA dimerisation process SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Kenyon, Julia; Prestwood, Liam; Lever, Andrew] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England. [Le Grice, Stuart] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. NR 0 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 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S22 EP S22 AR P41 PG 1 WC Virology SC Virology GA 240LY UT WOS:000326099100068 ER PT J AU Le Grice, S Lapkouski, M Tian, L Miller, J Nowak, E Potrzebowski, W Konarev, P Rausch, J Bona, M Svergun, D Bujnicki, J Nowotny, M Yang, W AF Le Grice, Stuart Lapkouski, Mikalai Tian, Lan Miller, Jennifer Nowak, Elzbieta Potrzebowski, Wojciech Konarev, Peter Rausch, Jason Bona, Marion Svergun, Dmitri Bujnicki, Janusz Nowotny, Marcin Yang, Wei TI Novel insights from structural analysis of lentiviral and gammaretroviral reverse transcriptases in complex with RNA/DNA hybrids SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Le Grice, Stuart; Miller, Jennifer; Rausch, Jason; Bona, Marion] NCI, HIV DRP, Frederick, MD 21701 USA. [Lapkouski, Mikalai; Tian, Lan; Yang, Wei] NIDDK, NIH, Bethesda, MD USA. [Nowak, Elzbieta; Potrzebowski, Wojciech; Bujnicki, Janusz; Nowotny, Marcin] Int Inst Mol & Cell Biol, Warsaw, Poland. [Konarev, Peter; Svergun, Dmitri] DESY, European Mol Biol Lab, Hamburg, Germany. NR 2 TC 0 Z9 0 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S23 EP S23 AR P46 PG 1 WC Virology SC Virology GA 240LY UT WOS:000326099100072 ER PT J AU Lyonnais, S Dufau, L Reboud-Ravaux, M Marquet, R Paillart, JC Gatell, JM Gorelick, R Tisne, C Mirambeau, G AF Lyonnais, Sebastien Dufau, Laure Reboud-Ravaux, Michele Marquet, Roland Paillart, Jean-Christophe Maria Gatell, Jose Gorelick, Rob Tisne, Carine Mirambeau, Gilles TI RNA remarkably promotes HIV-1 protease fast turnover for NCp15 processing in mild acidic conditions leading to condensation of HIV-1 nucleocapsid SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Lyonnais, Sebastien; Maria Gatell, Jose; Mirambeau, Gilles] IDIBAPS, Barcelona, Spain. [Dufau, Laure; Reboud-Ravaux, Michele; Mirambeau, Gilles] UPMC, Paris, France. [Marquet, Roland; Paillart, Jean-Christophe] Univ Strasbourg, CNRS, IBMC, Strasbourg, France. [Gorelick, Rob] NCI Frederick, ACVP, SAIC, Frederick, MD USA. [Tisne, Carine] Univ Paris 05, CNRS, Paris, France. OI Lyonnais, Sebastien/0000-0002-3154-8568 NR 0 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S26 EP S26 AR P61 PG 1 WC Virology SC Virology GA 240LY UT WOS:000326099100082 ER PT J AU Martin, MA AF Martin, Malcolm A. TI SHIVs, monkeys, and anti-HIV-1 neutralizing antibodies SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Martin, Malcolm A.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 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 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S8 EP S8 AR O41 PG 1 WC Virology SC Virology GA 240LY UT WOS:000326099100029 ER PT J AU Sette, P Nagashima, K Piper, R Bouamr, F AF Sette, Paola Nagashima, Kunio Piper, Robert Bouamr, Fadila TI Ubiquitin conjugation to Gag is essential for ESCRT-mediated HIV-1 budding SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Sette, Paola; Bouamr, Fadila] NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] NCI Frederick, Image Anal Lab, Adv Technol Program, SAIC Frederick, Bethesda, MD USA. [Piper, Robert] Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 19 PY 2013 VL 10 SU 1 BP S1 EP S2 AR O5 PG 2 WC Virology SC Virology GA 240LY UT WOS:000326099100005 ER PT J AU Nishihara, R Wu, KN Lochhead, P Morikawa, T Liao, XY Qian, ZR Inamura, K Kim, SA Kuchiba, A Yamauchi, M Imamura, Y Willett, WC Rosner, BA Fuchs, CS Giovannucci, E Ogino, S Chan, AT AF Nishihara, Reiko Wu, Kana Lochhead, Paul Morikawa, Teppei Liao, Xiaoyun Qian, Zhi Rong Inamura, Kentaro Kim, Sun A. Kuchiba, Aya Yamauchi, Mai Imamura, Yu Willett, Walter C. Rosner, Bernard A. Fuchs, Charles S. Giovannucci, Edward Ogino, Shuji Chan, Andrew T. TI Long-Term Colorectal-Cancer Incidence and Mortality after Lower Endoscopy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COLLEGE-OF-RADIOLOGY; SOCIETY TASK-FORCE; NEGATIVE COLONOSCOPY; AMERICAN-COLLEGE; SCREENING COLONOSCOPY; INTERVAL CANCERS; FAMILY-HISTORY; COLON-CANCER; RISK AB BackgroundColonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain. MethodsWe examined the association of the use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal-cancer incidence (through June 2010) and colorectal-cancer mortality (through June 2012) among participants in the Nurses' Health Study and the Health Professionals Follow-up Study. ResultsAmong 88,902 participants followed over a period of 22 years, we documented 1815 incident colorectal cancers and 474 deaths from colorectal cancer. With endoscopy as compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.57 (95% confidence interval [CI], 0.45 to 0.72) after polypectomy, 0.60 (95% CI, 0.53 to 0.68) after negative sigmoidoscopy, and 0.44 (95% CI, 0.38 to 0.52) after negative colonoscopy. Negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate hazard ratio, 0.73; 95% CI, 0.57 to 0.92). Multivariate hazard ratios for death from colorectal cancer were 0.59 (95% CI, 0.45 to 0.76) after screening sigmoidoscopy and 0.32 (95% CI, 0.24 to 0.45) after screening colonoscopy. Reduced mortality from proximal colon cancer was observed after screening colonoscopy (multivariate hazard ratio, 0.47; 95% CI, 0.29 to 0.76) but not after sigmoidoscopy. As compared with colorectal cancers diagnosed in patients more than 5 years after colonoscopy or without any prior endoscopy, those diagnosed in patients within 5 years after colonoscopy were more likely to be characterized by the CpG island methylator phenotype (CIMP) (multivariate odds ratio, 2.19; 95% CI, 1.14 to 4.21) and microsatellite instability (multivariate odds ratio, 2.10; 95% CI, 1.10 to 4.02). ConclusionsColonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal-cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have CIMP and microsatellite instability. C1 [Nishihara, Reiko; Lochhead, Paul; Morikawa, Teppei; Liao, Xiaoyun; Qian, Zhi Rong; Inamura, Kentaro; Kim, Sun A.; Kuchiba, Aya; Yamauchi, Mai; Imamura, Yu; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nishihara, Reiko; Lochhead, Paul; Morikawa, Teppei; Liao, Xiaoyun; Qian, Zhi Rong; Inamura, Kentaro; Kim, Sun A.; Kuchiba, Aya; Yamauchi, Mai; Imamura, Yu; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Nishihara, Reiko; Wu, Kana; Kuchiba, Aya; Willett, Walter C.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, Walter C.; Giovannucci, Edward; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosner, Bernard A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wu, Kana; Willett, Walter C.; Rosner, Bernard A.; Fuchs, Charles S.; Giovannucci, Edward; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Lochhead, Paul] Univ Aberdeen, Inst Med Sci, Gastrointestinal Res Grp, Aberdeen, Scotland. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo 113, Japan. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St,GRJ 825C, Boston, MA 02114 USA. EM achan@partners.org RI Kim, Sun A/L-4239-2013 OI Kim, Sun A/0000-0002-0891-2093 FU National Institutes of Health FX Funded by the National Institutes of Health and others. NR 39 TC 312 Z9 318 U1 4 U2 30 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 SEP 19 PY 2013 VL 369 IS 12 BP 1095 EP 1105 DI 10.1056/NEJMoa1301969 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 220BD UT WOS:000324554800007 PM 24047059 ER PT J AU Crawford, G Enders, A Gileadi, U Stankovic, S Zhang, Q Lambe, T Crockford, TL Lockstone, HE Freeman, A Arkwright, PD Smart, JM Ma, CS Tangye, SG Goodnow, CC Cerundolo, V Godfrey, DI Su, HC Randall, KL Cornall, RJ AF Crawford, Greg Enders, Anselm Gileadi, Uzi Stankovic, Sanda Zhang, Qian Lambe, Teresa Crockford, Tanya L. Lockstone, Helen E. Freeman, Alexandra Arkwright, Peter D. Smart, Joanne M. Ma, Cindy S. Tangye, Stuart G. Goodnow, Christopher C. Cerundolo, Vincenzo Godfrey, Dale I. Su, Helen C. Randall, Katrina L. Cornall, Richard J. TI DOCK8 is critical for the survival and function of NKT cells SO BLOOD LA English DT Article ID KILLER T-CELLS; GERMINAL CENTER FORMATION; ALDRICH SYNDROME PROTEIN; TERMINAL MATURATION; IMMUNE-RESPONSES; IN-VIVO; HOMEOSTASIS; DEFICIENCY; MUTATIONS; SAP AB Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1 1 NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease. C1 [Crawford, Greg; Gileadi, Uzi; Lambe, Teresa; Crockford, Tanya L.; Cerundolo, Vincenzo; Cornall, Richard J.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DU, England. [Enders, Anselm; Goodnow, Christopher C.; Randall, Katrina L.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Enders, Anselm; Goodnow, Christopher C.; Randall, Katrina L.] Australian Natl Univ, Australian Phen Facil, Canberra, ACT 2601, Australia. [Stankovic, Sanda; Godfrey, Dale I.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. [Zhang, Qian; Su, Helen C.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Lockstone, Helen E.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Freeman, Alexandra] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester, Lancs, England. [Smart, Joanne M.] Royal Childrens Hosp, Dept Allergy & Immunol, Melbourne, Vic, Australia. [Ma, Cindy S.; Tangye, Stuart G.] Univ New S Wales, Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW, Australia. [Ma, Cindy S.; Tangye, Stuart G.] Univ New S Wales, Fac Med, St Vincents Clin Sch, Darlinghurst, NSW, Australia. [Randall, Katrina L.] Australian Natl Univ, Canberra Hosp, Dept Immunol, Canberra, ACT, Australia. [Randall, Katrina L.] Australian Natl Univ, Sch Med, Canberra, ACT, Australia. RP Cornall, RJ (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DU, England. EM richard.cornall@ndm.ox.ac.uk RI Arkwright, Peter/C-5149-2012; Enders, Anselm/B-1165-2011; Tangye, Stuart/H-4023-2014; Su, Helen/H-9541-2015; Lambe, Teresa/E-5733-2016; OI Enders, Anselm/0000-0001-5933-6463; Arkwright, Peter/0000-0002-7411-5375; Su, Helen/0000-0002-5582-9110; Lambe, Teresa/0000-0001-7711-897X; Cerundolo, Vincenzo/0000-0003-0040-3793; Zhang, Qian/0000-0002-9040-3289 FU Medical Research Council; National Institute for Health Research Biomedical Research Centre Program; National Institutes of Medical Research; Australian National Health and Medical Research Council (NHMRC); Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; NHMRC [GNT1022922] FX This work was supported by the Medical Research Council, National Institute for Health Research Biomedical Research Centre Program, National Institutes of Medical Research, Australian National Health and Medical Research Council (NHMRC), and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The authors acknowledge the following personal awards: Medical Research Council Centenary Early Career Award (to G.C.), NHMRC Career Development Fellowship (to A. E.), NHMRC Senior Principal Research Fellowship (to D. I. G.), NHMRC Career Development Fellowship (to C. S. M.), NHMRC grant GNT1022922 (to K. L. R.), and NHMRC Principal Research Fellowship (to S.G.T.). NR 50 TC 27 Z9 27 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 19 PY 2013 VL 122 IS 12 BP 2052 EP 2061 DI 10.1182/blood-2013-02-482331 PG 10 WC Hematology SC Hematology GA 224AY UT WOS:000324854800015 PM 23929855 ER PT J AU Aoyama, K Saha, A Tolar, J Riddle, MJ Veenstra, RG Taylor, PA Blomhoff, R Panoskaltsis-Mortari, A Klebanoff, CA Socie, G Munn, DH Murphy, WJ Serody, JS Fulton, LM Teshima, T Chandraratna, RA Dmitrovsky, E Guo, YX Noelle, RJ Blazar, BR AF Aoyama, Kazutoshi Saha, Asim Tolar, Jakub Riddle, Megan J. Veenstra, Rachelle G. Taylor, Patricia A. Blomhoff, Rune Panoskaltsis-Mortari, Angela Klebanoff, Christopher A. Socie, Gerard Munn, David H. Murphy, William J. Serody, Jonathan S. Fulton, LeShara M. Teshima, Takanori Chandraratna, Roshantha A. Dmitrovsky, Ethan Guo, Yanxia Noelle, Randolph J. Blazar, Bruce R. TI Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; DENDRITIC CELLS; INTERFERON-GAMMA; FOXP3 EXPRESSION; RECEPTOR-ALPHA; TUMOR ACTIVITY; INTEGRIN; PATHWAY; PATHOPHYSIOLOGY; LYMPHOCYTES AB Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RAR alpha (dnRAR alpha) showed markedly diminished lethality. The dnRAR alpha transgenic T cells showed reduced Th1 differentiation and alpha 4 beta 7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties. C1 [Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub; Riddle, Megan J.; Veenstra, Rachelle G.; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. [Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub; Riddle, Megan J.; Veenstra, Rachelle G.; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN USA. [Blomhoff, Rune] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. [Klebanoff, Christopher A.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Socie, Gerard] Univ Paris 07, Hop St Louis, AP HP, Serv Hematol Greffe, Paris, France. [Socie, Gerard] INSERM, Unite U940, Paris, France. [Munn, David H.] Med Coll Georgia, Dept Pediat, Augusta, GA 30912 USA. [Munn, David H.] Med Coll Georgia, Immunotherapy Ctr, Augusta, GA 30912 USA. [Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Serody, Jonathan S.; Fulton, LeShara M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Teshima, Takanori] Hokkaido Univ, Grad Sch Med, Dept Hematol, Sapporo, Hokkaido, Japan. [Chandraratna, Roshantha A.] IO Therapeut Inc, Drug Discovery & Dev, Santa Ana, CA USA. [Dmitrovsky, Ethan] Norris Cotton Canc Ctr, Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Lebanon, NH USA. [Guo, Yanxia; Noelle, Randolph J.] Norris Cotton Canc Ctr, Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH USA. RP Blazar, BR (reprint author), Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. EM blaza001@umn.edu OI Serody, Jonathan/0000-0003-4568-1092; Tolar, Jakub/0000-0002-0957-4380 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Cancer Institute [R01 AI34495, R01 HL56067, P01 AI056299, R01-CA062275]; Mochida Memorial Foundation FX This work was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, and National Cancer Institute (R01 AI34495, R01 HL56067, and P01 AI056299) (B. R. B.) and R01-CA062275 and the Mochida Memorial Foundation (K. A.). E. D. is an American Cancer Society Professor supported by a generous gift from the F. M. Kirby Foundation. NR 50 TC 11 Z9 12 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 19 PY 2013 VL 122 IS 12 BP 2125 EP 2134 DI 10.1182/blood-2012-11-470252 PG 10 WC Hematology SC Hematology GA 224AY UT WOS:000324854800022 PM 23814022 ER PT J AU van Doremalen, N Bushmaker, T Munster, VJ AF van Doremalen, N. Bushmaker, T. Munster, V. J. TI Stability of Middle East respiratory syndrome coronavirus (MERS-CoV) under different environmental conditions SO EUROSURVEILLANCE LA English DT Article ID CLINICAL-FEATURES; INFECTION AB The stability of Middle East respiratory syndrome coronavirus (MERS-CoV) was determined at 20 degrees C - 40% relative humidity (RH); 30 degrees C - 30% RH and 30 degrees C - 80% RH. MERS-CoV was more stable at low temperature/low humidity conditions and could still be recovered after 48 hours. During aerosolisation of MERS-CoV, no decrease in stability was observed at 20 degrees C - 40% RH. These data suggest the potential of MERS-CoV to be transmitted via contact or fomite transmission due to prolonged environmental presence. C1 [van Doremalen, N.; Bushmaker, T.; Munster, V. J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP van Doremalen, N (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM vincent.munster@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX The authors would like to thank Drs. Bart Haagmans and Ron Fouchier, Erasmus Medical Center, Rotterdam, The Netherlands for providing MERS-CoV (isolate HCoV-EMC/2012), Emmie de Wit and Matt Lackemeyer for excellent technical assistance and helpful discussions, Anita Mora for assistance with the figures and Kui Shen for assistance with statistical analyses. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 19 TC 30 Z9 30 U1 0 U2 8 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD SEP 19 PY 2013 VL 18 IS 38 BP 7 EP 10 AR 20590 PG 4 WC Infectious Diseases SC Infectious Diseases GA 222JH UT WOS:000324726500002 ER PT J AU Noinaj, N Kuszak, AJ Gumbart, JC Lukacik, P Chang, HS Easley, NC Lithgow, T Buchanan, SK AF Noinaj, Nicholas Kuszak, Adam J. Gumbart, James C. Lukacik, Petra Chang, Hoshing Easley, Nicole C. Lithgow, Trevor Buchanan, Susan K. TI Structural insight into the biogenesis of beta-barrel membrane proteins SO NATURE LA English DT Article ID GRAM-NEGATIVE BACTERIA; OUTER-MEMBRANE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; MOLECULAR-DYNAMICS; ASSEMBLY MACHINERY; ESSENTIAL COMPONENT; BAM COMPLEX; MITOCHONDRIA; CHANNEL AB beta-barrel membrane proteins are essential for nutrient import, signalling, motility and survival. InGram-negative bacteria, the beta-barrel assembly machinery (BAM) complex is responsible for the biogenesis of beta-barrel membrane proteins, with homologous complexes found in mitochondria and chloroplasts. Here we describe the structure of BamA, the central and essential component of the BAM complex, from two species of bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. BamA consists of a large periplasmic domain attached to a 16-strand transmembrane beta-barrel domain. Three structural features shed light on the mechanism by which BamA catalyses beta-barrel assembly. First, the interior cavity is accessible in one BamA structure and conformationally closed in the other. Second, an exterior rim of the beta-barrel has a distinctly narrowed hydrophobic surface, locally destabilizing the outer membrane. And third, the beta-barrel can undergo lateral opening, suggesting a route from the interior cavity in BamA into the outer membrane. C1 [Noinaj, Nicholas; Kuszak, Adam J.; Chang, Hoshing; Easley, Nicole C.; Buchanan, Susan K.] NIDDK, NIH, Bethesda, MD 20892 USA. [Gumbart, James C.] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA. [Lukacik, Petra] Diamond Light Source Ltd, Oxford OX11 0DE, England. [Lithgow, Trevor] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. RP Buchanan, SK (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases; NIH [K22-AI100927, R01-GM67887]; Diamond Light Source; ARC Discovery Project [DP120101878]; ARC Linkage International Grant [LX0776170]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; Pittsburgh Supercomputing Center [RC2GM093307] FX We thank H. Bernstein and R. Ieva for providing JCM-166 cells, J. Beckwith and R. Misra for providing antibodies, and A. M. Stanley and T. Barnard for discussions and comments on the manuscript. N. N., A. J. K., N. C. E., H. C. and S. K. B. are supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. J. C. G. acknowledges support from the NIH under grants K22-AI100927 and R01-GM67887. P. L. is supported by a postdoctoral fellowship through the Diamond Light Source. T. L. is an Australian Research Council (ARC) Federation Fellow and acknowledges support from ARC Discovery Project (DP120101878) and ARC Linkage International Grant (LX0776170). We thank the respective staffs at the Southeast Regional Collaborative Access Team (SER-CAT) and General Medicine and Cancer Institute's Collaborative Access Team (GM/CA-CAT) beamlines at the Advanced Photon Source, Argonne National Laboratory and the Diamond Light Source for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38 (SER-CAT), and by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357 (GM/CA-CAT). Anton computer time was provided by the National Resource for Biomedical Supercomputing and the Pittsburgh Supercomputing Center through Grant RC2GM093307 from the NIH, using a machine donated by DE Shaw Research. NR 60 TC 144 Z9 146 U1 5 U2 94 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 19 PY 2013 VL 501 IS 7467 BP 385 EP + DI 10.1038/nature12521 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219XT UT WOS:000324545700038 PM 23995689 ER PT J AU Amato, R Scumaci, D D'Antona, L Iuliano, R Menniti, M Di Sanzo, M Faniello, MC Colao, E Malatesta, P Zingone, A Agosti, V Costanzo, FS Mileo, AM Paggi, MG Lang, F Cuda, G Lavia, P Perrotti, N AF Amato, R. Scumaci, D. D'Antona, L. Iuliano, R. Menniti, M. Di Sanzo, M. Faniello, M. C. Colao, E. Malatesta, P. Zingone, A. Agosti, V. Costanzo, F. S. Mileo, A. M. Paggi, M. G. Lang, F. Cuda, G. Lavia, P. Perrotti, N. TI Sgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells SO ONCOGENE LA English DT Article DE Sgk1; RANBP1; taxol sensitivity; mitotic microtubule stabilization ID INDUCIBLE PROTEIN-KINASE; CANCER-CELLS; BINDING PROTEIN-1; MAMMALIAN-CELLS; MITOTIC SPINDLE; DOWN-REGULATION; SERUM; ACTIVATION; PHOSPHORYLATION; IDENTIFICATION AB The serum- and glucocorticoid-regulated kinase (Sgk1) is essential for hormonal regulation of epithelial sodium channel-mediated sodium transport and is involved in the transduction of growth factor-dependent cell survival and proliferation signals. Growing evidence now points to Sgk1 as a key element in the development and/or progression of human cancer. To gain insight into the mechanisms through which Sgk1 regulates cell proliferation, we adopted a proteomic approach to identify up- or downregulated proteins after Sgk1-specific RNA silencing. Among several proteins, the abundance of which was found to be up- or downregulated upon Sgk1 silencing, we focused our attention of RAN-binding protein 1 (RANBP1), a major effector of the GTPase RAN. We report that Sgk1-dependent regulation of RANBP1 has functional consequences on both mitotic microtubule activity and taxol sensitivity of cancer cells. C1 [Amato, R.; D'Antona, L.; Menniti, M.; Perrotti, N.] Magna Graecia Univ Catanzaro, Dept Human Hlth, Catanzaro, Italy. [Scumaci, D.; Iuliano, R.; Di Sanzo, M.; Faniello, M. C.; Agosti, V.; Costanzo, F. S.; Cuda, G.] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy. [Iuliano, R.; Colao, E.; Malatesta, P.; Perrotti, N.] Univ Hosp, Unit Med Genet & Pathol, Policlin Mater Domini, Catanzaro, Italy. [Zingone, A.] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mileo, A. M.; Paggi, M. G.] Natl Canc Inst Regina Elena, Dept Dev Therapeut Programs, Rome, Italy. [Lang, F.] Univ Tubingen, Dept Physiol, Tubingen, Germany. [Lavia, P.] Univ Roma La Sapienza, CNR, IBPM Inst Mol Biol & Pathol, I-00185 Rome, Italy. RP Lavia, P (reprint author), Univ Roma La Sapienza, CNR, IBPM Inst Mol Biol & Pathol, Piazzale Aldo Moro 5, I-00185 Rome, Italy. EM patrizia.lavia@uniroma1.it; perrotti@unicz.it RI Cuda, Giovanni/F-5359-2012; OI Cuda, Giovanni/0000-0001-6313-1866; AGOSTI, Valter/0000-0001-6785-093X; FANIELLO, Concetta Maria/0000-0001-6938-2754; COSTANZO, Francesco Saverio/0000-0002-3096-9416; Lavia, Patrizia/0000-0003-3310-6701 FU Italian Association for Cancer Research (AIRC) [IG10164]; INAIL, CZ FX This work was supported in part by the Italian Association for Cancer Research (AIRC grant IG10164 to PL). RA was supported in part by INAIL, CZ. NR 42 TC 15 Z9 15 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 19 PY 2013 VL 32 IS 38 BP 4572 EP 4578 DI 10.1038/onc.2012.470 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 223SW UT WOS:000324831300013 PM 23108393 ER PT J AU Bao, JJ Huck, D Gunther, LK Sellers, JR Sakamoto, T AF Bao, Jianjun Huck, Daniel Gunther, Laura K. Sellers, James R. Sakamoto, Takeshi TI Actin Structure-Dependent Stepping of Myosin 5a and 10 during Processive Movement SO PLOS ONE LA English DT Article ID MOLECULE FLUORESCENCE POLARIZATION; HAND-OVER-HAND; F-ACTIN; BUNDLED ACTIN; COILED-COIL; NECK LENGTH; V MOLECULES; FILOPODIA; MOTOR; PROTEINS AB How myosin 10, an unconventional myosin, walks processively along actin is still controversial. Here, we used single molecule fluorescence techniques, TIRF and FIONA, to study the motility and the stepping mechanism of dimerized myosin 10 heavy-meromyosin-like fragment on both single actin filaments and two-dimensional F-actin rafts crosslinked by fascin or a-actinin. As a control, we also tracked and analyzed the stepping behavior of the well characterized processive motor myosin 5a. We have shown that myosin 10 moves processively along both single actin filaments and F-actin rafts with a step size of 31 nm. Moreover, myosin 10 moves more processively on fascin-F-actin rafts than on a-actinin-F-actin rafts, whereas myosin 5a shows no such selectivity. Finally, on fascin-F-actin rafts, myosin 10 has more frequent side steps to adjacent actin filaments than myosin 5a in the F-actin rafts. Together, these results reveal further single molecule features of myosin 10 on various actin structures, which may help to understand its cellular functions. C1 [Bao, Jianjun; Huck, Daniel; Gunther, Laura K.; Sakamoto, Takeshi] Wayne State Univ, Dept Phys & Astron, Detroit, MI 48202 USA. [Sakamoto, Takeshi] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48202 USA. [Sellers, James R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Sakamoto, T (reprint author), Wayne State Univ, Dept Phys & Astron, Detroit, MI 48202 USA. EM ee4243@wayne.edu OI Huck, Daniel/0000-0003-4221-8078 FU National Institutes of Health [HL089350]; Department of Physics and Astronomy, Wayne State University FX This work was supported by grants from the National Institutes of Health (career development grant HL089350 to TS), the start-up fund from the Department of Physics and Astronomy, Wayne State University (to TS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 7 Z9 7 U1 1 U2 12 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 SEP 19 PY 2013 VL 8 IS 9 AR e74936 DI 10.1371/journal.pone.0074936 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 223BC UT WOS:000324777300055 PM 24069366 ER PT J AU Yan, B Li, H Yang, XP Shao, JF Jang, M Guan, DG Zou, SG Van Waes, C Chen, Z Zhan, M AF Yan, Bin Li, Huai Yang, Xinping Shao, Jiaofang Jang, Minyoung Guan, Daogang Zou, Sige Van Waes, Carter Chen, Zhong Zhan, Ming TI Unraveling Regulatory Programs for NF-kappaB, p53 and MicroRNAs in Head and Neck Squamous Cell Carcinoma SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; GROWTH-FACTOR; IN-VIVO; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTORS; MATRIX FACTORIZATION; MALIGNANT PHENOTYPE; SIGNAL PATHWAYS; BINDING-SITES; CANCER AB In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant activation of NF-kappaB (NF-kappa B), other transcription factors and microRNAs, which promote tumor pathogenesis. However, how these factors and microRNAs interact to globally modulate gene expression and mediate oncogenesis is not fully understood. We devised a novel bioinformatics method to uncover interactive relationships between transcription factors or microRNAs and genes. This approach is based on matrix decomposition modeling under the joint constraints of sparseness and regulator-target connectivity, and able to integrate gene expression profiling and binding data of regulators. We employed this method to infer the gene regulatory networks in HNSCC. We found that the majority of the predicted p53 targets overlapped with those for NF-kappa B, suggesting that the two transcription factors exert a concerted modulation on regulatory programs in tumor cells. We further investigated the interrelationships of p53 and NF-kappa B with five additional transcription factors, AP1, CEBPB, EGR1, SP1 and STAT3, and microRNAs mir21 and mir34ac. The resulting gene networks indicate that interactions among NF-kappa B, p53, and the two miRNAs likely regulate progression of HNSCC. We experimentally validated our findings by determining expression of the predicted NF-kappa B and p53 target genes by siRNA knock down, and by examining p53 binding activity on promoters of predicted target genes in the tumor cell lines. Our results elucidating the cross-regulations among NF-kappa B, p53, and microRNAs provide insights into the complex regulatory mechanisms underlying HNSCC, and shows an efficient approach to inferring gene regulatory programs in biological complex systems. C1 [Yan, Bin; Shao, Jiaofang; Guan, Daogang] Hong Kong Baptist Univ, Dept Biol, Kowloon, Hong Kong, Peoples R China. [Li, Huai; Zou, Sige] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Yang, Xinping; Jang, Minyoung; Van Waes, Carter; Chen, Zhong] NIDCD, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Jang, Minyoung] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Jang, Minyoung] Pfizer, Bethesda, MD USA. [Zhan, Ming] Weill Cornell Med Coll, Methodist Hosp, Res Inst, Houston, TX USA. RP Yan, B (reprint author), Hong Kong Baptist Univ, Dept Biol, Kowloon, Hong Kong, Peoples R China. EM bin1999@hkbu.edu.hk; chenz@nidcd.nih.gov; mzhan@tmhs.org OI Guan, Daogang/0000-0003-1414-0189 FU National Institute on Aging, National Institutes of Health (NIH); Grant of Science Faculty of Hong Kong Baptist University [3840062, FRG2/12-13/066]; Intramural Research Programs of National Institute on Deafness and Communication Disorders, NIH [ZIA-DC-000074]; NIH; Pfizer FX Authors would like thank funding supports from: National Institute on Aging, National Institutes of Health (NIH) to MZ BY HL SZ; Grant of Science Faculty of Hong Kong Baptist University [3840062] and [FRG2/12-13/066] to BY; Intramural Research Programs of National Institute on Deafness and Communication Disorders, NIH [ZIA-DC-000074] to ZC CVW XY; Clinical Research Training Program by NIH and Pfizer to MJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 12 Z9 13 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 19 PY 2013 VL 8 IS 9 AR e73656 DI 10.1371/journal.pone.0073656 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 223BC UT WOS:000324777300017 PM 24069219 ER PT J AU Majdazari, A Stubbusch, J Muller, CM Hennchen, M Weber, M Deng, CX Mishina, Y Schutz, G Deller, T Rohrer, H AF Majdazari, Afsaneh Stubbusch, Jutta Mueller, Christian M. Hennchen, Melanie Weber, Marlen Deng, Chu-Xia Mishina, Yuji Schuetz, Guenther Deller, Thomas Rohrer, Hermann TI Dendrite Complexity of Sympathetic Neurons Is Controlled during Postnatal Development by BMP Signaling SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SUPERIOR CERVICAL-GANGLION; NERVE GROWTH-FACTOR; BONE MORPHOGENETIC PROTEINS; CONDITIONAL KNOCKOUT MICE; IN-VIVO; CHOLINERGIC DIFFERENTIATION; TRANSCRIPTION FACTOR; TGF-BETA/BMP; EXPRESSION; CELLS AB Dendrite development is controlled by the interplay of intrinsic and extrinsic signals affecting initiation, growth, and maintenance of complex dendrites. Bone morphogenetic proteins (BMPs) stimulate dendrite growth in cultures of sympathetic, cortical, and hippocampal neurons but it was unclear whether BMPs control dendrite morphology in vivo. Using a conditional knock-out strategy to eliminate Bmpr1a and Smad4 in immature noradrenergic sympathetic neurons we now show that dendrite length, complexity, and neuron cell body size are reduced in adult mice deficient of Bmpr1a. The combined deletion of Bmpr1a and Bmpr1b causes no further decrease in dendritic features. Sympathetic neurons devoid of Bmpr1a/1b display normal Smad1/5/8 phosphorylation, which suggests that Smad-independent signaling paths are involved in dendritic growth control downstream of BMPR1A/B. Indeed, in the Smad4 conditional knock-out dendrite and cell body size are not affected and dendrite complexity and number are increased. Together, these results demonstrate an in vivo function for BMPs in the generation of mature sympathetic neuron dendrites. BMPR1 signaling controls dendrite complexity postnatally during the major dendritic growth period of sympathetic neurons. C1 [Majdazari, Afsaneh; Stubbusch, Jutta; Hennchen, Melanie; Weber, Marlen; Rohrer, Hermann] Max Planck Inst Brain Res, Res Grp Dev Neurobiol, Frankfurt, Germany. [Mueller, Christian M.; Deller, Thomas] Goethe Univ Frankfurt, Ctr Neurosci, Inst Clin Neuroanat, D-60054 Frankfurt, Germany. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Schuetz, Guenther] German Canc Res Ctr, Dept Mol Biol Cell 1, D-69120 Heidelberg, Germany. RP Rohrer, H (reprint author), Max Planck Inst Brain Res, Res Grp Dev Neurobiol, Deutschordenstr 46, Frankfurt, Germany. EM Hermann.rohrer@brain.mpg.de RI deng, chuxia/N-6713-2016 FU Deutsche Forschungsgemeinschaft [RO 2551/1.1, DE 551/9-1] FX This work was supported by a grant from the Deutsche Forschungsgemeinschaft to H. R. (RO 2551/1.1) and T. D. (DE 551/9-1). We thank Uwe Ernsberger for comments on this paper, Pamela Lein for helpful suggestions, Domenico del Turco, Mirko Schmidt, and Leslie Huber for advice, and Sabine Stanzel, Julia Andres, and Melanie Pulver for excellent technical assistance. NR 83 TC 7 Z9 7 U1 0 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 SEP 18 PY 2013 VL 33 IS 38 BP 15132 EP 15144 DI 10.1523/JNEUROSCI.4748-12.2013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 220LW UT WOS:000324586500020 PM 24048844 ER PT J AU Brar, SS Petrovich, RM Williams, JG Mason, JM AF Brar, Sukhdev S. Petrovich, Robert M. Williams, Jason G. Mason, James M. TI Phosphorylation at Serines 216 and 221 Is Important for Drosophila HeT-A Gag Protein Stability SO PLOS ONE LA English DT Article ID CYCLOSPORINE-A; PERMEABILITY TRANSITION; IN-VIVO; CYCLOPHILIN; TELOMERES; VIRUS; TRANSPORT; KINASES; CELLS; HIV AB Telomeres from Drosophila appear to be very different from those of other organisms - in size and the mechanism of their maintenance. In the absence of the enzyme telomerase, Drosophila telomeres are maintained by retrotransposition of three elements, HeT-A, TART, and TAHRE, but details of their transposition mechanisms are not known. Here we characterized some biochemical characteristics of the HeT-A Gag protein encoded by the HeT-A element to understand this mechanism. The HeT-A Gag protein when overexpressed in S2 cells was localized to the nucleus but was resistant to high salt, detergents and nuclease extraction treatments. Analysis of the HeT-A Gag protein by tandem mass spectrophotometry revealed that serines 216 and 221 are phosphorylated. Substituting these serines with alanine or aspartic acid by site-directed mutagenesis did not result in any changes in HeT-A Gag translocation across the nucleus, suggesting that phosphorylation of these sites is not associated with HeT-A Gag translocation, but time course experiments showed that these phosphorylation sites are important for Gag-protein stability. C1 [Brar, Sukhdev S.; Mason, James M.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Petrovich, Robert M.; Williams, Jason G.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Mason, JM (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM masonj@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was funded by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no current external funding sources for this study. NR 48 TC 0 Z9 0 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2013 VL 8 IS 9 AR e75381 DI 10.1371/journal.pone.0075381 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 221YD UT WOS:000324695900113 PM 24058682 ER PT J AU Verhein, KC Salituro, FG Ledeboer, MW Fryer, AD Jacoby, DB AF Verhein, Kirsten C. Salituro, Francesco G. Ledeboer, Mark W. Fryer, Allison D. Jacoby, David B. TI Dual p38/JNK Mitogen Activated Protein Kinase Inhibitors Prevent Ozone-Induced Airway Hyperreactivity in Guinea Pigs SO PLOS ONE LA English DT Article ID P38 MAP KINASE; PULMONARY PARASYMPATHETIC NERVES; M2 MUSCARINIC RECEPTORS; MAJOR BASIC-PROTEIN; CYTOKINE PRODUCTION; SIGNALING PATHWAYS; EPITHELIAL-CELLS; TERMINAL KINASE; SMOOTH-MUSCLE; HYPERRESPONSIVENESS AB Ozone exposure causes airway hyperreactivity and increases hospitalizations resulting from pulmonary complications. Ozone reacts with the epithelial lining fluid and airway epithelium to produce reactive oxygen species and lipid peroxidation products, which then activate cell signaling pathways, including the mitogen activated protein kinase (MAPK) pathway. Both p38 and c-Jun NH2 terminal kinase (JNK) are MAPK family members that are activated by cellular stress and inflammation. To test the contribution of both p38 and JNK MAPK to ozone-induced airway hyperreactivity, guinea pigs were pretreated with dual p38 and JNK MAPK inhibitors (30 mg/kg, ip) 60 minutes before exposure to 2 ppm ozone or filtered air for 4 hours. One day later airway reactivity was measured in anesthetized animals. Ozone caused airway hyperreactivity one day post-exposure, and blocking p38 and JNK MAPK completely prevented ozone-induced airway hyperreactivity. Blocking p38 and JNK MAPK also suppressed parasympathetic nerve activity in air exposed animals, suggesting p38 and JNK MAPK contribute to acetylcholine release by airway parasympathetic nerves. Ozone inhibited neuronal M-2 muscarinic receptors and blocking both p38 and JNK prevented M-2 receptor dysfunction. Neutrophil influx into bronchoalveolar lavage was not affected by MAPK inhibitors. Thus p38 and JNK MAPK mediate ozone-induced airway hyperreactivity through multiple mechanisms including prevention of neuronal M-2 receptor dysfunction. C1 [Verhein, Kirsten C.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Fryer, Allison D.; Jacoby, David B.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Salituro, Francesco G.; Ledeboer, Mark W.] Vertex Pharmaceut Inc, Cambridge, MA USA. RP Verhein, KC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM verheinkc@niehs.nih.gov RI Fryer, Allison/F-2420-2014; OI Fryer, Allison/0000-0003-1712-9831; Jacoby, David/0000-0003-2195-9512 FU American Heart Association [0810148Z]; National Institutes of Health [HL55543, ES014601, HL54659, HL071795, RR023424] FX This work was funded by the American Heart Association 0810148Z (to KCV) and the National Institutes of Health HL55543 (to ADF), ES014601 (to ADF), HL54659 (to DBJ), HL071795 (to DBJ), and RR023424 (to DBJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 47 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2013 VL 8 IS 9 AR e75351 DI 10.1371/journal.pone.0075351 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 221YD UT WOS:000324695900109 PM 24058677 ER PT J AU Comeau, DC Dogan, RI Ciccarese, P Cohen, KB Krallinger, M Leitner, F Lu, ZY Peng, YF Rinaldi, F Torii, M Valencia, A Verspoor, K Wiegers, TC Wu, CH Wilbur, WJ AF Comeau, Donald C. Dogan, Rezarta Islamaj Ciccarese, Paolo Cohen, Kevin Bretonnel Krallinger, Martin Leitner, Florian Lu, Zhiyong Peng, Yifan Rinaldi, Fabio Torii, Manabu Valencia, Alfonso Verspoor, Karin Wiegers, Thomas C. Wu, Cathy H. Wilbur, W. John TI BioC: a minimalist approach to interoperability for biomedical text processing SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID COMPARATIVE TOXICOGENOMICS DATABASE; INFORMATION EXTRACTION; RESOURCE; BIOLOGY AB A vast amount of scientific information is encoded in natural language text, and the quantity of such text has become so great that it is no longer economically feasible to have a human as the first step in the search process. Natural language processing and text mining tools have become essential to facilitate the search for and extraction of information from text. This has led to vigorous research efforts to create useful tools and to create humanly labeled text corpora, which can be used to improve such tools. To encourage combining these efforts into larger, more powerful and more capable systems, a common interchange format to represent, store and exchange the data in a simple manner between different language processing systems and text mining tools is highly desirable. Here we propose a simple extensible mark-up language format to share text documents and annotations. The proposed annotation approach allows a large number of different annotations to be represented including sentences, tokens, parts of speech, named entities such as genes or diseases and relationships between named entities. In addition, we provide simple code to hold this data, read it from and write it back to extensible mark-up language files and perform some sample processing. We also describe completed as well as ongoing work to apply the approach in several directions. C1 [Comeau, Donald C.; Dogan, Rezarta Islamaj; Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Ciccarese, Paolo] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ciccarese, Paolo] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Cohen, Kevin Bretonnel] Univ Colorado Denver, Sch Med, Ctr Computat Pharmacol, Aurora, CO 80045 USA. [Krallinger, Martin; Leitner, Florian; Valencia, Alfonso] Spanish Natl Canc Res Ctr, Struct & Computat Biol Grp, E-28029 Madrid, Spain. [Peng, Yifan; Torii, Manabu; Wu, Cathy H.] Univ Delaware, Dept Comp & Informat Sci, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, CH-8050 Zurich, Switzerland. [Verspoor, Karin] Univ Melbourne, Victoria Res Lab, Natl ICT Australia NICTA, Parkville, Vic 3010, Australia. [Wiegers, Thomas C.] N Carolina State Univ, Dept Biol, Raleigh, NC 27695 USA. RP Dogan, RI (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM Rezarta.Islamaj@nih.gov RI Valencia, Alfonso/I-3127-2015; Verspoor, Karin/G-6034-2016; Peng, Yifan/M-1605-2016; OI Valencia, Alfonso/0000-0002-8937-6789; Rinaldi, Fabio/0000-0001-5718-5462; Verspoor, Karin/0000-0002-8661-1544; Peng, Yifan/0000-0001-9309-8331; Leitner, Florian/0000-0003-4458-504X; Torii, Manabu/0000-0002-4825-0696 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine; National Library of Medicine [G08LM010720]; National Institutes of Health [NIH 5R01 LM009254-07, NIH 5R01 LM008111-08]; National Science Foundation [DBI-1062520]; Swiss National Science Foundation [105315_130558/1] FX Intramural Research Program of the National Institutes of Health, National Library of Medicine to D. C. C., R. I. D., Z.L. and W.J.W; National Library of Medicine [G08LM010720] to C. H. W.; National Institutes of Health [NIH 5R01 LM009254-07, NIH 5R01 LM008111-08] to K. B. C.; National Science Foundation [DBI-1062520] to Y.P., M. T. and C. H. W.; and Swiss National Science Foundation [105315_130558/1] to F.R. NR 64 TC 12 Z9 12 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD SEP 18 PY 2013 AR bat064 DI 10.1093/database/bat064 PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 220XL UT WOS:000324620500001 ER PT J AU Chen, RJ Wang, CC Meng, X Chen, HL Thach, TQ Wong, CM Kan, HD AF Chen, Renjie Wang, Cuicui Meng, Xia Chen, Honglei Thuan Quoc Thach Wong, Chit-Ming Kan, Haidong TI Both low and high temperature may increase the risk of stroke mortality SO NEUROLOGY LA English DT Article ID HEART-DISEASE MORTALITY; AMBIENT-TEMPERATURE; AIR-POLLUTION; EPIDEMIOLOGIC EVIDENCE; TIME-SERIES; OUTDOOR TEMPERATURE; HOSPITAL ADMISSIONS; NONLINEAR MODELS; GLOBAL VARIATION; WEATHER AB Objective: To examine temperature in relation to stroke mortality in a multicity time series study in China. Methods: We obtained data on daily temperature and mortality from 8 large cities in China. We used quasi-Poisson generalized additive models and distributed lag nonlinear models to estimate the accumulative effects of temperature on stroke mortality across multiple days, adjusting for long-term and seasonal trends, day of the week, air pollution, and relative humidity. We applied the Bayesian hierarchical model to pool city-specific effect estimates. Results: Both cold and hot temperatures were associated with increased risk of stroke mortality. The potential effect of cold temperature might last more than 2 weeks. The pooled relative risks of extreme cold (first percentile of temperature) and cold (10th percentile of temperature) temperatures over lags 0-14 days were 1.39 (95% posterior intervals [PI] 1.18-1.64) and 1.11 (95% PI 1.06-1.17), compared with the 25th percentile of temperature. In contrast, the effect of hot temperature was more immediate. The relative risks of stroke mortality over lags 0-3 days were 1.06 (95% PI 1.02-1.10) for extreme hot temperature (99th percentile of temperature) and 1.14 (95% PI 1.05-1.24) for hot temperature (90th percentile of temperature), compared with the 75th percentile of temperature. Conclusions: This study showed that both cold and hot temperatures were associated with increased risk of stroke mortality in China. Our findings may have important implications for stroke prevention in China. C1 [Chen, Renjie; Wang, Cuicui; Meng, Xia; Kan, Haidong] Fudan Univ, Res Inst Changing Global Environm, Sch Publ Hlth, Key Lab Publ Hlth Safety,Minist Educ, Shanghai 200433, Peoples R China. [Chen, Renjie; Wang, Cuicui; Meng, Xia; Kan, Haidong] Fudan Univ, Fudan Tyndall Ctr, Shanghai 200433, Peoples R China. [Chen, Renjie; Wang, Cuicui; Meng, Xia; Kan, Haidong] Fudan Univ, Shanghai Key Lab Atmospher Particle Pollut & Prev, Shanghai 200433, Peoples R China. [Chen, Honglei] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Thuan Quoc Thach; Wong, Chit-Ming] Univ Hong Kong, Sch Publ Hlth, Dept Community Med, Hong Kong, Hong Kong, Peoples R China. RP Kan, HD (reprint author), Fudan Univ, Res Inst Changing Global Environm, Sch Publ Hlth, Key Lab Publ Hlth Safety,Minist Educ, Shanghai 200433, Peoples R China. EM haidongkan@gmail.com OI , Cuicui/0000-0002-0540-873X; Chen, Honglei/0000-0003-3446-7779 FU National Basic Research Program (973 program) of China [2011CB503802]; Gong-Yi Program of China Ministry of Environmental Protection [201209008]; National Natural Science Foundation of China [81222036]; Shanghai Municipal Committee of Science and Technology [12dz1202602]; Shanghai Health Bureau [GWDTR201212]; NIH, the National Institute of Environmental Health Sciences FX Supported by the National Basic Research Program (973 program) of China (2011CB503802), Gong-Yi Program of China Ministry of Environmental Protection (201209008), National Natural Science Foundation of China (81222036), Shanghai Municipal Committee of Science and Technology (12dz1202602), and Shanghai Health Bureau (GWDTR201212). Dr. Honglei Chen is supported by the Intramural Program of NIH, the National Institute of Environmental Health Sciences. NR 40 TC 33 Z9 36 U1 4 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 17 PY 2013 VL 81 IS 12 BP 1064 EP 1070 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EK UT WOS:000330767900011 PM 23946311 ER PT J AU Tycko, R AF Tycko, Robert TI NMR at Low and Ultra low Temperatures SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID DYNAMIC NUCLEAR-POLARIZATION; SOLID-STATE NMR; VILLIN HEADPIECE SUBDOMAIN; OPTICALLY PUMPED NMR; GAAS QUANTUM-WELLS; ANGLE-SPINNING NMR; LEVEL FILLING NU=1; MAGNETIC-RESONANCE; ELECTRONIC STATES; GALLIUM-ARSENIDE AB Solid state nuclear magnetic resonance (NMR) measurements at low temperatures have been common in physical sciences for many years and are becoming increasingly important in studies of biomolecular systems. This Account reviews a diverse set of projects from my laboratory, dating back to the early 19905, that illustrate the motivations for low-temperature solid state NMR, the types of information that are available from the measurements, and likely directions for future research. These projects include NMR studies of both physical and biological systems, performed at low (cooled with nitrogen, down to 77 K) and ultralow (cooled with helium, below 77 K) temperatures, and performed with and without magic-angle spinning (MAS). NMR studies of physical systems often focus on phenomena that occur only at low temperatures. Two examples from my laboratory are studies of molecular rotation and orientational ordering in solid C-60 at low temperatures and studies of unusual electronic states, called skyrmions, in two-dimensionally confined electron systems within semiconductor quantum wells. To study quantum wells, we used optical pumping of nuclear spin polarizations to enhance their NMR signals. The optical pumping phenomenon exists only at ultralow temperatures. In studies of biomolecular systems, low-temperature NMR has several motivations. In some cases, low temperatures suppress molecular tumbling, thereby permitting solid state NMR measurements on soluble proteins. Studies of AIDS-related peptide/antibody complexes illustrate this effect. In other cases, low temperatures suppress conformational exchange, thereby permitting quantitation of conformational distributions. Studies of chemically denatured states of the model protein HP35 illustrate this effect. Low temperatures and rapid freeze-quenching can also be used to trap transient intermediate states in a non-equilibrium kinetic process, as shown in studies of a transient intermediate in the rapid folding pathway of HP35. NMR sensitivity generally increases with decreasing sample temperature. Therefore, it can be useful to carry out experiments at the lowest possible temperatures, particularly in studies of biomolecular systems in frozen solutions. However, solid state NMR studies of biomolecular systems generally require rapid MAS. A novel MAS NMR probe design that uses nitrogen gas for sample spinning and cold helium only for sample cooling allows a wide variety of solid state NMR measurements to be performed on biomolecular systems at 20-25 K, where signals are enhanced by factors of 12-15 relative to measurements at room temperature. MAS NMR at ultralow temperatures also facilitates dynamic nuclear polarization (DNP), allowing sizeable additional signal enhancements and large absolute NMR signal amplitudes with relatively low microwave powers. Current research in my laboratory seeks to develop and exploit DNP-enhanced MAS NMR at ultralow temperatures, for example, in studies of transient intermediates in protein folding and aggregation processes and studies of peptide/protein complexes that can be prepared only at low concentrations. C1 [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; NIH Intramural AIDS Targeted Antiviral Program FX Work described in this Account was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and by the NIH Intramural AIDS Targeted Antiviral Program. I thank current and past members of my laboratory for their many contributions to this work. Data shown in the figures were acquired by Gary Dabbagh, Sean Barrett, Simon Sharpe, Kan-Nian Hu, and Kent Thurber. NR 46 TC 31 Z9 31 U1 7 U2 82 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 EI 1520-4898 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD SEP 17 PY 2013 VL 46 IS 9 BP 1923 EP 1932 DI 10.1021/ar300358z PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 294BO UT WOS:000330017600003 PM 23470028 ER PT J AU DellaValle, CT Wheeler, DC Deziel, NC De Roos, AJ Cerhan, JR Cozen, W Severson, RK Flory, AR Locke, SJ Colt, JS Hartge, P Ward, MH AF DellaValle, Curt T. Wheeler, David C. Deziel, Nicole C. De Roos, Anneclaire J. Cerhan, James R. Cozen, Wendy Severson, Richard K. Flory, Abigail R. Locke, Sarah J. Colt, Joanne S. Hartge, Patricia Ward, Mary H. TI Environmental Determinants of Polychlorinated Biphenyl Concentrations in Residential Carpet Dust SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID IN-HOUSE DUST; POLYCYCLIC AROMATIC-HYDROCARBONS; POLYBROMINATED DIPHENYL ETHERS; PASSIVE AIR SAMPLERS; INDOOR AIR; SPATIAL-DISTRIBUTION; INDUSTRIAL-AREA; HUMAN EXPOSURE; PCBS; URBAN AB Polychlorinated biphenyls (PCBs), banned in the United Sates in the fate 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of five PCB congeners (105, 138, 153, 170, and 180) in carpet dust collected between 1998 and 2000 from 1187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad; percentage of developed land; number of industrial facilities within 2 km of residences; and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCB levels [all congeners < maximum practical qnantitation limit.(MPQL) vs at least one congener >= MPQL to < median concentration vs at least one congener > median concentration] were positively associated with either percentage of developed land [odds ratio (OR) range 1.01-1.04 for each percentage increase] or population density (OR 1.08 for every 1000/mi(2)) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations. C1 [DellaValle, Curt T.; Deziel, Nicole C.; Locke, Sarah J.; Colt, Joanne S.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23219 USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Cerhan, James R.] Mayo Clin, Div Epidemiol, Coll Med, Rochester, MN 55905 USA. [Cozen, Wendy] Univ So Calif, Los Angeles, CA 90089 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Flory, Abigail R.] WESTAT Corp, Rockville, MD 20850 USA. [Hartge, Patricia] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP DellaValle, CT (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM dellavallec@mail.nih.gov OI Cerhan, James/0000-0002-7482-178X FU National Cancer Institute's Surveillance, Epidemiology and End Results Program [N01-PC-35139, N01 PC065064, NO1-PC-67008, N01-PC-71105, N01-PC67009, P01 CA17054, P30 ES07048, P30 CA014089]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02] FX We thank Lonn Tremblay (Information Management Services, Inc., Silver Spring, MD) for assistance in data processing and preparation. We also thank Laura Gold, Robert Mathes, Hozefa Divan, and Jim Giglierano and his staff at the Iowa Geologic Survey for their efforts in ground checking residential locations. This study was supported by the National Cancer Institute's Surveillance, Epidemiology and End Results Program under Contracts N01-PC-35139, N01 PC065064, NO1-PC-67008, N01-PC-71105, N01-PC67009, P01 CA17054, P30 ES07048, and P30 CA014089 and by the Centers for Disease Control and Prevention's National Program of Cancer Registries, under Agreement U55/CCR921930-02. NR 59 TC 7 Z9 7 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD SEP 17 PY 2013 VL 47 IS 18 BP 10405 EP 10414 DI 10.1021/es401447w PG 10 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 295DE UT WOS:000330096000042 PM 23952055 ER PT J AU Corrotte, M Almeida, PE Tam, C Castro-Gomes, T Fernandes, MC Millis, BA Cortez, M Miller, H Song, WX Maugel, TK Andrews, NW AF Corrotte, Matthias Almeida, Patricia E. Tam, Christina Castro-Gomes, Thiago Fernandes, Maria Cecilia Millis, Bryan A. Cortez, Mauro Miller, Heather Song, Wenxia Maugel, Timothy K. Andrews, Norma W. TI Caveolae internalization repairs wounded cells and muscle fibers SO ELIFE LA English DT Article ID PLASMA-MEMBRANE-REPAIR; CLATHRIN-INDEPENDENT ENDOCYTOSIS; ACID SPHINGOMYELINASE GENE; MUSCULAR-DYSTROPHY; ENDOPLASMIC-RETICULUM; LIPID RAFTS; VESICLES; CERAMIDE; DYNAMIN; EXOCYTOSIS AB Rapid repair of plasma membrane wounds is critical for cellular survival. Muscle fibers are particularly susceptible to injury, and defective sarcolemma resealing causes muscular dystrophy. Caveolae accumulate in dystrophic muscle fibers and caveolin and cavin mutations cause muscle pathology, but the underlying mechanism is unknown. Here we show that muscle fibers and other cell types repair membrane wounds by a mechanism involving Ca2+-triggered exocytosis of lysosomes, release of acid sphingomyelinase, and rapid lesion removal by caveolar endocytosis. Wounding or exposure to sphingomyelinase triggered endocytosis and intracellular accumulation of caveolar vesicles, which gradually merged into larger compartments. The pore-forming toxin SLO was directly visualized entering cells within caveolar vesicles, and depletion of caveolin inhibited plasma membrane resealing. Our findings directly link lesion removal by caveolar endocytosis to the maintenance of plasma membrane and muscle fiber integrity, providing a mechanistic explanation for the muscle pathology associated with mutations in caveolae proteins. C1 [Corrotte, Matthias; Almeida, Patricia E.; Tam, Christina; Castro-Gomes, Thiago; Fernandes, Maria Cecilia; Cortez, Mauro; Miller, Heather; Song, Wenxia; Andrews, Norma W.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Almeida, Patricia E.] CAPES Fdn, Brazil Minist Educ, Brasilia, DF, Brazil. [Millis, Bryan A.] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD USA. [Maugel, Timothy K.] Univ Maryland, Lab Biol Ultrastruct, College Pk, MD 20742 USA. RP Andrews, NW (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. EM andrewsn@umd.edu RI Gomes, Thiago/H-5567-2015; Cortez Veliz, Mauro Javier/J-3119-2012 OI Cortez Veliz, Mauro Javier/0000-0002-4935-1931 FU National Institutes of Health [R01 GM064625, R37 AI34867]; National Council for Scientific and Technological Developement - Ciencia sem Fronteiras Program, Brazil [200890/2012-3]; CAPES Foundation, Ministry of Education of Brazil FX National Institutes of Health R01 GM064625 Norma W Andrews; National Institutes of Health R37 AI34867 Norma W Andrews; National Council for Scientific and Technological Developement - Ciencia sem Fronteiras Program, Brazil 200890/2012-3 Thiago Castro-Gomes; CAPES Foundation, Ministry of Education of Brazil Patricia E Almeida NR 66 TC 33 Z9 33 U1 2 U2 9 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 17 PY 2013 VL 2 AR e00926 DI 10.7554/eLife.00926 PG 30 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274SS UT WOS:000328627100001 PM 24052812 ER PT J AU Sabater-Lleal, M Huang, J Chasman, D Naitza, S Dehghan, A Johnson, AD Teumer, A Reiner, AP Folkersen, L Basu, S Rudnicka, AR Trompet, S Malarstig, A Baumert, J Bis, JC Guo, XQ Hottenga, JJ Shin, SY Lopez, LM Lahti, J Tanaka, T Yanek, LR Oudot-Mellakh, T Wilson, JF Navarro, P Huffman, JE Zemunik, T Redline, S Mehra, R Pulanic, D Rudan, I Wright, AF Kolcic, I Polasek, O Wild, SH Campbell, H Curb, JD Wallace, R Liu, SM Eaton, CB Becker, DM Becker, LC Bandinelli, S Raikkonen, K Widen, E Palotie, A Fornage, M Green, D Gross, M Davies, G Harris, SE Liewald, DC Starr, JM Williams, FMK Grant, PJ Spector, TD Strawbridge, RJ Silveira, A Sennblad, B Rivadeneira, F Uitterlinden, AG Franco, OH Hofman, A van Dongen, J Willemsen, G Boomsma, DI Yao, J Jenny, NS Haritunians, T McKnight, B Lumley, T Taylor, KD Rotter, JI Psaty, BM Peters, A Gieger, C Illig, T Grotevendt, A Homuth, G Volzke, H Kocher, T Goel, A Franzosi, MG Seedorf, U Clarke, R Steri, M Tarasov, KV Sanna, S Schlessinger, D Stott, DJ Sattar, N Buckley, BM Rumley, A Lowe, GD McArdle, WL Chen, MH Tofler, GH Song, J Boerwinkle, E Folsom, AR Rose, LM Franco-Cereceda, A Teichert, M Ikram, MA Mosley, TH Bevan, S Dichgans, M Rothwell, PM Sudlow, CLM Hopewell, JC Chambers, JC Saleheen, D Kooner, JS Danesh, J Nelson, CP Erdmann, J Reilly, MP Kathiresan, S Schunkert, H Morange, PE Ferrucci, L Eriksson, JG Jacobs, D Deary, IJ Soranzo, N Witteman, JCM de Geus, EJC Tracy, RP Hayward, C Koenig, W Cucca, F Jukema, JW Eriksson, P Seshadri, S Markus, HS Watkins, H Samani, NJ Wallaschofski, H Smith, NL Tregouet, D Ridker, PM Tang, WH Strachan, DP Hamsten, A O'Donnell, CJ AF Sabater-Lleal, Maria Huang, Jie Chasman, Daniel Naitza, Silvia Dehghan, Abbas Johnson, Andrew D. Teumer, Alexander Reiner, Alex P. Folkersen, Lasse Basu, Saonli Rudnicka, Alicja R. Trompet, Stella Malarstig, Anders Baumert, Jens Bis, Joshua C. Guo, Xiuqing Hottenga, Jouke J. Shin, So-Youn Lopez, Lorna M. Lahti, Jari Tanaka, Toshiko Yanek, Lisa R. Oudot-Mellakh, Tiphaine Wilson, James F. Navarro, Pau Huffman, Jennifer E. Zemunik, Tatijana Redline, Susan Mehra, Reena Pulanic, Drazen Rudan, Igor Wright, Alan F. Kolcic, Ivana Polasek, Ozren Wild, Sarah H. Campbell, Harry Curb, J. David Wallace, Robert Liu, Simin Eaton, Charles B. Becker, Diane M. Becker, Lewis C. Bandinelli, Stefania Raikkonen, Katri Widen, Elisabeth Palotie, Aarno Fornage, Myriam Green, David Gross, Myron Davies, Gail Harris, Sarah E. Liewald, David C. Starr, John M. Williams, Frances M. K. Grant, Peter J. Spector, Timothy D. Strawbridge, Rona J. Silveira, Angela Sennblad, Bengt Rivadeneira, Fernando Uitterlinden, Andre G. Franco, Oscar H. Hofman, Albert van Dongen, Jenny Willemsen, Gonneke Boomsma, Dorret I. Yao, Jie Jenny, Nancy Swords Haritunians, Talin McKnight, Barbara Lumley, Thomas Taylor, Kent D. Rotter, Jerome I. Psaty, Bruce M. Peters, Annette Gieger, Christian Illig, Thomas Grotevendt, Anne Homuth, Georg Voelzke, Henry Kocher, Thomas Goel, Anuj Franzosi, Maria Grazia Seedorf, Udo Clarke, Robert Steri, Maristella Tarasov, Kirill V. Sanna, Serena Schlessinger, David Stott, David J. Sattar, Naveed Buckley, Brendan M. Rumley, Ann Lowe, Gordon D. McArdle, Wendy L. Chen, Ming-Huei Tofler, Geoffrey H. Song, Jaejoon Boerwinkle, Eric Folsom, Aaron R. Rose, Lynda M. Franco-Cereceda, Anders Teichert, Martina Ikram, M. Arfan Mosley, Thomas H. Bevan, Steve Dichgans, Martin Rothwell, Peter M. Sudlow, Cathie L. M. Hopewell, Jemma C. Chambers, John C. Saleheen, Danish Kooner, Jaspal S. Danesh, John Nelson, Christopher P. Erdmann, Jeanette Reilly, Muredach P. Kathiresan, Sekar Schunkert, Heribert Morange, Pierre-Emmanuel Ferrucci, Luigi Eriksson, Johan G. Jacobs, David Deary, Ian J. Soranzo, Nicole Witteman, Jacqueline C. M. de Geus, Eco J. C. Tracy, Russell P. Hayward, Caroline Koenig, Wolfgang Cucca, Francesco Jukema, J. Wouter Eriksson, Per Seshadri, Sudha Markus, Hugh S. Watkins, Hugh Samani, Nilesh J. Wallaschofski, Henri Smith, Nicholas L. Tregouet, David Ridker, Paul M. Tang, Weihong Strachan, David P. Hamsten, Anders O'Donnell, Christopher J. CA VTE Consortium STROKE Consortium WTCCC2 CD4 Consortium CARDIoGRAM Consortium TI Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease SO CIRCULATION LA English DT Article DE cardiovascular diseases; fibrinogen; gene expression; genome-wide association study ID CORONARY-HEART-DISEASE; INDIVIDUAL PARTICIPANT METAANALYSIS; RISK-FACTORS; MYOCARDIAL-INFARCTION; GENE-EXPRESSION; ARTERY-DISEASE; HEMOSTASIS; GENOTYPES; VARIANTS; HEALTH AB Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism. C1 [Sabater-Lleal, Maria; Malarstig, Anders; Strawbridge, Rona J.; Silveira, Angela; Sennblad, Bengt; Hofman, Albert] Karolinska Inst, Karolinska Univ Hosp Solna, Cardiovasc Genet & Genom Grp, Atherosclerosis Res Unit,Dept Med, Stockholm, Sweden. Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. Univ Oxford, Dept Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Franzosi, Maria Grazia] IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Med, Milan, Italy. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, D-48149 Munster, Germany. [Huang, Jie; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Huang, Jie; Johnson, Andrew D.; O'Donnell, Christopher J.] US Natl Heart Lung & Blood Inst, Div Intramural Res, Bethesda, MD USA. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Chen, Ming-Huei] Boston Univ, Dept Biostat, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chasman, Daniel; Rose, Lynda M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [Naitza, Silvia; Steri, Maristella; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Taylor, Kent D.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Ikram, M. Arfan; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus MC Univ Med Ctr, Dept Radiol & Neurol, Rotterdam, Netherlands. [Dehghan, Abbas; Rivadeneira, Fernando; Uitterlinden, Andre G.; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C. M.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Teumer, Alexander; Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Watkins, Hugh] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Sect Study Hlth Pomerania SHIP, Greifswald, Germany. [Kocher, Thomas] Univ Med Greifswald, Policlin Restorat Dent Periodontol & Endodontol, Dept Periodontol, Greifswald, Germany. [Rumley, Ann] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Div Epidemiol, Sch Publ Hlth, Houston, TX 77030 USA. [Green, David] Northwestern Univ, Div Hematol Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. [Gross, Myron] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Stott, David J.] Univ Glasgow, Sch Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [McKnight, Barbara; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Taylor, Kent D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Lopez, Lorna M.; Davies, Gail; Harris, Sarah E.; Liewald, David C.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Harris, Sarah E.] Univ Edinburgh, Med Genet Sect, Mol Med Ctr, Inst Genet & Mol Med,Western Gen Hosp, Edinburgh, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Western Gen Hosp, Geriatr Med Unit, Edinburgh, Midlothian, Scotland. [Morange, Pierre-Emmanuel] Aix Marseille Univ, INSERM, NORT, UMR S 1062, Marseille, France. [Tregouet, David] INSERM, UMR S 937, Paris, France. [Tregouet, David] Univ Paris 06, ICAN Inst Cardiometab & Nutr, Paris, France. [Zemunik, Tatijana] Univ Split, Fac Med, Split, Croatia. [Pulanic, Drazen] Clin Hosp Ctr Zagreb, Div Hematol, Dept Med, Zagreb, Croatia. [Pulanic, Drazen] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Huffman, Jennifer E.; Wright, Alan F.; Hayward, Caroline] Western Gen Hosp, Inst Genet & Mol Med, Human Genet Unit, MRC, Edinburgh EH4 2XU, Midlothian, Scotland. [Navarro, Pau] MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Sch Med, Dept Publ Hlth, Split, Croatia. [Wilson, James F.; Wild, Sarah H.; Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Rudnicka, Alicja R.; Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Rumley, Ann; Lowe, Gordon D.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Baumert, Jens; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Peters, Annette] Munich Heart Alliance, Munich, Germany. [Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Tanaka, Toshiko] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Basu, Saonli] Azienda Sanit Firenze, Unit, Florence, Italy. [Shin, So-Youn] Wellcome Trust Sanger Inst, Hinxton, England. [Williams, Frances M. K.; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Grant, Peter J.] Univ Leeds, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England. [Shin, So-Youn] Univ Bristol, MRC, Ctr CAiTE, Sch Social & Community Med, Bristol, Avon, England. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Peters, Annette] Wellcome Trust Sanger Inst, Cambridge, England. [Peters, Annette] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Peters, Annette] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Peters, Annette] Univ Cent Hosp, Helsinki, Finland. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Hottenga, Jouke J.; van Dongen, Jenny; Willemsen, Gonneke; Boomsma, Dorret I.; de Geus, Eco J. C.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Hottenga, Jouke J.; van Dongen, Jenny; Willemsen, Gonneke; Boomsma, Dorret I.; de Geus, Eco J. C.] Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Folsom, Aaron R.; Tang, Weihong] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Song, Jaejoon] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS USA. [Yao, Jie; Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Guo, Xiuqing] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90509 USA. [Tracy, Russell P.] Univ Vermont, Ctr Clin & Translat Sci, Burlington, VT 05405 USA. [Jenny, Nancy Swords] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Rumley, Ann] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rumley, Ann] Fred Hutchinson Canc Res Ctr, Div Hlth Sci, Seattle, WA 98104 USA. [Eaton, Charles B.] Brown Univ, Ctr Primary Care & Prevent, Alpert Med Sch, Providence, RI 02912 USA. [Liu, Simin] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA 90024 USA. [Liu, Simin] Univ Calif Los Angeles, Program Genom & Nutr, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Liu, Simin] Univ Calif Los Angeles, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA. [Wallace, Robert] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Wallace, Robert] Univ Iowa, Dept Internal Med, Coll Publ Hlth, Iowa City, IA 52242 USA. [Curb, J. David] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Curb, J. David] Pacific Hlth Res Inst, Honolulu, HI USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Boston, MA 02115 USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Mehra, Reena] Case Med Ctr, Dept Med, Cleveland, OH USA. [Ferrucci, Luigi; Eriksson, Per] Karolinska Inst, Karolinska Univ Hosp Solna, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden. [Hopewell, Jemma C.] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Ctr Noncommunicable Dis, Karachi, Pakistan. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, Leicester Natl Inst Hlth Res, Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Deutsch Zentrum Herz Kreislauf Forsch, D-23538 Lubeck, Germany. [Reilly, Muredach P.] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Kathiresan, Sekar] Cardiovasc Res Ctr, Boston, MA USA. [Kathiresan, Sekar] Ctr Human Genet Res, Boston, MA USA. [Kathiresan, Sekar] Gen Hosp, Boston, MA USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Kathiresan, Sekar] Broad Inst Harvard & MIT, Julius Ctr, Program Med & Populat Genet, Cambridge, MA USA. [Tang, Weihong] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. [Chasman, Daniel] Brigham & Womens Hosp, Womens Genome Hlth Study, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [Teichert, Martina] Erasmus MC, Dept Epidemiol, Rotterdam Study, Rotterdam, Netherlands. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Heart & Vasc Hlth Study, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Vet Affairs Off Res & Dev, Seattle, WA USA. [Markus, Hugh S.] Univ London, Stroke & Dementia Res Ctr, London, England. [Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Sudlow, Cathie L. M.] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. RP Hamsten, A (reprint author), Karolinska Univ Hosp Solna, Atherosclerosis Res Unit, Ctr Mol Med, Bldg L8 03, S-17176 Stockholm, Sweden. EM Anders.Hamsten@ki.se; odonnellc@nhlbi.nih.gov RI Erdmann, Jeanette/P-7513-2014; Peters, Annette/A-6117-2011; Tregouet, David-Alexandre/E-3961-2016; Rudan, Igor/I-1467-2012; Hayward, Caroline/M-8818-2016; Johnson, Andrew/G-6520-2013; Naitza, Silvia/D-5620-2017; Kolcic, Ivana/E-2713-2017; Altshuler, David/A-4476-2009; Schreiber, Stefan/B-6748-2008; Liu, Simin/I-3689-2014; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Deloukas, Panos/B-2922-2013; Willenborg, Christina/D-2668-2012; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Blackwell, Jenefer/H-3015-2015 OI Watkins, Hugh/0000-0002-5287-9016; Eriksson, Johan/0000-0002-2516-2060; Folkersen, Lasse/0000-0003-0708-9530; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; de Geus, Eco/0000-0001-6022-2666; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Sabater Lleal, Maria/0000-0002-0128-379X; sanna, serena/0000-0002-3768-1749; Mehra, Reena/0000-0002-6222-2675; Seedorf, Udo/0000-0003-4652-5358; Steri, Anna Maristella/0000-0001-5869-3872; Erdmann, Jeanette/0000-0002-4486-6231; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Bevan, Steve/0000-0003-0490-6830; Navarro, Pau/0000-0001-5576-8584; Rudan, Igor/0000-0001-6993-6884; Hayward, Caroline/0000-0002-9405-9550; Kolcic, Ivana/0000-0001-7918-6052; Ikram, Mohammad Arfan/0000-0003-0372-8585; Williams, Frances/0000-0002-2998-2744; Altshuler, David/0000-0002-7250-4107; Schreiber, Stefan/0000-0003-2254-7771; Liu, Simin/0000-0003-2098-3844; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Deloukas, Panos/0000-0001-9251-070X; Willenborg, Christina/0000-0001-5217-6882; Strawbridge, Rona/0000-0001-8506-3585; FU European Community [LSHM-CT-2007-037273]; AstraZeneca; British Heart Foundation (BHF); Wellcome Trust075491/Z/04; Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Heart-Lung Foundation; Torsten and Ragnar Soderberg Foundation; Karolinska Institutet; Stockholm County Council; Foundation for Strategic Research; BHF Center of Research Excellence, Oxford; Magnus Bergvall Foundation; European Union [PIEF-GA-2009-252361]; National Heart, Lung, and Blood Institute's (NHLBI's) [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140, DK063491]; National Institute on Aging (NIA); National Institute for Neurological Disorders and Stroke [R01 AG033193, NS017950]; NHLBI [HL043851, HL080467, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084]; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; NIA [NO1-AG-1-2109, AG-023629, AG-15928, AG-20098, AG-027058]; National Institutes of Health (NIH), NIA; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; NWO [vici, 918-76-619, veni, 916.12.154]; EUR Fellowship; Netherlands Heart Foundation [2009B102, NHS 92345]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 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; Leibniz Supercomputing Center of the Bavarian Academy of Sciences and Humanities (HLRB) [h1231]; Federal Ministry of Education and Research; Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania [03IS2061A]; National Human Genome Research Institute [U01-HG-004729, U01-HG-004446, U01-HG-004424]; European Union's 7th Framework Program [HEALTH-F2-2009-223004]; Netherlands Consortium of Healthy Aging (NGI) [05060810]; Scottish Executive Chief Scientist Office, Health Services Research Committee [CZG/4/306]; National Institute of Neurological Disorders and Stroke; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases; Zoll LifeCor; Medtronic; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; Research Into Ageing [LBC1936]; Help the Aged/Research Into Ageing (Disconnected Mind); BBSRC [LBC1921]; BBSRC; Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative; Program Hospitalier de la Recherche Clinique; Fondation pour la Recherche Medicale; La Region Ile de France; Medical Research Council (UK); European Commission [LSHG-CT-2006-018947]; Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; UK National Blood Service controls; Wellcome Trust; BHF Center of Research Excellence, Oxford, UK; Reynolds Foundation; Boehringer Ingelheim; Philips Medical Systems; Government of Rheinland-Pfalz; Johannes-Gutenberg University of Mainz; MAIFOR; Fondation de France; French Ministry of Research; Institut National de la Sante et de la Recherche Medicale; NIH [NHLBI R01HL089650-02, N01-AG-12100, P01 HL098055, P01HL076491-06, R01DK080732, P01HL087018, 1RO1HL103931-01]; Deutsche Forschungsgemeinschaft; German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network [NGFN-2]; EU [LSHM-CT-2006-037593, LSHM-CT-2004-503485, HEALTH-F2-2008-201668]; BMBF/ANR [01KU0908A]; Sanofi/Aventis; Roche; Dade Behring/Siemens; US NIH; NHLBI's STAMPEED genomics research program [R01 HL087676]; Canadian Institutes of Health Research; Cardiovascular Institute of the University of Pennsylvania; MedStar Research Institute; Washington Hospital Center; GlaxoSmithKline; GlaxoSmithKline through an Alternate Drug Discovery Initiative Research Alliance Award; University of Pennsylvania School of Medicine; CIHR [MOP-82810, MOP172605, MOP77682]; CFI [11966]; HSFO [NA6001]; BHF; UK Medical Research Council; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); German Migraine & Headache Society; Berlin Chemie; Boots Healthcare; Glaxo-Smith-Kline; McNeil Pharma; MSD Sharp Dohme; Pfizer; Institute of Epidemiology and Social Medicine, University of Muenster; Medical Research Council UK; Cancer Research UK; Canadian Institutes for Health Research; Heart and Stroke Foundation of Ontario; Sanofi-Aventis; King Pharmaceuticals; T.F.C. Frost charity; Macular Disease Society; Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Research Institute for Diseases in the Elderly; European Commission (DG XII); Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012]; NGI/NWO [050-060-810]; NWO (Vici) [918-76-619]; Swedish Heart & Lung Foundation; Stockholm County Council (ALF); Netherlands Organisation for Scientific Research (NWO); Italian Ministry of University and Research; Veneto Region; Cariverona Foundation, Verona; Helmholtz Zentrum Munchen-National Research Center for Environmental Health; German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; German National Genome Research Network; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; N.H.L.B.I [HHSN268201200036C, HL080295, HL087652, HL105756, R01-HL085251, HL087647, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; [R01-HL-084099] FX PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation (BHF), the Wellcome Trust (contract 075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research, and the Stockholm County Council. Drs Hopewell and Clarke acknowledge support from the BHF Center of Research Excellence, Oxford. Dr Sennblad acknowledges funding from the Magnus Bergvall Foundation. Dr Sabater-Lleal is a recipient of a Marie Curie Intra European Fellowship within the 7th Framework Program of the European Union (PIEF-GA-2009-252361) to investigate the genetic regulation of plasma fibrinogen. FHS was partially supported by the National Heart, Lung, and Blood Institute's (NHLBI's) Framingham Heart Study (contract N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. Partial investigator support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases K24 DK080140 (J.B. Meigs), the National Institute on Aging (NIA), and National Institute for Neurological Disorders and Stroke (R01 AG033193, NS017950; Dr Seshadri). The WGHS is supported by HL043851 and HL080467 from the NHLBI and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation, and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The SardiNIA ("Progenia") team was supported by contract NO1-AG-1-2109 from the NIA. We thank the many individuals who generously participated in this study, the mayors and citizens of the Sardinian towns involved, the head of the Public Health Unit ASL4, and the province of Ogliastra for their volunteerism and cooperation. In addition, we are grateful to the mayor and the administration in Lanusei for providing and furnishing the clinic site. We are grateful to the physicians Angelo Scuteri, Marco Orru, Maria Grazia Pilia, Liana Ferreli, and Francesco Loi, as well as nurses Paola Loi, Monica Lai, and Anna Cau, who carried out participant physical examinations; the recruitment personnel Susanna Murino; Mariano Dei, Sandra Lai, Antonella Mulas, Luca Usala, Andrea Maschio, and Fabio Busonero for genotyping; and Maria Grazia Piras and Monica Lobina for fibrinogen phenotyping. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NIA. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam.; Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (No. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project No. 050-060-810. Dr Witteman is supported by NWO grant (vici, 918-76-619). Dr Dehghan is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. Dr Ikram was supported by the Netherlands Heart Foundation (2009B102). 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 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg, West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg, West Pomerania. Computing resources have been made available by the Leibniz Supercomputing Center of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). The University of Greifswald is a member of the Center of Knowledge Interchange program of Siemens AG and the Cache Campus program of the InterSystems GmbH. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (03IS2061A). The Coronary Artery Risk Development in Young Adults (CARDIA) study is funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from the NHLBI to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the National Human Genome Research Institute. Statistical analyses were supported by grants U01-HG-004729 and R01-HL-084099 to Dr Fornage. PROSPER received funding from the European Union's 7th Framework Program (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004. For part of the genotyping, we received funding from the Netherlands Consortium of Healthy Aging (NGI; 05060810). Measurement of serum fibrinogen was supported by a grant from the Scottish Executive Chief Scientist Office, Health Services Research Committee grant CZG/4/306. This work was performed as part of an ongoing collaboration of the PROSPER study group in the universities of Leiden, Glasgow and Cork. Dr Jukema is an established clinical investigator of the Netherlands Heart Foundation (2001 D 032). This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and HHSN268201200036C and NHLBI grants HL080295, HL087652, and HL105756, with additional contribution from the National Institute of Neurological Disorders and Stroke. 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.; DNA handling and genotyping were supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center and the Cedars-Sinai Board of Governors' Chair in Medical Genetics (Dr Rotter); support for genotyping in CHS blacks was also provided by NHLBI R01-HL085251. Dr Psaty is a member of the data safety monitoring board for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and a member of the Steering Committee for the Yale Open Data Access Project funded by Medtronic. We thank the LBC1936 and LBC1921 participants and research team members. We thank the nurses and staff at the Wellcome Trust Clinical Research Facility, where subjects were tested and the genotyping was performed. The whole genome association study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; reference BB/F019394/1). The LBC1936 research was supported by a program grant from Research Into Ageing and continues with program grants from Help the Aged/Research Into Ageing (Disconnected Mind). The LBC1921 data collection was funded by the BBSRC. The study was conducted within the University of Edinburgh Center for Cognitive Ageing and Cognitive Epidemiology (http://www.ccace.ed.ac.uk/), supported by the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC), and Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative. Dr Lopez is the beneficiary of a postdoctoral grant from the AXA Research Fund. The MARTHA project was supported by a grant from the Program Hospitalier de la Recherche Clinique. Dr Oudot-Mellakh was supported by a grant from the Fondation pour la Recherche Medicale. Statistical analyses conducted in MARTHA benefit from the C2BIG computing center funded by the Fondation pour la Recherche Medicale and La Region Ile de France. The CROATIA-Split study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (contract LSHG-CT-2006-018947), and Republic of Croatia Ministry of Science, Education and Sports research grants to Dr Rudan (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to the University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (contract LSHG-CT-2006-018947), and Republic of Croatia Ministry of Science, Education and Sports research grants to Dr Rudan (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh, and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum Munchen, Neuherberg, Germany. The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to Dr Rudan (108-1080315-0302).; We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to the University of Split and S. Gamble, C. Hind, M. L. Perez, C. R. Stribling, S. Taylor, and A. Wilk of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and of the UK National Blood Service controls funded by the Wellcome Trust. A membership list of WTCCC2 can be found in the online-only Data Supplement. The C4D Consortium comprises CHD cases and controls of European origin from PROCARDIS and the Heart Protection Study and of South Asian origin from the LOLIPOP and PROMIS studies. Data analyzed with respect to risk of CHD all relate to the European-origin participants from PROCARDIS and HPS. We would like to acknowledge the UK Twins Study and WTCCC2-National Blood Service Collection for providing population controls. Drs Hopewell and Clarke acknowledge support from the BHF Center of Research Excellence, Oxford, UK. CARDIoGRAM: The ADVANCE study was supported by a grant from the Reynolds Foundation and NHLBI grant HL087647. Genetic analyses of CADomics were supported by a research grant from Boehringer Ingelheim. Recruitment and analysis of the CADomics cohort were supported by grants from Boehringer Ingelheim and Philips Medical Systems, by the Government of Rheinland-Pfalz in the context of the "Stiftung Rheinland-Pfalz fur Innovation," by the research program "Wissen schafft Zukunft," by the Johannes-Gutenberg University of Mainz in the context of the "Schwerpunkt Vaskulare Pravention" and the "MAIFOR grant 2001," and by grants from the Fondation de France, the French Ministry of Research, and the Institut National de la Sante et de la Recherche Medicale. The deCODE CAD/MI Study was sponsored by NIH grant NHLBI R01HL089650-02. The German MI Family Studies (GerMIFS I-III [KORA]) were supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus), the EU-funded integrated project Cardiogenics (LSHM-CT-2006-037593), and the binational BMBF/ANR-funded project CARDomics (01KU0908A). LURIC has received funding from the EU framework 6-funded Integrated Project "Bloodomics" (LSHM-CT-2004-503485), and the EU framework 7-funded Integrated Project AtheroRemo (HEALTH-F2-2008-201668), as well as Sanofi/Aventis, Roche, Dade Behring/Siemens, and AstraZeneca. The MIGen study was funded by the US NIH and NHLBI's STAMPEED genomics research program through R01 HL087676. Ron Do from the MIGen study is supported by a Canada Graduate Doctoral Scholarship from the Canadian Institutes of Health Research. Recruitment of PennCATH was supported by the Cardiovascular Institute of the University of Pennsylvania. Recruitment of the MedStar sample was supported in part by the MedStar Research Institute and the Washington Hospital Center and by a research grant from GlaxoSmithKline. Genotyping of PennCATH and Medstar was performed at the Center for Applied Genomics at the Children's Hospital of Philadelphia and supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative Research Alliance Award (Dr Reilly) with the University of Pennsylvania School of Medicine. The Ottawa Heart Genomic Study was supported by CIHR No. MOP-82810, CFI No. 11966, HSFO No. NA6001, CIHR No.; MOP172605, and CIHR No. MOP77682. The WTCCC Study was funded by the Wellcome Trust. Recruitment of cases for the WTCCC Study was carried out by the BHF Family Heart Study Research Group and supported by the BHF and the UK Medical Research Council. Dr Samani hold a chair funded by the BHF. The Age, Gene/Environment Susceptibility Reykjavik Study has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Cleveland Clinic GeneBank study was supported by NIH grants P01 HL098055, P01HL076491-06, R01DK080732, P01HL087018, and 1RO1HL103931-01. The collection of clinical and sociodemographic data in the Dortmund Health Study was supported by the German Migraine & Headache Society and by unrestricted grants of equal share from AstraZeneca, Berlin Chemie, Boots Healthcare, Glaxo-Smith-Kline, McNeil Pharma (former Woelm Pharma), MSD Sharp & Dohme, and Pfizer to the University of Muenster. Blood collection was done through funds from the Institute of Epidemiology and Social Medicine, University of Muenster. The EPIC-Norfolk study is supported by the Medical Research Council UK and Cancer Research UK. The EpiDREAM study is supported by the Canadian Institutes for Health Research, Heart and Stroke Foundation of Ontario, Sanofi-Aventis, GlaxoSmithKline, and King Pharmaceuticals. Funding for Andrew Lotery from the LEEDS study was provided by tha T.F.C. Frost charity and the Macular Disease Society. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012), the NGI/NWO project 050-060-810 and Research Institute for Diseases in the Elderly (RIDE). Dr Dehghan is supported by a grant from NWO (Vici, 918-76-619). The SAS study was funded by the BHF. The Swedish Research Council, the Swedish Heart & Lung Foundation, and the Stockholm County Council (ALF) supported the SHEEP study. SMILE was funded by the Netherlands Heart foundation (NHS 92345). F. R. Rosendaal is a recipient of the Spinoza Award of the Netherlands Organisation for Scientific Research (NWO), which was used for part of this work. The Verona Heart Study was funded by grants from the Italian Ministry of University and Research, the Veneto Region, and the Cariverona Foundation, Verona. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. We thank the staff and participants of the ARIC study for their important contributions. The KORA (Kooperative Gesundheitsforschung in der Region Augsburg) research platform was initiated and financed by the Helmholtz Zentrum Munchen-National Research Center for Environmental Health, which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria.; Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus) and within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. NR 39 TC 45 Z9 46 U1 0 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 17 PY 2013 VL 128 IS 12 BP 1310 EP 1324 DI 10.1161/CIRCULATIONAHA.113.002251 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 219BC UT WOS:000324477900015 PM 23969696 ER PT J AU Graham, BB Chabon, J Gebreab, L Poole, J Debella, E Davis, L Tanaka, T Sanders, L Dropcho, N Bandeira, A Vandivier, RW Champion, HC Butrous, G Wang, XJ Wynn, TA Tuder, RM AF Graham, Brian B. Chabon, Jacob Gebreab, Liya Poole, Jennifer Debella, Elias Davis, Laura Tanaka, Takeshi Sanders, Linda Dropcho, Nina Bandeira, Angela Vandivier, R. William Champion, Hunter C. Butrous, Ghazwan Wang, Xiao-Jing Wynn, Thomas A. Tuder, Rubin M. TI Transforming Growth Factor-beta Signaling Promotes Pulmonary Hypertension Caused by Schistosoma Mansoni SO CIRCULATION LA English DT Article DE hypertension; pulmonary; schistosomiasis; transforming growth factor beta ID ARTERIAL-HYPERTENSION; VASCULAR-DISEASE; INFLAMMATION AB Background The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor- (TGF-) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. Methods and Results Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for approximate to 60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF- signaling, as pharmacological blockade of the TGF- ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF- signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF- signaling in their remodeled pulmonary arteries. Conclusion Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF- signaling. C1 [Graham, Brian B.; Chabon, Jacob; Gebreab, Liya; Poole, Jennifer; Debella, Elias; Davis, Laura; Tanaka, Takeshi; Sanders, Linda; Dropcho, Nina; Vandivier, R. William] Div Pulm Sci & Crit Care Med, Program Translat Lung Res, Aurora, CO USA. [Wang, Xiao-Jing] Dept Pathol, Aurora, CO USA. [Bandeira, Angela] Univ Pernambuco Recife, Mem S Jose Hosp, Recife, PE, Brazil. [Champion, Hunter C.] Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA. [Butrous, Ghazwan] Univ Kent, Sch Pharm, Canterbury CT2 7NZ, Kent, England. [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Graham, BB (reprint author), Univ Colorado Denver, Div Pulm Sci & Crit Care Med, 12700 E 19th Ave,C-272, Aurora, CO 80045 USA. EM brian.graham@ucdenver.edu FU Pfizer Advancing Science Through Pfizer Investigator-Research Exchange grants; Flight Attendant Medical Research Institute [092054_CIA]; Cardiovascular Medical Research and Education Fund; National Institutes of Health [RC1HL100849, K08HL105536] FX This study was supported by Parker B. Francis, National Institutes of Health K08HL105536, and Pfizer Advancing Science Through Pfizer Investigator-Research Exchange grants to Dr Graham; Career Investigator Award (092054_CIA) from the Flight Attendant Medical Research Institute to Dr Vandivier; and the Cardiovascular Medical Research and Education Fund and National Institutes of Health RC1HL100849 to Dr Tuder. NR 27 TC 22 Z9 25 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 17 PY 2013 VL 128 IS 12 BP 1354 EP 1364 DI 10.1161/CIRCULATIONAHA.113.003072 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 219BC UT WOS:000324477900020 PM 23958565 ER PT J AU Decker, BK Palmore, TN AF Decker, Brooke K. Palmore, Tara N. TI Universal decolonization was better than MRSA screening and isolation for preventing nosocomial ICU infections SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Decker, Brooke K.; Palmore, Tara N.] NIH, Bethesda, MD 20892 USA. RP Decker, BK (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Decker M.D., Brooke K/0000-0002-3404-9115 NR 2 TC 1 Z9 1 U1 0 U2 0 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 SEP 17 PY 2013 VL 159 IS 6 AR JC4 DI 10.7326/0003-4819-159-6-201309170-02004 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 234EY UT WOS:000325625900003 PM 24042387 ER PT J AU Crea, F Sun, L Pikor, L Frumento, P Lam, WL Helgason, CD AF Crea, F. Sun, L. Pikor, L. Frumento, P. Lam, W. L. Helgason, C. D. TI Mutational analysis of Polycomb genes in solid tumours identifies PHC3 amplification as a possible cancer-driving genetic alteration SO BRITISH JOURNAL OF CANCER LA English DT Article DE Polycomb; lung cancer; endometrial cancer ID LUNG-CANCER; REPRESSION; PATHWAYS; EZH2 AB Background: Polycomb group genes (PcGs) are epigenetic effectors implicated in most cancer hallmarks. The mutational status of all PcGs has never been systematically assessed in solid tumours. Methods: We conducted a multi-step analysis on publically available databases and patient samples to identify somatic aberrations of PcGs. Results: Data from more than 1000 cancer patients show for the first time that the PcG member PHC3 is amplified in three epithelial neoplasms (rate: 8-35%). This aberration predicts poorer prognosis in lung and uterine carcinomas (P < 0.01). Gene amplification correlates with mRNA overexpression (P < 0.01), suggesting a functional role of this aberration. Conclusion: PHC3 amplification may emerge as a biomarker and potential therapeutic target in a relevant fraction of epithelial tumours. C1 [Crea, F.; Helgason, C. D.] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Sun, L.] Frederick Natl Lab Canc Res, Hematopoiesis & Stem Cell Biol Sect, Lab Canc Prevent, Frederick, MD 21702 USA. [Pikor, L.; Lam, W. L.] British Columbia Canc Res Ctr, Genet Unit, Vancouver, BC V5Z 1L3, Canada. [Frumento, P.] Karolinska Inst, Inst Environm Med, Biostat Unit, S-10401 Stockholm, Sweden. [Helgason, C. D.] Univ British Columbia, Dept Surg, Vancouver, BC V5Z 4E3, Canada. RP Helgason, CD (reprint author), British Columbia Canc Res Ctr, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM fcrea@bccrc.ca; chelgaso@bccrc.ca RI Crea, Francesco /I-8383-2015; Sun, Lei/J-9943-2015; OI Crea, Francesco/0000-0002-4903-2973 NR 18 TC 3 Z9 3 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 17 PY 2013 VL 109 IS 6 BP 1699 EP 1702 DI 10.1038/bjc.2013.454 PG 4 WC Oncology SC Oncology GA 223NN UT WOS:000324812600041 PM 23942079 ER PT J AU Prasad, V AF Prasad, Vinay TI Why resident physicians stay late SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material C1 Fellow Natl Canc Inst, Med Oncol Branch, NIH, Bethesda, MD USA. RP Prasad, V (reprint author), Fellow Natl Canc Inst, Med Oncol Branch, NIH, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD SEP 17 PY 2013 VL 185 IS 13 BP 1184 EP 1184 DI 10.1503/cmaj.130528 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 219SK UT WOS:000324529300047 PM 24003103 ER PT J AU Bretherick, KL Schuetz, JM Morton, LM Purdue, MP Conde, L Gallagher, RP Connors, JM Gascoyne, RD Berry, BR Armstrong, B Kricker, A Vajdic, CM Grulich, A Hjalgrim, H Smedby, KE Skibola, CF Rothman, N Spinelli, JJ Brooks-Wilson, AR AF Bretherick, Karla L. Schuetz, Johanna M. Morton, Lindsay M. Purdue, Mark P. Conde, Lucia Gallagher, Richard P. Connors, Joseph M. Gascoyne, Randy D. Berry, Brian R. Armstrong, Bruce Kricker, Anne Vajdic, Claire M. Grulich, Andrew Hjalgrim, Henrik Smedby, Karin E. Skibola, Christine F. Rothman, Nathaniel Spinelli, John J. Brooks-Wilson, Angela R. TI Sex- and Subtype-Specific Analysis of H2AFX Polymorphisms in Non-Hodgkin Lymphoma SO PLOS ONE LA English DT Article ID B-CELL LYMPHOMA; DOUBLE-STRAND BREAKS; YIN YANG 1; HISTONE H2AX; REPRODUCTIVE FACTORS; GENETIC-VARIANTS; RISK; CANCER; PROGRESSION; WOMEN AB H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p = 0.007 for rs604714) and all B-cell lymphomas (p = 0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p = 0.002); a sex-stratified analysis revealed that the association was confined to females (p = 0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B-cell lymphoma (OR = 0.92, 95% CI = 0.86-0.99, p = 0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus. C1 [Bretherick, Karla L.; Schuetz, Johanna M.; Brooks-Wilson, Angela R.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Bretherick, Karla L.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Morton, Lindsay M.; Purdue, Mark P.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Conde, Lucia; Skibola, Christine F.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Gallagher, Richard P.; Spinelli, John J.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Connors, Joseph M.] BC Canc Agcy, Div Med Oncol, Vancouver, BC, Canada. [Connors, Joseph M.; Gascoyne, Randy D.] BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC, Canada. [Gascoyne, Randy D.] BC Canc Agcy, Dept Pathol, Vancouver, BC, Canada. [Berry, Brian R.] Royal Jubilee Hosp, Dept Pathol, Victoria, BC, Canada. [Armstrong, Bruce; Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Vajdic, Claire M.] Univ New S Wales, Fac Med, Prince Wales Clin Sch, Adult Canc Program,Lowy Canc Res Ctr, Sydney, NSW, Australia. [Grulich, Andrew] Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW 2052, Australia. [Hjalgrim, Henrik] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Smedby, Karin E.] Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Brooks-Wilson, Angela R.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. RP Brooks-Wilson, AR (reprint author), BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. EM abrooks-wilson@bcgsc.ca RI Conde, Lucia/D-9295-2011; Tang, Macy/B-9798-2014; Brooks-Wilson, Angela/E-9399-2012; Spinelli, John/B-6210-2013; Morton, Lindsay/B-5234-2015; Armstrong, Bruce/K-9464-2015; Purdue, Mark/C-9228-2016; OI Bretherick, Karla/0000-0002-6606-802X; Brooks-Wilson, Angela/0000-0003-1009-6408; Morton, Lindsay/0000-0001-9767-2310; Armstrong, Bruce/0000-0001-8940-7525; Purdue, Mark/0000-0003-1177-3108; Vajdic, Claire/0000-0002-3612-8298 FU Michael Smith Foundation for Health Research; Canadian Institutes of Health Research (CIHR) [MOP86528] FX KLB is funded by postdoctoral fellowships from the Michael Smith Foundation for Health Research (http://www.msfhr.org/) and the Canadian Institutes of Health Research (CIHR) (http://www.cihr-irsc.gc.ca/e/193.html). This study was funded by a grant from CIHR (MOP86528) to ARB-W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 17 PY 2013 VL 8 IS 9 AR e74619 DI 10.1371/journal.pone.0074619 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219YJ UT WOS:000324547300046 PM 24069324 ER PT J AU Samie, M Wang, X Zhang, XL Goschka, A Li, XR Cheng, XP Gregg, E Azar, M Zhuo, Y Garrity, AG Gao, Q Slaugenhaupt, S Pickel, J Zolov, SN Weisman, LS Lenk, GM Titus, S Bryant-Genevier, M Southall, N Juan, M Ferrer, M Xu, HX AF Samie, Mohammad Wang, Xiang Zhang, Xiaoli Goschka, Andrew Li, Xinran Cheng, Xiping Gregg, Evan Azar, Marlene Zhuo, Yue Garrity, Abigail G. Gao, Qiong Slaugenhaupt, Susan Pickel, Jim Zolov, Sergey N. Weisman, Lois S. Lenk, Guy M. Titus, Steve Bryant-Genevier, Marthe Southall, Noel Juan, Marugan Ferrer, Marc Xu, Haoxing TI A TRP Channel in the Lysosome Regulates Large Particle Phagocytosis via Focal Exocytosis SO DEVELOPMENTAL CELL LA English DT Article ID MUCOLIPIDOSIS TYPE-IV; INTRACELLULAR CA2+ STORES; PLASMA-MEMBRANE REPAIR; PHAGOSOME MATURATION; HUMAN NEUTROPHILS; MACROPHAGES; CALCIUM; SECRETION; DYNAMICS; TRAFFICKING AB Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P-2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+-dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo. C1 [Samie, Mohammad; Wang, Xiang; Zhang, Xiaoli; Goschka, Andrew; Li, Xinran; Cheng, Xiping; Gregg, Evan; Azar, Marlene; Zhuo, Yue; Garrity, Abigail G.; Gao, Qiong; Xu, Haoxing] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Lenk, Guy M.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Zolov, Sergey N.; Weisman, Lois S.] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Zolov, Sergey N.; Weisman, Lois S.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Slaugenhaupt, Susan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol Genet,Ctr Human Genet Res, Boston, MA 02114 USA. [Pickel, Jim] NIH, NIMH Transgen, Bethesda, MD 20892 USA. [Titus, Steve; Bryant-Genevier, Marthe; Southall, Noel; Juan, Marugan; Ferrer, Marc] NIH, NCATS, NCGC, Rockville, MD 20850 USA. RP Xu, HX (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. EM haoxingx@umich.edu RI Southall, Noel/H-8991-2012; Lenk, Guy/Q-1226-2016 OI Southall, Noel/0000-0003-4500-880X; Lenk, Guy/0000-0001-8092-1405 FU National Institutes of Health (NIH) [NS062792, MH096595, AR060837, GM24872, NS064015] FX This work was supported by National Institutes of Health (NIH) (NS062792, MH096595, AR060837 to H.X, GM24872 to M. Meisler, and NS064015 to L.S.W). We are grateful to Dr. Loren Looger for the GCaMP3 construct, Drs. Norma Andrews and Thomas Sudhof for the Syt-VII construct, Florence Niedergang and Robert Edwards for VAMP7 constructs, Ed Stuenkel for the TeNT construct, Johnny Fares for ML1-overexpressing or knockdown RAW macrophages, Gregg Sobocinski for assistance in confocal imaging, and Richard Hume and Miriam Meisler for comments on an earlier version of the manuscript. We appreciate the encouragement and helpful comments from other members of the Xu laboratory. NR 53 TC 58 Z9 58 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD SEP 16 PY 2013 VL 26 IS 5 BP 511 EP 524 DI 10.1016/j.devcel.2013.08.003 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 243GF UT WOS:000326304200006 PM 23993788 ER PT J AU Virnik, K Hockenbury, M Ni, YS Beren, J Pavlakis, GN Felber, BK Berkower, I AF Virnik, Konstantin Hockenbury, Max Ni, Yisheng Beren, Joel Pavlakis, George N. Felber, Barbara K. Berkower, Ira TI Live attenuated rubella vectors expressing SIV and HIV vaccine antigens replicate and elicit durable immune responses in rhesus macaques SO RETROVIROLOGY LA English DT Article DE Live viral vector; Rubella vaccine strain RA27/3; Rhesus macaque; HIV MPER; SIV Gag; Highly immunogenic; Long lasting; Memory B cells ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; VIRAL VECTORS; CELL RESPONSES; CAPSID PROTEIN; CHALLENGE; ENVELOPE; NEUTRALIZATION; DESIGN; MEMORY AB Background: Live attenuated viruses are among our most potent and effective vaccines. For human immunodeficiency virus, however, a live attenuated strain could present substantial safety concerns. We have used the live attenuated rubella vaccine strain RA27/3 as a vector to express SIV and HIV vaccine antigens because its safety and immunogenicity have been demonstrated in millions of children. One dose protects for life against rubella infection. In previous studies, rubella vectors replicated to high titers in cell culture while stably expressing SIV and HIV antigens. Their viability in vivo, however, as well as immunogenicity and antibody persistence, were unknown. Results: This paper reports the first successful trial of rubella vectors in rhesus macaques, in combination with DNA vaccines in a prime and boost strategy. The vectors grew robustly in vivo, and the protein inserts were highly immunogenic. Antibody titers elicited by the SIV Gag vector were greater than or equal to those elicited by natural SIV infection. The antibodies were long lasting, and they were boosted by a second dose of replication- competent rubella vectors given six months later, indicating the induction of memory B cells. Conclusions: Rubella vectors can serve as a vaccine platform for safe delivery and expression of SIV and HIV antigens. By presenting these antigens in the context of an acute infection, at a high level and for a prolonged duration, these vectors can stimulate a strong and persistent immune response, including maturation of memory B cells. Rhesus macaques will provide an ideal animal model for demonstrating immunogenicity of novel vectors and protection against SIV or SHIV challenge. C1 [Virnik, Konstantin; Hockenbury, Max; Ni, Yisheng; Berkower, Ira] FDA, Ctr Biol, Div Viral Prod, Lab Immunoregulat,Off Vaccines, Bethesda, MD 20892 USA. [Beren, Joel] Ctr Biol, Div Vet Serv, Bethesda, MD 20892 USA. [Pavlakis, George N.] NCI, Human Retrovirus Sect, Frederick, MD 21702 USA. [Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. [Beren, Joel] FDA, CDER, OCTEC, Silver Spring, MD 20993 USA. RP Berkower, I (reprint author), FDA, Ctr Biol, Div Viral Prod, Lab Immunoregulat,Off Vaccines, NIH Campus, Bethesda, MD 20892 USA. EM ira.berkower@fda.hhs.gov FU NIH Intramural AIDS Targeted Research Program FX The authors wish to thank Lewis Shankle of CBER and Dr. Deborah Weiss of Advanced BioScience Laboratories, Inc. for their essential contributions to this work; K. Broderick and N. Sardesai of Inovio Pharmaceuticals, Inc. for the DNA delivery method; Dr. Margherita Rosati of NCI Frederick and Dr. Carol Weiss of CBER for helpful discussions; and Dr. John Moore for providing SOSIP gp140 trimers. This research was supported in part by the NIH Intramural AIDS Targeted Research Program. NR 47 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 16 PY 2013 VL 10 AR 99 DI 10.1186/1742-4690-10-99 PG 15 WC Virology SC Virology GA 228CZ UT WOS:000325164100002 PM 24041113 ER PT J AU Madsen, DH Leonard, D Masedunskas, A Moyer, A Jurgensen, HJ Peters, DE Amornphimoltham, P Selvarj, A Yamada, SS Brenner, DA Burgdorf, S Engelholm, LH Behrendt, N Holmbeck, K Weigert, R Bugge, TH AF Madsen, Daniel H. Leonard, Daniel Masedunskas, Andrius Moyer, Amanda Juergensen, Henrik Jessen Peters, Diane E. Amornphimoltham, Panomwat Selvarj, Arul Yamada, Susan S. Brenner, David A. Burgdorf, Sven Engelholm, Lars H. Behrendt, Niels Holmbeck, Kenn Weigert, Roberto Bugge, Thomas H. TI M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway SO JOURNAL OF CELL BIOLOGY LA English DT Article ID INTRAVITAL 2-PHOTON MICROSCOPY; INTRACELLULAR COLLAGEN; MATRIX METALLOPROTEINASES; ENDOCYTIC RECEPTOR; TARGETED DELETION; ENDOTHELIAL-CELLS; DENDRITIC CELLS; IN-VIVO; PHAGOCYTOSIS; FIBROBLASTS AB Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase-dependent manner and was subsequently routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Co/1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation of the collagen receptors mannose receptor (Mrc1) and urokinase plasminogen activator receptor-associated protein (Endo180 and Mrc2) impaired this intracellular collagen degradation pathway. This study demonstrates the importance of receptor-mediated cellular uptake to collagen turnover in vivo and identifies a key role of M2-like macrophages in this process. C1 [Madsen, Daniel H.; Masedunskas, Andrius; Moyer, Amanda; Juergensen, Henrik Jessen; Peters, Diane E.; Selvarj, Arul; Bugge, Thomas H.] NIDCD, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. [Masedunskas, Andrius; Amornphimoltham, Panomwat; Weigert, Roberto] NIDCD, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Juergensen, Henrik Jessen; Engelholm, Lars H.; Behrendt, Niels] NIDCD, Matrix Metalloprotemase Sectiori, NIH, Bethesda, MD 20892 USA. [Madsen, Daniel H.; Juergensen, Henrik Jessen; Engelholm, Lars H.; Behrendt, Niels] Univ Copenhagen, Rigshosp Biotech Res & Innovat Ctr, Finsen Lab, DK-2100 Copenhagen, Denmark. [Brenner, David A.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Peters, Diane E.] Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. RP Bugge, TH (reprint author), NIDCD, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467; Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU National Institute of Dental and Craniofacial Research Intramural Research Program; Lundbeck Foundation; Danish Cancer Society; Danish Cancer Research Foundation; Novo Nordisk Foundation; Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer); Grosserer Alfred Nielsen og Hustrus Foundation; Copenhagen University Hospital [5 R01 GM041804, 2 P42 ES010337]; German Research Foundation (Deutsche Forschungsgemeinschaft) [SFB645-C1] FX Supported by the National Institute of Dental and Craniofacial Research Intramural Research Program (T.H. Bugge), the Lundbeck Foundation (D.H. Madsen), The Danish Cancer Society, the Danish Cancer Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, the Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer), the Grosserer Alfred Nielsen og Hustrus Foundation (L.H. Engelholm and N. Behrendt), by a personal grant from Copenhagen University Hospital (H. J. Jurgensen), grants 5 R01 GM041804 and 2 P42 ES010337 (D.A. Brenner), and German Research Foundation (Deutsche Forschungsgemeinschaft) grant SFB645-C1 (S. Burgdorf). NR 68 TC 41 Z9 42 U1 4 U2 22 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 16 PY 2013 VL 202 IS 6 BP 951 EP 966 DI 10.1083/jcb.201301081 PG 16 WC Cell Biology SC Cell Biology GA 220EM UT WOS:000324564900012 PM 24019537 ER PT J AU Naumova, AK Fayer, S Leung, J Boateng, KA Camerini-Otero, RD Taketo, T AF Naumova, Anna K. Fayer, Shawn Leung, Jacky Boateng, Kingsley A. Camerini-Otero, R. Daniel Taketo, Teruko TI Dynamics of Response to Asynapsis and Meiotic Silencing in Spermatocytes from Robertsonian Translocation Carriers SO PLOS ONE LA English DT Article ID SEX-CHROMOSOME INACTIVATION; HISTONE VARIANT H3.3; HETEROCHROMATIN FORMATION; RECIPROCAL TRANSLOCATION; MAMMALIAN MEIOSIS; X-CHROMOSOME; MALE-MICE; MOUSE; CHROMATIN; REPAIR AB Failure of homologous synapsis during meiotic prophase triggers transcriptional repression. Asynapsis of the X and Y chromosomes and their consequent silencing is essential for spermatogenesis. However, asynapsis of portions of autosomes in heterozygous translocation carriers may be detrimental for meiotic progression. In fact, a wide range of phenotypic outcomes from meiotic arrest to normal spermatogenesis have been described and the causes of such a variation remain elusive. To better understand the consequences of asynapsis in male carriers of Robertsonian translocations, we focused on the dynamics of recruitment of markers of asynapsis and meiotic silencing at unsynapsed autosomal trivalents in the spermatocytes of Robertsonian translocation carrier mice. Here we report that the enrichment of breast cancer 1 (BRCA1) and histone gamma H2AX at unsynapsed trivalents declines during the pachytene stage of meiosis and differs from that observed in the sex body. Furthermore, histone variant H3.3S31, which associates with the sex chromosomes in metaphase I/anaphase I spermatocytes, localizes to autosomes in 12% and 31% of nuclei from carriers of one and three translocations, respectively. These data suggest that the proportion of spermatocytes with markers of meiotic silencing of unsynapsed chromatin (MSUC) at trivalents depends on both, the stage of meiosis and the number of translocations. This may explain some of the variability in phenotypic outcomes associated with Robertsonian translocations. In addition our data suggest that the dynamics of response to asynapsis in Robertsonian translocations differs from the response to sex chromosomal asynapsis in the male germ line. C1 [Naumova, Anna K.; Taketo, Teruko] McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. [Naumova, Anna K.; Fayer, Shawn] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Naumova, Anna K.; Taketo, Teruko] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada. [Leung, Jacky] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. [Boateng, Kingsley A.; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD USA. [Taketo, Teruko] McGill Univ, Dept Surg, Montreal, PQ H3A 2T5, Canada. RP Naumova, AK (reprint author), McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. EM anna.naoumova@mcgill.ca FU Natural Sciences and Engineering Research Council of Canada Discovery Grants program; McGill University Work Study program; Human Genetics Department of McGill University; NIDDK Intramural Research Program FX This work was supported by funds from the Natural Sciences and Engineering Research Council of Canada Discovery Grants program (to A.N. and T.T.), the McGill University Work Study program (J.L.), the Human Genetics Department of McGill University (to S.F.); and partly supported by the NIDDK Intramural Research Program (to R.D.C.-O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 5 Z9 5 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2013 VL 8 IS 9 AR e75970 DI 10.1371/journal.pone.0075970 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219GJ UT WOS:000324494000171 PM 24066189 ER PT J AU Safdar, H Cleuren, ACA Cheung, KL Gonzalez, FJ Vos, HL Inoue, Y Reitsma, PH van Vlijmen, BJM AF Safdar, Huma Cleuren, Audrey C. A. Cheung, Ka Lei Gonzalez, Frank J. Vos, Hans L. Inoue, Yusuke Reitsma, Pieter H. van Vlijmen, Bart J. M. TI Regulation of the F11, Klkb1, Cyp4v3 Gene Cluster in Livers of Metabolically Challenged Mice SO PLOS ONE LA English DT Article ID BLOOD-COAGULATION FACTOR; ESTROGEN-RECEPTOR-ALPHA; HEPATOCYTE NUCLEAR FACTOR-4-ALPHA; DEEP-VEIN THROMBOSIS; ACTIVATED FACTOR-XII; FACTOR 4-ALPHA; EXPRESSION; PREKALLIKREIN; HNF-4-ALPHA; LOCUS AB Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4 alpha, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements. C1 [Safdar, Huma; Cleuren, Audrey C. A.; Cheung, Ka Lei; Vos, Hans L.; Reitsma, Pieter H.; van Vlijmen, Bart J. M.] Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands. [Safdar, Huma; Cleuren, Audrey C. A.; Cheung, Ka Lei; Vos, Hans L.; Reitsma, Pieter H.; van Vlijmen, Bart J. M.] Leiden Univ Med Ctr, Dept Thrombosis & Hemostasis, Leiden, Netherlands. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Inoue, Yusuke] Gunma Univ, Grad Sch Engn, Dept Chem & Chem Biol, Kiryu, Gunma, Japan. RP Safdar, H (reprint author), Leiden Univ Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands. EM h.safdar@lumc.nl FU Dutch Organization for Scientific Research (NWO-TOP) [40-00812-98-07-045]; Netherlands Heart Foundation [2006B0045] FX This project is financially supported by the Dutch Organization for Scientific Research (NWO-TOP Grant #40-00812-98-07-045). The research of Audrey C.A. Cleuren was supported by grant 2006B0045 from the Netherlands Heart Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 2 Z9 2 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 SEP 16 PY 2013 VL 8 IS 9 AR e74637 DI 10.1371/journal.pone.0074637 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219GJ UT WOS:000324494000131 PM 24066149 ER PT J AU Ebrahim, S Kachar, B AF Ebrahim, Seham Kachar, Bechara TI Myosin transcellular networks regulate epithelial apical geometry SO CELL CYCLE LA English DT Editorial Material ID JUNCTIONS C1 [Ebrahim, Seham; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. EM kacharb@nidcd.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2013 VL 12 IS 18 BP 2931 EP 2932 DI 10.4161/cc.26229 PG 2 WC Cell Biology SC Cell Biology GA 301JI UT WOS:000330528200009 PM 23974088 ER PT J AU Hall, EC Engels, EA Montgomery, RA Segev, DL AF Hall, Erin C. Engels, Eric A. Montgomery, Robert A. Segev, Dorry L. TI Cancer Risk After ABO-Incompatible Living-Donor Kidney Transplantation SO TRANSPLANTATION LA English DT Article DE Incompatible transplantation; Cancer; Living-donor kidney transplantation ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MERKEL CELL-CARCINOMA; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; UNITED-STATES; RENAL-TRANSPLANTATION; ORGAN-TRANSPLANTATION; HIV-INFECTION; RECIPIENTS; IMMUNOSUPPRESSION; SPLENECTOMY AB Background. Recipients of ABO-incompatible (ABOi) living-donor kidney transplants often undergo more intense immunosuppression than their ABO-compatible counterparts. It is unknown if this difference leads to higher cancer risk after transplantation. Single-center studies are too small and lack adequate duration of follow-up to answer this question. Methods. We identified 318 ABOi recipients in the Transplant Cancer Match Study, a national linkage between the Scientific Registry of Transplant Recipients and population-based U.S. cancer registries. Seven cancers (non-Hodgkin lymphoma, Merkel cell carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, thyroid cancer, pancreatic cancer, and testicular cancer) were identified among ABOi recipients. We then matched ABOi recipients to ABO-compatible controls by age, gender, race, human leukocyte antigen mismatch, retransplantation, and transplant year. Results. There was no demonstrable association between ABOi and cancer in unadjusted (incidence rate ratio, 0.83; 95% confidence interval, 0.33-1.71; P=0.3) or matched control (incidence rate ratio, 0.99; 95% confidence interval, 0.38-2.23; P=0.5) analyses. Conclusion. To the extent that could be determined in this registry study, current desensitization protocols are not associated with increased risk of cancer after transplantation. C1 [Hall, Erin C.; Montgomery, Robert A.; Segev, Dorry L.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. [Hall, Erin C.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Segev, DL (reprint author), Johns Hopkins Med Inst, 720 Rutland Ave,Ross 771B, Baltimore, MD 21205 USA. EM dorry@jhmi.edu FU National Cancer Institute; National Institutes of Health [T32CA126607]; Clinical and Laboratory Research Training for Surgical Oncologists FX This research was supported in part by the Intramural Research Program of the National Cancer Institute and by the National Institutes of Health training grant number T32CA126607, Clinical and Laboratory Research Training for Surgical Oncologists (E. C. H.). E. A. E. was funded by the Intramural Research Program of the National Cancer Institute. NR 28 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD SEP 15 PY 2013 VL 96 IS 5 BP 476 EP 479 DI 10.1097/TP.0b013e318299dc0e PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299FX UT WOS:000330382400013 PM 23799426 ER PT J AU Katz, LS Geras-Raaka, E Gershengorn, MC AF Katz, Liora S. Geras-Raaka, Elizabeth Gershengorn, Marvin C. TI Reprogramming Adult Human Dermal Fibroblasts to Islet-Like Cells by Epigenetic Modification Coupled to Transcription Factor Modulation SO STEM CELLS AND DEVELOPMENT LA English DT Article ID PANCREATIC BETA-CELLS; EMBRYONIC STEM-CELLS; INSULIN-PRODUCING CELLS; HISTONE DEACETYLASE INHIBITORS; ENDOCRINE PANCREAS; DIRECT CONVERSION; DNA METHYLATION; PRECURSOR CELLS; EFFICIENT DIFFERENTIATION; GENE-TRANSCRIPTION AB In this article, we describe novel conditions for culture, expansion, and transdifferentiation of primary human dermal fibroblasts (hDFs) to induce expression of transcription factors (TFs) and hormones characteristic of the islets of Langerhans. We show that histones associated with the insulin gene are hyperacetylated and that insulin gene DNA is less methylated in islet cells compared to cells that do not express insulin. Using two compounds that alter the epigenetic signature of cells, romidepsin (Romi), a histone deacetylase inhibitor, and 5-Azacytidine (5-AzC), a chemical analogue of cytidine that cannot be methylated, we show that hDFs exhibit a distinctive regulation of expression of TFs involved in islet development as well as of induction of glucagon and insulin. Overexpression of Pdx1, a TF important for islet differentiation, and silencing of musculoaponeurotic fibrosarcoma oncogene homolog B, a TF that is expressed in mature glucagon-producing cells, result in induction of insulin to a higher level compared to Romi and 5-AzC alone. The cells obtained from this protocol exhibit glucose-stimulated insulin secretion and lower blood glucose levels of diabetic mice. These data show that fully differentiated nonislet-derived cells could be made to transdifferentiate to islet-like cells and that combining epigenetic modulation with TF modulation leads to enhanced insulin expression. C1 [Katz, Liora S.; Geras-Raaka, Elizabeth; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU NIDDK, NIH [Z01 DK011007]; SNSF [PBGEP3-139875] FX This work is supported by the Intramural Research Program, NIDDK, NIH, Z01 DK011007 and by the SNSF PBGEP3-139875 award to LSK. NR 75 TC 8 Z9 10 U1 0 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD SEP 15 PY 2013 VL 22 IS 18 BP 2551 EP 2560 DI 10.1089/scd.2013.0134 PG 10 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 246AF UT WOS:000326506900010 PM 23627894 ER PT J AU Engels, EA Madeleine, MM AF Engels, Eric A. Madeleine, Margaret M. TI Invited Commentary: Biological and Clinical Insights From Epidemiologic Research Into HIV, HPV, and Anal Cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE acquired immunodeficiency syndrome; anal cancer; combination antiretroviral therapy; human immunodeficiency virus; human papillomavirus; immunosuppression; screening ID HUMAN-PAPILLOMAVIRUS; UNITED-STATES; METAANALYSIS; POPULATION; INFECTION; LESIONS; PEOPLE; BURDEN; RISK; AIDS AB Anal cancer is common among people infected with human immunodeficiency virus (HIV). This cancer is caused by human papillomavirus, and immunosuppression likely contributes to its development. In this issue of the Journal, Bertisch et al. (Am J Epidemiol. 2013;178(6):877-884) present the results of a case-control study of anal cancer among HIV-infected people in Switzerland. They demonstrate that anal cancer risk is increased in association with a low CD4+ cell count (a clinical measurement of immune status). In particular, HIV-induced immunosuppression was most severe among cases approximately 6-7 years prior to the diagnosis of anal cancer. A plausible biological interpretation is that immunosuppression is important at an early stage of the development of anal cancer, but that the neoplastic process becomes irreversible over time with persistent human papillomavirus infection and genetic damage. With current efforts to provide earlier combination antiretroviral therapy to HIV-infected people, anal cancer incidence may start to decline. Bertisch et al. also demonstrate a strong association between serum antibodies against the human papillomavirus type 16 protein E6 and anal cancer risk, highlighting the role of this viral oncoprotein in carcinogenesis. Additional biomarkers could help refine clinical approaches to anal cancer screening and prevention for the HIV-infected population. C1 [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Madeleine, Margaret M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98195 USA. [Madeleine, Margaret M.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9606 Med Ctr Dr,Room 6E226, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU NCI NIH HHS [R01 CA170386] NR 18 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2013 VL 178 IS 6 BP 885 EP 887 DI 10.1093/aje/kwt149 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 227YC UT WOS:000325150600009 PM 23900552 ER PT J AU Luo, JH Rossouw, J Tong, E Giovino, GA Lee, CC Chen, C Ockene, JK Qi, LH Margolis, KL AF Luo, Juhua Rossouw, Jacques Tong, Elisa Giovino, Gary A. Lee, Cathy C. Chen, Chu Ockene, Judith K. Qi, Lihong Margolis, Karen L. TI Smoking and Diabetes: Does the Increased Risk Ever Go Away? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE risk factors; smoking; smoking cessation; type 2 diabetes ID BASE-LINE CHARACTERISTICS; MIDDLE-AGED MEN; CIGARETTE-SMOKING; UNITED-STATES; WEIGHT-GAIN; INSULIN-RESISTANCE; CESSATION; MELLITUS; PARTICIPANTS; HAZARDS AB Recent studies reported that smoking cessation leads to higher short-term risk of type 2 diabetes than continuing to smoke. However, the duration of increased diabetes risk following smoking cessation needs further investigation. We followed 135,906 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative between September 1, 1993, and December 31, 1998, over an average of 11 years to examine the association between smoking cessation and risk of diabetes using Cox proportional hazard multivariable-adjusted regression models. Compared with that for never smokers, the risk for diabetes was significantly elevated in current smokers (hazard ratio = 1.28, 95% confidence interval: 1.20, 1.36) but was even higher in women who quit smoking during the first 3 years of follow-up (hazard ratio = 1.43, 95% confidence interval: 1.26, 1.63). Among former smokers, the risk of diabetes decreased significantly as the time since quitting increased and was equal to that of never smokers following a cessation period of 10 years. In new quitters with low cumulative exposure (<20 pack-years), diabetes risk was not elevated following smoking cessation. In conclusion, the risk of diabetes in former smokers returns to that in never smokers 10 years after quitting, and even more quickly in lighter smokers. C1 [Luo, Juhua] W Virginia Univ, Dept Community Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Rossouw, Jacques] NHLBI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tong, Elisa] Univ Calif Davis, Med Ctr, Div Gen Internal Med, Sacramento, CA 95817 USA. [Giovino, Gary A.] SUNY Buffalo, Dept Community Hlth & Hlth Behav, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. [Lee, Cathy C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Internal Med, Div Geriatr, Los Angeles, CA 90095 USA. [Lee, Cathy C.] Vet Affairs Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. [Chen, Chu] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA USA. [Qi, Lihong] Univ Calif Davis, Div Biostat, Dept Publ Hlth Sci, Sch Med, Davis, CA 95616 USA. [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. RP Luo, JH (reprint author), Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, 1025 East 7th St, Bloomington, IN 47405 USA. EM juhluo@indiana.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; [HHSN268201100003C] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221, and by HHSN268201100003C. NR 41 TC 11 Z9 11 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2013 VL 178 IS 6 BP 937 EP 945 DI 10.1093/aje/kwt071 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 227YC UT WOS:000325150600016 PM 23817918 ER PT J AU Roberts, WC Filardo, G Ko, JM Siegel, RJ Dollar, AL Ross, EM Shirani, J AF Roberts, William C. Filardo, Giovanni Ko, Jong Mi Siegel, Robert J. Dollar, Allen L. Ross, Elizabeth M. Shirani, Jamshid TI Comparison of Total 12-Lead QRS Voltage in a Variety of Cardiac Conditions and Its Usefulness in Predicting Increased Cardiac Mass SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; IDIOPATHIC DILATED CARDIOMYOPATHY; NECROPSY PATIENTS; ELECTROCARDIOGRAPHIC OBSERVATIONS; SYSTEMIC HYPERTENSION; DIAGNOSIS; CRITERIA; DISEASE; RATIO; REGURGITATION AB Echocardiography provides a more accurate method to determine increased cardiac mass than does electrocardiography. Nevertheless, most offices of physicians do not possess echocardiographic machines, but many possess electrocardiographic machines. Many electrocardiographic criteria have been used to determine increased cardiac mass, but few of the criteria have been measured against cardiac weight determined at necropsy or after cardiac transplantation. Such was the purpose of the present study. Cardiac weight at necropsy or after transplantation was determined in 359 patients with 11 different cardiac conditions, and total 12-lead electrocardiographic QRS voltage (from the peak of the R wave to the nadir of either the Q or the S wave, whichever was deeper) was measured in each patient. Even in hearts with massively increased cardiac mass (>1,000 g), the total 12-lead QRS voltage was clearly increased (>175 mm) in only 94%, but this criterion was superior to that of previously described electrocardiographic criteria for "left ventricular hypertrophy." Hearts with excessive adipose tissue infrequently had increased total 12-lead QRS voltage despite increased cardiac weight. Likewise, patients with fatal cardiac amyloidosis had hearts of increased weight but quite low total 12-lead QRS voltage. In conclusion, 12-lead QRS voltage is useful in predicting increased cardiac mass, but that predictability is dependent in part on the cause of the increased cardiac mass. (C) 2013 Elsevier Inc. All rights reserved. C1 [Roberts, William C.] Baylor Hlth Care Syst, Dept Internal Med, Dallas, TX USA. [Roberts, William C.] Baylor Hlth Care Syst, Dept Pathol, Dallas, TX USA. [Roberts, William C.; Ko, Jong Mi] Baylor Heart & Vasc Inst, Dallas, TX USA. [Filardo, Giovanni] Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Filardo, Giovanni] Baylor Univ, Med Ctr, Dallas, TX USA. [Filardo, Giovanni] Heart Hosp Baylor, Plano, TX USA. [Filardo, Giovanni] So Methodist Univ, Dallas, TX 75275 USA. [Siegel, Robert J.; Dollar, Allen L.; Ross, Elizabeth M.; Shirani, Jamshid] NHLBI, Pathol Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, WC (reprint author), Baylor Hlth Care Syst, Dept Internal Med, Dallas, TX USA. EM wc.roberts@baylorhealth.edu FU Baylor Health Care System Foundation FX This work was supported by grants from Baylor Health Care System Foundation. NR 31 TC 13 Z9 13 U1 0 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 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2013 VL 112 IS 6 BP 904 EP 909 DI 10.1016/j.amjcard.2013.04.061 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 224PN UT WOS:000324900700024 PM 23768457 ER PT J AU Wilson, RA Teng, L Bachmeyer, KM Bissonnette, MLZ Husain, AN Parham, DM Triche, TJ Wing, MR Gastier-Foster, JM Barr, FG Hawkins, DS Anderson, JR Skapek, SX Volchenboum, SL AF Wilson, Raphael A. Teng, Ling Bachmeyer, Karen M. Bissonnette, Mei Lin Z. Husain, Aliya N. Parham, David M. Triche, Timothy J. Wing, Michele R. Gastier-Foster, Julie M. Barr, Frederic G. Hawkins, Douglas S. Anderson, James R. Skapek, Stephen X. Volchenboum, Samuel L. TI A Novel Algorithm for Simplification of Complex Gene Classifiers in Cancer SO CANCER RESEARCH LA English DT Article ID CHILDRENS ONCOLOGY GROUP; ALVEOLAR RHABDOMYOSARCOMA; SURVIVAL PREDICTION; EXPRESSION; IMMUNOHISTOCHEMISTRY; CLASSIFICATION; CHILDHOOD; MARKER; TUMORS; PAX3 AB The clinical application of complex molecular classifiers as diagnostic or prognostic tools has been limited by the time and cost needed to apply them to patients. Using an existing 50-gene expression signature known to separate two molecular subtypes of the pediatric cancer rhabdomyosarcoma, we show that an exhaustive iterative search algorithm can distill this complex classifier down to two or three features with equal discrimination. We validated the two-gene signatures using three separate and distinct datasets, including one that uses degraded RNA extracted from formalin-fixed, paraffin-embedded material. Finally, to show the generalizability of our algorithm, we applied it to a lung cancer dataset to find minimal gene signatures that can distinguish survival. Our approach can easily be generalized and coupled to existing technical platforms to facilitate the discovery of simplified signatures that are ready for routine clinical use. (C)2013 AACR. C1 [Wilson, Raphael A.; Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Div Hematol Oncol, Dallas, TX USA. [Wilson, Raphael A.; Skapek, Stephen X.] Childrens Med Ctr, Dallas, TX 75235 USA. [Parham, David M.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Triche, Timothy J.] Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA. [Triche, Timothy J.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Wing, Michele R.; Gastier-Foster, Julie M.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Wing, Michele R.; Gastier-Foster, Julie M.] Ohio State Univ, Lab Med, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Wing, Michele R.; Gastier-Foster, Julie M.] Ohio State Univ, Dept Pathol & Pediat, Columbus, OH 43210 USA. [Barr, Frederic G.] NCI, Bethesda, MD 20892 USA. [Hawkins, Douglas S.] Univ Washington, Dept Pediat, Div Hematol Oncol, Seattle, WA 98195 USA. [Hawkins, Douglas S.] Seattle Childrens Hosp, Seattle, WA USA. [Anderson, James R.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Biostat, Omaha, NE USA. [Teng, Ling; Bachmeyer, Karen M.; Volchenboum, Samuel L.] Univ Chicago, Dept Pediat, Sect Pediat Hematol Oncol, Chicago, IL 60637 USA. [Bissonnette, Mei Lin Z.; Husain, Aliya N.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Volchenboum, Samuel L.] Univ Chicago, Ctr Res Informat, Chicago, IL 60637 USA. [Volchenboum, Samuel L.] Univ Chicago, Computat Inst, Chicago, IL 60637 USA. RP Volchenboum, SL (reprint author), Univ Chicago, 900 E 57th St,KCBD 5130, Chicago, IL 60637 USA. EM stephen.skapek@utsouthwestern.edu OI Wilson, Raphael/0000-0003-3325-6734 FU St. Baldrick's Foundation; NIH [RC2 CA148216]; Intramural Research Program of the National Cancer Institute FX This work was supported by funding from the St. Baldrick's Foundation (J.R. Anderson, D.S. Hawkins, S.X. Skapek, S.L. Volchenboum), NIH RC2 CA148216 (J.R. Anderson, J.M. Gastier-Foster, D.S. Hawkins, S.X. Skapek, T.J Triche), and the Intramural Research Program of the National Cancer Institute (F.G. Barr). NR 22 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2013 VL 73 IS 18 BP 5625 EP 5632 DI 10.1158/0008-5472.CAN-13-0324 PG 8 WC Oncology SC Oncology GA 223LK UT WOS:000324806300004 PM 23913937 ER PT J AU Cronin, JC Watkins-Chow, DE Incao, A Hasskamp, JH Schonewolf, N Aoude, LG Hayward, NK Bastian, BC Dummer, R Loftus, SK Pavan, WJ AF Cronin, Julia C. Watkins-Chow, Dawn E. Incao, Art Hasskamp, Joanne H. Schoenewolf, Nicola Aoude, Lauren G. Hayward, Nicholas K. Bastian, Boris C. Dummer, Reinhard Loftus, Stacie K. Pavan, William J. TI SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis SO CANCER RESEARCH LA English DT Article ID UBIQUITIN-PROTEASOME PATHWAY; WAARDENBURG-SYNDROME; LINEAGE SURVIVAL; MITF; MUTATIONS; EXPRESSION; MOUSE; PROGRESSION; ACTIVATION; PROTEIN AB The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G(1) phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma. (C) 2013 AACR. C1 [Cronin, Julia C.; Watkins-Chow, Dawn E.; Incao, Art; Loftus, Stacie K.; Pavan, William J.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Hasskamp, Joanne H.] Medstar Franklin Sq Med Ctr, Maryland Melanoma Ctr, Baltimore, MD USA. [Schoenewolf, Nicola; Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Aoude, Lauren G.; Hayward, Nicholas K.] Queensland Inst Med Res, Oncogenom Lab, Brisbane, Qld 4006, Australia. [Bastian, Boris C.] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. RP Loftus, SK (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A51, Bethesda, MD 20892 USA. EM sloftus@mail.nih.gov RI Aoude, Lauren/C-7484-2014; hayward, nicholas/C-1367-2015; OI Aoude, Lauren/0000-0003-1448-3923; hayward, nicholas/0000-0003-4760-1033; Watkins-Chow, Dawn/0000-0002-4355-0868 FU National Human Genome Research Institute, NIH; National Health and Medical Research Council of Australia (NHMRC) FX This work was supported by the National Human Genome Research Institute, NIH, and the National Health and Medical Research Council of Australia (NHMRC). N.K. Hayward is supported by a Senior Principal Research Fellowship from the NHMRC. NR 47 TC 17 Z9 17 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2013 VL 73 IS 18 BP 5709 EP 5718 DI 10.1158/0008-5472.CAN-12-4620 PG 10 WC Oncology SC Oncology GA 223LK UT WOS:000324806300011 PM 23913827 ER PT J AU Zhang, SY Huang, WC Zhang, L Zhang, CY Lowery, FJ Ding, ZX Guo, H Wang, H Huang, SY Sahin, AA Aldape, KD Steeg, PS Yu, D AF Zhang, Siyuan Huang, Wen-Chien Zhang, Lin Zhang, Chenyu Lowery, Frank J. Ding, Zhaoxi Guo, Hua Wang, Hai Huang, Suyun Sahin, Aysegul A. Aldape, Kenneth D. Steeg, Patricia S. Yu, Dihua TI Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases SO CANCER RESEARCH LA English DT Article ID NERVOUS-SYSTEM METASTASES; TRASTUZUMAB RESISTANCE; CELL-LINES; IN-VITRO; ACTIVATION; BARRIER; INHIBITION; LAPATINIB; HER2; MECHANISMS AB Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis. (C) 2013 AACR. C1 [Zhang, Siyuan; Huang, Wen-Chien; Zhang, Lin; Zhang, Chenyu; Lowery, Frank J.; Ding, Zhaoxi; Guo, Hua; Wang, Hai; Yu, Dihua] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Huang, Suyun] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Sahin, Aysegul A.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Zhang, Lin; Lowery, Frank J.; Yu, Dihua] Grad Sch Biomed Sci Houston, Canc Biol Program, Houston, TX USA. [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Zhang, Siyuan] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. RP Yu, D (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Box 108, Houston, TX 77030 USA. EM dyu@mdanderson.org RI Zhang, Siyuan/A-1276-2014; OI Zhang, Siyuan/0000-0003-0910-3666; Lowery, Frank/0000-0002-4620-5293 FU DOD Center of Excellence grant [W81XWH-06-2-0033]; NIH [1K99CA158066-01]; Department of Defense Postdoctoral Fellowship [W81XWH-11-1-0003]; Isaiah J. Fidler Graduate Fellowship in Cancer Metastasis [PO1-CA099031, RO1-CA112567-06]; Breast Cancer Foundation Promise Grant [KG091020]; Cancer Prevention Research Institute of Texas [RP100726]; Mackay Memorial Hospital, Taipei, Taiwan FX This work was supported by DOD Center of Excellence grant (P.S. Steeg) subproject W81XWH-06-2-0033 (D. Yu), NIH Pathway to Independence grant 1K99CA158066-01 (S. Zhang), Department of Defense Postdoctoral Fellowship W81XWH-11-1-0003 (C. Zhang), Isaiah J. Fidler Graduate Fellowship in Cancer Metastasis (F.J. Lowery), PO1-CA099031 project 4 (D. Yu), RO1-CA112567-06 (D. Yu), Susan G. Komen Breast Cancer Foundation Promise Grant KG091020 (D. Yu), and Cancer Prevention Research Institute of Texas Grant RP100726 (D. Yu). Dr. D. Yu is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at MD Anderson Cancer Center. W.-C. Huang is partially sponsored by Mackay Memorial Hospital, Taipei, Taiwan. NR 33 TC 31 Z9 32 U1 1 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2013 VL 73 IS 18 BP 5764 EP 5774 DI 10.1158/0008-5472.CAN-12-1803 PG 11 WC Oncology SC Oncology GA 223LK UT WOS:000324806300016 PM 23913825 ER PT J AU Beard, RE Abate-Daga, D Rosati, SF Zheng, ZL Wunderlich, JR Rosenberg, SA Morgan, RA AF Beard, Rachel E. Abate-Daga, Daniel Rosati, Shannon F. Zheng, Zhili Wunderlich, John R. Rosenberg, Steven A. Morgan, Richard A. TI Gene Expression Profiling using Nanostring Digital RNA Counting to Identify Potential Target Antigens for Melanoma Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTIBODY-BASED IMMUNOTHERAPY; T-CELLS; CANCER REGRESSION; TRAG-3 ANTIGEN; BREAST-CANCER; MAGE-A; RECEPTOR; IDENTIFICATION; THERAPY; CSPG4 AB Purpose: The success of immunotherapy for the treatment of metastatic cancer is contingent on the identification of appropriate target antigens. Potential targets must be expressed on tumors but show restricted expression on normal tissues. To maximize patient eligibility, ideal target antigens should be expressed on a high percentage of tumors within a histology and, potentially, in multiple different malignancies. Design: A Nanostring probeset was designed containing 97 genes, 72 of which are considered potential candidate genes for immunotherapy. Five established melanoma cell lines, 59 resected metastatic melanoma tumors, and 31 normal tissue samples were profiled and analyzed using Nanostring technology. Results: Of the 72 potential target genes, 33 were overexpressed in more than 20% of studied melanoma tumor samples. Twenty of those genes were identified as differentially expressed between normal tissues and tumor samples by ANOVA analysis. Analysis of normal tissue gene expression identified seven genes with limited normal tissue expression that warrant further consideration as potential immunotherapy target antigens: CSAG2, MAGEA3, MAGEC2, IL13RA2, PRAME, CSPG4, and SOX10. These genes were highly overexpressed on a large percentage of the studied tumor samples, with expression in a limited number of normal tissue samples at much lower levels. Conclusion: The application of Nanostring RNA counting technology was used to directly quantitate the gene expression levels of multiple potential tumor antigens. Analysis of cell lines, 59 tumors, and normal tissues identified seven potential immunotherapy targets for the treatment of melanoma that could increase the number of patients potentially eligible for adoptive immunotherapy. (C) 2013 AACR. C1 [Beard, Rachel E.; Abate-Daga, Daniel; Rosati, Shannon F.; Zheng, Zhili; Wunderlich, John R.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20891 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, 10 Ctr Dr,Bldg 10 Hatfield CRC,Rm 3-5942, Bethesda, MD 20891 USA. EM rmorgan@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This work is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 50 TC 13 Z9 13 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2013 VL 19 IS 18 BP 4941 EP 4950 DI 10.1158/1078-0432.CCR-13-1253 PG 10 WC Oncology SC Oncology GA 219NF UT WOS:000324513000007 PM 24021875 ER PT J AU Sun, XZ Gierach, GL Sandhu, R Williams, T Midkiff, BR Lissowska, J Wesolowska, E Boyd, NF Johnson, NB Figueroa, JD Sherman, ME Troester, MA AF Sun, Xuezheng Gierach, Gretchen L. Sandhu, Rupninder Williams, Tyisha Midkiff, Bentley R. Lissowska, Jolanta Wesolowska, Ewa Boyd, Norman F. Johnson, Nicole B. Figueroa, Jonine D. Sherman, Mark E. Troester, Melissa A. TI Relationship of Mammographic Density and Gene Expression: Analysis of Normal Breast Tissue Surrounding Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR CHARACTERISTICS; MICROENVIRONMENTAL INFLUENCES; WOMENS HEALTH; RISK-FACTORS; STROMA; PROGRESSION; CARCINOMAS; PATTERNS; ASSOCIATION; MALIGNANCY AB Purpose: Previous studies of breast tissue gene expression have shown that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 patients with breast cancer from the population-based Polish Women's Breast Cancer Study. Experimental Design: Breast cancer cases were classified on the basis of a previously reported, biologically defined extratumoral gene expression signature with two subtypes: an Active subtype, which is associated with high expression of genes related to fibrosis and wound response, and an Inactive subtype, which has high expression of cellular adhesion genes. Mammographic density of the contralateral breast was assessed using pretreatment mammograms and a quantitative, reliable computer-assisted thresholding method. Breast tissue composition was evaluated on the basis of digital image analysis of tissue sections. Results: The Inactive extratumoral subtype was associated with significantly higher percentage mammographic density (PD) and dense area (DA) in univariate analysis (PD: P = 0.001; DA: P = 0.049) and in multivariable analyses adjusted for age and body mass index (PD: P = 0.004; DA: P = 0.049). Inactive/higher mammographic density tissue was characterized by a significantly higher percentage of stroma and a significantly lower percentage of adipose tissue, with no significant change in epithelial content. Analysis of published gene expression signatures suggested that Inactive/higher mammographic density tissue expressed increased estrogen response and decreased TGF-beta signaling. Conclusions: By linking novel molecular phenotypes with mammographic density, our results indicate that mammographic density reflects broad transcriptional changes, including changes in both epithelia-and stroma-derived signaling. (C) 2013 AACR. C1 [Sun, Xuezheng; Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Sandhu, Rupninder; Midkiff, Bentley R.; Troester, Melissa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Gierach, Gretchen L.; Figueroa, Jonine D.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Williams, Tyisha] Trinity Univ, Dept Biol, San Antonio, TX 78212 USA. [Lissowska, Jolanta; Wesolowska, Ewa] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta; Wesolowska, Ewa] Inst Oncol, Warsaw, Poland. [Boyd, Norman F.] Ontario Canc Inst, Campbell Family Inst Breast Canc Res, Toronto, ON M4X 1K9, Canada. [Johnson, Nicole B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Troester, MA (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435,135 Dauer Dr, Chapel Hill, NC 27599 USA. EM troester@unc.edu RI Gierach, Gretchen/E-1817-2016; OI Gierach, Gretchen/0000-0002-0165-5522; Lissowska, Jolanta/0000-0003-2695-5799 FU National Cancer Institute [U01-ES019472, R01-CA138255]; Breast SPORE Career Development Award [P50CA058223]; Avon Foundation; Intramural Research Program of the NIH, National Cancer Institute FX This project was supported by grants from the National Cancer Institute (U01-ES019472 and R01-CA138255), a Breast SPORE (P50CA058223) Career Development Award (to M. A. Troester), and a grant from the Avon Foundation. This work was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute. NR 56 TC 19 Z9 19 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2013 VL 19 IS 18 BP 4972 EP 4982 DI 10.1158/1078-0432.CCR-13-0029 PG 11 WC Oncology SC Oncology GA 219NF UT WOS:000324513000010 PM 23918601 ER PT J AU Zhang, G He, PJ Tan, HS Budhu, A Gaedcke, J Ghadimi, BM Ried, T Yfantis, HG Lee, DH Maitra, A Hanna, N Alexander, HR Hussain, SP AF Zhang, Geng He, Peijun Tan, Hanson Budhu, Anuradha Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Yfantis, Harris G. Lee, Dong H. Maitra, Anirban Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI Integration of Metabolomics and Transcriptomics Revealed a Fatty Acid Network Exerting Growth Inhibitory Effects in Human Pancreatic Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PALMITATE-INDUCED APOPTOSIS; BREAST-CANCER; MASS-SPECTROMETRY; SYSTEMS BIOLOGY; METABOLISM; CELLS; IDENTIFICATION; PROLIFERATION; FRAMEWORK; RESPONSES AB Purpose: To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics. Experimental Design: Weconducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles. Results: Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells. Conclusions: Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. (C) 2013 AACR. C1 [Zhang, Geng; He, Peijun; Tan, Hanson; Budhu, Anuradha; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Yfantis, Harris G.; Lee, Dong H.] Johns Hopkins Univ, Sch Med, Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Maitra, Anirban] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Dept Surg, Div Surg Oncol, Baltimore, MD 21201 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med, Dept Gen & Visceral Surg, Gottingen, Germany. RP Hussain, SP (reprint author), NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 3044B, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 49 TC 35 Z9 35 U1 3 U2 45 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2013 VL 19 IS 18 BP 4983 EP 4993 DI 10.1158/1078-0432.CCR-13-0209 PG 11 WC Oncology SC Oncology GA 219NF UT WOS:000324513000011 PM 23918603 ER PT J AU Weber, G Caruana, I Rouce, RH Barrett, AJ Gerdemann, U Leen, AM Rabin, KR Bollard, CM AF Weber, Gerrit Caruana, Ignazio Rouce, Rayne H. Barrett, A. John Gerdemann, Ulrike Leen, Ann M. Rabin, Karen R. Bollard, Catherine M. TI Generation of Tumor Antigen-Specific T Cell Lines from Pediatric Patients with Acute Lymphoblastic Leukemia-Implications for Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID DONOR LEUKOCYTE INFUSIONS; MINIMAL RESIDUAL DISEASE; CHRONIC MYELOID-LEUKEMIA; WT1 PEPTIDE VACCINATION; ADOPTIVE IMMUNOTHERAPY; ANTITUMOR IMMUNITY; COMPLETE REMISSION; GENE-EXPRESSION; HEALTHY DONORS; 2ND REMISSION AB Purpose: Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy. Experimental Design: Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Results: T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-gamma-enzyme-linked immunospot (ELISpot) and Cr-51-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short-and long-term coculture experiments. Conclusion: This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL. (C) 2013 AACR. C1 [Weber, Gerrit; Caruana, Ignazio; Gerdemann, Ulrike; Leen, Ann M.; Bollard, Catherine M.] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Weber, Gerrit; Caruana, Ignazio; Rouce, Rayne H.; Gerdemann, Ulrike; Leen, Ann M.; Rabin, Karen R.; Bollard, Catherine M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Bollard, Catherine M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Bollard, Catherine M.] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. [Weber, Gerrit; Caruana, Ignazio; Gerdemann, Ulrike; Leen, Ann M.; Bollard, Catherine M.] Methodist Hosp, Houston, TX 77030 USA. [Weber, Gerrit; Caruana, Ignazio; Rouce, Rayne H.; Gerdemann, Ulrike; Leen, Ann M.; Rabin, Karen R.; Bollard, Catherine M.] Texas Childrens Hosp, Houston, TX 77030 USA. [Rouce, Rayne H.; Rabin, Karen R.] Texas Childrens Canc Ctr, Houston, TX USA. [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Bollard, CM (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, 1102 Bates St,Suite 1770-01, Houston, TX 77030 USA. EM cmbollar@txch.org OI Caruana, Ignazio/0000-0002-9250-0605 FU NIH [1P01CA148600-01]; Cancer Prevention and Research Institute of Texas (CPRIT) [RP100484]; Leukemia Lymphoma Society; Gillson Longenbaugh Foundation; Kurt Groten Family Research Scholars' Program; St. Baldrick's Pediatric Cancer Foundation FX This work was supported in parts by NIH grant 1P01CA148600-01 and Cancer Prevention and Research Institute of Texas (CPRIT) grant RP100484. C. M. Bollard was also supported by the career development award from the Leukemia Lymphoma Society and an award from the Gillson Longenbaugh Foundation. K. R. Rabin was supported by the Kurt Groten Family Research Scholars' Program, the Gillson Longenbaugh Foundation, and the St. Baldrick's Pediatric Cancer Foundation. NR 50 TC 18 Z9 19 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2013 VL 19 IS 18 BP 5079 EP 5091 DI 10.1158/1078-0432.CCR-13-0955 PG 13 WC Oncology SC Oncology GA 219NF UT WOS:000324513000019 PM 23838315 ER PT J AU Qiu, P Li, Y Shiloach, J Cui, XZ Sun, JF Trinh, L Kubler-Kielb, J Vinogradov, E Mani, H Al-Hamad, M Fitz, Y Eichacker, PQ AF Qiu, Ping Li, Yan Shiloach, Joseph Cui, Xizhong Sun, Junfeng Trinh, Loc Kubler-Kielb, Joanna Vinogradov, Evgeny Mani, Haresh Al-Hamad, Mariam Fitz, Yvonne Eichacker, Peter Q. TI Bacillus anthracis Cell Wall Peptidoglycan but Not Lethal or Edema Toxins Produces Changes Consistent With Disseminated Intravascular Coagulation in a Rat Model SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE anthrax infection; sepsis; coagulopathy; thrombocytopenia; Bacillus anthracis; disseminated intravascular coagulation; peptidoglycan; lethal toxin; edema toxin ID TISSUE FACTOR EXPRESSION; INHALATIONAL ANTHRAX; ESCHERICHIA-COLI; PROCOAGULANT ACTIVITY; PROTECTIVE ANTIGEN; ANIMAL-MODELS; INFECTION; SEPSIS; PATHOLOGY; SHOCK AB Background. Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC. Methods and Results. To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P=.78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAT), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAT level (P <=.05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P <=.05 for all comparisons except for PAT level). Conclusion. DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET. C1 [Qiu, Ping; Li, Yan; Cui, Xizhong; Sun, Junfeng; Al-Hamad, Mariam; Fitz, Yvonne; Eichacker, Peter Q.] Natl Inst Diabet, Dept Crit Care Med, Ctr Clin, Bethesda, MD USA. [Shiloach, Joseph; Trinh, Loc] Natl Inst Diabet, Bethesda, MD USA. [Kubler-Kielb, Joanna] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Mani, Haresh] Fairfax Hosp, Inova, Fairfax, VA USA. [Vinogradov, Evgeny] Natl Res Council Canada, Ottawa, ON, Canada. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.nih.gov OI Vinogradov, Evgeny/0000-0002-5364-1376 FU Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported by the Clinical Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 50 TC 7 Z9 9 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2013 VL 208 IS 6 BP 978 EP 989 DI 10.1093/infdis/jit247 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 219MD UT WOS:000324510200014 PM 23737601 ER PT J AU Heller, T Werner, JM Rahman, F Mizukoshi, E Sobao, Y Gordon, AM Sheets, A Sherker, AH Kessler, E Bean, KS Herrine, SK Stevens, M Schmitt, J Rehermann, B AF Heller, Theo Werner, Jens Martin Rahman, Fareed Mizukoshi, Eishiro Sobao, Yuji Gordon, Ann Marie Sheets, Arlene Sherker, Averell H. Kessler, Ellen Bean, Kathleen S. Herrine, Steven K. Stevens, M'Lou Schmitt, James Rehermann, Barbara TI Occupational Exposure to Hepatitis C Virus: Early T-Cell Responses in the Absence of Seroconversion in a Longitudinal Cohort Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE exposure; needlestick; antibody; T cell; hepatitis; healthcare worker ID HEALTH-CARE WORKERS; INJECTION-DRUG USERS; IMMUNE-RESPONSES; DETECTABLE VIREMIA; INFECTION; HCV; PERSISTENCE; RISK; TRANSMISSION; INDUCTION AB Background. T-cell responses have been described in seronegative patients who test negative for hepatitis C virus (HCV) RNA despite frequent HCV exposure. However, the cross-sectional design of those studies did not clarify whether T cells were indeed induced by low-level HCV exposure without seroconversion or whether they resulted from regular acute infection with subsequent antibody loss. Methods. Over a 10-year period, our longitudinal study recruited 72 healthcare workers with documented HCV exposure. We studied viremia and antibody and T-cell responses longitudinally for 6 months. Results. All healthcare workers remained negative for HCV RNA and antibodies. However, 48% developed proliferative T-cell response and 42% developed responses in interferon-gamma enzyme-linked immunosorbent spot assays, with 29 healthy HCV-unexposed controls used to define assay cutoffs. The response prevalence was associated with the transmission risk score. T-cell responses peaked at week 4 and returned to baseline by week 12 after exposure. They predominantly targeted nonstructural HCV proteins, which are not part of the HCV particle and thus must have been synthesized in infected cells. Conclusions. Subclinical transmission of HCV occurs frequently, resulting in infection and synthesis of nonstructural proteins despite undetectable systemic viremia. T-cell responses are more sensitive indicators of this low-level HCV exposure than antibodies. C1 [Heller, Theo; Werner, Jens Martin; Rahman, Fareed; Mizukoshi, Eishiro; Sobao, Yuji; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gordon, Ann Marie; Sheets, Arlene] Medstar Washington Hosp Ctr, Washington, DC USA. [Sherker, Averell H.] Medstar Washington Hosp Ctr, Ctr Liver Dis, Washington, DC USA. [Kessler, Ellen; Bean, Kathleen S.] Inova Fairfax Hosp, Falls Church, VA USA. [Herrine, Steven K.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Stevens, M'Lou; Schmitt, James] NIH, Occupat Med Serv, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, NIH, DHHS, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. EM rehermann@nih.gov OI Werner, Jens/0000-0001-7156-4370 FU National Institute for Diabetes, Digestive and Kidney Diseases, National Institute of Health; Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany [We-4675/1-1] FX This study was supported by the National Institute for Diabetes, Digestive and Kidney Diseases, National Institute of Health Intramural Research Program, and by the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany (We-4675/1-1 to JMW). NR 31 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2013 VL 208 IS 6 BP 1020 EP 1025 DI 10.1093/infdis/jit270 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 219MD UT WOS:000324510200018 PM 23801608 ER PT J AU Olkowski, S Forshey, BM Morrison, AC Rocha, C Vilcarromero, S Halsey, ES Kochel, TJ Scott, TW Stoddard, ST AF Olkowski, Sandra Forshey, Brett M. Morrison, Amy C. Rocha, Claudio Vilcarromero, Stalin Halsey, Eric S. Kochel, Tadeusz J. Scott, Thomas W. Stoddard, Steven T. TI Reduced Risk of Disease During Postsecondary Dengue Virus Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE dengue; dengue fever; antibody cross-protection; seroepidemiology ID POLYMERASE-CHAIN-REACTION; ORIGINAL ANTIGENIC SIN; HEMORRHAGIC-FEVER; VACCINE DEVELOPMENT; ANTIBODY; PERU; TRANSMISSION; IQUITOS; NEUTRALIZATION; SEROTYPES AB Background. Antibodies induced by infection with any 1 of 4 dengue virus (DENV) serotypes (DENV-1-4) may influence the clinical outcome of subsequent heterologous infections. To quantify potential cross-protective effects, we estimated disease risk as a function of DENV infection, using data from longitudinal studies performed from September 2006 through February 2011 in Iquitos, Peru, during periods of DENV-3 and DENV-4 transmission. Methods. DENV infections before and during the study period were determined by analysis of serial serum samples with virus neutralization tests. Third and fourth infections were classified as postsecondary infections. Dengue fever cases were detected by door-to-door surveillance for acute febrile illness. Results. Among susceptible participants, 39% (420/1077) and 53% (1595/2997) seroconverted to DENV-3 and DENV-4, respectively. Disease was detected in 7% of DENV-3 infections and 10% of DENV-4 infections. Disease during postsecondary infections was reduced by 93% for DENV-3 and 64% for DENV-4, compared with primary and secondary infections. Despite lower disease rates, postsecondary infections constituted a significant proportion of apparent infections (14% [for DENV-3 infections], 45% [for DENV-4 infections]). Conclusions. Preexisting heterotypic antibodies markedly reduced but did not eliminate the risk of disease in this study population. These results improve understanding of how preinfection history can be associated with dengue outcomes and DENV transmission dynamics. C1 [Olkowski, Sandra; Morrison, Amy C.; Scott, Thomas W.; Stoddard, Steven T.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Forshey, Brett M.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Scott, Thomas W.; Stoddard, Steven T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Forshey, Brett M.; Morrison, Amy C.; Rocha, Claudio; Vilcarromero, Stalin; Halsey, Eric S.; Kochel, Tadeusz J.] Naval Med Res Unit Six, Dept Virol, Lima, Peru. RP Olkowski, S (reprint author), Univ Calif Davis, Dept Entomol, 1 Shields Ave, Davis, CA 95616 USA. EM smolkowski@ucdavis.edu OI Vilcarromero, Stalin/0000-0002-9097-0638 FU National Institutes of Health [R01 AI06934]; US Military Infectious Disease Research Program [S0147_07_LI, S0216_09_LI, S0263_10_LI]; Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the National Institutes of Health (grant R01 AI06934) and the US Military Infectious Disease Research Program (grants S0147_07_LI, S0216_09_LI, and S0263_10_LI); the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security (to T. W. S.); and the Fogarty International Center, National Institutes of Health (to T. W. S.). NR 50 TC 38 Z9 39 U1 0 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2013 VL 208 IS 6 BP 1026 EP 1033 DI 10.1093/infdis/jit273 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 219MD UT WOS:000324510200019 PM 23776195 ER PT J AU La Rosa, C Longmate, J Lacey, SF Kaltcheva, T Sharan, R Marsano, D Kwon, P Drake, J Williams, B Denison, S Broyer, S Couture, L Nakamura, R Dadwal, S Kelsey, MI Krieg, AM Diamond, DJ Zaia, JA AF La Rosa, Corinna Longmate, Jeff Lacey, Simon F. Kaltcheva, Teodora Sharan, Rahul Marsano, Denise Kwon, Peter Drake, Jennifer Williams, Brenda Denison, Sharon Broyer, Suenell Couture, Larry Nakamura, Ryotaro Dadwal, Sanjeet Kelsey, Morris I. Krieg, Arthur M. Diamond, Don J. Zaia, John A. TI Clinical Evaluation of Safety and Immunogenicity of PADRE-Cytomegalovirus (CMV) and Tetanus-CMV Fusion Peptide Vaccines With or Without PF03512676 Adjuvant (vol 205, pg 1294, 2012) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Correction C1 [La Rosa, Corinna; Lacey, Simon F.; Kaltcheva, Teodora; Sharan, Rahul; Marsano, Denise; Kwon, Peter; Diamond, Don J.; Zaia, John A.] City Hope Comprehens Canc Ctr, City Hope, Div Translat Vaccine Res, Duarte, CA USA. [La Rosa, Corinna; Lacey, Simon F.; Kaltcheva, Teodora; Sharan, Rahul; Marsano, Denise; Kwon, Peter; Diamond, Don J.; Zaia, John A.] City Hope Comprehens Canc Ctr, City Hope, Dept Virol, Duarte, CA USA. [Longmate, Jeff] City Hope Comprehens Canc Ctr, City Hope, Dept Informat Sci, Div Biostat, Duarte, CA USA. [Drake, Jennifer; Williams, Brenda] City Hope Comprehens Canc Ctr, City Hope, Dept Informat Sci, Duarte, CA USA. [Drake, Jennifer; Williams, Brenda] City Hope Comprehens Canc Ctr, City Hope, Gen Clin Res Ctr, Duarte, CA USA. [Denison, Sharon] City Hope Comprehens Canc Ctr, City Hope, Dept Inpatient Pharm, Duarte, CA USA. [Broyer, Suenell; Couture, Larry] City Hope Comprehens Canc Ctr, City Hope, Ctr Appl Technol Dev, Duarte, CA USA. [Nakamura, Ryotaro] City Hope Comprehens Canc Ctr, City Hope, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA USA. [Dadwal, Sanjeet] City Hope Comprehens Canc Ctr, City Hope, Beckman Res Inst, Div Infect Dis, Duarte, CA USA. [Kelsey, Morris I.] NCI, Rapid Access Intervent Dev Program, Dev Therapeut Program, Frederick, MD 21701 USA. [Krieg, Arthur M.] Atlas Venture, Cambridge, MA USA. RP La Rosa, C (reprint author), City Hope Comprehens Canc Ctr, City Hope, Div Translat Vaccine Res, Duarte, CA USA. NR 1 TC 1 Z9 1 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2013 VL 208 IS 6 BP 1038 EP 1038 DI 10.1093/infdis/jit282 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 219MD UT WOS:000324510200022 ER PT J AU Makris, SL Euling, SY Gray, LE Benson, R Foster, PMD AF Makris, Susan L. Euling, Susan Y. Gray, L. Earl, Jr. Benson, Robert Foster, Paul M. D. TI Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Dibutyl phthalate; Risk assessment; Toxicogenomic ID N-BUTYL PHTHALATE; IN-UTERO EXPOSURE; FETAL-RAT TESTIS; DOSE-DEPENDENT ALTERATIONS; DI(N-BUTYL) PHTHALATE; GENE-EXPRESSION; TESTICULAR DYSGENESIS; LATE-GESTATION; LATE PREGNANCY; TRACT LESIONS AB A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts led to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data. Published by Elsevier Inc. C1 [Makris, Susan L.; Euling, Susan Y.] US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Gray, L. Earl, Jr.] US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Benson, Robert] US EPA, Denver, CO 80202 USA. [Foster, Paul M. D.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Makris, SL (reprint author), US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Mail Code 8623P,1200 Penn Ave NW, Washington, DC 20460 USA. EM makris.susan@epa.gov NR 64 TC 7 Z9 7 U1 0 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2013 VL 271 IS 3 BP 336 EP 348 DI 10.1016/j.taap.2010.09.006 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 221OZ UT WOS:000324669500005 PM 20849870 ER PT J AU You, Q Holt, M Yin, H Li, GY Hu, CJ Ju, C AF You, Qiang Holt, Michael Yin, Hao Li, Guiying Hu, Cheng-Jun Ju, Cynthia TI Role of hepatic resident and infiltrating macrophages in liver repair after acute injury SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Acetaminophen; Kupffer cells; Microvasculature; Angiogenesis ID SKELETAL-MUSCLE REGENERATION; INGESTED APOPTOTIC CELLS; ANGIOGENIC SWITCH; ACETAMINOPHEN HEPATOTOXICITY; BREAST-CANCER; MICE; INFLAMMATION; EXPRESSION; VEGF; HIF-1-ALPHA AB Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury. (C) 2013 Elsevier Inc. All rights reserved. C1 [You, Qiang] Nanjing Med Univ, Dept Biotherapy, Affiliated Hosp 2, Nanjing 210011, Jiangsu, Peoples R China. [You, Qiang; Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. [Ju, Cynthia] Univ Colorado, Integrated Dept Immunol, Aurora, CO 80045 USA. [Holt, Michael] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Yin, Hao] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Li, Guiying] Jilin Univ, Coll Life Sci, Minist Educ, Key Lab Mol Enzymol & Engn, Changchun 130023, Jilin, Peoples R China. [Hu, Cheng-Jun] Univ Colorado, Dept Craniofacial Biol, Aurora, CO 80045 USA. RP Ju, C (reprint author), Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Anschutz Med Campus, Aurora, CO 80045 USA. EM cynthia.ju@ucdenver.edu FU U.S. National Institutes of Health [RO1 ES012914]; ALSAM Foundation Skaggs Scholars Program Award FX U.S. National Institutes of Health grant RO1 ES012914 (to C.J.) and The ALSAM Foundation Skaggs Scholars Program Award (to C.J.). NR 36 TC 27 Z9 28 U1 2 U2 32 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2013 VL 86 IS 6 BP 836 EP 843 DI 10.1016/j.bcp.2013.07.006 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 217MD UT WOS:000324362700014 PM 23876342 ER PT J AU Walker, EF Trotman, HD Pearce, BD Addington, J Cadenhead, KS Cornblatt, BA Heinssen, R Mathalon, DH Perkins, DO Seidman, LJ Tsuang, MT Cannon, TD McGlashan, TH Woods, SW AF Walker, Elaine F. Trotman, Hanan D. Pearce, Brad D. Addington, Jean Cadenhead, Kristin S. Cornblatt, Barbara A. Heinssen, Robert Mathalon, Daniel H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Cannon, Tyrone D. McGlashan, Thomas H. Woods, Scott W. TI Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cortisol; high-risk; longitudinal; prodrome; psychosis; stress ID ULTRA-HIGH-RISK; DEHYDROEPIANDROSTERONE-SULFATE LEVELS; PITUITARY-ADRENAL AXIS; RECEPTOR MESSENGER-RNA; 1ST-EPISODE PSYCHOSIS; SCHIZOPHRENIC-PATIENTS; HIPPOCAMPAL VOLUME; DOPAMINE RELEASE; STRESS; BRAIN AB Background: Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity. Methods: Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol. Results: Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted. Conclusions: The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research. C1 [Walker, Elaine F.; Trotman, Hanan D.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Pearce, Brad D.] Emory Univ, Ctr Translat Neurosci & Computat & Life Sci, Atlanta, GA 30322 USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Heinssen, Robert] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Tsuang, Ming T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Tsuang, Ming T.] Univ Calif Irvine, Dept Psychiat, Irvine, CA 92717 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. RP Walker, EF (reprint author), Emory Univ, Dept Psychol, 303 Psychol Bldg,532 N Kilgo Circle,36 Eagle Row, Atlanta, GA 30322 USA. EM psyefw@emory.edu OI Mathalon, Daniel/0000-0001-6090-4974 FU National Institute of Mental Health [U01MH081988, U01MHMH081988, R01 MH 60720, U01 MH08022, K24 MH76191, U01 MH081902, U01 MH82022, 1-R21- MH083138-1, 1R01-MH092512, 5R2-R21-MH079189, 1-R21-MH068513]; Emory Neuroscience Initiative Grant [UR01 MH081944]; Ontario Mental Health Foundation; Schizophrenia Society of Ontario; National Alliance for Research on Schizophrenia and Depression (NARSAD); Staglin Music Festival for Mental Health; Stanley Medical Research Institute; Janssen Pharmaceuticals; Personality Disorder Research Foundation; Eli Lilly and Company; San Francisco Foundation; AstraZeneca Pharmaceuticals; Bristol-Myers Squibb; Otsuka Pharmaceutical Co Ltd; Dainippon Sumitomo Pharma; GlaxoSmithKline; Forest Labs; Shire; National Institute on Aging; Commonwealth of Massachusetts Department of Mental Health, NARSAD; Sidney R. Baer Jr. Foundation; NARSAD; Donaghue foundation; Stanley foundation; UCB Pharma; Pfizer FX This research was supported by National Institute of Mental Health Grants U01MH081988 (to EFW); U01MHMH081988 (to JA); U01MHMH081988 (to BAC); U01MHMH081988, R01 MH 60720, U01 MH08022, and K24 MH76191 (to KSC); U01 MH081902 (to TDC); U01MHMH081988 (to DOP); U01MHMH081988 (to LJS); U01MHMH081988 and U01 MH82022 (to SWW); 1-R21- MH083138-1, 1R01-MH092512, 5R2-R21-MH079189, 1-R21-MH068513, and the Emory Neuroscience Initiative Grant (to BDP); and UR01 MH081944 (to MTT).; Dr. Addington has received investigator-initiated research funding support from multiple not-for-profit entities, including the National Institute of Mental Health, Ontario Mental Health Foundation, and the Schizophrenia Society of Ontario. Dr. Addington has served as a consultant for Pfizer, AstraZeneca Pharmaceuticals, and Janssen Pharmaceuticals. Dr. Cadenhead has received investigator-initiated research funding support from the National Institute of Mental Health and has no biomedical financial interests or potential conflicts of interests to report. Dr. Cannon has received investigator-initiated research funding support from multiple not-for-profit entities, including the National Institute of Mental Health, National Alliance for Research on Schizophrenia and Depression (NARSAD), and the Staglin Music Festival for Mental Health. Dr. Cannon has served as a consultant for Janssen Pharmaceuticals and Eli Lilly and Company. Dr. Cornblatt has received investigator-initiated research funding support from not-for-profit entities including the National Institute of Mental Health and the Stanley Medical Research Institute. She has also served as a consultant for Eli Lilly and Company, Bristol-Myers Squibb, and Janssen Pharmaceuticals and has received unrestricted educational grants from Janssen Pharmaceuticals. Dr. Cornblatt has also served as a consultant for Hoffman La Roche. Dr. Heinssen is an employee of the nonprofit National Institutes of Health and reports no biomedical financial interests or potential conflicts of interest. Dr. Mathalon has received investigator-initiated research funding support from not-for-profit entities, including the National Institute of Mental Health. He has served as a scientific consultant to Bristol Myers Squibb. Dr. McGlashan has received investigator-initiated research funding support from the National Institute of Mental Health, the Personality Disorder Research Foundation, and Eli Lilly and Company. Dr. McGlashan has served as a consultant for Eli Lilly and Company, Pfizer, Solvay/Wyeth, and Roche Pharmaceuticals. Dr. Pearce reports no biomedical financial interests or potential conflicts of interest Dr. Perkins has received investigator-initiated research funding support from not-for-profit entities, including the National Institute of Mental Health and The San Francisco Foundation. In the past, Dr. Perkins received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Otsuka Pharmaceutical Co Ltd, Eli Lilly and Company, Janssen Pharmaceuticals, and Pfizer and consulting and educational fees from Dainippon Sumitomo Pharma, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceuticals, GlaxoSmithKline, Forest Labs, Pfizer, and Shire. Dr. Seidman has received investigator-initiated research funding support from multiple not-for-profit entities, including the National Institute of Mental Health, the National Institute on Aging, the Commonwealth of Massachusetts Department of Mental Health, NARSAD, and the Sidney R. Baer Jr. Foundation. He has not received funding from for-profit-entities in the past 12 months. In the past, he received unrestricted educational support from Janssen Pharmaceuticals and has served as a consultant for Shire. Dr. Tsuang has received investigator-initiated research funding support from multiple not-for-profit entities, including the National Institute of Mental Health and has received research grants from Janssen Pharmaceuticals. Dr. Trotman reports no biomedical financial interests or potential conflicts of interest.; Dr. Walker has received investigator-initiated research funding support from not-for-profit entities, including the National Institute of Mental Health and NARSAD and reports no biomedical financial interests or potential conflicts of interest. Dr. Woods has received investigator-initiated research funding support from multiple not-for-profit entities, including the National Institute of Mental Health, the Donaghue and Stanley foundations, and NARSAD. In addition, he has received investigator-initiated research funding support from multiple for-profit entities, including UCB Pharma and Bristol-Myers Squibb and has consulted for Otsuka and Schering-Plough. Dr. Woods has not served on speaker's bureaus. NR 57 TC 56 Z9 58 U1 3 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2013 VL 74 IS 6 BP 410 EP 417 DI 10.1016/j.biopsych.2013.02.016 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 213IZ UT WOS:000324051200006 PM 23562006 ER PT J AU Hahn, B Harvey, AN Concheiro-Guisan, M Huestis, MA Holcomb, HH Gold, JM AF Hahn, Britta Harvey, Alexander N. Concheiro-Guisan, Marta Huestis, Marilyn A. Holcomb, Henry H. Gold, James M. TI A Test of the Cognitive Self-Medication Hypothesis of Tobacco Smoking in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cognitive deficits; nicotine; schizophrenia; self-medication; smoking; withdrawal ID NICOTINIC RECEPTOR MECHANISMS; CIGARETTE-SMOKING; TRANSDERMAL NICOTINE; PSYCHIATRIC-SYMPTOMS; FAGERSTROM TEST; WORKING-MEMORY; NASAL SPRAY; PERFORMANCE; DEFICITS; TASK AB Background: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. Methods: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. Results: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. Conclusions: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts. C1 [Hahn, Britta; Harvey, Alexander N.; Holcomb, Henry H.; Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. [Concheiro-Guisan, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, Baltimore, MD USA. RP Hahn, B (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Catonsville, MD 21228 USA. EM bhahn@mprc.umaryland.edu FU Intramural Research Program of the National Institutes of Health; National Institute on Drug Abuse; National Institute on Drug Abuse Residential Research Support Services Contract [N01DA-5-9909] FX This project was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, and National Institute on Drug Abuse Residential Research Support Services Contract N01DA-5-9909 (Kelly PI). We would like to thank Dr. Bernard Fischer for his help with medical clearances of study volunteers, Dr. Robert McMahon for statistical advice, and Sharon August and Leeka Hubzin for their help with subject recruitment. Thanks go to Dr. Ian Stolerman for helpful comments on this manuscript. We also thank all volunteers participating in this study. NR 67 TC 20 Z9 20 U1 3 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2013 VL 74 IS 6 BP 436 EP 443 DI 10.1016/j.biopsych.2013.03.017 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 213IZ UT WOS:000324051200009 PM 23660272 ER PT J AU Moran, LV Tagamets, MA Sampath, H O'Donnell, A Stein, EA Kochunov, P Hong, LE AF Moran, Lauren V. Tagamets, Malle A. Sampath, Hemalatha O'Donnell, Alan Stein, Elliot A. Kochunov, Peter Hong, L. Elliot TI Disruption of Anterior Insula Modulation of Large-Scale Brain Networks in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anterior insula; central executive network; default mode network; imaging; salience network; schizophrenia ID LIKELIHOOD ESTIMATION METAANALYSIS; DEFAULT-MODE; FUNCTIONAL CONNECTIVITY; SUSTAINED ATTENTION; PREFRONTAL CORTEX; WORKING-MEMORY; FMRI; DISORDERS; PERFORMANCE; CORE AB Background: Systems level modeling of functional magnetic resonance imaging data has demonstrated dysfunction of several large-scale brain networks in schizophrenia. Anomalies across multiple functional networks associated with schizophrenia could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. The right anterior insula has been shown to modulate activity in the central executive and default mode networks in healthy individuals. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in schizophrenia and associated with cognitive deficits. Methods: In 44 patients with schizophrenia and 44 healthy control subjects, we used seed-based resting state functional connectivity functional magnetic resonance imaging analysis to examine connectivity between right insular subregions and central executive/default mode network regions. We also performed two directed connectivity analyses of resting state data: Granger analysis and confirmatory structural equation modeling. Between-group differences in path coefficients were used to evaluate anterior insula modulation of central executive and default mode networks. Cognitive performance was assessed with the rapid visual information processing task, a test of sustained attention. Results: With multiple connectivity techniques, we found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with schizophrenia. The strength of right anterior insula modulation of these networks predicted cognitive performance. Conclusions: Individuals with schizophrenia have impaired right anterior insula modulation of large-scale brain networks. The right anterior insula might be an emergent pathophysiological gateway in schizophrenia. C1 [Moran, Lauren V.; Tagamets, Malle A.; Sampath, Hemalatha; O'Donnell, Alan; Kochunov, Peter; Hong, L. Elliot] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA. [Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP Moran, LV (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, POB 21247, Catonsville, MD 21228 USA. EM lmoran@mprc.umaryland.edu FU National Institutes of Health [T32MH067533, R01DA027680, R01MH085646, R21DA033817]; National Institute on Drug Abuse Intramural Research Program, National Institutes of Health FX Financial support was received from National Institutes of Health Grants T32MH067533, R01DA027680, R01MH085646, and R21DA033817. This research was also supported by the National Institute on Drug Abuse Intramural Research Program, National Institutes of Health. NR 63 TC 47 Z9 50 U1 1 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2013 VL 74 IS 6 BP 467 EP 474 DI 10.1016/j.biopsych.2013.02.029 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 213IZ UT WOS:000324051200013 PM 23623456 ER PT J AU Yang, WC Guo, DY Harris, MA Cui, Y Gluhak-Heinrich, J Wu, JJ Chen, XD Skinner, C Nyman, JS Edwards, JR Mundy, GR Lichtler, A Kream, BE Rowe, DW Kalajzic, I David, V Quarles, DL Villareal, D Scott, G Ray, M Liu, S Martin, JF Mishina, Y Harris, SE AF Yang, Wuchen Guo, Dayong Harris, Marie A. Cui, Yong Gluhak-Heinrich, Jelica Wu, Junjie Chen, Xiao-Dong Skinner, Charles Nyman, Jeffry S. Edwards, James R. Mundy, Gregory R. Lichtler, Alex Kream, Barbara E. Rowe, David W. Kalajzic, Ivo David, Val Quarles, Darryl L. Villareal, Demetri Scott, Greg Ray, Manas Liu, S. Martin, James F. Mishina, Yuji Harris, Stephen E. TI Bmp2 in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE Bmp2; Osteoblasts; Angiogenesis; Mesenchymal stem cells; VegfA; alpha-SMA plus cells ID PROGENITOR CELLS; DISTRACTION OSTEOGENESIS; MORPHOGENETIC PROTEIN-2; GENE-TRANSCRIPTION; IN-VIVO; EXPRESSION; DIFFERENTIATION; ANGIOGENESIS; VEGF; MATRIX AB We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO(ob) osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (alpha-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in alpha-SMA(+) MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells. C1 [Yang, Wuchen; Harris, Marie A.; Cui, Yong; Gluhak-Heinrich, Jelica; Villareal, Demetri; Harris, Stephen E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Periodont, San Antonio, TX 78229 USA. [Yang, Wuchen] Univ Connecticut, Ctr Hlth, Dept Craniofacial Sci, Farmington, CT 06030 USA. [Guo, Dayong] Univ Missouri, Dept Oral Biol, Kansas City, MO 64108 USA. [Guo, Dayong] Regeneron Inc, Tarrytown, NY 10591 USA. [Wu, Junjie; Chen, Xiao-Dong; Skinner, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA. [Nyman, Jeffry S.; Edwards, James R.; Mundy, Gregory R.] Vanderbilt Univ, Med Ctr, Dept Orthopaed Surg & Rehabil, Nashville, TN 37232 USA. [Nyman, Jeffry S.; Edwards, James R.; Mundy, Gregory R.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Bone Biol, Nashville, TN 37232 USA. [Lichtler, Alex; Kream, Barbara E.; Rowe, David W.; Kalajzic, Ivo] Univ Connecticut, Ctr Hlth, Ctr Regenerat Med & Skeletal Dev, Farmington, CT USA. [David, Val; Quarles, Darryl L.] Univ Tennessee, Hlth Sci Ctr, Dept Med, Memphis, TN 38104 USA. [Scott, Greg; Ray, Manas] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Liu, S.] Genzyme Co, Endocrine & Renal Sci, Framingham, MA 01701 USA. [Martin, James F.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Harris, SE (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Periodont, San Antonio, TX 78229 USA. EM harris@uthscsa.edu RI Nyman, Jeffry/L-5736-2013 FU US National Institutes of Health [R01 AR054616, AR44728, R01DE020843, ES071003-11] FX This work was supported by the US National Institutes of Health [grant numbers R01 AR054616 and AR44728 to S.E.H.; R01DE020843 and ES071003-11 to Y.M.]. Deposited in PMC for release after 12 months. NR 60 TC 20 Z9 20 U1 0 U2 18 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2013 VL 126 IS 18 BP 4085 EP 4098 DI 10.1242/jcs.118596 PG 14 WC Cell Biology SC Cell Biology GA 217SK UT WOS:000324380700004 PM 23843612 ER PT J AU Myles, IA Fontecilla, NM Janelsins, BM Vithayathil, PJ Segre, JA Datta, SK AF Myles, Ian A. Fontecilla, Natalia M. Janelsins, Brian M. Vithayathil, Paul J. Segre, Julia A. Datta, Sandip K. TI Parental Dietary Fat Intake Alters Offspring Microbiome and Immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ENHANCES HEPATIC INFLAMMATION; PATHOGENIC T(H)17 CELLS; REGULATORY T-CELLS; HYGIENE HYPOTHESIS; GUT MICROBIOTA; HISTONE MODIFICATION; ENDOTOXIN EXPOSURE; DISEASE; MICE; ACIDS AB Mechanisms underlying modern increases in prevalence of human inflammatory diseases remain unclear. The hygiene hypothesis postulates that decreased microbial exposure has, in part, driven this immune dysregulation. However, dietary fatty acids also influence immunity, partially through modulation of responses to microbes. Prior reports have described the direct effects of high-fat diets on the gut microbiome and inflammation, and some have additionally shown metabolic consequences for offspring. Our study sought to expand on these previous observations to identify the effects of parental diet on offspring immunity using mouse models to provide insights into challenging aspects of human health. To test the hypothesis that parental dietary fat consumption during gestation and lactation influences offspring immunity, we compared pups of mice fed either a Western diet (WD) fatty acid profile or a standard low-fat diet. All pups were weaned onto the control diet to specifically test the effects of early developmental fat exposure on immune development. Pups from WD breeders were not obese or diabetic, but still had worse outcomes in models of infection, autoimmunity, and allergic sensitization. They had heightened colonic inflammatory responses, with increased circulating bacterial LPS and muted systemic LPS responsiveness. These deleterious impacts of the WD were associated with alterations of the offspring gut microbiome. These results indicate that parental fat consumption can leave a "lard legacy" impacting offspring immunity and suggest inheritable microbiota may contribute to the modern patterns of human health and disease. C1 [Myles, Ian A.; Fontecilla, Natalia M.; Janelsins, Brian M.; Vithayathil, Paul J.; Datta, Sandip K.] NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Segre, Julia A.] NHGRI, Epithelial Biol Sect, NIH, Bethesda, MD 20892 USA. RP Datta, SK (reprint author), NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 33,Room 2W10A, Bethesda, MD 20892 USA. EM dattas@niaid.nih.gov OI Datta, Sandip/0000-0003-0243-7815 FU Office of Dietary Supplements; National Institutes of Health Intramural Research Program at National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute FX This work was supported by the Office of Dietary Supplements and the National Institutes of Health Intramural Research Program at National Institute of Allergy and Infectious Diseases and National Human Genome Research Institute. NR 60 TC 38 Z9 38 U1 5 U2 41 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 SEP 15 PY 2013 VL 191 IS 6 BP 3200 EP 3209 DI 10.4049/jimmunol.1301057 PG 10 WC Immunology SC Immunology GA 215JV UT WOS:000324206900039 PM 23935191 ER PT J AU Chu, J Song, HH Zarember, KA Mills, TA Gallin, JI AF Chu, Jessica Song, Helen H. Zarember, Kol A. Mills, Teresa A. Gallin, John I. TI Persistence of the Bacterial Pathogen Granulibacter bethesdensis in Chronic Granulomatous Disease Monocytes and Macrophages Lacking a Functional NADPH Oxidase SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LEGIONELLA-PNEUMOPHILA; INTERFERON-GAMMA; IFN-GAMMA; INTRACELLULAR MULTIPLICATION; ALVEOLAR MACROPHAGES; LEGIONNAIRES-DISEASE; BRUCELLA-MELITENSIS; RESPIRATORY BURST; ESCHERICHIA-COLI; REACTIVE OXYGEN AB Granulibacter bethesdensis is a Gram-negative pathogen in patients with chronic granulomatous disease (CGD), a deficiency in the phagocyte NADPH oxidase. Repeated isolation of genetically identical strains from the same patient over years, and prolonged waxing and waning seropositivity in some subjects, raises the possibility of long-term persistence. G. bethesdensis resists killing by serum, CGD polymorphonuclear leukocytes (PMN), and antimicrobial peptides, indicating resistance to nonoxidative killing mechanisms. Although G. bethesdensis extends the survival of PMN, persistent intracellular bacterial survival might rely on longer-lived macrophages and their precursor monocytes. Therefore, we examined phagocytic killing by primary human monocytes and monocyte-derived macrophages (MDM). Cells from both normal and CGD subjects internalized G. bethesdensis similarly. G. bethesdensis stimulated superoxide production in normal monocytes, but to a lesser degree than in normal PMN. Normal but not CGD monocytes and MDM killed G. bethesdensis and required in vitro treatment with IFN-gamma to maintain this killing effect. Although in vitro IFN-gamma did not enhance G. bethesdensis killing in CGD monocytes, it restricted growth in proportion to CGD PMN residual superoxide production, providing a potential method to identify patients responsive to IFN-gamma therapy. In IFN-gamma-treated CGD MDM, G. bethesdensis persisted for the duration of the study (7 d) without decreasing viability of the host cells. These results indicate that G. bethesdensis is highly resistant to oxygen-independent microbicides of myeloid cells, requires an intact NADPH oxidase for clearance, and can persist long-term in CGD mononuclear phagocytes, most likely relating to the persistence of this microorganism in infected CGD patients. C1 [Chu, Jessica; Song, Helen H.; Zarember, Kol A.; Mills, Teresa A.; Gallin, John I.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Gallin, JI (reprint author), NIAID, NIH, Bldg 10,Room 6-2551, Bethesda, MD 20892 USA. EM jgallin@nih.gov OI Chu, Jessica/0000-0002-5763-873X FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 79 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2013 VL 191 IS 6 BP 3297 EP 3307 DI 10.4049/jimmunol.1300200 PG 11 WC Immunology SC Immunology GA 215JV UT WOS:000324206900048 PM 23956436 ER PT J AU Michael, HT Ito, D McCullar, V Zhang, B Miller, JS Modiano, JF AF Michael, Helen T. Ito, Daisuke McCullar, Valarie Zhang, Bin Miller, Jeffrey S. Modiano, Jaime F. TI Isolation and characterization of canine natural killer cells SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Canine; NK cells; Interleukins ID CYTOTOXIC FACTOR NKCF; IG-LIKE RECEPTORS; MARROW TRANSPLANTATION; BLOOD-LYMPHOCYTES; PERIPHERAL-BLOOD; T-LYMPHOCYTES; DOGS; LEUKEMIAS; PROLIFERATION; IRRADIATION AB NM cells are non-T, non-B lymphocytes that kill target cells without previous activation. The immunophenotype and function of these cells in humans and mice are well defined, but canine NM cells remain incompletely characterized. Our objectives were to isolate and culture canine peripheral blood NM cells, and to define their immunophenotype and killing capability. PBMC were obtained from healthy dogs and T cells were depleted by immunomagnetic separation. The residual cells were cultured in media supplemented with IL-2, IL-15 or both, or with mouse embryonic liver (EL) feeder cells. Non-T, non-B lymphocytes survived and expanded in these cultures. IL-2 was necessary and sufficient for survival; the addition of IL-15 was necessary for expansion, but IL-15 alone did not support survival. Culture with EL cells and IL-2 also fostered survival and expansion. The non-T, non-B lymphocytes uniformly expressed CD45, MHC I, and showed significant cytotoxic activity against CTAC targets. Expression of MHC II, CD11/18 was restricted to subsets of these cells. The data show that cells meeting the criteria for NM cells in other species, i.e., non-T, non-B lymphocytes with cytotoxic activity, can be expanded from canine PBMC by T-cell depletion and culture with cytokines or feeder cells. Published by Elsevier B.V. C1 [Michael, Helen T.; Ito, Daisuke; Modiano, Jaime F.] Univ Minnesota, Coll Vet Med, Dept Vet Clin Sci, St Paul, MN 55108 USA. [Ito, Daisuke; McCullar, Valarie; Zhang, Bin; Miller, Jeffrey S.; Modiano, Jaime F.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [McCullar, Valarie; Zhang, Bin; Miller, Jeffrey S.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Miller, Jeffrey S.; Modiano, Jaime F.] Univ Minnesota, Ctr Immunol, Minneapolis, MN 55455 USA. [Michael, Helen T.] NCI, NIH, Bethesda, MD 20815 USA. [Michael, Helen T.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. RP Michael, HT (reprint author), 37 Convent Dr,Bldg 37,Room 5002, Bethesda, MD 20814 USA. EM helen.michael@nih.gov RI Ito, Daisuke/C-7593-2014; OI Ito, Daisuke/0000-0003-1350-637X; Miller, Jeffrey S/0000-0002-0339-4944; Modiano, Jaime/0000-0001-6398-7648 FU National Institutes of Health of the United States Public Health Service [P30 CA77598]; University of Minnesota Companion Animal Grant; University of Minnesota Animal Cancer Care and Research Program/Comparative Oncology Research Fund FX We thank Megan Duckett for expert technical help. We would like to acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by grant P30 CA77598 from the National Institutes of Health of the United States Public Health Service. This project was supported in part by a University of Minnesota Companion Animal Grant and by the University of Minnesota Animal Cancer Care and Research Program/Comparative Oncology Research Fund. NR 46 TC 7 Z9 7 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD SEP 15 PY 2013 VL 155 IS 3 BP 211 EP 217 DI 10.1016/j.vetimm.2013.06.013 PG 7 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 218TQ UT WOS:000324455800009 PM 23876304 ER PT J AU Keffer, JL Huecas, S Hammill, JT Wipf, P Andreu, JM Bewley, CA AF Keffer, Jessica L. Huecas, Sonia Hammill, Jared T. Wipf, Peter Andreu, Jose M. Bewley, Carole A. TI Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Bacterial cytoskeleton; Antibiotics; Natural products; Drug resistant bacteria ID DIVISION PROTEIN FTSZ; SMALL-MOLECULE INHIBITORS; CELL-DIVISION; ESCHERICHIA-COLI; ANTISTAPHYLOCOCCAL ACTIVITY; DRUG DISCOVERY; ANTIBIOTICS; TARGET; POTENT AB The bacterial cell division protein FtsZ polymerizes in a GTP-dependent manner to form a Z-ring that marks the plane of division. As a validated antimicrobial target, considerable efforts have been devoted to identify small molecule FtsZ inhibitors. We recently discovered the chrysophaentins, a novel suite of marine natural products that inhibit FtsZ activity in vitro. These natural products along with a synthetic hemi-chrysophaentin exhibit strong antimicrobial activity toward a broad spectrum of Gram-positive pathogens. To define their mechanisms of FtsZ inhibition and determine their in vivo effects in live bacteria, we used GTPase assays and fluorescence anisotropy to show that hemi-chrysophaentin competitively inhibits FtsZ activity. Furthermore, we developed a model system using a permeable Escherichia coli strain, envA1, together with an inducible FtsZ-yellow fluorescent protein construct to show by fluorescence microscopy that both chrysophaentin A and hemi-chrysophaentin disrupt Z-rings in live bacteria. We tested the E. coli system further by reproducing phenotypes observed for zantrins Z1 and Z3, and demonstrate that the alkaloid berberine, a reported FtsZ inhibitor, exhibits auto-fluorescence, making it incompatible with systems that employ GFP or YFP tagged FtsZ. These studies describe unique examples of nonnucleotide, competitive FtsZ inhibitors that disrupt FtsZ in vivo, together with a model system that should be useful for in vivo testing of FtsZ inhibitor leads that have been identified through in vitro screens but are unable to penetrate the Gram-negative outer membrane. Published by Elsevier Ltd. C1 [Keffer, Jessica L.; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Huecas, Sonia; Andreu, Jose M.] CSIC, Ctr Invest Biol, Madrid, Spain. [Hammill, Jared T.; Wipf, Peter] Univ Pittsburgh, Ctr Chem Methodol & Lib Dev, Pittsburgh, PA USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov RI Huecas, Sonia/K-1754-2014; OI Huecas, Sonia/0000-0002-6419-441X; Keffer, Jessica/0000-0002-0302-3588; Andreu, Jose M/0000-0001-8064-6933 FU National Institutes of Health (NIDDK); NIGMS [P50-GM067082]; Plan Nacional de Investigacion BFU [2011-23416]; CAM [S2010/BMD-2353]; Office of the Director, NIH FX We thank W. Margolin, H. Erikson, K. Young, and E. Harry for plasmids or bacterial strains; N. Dwyer (NIDDK) for assistance with confocal microscopy; and H. Erikson and A. Plaza for contributive discussion. This work was supported in part by the Intramural Research Program, National Institutes of Health (NIDDK), by NIGMS P50-GM067082 (P.W.), and by Plan Nacional de Investigacion BFU 2011-23416 and CAM S2010/BMD-2353 (J.M.A.). J.LK. acknowledges an Intramural AIDS Research Fellowship, Office of the Director, NIH. NR 34 TC 12 Z9 13 U1 6 U2 45 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 SEP 15 PY 2013 VL 21 IS 18 BP 5673 EP 5678 DI 10.1016/j.bmc.2013.07.033 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 210BI UT WOS:000323803900003 PM 23932448 ER PT J AU James, JM Nalbandian, A Mukouyama, YS AF James, Jennifer M. Nalbandian, Ani Mukouyama, Yoh-suke TI TGF beta signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin SO DEVELOPMENT LA English DT Article DE TGF beta; Dermal lymphangiogenesis; LEC sprouting ID GROWTH-FACTOR-C; CANCER PROGRESSION; VESSEL DEVELOPMENT; VEGF RECEPTOR-3; CELL-MEMBRANE; MICE CAUSES; INHIBITION; ANGIOGENESIS; VASCULATURE; ENDOTHELIUM AB Dermal lymphatic endothelial cells (LECs) emerge from the dorsolateral region of the cardinal veins within the anterior trunk to form an intricate, branched network of lymphatic vessels during embryogenesis. Multiple growth factors and receptors are required for specification and maintenance of LECs, but the mechanisms coordinating LEC movements and morphogenesis to develop three-dimensional lymphatic network architecture are not well understood. Here, we demonstrate in mice that precise LEC sprouting is a key process leading to stereotypical lymphatic network coverage throughout the developing skin, and that transforming growth factor beta (TGF beta) signaling is required for LEC sprouting and proper lymphatic network patterning in vivo. We utilized a series of conditional mutants to ablate the TGF beta receptors Tgfbr1 (Alk5) and Tgfbr2 in LECs. To analyze lymphatic defects, we developed a novel, whole-mount embryonic skin imaging technique to visualize sprouting lymphangiogenesis and patterning at the lymphatic network level. Loss of TGF beta signaling in LECs leads to a severe reduction in local lymphangiogenic sprouting, resulting in a significant decrease in global lymphatic network branching complexity within the skin. Our results also demonstrate that TGF beta signaling negatively regulates LEC proliferation during lymphatic network formation. These data suggest a dual role for TGF beta signaling during lymphatic network morphogenesis in the skin, such that it enhances LEC sprouting and branching complexity while attenuating LEC proliferation. C1 [James, Jennifer M.; Nalbandian, Ani; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10-6C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health [HL005702-07] FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health [HL005702-07 to Y.M. Deposited in PMC for release after 12 months. NR 49 TC 28 Z9 28 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 15 PY 2013 VL 140 IS 18 BP 3903 EP 3914 DI 10.1242/dev.095026 PG 12 WC Developmental Biology SC Developmental Biology GA 208RZ UT WOS:000323698100019 PM 23946447 ER PT J AU Li, AR Ahsen, OO Liu, JJ Du, C McKee, ML Yang, Y Wasco, W Newton-Cheh, CH O'Donnell, CJ Fujimoto, JG Zhou, C Tanzi, RE AF Li, Airong Ahsen, Osman O. Liu, Jonathan J. Du, Chuang McKee, Mary L. Yang, Yan Wasco, Wilma Newton-Cheh, Christopher H. O'Donnell, Christopher J. Fujimoto, James G. Zhou, Chao Tanzi, Rudolph E. TI Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography SO HUMAN MOLECULAR GENETICS LA English DT Article ID VENTRICULAR DIASTOLIC FUNCTION; GENOME-WIDE ASSOCIATION; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; RETINAL BLOOD-FLOW; HYPERTROPHIC CARDIOMYOPATHY; ATRIAL-FIBRILLATION; FILLING PRESSURE; PROGNOSTIC VALUE; GENE-EXPRESSION AB The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits. C1 [Li, Airong; Yang, Yan; Wasco, Wilma; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [McKee, Mary L.] Massachusetts Gen Hosp, Program Membrane Biol, Charlestown, MA 02129 USA. [Newton-Cheh, Christopher H.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. [Ahsen, Osman O.; Liu, Jonathan J.; Fujimoto, James G.; Zhou, Chao] MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, Cambridge, MA 02139 USA. [Du, Chuang] Tufts Univ, Sch Med, Ctr Neurosci Res, Boston, MA 02111 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Zhou, Chao] Lehigh Univ, Dept Elect & Comp & Engn, Bethlehem, PA 18015 USA. RP Tanzi, RE (reprint author), Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, 114 16th St, Charlestown, MA 02129 USA. EM chaozhou@lehigh.edu; tanzi@helix.mgh.harvard.edu RI Zhou, Chao/A-1327-2007; Ahsen, Osman/K-4524-2015 OI Ahsen, Osman/0000-0003-4811-3429 FU Cure Alzheimer's Fund; National Institute of Health [R01AG014713, R01MH60009, R01CA75289, R01HL095717, R00EB010071, R03AR063271]; Air Force Office of Scientific Research [FA9550-07-1-0014]; Massachusetts General Hospital ECOR Award; Boston Area Diabetes and Endocrinology Research Center [DK 57521]; Center for the Study of Inflammatory Bowel Disease [DK 43351] FX This work was supported by the Cure Alzheimer's Fund to R. E. T., the National Institute of Health (R01AG014713 and R01MH60009 to R. E. T.; R01CA75289 and R01HL095717 to J.G.F.; R00EB010071 to C.Z.; R03AR063271 to A. L.), the Air Force Office of Scientific Research (FA9550-07-1-0014 to J.G.F.) and a Massachusetts General Hospital ECOR Award to A. L. The Microscopy Core Facility at the MGH Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center (DK 57521) and the Center for the Study of Inflammatory Bowel Disease (DK 43351). NR 81 TC 5 Z9 5 U1 2 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2013 VL 22 IS 18 BP 3798 EP 3806 DI 10.1093/hmg/ddt230 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 207FD UT WOS:000323582000015 PM 23696452 ER PT J AU Rositch, AF Koshiol, J Hudgens, MG Razzaghi, H Backes, DM Pimenta, JM Franco, EL Poole, C Smith, JS AF Rositch, Anne F. Koshiol, Jill Hudgens, Michael G. Razzaghi, Hilda Backes, Danielle M. Pimenta, Jeanne M. Franco, Eduardo L. Poole, Charles Smith, Jennifer S. TI Patterns of persistent genital human papillomavirus infection among women worldwide: A literature review and meta-analysis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE human papillomavirus; HPV; duration; persistence; clearance; natural history; repeat testing; literature review; screening; cervical cancer; meta-analysis ID CERVICAL INTRAEPITHELIAL NEOPLASIA; RISK HUMAN-PAPILLOMAVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; CYTOLOGICALLY NORMAL WOMEN; 5-YEAR FOLLOW-UP; FEMALE UNIVERSITY-STUDENTS; POPULATION-BASED COHORT; CAPTURE-II ASSAY; YOUNG-WOMEN AB Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV-positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was 10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6 to 12 months. Repeat HPV testing at 12-month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections. C1 [Rositch, Anne F.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Rositch, Anne F.; Razzaghi, Hilda; Backes, Danielle M.; Poole, Charles; Smith, Jennifer S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Koshiol, Jill] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hudgens, Michael G.] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Backes, Danielle M.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Pimenta, Jeanne M.] GlaxoSmithKline, Worldwide Epidemiol, Stockley Pk, Middx, England. [Franco, Eduardo L.] McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. [Smith, Jennifer S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Rositch, AF (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Room E6133, Baltimore, MD 21205 USA. EM arositch@jhsph.edu OI Franco, Eduardo/0000-0002-4409-8084; Rositch, Anne/0000-0002-0403-8482 FU GlaxoSmithKline FX Grant sponsor: GlaxoSmithKline NR 111 TC 40 Z9 43 U1 3 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2013 VL 133 IS 6 BP 1271 EP 1285 DI 10.1002/ijc.27828 PG 15 WC Oncology SC Oncology GA 178HH UT WOS:000321436300001 PM 22961444 ER PT J AU Alter, BP Giri, N Savage, SA Quint, WGV de Koning, MN Schiffman, M AF Alter, Blanche P. Giri, Neelam Savage, Sharon A. Quint, Wim G. V. de Koning, Maurits N. C. Schiffman, Mark TI Squamous cell carcinomas in patients with Fanconi anemia and dyskeratosis congenita: A search for human papillomavirus SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Fanconi anemia; dyskeratosis congenita; squamous cell carcinoma; human papillomavirus ID BROAD-SPECTRUM; CANCER; DNA; PCR AB Patients with Fanconi anemia (FA) and dyskeratosis congenita (DC) are at high risk of head and neck squamous cell carcinomas (HNSCC) and anogenital squamous cell carcinomas (SCC). In the general population, these sites (particularly oropharyngeal SCC) may be associated with infection with human papillomavirus (HPV). In FA and DC, however, the majority of HNSCC occur in the oral cavity. We investigated the HPV status of HNSCC and vulvar SCC from nine patients with FA and four with DC using a very sensitive PCR assay, and found HPV16 DNA in only a single vulvar tumor from one patient with FA, and in none of the HNSCC. These results suggest that HPV may not be the cause of SCC in patients with FA or DC, and that vaccination may not reduce the incidence of HNSCC in these patients. What's new? The incidence of squamous cell carcinoma (SCC) of the oral cavity and gynecologic tract in patients with Fanconi anemia suggests a link to human papillomavirus (HPV) infection. However, the possibility of an association has not been studied extensively, and studies that have been conducted have produced conflicting results. This analysis of tumors from patients with Fanconi anemia or dyskeratosis congenita yielded no evidence for HPV causality, indicating that HPV vaccination may not reduce the incidence of SCC in these patients. The findings warrant etiological investigation into non-HPV mechanisms of SCC in these populations. C1 [Alter, Blanche P.; Giri, Neelam; Savage, Sharon A.; Schiffman, Mark] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Quint, Wim G. V.; de Koning, Maurits N. C.] DDL Diagnost Lab, Rijswijk, Netherlands. RP Alter, BP (reprint author), NCI, 6120 Execut Blvd,Execut Plaza South 7020, Rockville, MD 20852 USA. EM alterb@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU National Institutes of Health; National Cancer Institute FX Grant sponsor: This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. NR 13 TC 17 Z9 17 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2013 VL 133 IS 6 BP 1513 EP 1515 DI 10.1002/ijc.28157 PG 3 WC Oncology SC Oncology GA 178HH UT WOS:000321436300026 PM 23558727 ER PT J AU Kwon, HS Johnson, TV Joe, MK Abu-Asab, M Zhang, J Chan, CC Tomarev, SI AF Kwon, Heung Sun Johnson, Thomas V. Joe, Myung Kuk Abu-Asab, Mones Zhang, Jun Chan, Chi Chao Tomarev, Stanislav I. TI Myocilin Mediates Myelination in the Peripheral Nervous System through ErbB2/3 Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OPEN-ANGLE GLAUCOMA; SCHWANN-CELLS; WALLERIAN DEGENERATION; MUTATIONS; GLIOMEDIN; RANVIER; GENE; EXPRESSION; PROTEINS; NODES AB The glaucoma-associated gene, myocilin, is expressed in ocular and non-ocular tissues including the peripheral nervous system, but its functions in these tissues remain poorly understood. We demonstrate that in sciatic nerve, myocilin is expressed in Schwann cells with high concentrations at the nodes of Ranvier. There, myocilin interacts with gliomedin, neurofascin, and NrCAM, which are essential for node formation and function. Treatment of isolated dorsal root ganglion cultures with myocilin stimulates clustering of the nodal proteins neurofascin and sodium channel Na(v)1.2. Sciatic nerves of myocilin null mice express reduced levels of several myelin-associated and basal membrane proteins compared with those of wild-type littermates. They also demonstrate reduced myelin sheath thickness and partial disorganization of the nodes. Myocilin signaling through ErbB2/3 receptors may contribute to these observed effects. Myocilin binds to ErbB2/ErbB3, activates these receptors, and affects the downstream PI3K-AKT signaling pathway. These data implicate a role for myocilin in the development and/or maintenance of myelination and nodes of Ranvier in sciatic nerve. C1 [Kwon, Heung Sun; Johnson, Thomas V.; Joe, Myung Kuk; Tomarev, Stanislav I.] NEI, SRGCB, LRCMB, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones; Zhang, Jun; Chan, Chi Chao] NEI, Histol Core, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, SRGCB, LRCMB, NIH, Bldg 6,Rm 212,6 Ctr Dr, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov RI Johnson, Thomas/C-9351-2011; OI Johnson, Thomas/0000-0002-5372-5457; Abu-Asab, Mones/0000-0002-4047-1232 FU Intramural Research Program of the NEI, National Institutes of Health FX This work was supported by the Intramural Research Program of the NEI, National Institutes of Health. NR 48 TC 14 Z9 23 U1 0 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 SEP 13 PY 2013 VL 288 IS 37 BP 26357 EP 26371 DI 10.1074/jbc.M112.446138 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302HM UT WOS:000330594500002 PM 23897819 ER PT J AU Heissler, SM Liu, X Korn, ED Sellers, JR AF Heissler, Sarah M. Liu, Xiong Korn, Edward D. Sellers, James R. TI Kinetic Characterization of the ATPase and Actin-activated ATPase Activities of Acanthamoeba castellanii Myosin-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VERTEBRATE NONMUSCLE MYOSIN; MOTOR DOMAIN; DICTYOSTELIUM-DISCOIDEUM; II-C; ADENOSINE-TRIPHOSPHATASE; 50/20-KDA JUNCTION; MGATPASE ACTIVITY; IN-VITRO; ISOFORM; PHOSPHORYLATION AB Phosphorylation of Ser-639 in loop-2 of the catalytic motor domain of the heavy chain of Acanthamoeba castellanii myosin-2 and the phosphomimetic mutation S639D have been shown previously to down-regulate the actin-activated ATPase activity of both the full-length myosin and single-headed subfragment-1 (Liu, X., Lee, D. Y., Cai, S., Yu, S., Shu, S., Levine, R. L., and Korn, E. D. (2013) Proc. Natl. Acad. Sci. U. S. A. 110, E23-E32). In the present study we determined the kinetic constants for each step in the myosin and actomyosin ATPase cycles of recombinant wild-type S1 and S1-S639D. The kinetic parameter predominantly affected by the S639D mutation is the actin-activated release of inorganic phosphate from the acto myosin.ADP.P-i complex, which is the rate-limiting step in the steady-state actomyosin ATPase cycle. As consequence of this change, the duty ratio of this conventional myosin decreases. We speculate on the effect of Ser-639 phosphorylation on the processive behavior of myosin-2 filaments. C1 [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-R3519, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov NR 46 TC 3 Z9 3 U1 0 U2 12 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 SEP 13 PY 2013 VL 288 IS 37 BP 26709 EP 26720 DI 10.1074/jbc.M113.485946 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302HM UT WOS:000330594500036 PM 23897814 ER PT J AU Murphy, E Steenbergen, C AF Murphy, Elizabeth Steenbergen, Charles TI Did a Classic Preconditioning Study Provide a Clue to the Identity of the Mitochondrial Permeability Transition Pore? SO CIRCULATION RESEARCH LA English DT Editorial Material ID ISCHEMIA-REPERFUSION INJURY; MYOCARDIAL-ISCHEMIA; CELLULAR BIOLOGY; EUROPEAN-SOCIETY; WORKING GROUP; ATP SYNTHASE; MECHANISMS; CARDIOPROTECTION; INHIBITION; PROTECTION AB A classic article by Murry et al published in 1990 in Circulation Research showed that preconditioning slowed the rate of ATP breakdown during a subsequent sustained period of ischemia. The mechanism responsible for reduced ATP breakdown is still unknown, but perhaps it is related to the inhibition of F1-F0 ATPase. This is an attractive hypothesis, given several recent studies suggesting that the F1-F0 ATPase can form the mitochondrial permeability transition pore. C1 [Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Murphy1@mail.nih.gov FU Intramural NIH HHS [Z01 ES010004-28, ZIA HL002066-06] NR 34 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP 13 PY 2013 VL 113 IS 7 BP 852 EP 855 DI 10.1161/CIRCRESAHA.113.301950 PG 4 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 286OW UT WOS:000329479600009 PM 24030020 ER PT J AU Bystrom, J Thomson, SJ Johansson, J Edin, ML Zeldin, DC Gilroy, DW Smith, AM Bishop-Bailey, D AF Bystrom, Jonas Thomson, Scott J. Johansson, Jorgen Edin, Matthew L. Zeldin, Darryl C. Gilroy, Derek W. Smith, Andrew M. Bishop-Bailey, David TI Inducible CYP2J2 and Its Product 11,12-EET Promotes Bacterial Phagocytosis: A Role for CYP2J2 Deficiency in the Pathogenesis of Crohn's Disease? SO PLOS ONE LA English DT Article ID HUMAN CYTOCHROME-P450 2J2; LISTERIA-MONOCYTOGENES; ULCERATIVE-COLITIS; ACUTE-INFLAMMATION; SMOOTH-MUSCLE; IN-VITRO; EXPRESSION; RECEPTOR; MACROPHAGES; METABOLITES AB The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNF alpha release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease. C1 [Bystrom, Jonas] Queen Mary Univ, William Harvey Res Inst, London, England. [Thomson, Scott J.; Bishop-Bailey, David] Univ London Royal Vet Coll, London, England. [Johansson, Jorgen] Umea Univ, Dept Mol Biol, Umea, Sweden. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Gilroy, Derek W.; Smith, Andrew M.] UCL, Dept Med, London, England. RP Bishop-Bailey, D (reprint author), Univ London Royal Vet Coll, London, England. EM dbishopbailey@rvc.ac.uk OI Edin, Matthew/0000-0002-7042-500X; Johansson, Jorgen/0000-0002-0904-497X FU British Heart Foundation [PG/08/070/25464, PG/11/39/28890]; Intramural Research Programs of the National Institutes of Health, NIEHS; ERC [260764-RNAntibiotics] FX This work was funded by grants from the British Heart Foundation (PG/08/070/25464; PG/11/39/28890), and the Intramural Research Programs of the National Institutes of Health, NIEHS (D.C.Z.). JJ was funded by ERC Starting Grant 260764-RNAntibiotics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 11 Z9 11 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2013 VL 8 IS 9 AR e75107 DI 10.1371/journal.pone.0075107 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218BU UT WOS:000324408400109 PM 24058654 ER PT J AU Fujita, M Mahanty, S Zoghbi, SS Araneta, MDF Hong, J Pike, VW Innis, RB Nash, TE AF Fujita, Masahiro Mahanty, Siddhartha Zoghbi, Sami S. Araneta, Maria Desiree Ferraris Hong, Jinsoo Pike, Victor W. Innis, Robert B. Nash, Theodore E. TI PET Reveals Inflammation around Calcified Taenia solium Granulomas with Perilesional Edema SO PLOS ONE LA English DT Article ID BENZODIAZEPINE-RECEPTOR; TRANSLOCATOR PROTEIN; IN-VIVO; 18 KDA; NEUROCYSTICERCOSIS; BRAIN; METHOTREXATE; RADIOLIGAND; EXPRESSION; BIOMARKER AB Objective: Neurocysticercosis, an infection with the larval form of the tapeworm, Taenia solium, is the cause of 29% of epilepsy in endemic regions. Epilepsy in this population is mostly associated with calcified granulomas; at the time of seizure recurrence 50% of those with calcifications demonstrate transient surrounding perilesional edema. Whether edema is consequence of the seizure, or a result of host inflammation directed against parasite antigens or other processes is unknown. To investigate whether perilesional edema is due to inflammation, we imaged a marker of neuroinflammation, translocater protein (TSPO), using positron emission tomography (PET) and the selective ligand C-11-PBR28. Methods: In nine patients with perilesional edema, degenerating cyst or both, PET findings were compared to the corresponding magnetic resonance images. Degenerating cysts were also studied because unlike perilesional edema, degenerating cysts are known to have inflammation. In three of the nine patients, changes in C-11-PBR28 binding were also studied over time. C-11-PBR28 binding was compared to the contralateral un-affected region. Results: C-11-PBR28 binding increased by a mean of 13% in perilesional edema or degenerating cysts (P = 0.0005, n = 13 in nine patients). Among these 13 lesions, perilesional edema (n = 10) showed a slightly smaller increase of 10% compared to the contralateral side (P = 0.005) than the three degenerating cysts. In five lesions with perilesional edema in which repeated measurements of C-11-PBR28 binding were done, increased binding lasted for 2-9 months. Conclusions: Increased TSPO in perilesional edema indicates an inflammatory etiology. The long duration of increased TSPO binding after resolution of the original perilesional edema and the pattern of periodic episodes is consistent with intermittent exacerbation from a continued baseline presence of low level inflammation. Novel anti-inflammatory measures may be useful in the prevention or treatment of seizures in this population. C1 [Fujita, Masahiro; Zoghbi, Sami S.; Araneta, Maria Desiree Ferraris; Hong, Jinsoo; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Mahanty, Siddhartha; Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM FujitaM@intra.nimh.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 FU Intramural Research Programs of the National Institute of Mental Health; National Institutes of Allergy and Infectious Diseases, National Institutes of Health, United States of America FX This research was supported by the Intramural Research Programs of the National Institute of Mental Health and the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 10 Z9 10 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2013 VL 8 IS 9 AR e74052 DI 10.1371/journal.pone.0074052 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218BU UT WOS:000324408400049 PM 24058514 ER PT J AU Klein, AP Lindstrom, S Mendelsohn, JB Steplowski, E Arslan, AA Bueno-de-Mesquita, HB Fuchs, CS Gallinger, S Gross, M Helzlsouer, K Holly, EA Jacobs, EJ LaCroix, A Li, DH Mandelson, MT Olson, SH Petersen, GM Risch, HA Stolzenberg-Solomon, RZ Zheng, W Amundadottir, L Albanes, D Allen, NE Bamlet, WR Boutron-Ruault, MC Buring, JE Bracci, PM Canzian, F Clipp, S Cotterchio, M Duell, EJ Elena, J Gaziano, JM Giovannucci, EL Goggins, M Hallmans, G Hassan, M Hutchinson, A Hunter, DJ Kooperberg, C Kurtz, RC Liu, SM Overvad, K Palli, D Patel, AV Rabe, KG Shu, XO Slimani, N Tobias, GS Trichopoulos, D Van den Eeden, SK Vineis, P Virtamo, J Wactawski-Wende, J Wolpin, BM Yu, H Yu, K Zeleniuch-Jacquotte, A Chanock, SJ Hoover, RN Hartge, P Kraft, P AF Klein, Alison P. Lindstroem, Sara Mendelsohn, Julie B. Steplowski, Emily Arslan, Alan A. Bueno-de-Mesquita, H. Bas Fuchs, Charles S. Gallinger, Steven Gross, Myron Helzlsouer, Kathy Holly, Elizabeth A. Jacobs, Eric J. LaCroix, Andrea Li, Donghui Mandelson, Margaret T. Olson, Sara H. Petersen, Gloria M. Risch, Harvey A. Stolzenberg-Solomon, Rachael Z. Zheng, Wei Amundadottir, Laufey Albanes, Demetrius Allen, Naomi E. Bamlet, William R. Boutron-Ruault, Marie-Christine Buring, Julie E. Bracci, Paige M. Canzian, Federico Clipp, Sandra Cotterchio, Michelle Duell, Eric J. Elena, Joanne Gaziano, J. Michael Giovannucci, Edward L. Goggins, Michael Hallmans, Goeran Hassan, Manal Hutchinson, Amy Hunter, David J. Kooperberg, Charles Kurtz, Robert C. Liu, Simin Overvad, Kim Palli, Domenico Patel, Alpa V. Rabe, Kari G. Shu, Xiao-Ou Slimani, Nadia Tobias, Geoffrey S. Trichopoulos, Dimitrios Van den Eeden, Stephen K. Vineis, Paolo Virtamo, Jarmo Wactawski-Wende, Jean Wolpin, Brian M. Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Chanock, Stephen J. Hoover, Robert N. Hartge, Patricia Kraft, Peter TI An Absolute Risk Model to Identify Individuals at Elevated Risk for Pancreatic Cancer in the General Population SO PLOS ONE LA English DT Article ID COHORT-CONSORTIUM PANSCAN; GENOME-WIDE ASSOCIATION; ABO BLOOD-GROUP; POOLED-ANALYSIS; FAMILY-HISTORY; HEREDITARY PANCREATITIS; GENETIC EPIDEMIOLOGY; SUSCEPTIBILITY; METAANALYSIS; MUTATIONS AB Purpose: We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer. Patients and Methods: Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates. Results: Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U. S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk. Conclusion: Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors. C1 [Klein, Alison P.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21218 USA. [Klein, Alison P.] Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD USA. [Klein, Alison P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lindstroem, Sara; Giovannucci, Edward L.; Hunter, David J.; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lindstroem, Sara; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Mendelsohn, Julie B.; Stolzenberg-Solomon, Rachael Z.; Amundadottir, Laufey; Albanes, Demetrius; Tobias, Geoffrey S.; Yu, Kai; Chanock, Stephen J.; Hoover, Robert N.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Steplowski, Emily] Informat Management Serv Inc, Silver Spring, MD USA. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Wolpin, Brian M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Wolpin, Brian M.] Harvard Univ, Sch Med, Boston, MA USA. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med Pathol, Minneapolis, MN 55455 USA. [Helzlsouer, Kathy] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Helzlsouer, Kathy] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Helzlsouer, Kathy] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Holly, Elizabeth A.; Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [LaCroix, Andrea; Mandelson, Margaret T.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Li, Donghui; Hassan, Manal] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Mandelson, Margaret T.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Petersen, Gloria M.; Bamlet, William R.; Rabe, Kari G.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Risch, Harvey A.; Yu, Herbert] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, New Haven, CT 06510 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Allen, Naomi E.] UK Biobank, Oxford, England. [Boutron-Ruault, Marie-Christine] INSERM, Villejuif, France. [Boutron-Ruault, Marie-Christine] Inst Gustave Roussy, Villejuif, France. [Buring, Julie E.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, J. Michael] Harvard Univ, Sch Med, Boston, MA USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Clipp, Sandra] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Cotterchio, Michelle] Canc Care Ontario, Toronto, ON, Canada. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr Environm & Canc, Barcelona, Spain. [Elena, Joanne] NCI, Div Canc Control & Populat Sci, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovannucci, Edward L.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Hallmans, Goeran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Hutchinson, Amy] NCI Frederick, SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD USA. [Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Program Biostat & Biomath, Seattle, WA 98104 USA. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Liu, Simin] Univ Calif Los Angeles, Ctr Metab Dis Prevent, Dept Epidemiol, Los Angeles, CA USA. [Liu, Simin] Univ Calif Los Angeles, Dept Med, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA. [Liu, Simin] Univ Calif Los Angeles, Dept Obstet & Gynecol, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA. [Overvad, Kim] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark. [Palli, Domenico] ISPO Florence, Canc Res & Prevent Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Slimani, Nadia] Int Agcy Res Canc, F-69372 Lyon, France. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Van den Eeden, Stephen K.] Kaiser Permanente, Div Res, Northern Calif Reg, Oakland, CA USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, London, England. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Klein, AP (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21218 USA. EM aklein1@jhmi.edu RI Gallinger, Steven/E-4575-2013; Liu, Simin/I-3689-2014; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Liu, Simin/0000-0003-2098-3844; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Duell, Eric J/0000-0001-5256-0163; PALLI, Domenico/0000-0002-5558-2437; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU NCI [R01CA034588, R01CA098661, P30CA016087, P50CA62924, R01CA97075, NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; National Institute of Environmental Health Sciences [ES000260]; National Heart, Lung, and Blood Institute, NIH [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]; NCI, NIH [5R01CA098870, P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467]; Lustgarten Foundation for Pancreatic Cancer Research; National Cancer Institute extramural research grant [R01 CA82729, R37 CA70867]; Intramural Research Program of National Cancer Institute (Division of Cancer Epidemiology and Genetics); NIH [RO1 CA98380]; National Cancer Institute [CA59706, CA108370, CA109767, CA89726, CA98889]; Rombauer Pancreatic Cancer Research Fund; NIH as part of the PACGENE consortium [R01 CA97075]; Intramural Research Program of the NCI, NIH, and through U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX The NYU Women's Health Study is supported by research grants R01CA034588, R01CA098661, center grant P30CA016087 from the NCI and the center grant ES000260 from the National Institute of Environmental Health Sciences. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The authors would like to acknowledge Traci Hammer, Jodi Cogswell, Hugues Sicotte, Ann Oberg, Janet Olson, Martha Matsumoto, and Dennis Robinson. The Yale University study was supported by grant number 5R01CA098870 from the NCI, NIH. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. The PHS, NHS, HPFS and WHS at Harvard were supported by the NCI, NIH (Grants No. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467). The work at Johns Hopkins University was supported by the NCI (Grants P50CA62924 and R01CA97075) and the Lustgarten Foundation for Pancreatic Cancer Research. The Shanghai Men's Health Study was supported by the National Cancer Institute extramural research grant [R01 CA82729]. The Shanghai Women's Health Study was supported by the National Cancer Institute extramural research grant [R37 CA70867] and, partially for biological sample collection, by the Intramural Research Program of National Cancer Institute (Division of Cancer Epidemiology and Genetics). The authors are in debt to the contributions of Drs. Yu-Tang Gao and Yong-Bing Xiang in these two cohort studies. The studies would not be possible without the continuing support and devotion from the study participants and staff of the SMHS and SWHS. Memorial Sloan Kettering Cancer Center acknowledges the work of Jennifer A. Simon and Irene Orlow. The work at MD Anderson was supported by NIH grant RO1 CA98380. The UCSF study was supported in part by National Cancer Institute grants CA59706, CA108370, CA109767, CA89726 (E. A. Holly, PI) and CA98889 (E. J. Duell, PI) and by the Rombauer Pancreatic Cancer Research Fund. The University of Toronto study was supported by grants from the NIH (R01 CA97075, as part of the PACGENE consortium), The Lustgarten Foundation for Pancreatic Cancer Research and the Ontario Cancer Research Network. The authors acknowledge the Pancreatic Cancer Canada Foundation (www.pancreaticcancercanada.ca) for their continued support of research into the early detection of pancreatic cancer, and the Pancreas Cancer Screening Study at Mount Sinai Hospital and Princess Margaret Hospital. The authors acknowledge Ayelet Borgida and Heidi Rothenmund for their dedicated contributions towards data collection and study co-ordination.; PLCO was supported by individual contracts from the NCI to the University of Colorado Denver NO1-CN-25514, Georgetown University NO1-CN-25522, Pacific Health Research Institute NO1-CN-25515, Henry Ford Health System NO1-CN-25512, University of Minnesota, NO1-CN-25513, Washington University NO1-CN-25516, University of Pittsburgh NO1-CN-25511, University of Utah NO1-CN-25524, Marshfield Clinic Research Foundation NO1-CN-25518, University of Alabama at Birmingham NO1-CN-75022, Westat, Inc. NO1-CN-25476, University of California, Los Angeles NO1-CN-25404. The ATBC Study was supported by funding provided by the Intramural Research Program of the NCI, NIH, and through U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI. For the EPIC cohorts, all coauthors coordinated the initial recruitment and management of the studies. The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. The work described in this paper was carried out with the support of the European Commission: Public Health and Consumer Protection Directorate 1993-2004; Research Directorate-General 2005-."; Ligue contre le Cancer, Societe 3M, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); ISCIII RETIC (RD06/0020) of the Spanish Ministry of Health, The participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (United Kingdom); Greek Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for Research on Cancer (AIRC) (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (the Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Vasterbotten (Sweden). CLUE II was supported by National Institute of Aging grant (5U01AG018033) and National Cancer Institute grants (CA105069, CA73790). The authors express their appreciation to the participants of the CLUE II cohort and thank the staff at the George W. Comstock Center for Public Health Research and Prevention for their dedication and contributions to the study: Judy HoffmanBolton, Clara Krumpe, Kitty Spoonire and Betty Miner. The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The authors thank all of the men and women in the Cancer Prevention Study II Nutrition Cohort for their many years of dedicated participation in the study. The authors wish to thank Debbie Winn, Daniela Seminara and Scott Rogers for assisting with funding coordination for the project and Donghui Li for supporting the study with supplemental grant CA98380. 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.; The authors acknowledge the contribution of the staff of the Core Genotyping Facility, specifically, Zhaoming Wang, Chenwei Liu, Xiang Deng, Laurie Burdett, Aurelie Vogt, and Belynda Hicks. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 37 Z9 39 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2013 VL 8 IS 9 AR e72311 DI 10.1371/journal.pone.0072311 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218BU UT WOS:000324408400005 PM 24058443 ER PT J AU Mann, ZF Chang, W Lee, KY King, KA Kelley, MW AF Mann, Zoe F. Chang, Weise Lee, Kyu Yup King, Kelly A. Kelley, Matthew W. TI Expression and Function of Scleraxis in the Developing Auditory System SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR SCLERAXIS; DEVELOPING MAMMALIAN COCHLEA; II COLLAGEN DISTRIBUTION; LOOP-HELIX PROTEINS; INNER-EAR; TECTORIAL MEMBRANE; EXTRACELLULAR-MATRIX; MESSENGER-RNA; HAIR-CELLS; CELLULAR-DIFFERENTIATION AB A study of genes expressed in the developing inner ear identified the bHLH transcription factor Scleraxis (Scx) in the developing cochlea. Previous work has demonstrated an essential role for Scx in the differentiation and development of tendons, ligaments and cells of chondrogenic lineage. Expression in the cochlea has been shown previously, however the functional role for Scx in the cochlea is unknown. Using a Scx-GFP reporter mouse line we examined the spatial and temporal patterns of Scx expression in the developing cochlea between embryonic day 13.5 and postnatal day 25. Embryonically, Scx is expressed broadly throughout the cochlear duct and surrounding mesenchyme and at postnatal ages becomes restricted to the inner hair cells and the interdental cells of the spiral limbus. Deletion of Scx results in hearing impairment indicated by elevated auditory brainstem response (ABR) thresholds and diminished distortion product otoacoustic emission (DPOAE) amplitudes, across a range of frequencies. No changes in either gross cochlear morphology or expression of the Scx target genes Col2A, Bmp4 or Sox9 were observed in Scx(-/-) mutants, suggesting that the auditory defects observed in these animals may be a result of unidentified Scx-dependent processes within the cochlea. C1 [Mann, Zoe F.; Chang, Weise; Kelley, Matthew W.] NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD USA. [Lee, Kyu Yup] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD USA. [King, Kelly A.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD USA. RP Mann, ZF (reprint author), NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD USA. EM mannz@nidcd.nih.gov FU NIH FX This work was fully funded and supported by the NIH intramural research program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 2 Z9 2 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2013 VL 8 IS 9 AR e75521 DI 10.1371/journal.pone.0075521 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218BU UT WOS:000324408400117 PM 24058692 ER PT J AU Medrano-Gracia, P Cowan, BR Bluemke, DA Finn, JP Kadish, AH Lee, DC Lima, JAC Suinesiaputra, A Young, AA AF Medrano-Gracia, Pau Cowan, Brett R. Bluemke, David A. Finn, J. Paul Kadish, Alan H. Lee, Daniel C. Lima, Joao A. C. Suinesiaputra, Avan Young, Alistair A. TI Atlas-based analysis of cardiac shape and function: correction of regional shape bias due to imaging protocol for population studies SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Cardiovascular magnetic resonance; Atlas; Bias correction ID CARDIOVASCULAR MAGNETIC-RESONANCE; LEFT-VENTRICULAR MASS; HEART; MRI; CONSTRUCTION; PARTICIPANTS; RATIONALE; ANATOMY; DESIGN AB Background: Cardiovascular imaging studies generate a wealth of data which is typically used only for individual study endpoints. By pooling data from multiple sources, quantitative comparisons can be made of regional wall motion abnormalities between different cohorts, enabling reuse of valuable data. Atlas-based analysis provides precise quantification of shape and motion differences between disease groups and normal subjects. However, subtle shape differences may arise due to differences in imaging protocol between studies. Methods: A mathematical model describing regional wall motion and shape was used to establish a coordinate system registered to the cardiac anatomy. The atlas was applied to data contributed to the Cardiac Atlas Project from two independent studies which used different imaging protocols: steady state free precession (SSFP) and gradient recalled echo (GRE) cardiovascular magnetic resonance (CMR). Shape bias due to imaging protocol was corrected using an atlas-based transformation which was generated from a set of 46 volunteers who were imaged with both protocols. Results: Shape bias between GRE and SSFP was regionally variable, and was effectively removed using the atlas-based transformation. Global mass and volume bias was also corrected by this method. Regional shape differences between cohorts were more statistically significant after removing regional artifacts due to imaging protocol bias. Conclusions: Bias arising from imaging protocol can be both global and regional in nature, and is effectively corrected using an atlas-based transformation, enabling direct comparison of regional wall motion abnormalities between cohorts acquired in separate studies. C1 [Medrano-Gracia, Pau; Cowan, Brett R.; Suinesiaputra, Avan; Young, Alistair A.] Univ Auckland, Fac Med & Hlth Sci, Dept Anat Radiol, Auckland 1142, New Zealand. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Finn, J. Paul] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Kadish, Alan H.; Lee, Daniel C.] Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Donald W Reynolds Cardiovasc Clin Res Ctr, Baltimore, MD USA. RP Young, AA (reprint author), Univ Auckland, Fac Med & Hlth Sci, Dept Anat Radiol, 85 Pk Rd, Auckland 1142, New Zealand. EM a.young@auckland.ac.nz OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute, NIH [R01HL087773] FX R01HL087773 from the National Heart, Lung, and Blood Institute, NIH. NR 23 TC 11 Z9 11 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD SEP 13 PY 2013 VL 15 AR 80 DI 10.1186/1532-429X-15-80 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 223CD UT WOS:000324780400001 PM 24033990 ER PT J AU Beigi, RH Goldkind, SF Jevaji, I AF Beigi, Richard H. Goldkind, Sara F. Jevaji, Indira TI Research on vaccines and antimicrobials during pregnancy: Challenges and opportunities SO VACCINE LA English DT Editorial Material ID IMMUNIZATION; INFLUENZA; WOMEN C1 [Beigi, Richard H.] Univ Pittsburgh Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Div Reprod Infect Dis, Pittsburgh, PA 15213 USA. [Beigi, Richard H.] Univ Pittsburgh Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Div Obstet Specialties, Pittsburgh, PA 15213 USA. [Goldkind, Sara F.] US FDA, Off Good Clin Practice, Off Commissioner, Silver Spring, MD USA. [Jevaji, Indira] NIH, Off Res Womens Hlth, Div Program Coordinat Planning & Strateg Initiat, Off Director, Bethesda, MD 20892 USA. RP Beigi, RH (reprint author), Univ Pittsburgh Med Ctr, Magee Womens Hosp, 300 Halket St, Pittsburgh, PA 15213 USA. EM rbeigi@mail.magee.edu NR 8 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 13 PY 2013 VL 31 IS 40 BP 4261 EP 4263 DI 10.1016/j.vaccine.2013.05.060 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219MG UT WOS:000324510500001 PM 23978280 ER PT J AU Sheffield, JS Munoz, FM Beigi, RH Rasmussen, SA Edwards, KM Read, JS Heine, RP Ault, KA Swamy, GK Jevaji, I Spong, CY Fortner, KB Patel, SM Nesin, M AF Sheffield, Jeanne S. Munoz, Flor M. Beigi, Richard H. Rasmussen, Sonja A. Edwards, Kathryn M. Read, Jennifer S. Heine, R. Phillips Ault, Kevin A. Swamy, Geeta K. Jevaji, Indira Spong, Catherine Y. Fortner, Kimberly B. Patel, Shital M. Nesin, Mirjana TI Research on vaccines during pregnancy: Reference values for vital signs and laboratory assessments SO VACCINE LA English DT Article DE Laboratory assessment; Toxicity grading scale; Maternal immunization AB The Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health organized a series of conferences, "Enrolling Pregnant Women in Clinical Trials of Vaccines and Therapeutics", to discuss enrollment and safety assessments of pregnant women in clinical trials of vaccines. Experts in obstetrics, maternal fetal medicine, infectious diseases, pediatrics, neonatology, genetics, vaccinology and clinical trial design were charged with identifying normal ranges for vital signs and laboratory assessments in pregnancy. A grading system for adverse events was then developed (C) 2013 Elsevier Ltd. All rights reserved. C1 [Sheffield, Jeanne S.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Div Maternal Fetal Med, Dallas, TX 75390 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Pediat Mol Virol & Microbiol, Houston, TX 77030 USA. [Beigi, Richard H.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Edwards, Kathryn M.] Vanderbilt Univ, Dept Pediat, Vanderbilt Vaccine Res Program, Nashville, TN 37232 USA. [Read, Jennifer S.] US Dept HHS, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Off Secretary, Washington, DC 20201 USA. [Heine, R. Phillips; Swamy, Geeta K.] Duke Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Durham, NC 27710 USA. [Ault, Kevin A.] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30303 USA. [Ault, Kevin A.] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30303 USA. [Ault, Kevin A.] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30303 USA. [Jevaji, Indira] NIH, USA Div ESRD Populat & Community Hlth DEPCH, Ctr Medicare & Medicaid Serv CMS, Qual Improvement Grp,Ctr Clin Stand & Qual,Off Re, Bethesda, MD 20817 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Fortner, Kimberly B.] Vanderbilt Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Nashville, TN 37232 USA. [Patel, Shital M.] Baylor Coll Med, Dept Med Mol Virol & Microbiol, Houston, TX 77030 USA. [Nesin, Mirjana] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20817 USA. RP Nesin, M (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM jeanne.sheffield@utsouthwestern.edu NR 9 TC 14 Z9 14 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 13 PY 2013 VL 31 IS 40 BP 4264 EP 4273 DI 10.1016/j.vaccine.2013.07.031 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219MG UT WOS:000324510500002 PM 23906887 ER PT J AU Munoz, FM Sheffield, JS Beigi, RH Read, JS Swamy, GK Jevaji, I Rasmussen, SA Edwards, KM Fortner, KB Patel, SM Spong, CY Ault, K Heine, RP Nesin, M AF Munoz, Flor M. Sheffield, Jeanne S. Beigi, Richard H. Read, Jennifer S. Swamy, Geeta K. Jevaji, Indira Rasmussen, Sonja A. Edwards, Kathryn M. Fortner, Kimberly B. Patel, Shital M. Spong, Catherine Y. Ault, Kevin Heine, R. Philips Nesin, Mirjana TI Research on vaccines during pregnancy: Protocol design and assessment of safety SO VACCINE LA English DT Article DE Safety; Maternal immunization; Adverse events; Pregnancy studies; Definitions; Clinical trials ID NEWBORN-INFANTS; MALFORMATIONS; IMMUNIZATION; PREVENTION AB The Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health organized a series of conferences, entitled "Enrolling Pregnant Women in Clinical Trials of Vaccines and Therapeutics", to discuss study design and the assessment of safety in clinical trials conducted in pregnant women. A panel of experts was charged with developing guiding principles for the design of clinical trials and the assessment of safety of vaccines during pregnancy. Definitions and a grading system to evaluate local and systemic reactogenicity, adverse events, and other events associated with pregnancy and delivery were developed. The purpose of this report is to provide investigators interested in vaccine research in pregnancy with a basic set of tools to design and implement maternal immunization studies which may be conducted more efficiently using consistent definitions and grading of adverse events to allow the comparison of safety reports from different trials. These guidelines and safety assessment tools may be modified to meet the needs of each particular protocol based on evidence collected as investigators use them in clinical trials in different settings and share their findings and expertise. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Munoz, Flor M.] Baylor Coll Med, Dept Pediat Mol Virol & Microbiol, Houston, TX 77030 USA. [Sheffield, Jeanne S.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Div Maternal Fetal Med, Dallas, TX 75390 USA. [Beigi, Richard H.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Read, Jennifer S.] US Dept HHS, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Off Secretary, Washington, DC 20201 USA. [Swamy, Geeta K.; Heine, R. Philips] Duke Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Durham, NC 27710 USA. [Jevaji, Indira] NIH, Off Res Womens Hlth, Off Director, Bethesda, MD 20817 USA. [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Edwards, Kathryn M.] Vanderbilt Univ, Dept Pediat, Vanderbilt Vaccine Res Program, Nashville, TN 37232 USA. [Fortner, Kimberly B.] Vanderbilt Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Nashville, TN 37232 USA. [Patel, Shital M.] Baylor Coll Med, Dept Med Mol Virol & Microbiol, Houston, TX 77030 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Ault, Kevin] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30303 USA. [Ault, Kevin] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30303 USA. [Ault, Kevin] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30303 USA. [Nesin, Mirjana] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20817 USA. RP Munoz, FM (reprint author), Baylor Coll Med, 1 Baylor Plaza,Suite 221-D,BCM 280, Houston, TX 77030 USA. EM florm@bcm.edu; nesinm@gmail.com NR 43 TC 15 Z9 15 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 13 PY 2013 VL 31 IS 40 BP 4274 EP 4279 DI 10.1016/j.vaccine.2013.07.042 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219MG UT WOS:000324510500003 PM 23906888 ER PT J AU Apps, R Carrington, M AF Apps, Richard Carrington, Mary TI Response to Comment on "Influence of HLA-C Expression Level on HIV Control" SO SCIENCE LA English DT Editorial Material ID SURFACE EXPRESSION; ASSOCIATION; BINDING C1 [Apps, Richard; Carrington, Mary] Sci Applicat Int Corp Frederick Inc, Canc & Inflammat Program, Lab Expt Immunol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Apps, Richard; Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Apps, Richard; Carrington, Mary] Harvard Univ, Cambridge, MA 02139 USA. RP Carrington, M (reprint author), Sci Applicat Int Corp Frederick Inc, Canc & Inflammat Program, Lab Expt Immunol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM carringm@mail.nih.gov NR 9 TC 1 Z9 1 U1 1 U2 26 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 13 PY 2013 VL 341 IS 6151 DI 10.1126/science.1241854 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215ZA UT WOS:000324248800020 PM 24031003 ER PT J AU Mousavi, K Zare, H Dell'Orso, S Grontved, L Gutierrez-Cruz, G Derfoul, A Hager, GL Sartorelli, V AF Mousavi, Kambiz Zare, Hossein Dell'Orso, Stefania Grontved, Lars Gutierrez-Cruz, Gustavo Derfoul, Assia Hager, Gordon L. Sartorelli, Vittorio TI eRNAs Promote Transcription by Establishing Chromatin Accessibility at Defined Genomic Loci SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; GENE-EXPRESSION; SKELETAL-MUSCLE; NONCODING RNAS; REMODELING COMPLEXES; REGULATORY ELEMENTS; MYOD TRANSCRIPTION; MOUSE DEVELOPMENT; MYOGENIN GENE; CORE ENHANCER AB Transcription factors and DNA regulatory binding motifs are fundamental components of the gene regulatory network. Here, by using genome-wide binding profiling, we show extensive occupancy of transcription factors of myogenesis (MyoD and Myogenin) at extragenic enhancer regions coinciding with RNA synthesis (i.e., eRNA). In particular, multiple regions were transcribed to eRNA within the regulatory region of MYOD1, including previously characterized distal regulatory regions (DRR) and core enhancer (CE). While (CE)RNA enhanced RNA polymerase II (Pol II) occupancy and transcription at MYOD1, DRR RNA acted to activate the downstream myogenic genes. The deployment of transcriptional machinery to appropriate loci is contingent on chromatin accessibility, a rate-limiting step preceding Pol II assembly. By nuclease sensitivity assay, we found that eRNAs regulate genomic access of the transcriptional complex to defined regulatory regions. In conclusion, our data suggest that eRNAs contribute to establishing a cell-type-specific transcriptional circuitry by directing chromatin-remodeling events. C1 [Mousavi, Kambiz; Zare, Hossein; Dell'Orso, Stefania; Gutierrez-Cruz, Gustavo; Derfoul, Assia; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Grontved, Lars; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Mousavi, K (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM kambizmousavi@gmail.com; sartorev@mail.nih.gov OI Grontved, Lars/0000-0002-6735-8483 FU Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health FX We thank Dr. Hong-Wei Sun (Biodata Mining and Discovery Section, NIAMS) for initial MyoD binding analysis; Dr. Stephen J. Tapscott for sharing reagents; Drs. Rahul Roychoudhuri, Ofir Hakim, and Weiqun Peng for stimulating discussions; and Dr. Miroslav Koulnis for assistance with illustrations. This work was supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health. K. M. and V. S. conceived of the experiments; K. M., S.D.O., L. G., G.G.-C., and A. D. performed the experiments and analyzed data; and H.Z. designed and conducted the analyses. K. M., H.Z., G. L. H., and V. S. wrote the manuscript. NR 74 TC 128 Z9 133 U1 0 U2 14 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 SEP 12 PY 2013 VL 51 IS 5 BP 606 EP 617 DI 10.1016/j.molcel.2013.07.022 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 296MP UT WOS:000330189500008 PM 23993744 ER PT J AU Ghosh, AK Parham, GL Martyr, CD Nyalapatla, PR Osswald, HL Agniswamy, J Wang, YF Amano, M Weber, IT Mitsuya, H AF Ghosh, Arun K. Parham, Garth L. Martyr, Cuthbert D. Nyalapatla, Prasanth R. Osswald, Heather L. Agniswamy, Johnson Wang, Yuan-Fang Amano, Masayuki Weber, Irene T. Mitsuya, Hiroaki TI Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein-Ligand X-ray Studies SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANT MUTANTS; IN-VITRO; COMPLEXES; ALCOHOLS; GRL-0519; ETHERS; PI AB The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles. C1 [Ghosh, Arun K.; Parham, Garth L.; Martyr, Cuthbert D.; Nyalapatla, Prasanth R.; Osswald, Heather L.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Parham, Garth L.; Martyr, Cuthbert D.; Nyalapatla, Prasanth R.; Osswald, Heather L.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol Mol Basis Dis, Atlanta, GA 30303 USA. [Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Hematol, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU National Institutes of Health [GM53386, GM62920]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Welfare, and Labor of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases of Monbu-Kagakusho FX This research was supported by the National Institutes of Health (grant nos. GM53386 to A.K.G. and GM62920 to I.T.W.). This work Was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and was supported in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. We thank Dr. Kalapala Venkateswara Rao (Purdue University) for helpful discussions. NR 39 TC 14 Z9 15 U1 1 U2 9 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 SEP 12 PY 2013 VL 56 IS 17 BP 6792 EP 6802 DI 10.1021/jm400768f PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295DS UT WOS:000330097400021 PM 23947685 ER PT J AU Gangjee, A Zhao, Y Raghavan, S Rohena, CC Mooberry, SL Hamel, E AF Gangjee, Aleem Zhao, Ying Raghavan, Sudhir Rohena, Cristina C. Mooberry, Susan L. Hamel, Ernest TI Structure-Activity Relationship and in Vitro and in Vivo Evaluation of the Potent Cytotoxic Anti-microtubule Agent N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidi n-4-aminium Chloride and Its Analogues As Antitumor Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID III BETA-TUBULIN; VASCULAR DISRUPTING AGENTS; CELL LUNG-CANCER; TARGETING AGENTS; COLCHICINE SITE; MULTIDRUG-RESISTANCE; EXPRESSION; MECHANISMS; COMBRETASTATIN-A4; POLYMERIZATION AB A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound (+/-)-1 center dot HCl as an anti-microtubule agent. The structure activity relationship indicates that the N-methyl and a 4N-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30. HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (+/-)-1 center dot HCl. In addition, 30 center dot HCl inhibited cancer cell proliferation regardless of Pgp or beta III-tubulin status, both of which are known to cause clinical resistance to several antitubulin agents. In vivo efficacy of 30 center dot HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30 center dot HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an C1 [Gangjee, Aleem; Zhao, Ying; Raghavan, Sudhir; Hamel, Ernest] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Rohena, Cristina C.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Expt & Dev Therapeut Program, San Antonio, TX 78229 USA. [Hamel, Ernest] NIH, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Gangjee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. EM gangjee@duq.edu; mooberry@uthscsa.edu RI Raghavan, Sudhir/C-8871-2011 OI Raghavan, Sudhir/0000-0001-5449-362X FU National Cancer Institute [CA142868]; NMR [NMR CHE 0614785]; CTRC Cancer Center Support Grant [P30 CA054174]; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence FX We gratefully acknowledge the support of the Developmental Therapeutics Program (DTP), Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, for performing the in vitro antitumor evaluation in their 60 tumor preclinical screening program and for conducting the in vivo xenograft studies. Grant support from the National Cancer Institute, CA142868 (A.G., S.L.M.), is acknowledged as well as support provided by an NSF equipment grant for NMR instrument (NMR CHE 0614785), the CTRC Cancer Center Support Grant, P30 CA054174, and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.). NR 42 TC 7 Z9 7 U1 2 U2 9 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 SEP 12 PY 2013 VL 56 IS 17 BP 6829 EP 6844 DI 10.1021/jm400639z PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295DS UT WOS:000330097400024 PM 23895532 ER PT J AU Frolova, LV Magedov, IV Romero, AE Karki, M Otero, I Hayden, K Evdokimov, NM Banuls, LMY Rastogi, SK Smith, WR Lu, SL Kiss, R Shuster, CB Hamel, E Betancourt, T Rogelj, S Kornienko, A AF Frolova, Liliya V. Magedov, Igor V. Romero, Anntherese E. Karki, Menuka Otero, Isaiah Hayden, Kathryn Evdokimov, Nikolai M. Banuls, Laetitia Moreno Y. Rastogi, Shiva K. Smith, W. Ross Lu, Shi-Long Kiss, Robert Shuster, Charles B. Hamel, Ernest Betancourt, Tania Rogelj, Snezna Kornienko, Alexander TI Exploring Natural Product Chemistry and Biology with Multicomponent Reactions. 5. Discovery of a Novel Tubulin-Targeting Scaffold Derived from the Rigidin Family of Marine Alkaloids SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CANCER-CELL-LINES; ANTIVIRAL ACTIVITY; ANTIMITOTIC AGENT; ANTICANCER DRUGS; ADENOSINE KINASE; COLCHICINE SITE; ANALOGS; DERIVATIVES; INHIBITORS; PYRROLE AB We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [H-3]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents. C1 [Frolova, Liliya V.; Magedov, Igor V.; Otero, Isaiah; Evdokimov, Nikolai M.] New Mexico Inst Min & Technol, Dept Chem, Socorro, NM 87801 USA. [Romero, Anntherese E.; Hayden, Kathryn; Rogelj, Snezna] New Mexico Inst Min & Technol, Dept Biol, Socorro, NM 87801 USA. [Karki, Menuka; Shuster, Charles B.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Banuls, Laetitia Moreno Y.; Kiss, Robert] Univ Libre Brussels, Inst Pharm, Toxicol Lab, Brussels, Belgium. [Banuls, Laetitia Moreno Y.; Kiss, Robert] Univ Libre Brussels, Inst Pharm, Lab Chim Analyt Toxicol & Chim Phys Appl, Brussels, Belgium. [Lu, Shi-Long] Univ Colorado, Dept Otolaryngol, Aurora, CO 80045 USA. [Lu, Shi-Long] Univ Colorado, Dept Dermatol & Pathol, Aurora, CO 80045 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Rastogi, Shiva K.; Smith, W. Ross; Betancourt, Tania; Kornienko, Alexander] Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA. RP Frolova, LV (reprint author), New Mexico Inst Min & Technol, Dept Chem, Socorro, NM 87801 USA. EM lfrolova@nmt.edu; a_k76@txstate.edu FU National Institute of General Medical Sciences [P20GM103451]; National Cancer Institute [CA-135579]; National Science Foundation (NSF) [0946998]; Texas State University; Texas Emerging Technology fund FX This project was supported by grants from the National Institute of General Medical Sciences (P20GM103451), National Cancer Institute (CA-135579), and National Science Foundation (NSF Award 0946998). A.K. is grateful to the Texas State University for start-up funding. T.B. thanks the Texas Emerging Technology fund for start-up support. Mary R. Reisenauer is thanked for performing the MTT assay with compounds 24b-e. LM.Y.B. and R.K are Research Assistant and Director of Research, respectively, with the Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium). NR 55 TC 18 Z9 19 U1 3 U2 33 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 SEP 12 PY 2013 VL 56 IS 17 BP 6886 EP 6900 DI 10.1021/jm400711t PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295DS UT WOS:000330097400028 PM 23927793 ER PT J AU Colaneri, A Wang, TY Pagadala, V Kittur, J Staffa, NG Peddada, SD Isganaitis, E Patti, ME Birnbaumer, L AF Colaneri, Alejandro Wang, Tianyuan Pagadala, Vijayakanth Kittur, Jaya Staffa, Nickolas G., Jr. Peddada, Shyamal D. Isganaitis, Elvira Patti, Mary Elizabeth Birnbaumer, Lutz TI A Minimal Set of Tissue-Specific Hypomethylated CpGs Constitute Epigenetic Signatures of Developmental Programming SO PLOS ONE LA English DT Article ID LARGE GENE LISTS; DNA METHYLATION; ISLAND SHORES; GENOME; REVEALS; REGIONS; DISEASE; METHYLOME; CANCER; MOUSE AB Background: Cell specific states of the chromatin are programmed during mammalian development. Dynamic DNA methylation across the developing embryo guides a program of repression, switching off genes in most cell types. Thus, the majority of the tissue specific differentially methylated sites (TS-DMS) must be un-methylated CpGs. Methodology and Principal Findings: Comparison of expanded Methyl Sensitive Cut Counting data (eMSCC) among four tissues (liver, testes, brain and kidney) from three C57BL/6J mice, identified 138,052 differentially methylated sites of which 23,270 contain CpGs un-methylated in only one tissue (TS-DMS). Most of these CpGs were located in intergenic regions, outside of promoters, CpG islands or their shores, and up to 20% of them overlapped reported active enhancers. Indeed, tissue-specific enhancers were up to 30 fold enriched in TS-DMS. Testis showed the highest number of TS-DMS, but paradoxically their associated genes do not appear to be specific to the germ cell functions, but rather are involved in organism development. In the other tissues the differentially methylated genes are associated with tissue-specific physiological or anatomical functions. The identified sets of TS-DMS quantify epigenetic distances between tissues, generated during development. We applied this concept to measure the extent of reprogramming in the liver of mice exposed to in utero or early postnatal nutritional stress. Different protocols of food restriction reprogrammed the liver methylome in different but reproducible ways. Conclusion and Significance: Thus, each identified set of differentially methylated sites constituted an epigenetic signature that traced the developmental programing or the early nutritional reprogramming of each exposed mouse. We propose that our approach has the potential to outline a number of disease-associated epigenetic states. The composition of differentially methylated CpGs may vary with each situation, behaving as a composite variable, which can be used as a pre-symptomatic marker for disease. C1 [Colaneri, Alejandro; Wang, Tianyuan; Pagadala, Vijayakanth; Kittur, Jaya; Staffa, Nickolas G., Jr.; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Isganaitis, Elvira; Patti, Mary Elizabeth] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Colaneri, A (reprint author), Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. EM acolaneri_2000@yahoo.com.ar; birnbau1@niehs.nih.gov FU National Institutes of Health [Z01-ES-103006]; American Diabetes Association; Graetz Foundation; Lilly Foundation; Lawson-Wilkins Pediatric Endocrine Society; Joslin DERC [5P30 DK036836-23] FX This work was supported by the Intramural Research Program of the National Institutes of Health [2009 NIH Director's Challenge Award and Project Z01-ES-103006 to L. B.]. The authors gratefully acknowledge research grant support from the American Diabetes Association (research grant and mentored postdoctoral fellowship awards to M. E. P.), the Graetz Foundation (to M. E. P.), the Lilly Foundation (to M. E. P.), and the Lawson-Wilkins Pediatric Endocrine Society (to E. I.). This work was also supported in part by the Joslin DERC [5P30 DK036836-23]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 11 Z9 11 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 12 PY 2013 VL 8 IS 9 AR e72670 DI 10.1371/journal.pone.0072670 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242KO UT WOS:000326240100015 PM 24069155 ER PT J AU Nguyen, VQ Ranjan, A Stengel, F Wei, D Aebersold, R Wu, C Leschziner, AE AF Nguyen, Vu Q. Ranjan, Anand Stengel, Florian Wei, Debbie Aebersold, Ruedi Wu, Carl Leschziner, Andres E. TI Molecular Architecture of the ATP-Dependent Chromatin-Remodeling Complex SWR1 SO CELL LA English DT Article ID NUCLEOSOME CORE PARTICLE; TILT RECONSTRUCTION METHOD; EM STRUCTURE DETERMINATION; ACTIN-RELATED PROTEINS; ELECTRON-MICROSCOPY; CRYSTAL-STRUCTURE; CRYO-EM; MACROMOLECULAR COMPLEXES; CONFORMATIONAL-CHANGES; DNA TRANSLOCATION AB The ATP-dependent chromatin-remodeling complex SWR1 exchanges a variant histone H2A.Z/H2B dimer for a canonical H2A/H2B dimer at nucleosomes flanking histone-depleted regions, such as promoters. This localization of H2A.Z is conserved throughout eukaryotes. SWR1 is a 1 megadalton complex containing 14 different polypeptides, including the AAA+ ATPases Rvb1 and Rvb2. Using electron microscopy, we obtained the three-dimensional structure of SWR1 and mapped its major functional components. Our data show that SWR1 contains a single heterohexameric Rvb1/Rvb2 ring that, together with the catalytic subunit Swr1, brackets two independently assembled multisubunit modules. We also show that SWR1 undergoes a large conformational change upon engaging a limited region of the nucleosome core particle. Our work suggests an important structural role for the Rvbs and a distinct substrate-handling mode by SWR1, thereby providing a structural framework for understanding the complex dimer-exchange reaction. C1 [Nguyen, Vu Q.; Leschziner, Andres E.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Ranjan, Anand; Wei, Debbie; Wu, Carl] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Stengel, Florian; Aebersold, Ruedi] ETH, Inst Mol Syst Biol, Dept Biol, CH-8092 Zurich, Switzerland. [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8057 Zurich, Switzerland. [Wu, Carl] HHMI Janelia Farm Res Campus, Ashburn, VA 20147 USA. RP Leschziner, AE (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM aleschziner@mcb.harvard.edu FU National Science Foundation (NSF) [ECS-0335765]; Harvard's FAS Science Division Research Computing Group; National Institutes of Health (NIH) [GM007598]; NSF Graduate Research Fellowship; Leukemia and Lymphoma Society FX We would like to thank Sjors Scheres (LMB-MRC, Cambridge), Pawel Penczek (University of Texas, Houston), John Rubinstein (University of Toronto), and Niko Grigorieff (Janelia Farm) for technical advice, Katerina Toropova, Rogelio Hernandez-Lopez, and Michael Cianfrocco in the Leschziner Lab for contributions during this work, Samara Reck-Peterson (Harvard Medical School), Andrew Richardson, Yoel Stuart, Beka Buckman, and Steve Klosterman (Harvard University) for feedback on the manuscript, Rachelle Gaudet and Nicole Francis (Harvard University) for advice, and Locksley for moral support. EM data were collected at Harvard's Center for Nanoscale Systems, a member of the National Nanotechnology Infrastructure Network and supported by the National Science Foundation (NSF) (ECS-0335765). Computation was performed in part on the Odyssey cluster supported by Harvard's FAS Science Division Research Computing Group. V. Q. N. was supported by the Joint Training Program in Molecules, Cells and Organisms funded by the National Institutes of Health (NIH) (GM007598) and a NSF Graduate Research Fellowship. A. R. was supported in part by a fellowship from the Leukemia and Lymphoma Society. F. S. is a Sir Henry Wellcome Fellow (Wellcome Trust Grant 095951). A. E. L. was supported in part by a fellowship from the Alfred P. Sloan Foundation. This project was supported by grants from the NIH (R01 GM092895A) (to A. E. L.), ETH Zurich (to R. A.), the Commission of the European Communities through the PROSPETS consortium (EU FP7 projects 201648 and 233226 to R. A.), the European Research Council (ERC-2008AdG 233226 to R. A.), the Center for Cancer Research, National Cancer Insti-tute (to A. R., D. W., and C. W.), and the Howard Hughes Medical Institute (C. W.). NR 71 TC 43 Z9 44 U1 1 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 12 PY 2013 VL 154 IS 6 BP 1220 EP 1231 DI 10.1016/j.cell.2013.08.018 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 215VQ UT WOS:000324239300012 PM 24034246 ER PT J AU Ranjan, A Mizuguchi, G FitzGerald, PC Wei, D Wang, F Huang, YZ Luk, E Woodcock, CL Wu, C AF Ranjan, Anand Mizuguchi, Gaku FitzGerald, Peter C. Wei, Debbie Wang, Feng Huang, Yingzi Luk, Ed Woodcock, Christopher L. Wu, Carl TI Nucleosome-free Region Dominates Histone Acetylation in Targeting SWR1 to Promoters for H2A.Z Replacement SO CELL LA English DT Article ID CHROMATIN REMODELING COMPLEX; SACCHAROMYCES-CEREVISIAE GENOME; HEAT-SHOCK GENES; VARIANT HTZ1; BIDIRECTIONAL PROMOTERS; CRYSTAL-STRUCTURE; CORE PARTICLE; CELL-CYCLE; YEAST; TRANSCRIPTION AB The histone variant H2A.Z is a genome-wide signature of nucleosomes proximal to eukaryotic regulatory DNA. Whereas the multisubunit chromatin remodeler SWR1 is known to catalyze ATP-dependent deposition of H2A.Z, the mechanism of SWR1 recruitment to S. cerevisiae promoters has been unclear. A sensitive assay for competitive binding of dinucleosome substrates revealed that SWR1 preferentially binds long nucleosome-free DNA and the adjoining nucleosome core particle, allowing discrimination of gene promoters over gene bodies. Analysis of mutants indicates that the conserved Swc2/YL1 subunit and the adenosine triphosphatase domain of Swr1 are mainly responsible for binding to substrate. SWR1 binding is enhanced on nucleosomes acetylated by the NuA4 histone acetyltransferase, but recognition of nucleosome-free and nucleosomal DNA is dominant over interaction with acetylated histones. Such hierarchical cooperation between DNA and histone signals expands the dynamic range of genetic switches, unifying classical gene regulation by DNA-binding factors with ATP-dependent nucleosome remodeling and posttranslational histone modifications. C1 [Ranjan, Anand; Wei, Debbie; Wang, Feng; Huang, Yingzi; Wu, Carl] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. [Mizuguchi, Gaku; Wu, Carl] Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA 20147 USA. [Luk, Ed] SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. [Woodcock, Christopher L.] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. [Woodcock, Christopher L.] Univ Massachusetts, Program Mol & Cellular Biol, Amherst, MA 01003 USA. RP Ranjan, A (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ranjana@mail.nih.gov; wuc@janelia.hhmi.org OI Luk, Ed/0000-0002-6619-2258 FU Leukemia and Lymphoma Society fellowship; Janelia Farm Research Campus, Howard Hughes Medical Institute; Center for Cancer Research, National Cancer Institute FX We thank Dr. Joseph Wall, STEM facility, Biology Department, Brookhaven Laboratories, Upton, NY, and his staff for conducting STEM mass measurements; Karolin Luger's laboratory for sharing unpublished data on Swc2; Wei-Hua Wu for the kind gift of yeast strains; Sameet Mehta for bioinformatics; and Michael Lichten, Sean Eddy, Claude Klee, Joseph Landry, members of our laboratory and reviewers for helpful comments. This work was supported by a Leukemia and Lymphoma Society fellowship (to A.R.), by the Janelia Farm Research Campus, Howard Hughes Medical Institute (to C.W. and G.M.), and by the Center for Cancer Research, National Cancer Institute. NR 69 TC 58 Z9 59 U1 2 U2 42 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 12 PY 2013 VL 154 IS 6 BP 1232 EP 1245 DI 10.1016/j.cell.2013.08.005 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 215VQ UT WOS:000324239300013 PM 24034247 ER PT J AU Lu, JX Qiang, W Yau, WM Schwieters, CD Meredith, SC Tycko, R AF Lu, Jun-Xia Qiang, Wei Yau, Wai-Ming Schwieters, Charles D. Meredith, Stephen C. Tycko, Robert TI Molecular Structure of beta-Amyloid Fibrils in Alzheimer's Disease Brain Tissue SO CELL LA English DT Article ID PROTEIN A-BETA; DISTANCE MEASUREMENTS; SENILE PLAQUES; IN-VIVO; SHEET; OLIGOMERS; POLYMORPHISM; DEPOSITION; A-BETA-40; PEPTIDE AB In vitro, beta-amyloid (A beta) peptides form polymorphic fibrils, with molecular structures that depend on growth conditions, plus various oligomeric and protofibrillar aggregates. Here, we investigate structures of human brain-derived A beta fibrils, using seeded fibril growth from brain extract and data from solid-state nuclear magnetic resonance and electron microscopy. Experiments on tissue from two Alzheimer's disease (AD) patients with distinct clinical histories showed a single predominant 40 residue A beta (A beta 40) fibril structure in each patient; however, the structures were different from one another. A molecular structural model developed for A beta 40 fibrils from one patient reveals features that distinguish in-vivo-from in-vitro-produced fibrils. The data suggest that fibrils in the brain may spread from a single nucleation site, that structural variations may correlate with variations in AD, and that structure-specific amyloid imaging agents may be an important future goal. C1 [Lu, Jun-Xia; Qiang, Wei; Yau, Wai-Ming; Tycko, Robert] NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Meredith, Stephen C.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Meredith, Stephen C.] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. RP Tycko, R (reprint author), NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology of the National Institutes of Health; N.I.H. [R01 NS042852] FX Supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Center for Information Technology of the National Institutes of Health, and by N.I.H. grant R01 NS042852 (to S.C.M.). We thank Dr. Reed Wickner for assistance with gene sequencing and Dr. Peter Pytel for assistance with histopathology. Calculations were performed on the Biowulf Linux cluster at the N.I.H. NR 70 TC 305 Z9 309 U1 30 U2 291 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 12 PY 2013 VL 154 IS 6 BP 1257 EP 1268 DI 10.1016/j.cell.2013.08.035 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 215VQ UT WOS:000324239300015 PM 24034249 ER PT J AU Nakashima, A Takeuchi, H Imai, T Saito, H Kiyonari, H Abe, T Chen, M Weinstein, LS Yu, CR Storm, DR Nishizumi, H Sakano, H AF Nakashima, Ai Takeuchi, Haruki Imai, Takeshi Saito, Harumi Kiyonari, Hiroshi Abe, Takaya Chen, Min Weinstein, Lee S. Yu, C. Ron Storm, Daniel R. Nishizumi, Hirofumi Sakano, Hitoshi TI Agonist-Independent GPCR Activity Regulates Anterior-Posterior Targeting of Olfactory Sensory Neurons SO CELL LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MAMMALIAN ODORANT RECEPTORS; BETA(2)-ADRENERGIC RECEPTOR; BETA-2-ADRENERGIC RECEPTOR; GENE-EXPRESSION; MAP TOPOGRAPHY; MOUSE; BULB; ACTIVATION; SYSTEM AB G-protein-coupled receptors (GPCRs) are known to possess two different conformations, active and inactive, and they spontaneously alternate between the two in the absence of ligands. Here, we analyzed the agonist-independent GPCR activity for its possible role in receptor-instructed axonal projection. We generated transgenic mice expressing activity mutants of the beta 2-adrenergic receptor, a well-characterized GPCR with the highest homology to odorant receptors (ORs). We found that mutants with altered agonist-independent activity changed the transcription levels of axon-targeting molecules-e.g., Neuropilin-1 and Plexin-A1-but not of glomerular segregation molecules-e.g., Kirrel2 and Kirrel3-thus causing shifts in glomerular locations along the anterior-posterior (A-P) axis. Knockout and in vitro experiments demonstrated that G(s), but not G(olf), is responsible for mediating the agonist-independent GPCR activity. We conclude that the equilibrium of conformational transitions set by each OR is the major determinant of expression levels of A-P-targeting molecules. C1 [Nakashima, Ai; Takeuchi, Haruki; Imai, Takeshi; Saito, Harumi; Nishizumi, Hirofumi; Sakano, Hitoshi] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1130032, Japan. [Nakashima, Ai; Takeuchi, Haruki; Sakano, Hitoshi] Univ Fukui, Sch Med Sci, Dept Brain Funct, Fukui 9101193, Japan. [Imai, Takeshi] RIKEN Ctr Dev Biol, Lab Sensory Circuit Format, Kobe, Hyogo 6500047, Japan. [Imai, Takeshi] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. [Kiyonari, Hiroshi; Abe, Takaya] RIKEN Ctr Dev Biol, Lab Anim Resources & Genet Engn, Kobe, Hyogo 6500047, Japan. [Chen, Min; Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Yu, C. Ron] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Storm, Daniel R.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Sakano, H (reprint author), Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1130032, Japan. EM sakano@mail.ecc.u-tokyo.ac.jp RI Imai, Takeshi/L-2201-2013; Kiyonari, Hiroshi/N-7936-2015 OI Imai, Takeshi/0000-0002-8449-0080; FU PRESTO program of Japan Science and Technology Corporation; Toray Science Foundation; Sumitomo Foundation; Nakajima Foundation; Mitsubishi Foundation; Japan Foundation for Applied Enzymology; Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; MEXT of Japan FX We thank R. Axel for Golf-KO mice; R. Kobayakawa and K. Kobayakawa for Omacs-cre mice; T. Hirata for antibodies against Nrp1; H. Ueno for antibodies against Kirrel3; F. Suto and Y. Hiromi for antibodies against PlxnA1; S. Suzuki and A. Miyajima for FACS analysis; A. Katsuyama for technical assistance; J.-P. Changeux, L. Luo, O. Nureki, and H. Kato for insightful discussion; and J. Ngai, L. Buck, and our laboratory members for valuable comments. This research was supported by the PRESTO program of Japan Science and Technology Corporation (T.I.), Toray Science Foundation (H.S.), Sumitomo Foundation (T.I.), Nakajima Foundation (T.I.), Mitsubishi Foundation (H.S. and T.I.), Japan Foundation for Applied Enzymology (T.I., H.T., H.N., and H.S.), grants in aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (T.I., H.N., H.T., and H.S.), and a Specially Promoted Research Grant from MEXT of Japan (H.S.). NR 57 TC 40 Z9 40 U1 0 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 12 PY 2013 VL 154 IS 6 BP 1314 EP 1325 DI 10.1016/j.cell.2013.08.033 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 215VQ UT WOS:000324239300019 PM 24034253 ER PT J AU Van Laethem, F Tikhonova, AN Pobezinsky, LA Tai, XG Kimura, MY Le Saout, C Guinter, TI Adams, A Sharrow, SO Bernhardt, G Feigenbaum, L Singer, A AF Van Laethem, Francois Tikhonova, Anastasia N. Pobezinsky, Leonid A. Tai, Xuguang Kimura, Motoko Y. Le Saout, Cecile Guinter, Terry I. Adams, Anthony Sharrow, Susan O. Bernhardt, Guenter Feigenbaum, Lionel Singer, Alfred TI Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire SO CELL LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; TYROSINE KINASE P56(LCK); ANTIGEN RECEPTOR; AMINO-ACIDS; GAMMA-DELTA; CD4; MHC; ACTIVATION; ADHESION; P56LCK AB Thymic selection requires signaling by the protein tyrosine kinase Lck to generate T cells expressing alpha beta T cell antigen receptors (TCR). For reasons not understood, the thymus selects only alpha beta TCR that are restricted by major histocompatibility complex (MHC)-encoded determinants. Here, we report that Lck proteins that were coreceptor associated promoted thymic selection of conventionally MHC-restricted TCR, but Lck proteins that were coreceptor free promoted thymic selection of MHC-independent TCR. Transgenic TCR with MHC-independent specificity for CD155 utilized coreceptor-free Lck to signal thymic selection in the absence of MHC, unlike any transgenic TCR previously described. Thus, the thymus can select either MHC-restricted or MHC-independent alpha beta TCR depending on whether Lck is coreceptor associated or coreceptor free. We conclude that the intracellular state of Lck determines the specificity of thymic selection and that Lck association with coreceptor proteins during thymic selection is the mechanism by which MHC restriction is imposed on a randomly generated alpha beta TCR repertoire. C1 [Van Laethem, Francois; Tikhonova, Anastasia N.; Pobezinsky, Leonid A.; Tai, Xuguang; Kimura, Motoko Y.; Guinter, Terry I.; Adams, Anthony; Sharrow, Susan O.; Singer, Alfred] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Le Saout, Cecile] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Bernhardt, Guenter] Hannover Med Sch, Inst Immunol, D-30625 Hannover, Germany. [Feigenbaum, Lionel] NCI Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. EM singera@nih.gov RI Bernhardt, Gunter/F-6946-2012; Tikhonova, Anastasia/F-1186-2015 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Richard Hodes, Hyun Park, and Ruth Etzensperger for critically reading the manuscript; Joy Williams for thymic epithelial cell preparations; and Peter Sun and Jinghua Lu for helpful discussion. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 38 TC 39 Z9 39 U1 3 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 12 PY 2013 VL 154 IS 6 BP 1326 EP 1341 DI 10.1016/j.cell.2013.08.009 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 215VQ UT WOS:000324239300020 PM 24034254 ER PT J AU Zhang, J Espinoza, LA Kinders, RJ Lawrence, SM Pfister, TD Zhou, M Veenstra, TD Thorgeirsson, SS Jessup, JM AF Zhang, J. Espinoza, L. A. Kinders, R. J. Lawrence, S. M. Pfister, T. D. Zhou, M. Veenstra, T. D. Thorgeirsson, S. S. Jessup, J. M. TI NANOG modulates stemness in human colorectal cancer SO ONCOGENE LA English DT Article DE NANOG; NANOGP8; stemness; colorectal cancer; cancer stem cell ID TRANSCRIPTIONAL NETWORK; GENE-EXPRESSION; DEFINED FACTORS; GROUND-STATE; SELF-RENEWAL; IN-VIVO; CELLS; PLURIPOTENCY; SOX2; CARCINOMAS AB NANOG is a stem cell transcription factor that is essential for embryonic development, reprogramming normal adult cells and malignant transformation and progression. The nearly identical retrogene NANOGP8 is expressed in multiple cancers, but generally not in normal tissues and its function is not well defined. Our postulate is that NANOGP8 directly modulates the stemness of individual human colorectal carcinoma (CRC) cells. Stemness was measured in vitro as the spherogenicity of single CRC cells in serum-free medium and the size of the side population (SP) and in vivo as tumorigenicity and experimental metastatic potential in NOD/SCID mice. We found that 80% of clinical liver metastases express a NANOG with 75% of the positive metastases containing NANOGP8 transcripts. In all, 3-62% of single cells within six CRC lines form spheroids in serum-free medium in suspension. NANOGP8 is translated into protein. The relative expression of a NANOG gene increased 8- to 122-fold during spheroid formation, more than the increase in OCT4 or SOX2 transcripts with NANOGP8 the more prevalent family member. Short hairpin RNA (shRNA) to NANOG not only inhibits spherogenicity but also reduces expression of OCT4 and SOX2, the size of the SP and tumor growth in vivo. Inhibition of NANOG gene expression is associated with inhibition of proliferation and decreased phosphorylation of G2-related cell-cycle proteins. Overexpression of NANOGP8 rescues single-cell spherogenicity when NANOG gene expression is inhibited and increases the SP in CRC. Thus, NANOGP8 can substitute for NANOG in directly promoting stemness in CRC. C1 [Zhang, J.; Espinoza, L. A.; Thorgeirsson, S. S.; Jessup, J. M.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kinders, R. J.; Lawrence, S. M.; Pfister, T. D.] SAIC Frederick Inc, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Zhou, M.; Veenstra, T. D.] SAIC Frederick, Lab Prote & Analyt Technol, Frederick Natl Lab Canc Res, Frederick, MD USA. [Jessup, J. M.] Div Canc Treatment & Diag, Canc Diag Program, Rockville, MD USA. RP Jessup, JM (reprint author), Canc Diag Program, Diagnost Evaluat Branch, Bethesda, MD 20892 USA. EM jessupj@mail.nih.gov FU Center for Cancer Research of the NCI [ZIA BC 011199]; Department of Defense [W81XWH-11-1-0327] FX We acknowledge the valuable advice and support of Drs Elizabeth Conner and Valentina Factor. Also, we gratefully acknowledge the support provided by the Center for Cancer Research of the NCI for Project ZIA BC 011199 and by the Department of Defense for Grant Number W81XWH-11-1-0327. The opinions expressed in this manuscript are those of the authors and do not necessarily represent those of the National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services or the Department of the Army. NR 56 TC 27 Z9 32 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 12 PY 2013 VL 32 IS 37 BP 4397 EP 4405 DI 10.1038/onc.2012.461 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 218AF UT WOS:000324404200008 PM 23085761 ER PT J AU Ilnytska, O Santiana, M Hsu, NY Du, WL Chen, YH Viktorova, EG Belov, G Brinker, A Storch, J Moore, C Dixon, JL Altan-Bonnet, N AF Ilnytska, Olha Santiana, Marianita Hsu, Nai-Yun Du, Wen-Li Chen, Ying-Han Viktorova, Ekaterina G. Belov, Georgy Brinker, Anita Storch, Judith Moore, Christopher Dixon, Joseph L. Altan-Bonnet, Nihal TI Enteroviruses Harness the Cellular Endocytic Machinery to Remodel the Host Cell Cholesterol Landscape for Effective Viral Replication SO CELL HOST & MICROBE LA English DT Article ID CLATHRIN-INDEPENDENT ENDOCYTOSIS; PICK C1-LIKE 1; PLASMA-MEMBRANE; ALZHEIMERS-DISEASE; RNA REPLICATION; POLIOVIRUS RNA; IN-VITRO; RECYCLING ENDOSOME; VIRUS-REPLICATION; PROTEIN AB Cholesterol is a critical component of cellular membranes, regulating assembly and function of membrane-based protein/lipid complexes. Many RNA viruses, including enteroviruses, remodel host membranes to generate organelles with unique lipid blueprints on which they assemble replication complexes and synthesize viral RNA. Here we find that clathrin-mediated endocytosis (CME) is harnessed by enteroviruses to traffic cholesterol from the plasma membrane (PM) and extracellular medium to replication organelles, where cholesterol then regulates viral polyprotein processing and facilitates genome synthesis. When CME is disrupted, cellular cholesterol pools are instead stored in lipid droplets, cholesterol cannot be trafficked to replication organelles, and replication is inhibited. In contrast, replication is stimulated in cholesterol-elevated cells like those lacking caveolins or those from Niemann-Pick disease patients. Our findings indicate cholesterol as a critical determinant for enteroviral replication and outline roles for the endocytic machinery in both the enteroviral life cycle and host cell cholesterol homeostasis. C1 [Ilnytska, Olha; Santiana, Marianita; Hsu, Nai-Yun; Du, Wen-Li; Chen, Ying-Han; Viktorova, Ekaterina G.; Altan-Bonnet, Nihal] Rutgers State Univ, Lab Host Pathogen Dynam, Newark, NJ 07102 USA. [Viktorova, Ekaterina G.; Belov, Georgy] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Brinker, Anita; Storch, Judith; Dixon, Joseph L.] Rutgers State Univ, Ctr Lipid Res, New Brunswick, NJ 08901 USA. [Moore, Christopher] GlaxoSmithKline, Infect Dis Med Discovery & Dev, Res Triangle Pk, NC 27709 USA. RP Altan-Bonnet, N (reprint author), NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM nihal.altan-bonnet@nih.gov RI Belov, George/B-4625-2008; DU, WENLI/I-4940-2013; OI Belov, George/0000-0002-0892-1731; DU, WENLI/0000-0002-1262-0114; Storch, Judith/0000-0001-5482-1777 FU NIH [R01AI091985, DK38389]; NSF [MCB-0822058]; Ara Parseghian Medical Research Foundation; National Center for Research Resources [RR-021120] FX We thank Jennifer Lippincott-Schwartz, Ellie Ehrenfeld, Cathy Jackson, Sandy Simon, Gregoire Altan-Bonnet, Nan Gao, Radek Dobrowolski, and Eckard Wimmer for critical reading of the manuscript; and Ilya Raskin, Carolyn Ott, and Elise Shumsky for technical support. Awards from NIH R01AI091985 and NSF MCB-0822058 supported N.A.-B.; NIH DK38389 and Ara Parseghian Medical Research Foundation supported J.S.; National Center for Research Resources RR-021120 supported J.L.D. NR 63 TC 46 Z9 46 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 11 PY 2013 VL 14 IS 3 BP 281 EP 293 DI 10.1016/j.chom.2013.08.002 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1JH UT WOS:000330852000008 PM 24034614 ER PT J AU Molloy, MJ Grainger, JR Bouladoux, N Hand, TW Koo, LY Naik, S Quinones, M Dzutsev, AK Gao, JL Trinchieri, G Murphy, PM Belkaid, Y AF Molloy, Michael J. Grainger, John R. Bouladoux, Nicolas Hand, Timothy W. Koo, Lily Y. Naik, Shruti Quinones, Mariam Dzutsev, Amiran K. Gao, Ji-Liang Trinchieri, Giorgio Murphy, Philip M. Belkaid, Yasmine TI Intraluminal Containment of Commensal Outgrowth in the Gut during Infection-Induced Dysbiosis SO CELL HOST & MICROBE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; ACUTE GASTROINTESTINAL INFECTION; METHIONYL-LEUCYL-PHENYLALANINE; FORMYLPEPTIDE RECEPTOR FPR; INVASIVE ESCHERICHIA-COLI; T-CELL RESPONSES; CROHNS-DISEASE; TOXOPLASMA-GONDII; JUVENILE PERIODONTITIS; MICROBIOTA AB Shifts in commensal microbiota composition are emerging as a hallmark of gastrointestinal inflammation. In particular, outgrowth of gamma-proteobacteria has been linked to the etiology of inflammatory bowel disease and the pathologic consequences of infections. Here we show that following acute Toxoplasma gondii gastrointestinal infection of mice, control of commensal outgrowth is a highly coordinated process involving both the host response and microbial signals. Notably, neutrophil emigration to the intestinal lumen results in the generation of organized intraluminal structures that encapsulate commensals and limit their contact with the epithelium. Formation of these luminal casts depends on the high-affinity N-formyl peptide receptor, Fpr1. Consequently, after infection, mice deficient in Fpr1 display increased microbial translocation, poor commensal containment, and increased mortality. Altogether, our study describes a mechanism by which the host rapidly contains commensal pathobiont outgrowth during infection. Further, these results reveal Fpr1 as a major mediator of host commensal interaction during dysbiosis. C1 [Molloy, Michael J.; Grainger, John R.; Bouladoux, Nicolas; Hand, Timothy W.; Naik, Shruti; Belkaid, Yasmine] NIAID, NIH, Parasit Dis Lab, Program Barrier Immun & Repair,Mucosal Immunol Se, Bethesda, MD 20892 USA. [Koo, Lily Y.] NIAID, NIH, Biol Imaging Facil, Bethesda, MD 20892 USA. [Quinones, Mariam] NIAID, NIH, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. [Gao, Ji-Liang; Murphy, Philip M.] NIAID, NIH, Lab Mol Immunol, Mol Signaling Sect, Bethesda, MD 20892 USA. [Dzutsev, Amiran K.; Trinchieri, Giorgio] Natl Canc Inst, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Belkaid, Y (reprint author), NIAID, NIH, Parasit Dis Lab, Program Barrier Immun & Repair,Mucosal Immunol Se, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov OI Grainger, John/0000-0002-4052-5923 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Dr. Lora Hooper and Shipra Vaishnava (UT Southwestern) for sharing protocols; the NIAID gnotobiotic facility staff and in particular Cesar Acevedo and Dana Trageser-Cesler; Dr. Kevin Holmes and the NIAID sorting facility; Kim Beacht for technical assistance; and the NIAID Biological Imaging Facility. We thank Clayton Deming for thoughtful discussion and Amiko Uchida for critical reading of the manuscript. NR 58 TC 35 Z9 35 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 11 PY 2013 VL 14 IS 3 BP 318 EP 328 DI 10.1016/j.chom.2013.08.003 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1JH UT WOS:000330852000011 PM 24034617 ER PT J AU Moeller, AH Shilts, M Li, YY Rudicell, RS Lonsdorf, EV Pusey, AE Wilson, ML Hahn, BH Ochman, H AF Moeller, Andrew H. Shilts, Meghan Li, Yingying Rudicell, Rebecca S. Lonsdorf, Elizabeth V. Pusey, Anne E. Wilson, Michael L. Hahn, Beatrice H. Ochman, Howard TI SIV-Induced Instability of the Chimpanzee Gut Microbiome SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; HIV-INFECTION; SCHWEINFURTHII; ENTEROTYPES; AIDS AB Simian immunodeficiency virus of chimpanzees (SIVcpz) is the ancestor of human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS) in humans. Like HIV-1-infected humans, SIVcpz-infected chimpanzees can develop AIDS-like symptoms. Because SIVcpz/HIV-1 may disrupt regulation of the gut microbiome and because it has not been possible to sample individual humans pre- and postinfection, we investigated the influence of infection on gut communities through long-term monitoring of chimpanzees from Gombe National Park, Tanzania. SIVcpz infection accelerated the rate of change in gut microbiota composition within individuals for periods of years after the initial infection and led to gut communities marked by high frequencies of pathogen-containing bacterial genera absent from SIVcpz-negative individuals. Our results indicate that immune function maintains temporally stable gut communities that are lost when individuals become infected with SIVcpz. C1 [Moeller, Andrew H.; Shilts, Meghan; Ochman, Howard] Yale Univ, Dept Ecol & Evolut Biol, New Haven, CT 06511 USA. [Li, Yingying; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med & Microbiol, Philadelphia, PA 19104 USA. [Rudicell, Rebecca S.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Lonsdorf, Elizabeth V.] Franklin & Marshall Coll, Dept Phys, Lancaster, PA 17604 USA. [Pusey, Anne E.] Duke Univ, Dept Evolut Anthropol, Durham, NC 27705 USA. [Wilson, Michael L.] Univ Minnesota, Dept Anthropol, Minneapolis, MN 55455 USA. RP Ochman, H (reprint author), Yale Univ, Dept Ecol & Evolut Biol, New Haven, CT 06511 USA. EM howard.ochman@yale.edu FU National Institutes of Health [R01 AI50529, R01 AI58715, R01 GM101209]; National Science Foundation; Howard Hughes Medical Institute Med-into-Grad Fellowship; National Science Foundation [2011119472] FX This work was made possible through grants from the National Institutes of Health (R01 AI50529 and R01 AI58715 to B. H. H. and R01 GM101209 to H.O.) and from the National Science Foundation (to A. E. P. and M. L. W.). Additionally, we thank the Jane Goodall Institute for supporting collection of fecal samples from chimpanzees at the Gombe Stream Research Centre, the Tanzania Commission for Science and Technology, the Tanzania Wildlife Research Institute, and the Tanzania National Parks for permission to conduct research in Gombe. R. S. R. was funded by a Howard Hughes Medical Institute Med-into-Grad Fellowship, and A. H. M. is supported by predoctoral fellowship 2011119472 from the National Science Foundation. NR 31 TC 18 Z9 19 U1 1 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 11 PY 2013 VL 14 IS 3 BP 340 EP 345 DI 10.1016/j.chom.2013.08.005 PG 6 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1JH UT WOS:000330852000013 PM 24034619 ER PT J AU Henderson, DM Manca, M Haley, NJ Denkers, ND Nalls, AV Mathiason, CK Caughey, B Hoover, EA AF Henderson, Davin M. Manca, Matteo Haley, Nicholas J. Denkers, Nathaniel D. Nalls, Amy V. Mathiason, Candace K. Caughey, Byron Hoover, Edward A. TI Rapid Antemortem Detection of CWD Prions in Deer Saliva SO PLOS ONE LA English DT Article ID CHRONIC WASTING DISEASE; QUAKING-INDUCED CONVERSION; INFECTIOUS SCRAPIE PRIONS; ROCKY-MOUNTAIN ELK; SPONGIFORM ENCEPHALOPATHY; CEREBROSPINAL-FLUID; MULE DEER; CYCLIC AMPLIFICATION; TRANSGENIC MICE; PROTEIN AB Chronic wasting disease (CWD) is an efficiently transmitted prion disease of cervids, now identified in 22 United States, 2 Canadian provinces and Korea. One hallmark of CWD is the shedding of infectious prions in saliva, as demonstrated by bioassay in deer. It is also clear that the concentration of prions in saliva, blood, urine and feces is much lower than in the nervous system or lymphoid tissues. Rapid in vitro detection of CWD (and other) prions in body fluids and excreta has been problematic due to the sensitivity limits of direct assays (western blotting, ELISA) and the presence of inhibitors in these complex biological materials that hamper detection. Here we use real-time quaking induced conversion (RT-QuIC) to demonstrate CWD prions in both diluted and prion-enriched saliva samples from asymptomatic and symptomatic white-tailed deer. CWD prions were detected in 14 of 24 (58.3%) diluted saliva samples from CWD-exposed white-tailed deer, including 9 of 14 asymptomatic animals (64.2%). In addition, a phosphotungstic acid enrichment enhanced the RT-QuIC assay sensitivity, enabling detection in 19 of 24 (79.1%) of the above saliva samples. Bioassay in Tg[CerPrP] mice confirmed the presence of infectious prions in 2 of 2 RT-QuIC-positive saliva samples so examined. The modified RT-QuIC analysis described represents a non-invasive, rapid ante-mortem detection of prions in complex biologic fluids, excreta, or environmental samples as well as a tool for exploring prion trafficking, peripheralization, and dissemination. C1 [Henderson, Davin M.; Haley, Nicholas J.; Denkers, Nathaniel D.; Nalls, Amy V.; Mathiason, Candace K.; Hoover, Edward A.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Manca, Matteo; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. [Manca, Matteo] Univ Cagliari, Dept Biomed Sci, Monserrato, Italy. RP Hoover, EA (reprint author), Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. EM Edward.Hoover@colostate.edu RI Mathiason, Candace/E-7843-2017 OI Mathiason, Candace/0000-0002-5920-4556 FU NIH NINDS [R01 NS-061902]; Morris Animal Foundation [D12ZO-045]; NIAID; Sardinia Regional Government FX Supported by NIH NINDS grant R01 NS-061902 and by grant D12ZO-045 from the Morris Animal Foundation. This work was also supported in part by the Intramural Research Program of the NIAID. We gratefully acknowledge the Sardinia Regional Government for the financial support of Matteo Manca through his Ph.D. scholarship (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007-2013). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 21 Z9 21 U1 5 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2013 VL 8 IS 9 AR e74377 DI 10.1371/journal.pone.0074377 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 248VW UT WOS:000326734500087 PM 24040235 ER PT J AU Ni, T Yang, YQ Hafez, D Yang, WJ Kiesewetter, K Wakabayashi, Y Ohler, U Peng, WQ Zhu, J AF Ni, Ting Yang, Yanqin Hafez, Dina Yang, Wenjing Kiesewetter, Kurtis Wakabayashi, Yoshi Ohler, Uwe Peng, Weiqun Zhu, Jun TI Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy SO BMC GENOMICS LA English DT Article ID MESSENGER-RNA POLYADENYLATION; 3' UNTRANSLATED REGIONS; CLEAVAGE FACTOR-I; ALTERNATIVE POLYADENYLATION; MOLECULAR-MECHANISMS; GENE-EXPRESSION; TRANSCRIPTION; SITES; WIDESPREAD; CANCER AB Background: Polyadenylation is a key regulatory step in eukaryotic gene expression and one of the major contributors of transcriptome diversity. Aberrant polyadenylation often associates with expression defects and leads to human diseases. Results: To better understand global polyadenylation regulation, we have developed a polyadenylation sequencing (PA-seq) approach. By profiling polyadenylation events in 13 human tissues, we found that alternative cleavage and polyadenylation (APA) is prevalent in both protein-coding and noncoding genes. In addition, APA usage, similar to gene expression profiling, exhibits tissue-specific signatures and is sufficient for determining tissue origin. A 3' untranslated region shortening index (USI) was further developed for genes with tandem APA sites. Strikingly, the results showed that different tissues exhibit distinct patterns of shortening and/or lengthening of 3' untranslated regions, suggesting the intimate involvement of APA in establishing tissue or cell identity. Conclusions: This study provides a comprehensive resource to uncover regulated polyadenylation events in human tissues and to characterize the underlying regulatory mechanism. C1 [Ni, Ting; Yang, Yanqin; Yang, Wenjing; Kiesewetter, Kurtis; Wakabayashi, Yoshi; Zhu, Jun] NHLBI, NIH, Genet & Dev Biol Ctr, Bethesda, MD 20892 USA. [Ni, Ting] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Ni, Ting] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Hafez, Dina; Ohler, Uwe] Duke Univ, Dept Comp Sci, Durham, NC 27708 USA. [Yang, Wenjing; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Ohler, Uwe] Duke Univ, Med Ctr, Inst Genome Sci & Policy, Durham, NC 27708 USA. RP Ni, T (reprint author), NHLBI, NIH, Genet & Dev Biol Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tingni@fudan.edu.cn; jun.zhu@nih.gov FU Intramural Research Program of National Heart Lung and Blood Institute (NHLBI); National Institutes of Health (NIH); National Basic Research Program of China [2013CB530700]; National Science Foundation of China [31271348] FX We are grateful to Dr. Delong Liu for the help of gene expression analysis between PA-seq and microarray data. We are indebted to Drs. Kang Tu, Yuan Gao for their advices on data analysis. This work is supported by the Intramural Research Program of National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), the National Basic Research Program of China (2013CB530700), and the National Science Foundation of China (31271348). NR 53 TC 9 Z9 9 U1 1 U2 4 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 SEP 11 PY 2013 VL 14 AR 615 DI 10.1186/1471-2164-14-615 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 222UJ UT WOS:000324756900001 PM 24025092 ER PT J AU Tremblay, A Hosseini, P Li, SX Alkharouf, NW Matthews, BF AF Tremblay, Arianne Hosseini, Parsa Li, Shuxian Alkharouf, Nadim W. Matthews, Benjamin F. TI Analysis of Phakopsora pachyrhizi transcript abundance in critical pathways at four time-points during infection of a susceptible soybean cultivar using deep sequencing SO BMC GENOMICS LA English DT Article DE Deep sequencing; Transcript abundance; Phakopsora pachyrhizi; Plant-pathogen interaction; Soybean; Soybean rust ID FUNGUS UROMYCES-FABAE; MEMBRANE H+-ATPASE; SPORE GERMINATION; GENE-EXPRESSION; RNA-SEQ; MITOCHONDRIAL BIOGENESIS; CONIDIAL GERMINATION; RIBONUCLEIC-ACIDS; RUST RESISTANCE; UNITED-STATES AB Background: Phakopsora pachyrhizi, the causal agent responsible for soybean rust, is among the top hundred most virulent plant pathogens and can cause soybean yield losses of up to 80% when appropriate conditions are met. We used mRNA-Seq by Illumina to analyze pathogen transcript abundance at 15 seconds (s), 7 hours (h), 48 h, and 10 days (d) after inoculation (ai) of susceptible soybean leaves with P. pachyrhizi to gain new insights into transcript abundance in soybean and the pathogen at specific time-points during the infection including the uredinial stage. Results: Over three million five hundred thousand sequences were obtained for each time-point. Energy, nucleotide metabolism, and protein synthesis are major priorities for the fungus during infection and development as indicated by our transcript abundance studies. At all time-points, energy production is a necessity for P. pachyrhizi, as indicated by expression of many transcripts encoding enzymes involved in oxidative phosphorylation and carbohydrate metabolism (glycolysis, glyoxylate and dicarboxylate, pentose phosphate, pyruvate). However, at 15 sai, transcripts encoding enzymes involved in ATP production were highly abundant in order to provide enough energy for the spore to germinate, as observed by the expression of many transcripts encoding proteins involved in electron transport. At this early time-point, transcripts encoding proteins involved in RNA synthesis were also highly abundant, more so than transcripts encoding genes involved in DNA and protein synthesis. At 7 hai, shortly after germination during tube elongation and penetration, transcripts encoding enzymes involved in deoxyribonucleotide and DNA synthesis were highly abundant. At 48 hai, transcripts encoding enzymes involved in amino acid metabolism were highly abundant to provide for increased protein synthesis during haustoria maturation. During sporulation at 10 dai, the fungus still required carbohydrate metabolism, but there also was increased expression of transcripts encoding enzymes involved in fatty acid metabolism. Conclusion: This information provides insight into molecular events and their timing throughout the life cycle of the P. pachyrhizi, and it may be useful in the development of new methods of broadening resistance of soybean to soybean rust. C1 [Tremblay, Arianne; Matthews, Benjamin F.] USDA ARS, Soybean Genom & Improvement Lab, Beltsville, MD 20705 USA. [Hosseini, Parsa] George Mason Univ, Fairfax, VA 22030 USA. [Hosseini, Parsa] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Li, Shuxian] USDA ARS, Crop Genet Res Unit, Stoneville, MS 38776 USA. [Alkharouf, Nadim W.] Towson Univ, Fischer Coll Sci & Math, Towson, MD 21252 USA. [Tremblay, Arianne] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. RP Tremblay, A (reprint author), USDA ARS, Soybean Genom & Improvement Lab, Beltsville, MD 20705 USA. EM arianne@umbc.edu FU United Soybean Board project [T0258]; Intramural Research Program of the National Institutes of Health, National Library of Medicine FX The authors thank Alicia Beavers for her excellent technical assistance, and Richard Joost, Eric Brewer, for their careful critical review of the manuscript. The authors gratefully acknowledge support from United Soybean Board project number T0258. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. Mention of trade name, proprietary product or vendor does not constitute a guarantee or warranty of the product by the U. S. Department of Agriculture or imply its approval to the exclusion of other products or vendors that also may be suitable. NR 62 TC 11 Z9 11 U1 0 U2 27 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 SEP 11 PY 2013 VL 14 AR 614 DI 10.1186/1471-2164-14-614 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 219QH UT WOS:000324522700001 PM 24025037 ER PT J AU Simonyan, K Berman, BD Herscovitch, P Hallett, M AF Simonyan, Kristina Berman, Brian D. Herscovitch, Peter Hallett, Mark TI Abnormal Striatal Dopaminergic Neurotransmission during Rest and Task Production in Spasmodic Dysphonia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; TRANSGENIC MOUSE MODEL; D2 RECEPTOR-BINDING; KNOCK-IN MOUSE; DYT1 DYSTONIA; BASAL GANGLIA; CONTINUOUS-INFUSION; SPASTIC DYSPHONIA; C-11 RACLOPRIDE; MOTOR DEFICITS AB Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [C-11]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D-2/D-3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC Delta BP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC Delta BP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC Delta BP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC Delta BP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D-2/D-3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder. C1 [Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Otolaryngol, New York, NY 10029 USA. [Berman, Brian D.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Berman, Brian D.] Univ Colorado, Dept Neurol, Denver, CO 80045 USA. [Herscovitch, Peter] NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. RP Simonyan, K (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM kristina.simonyan@mssm.edu OI Simonyan, Kristina/0000-0001-7444-0437 FU NIDCD Grant [R00DC009629]; Intramural Program of the National Institute of Neurological Disorders and Stroke; NIH Clinical Center FX This work was supported by NIDCD Grant R00DC009629 (K.S.), the Intramural Program of the National Institute of Neurological Disorders and Stroke, and the NIH Clinical Center. We thank Sandra B. Martin for assistance with patient recruitment and rating of the voice and speech samples, Dr. Pamela R. Kearney for participants' clinical evaluation, Richard Reynolds for help with data processing, and the staff at the PET Department of the NIH Clinical Center for assistance with PET data acquisition. NR 71 TC 10 Z9 10 U1 0 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 SEP 11 PY 2013 VL 33 IS 37 BP 14705 EP 14714 DI 10.1523/JNEUROSCI.0407-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 216WG UT WOS:000324316200009 PM 24027271 ER PT J AU Zavala, B Brittain, JS Jenkinson, N Ashkan, K Foltynie, T Limousin, P Zrinzo, L Green, AL Aziz, T Zaghloul, K Brown, P AF Zavala, Baltazar Brittain, John-Stuart Jenkinson, Ned Ashkan, Keyoumars Foltynie, Thomas Limousin, Patricia Zrinzo, Ludvic Green, Alexander L. Aziz, Tipu Zaghloul, Kareem Brown, Peter TI Subthalamic Nucleus Local Field Potential Activity during the Eriksen Flanker Task Reveals a Novel Role for Theta Phase during Conflict Monitoring SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL FRONTAL-CORTEX; INCREASES RESPONSE-TIME; BASAL GANGLIA; PARKINSONS-DISEASE; DECISION-MAKING; EEG; STIMULATION; DISORDERS; DOPAMINE; DYNAMICS AB The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the "hold-your-horses" function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinson's disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function. C1 [Zavala, Baltazar; Brittain, John-Stuart; Jenkinson, Ned; Green, Alexander L.; Aziz, Tipu; Brown, Peter] Univ Oxford, Nuffield Dept Clin Neurol, John Radcliffe Hosp, Funct Neurosurg Expt Neurol Grp, Oxford OX3 9DU, England. [Zavala, Baltazar; Zaghloul, Kareem] NIH, Surg Neurol Branch, Bethesda, MD USA. [Ashkan, Keyoumars] Kings Coll Hosp London, Dept Neurosurg, London SE5 9RS, England. [Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1 3BG, England. RP Brown, P (reprint author), Univ Oxford, Nuffield Dept Clin Neurol, John Radcliffe Hosp, Level 6,West Wing, Oxford OX3 9DU, England. EM peter.brown@ndcn.ox.ac.uk RI Jenkinson, Ned/B-1718-2009; Brown, Peter/J-4307-2016; OI Jenkinson, Ned/0000-0002-6803-486X; Brown, Peter/0000-0002-5201-3044; Brittain, John-Stuart/0000-0002-4172-190X; Zrinzo, Ludvic/0000-0002-6013-4946 FU Rhodes Trust; National Institutes of Health Oxford-Cambridge fellowship; Department of Health National Institute for Health Research UCL Biomedical Research Center; Monument Trust; Parkinson's Appeal for Deep Brain Stimulation; Medical Research Council; Department of Health National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Centre FX B.Z. is supported by the Rhodes Trust and the National Institutes of Health Oxford-Cambridge fellowship. T.F., P.L., and L.Z. are funded by the Department of Health National Institute for Health Research UCL Biomedical Research Center, The Monument Trust, and Parkinson's Appeal for Deep Brain Stimulation. P.B. is funded by the Medical Research Council and the Department of Health National Institute for Health Research Oxford Biomedical Research Centre; and A.L., T.A., and P.B. are funded by the National Institute for Health Research Oxford Biomedical Centre. We thank Simon Little and Huiling Tan for their help with data collection. NR 34 TC 21 Z9 22 U1 5 U2 17 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 SEP 11 PY 2013 VL 33 IS 37 BP 14758 EP U153 DI 10.1523/JNEUROSCI.1036-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 216WG UT WOS:000324316200014 PM 24027276 ER PT J AU Wang, XS Simon, R AF Wang, Xiaosheng Simon, Richard TI Identification of potential synthetic lethal genes to p53 using a computational biology approach SO BMC MEDICAL GENOMICS LA English DT Article DE Cancer; p53 mutations; Synthetic lethal genes; Gene expression profiles; Computational biology ID TUMOR-SUPPRESSOR FUNCTION; ACTIVATED PROTEIN-KINASE; CELL-CYCLE REGULATION; HUMAN CANCER-CELLS; MUTANT P53; CHOLINE KINASE; BREAST-CANCER; TRANSCRIPTIONAL REPRESSION; ANTICANCER THERAPY; SIGNALING PATHWAYS AB Background: Identification of genes that are synthetic lethal to p53 is an important strategy for anticancer therapy as p53 mutations have been reported to occur in more than half of all human cancer cases. Although genome-wide RNAi screening is an effective approach to finding synthetic lethal genes, it is costly and labor-intensive. Methods: To illustrate this approach, we identified potentially druggable genes synthetically lethal for p53 using three microarray datasets for gene expression profiles of the NCI-60 cancer cell lines, one next-generation sequencing (RNA-Seq) dataset from the Cancer Genome Atlas (TCGA) project, and one gene expression data from the Cancer Cell Line Encyclopedia (CCLE) project. We selected the genes which encoded kinases and had significantly higher expression in the tumors with functional p53 mutations (somatic mutations) than in the tumors without functional p53 mutations as the candidates of druggable synthetic lethal genes for p53. We identified important regulatory networks and functional categories pertinent to these genes, and performed an extensive survey of literature to find experimental evidence that support the synthetic lethality relationships between the genes identified and p53. We also examined the drug sensitivity difference between NCI-60 cell lines with functional p53 mutations and NCI-60 cell lines without functional p53 mutations for the compounds that target the kinases encoded by the genes identified. Results: Our results indicated that some of the candidate genes we identified had been experimentally verified to be synthetic lethal for p53 and promising targets for anticancer therapy while some other genes were putative targets for development of cancer therapeutic agents. Conclusions: Our study indicated that pre-screening of potential synthetic lethal genes using gene expression profiles is a promising approach for improving the efficiency of synthetic lethal RNAi screening. C1 [Wang, Xiaosheng] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. [Simon, Richard] NCI, NIH, Biometr Res Branch, Rockville, MD USA. RP Wang, XS (reprint author), Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. EM xiaosheng.wang@unmc.edu; rsimon@mail.nih.gov NR 83 TC 19 Z9 20 U1 0 U2 15 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 SEP 11 PY 2013 VL 6 AR 30 DI 10.1186/1755-8794-6-30 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 216XQ UT WOS:000324320500001 PM 24025726 ER PT J AU Gomelsky, M Galperin, MY AF Gomelsky, Mark Galperin, Michael Y. TI Bacterial second messengers, cGMP and c-di-GMP, in a quest for regulatory dominance SO EMBO JOURNAL LA English DT Editorial Material ID PROTEIN; AMP AB Bacteria and eukaryotes differ in the organization of their key signal-transduction pathways but share certain signalling components, including cyclic nucleotide second messengers. In this issue, a paper by British, Irish and Taiwanese scientists (An et al, 2013) describes a signal-transduction pathway that regulates virulence and biofilm formation in the bacterial plant pathogen Xanthomonas campestris. Remarkably, this pathway involves a cascade of two nucleotide second messengers, with cyclic GMP (cGMP), a typically eukaryotic messenger, directly regulating synthesis of cyclic dimeric GMP (c-di-GMP), a ubiquitous bacterial messenger. This study broadens the scope of cGMP-regulated processes in bacteria, offers structural insights into cGMP binding by bacterial cGMP receptors, and expands the range of bacteria using cGMP in signal transduction. Such multi-level regulatory cascades may well function in other organisms. C1 [Gomelsky, Mark] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Gomelsky, M (reprint author), Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. EM gomelsky@uwyo.edu; galperin@ncbi.nlm.nih.gov OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS; NCI NIH HHS [R21 CA167862, R21CA167862] NR 12 TC 10 Z9 10 U1 0 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 11 PY 2013 VL 32 IS 18 BP 2421 EP 2423 DI 10.1038/emboj.2013.193 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 216VG UT WOS:000324312700001 PM 23963313 ER PT J AU Das, R Liang, YH Mariano, J Li, J Huang, T King, A Tarasov, SG Weissman, AM Ji, XH Byrd, RA AF Das, Ranabir Liang, Yu-He Mariano, Jennifer Li, Jess Huang, Tao King, Aaren Tarasov, Sergey G. Weissman, Allan M. Ji, Xinhua Byrd, R. Andrew TI Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine SO EMBO JOURNAL LA English DT Article DE allostery; structural biology; ubiquitin; ubiquitination ID RETICULUM-ASSOCIATED DEGRADATION; CONJUGATING ENZYME UBE2G2; ENDOPLASMIC-RETICULUM; RING FINGER; LIGASE GP78; E3 LIGASE; COMPLEX; PROTEIN; DOMAIN; NMR AB RING finger proteins constitute the large majority of ubiquitin ligases (E3s) and function by interacting with ubiquitin-conjugating enzymes (E2s) charged with ubiquitin. How low-affinity RING-E2 interactions result in highly processive substrate ubiquitination is largely unknown. The RING E3, gp78, represents an excellent model to study this process. gp78 includes a high-affinity secondary binding region for its cognate E2, Ube2g2, the G2BR. The G2BR allosterically enhances RING: Ube2g2 binding and ubiquitination. Structural analysis of the RING: Ube2g2:G2BR complex reveals that a G2BR-induced conformational effect at the RING: Ube2g2 interface is necessary for enhanced binding of RING to Ube2g2 or Ube2g2 conjugated to Ub. This conformational effect and a key ternary interaction with conjugated ubiquitin are required for ubiquitin transfer. Moreover, RING: Ube2g2 binding induces a second allosteric effect, disrupting Ube2g2: G2BR contacts, decreasing affinity and facilitating E2 exchange. Thus, gp78 is a ubiquitination machine where multiple E2-binding sites coordinately facilitate processive ubiquitination. C1 [Das, Ranabir; Li, Jess; Huang, Tao; King, Aaren; Tarasov, Sergey G.; Byrd, R. Andrew] NCI, Ctr Canc Res, Struct Biophys Lab, Frederick, MD 21702 USA. [Liang, Yu-He; Ji, Xinhua] NCI, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Mariano, Jennifer; Weissman, Allan M.] NCI, Ctr Canc Res, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Ctr Canc Res, Struct Biophys Lab, POB B,Bldg 538, Frederick, MD 21702 USA. EM byrdra@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research FX X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beam line at the Advanced Photon Source, Argonne National Laboratory, supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. SAXS data were collected at the Argonne National Laboratory, 12C beam line. We gratefully acknowledge the assistance of Drs. Yun-Xing Wang and Xiaobing Zuo (SBL/NCI) in collecting and analysing the SAXS data. Numerous stimulating discussions with Yien Che Tsai and Meredith Metzger (LPDS/NCI) are gratefully acknowledged. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research. NR 37 TC 32 Z9 32 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 11 PY 2013 VL 32 IS 18 BP 2504 EP 2516 DI 10.1038/emboj.2013.174 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 216VG UT WOS:000324312700010 PM 23942235 ER PT J AU Tsao, CW Seshadri, S Beiser, AS Westwood, AJ DeCarli, C Au, R Himali, JJ Hamburg, NM Vita, JA Levy, D Larson, MG Benjamin, EJ Wolf, PA Vasan, RS Mitchell, GF AF Tsao, Connie W. Seshadri, Sudha Beiser, Alexa S. Westwood, Andrew J. DeCarli, Charles Au, Rhoda Himali, Jayandra J. Hamburg, Naomi M. Vita, Joseph A. Levy, Daniel Larson, Martin G. Benjamin, Emelia J. Wolf, Philip A. Vasan, Ramachandran S. Mitchell, Gary F. TI Relations of arterial stiffness and endothelial function to brain aging in the community SO NEUROLOGY LA English DT Article ID PULSE-WAVE VELOCITY; CORONARY-HEART-DISEASE; WHITE-MATTER HYPERINTENSITIES; FLOW-MEDIATED DILATION; SMALL-VESSEL DISEASE; BLOOD-PRESSURE; CARDIOVASCULAR EVENTS; ALZHEIMER-DISEASE; OLDER-ADULTS; RISK-FACTORS AB Objective: To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging. Methods: Stroke-and dementia-free Framingham Offspring Study participants (n = 1,587, 61 +/- 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively). Results: Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05). Conclusions: Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes. C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Div, Boston, MA 02215 USA. [Seshadri, Sudha; Beiser, Alexa S.; Westwood, Andrew J.; Au, Rhoda; Himali, Jayandra J.; Wolf, Philip A.] Boston Univ, Sch Med, Sch Publ Hlth, Dept Neurol, Boston, MA 02215 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sch Publ Hlth, Dept Med, Boston, MA 02215 USA. [Beiser, Alexa S.; Himali, Jayandra J.; Larson, Martin G.] Boston Univ, Sch Med, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [DeCarli, Charles] Univ Calif Davis, Sch Med, Dept Neurol, Ctr Neurosci, Davis, CA 95616 USA. Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Div Biostat, Davis, CA 95616 USA. [Levy, Daniel] NHLBI, Framingham, MA USA. [Tsao, Connie W.; Seshadri, Sudha; Beiser, Alexa S.; Au, Rhoda; Levy, Daniel; Larson, Martin G.; Benjamin, Emelia J.; Wolf, Philip A.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institute of Neurological Disorders and Stroke [NS17950]; National Institute on Aging [AG08122, AG16945]; National Heart, Lung, and Blood Institute (NIH/NHLBI) [N01-HC-25195, HL093029, 1R01HL60040, 1RO1HL70100] FX Supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the National Institute on Aging (AG08122, AG16945), and the National Heart, Lung, and Blood Institute (NIH/NHLBI contract to FHS no. N01-HC-25195, HL093029; 1R01HL60040; 1RO1HL70100). NR 42 TC 57 Z9 57 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 10 PY 2013 VL 81 IS 11 BP 984 EP 991 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EI UT WOS:000330767700013 PM 23935179 ER PT J AU Healer, J Thompson, JK Riglar, DT Wilson, DW Chiu, YHC Miura, K Chen, L Hodder, AN Long, CA Hansen, DS Baum, J Cowman, AF AF Healer, Julie Thompson, Jennifer K. Riglar, David T. Wilson, Danny W. Chiu, Yu-H. C. Miura, Kazutoyo Chen, Lin Hodder, Anthony N. Long, Carole A. Hansen, Diana S. Baum, Jake Cowman, Alan F. TI Vaccination with Conserved Regions of Erythrocyte-Binding Antigens Induces Neutralizing Antibodies against Multiple Strains of Plasmodium falciparum SO PLOS ONE LA English DT Article ID MALARIA PARASITE INVASION; INHIBITORY ANTIBODIES; RECEPTOR SPECIFICITY; WESTERN KENYA; GLYCOPHORIN-C; PROTEINS; MEROZOITES; PATHWAYS; EBA-175; EXPRESSION AB Background: A highly effective vaccine against Plasmodium falciparum malaria should induce potent, strain transcending immunity that broadly protects against the diverse population of parasites circulating globally. We aimed to identify vaccine candidates that fulfill the criteria. Methods: We have measured growth inhibitory activity of antibodies raised to a range of antigens to identify those that can efficiently block merozoite invasion for geographically diverse strains of P. falciparum. Results: This has shown that the conserved Region III-V, of the P. falciparum erythrocyte-binding antigen (EBA)-175 was able to induce antibodies that potently inhibit merozoite invasion across diverse parasite strains, including those reliant on invasion pathways independent of EBA-175 function. Additionally, the conserved RIII-V domain of EBA-140 also induced antibodies with strong in vitro parasite growth inhibitory activity. Conclusion: We identify an alternative, highly conserved region (RIV-V) of EBA-175, present in all EBA proteins, that is the target of potent, strain transcending neutralizing antibodies, that represents a strong candidate for development as a component in a malaria vaccine. C1 [Healer, Julie; Thompson, Jennifer K.; Riglar, David T.; Wilson, Danny W.; Chiu, Yu-H. C.; Chen, Lin; Hodder, Anthony N.; Hansen, Diana S.; Baum, Jake; Cowman, Alan F.] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. [Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Riglar, David T.; Chiu, Yu-H. C.; Hansen, Diana S.; Baum, Jake; Cowman, Alan F.] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia. RP Cowman, AF (reprint author), Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. EM cowman@wehi.edu.au FU National Health and Medical Research Council of Australia [637406, 1011453]; Victorian State Government Operational Infrastructure Support; Australian Government NHMRC IRIISS; Howard Hughes International Scholar [55007645]; Bill and Melinda Gates Foundation; PATH/MVI; USAID FX This work was funded by the National Health and Medical Research Council of Australia by a Program grant (637406) and a project grant (1011453). This work was also supported through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. AFC is a Howard Hughes International Scholar (55007645). This work was also supported by grants from the Bill and Melinda Gates Foundation, PATH/MVI, and USAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 16 Z9 17 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2013 VL 8 IS 9 AR e72504 DI 10.1371/journal.pone.0072504 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259PK UT WOS:000327538600007 PM 24039774 ER PT J AU Marenne, G Chanock, SJ Malats, N Genin, E AF Marenne, Gaelle Chanock, Stephen J. Malats, Nuria Genin, Emmanuelle TI Advantage of Using Allele-Specific Copy Numbers When Testing for Association in Regions with Common Copy Number Variants SO PLOS ONE LA English DT Article ID HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; STRUCTURAL VARIATION; HUMAN GENOME; SUSCEPTIBILITY; NUCLEOTIDE; RESOLUTION AB Copy number variants (CNV) can be called from SNP-arrays; however, few studies have attempted to combine both CNV and SNP calls to test for association with complex diseases. Even when SNPs are located within CNVs, two separate association analyses are necessary, to compare the distribution of bi-allelic genotypes in cases and controls (referred to as SNP-only strategy) and the number of copies of a region (referred to as CNV-only strategy). However, when disease susceptibility is actually associated with allele specific copy-number states, the two strategies may not yield comparable results, raising a series of questions about the optimal analytical approach. We performed simulations of the performance of association testing under different scenarios that varied genotype frequencies and inheritance models. We show that the SNP-only strategy lacks power under most scenarios when the SNP is located within a CNV; frequently it is excluded from analysis as it does not pass quality control metrics either because of an increased rate of missing calls or a departure from fitness for Hardy-Weinberg proportion. The CNV-only strategy also lacks power because the association testing depends on the allele which copy number varies. The combined strategy performs well in most of the scenarios. Hence, we advocate the use of this combined strategy when testing for association with SNPs located within CNVs. C1 [Marenne, Gaelle; Genin, Emmanuelle] Univ Paris Diderot, INSERM, UMR S946, Inst Univ Hematol, Paris, France. [Marenne, Gaelle; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Genin, Emmanuelle] Univ Bretagne Occidentale, INSERM, UMR 1078, Brest, France. [Genin, Emmanuelle] Ctr Hosp Reg Univ Brest, Brest, France. RP Genin, E (reprint author), Univ Paris Diderot, INSERM, UMR S946, Inst Univ Hematol, Paris, France. EM gaelle.marenne@gmail.com RI Malats, Nuria/H-7041-2015 OI Malats, Nuria/0000-0003-2538-3784 FU Instituto de Salud Carlos III (ISCIII) [FI09/00205]; Spanish Ministry of Science and Innovation; Acciones Integradas / Picasso program for collaboration between French and Spanish groups [HF2008-0069]; Region Ile-De-France FX This work was supported by a FIS grant (FI09/00205) from Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, by the Acciones Integradas / Picasso program for collaboration between French and Spanish groups (HF2008-0069) and by the Region Ile-De-France for travel grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2013 VL 8 IS 9 AR UNSP e75350 DI 10.1371/journal.pone.0075350 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259PK UT WOS:000327538600137 PM 24040408 ER PT J AU Smalls-Mantey, A Connors, M Sattentau, QJ AF Smalls-Mantey, Adjoa Connors, Mark Sattentau, Quentin J. TI Comparative Efficiency of HIV-1-Infected T Cell Killing by NK Cells, Monocytes and Neutrophils SO PLOS ONE LA English DT Article ID VIRUS-INFECTED-CELLS; NATURAL-KILLER-CELLS; MEDIATED CYTOTOXICITY; INFLUENZA-VIRUS; HLA-B; ANTIBODY; HIV; TRANSMISSION; ACTIVATION; MACROPHAGE AB HIV-1 infected cells are eliminated in infected individuals by a variety of cellular mechanisms, the best characterized of which are cytotoxic T cell and NK cell-mediated killing. An additional antiviral mechanism is antibody-dependent cellular cytotoxicity. Here we use primary CD4(+) T cells infected with the BaL clone of HIV-1 as target cells and autologous NK cells, monocytes, and neutrophils as effector cells, to quantify the cytotoxicity mediated by the different effectors. This was carried out in the presence or absence of HIV-1-specific antiserum to assess antibody-dependent cellular cytotoxicity. We show that at the same effector to target ratio, NK cells and monocytes mediate similar levels of both antibody-dependent and antibody-independent killing of HIV-1-infected T cells. Neutrophils mediated significant antibody-dependent killing of targets, but were less effective than monocytes or NK cells. These data have implications for acquisition and control of HIV-1 in natural infection and in the context of vaccination. C1 [Smalls-Mantey, Adjoa; Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Smalls-Mantey, Adjoa; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Smalls-Mantey, A (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM adjoa.smalls-mantey@path.ox.ac.uk FU National Institute of Allergy and Infectious Diseases [F31AI098409]; Medical Research Council United Kingdom [G0901732]; Dormeur Financial Services LTD FX The project described was supported by a personal grant number F31AI098409 to ASM from the National Institute of Allergy and Infectious Diseases, grant number G0901732 from the Medical Research Council United Kingdom, and Dormeur Financial Services LTD. QJS is a Jenner Vaccine Institute Investigator and a James Martin Senior Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 21 Z9 22 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2013 VL 8 IS 9 AR UNSP e74858 DI 10.1371/journal.pone.0074858 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259PK UT WOS:000327538600117 PM 24040353 ER PT J AU Asmuth, DM Ma, ZM Albanese, A Sandler, NG Devaraj, S Knight, TH Flynn, NM Yotter, T Garcia, JC Tsuchida, E Wu, TT Douek, DC Miller, CJ AF Asmuth, David M. Ma, Zhong-Min Albanese, Anthony Sandler, Netanya G. Devaraj, Sridevi Knight, Thomas H. Flynn, Neil M. Yotter, Tammy Garcia, Juan-Carlos Tsuchida, Emily Wu, Tsung-Teh Douek, Daniel C. Miller, Christopher J. TI Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy SO AIDS LA English DT Article DE bovine immunoglobulin; d-xylose absorption; gastrointestinal associated lymphoid tissue; gut permeability; HIV enteropathy; immune reconstitution; immunohistochemistry; intestinal fatty acid binding protein; monocyte chemotaxis protein-1 ID ACTIVE ANTIRETROVIRAL THERAPY; LYMPHATIC TISSUE FIBROSIS; VIRUS TYPE-1 INFECTION; AUREUS ENTEROTOXIN-B; T-CELL DEPLETION; ACQUIRED IMMUNODEFICIENCY SYNDROME; INTESTINAL BARRIER FUNCTION; DIETARY PLASMA-PROTEINS; DRIED PORCINE PLASMA; EARLY WEANED PIGS AB Objectives:To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy. Design:Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5g twice daily with a 4-week washout period and an optional 9-month extension study. Methods:HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms. Results:All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P=0.008) and improvements in stool consistency (P=0.008). Gut permeability was normal before and after the intervention, but d-xylose absorption increased in seven of eight participants. Mucosal CD4(+) lymphocyte densities increased by a median of 139.5cells/mm(2) from 213 to 322cells/mm(2) (P=0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P=0.039), and then fell below baseline in four of five who continued receiving SBI (P=0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4(+) lymphocyte densities (r=-0.74, P=0.046). Conclusion:SBI significantly increases intestinal mucosal CD4(+) lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy. C1 [Asmuth, David M.; Knight, Thomas H.; Flynn, Neil M.; Yotter, Tammy; Garcia, Juan-Carlos] Univ Calif Davis, Davis Med Sch, Sacramento, CA 95817 USA. [Asmuth, David M.; Albanese, Anthony; Miller, Christopher J.] Vet Adm Northern Calif Healthcare Syst, Sacramento, CA USA. [Ma, Zhong-Min; Miller, Christopher J.] Univ Calif Davis, Davis, CA 95817 USA. [Ma, Zhong-Min] Ctr Comparat Med, Davis, CA USA. [Sandler, Netanya G.; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Devaraj, Sridevi] Baylor Coll Med, Houston, TX 77030 USA. [Devaraj, Sridevi] Texas Childrens Hosp, Houston, TX 77030 USA. [Tsuchida, Emily] CARES Clin, Sacramento, CA USA. [Wu, Tsung-Teh] Mayo Clin, Rochester, MN USA. RP Asmuth, DM (reprint author), UC Davis Med Ctr, Div Infect & Immunol Dis, 4150 5 St,PSSB G500, Sacramento, CA 95817 USA. EM david.asmuth@ucdmc.ucdavis.edu OI Utay, Netanya/0000-0002-6407-8670 FU National Center for Research Resources (NCRR), a component of the National Institutes of Health [UL1 RR024146]; NIH Roadmap for Medical Research; Investigator-Initiated Studies Program of EnteraHealth, Inc. FX This research was made possible by Grant Number UL1 RR024146 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health, and NIH Roadmap for Medical Research. The contents do not necessarily represent the views of the Department of Veterans Affairs or the United States Government.; This clinical trial was supported in part by a research grant from the Investigator-Initiated Studies Program of EnteraHealth, Inc. The opinions expressed in this paper are those of the authors and do not necessarily represent those of EnteraHealth, Inc. NR 64 TC 29 Z9 29 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD SEP 10 PY 2013 VL 27 IS 14 BP 2207 EP 2217 DI 10.1097/QAD.0b013e328362e54c PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 248LZ UT WOS:000326702700007 PM 23660579 ER PT J AU Hauger, RL Olivares-Reyes, JA Braun, S Hernandez-Aranda, J Hudson, CC Gutknecht, E Dautzenberg, FM Oakley, RH AF Hauger, Richard L. Alberto Olivares-Reyes, J. Braun, Sandra Hernandez-Aranda, Judith Hudson, Christine C. Gutknecht, Eric Dautzenberg, Frank M. Oakley, Robert H. TI Desensitization of human CRF2(a) receptor signaling governed by agonist potency and beta arrestin2 recruitment SO REGULATORY PEPTIDES LA English DT Article DE beta arrestin2; Urocortin 1 (UCN1); Urocortin 2 (UCN2); Urocortin 3 (UCN3); Corticotropin releasing factor receptor (CRF) ID PROTEIN-COUPLED RECEPTORS; MECHANISM REGULATING STRESS; CRF RECEPTORS; POTENTIAL MECHANISM; HORMONE-RECEPTOR; FAMILY; PHOSPHORYLATION; ARRESTIN; CELLS; ENDOCYTOSIS AB The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100 nM) produced strong beta arrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1 mu M) generated only weak beta arrestin2 recruitment, beta arrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the beta arrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a beta arrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, beta arrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response. Published by Elsevier B.V. C1 [Hauger, Richard L.] San Diego VA Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA 92161 USA. [Hauger, Richard L.; Braun, Sandra] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. [Alberto Olivares-Reyes, J.; Hernandez-Aranda, Judith] CINVESTAV, IPN, Natl Polytech Inst, Ctr Res & Adv Studies,Dept Biochem, Mexico City 07360, DF, Mexico. [Hudson, Christine C.; Oakley, Robert H.] Xsira Pharmaceut Inc, Morrisville, NC 27560 USA. [Gutknecht, Eric; Dautzenberg, Frank M.] CNS Res, Johnson & Johnson Res & Dev, Beerse, Belgium. [Gutknecht, Eric] Vrije Univ Brussel, Inst Mol Biol & Biotechnol, Dept Mol & Biochem Pharmacol, B-1050 Brussels, Belgium. [Oakley, Robert H.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Hauger, RL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM rhauger@ucsd.edu FU BLR&D Merit Review grant from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development; VA Center of Excellence for Stress and Mental Health (CESAMH); NIH/NIA [AG018386]; NIH/NIMH RO1 [MH074697]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; CINVESTAV-IPN, a UC MEXUS-CONACYT; Fundacion Miguel Aleman; DVA; NIH/NIAID RO1 [AI36214] FX Dr. Hauger was supported by a BLR&D Merit Review grant from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. Dr. Hauger also received support from the VA Center of Excellence for Stress and Mental Health (CESAMH), and NIH/NIA (AG018386) and NIH/NIMH RO1 (MH074697) grants. Dr. Oakley received support from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, and completed a portion of the confocal microscopy experiments while he was employed at Xsira Pharmaceuticals (Morrisville, NC). Dr. Olivares-Reyes was supported by CINVESTAV-IPN, a UC MEXUS-CONACYT grant for collaborative projects, and a Grant for Research on Health from Fundacion Miguel Aleman 2010. Receptor internalization and cell surface receptor expression measurements were performed at the Flow Cytometry Research Core of the San Diego VA Research Service that is supported by DVA and a NIH/NIAID RO1 (AI36214). We also gratefully acknowledge Dr. Dimitri Grigoriadis and Neurocrine Biotechnology (La Jolla, CA) for generously providing NBI-30775 under an approved material transfer agreement. Dr. Robert Lefkowitz (HHMI, Duke University) kindly provided the beta arrestin KO and wild-type MEF cells under a material transfer agreement. NR 52 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 EI 1873-1686 J9 REGUL PEPTIDES JI Regul. Pept. PD SEP 10 PY 2013 VL 186 BP 62 EP 76 DI 10.1016/j.regpep.2013.06.009 PG 15 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 244CH UT WOS:000326364200010 PM 23820308 ER PT J AU Zhang, Q Hu, JH Ling, K AF Zhang, Qing Hu, Jinghua Ling, Kun TI Molecular views of Arf-like small GTPases in cilia and ciliopathies SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Arl; Small GTPase; Ciliopathy; Cilia ID BARDET-BIEDL-SYNDROME; POLYCYSTIC KIDNEY-DISEASE; GTP-BINDING PROTEINS; INTRAFLAGELLAR TRANSPORT; JOUBERT-SYNDROME; CAENORHABDITIS-ELEGANS; RAS SUPERFAMILY; DELTA-SUBUNIT; PDE-DELTA; GENE AB The primary cilia are microtubule-based organelles that protrude from most of the eukaryotic cells. Recognized as the cell's antenna, primary cilium functions as a signaling hub for many physiologically and developmentally important signaling cascades. Ciliary dysfunction causes a wide spectrum of syndromic human genetic diseases collectively termed "ciliopathies". Mounting evidences have shown that various small GTPases have been implicated in the context of cilia as well as human ciliopathies. However, how these small GTPases affect cilia formation and function remains poorly understood. Here we review and discuss the ciliary role of three Arf-like small GTPases (Arls), Ar13, ArI6, and Ar113b. (C) 2013 Elsevier Inc. All rights reserved. C1 [Zhang, Qing; Hu, Jinghua; Ling, Kun] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Hu, Jinghua; Ling, Kun] Mayo Clin, NIH Mayo Translat PKD Ctr, Rochester, MN USA. [Zhang, Qing; Hu, Jinghua] Mayo Clin, Dept Hypertens & Nephrol, Rochester, MN USA. RP Hu, JH (reprint author), Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. EM Hu.jinghua@mayo.edu; ling.kun@mayo.edu FU National Institutes of Health [1R01DK090038]; P30 center grant [P30DK90728]; Mayo Clinic Center for Cell Signaling in Gastroenterology [P30DK084567]; PKD Foundation Young Investigator Award [04YI09a]; National Cancer Institute (NCI) [1R01CA149039-01A1]; Susan G. Komen for the Cure [KG100902] FX We are sorry for not including all the references due to the space limitation. J.H. and coworkers were supported by the National Institutes of Health research grant 1R01DK090038 and P30 center grant P30DK90728, a Pilot and Feasibility Award from the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567), and the PKD Foundation Young Investigator Award 04YI09a. K.L. was supported by National Cancer Institute (NCI; 1R01CA149039-01A1), Susan G. Komen for the Cure (KG100902). NR 60 TC 11 Z9 12 U1 0 U2 7 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 SEP 10 PY 2013 VL 319 IS 15 SI SI BP 2316 EP 2322 DI 10.1016/j.yexcr.2013.03.024 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 218PQ UT WOS:000324445000003 PM 23548655 ER PT J AU Krzewski, K Cullinane, AR AF Krzewski, Konrad Cullinane, Andrew R. TI Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Rab GTPases; Immunodeficiencies; Griscelli Syndrome Type 2; Rab27a; Familial Hemophagocytic; Lymphohistiocytosis Type 3; Muc13-4 ID FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; HERMANSKY-PUDLAK-SYNDROME; IMMUNODEFICIENCY-VIRUS TYPE-1; LYSOSOME-RELATED ORGANELLES; NUCLEOTIDE EXCHANGE FACTOR; EPITHELIAL-CELLS; MYOSIN-VA; SURFACE EXPRESSION; GRANULE EXOCYTOSIS; PLASMA-MEMBRANE AB A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future. Published by Elsevier Inc. C1 [Krzewski, Konrad] Natl Inst Allergy & Infect Dis, Immunogenet Lab, Receptor Cell Biol Sect, Natl Inst Hlth, Rockville, MD 20852 USA. [Cullinane, Andrew R.] Natl Human Genome Res Inst, Med Genet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Cullinane, AR (reprint author), Natl Human Genome Res Inst, Med Genet Branch, Natl Inst Hlth, Bldg 10,Room 10C107A,10 Ctr Dr, Bethesda, MD 20892 USA. EM andrew.cullinane@nih.gov FU intramural programs of the National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute FX KK and ARC's work is supported by the intramural programs of the National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute respectively. The authors wish to thank William A. Gahl (NHGRI, NIH) for his helpful discussion and comments. NR 77 TC 6 Z9 7 U1 2 U2 6 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 SEP 10 PY 2013 VL 319 IS 15 SI SI BP 2360 EP 2367 DI 10.1016/j.yexcr.2013.06.012 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 218PQ UT WOS:000324445000009 PM 23810987 ER PT J AU Dunn, BK Srivastava, S Kramer, BS AF Dunn, Barbara K. Srivastava, Sudhir Kramer, Barnett S. TI The word "cancer": how language can corrupt thought SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID BREAST-CANCER; OVERDIAGNOSIS; DIAGNOSIS C1 [Dunn, Barbara K.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Dunn, BK (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. EM kramerb@mail.nih.gov NR 12 TC 3 Z9 3 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD SEP 10 PY 2013 VL 347 AR f5328 DI 10.1136/bmj.f5328 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 219RR UT WOS:000324527000007 PM 24022035 ER PT J AU Singh, SR AF Singh, Shree Ram TI Cancer stem cells: Recent developments and future prospects SO CANCER LETTERS LA English DT Editorial Material ID GROWTH C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Singh, SR (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU Intramural NIH HHS [Z99 CA999999] NR 7 TC 9 Z9 10 U1 0 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 10 PY 2013 VL 338 IS 1 SI SI BP 1 EP 2 DI 10.1016/j.canlet.2013.03.036 PG 2 WC Oncology SC Oncology GA 220ES UT WOS:000324565800001 PM 23583678 ER PT J AU Singh, SR AF Singh, Shree Ram TI Featuring the special issue guest editor: Shree Ram Singh, Ph.D. SO CANCER LETTERS LA English DT Editorial Material C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Singh, SR (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 10 PY 2013 VL 338 IS 1 SI SI BP 3 EP 3 DI 10.1016/j.canlet.2013.03.009 PG 1 WC Oncology SC Oncology GA 220ES UT WOS:000324565800002 PM 23523870 ER PT J AU Singh, SR AF Singh, Shree Ram TI Gastric cancer stem cells: A novel therapeutic target SO CANCER LETTERS LA English DT Review DE Stomach; Gastric epithelial cells; Gastric cancer; Stem cells; Cancer stem cells ID HELICOBACTER-PYLORI INFECTION; SIDE POPULATION CELLS; TUMOR-INITIATING CELLS; MARROW-DERIVED CELLS; DRIVE SELF-RENEWAL; EPITHELIAL-CELLS; MOUSE STOMACH; PROGENITOR CELLS; GASTROINTESTINAL-TRACT; PROSPECTIVE IDENTIFICATION AB Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer. Published by Elsevier Ireland Ltd. C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Singh, SR (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. I would like to thank Dr. Chhavi Chauhan for critical reading and Ashley DeVine for editing the manuscript. I apologize to all colleagues whose relevant contributions were not cited due to space limitations. NR 160 TC 28 Z9 31 U1 1 U2 40 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 SEP 10 PY 2013 VL 338 IS 1 SI SI BP 110 EP 119 DI 10.1016/j.canlet.2013.03.035 PG 10 WC Oncology SC Oncology GA 220ES UT WOS:000324565800018 PM 23583679 ER PT J AU Chang, J Lee, S Blackstone, C AF Chang, Jaerak Lee, Seongju Blackstone, Craig TI Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; AMYOTROPHIC-LATERAL-SCLEROSIS; AUTOSOMAL-DOMINANT; MEMBRANE-PROTEINS; S. CEREVISIAE; GTPASE SEY1P; ER NETWORK; LOCALIZATION; MORPHOLOGY; REQUIRES AB Hereditary spastic paraplegias are inherited neurological disorders characterized by progressive lower-limb spasticity and weakness. Although more than 50 genetic loci are known [spastic gait (SPG)1 to -57], over half of hereditary spastic paraplegia cases are caused by pathogenic mutations in four genes encoding proteins that function in tubular endoplasmic reticulum (ER) network formation: atlastin-1 (SPG3A), spastin (SPG4), reticulon 2 (SPG12), and receptor expression-enhancing protein 1 (SPG31). Here, we show that the SPG33 protein protrudin contains hydrophobic, intramembrane hairpin domains, interacts with tubular ER proteins, and functions in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections. Protrudin also interacts with KIF5 and harbors a Rab-binding domain, a noncanonical FYVE (Fab-1, YGL023, Vps27, and EEA1) domain, and a two phenylalanines in an acidic tract (FFAT) domain and, thus, may also function in the distribution of ER tubules via ER contacts with the plasma membrane or other organelles. C1 [Chang, Jaerak; Lee, Seongju; Blackstone, Craig] NINCDS, NIH, Cell Biol Sect, Neurogenet Branch, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINCDS, NIH, Cell Biol Sect, Neurogenet Branch, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX We thank J. Nagle and D. Kauffman for DNA sequencing, J.-H. Tao-Cheng and V. Crocker for electron microscopy, and A. Hoofring and E. Tyler for artwork. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 40 TC 13 Z9 13 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 10 PY 2013 VL 110 IS 37 BP 14954 EP 14959 DI 10.1073/pnas.1307391110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214IF UT WOS:000324125100040 PM 23969831 ER PT J AU Sakata, K Martinowich, K Woo, NH Schloesser, RJ Jimenez, DV Ji, YY Shen, LY Lu, B AF Sakata, Kazuko Martinowich, Keri Woo, Newton H. Schloesser, Robert J. Jimenez, Dennisse V. Ji, Yuanyuan Shen, Liya Lu, Bai TI Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CONDITIONED TASTE-AVERSION; LONG-TERM POTENTIATION; MESSENGER-RNA EXPRESSION; DEPRESSION-LIKE BEHAVIOR; NEUROTROPHIC FACTOR; FEAR EXTINCTION; PROTEIN-SYNTHESIS; PROMOTER IV; SYNAPTIC-TRANSMISSION; FIMBRIA-FORNIX AB Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders. C1 [Sakata, Kazuko; Woo, Newton H.; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Martinowich, Keri; Lu, Bai] NIH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Martinowich, Keri; Schloesser, Robert J.; Jimenez, Dennisse V.] NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. [Shen, Liya] NCI, NIH, Bethesda, MD 20892 USA. [Sakata, Kazuko] Univ Tennessee, Dept Pharmacol, Memphis, TN 38163 USA. [Martinowich, Keri; Jimenez, Dennisse V.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Martinowich, Keri] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Martinowich, Keri] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ji, Yuanyuan; Lu, Bai] GlaxoSmithKline, R&D China, Shanghai 201203, Peoples R China. [Lu, Bai] Tsinghua Univ, Sch Med, Beijing 100086, Peoples R China. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. EM bai.lu@biomed.tsinghua.edu.cn RI Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institute of Child Health and Human Development; National Institute of Mental Health; Japanese Society for Promotion of Science; National Alliance for Research on Schizophrenia and Depression Young Investigator Awards FX We thank Drs. K. Nakazawa, J. Hill, K. Christian, and A. Morozov for discussions and D. Abebe, V. Senetorov, S. Speransky, J. Greene, J. Chen, F. Papaleo, and N. Tompkins for technical assistance. This work was supported by National Institute of Child Health and Human Development and National Institute of Mental Health Intramural Research Programs. K. S. was supported in part by the Japanese Society for Promotion of Science, and K. M. and R. J. S. were supported in part by National Alliance for Research on Schizophrenia and Depression Young Investigator Awards. NR 61 TC 38 Z9 40 U1 1 U2 20 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 SEP 10 PY 2013 VL 110 IS 37 BP 15103 EP 15108 DI 10.1073/pnas.1222872110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 214IF UT WOS:000324125100065 PM 23980178 ER PT J AU Kim, DK Kim, HS Kim, AR Jang, GH Kim, HW Park, YH Kim, B Park, YM Beaven, MA Kim, YM Choi, WS AF Kim, Do Kyun Kim, Hyuk Soon Kim, A-Ram Jang, Geun Hyo Kim, Hyun Woo Park, Young Hwan Kim, Bokyung Park, Yeong Min Beaven, Michael A. Kim, Young Mi Choi, Wahn Soo TI The Scaffold Protein Prohibitin Is Required for Antigen-Stimulated Signaling in Mast Cells SO SCIENCE SIGNALING LA English DT Article ID FC-EPSILON-RI; BASOPHILIC LEUKEMIA-CELLS; TYROSINE PHOSPHORYLATION; PHOSPHOLIPASE C-GAMMA-1; ACTIVATION; IGE; RECEPTOR; KINASE; SYK; MICE AB The protein prohibitin (PHB) is implicated in diverse cellular processes, including cell signaling, transcriptional control, and mitochondrial function. We found that PHB was abundant in the intracellular granules of mast cells, which are critical for allergic responses to antigens. Thus, we investigated whether PHB played a role in signaling mediated by the high-affinity receptor for antigen-bound immunoglobulin E (IgE), Fc epsilon RI. PHB-specific small interfering RNAs (siRNAs) inhibited antigen-mediated signaling, degranulation, and cytokine secretion by mast cells in vitro. Knockdown of PHB inhibited the antigen-dependent association of the tyrosine kinase Syk with Fc epsilon RI and inhibited the activation of Syk. Fractionation studies revealed that PHB translocated from intracellular granules to plasma membrane lipid rafts in response to antigen, and knockdown of PHB suppressed the movement of Fc epsilon RI gamma and Syk into lipid rafts. Tyrosine phosphorylation of PHB by Lyn was observed early after exposure to antigen, and point mutations in PHB indicated that Tyr(114) and Tyr(259) were required for the recruitment of Syk to Fc epsilon RI gamma and mast cell activation. In mice, PHB-specific siRNAs inhibited antigen-initiated mast cell degranulation, passive cutaneous anaphylaxis, and passive systemic anaphylaxis. Together, these results suggest that PHB is essential for Fc epsilon RI-mediated mast cell activation and allergic responses in vivo, raising the possibility that PHB might serve as a therapeutic target for the treatment of allergic diseases. C1 [Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Jang, Geun Hyo; Kim, Hyun Woo; Park, Young Hwan; Kim, Bokyung; Park, Yeong Min; Choi, Wahn Soo] Konkuk Univ, Coll Med, Dept Immunol & Physiol, Chungju 380701, South Korea. [Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Jang, Geun Hyo; Kim, Hyun Woo; Park, Young Hwan; Kim, Bokyung; Park, Yeong Min; Choi, Wahn Soo] Konkuk Univ, Coll Med, Funct Genom Inst, Chungju 380701, South Korea. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul 132714, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Coll Med, Dept Immunol & Physiol, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU National Research Foundation of Korea (NRF); Korea government (MEST) [2011-0028873]; Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0028873). M. A. B. was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 42 TC 6 Z9 6 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 J9 SCI SIGNAL JI Sci. Signal. PD SEP 10 PY 2013 VL 6 IS 292 AR ra80 DI 10.1126/scisignal.2004098 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 213WF UT WOS:000324090400003 PM 24023254 ER PT J AU Xie, YL Chen, Z Albert, PS AF Xie, Yunlong Chen, Zhen Albert, Paul S. TI A crossed random effects modeling approach for estimating diagnostic accuracy from ordinal ratings without a gold standard SO STATISTICS IN MEDICINE LA English DT Article DE random effects models; endometriosis; MCEM algorithm ID MAXIMUM-LIKELIHOOD; ABSENCE; ALGORITHMS; TESTS; ERROR AB In diagnostic studies without a gold standard, the assumption on the dependence structure of the multiple tests or raters plays an important role in model performance. In case of binary disease status, both conditional independence and crossed random effects structure have been proposed and their performance investigated. Less attention has been paid to the situation where the true disease status is ordinal. In this paper, we propose crossed subject-specific and rater-specific random effects to account for the dependence structure and assess the robustness of the proposed model to misspecification in the random effects distributions. We applied the models to data from the Physician Reliability Study, which focuses on assessing the diagnostic accuracy in a population of raters for the staging of endometriosis, a gynecological disorder in women. Using this new methodology, we estimate the probability of a correct classification and show that regional experts can more easily classify the intermediate stage than resident physicians. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Xie, Yunlong; Chen, Zhen; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. EM chenzhe@mail.nih.gov FU National Institutes of health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank the associate editor and reviewers for providing the constructive comments. This research was supported by the Intramural Research Program of the National Institutes of health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the Center for Information Technology, the National Institutes of Health, for providing access to the high-performance computational capabilities of the Biowulf cluster. NR 16 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 10 PY 2013 VL 32 IS 20 BP 3472 EP 3485 DI 10.1002/sim.5784 PG 14 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 200ED UT WOS:000323049700006 PM 23529923 ER PT J AU Platt, RW Brookhart, MA Cole, SR Westreich, D Schisterman, EF AF Platt, Robert W. Brookhart, M. Alan Cole, Stephen R. Westreich, Daniel Schisterman, Enrique F. TI Reply to Taguri and Matsuyama SO STATISTICS IN MEDICINE LA English DT Editorial Material ID INFORMATION CRITERION; MODEL C1 McGill Univ, Dept Epidemiol, Biostatist & Occupat Hlth, Montreal, PQ H3A IA2, Canada. Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Duke Global Hlth Inst, Dept Obstet & Gynecol, Durham, NC 27710 USA. Natl Inst Child Hlth & Human Dev, Div Epidemiol, Stat & Prevent Res, Rockville, MD 20852 USA. RP Platt, RW (reprint author), McGill Univ, Dept Epidemiol, Biostatist & Occupat Hlth, Montreal, PQ H3A IA2, Canada. OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X NR 5 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 10 PY 2013 VL 32 IS 20 BP 3592 EP 3593 DI 10.1002/sim.5805 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 200ED UT WOS:000323049700015 PM 23943550 ER PT J AU Nagamachi, A Matsui, H Asou, H Ozaki, Y Aki, D Kanai, A Takubo, K Suda, T Nakamura, T Wolff, L Honda, H Inaba, T AF Nagamachi, Akiko Matsui, Hirotaka Asou, Hiroya Ozaki, Yuko Aki, Daisuke Kanai, Akinori Takubo, Keiyo Suda, Toshio Nakamura, Takuro Wolff, Linda Honda, Hiroaki Inaba, Toshiya TI Haploinsufficiency of SAMD9L, an Endosome Fusion Facilitator, Causes Myeloid Malignancies in Mice Mimicking Human Diseases with Monosomy 7 SO CANCER CELL LA English DT Article ID COLONY-STIMULATING FACTOR; FAMILIAL TUMORAL CALCINOSIS; MYELODYSPLASTIC SYNDROME; HEMATOPOIETIC PROGENITORS; LEUKEMIA; PROTEIN; MOUSE; LEUKEMOGENESIS; GENES; TRANSFORMATION AB Monosomy 7 and interstitial deletion of 7q (-7/7q-) are well-recognized nonrandom chromosomal abnormalities frequently found among patients with myelodysplastic syndromes (MDSs) and myeloid leukemias. We previously identified candidate myeloid tumor suppressor genes (SAMD9, SAMD9-like = SAMD9L, and Miki) in the 7q21.3 subband. We established SAMD9L-deficient mice and found that SAMD9L(+/-) mice as well as SAMD9L(-/-) mice develop myeloid diseases resembling human diseases associated with -7/7q-. SAMD9L-deficient hematopoietic stem cells showed enhanced colony formation potential and in vivo reconstitution ability. SAMD9L localizes in early endosomes. SAMD9L-deficient cells showed delays in homotypic endosome fusion, resulting in persistence of ligand-bound cytokine receptors. These findings suggest that haploinsufficiency of SAMD9L and/or SAMD9 gene(s) contributes to myeloid transformation. C1 [Nagamachi, Akiko; Matsui, Hirotaka; Asou, Hiroya; Ozaki, Yuko; Aki, Daisuke; Kanai, Akinori; Inaba, Toshiya] Hiroshima Univ, Dept Mol Oncol, Minami Ku, Hiroshima 7348553, Japan. [Nagamachi, Akiko; Matsui, Hirotaka; Asou, Hiroya; Ozaki, Yuko; Aki, Daisuke; Kanai, Akinori; Inaba, Toshiya] Hiroshima Univ, Leukemia Program Project, Minami Ku, Hiroshima 7348553, Japan. [Honda, Hiroaki] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, Hiroshima 7348553, Japan. [Takubo, Keiyo; Suda, Toshio] Keio Univ, Sch Med, Sakaguchi Lab Dev Biol, Dept Cell Differentiat,Shinjuku Ku, Tokyo 1608582, Japan. [Nakamura, Takuro] Japanese Fdn Canc Res, Inst Canc, Div Carcinogenesis, Tokyo 1350063, Japan. [Wolff, Linda] NCI, Leukemogenosis Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Honda, H (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM hhonda@hiroshima-u.ac.jp; tinaba@hiroshima-u.ac.jp RI Suda, Toshio/H-6761-2013 OI Suda, Toshio/0000-0001-7540-1771 FU Ministry of Education, Culture, Sports, Science and Technology of Japan FX We would like to thank Drs. M. Iwama for providing virus and methods for gene transfer to mouse bone marrow cells and Y. Ebihara for useful discussion. We thank Mrs. M. Nakamura, Mr. N. Yamasaki, and Mrs. R. Tai for excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 44 TC 16 Z9 17 U1 0 U2 2 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 SEP 9 PY 2013 VL 24 IS 3 BP 305 EP 317 DI 10.1016/j.ccr.2013.08.011 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 251DN UT WOS:000326908100010 PM 24029230 ER PT J AU Dennis, C Zanni, V Brasset, E Eymery, A Zhang, L Mteirek, R Jensen, S Rong, YKS Vaury, C AF Dennis, Cynthia Zanni, Vanessa Brasset, Emilie Eymery, Angeline Zhang, Liang Mteirek, Rana Jensen, Silke Rong, Yikang S. Vaury, Chantal TI "Dot COM'', a Nuclear Transit Center for the Primary piRNA Pathway in Drosophila SO PLOS ONE LA English DT Article ID SMALL RNAS; BIOGENESIS; MELANOGASTER; RETROVIRUSES; PROTEIN; GYPSY; ZAM; YB AB The piRNA pathway protects genomes by silencing mobile elements. Despite advances in understanding the processing events that generate piRNAs for silencing, little is known about how primary transcripts are transported from their genomic clusters to their processing centers. Using a model of the Drosophila COM/flamenco locus in ovarian somatic cells, we identified a prominent nuclear structure called Dot COM, which is enriched in long transcripts from piRNA clusters but located far from their transcription sites. Remarkably, transcripts from multiple clusters accumulate at Dot COM, which is often juxtaposed with Yb-bodies, the cytoplasmic processing centers for cluster transcripts. Genetic evidence suggests that the accumulation of precursor transcripts at Dot COM represents one of the most upstream events in the piRNA pathway. Our results provide new insights into the initial steps of the piRNA pathway, and open up a new research area important for a complete understanding of this conserved pathway. C1 [Dennis, Cynthia; Zanni, Vanessa; Brasset, Emilie; Eymery, Angeline; Mteirek, Rana; Jensen, Silke; Vaury, Chantal] Univ Auvergne, Clermont Univ, Clermont Ferrand, France. [Dennis, Cynthia; Zanni, Vanessa; Brasset, Emilie; Eymery, Angeline; Mteirek, Rana; Jensen, Silke; Vaury, Chantal] INSERM, U1103, Clermont Ferrand, France. [Dennis, Cynthia; Zanni, Vanessa; Brasset, Emilie; Eymery, Angeline; Mteirek, Rana; Jensen, Silke; Vaury, Chantal] CNRS, UMR 6293, Clermont Ferrand, France. [Zhang, Liang; Rong, Yikang S.] NCI, LBMB, NIH, Bethesda, MD 20892 USA. [Zanni, Vanessa] INRA AgroParisTech, UMR 1318, Versailles, France. RP Vaury, C (reprint author), Univ Auvergne, Clermont Univ, Clermont Ferrand, France. EM rongy@mail.nih.gov; chantal.vaury@udamail.fr RI Vaury, Chantal/I-4658-2015; Brasset, Emilie/J-6684-2015 OI Vaury, Chantal/0000-0002-7725-5760; FU Association pour la Recherche contre le Cancer [ARC 1139]; Ligue contre le Cancer; Region Auvergne and European Union (EU); Intramural Research Program of the National Cancer Institute, USA FX This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC 1139) and Ligue contre le Cancer. CD, VZ and EB received a grant from the Region Auvergne and European Union (EU). Research in YSR's laboratory is supported by the Intramural Research Program of the National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 9 Z9 9 U1 2 U2 15 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 SEP 9 PY 2013 VL 8 IS 9 AR e72752 DI 10.1371/journal.pone.0072752 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 244QV UT WOS:000326405300025 PM 24039799 ER PT J AU Metcalf, CJE Hampson, K Tatem, AJ Grenfell, BT Bjornstad, ON AF Metcalf, C. Jessica E. Hampson, Katie Tatem, Andrew J. Grenfell, Bryan T. Bjornstad, Ottar N. TI Persistence in Epidemic Metapopulations: Quantifying the Rescue Effects for Measles, Mumps, Rubella and Whooping Cough SO PLOS ONE LA English DT Article ID CRITICAL COMMUNITY SIZE; CHILDHOOD INFECTIONS; DYNAMICS; VACCINATION; SEASONALITY; STOCHASTICITY; POPULATION; STRATEGIES; MODEL AB Metapopulation rescue effects are thought to be key to the persistence of many acute immunizing infections. Yet the enhancement of persistence through spatial coupling has not been previously quantified. Here we estimate the metapopulation rescue effects for four childhood infections using global WHO reported incidence data by comparing persistence on island countries vs all other countries, while controlling for key variables such as vaccine cover, birth rates and economic development. The relative risk of extinction on islands is significantly higher, and approximately double the risk of extinction in mainland countries. Furthermore, as may be expected, infections with longer infectious periods tend to have the strongest metapopulation rescue effects. Our results quantitate the notion that demography and local community size controls disease persistence. C1 [Metcalf, C. Jessica E.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Metcalf, C. Jessica E.; Hampson, Katie; Tatem, Andrew J.; Grenfell, Bryan T.; Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Hampson, Katie] Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow, Lanark, Scotland. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Bjornstad, Ottar N.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA USA. RP Metcalf, CJE (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM charlotte.metcalf@zoo.ox.ac.uk OI Hampson, Katie/0000-0001-5392-6884 FU Royal Society; Bill and Melinda Gates Foundation [49446, 1032350]; NIH [R01 GM083983-01]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Wellcome Trust; Medical Research Council; NIH/NIAID [U19AI089674] FX This work was funded by the Royal Society (C.J.E.M.) Bill and Melinda Gates Foundation and grant NIH R01 GM083983-01 (C.J.E.M., B. T. G., O.N.B), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (C.J.E.M., B. T. G., O.N.B., A.J.T., K. H.), the Wellcome Trust (KH) and the Medical Research Council (KH). A.J.T is also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#49446 and #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 3 Z9 3 U1 1 U2 18 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 SEP 9 PY 2013 VL 8 IS 9 AR e74696 DI 10.1371/journal.pone.0074696 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 244QV UT WOS:000326405300190 PM 24040325 ER PT J AU Zeng, Y Cheng, LG Zhao, L Tan, QH Feng, QS Chen, HS Shen, K Li, JX Zhang, FY Cao, HQ Gregory, SG Yang, Z Gu, J Tao, W Tian, XL Hauser, ER AF Zeng, Yi Cheng, Lingguo Zhao, Ling Tan, Qihua Feng, Qiushi Chen, Huashuai Shen, Ke Li, Jianxin Zhang, Fengyu Cao, Huiqing Gregory, Simon G. Yang, Ze Gu, Jun Tao, Wei Tian, Xiao-Li Hauser, Elizabeth R. TI Interactions between Social/behavioral factors and ADRB2 genotypes may be associated with health at advanced ages in China SO BMC GERIATRICS LA English DT Article DE Health aging; Oldest-old; Social/behavioral factors; ADRB2 genotypes; GxE Interactions; Cognitive function; Self-reported health; Regular exercise; Social-leisure activities; Negative emotion ID BETA-ADRENERGIC-RECEPTORS; SELF-RATED HEALTH; BETA(2)-ADRENERGIC RECEPTOR; REPORTED HEALTH; MORTALITY; SURVIVAL; POLYMORPHISMS; STRESS; RISK; ADRENOCEPTORS AB Background: Existing literature indicates that ADRB2 gene is associated with health and longevity, but none of previous studies investigated associations of carrying the ADRB2 minor alleles and interactions between ADRB2 genotypes and social/behavioral factors(GxE) with health outcomes at advanced ages. This study intends to fill in this research gap. Method: We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90+. To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods. Results: Interaction between regular exercise and carrying rs1042718 minor allele is significantly and positively associated with good cognitive function; interaction between regular exercise and carrying rs1042718 or rs1042719 minor allele is significantly and positively associated with self-reported good health; and interaction between social-leisure activities and carrying rs1042719 minor allele is significantly and positively associated with self-reported good health. Carrying rs1042718 or rs1042719 minor alleles is significantly and negatively associated with negative emotion, but the ADRB2 SNPs are not significantly associated with cognitive function and self-reported health. Our structural equation analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular exercise and social-leisure activities with cognitive function and self-reported health, and negative association of negative emotion with cognitive function, were much stronger among carriers of rs1042718 or rs1042719 alleles, compared to the non-carriers. Conclusions: The results indicate significant positive associations of interactions between social/behavioral factors and the ADRB2 genotypes with health outcomes of cognitive function and self-reported health, and negative associations of carrying rs1042718 or rs1042719 minor alleles with negative emotion, at advanced ages in China. Our findings are exploratory rather than causal conclusions. This study implies that near-future health promotion programs considering individuals' genetic profiles, with appropriate protection of privacy/confidentiality, would yield increased benefits and reduced costs to the programs and their participants. C1 [Zeng, Yi; Chen, Huashuai] Duke Univ, Sch Med, Div Geriatr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA. [Zeng, Yi; Li, Jianxin] Duke Univ, Ctr Hlth Aging & Dev Studies, Durham, NC 27710 USA. [Zeng, Yi; Li, Jianxin] Peking Univ, Natl Sch Dev, Beijing 100871, Peoples R China. [Cheng, Lingguo] Nanjing Univ, Sch Business, Nanjing 210008, Jiangsu, Peoples R China. [Zhao, Ling; Cao, Huiqing; Tian, Xiao-Li] Peking Univ, Inst Mol Med, Dept Human Populat Genet, Beijing 100871, Peoples R China. [Tan, Qihua] Univ Southern Denmark, Inst Publ Hlth, Odense, Denmark. [Feng, Qiushi] Natl Univ Singapore, Dept Sociol, Singapore 117548, Singapore. [Chen, Huashuai] Xiang Tan Univ, Business Sch, Xiangtan, Peoples R China. [Shen, Ke] Fudan Univ, Inst Populat Res, Shanghai 200433, Peoples R China. [Li, Jianxin] Peking Univ, Dept Sociol, Beijing 100871, Peoples R China. [Zhang, Fengyu] NIMH, Gene Cognit & Psychosis Program, Baltimore, MD USA. [Zhang, Fengyu] Lieber Inst Brain Dev, Baltimore, MD USA. [Gregory, Simon G.; Hauser, Elizabeth R.] Duke Univ, Sch Med, Ctr Human Genet, Durham, NC 27710 USA. [Yang, Ze] Minist Hlth China, Beijing Hosp, Natl Inst Geriatr, Beijing, Peoples R China. [Gu, Jun; Tao, Wei] Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China. RP Zeng, Y (reprint author), Duke Univ, Sch Med, Div Geriatr, Ctr Study Aging & Human Dev, Box 3003, Durham, NC 27710 USA. EM zengyi68@gmail.com; tianxiaoli@pku.edu.cn RI Zhao, Ling/D-9005-2015; Feng, Qiushi/A-7483-2012 OI Feng, Qiushi/0000-0002-3572-4442 FU National Natural Science Foundation of China [71233001]; National Key Basic Research Program of China [2013CB530700]; NIA/NIH [R01 AG023627]; NIH Pepper Center Grant [P30AG028716] FX This study is part of a project funded by the National Natural Science Foundation of China (71233001) (YZ), National Key Basic Research Program of China (2013CB530700) (XLT), NIA/NIH (R01 AG023627) (YZ), NIH Pepper Center Grant (P30AG028716) (ERH). We are very grateful for the thoughtful comments provided by Danyu Lin, Chad Q. He, Dan Blazer, Jessica Sautter, Gerda Fillenbaum, and Chongming Yang. NR 61 TC 3 Z9 3 U1 2 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD SEP 9 PY 2013 VL 13 AR UNSP 91 DI 10.1186/1471-2318-13-91 PG 13 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 216FZ UT WOS:000324268700001 PM 24016068 ER PT J AU Neuman, KC AF Neuman, Keir C. TI The Tail That Wags the Dog: Topoisomerase IV ParC C-Terminal Domain Controls Strand Passage Activity through Multipartite Topology-Dependent Interactions with DNA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Editorial Material ID POSITIVELY SUPERCOILED DNA; II-ALPHA; CHIRAL DISCRIMINATION; MECHANISM; RELAXATION; GYRASE C1 NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural NIH HHS [ZIA HL001056-07] NR 14 TC 0 Z9 0 U1 3 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 9 PY 2013 VL 425 IS 17 BP 3025 EP 3028 DI 10.1016/j.jmb.2013.07.004 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 210UN UT WOS:000323860300001 PM 23851170 ER PT J AU Appella, D AF Appella, Daniel TI Engineering peptide nucleic acids at the atomic- and nanoscale to detect and quantify nucleic acids from pathogens SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Appella, Daniel] NIDDK, NIH, Bethesda, MD 20814 USA. EM appellad@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 2-COMSCI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402872 ER PT J AU Austin, CP AF Austin, Christopher P. TI Role of toxicology in the National Center for Advancing Translational Sciences (NCATS) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 29-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407208 ER PT J AU Barchi, JJ AF Barchi, Joseph J. TI Chemistry and biology of the Thomsen-Friedenreich antigen: From cancer to interstitial cystitis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Barchi, Joseph J.] NCI, Frederick, MD 21702 USA. EM barchij@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 47-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401129 ER PT J AU Bhirde, AA Jin, A Sousa, AA Iglesias-Bartolome, R Thompson, CN Gutkind, SJ Leapman, RD Sun, YP Chen, XY AF Bhirde, Ashwinkumar A. Jin, Albert Sousa, Alioscka A. Iglesias-Bartolome, Ramiro Thompson, Candice N. Gutkind, Silvio J. Leapman, Richard D. Sun, Ya-Ping Chen, Xiaoyuan TI Cellular interactions of carbon nanodots at the nanoscale SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bhirde, Ashwinkumar A.; Jin, Albert; Sousa, Alioscka A.; Thompson, Candice N.; Leapman, Richard D.; Chen, Xiaoyuan] Inst Biomed Imaging & Bioengn 1Natl, NIH, Bethesda, MD 20892 USA. [Iglesias-Bartolome, Ramiro; Gutkind, Silvio J.] Inst Dent & Craniofacial Res 2Natl, NIH, Bethesda, MD 20892 USA. [Sun, Ya-Ping] Clemson Univ, Dept Chem, Clemson, SC 29634 USA. EM bhirdea@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 533-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406316 ER PT J AU Bhirde, AA Chikkaveeraiah, BV Jin, AJ Wang, Z Zhang, GF Patel, V Gutkind, JS Walker, ARH Chen, XY AF Bhirde, Ashwinkumar A. Chikkaveeraiah, Bhaskara V. Jin, Albert J. Wang, Zhe Zhang, Guofeng Patel, Vyomesh Gutkind, J. Silvio Walker, Angela R. Hight Chen, Xiaoyuan TI Therapeutic nanotubes as highly efficient cancer drug delivery vehicles to counteract drug resistance SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bhirde, Ashwinkumar A.; Chikkaveeraiah, Bhaskara V.; Wang, Zhe; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Jin, Albert J.; Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20892 USA. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Walker, Angela R. Hight] NIST, Gaithersburg, MD 20899 USA. EM ashwinkumar.bhirde@nih.gov RI Hight Walker, Angela/C-3373-2009 OI Hight Walker, Angela/0000-0003-1385-0672 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 281-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402304 ER PT J AU Bolton, E AF Bolton, Evan TI Data exchange caveats and particulars, the devil is in the details SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 80-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401877 ER PT J AU Bolton, E Fu, G Thiessen, P Gindulyte, A AF Bolton, Evan Fu, Gang Thiessen, Paul Gindulyte, Asta TI PubChemRDF: Towards a semantic description of PubChem SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bolton, Evan; Fu, Gang; Thiessen, Paul; Gindulyte, Asta] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 58-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401855 ER PT J AU Bolton, E AF Bolton, Evan TI Social networking and PubChem SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 56-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401853 ER PT J AU Bolton, E AF Bolton, Evan TI Integration of patent information in PubChem SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Bolton, Evan] NIH, NCBI, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 38-CHAL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401381 ER PT J AU Brooks, BR Shao, YH Pickard, FC Simmonett, A AF Brooks, Bernard R. Shao, Yihan Pickard, Frank C. Simmonett, Andrew TI Recent Ewald techniques for the efficient calculation of multipole moment interactions and complex QM/MM systems SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Brooks, Bernard R.; Pickard, Frank C.] NHLBI, Lab Computat Biol, Bethesda, MD 20892 USA. [Shao, Yihan] Q Chem Inc, Bethesda, MD 20892 USA. [Simmonett, Andrew] Univ Georgia, Ctr Computat Chem, Athens, GA 30602 USA. EM brb@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 80-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402608 ER PT J AU Chikkaveeraiah, BV Bhirde, A Jin, A Chen, XY AF Chikkaveeraiah, Bhaskara V. Bhirde, Ashwinkumar Jin, Albert Chen, Xiaoyuan TI Real time and label-free detection of cellular response to targeted therapy using quartz crystal microbalance with dissipation monitoring SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Chikkaveeraiah, Bhaskara V.; Bhirde, Ashwinkumar; Jin, Albert; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Chikkaveeraiah, Bhaskara V.] NIH, Microfabricat & Microfluid Unit, Bethesda, MD 20892 USA. EM bhaskara.chikkaveeraiah@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 535-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406318 ER PT J AU Chikkaveeraiah, BV Bhirde, A Jin, A Chen, XY AF Chikkaveeraiah, Bhaskara V. Bhirde, Ashwinkumar Jin, Albert Chen, Xiaoyuan TI Paper based electrochemical sensor for cancer protein biomarker detection SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Chikkaveeraiah, Bhaskara V.; Bhirde, Ashwinkumar; Jin, Albert; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, Bethesda, MD 20892 USA. EM bhaskara.chikkaveeraiah@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 280-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402303 ER PT J AU Duveau, DY Godfrey, AG Hilliard, DW Masquelin, T Thomas, CJ AF Duveau, Damien Y. Godfrey, Alexander G. Hilliard, Darryl W. Masquelin, Thierry Thomas, Craig J. TI Synthesis of a library of C-glycosides using the automated synthesis laboratory (ASL) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Duveau, Damien Y.; Thomas, Craig J.] NIH, NCATS, Bethesda, MD 20892 USA. [Godfrey, Alexander G.; Hilliard, Darryl W.; Masquelin, Thierry] Eli Lilly & Co, Dept Discovery Chem Res, Indianapolis, IN 46285 USA. EM duveaudy@mail.nih.gov; agg@lilly.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 137-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405330 ER PT J AU Filikov, A Kumar, V Malhotra, SV AF Filikov, Anton Kumar, Vineet Malhotra, Sanjay V. TI Structural basis for stabilization of Nrf2 by chemopreventive agents and oxidative stress SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Filikov, Anton; Kumar, Vineet; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 120-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404779 ER PT J AU Filikov, A Pepe, A Kumar, V Malhotra, SV AF Filikov, Anton Pepe, Antonella Kumar, Vineet Malhotra, Sanjay V. TI Design of antiandrogens: Challenge of receptor modeling SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Filikov, Anton; Pepe, Antonella; Kumar, Vineet; Malhotra, Sanjay V.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. EM anton.filikov@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 103-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402630 ER PT J AU Fu, G Batchelor, C Dumontier, M Hastings, J Kucuk, H Schurer, S Vempati, U Willighagen, E Bolton, E AF Fu, Gang Batchelor, Colin Dumontier, Michel Hastings, Janna Kuecuek, Hande Schurer, Stephan Vempati, Uma Willighagen, Egon Bolton, Evan TI Semantic annotation of PubChem databases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Fu, Gang; Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Batchelor, Colin] Royal Soc Chem, Cambridge, England. [Dumontier, Michel] Carleton Univ, Dept Biol, Inst Biochem, Sch Comp Sci, Ottawa, ON K1S 5B6, Canada. [Hastings, Janna] European Bioinformat Inst, Cambridge, England. [Hastings, Janna] Univ Geneva, Geneva, Switzerland. [Kuecuek, Hande; Schurer, Stephan; Vempati, Uma] Univ Miami, Ctr Computat Sci, Miami, FL USA. [Schurer, Stephan] Univ Miami, Dept Mol & Cellular Pharmacol, Miami, FL USA. [Willighagen, Egon] Maastricht Univ, Dept Bioinformat BiGCaT, Maastricht, Netherlands. EM gang.fu@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 59-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401856 ER PT J AU Gangjee, A Pavana, RK Gentile, T Bai, RL Hamel, E Ihnat, MA Risinger, AL Mooberry, SL AF Gangjee, Aleem Pavana, Roheeth Kumar Gentile, Taylor Bai, Rouli Hamel, Ernest Ihnat, Michael A. Risinger, April L. Mooberry, Susan L. TI Steric induced conformational restriction: Design, synthesis, and biological evaluation of novel pyrrolo[3,2-d] pyrimidines as water soluble antitubulin agents with antiangiogenic and antitumor potential SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Gangjee, Aleem; Pavana, Roheeth Kumar; Gentile, Taylor] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Bai, Rouli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Ihnat, Michael A.] Univ Oklahoma, Dept Pharmaceut Sci, Coll Pharm, Oklahoma City, OK 73117 USA. [Risinger, April L.; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM kp.roheeth@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 316-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405066 ER PT J AU Gangjee, A Mohan, R Bai, RL Hamel, E Ihnat, M AF Gangjee, Aleem Mohan, Rishabh Bai, Ruoli Hamel, Ernest Ihnat, Michael TI Design, synthesis, and biological evaluation of substituted monocyclic pyrimidines with dual antiangiogenic and cytotoxic antitubulin activities as antitumor agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Gangjee, Aleem; Mohan, Rishabh] Duquesne Univ, Sch Pharm, Div Med Chem, Pittsburgh, PA 15282 USA. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Ihnat, Michael] Univ Oklahoma, Hlth Sci Ctr, Dept Pharmaceut Sci, Oklahoma City, OK 73117 USA. EM mohanr@duq.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 311-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405061 ER PT J AU Geer, LY Han, LY Wang, YL Bolton, EE He, SQ Yu, B AF Geer, Lewis Y. Han, Lianyi Wang, Yanli Bolton, Evan E. He, Siqian Yu, Bo TI Digital fractionation: Using NoSQL technology to extract biochemical data from big data repositories SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Geer, Lewis Y.; Han, Lianyi; Wang, Yanli; Bolton, Evan E.; He, Siqian; Yu, Bo] NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM lewis.geer@nih.gov RI Geer, Lewis/H-2714-2014 NR 0 TC 0 Z9 0 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 16-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401817 ER PT J AU Guha, R Braisted, J Jadhav, A Nyguen, DT Peryea, T Southall, N AF Guha, Rajarshi Braisted, John Jadhav, Ajit Nyguen, Dac-Trung Peryea, Tyler Southall, Noel TI Pushing chemical biology data through the pipes: Architecting and extending the BARD API SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Guha, Rajarshi; Braisted, John; Jadhav, Ajit; Nyguen, Dac-Trung; Peryea, Tyler; Southall, Noel] Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM rajarshi.guha@gmall.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 32-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401832 ER PT J AU Holland, RJ Maciag, AE Luthers, C Saavedra, JE Keefer, LK AF Holland, Ryan J. Maciag, Anna E. Luthers, Christina Saavedra, Joseph E. Keefer, Larry K. TI GSTP1-activated O-2-arylated diazeniumdiolate PABA/NO and second generation analogs enhance the cytotoxicity of docetaxel in nonsmall cell lung cancer (NSCLC) cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Holland, Ryan J.; Luthers, Christina; Keefer, Larry K.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Maciag, Anna E.; Saavedra, Joseph E.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. EM hollandrj@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 94-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407269 ER PT J AU Horkay, F Basser, PJ AF Horkay, Ferenc Basser, Peter J. TI Self-organization of cartilage biopolymers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Horkay, Ferenc; Basser, Peter J.] NIH, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 285-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407046 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI Structure and swelling behavior of cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Horkay, Ferenc; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NIH, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, NIH, Bethesda, MD 20892 USA. EM horkayf@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 16-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618400828 ER PT J AU Huang, XF Yin, ZJ Finn, MG Wang, Q Gildersleeve, J BenMohamed, L AF Huang, Xuefei Yin, Zhaojun Finn, M. G. Wang, Qian Gildersleeve, Jeffery BenMohamed, Lbachir TI Boosting the immune responses towards weak tumor associated carbohydrate antigens by organized display on virus-like particles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Huang, Xuefei; Yin, Zhaojun] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Finn, M. G.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Wang, Qian] Univ S Carolina, Dept Chem, Columbia, SC 29208 USA. [Gildersleeve, Jeffery] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [BenMohamed, Lbachir] Univ Calif Irvine, Cellular & Mol Immunol Lab, Irvine, CA 92697 USA. EM xuefei@chemistry.msu.edu RI Huang, Xuefei/G-3371-2014 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 12-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401095 ER PT J AU Hummer, G AF Hummer, Gerhard TI Periodic boundary conditions in molecular simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Hummer, Gerhard] NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 114-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402641 ER PT J AU Ivy, SP Takebe, N Harris, P AF Ivy, S. Percy Takebe, Naoko Harris, Pamela TI Identification of the tumor initiating cell and treatment strategies for its eradication by inhibiting embryonic pathway signaling SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Ivy, S. Percy; Takebe, Naoko; Harris, Pamela] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. EM ivyp@ctep.nci.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 168-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404823 ER PT J AU Jun, JH Ummanni, R Hanson, PR Malhotra, SV AF Jun, Jung Ho Ummanni, Ramesh Hanson, Paul R. Malhotra, Sanjay V. TI Design, synthesis, and in vitro cytotoxicity evaluation of seven-membered cyclic sulfamides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Jun, Jung Ho; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Ummanni, Ramesh] Indian Inst Chem Technol, Ctr Chem Biol, Hyderabad 500007, Andhra Pradesh, India. [Hanson, Paul R.] Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 134-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404792 ER PT J AU Kandi, SK Kumar, V Gerena, CEV Zayas, B Rawat, DS Malhotra, SV AF Kandi, Shamseer Kulangara Kumar, Vineet Gerena, Christian E. Velez Zayas, Beatriz Rawat, Diwan S. Malhotra, Sanjay V. TI Synthesis and investigation of the antitumor activity of 4-aminoquinoline and C-5-curcuminoids hybrids SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kandi, Shamseer Kulangara; Rawat, Diwan S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Kumar, Vineet; Malhotra, Sanjay V.] Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. [Gerena, Christian E. Velez; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 106-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404766 ER PT J AU Keefer, LK Maciag, AE Holland, RJ Saavedra, JE Ji, XH Kumari, V Kim, Y Shami, PJ AF Keefer, Larry K. Maciag, Anna E. Holland, Ryan J. Saavedra, Joseph E. Ji, Xinhua Kumari, Vandana Kim, Youseung Shami, Paul J. TI JS-K as a broad-spectrum anticancer agent: Lead optimization strategies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Keefer, Larry K.; Holland, Ryan J.; Kim, Youseung] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Maciag, Anna E.; Saavedra, Joseph E.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Ji, Xinhua; Kumari, Vandana] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Shami, Paul J.] Univ Utah, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA. EM keeferl@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 307-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405057 ER PT J AU Kim, S Han, LY Bolton, EE Bryant, SH AF Kim, Sunghwan Han, Lianyi Bolton, Evan E. Bryant, Stephen H. TI PubChem structure-activity relationship (SAR) clusters SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kim, Sunghwan; Han, Lianyi; Bolton, Evan E.; Bryant, Stephen H.] Natl Lib Med, Computat Biol Branch, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 344-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402851 ER PT J AU Kim, S AF Kim, Sunghwan TI PubChem and PubChem3D: Public chemical information resources for biological assay data analysis and drug discovery SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kim, Sunghwan] Natl Lib Med, Computat Biol Branch, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 33-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618400030 ER PT J AU Kulkarni, PM Jarbe, T Goldberg, S Barbarich-Marsteller, NR Thakur, GA AF Kulkarni, Pushkar M. Jarbe, Torbjorn Goldberg, Steven Barbarich-Marsteller, Nicole R. Thakur, Ganesh A. TI Novel positive allosteric modulators of CB1 cannabinoid receptor for the treatment of anorexia nervosa SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kulkarni, Pushkar M.; Thakur, Ganesh A.] Northeastern Univ, Boston, MA 02115 USA. [Jarbe, Torbjorn; Thakur, Ganesh A.] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Goldberg, Steven] NIDA, Preclin Pharmacol Sect, Biomed Res Ctr, Baltimore, MD 21224 USA. [Barbarich-Marsteller, Nicole R.] Columbia Univ, Preclin Eating Disorders Res Lab, New York, NY 10032 USA. EM pm.kulkarni@neu.edu; g.thakur@neu.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 84-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404744 ER PT J AU Kumar, V Patel, PC Kishore, D Joshi, N Kaur, S Banerjee, R Singh, B Malhotra, SV AF Kumar, Vineet Patel, Pradipkumar Chandubhai Kishore, D. Joshi, Nitin Kaur, Shahdeep Banerjee, Rinti Singh, Bhavani Malhotra, Sanjay V. TI 3,4-diaryl substituted isoxazole and pyrazole derivatives: Synthesis and evaluation of antitumor activity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kumar, Vineet; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Patel, Pradipkumar Chandubhai; Kishore, D.; Singh, Bhavani] Banasthali Vidyapith, Dept Chem, Banasthali 304022, Rajasthan, India. [Joshi, Nitin; Kaur, Shahdeep; Banerjee, Rinti] Indian Inst Technol Bombay Powai, Dept Biosci & Bioengn, Ctr Res Nanotechnol & Sci, Mumbai 400076, Maharashtra, India. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 299-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405049 ER PT J AU Kumar, V Patel, PC Kishore, D Joshi, N Kaur, S Banerjee, R Singh, B Malhotra, SV AF Kumar, Vineet Patel, Pradipkumar Chandubhai Kishore, D. Joshi, Nitin Kaur, Shahdeep Banerjee, Rinti Singh, Bhavani Malhotra, Sanjay V. TI Synthesis and biological evaluation of substituted 3,5-diaryl indole-5-carboxylic acid derivatives as anticancer agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Kumar, Vineet; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Patel, Pradipkumar Chandubhai; Kishore, D.; Singh, Bhavani] Banasthali Vidyapith, Dept Chem, Banasthali 304022, Rajasthan, India. [Joshi, Nitin; Kaur, Shahdeep; Banerjee, Rinti] Indian Inst Technol Bombay Powai, Dept Biosci & Bioengn, Ctr Res Nanotechnol & Sci, Bombay 400076, Maharashtra, India. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 297-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405047 ER PT J AU Lee, SJ Nauth, A Weber, C Czeskis, BA Hooker, JM Qu, WC Kim, SW Fowler, JS AF Lee, So Jeong Nauth, Alex Weber, Carina Czeskis, Boris A. Hooker, Jacob M. Qu, Wenchao Kim, Sung Won Fowler, Joanna S. TI Rapid synthesis of C-11 labeled indole using [C-11]cyanide SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Lee, So Jeong; Qu, Wenchao; Kim, Sung Won; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Lee, So Jeong; Fowler, Joanna S.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. [Kim, Sung Won] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD 20892 USA. [Czeskis, Boris A.; Hooker, Jacob M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nauth, Alex; Weber, Carina] Johannes Gutenberg Univ Mainz, Dept Chem, D-55122 Mainz, Germany. EM sjlee@bnl.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 64-NUCL PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405180 ER PT J AU Li, K Lv, ZL Li, QS AF Li, Ke Lv, Zhiliang Li, Qisheng TI In vitro and in vivo anti-hepatitis B virus activities of novel 2-pyridone derivatives SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Li, Ke; Lv, Zhiliang] Second Mil Med Univ, Coll Pharm, Dept Med Chem, Shanghai, Peoples R China. [Li, Qisheng] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM proflike@sina.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 246-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404898 ER PT J AU Malhotra, SV Kumar, V Gerena, CEVG Zayas, B AF Malhotra, Sanjay V. Kumar, Vineet Gerena, Christian E. Velez Gerena Zayas, Beatriz TI Mechanistic studies on the anticancer activity of imidazolium-based ionic liquids SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Malhotra, Sanjay V.; Kumar, Vineet] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Gerena, Christian E. Velez Gerena; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 118-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404777 ER PT J AU Malhotra, SV Tomaszewski, JE Kumar, V Difilippantonio, MJ Risbood, P Saha, S Raolji, GB Patro, B AF Malhotra, Sanjay V. Tomaszewski, Joseph E. Kumar, Vineet Difilippantonio, Michael J. Risbood, Prabhaker Saha, Sanjay Raolji, Gajendra B. Patro, Balaram TI Synthesis and screening for anticancer activity of sempervirine analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Malhotra, Sanjay V.; Kumar, Vineet] SAIC Frederick Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Tomaszewski, Joseph E.; Difilippantonio, Michael J.; Risbood, Prabhaker] NCI, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. [Saha, Sanjay; Raolji, Gajendra B.; Patro, Balaram] GVK Biosci Pvt Ltd, Div Med Chem, Hyderabad, Andhra Pradesh, India. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 119-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404778 ER PT J AU Manohar, S Pepe, A Gerena, CEV Zayas, B Rawat, DS Malhotra, SV AF Manohar, Sunny Pepe, Antonella Gerena, Christian E. Velez Zayas, Beatriz Rawat, Diwan S. Malhotra, Sanjay V. TI 4-Aminoquinoline-triazine hybrids: Synthesis and cytotoxicity study for anticancer activity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Manohar, Sunny; Rawat, Diwan S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Pepe, Antonella; Malhotra, Sanjay V.] Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. [Gerena, Christian E. Velez; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 124-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404783 ER PT J AU Nakagawa-Goto, K Hamel, E Ohkoshi, E Kenneth, BF Lee, KH Goto, M AF Nakagawa-Goto, Kyoko Hamel, Ernest Ohkoshi, Emika Kenneth, Bastow F. Lee, Kuo-Hsiung Goto, Masuo TI TEDB-TB analogs as new classes of tubulin inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Nakagawa-Goto, Kyoko] Kanazawa Univ, Dept Pharmaceut Sci, Kanazawa, Ishikawa 9201192, Japan. [Hamel, Ernest] NCI, Frederick, MD 21702 USA. [Ohkoshi, Emika; Kenneth, Bastow F.; Lee, Kuo-Hsiung; Goto, Masuo] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM kngoto@p.kanazawa-u.ac.jp RI GOTO, Kyoko/D-8389-2015 OI GOTO, Kyoko/0000-0002-1642-6538 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 94-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404754 ER PT J AU Nussinov, R Jang, H Lal, R Kagan, BL AF Nussinov, Ruth Jang, Hyunbum Lal, Ratnesh Kagan, Bruce L. TI Alzheimer's toxic amyloid oligomer insertion and ion channel formation in the membrane SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Nussinov, Ruth; Jang, Hyunbum] SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res, Nanobiol Program,NCI, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Lal, Ratnesh] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Lal, Ratnesh] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Lal, Ratnesh] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Psychiat, Los Angeles, CA 90024 USA. EM nussinor@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 208-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406016 ER PT J AU Patel, PR Mathews, LA Guha, R Shinn, P Lim, KH Keller, J Liu, D McKnight, C Duveau, DY Jiang, JK Mott, BT Michael, S Simeonov, A Ferrer, M Staudt, LM Thomas, CJ AF Patel, Paresma R. Mathews, Lesley A. Guha, Rajarshi Shinn, Paul Lim, Kian-Huat Keller, Jonathan Liu, Dongbo McKnight, Crystal Duveau, Damien Y. Jiang, Jian-kang Mott, Bryan T. Michael, Sam Simeonov, Anton Ferrer, Marc Staudt, Louis M. Thomas, Craig J. TI High-throughput combination screening identifies novel polypharmacologies for small molecules from a mechanistically defined library SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Patel, Paresma R.] SAIC Frederick Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Mathews, Lesley A.; Guha, Rajarshi; Shinn, Paul; Keller, Jonathan; Liu, Dongbo; McKnight, Crystal; Duveau, Damien Y.; Jiang, Jian-kang; Mott, Bryan T.; Michael, Sam; Simeonov, Anton; Ferrer, Marc; Thomas, Craig J.] NIH, NIH Chem Genom Ctr, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Lim, Kian-Huat; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM paresma.patel@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 327-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405076 ER PT J AU Perera, L AF Perera, Lalith TI Molecular insights into ribonucleotide insertion using molecular dynamics simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Perera, Lalith] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM lalithmperera@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 16-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402551 ER PT J AU Petukh, M Panchenko, A Alexov, E AF Petukh, Marharyta Panchenko, Anna Alexov, Emil TI Electrostatics plays significant role in changes of the protein-protein affinity due to missense mutations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Petukh, Marharyta; Alexov, Emil] Clemson Univ, Dept Phys, Clemson, SC 29634 USA. [Petukh, Marharyta; Panchenko, Anna] NLM, NIH, Bethesda, MA USA. EM mpetukh@clemson.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 213-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406021 ER PT J AU Pragani, R Davis, M Fox, J Liu, L Nelson, H Auld, D Li, J Shen, M Simeonov, A Boxer, M AF Pragani, Rajan Davis, Mindy Fox, Jennifer Liu, Li Nelson, Henrike Auld, Douglas Li, Julie Shen, Min Simeonov, Anton Boxer, Matthew TI Identification of ubiquitin-specific protease 2 (USP2) inhibitors that promote cell cycle arrest via cyclin D1 destabilization SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Pragani, Rajan; Davis, Mindy; Fox, Jennifer; Liu, Li; Nelson, Henrike; Li, Julie; Shen, Min; Simeonov, Anton; Boxer, Matthew] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Auld, Douglas] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. EM rpragani@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 127-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404785 ER PT J AU Riffle, JS Pothayee, N Hu, N Balasubramaniam, S Davis, RM Koretsky, A AF Riffle, Judy S. Pothayee, Nipon Hu, N. Balasubramaniam, S. Davis, Richey M. Koretsky, A. TI Influence of the molecular structure of core-corona nanoparticles on MRI relaxivities and images SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Riffle, Judy S.; Pothayee, Nipon; Hu, N.; Balasubramaniam, S.; Davis, Richey M.] Virginia Tech, Macromol & Interfaces Inst, Blacksburg, VA 24061 USA. [Koretsky, A.] NIH, Lab Funct Imaging, Bethesda, MD 20892 USA. EM jriffle@vt.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 21-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406680 ER PT J AU Robertson, JWF Reiner, JE Balijepalli, AK Burden, DL Burden, LK Kasianowicz, JJ AF Robertson, Joseph W. F. Reiner, Joseph E. Balijepalli, Arvind K. Burden, Daniel L. Burden, Lisa K. Kasianowicz, John J. TI Modification of protein nanopores with gold nanoparticles for single molecule temperature control SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Robertson, Joseph W. F.; Balijepalli, Arvind K.; Kasianowicz, John J.] NIST, Semicond & Dimens Metrol Div, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Reiner, Joseph E.] Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23284 USA. [Balijepalli, Arvind K.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. [Burden, Daniel L.] Wheaton Coll, Dept Chem, Wheaton, IL 60187 USA. [Burden, Lisa K.] Wheaton Coll, Dept Biol, Wheaton, IL 60187 USA. EM joseph.robertson@nist.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 407-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402424 ER PT J AU Saavedra, JE Holland, RJ Kim, Y Biswas, D Kumari, V Ji, XH Keefer, LK Maciag, A AF Saavedra, Joseph E. Holland, Ryan J. Kim, Youseung Biswas, Debanjan Kumari, Vandana Ji, Xinhua Keefer, Larry K. Maciag, Anna TI Design of nitric oxide (NO)-releasing/PARP inhibitor hybrid prodrugs targeted to glutathione S-transferase P1-overexpressing cancer cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Saavedra, Joseph E.; Maciag, Anna] Frederick Natl Lab Canc Res, Basic Sci Program, Ft Detrick, MD 21702 USA. [Holland, Ryan J.; Kim, Youseung; Biswas, Debanjan; Keefer, Larry K.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Kumari, Vandana; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM saavedjo@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 103-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407278 ER PT J AU Schneekloth, JS AF Schneekloth, John S. TI Chemical probes of protein sumoylation: Strategies and tactics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Schneekloth, John S.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM john.schneekloth@nih.gov RI Schneekloth, John/N-2590-2014 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 12-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405218 ER PT J AU Sharma, GVM Srikanth, G Ramesh, A Jayaram, V Singh, A Duscharla, D Ummanni, R Jun, JH Malhotra, SV AF Sharma, Gangavaram V. M. Srikanth, Gourisetti Ramesh, Adepu Jayaram, Vanakudoth Singh, Ashita Duscharla, Divya Ummanni, Ramesh Jun, Jung Ho Malhotra, Sanjay V. TI Synthesis and investigation of the anticancer activity of imidazole-based new compounds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Sharma, Gangavaram V. M.; Srikanth, Gourisetti; Ramesh, Adepu; Jayaram, Vanakudoth] Indian Inst Chem Technol, Organ & Biomol Chem Div, CSIR, Hyderabad 500007, Andhra Pradesh, India. [Singh, Ashita; Duscharla, Divya; Ummanni, Ramesh] Indian Inst Chem Technol, Ctr Chem Biol, CSIR, Hyderabad 500007, Andhra Pradesh, India. [Jun, Jung Ho; Malhotra, Sanjay V.] Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 104-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404764 ER PT J AU Song, YL Fu, XD Zhang, L Wang, HY Zeng, W Zhu, J Agama, K Dexheimer, T Pommier, Y AF Song, Yunlong Fu, Xiaodan Zhang, Ling Wang, Hongyu Zeng, Wei Zhu, Ju Agama, Keli Dexheimer, Tom Pommier, Yves TI Structure-based discovery of novel indenoquinolones targeting wild-type and camptothecin-resistant R364H mutant of topoisomerase I SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Song, Yunlong; Fu, Xiaodan; Zhang, Ling; Wang, Hongyu; Zeng, Wei; Zhu, Ju] Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China. [Agama, Keli; Dexheimer, Tom; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM ylsong@smmu.edu.cn NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 166-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404821 ER PT J AU Teicher, BA Teicher, BA AF Teicher, Beverly A. Teicher, Beverly A. TI Antibody drug conjugates SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Teicher, Beverly A.; Teicher, Beverly A.] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. EM teicherba@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 178-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404833 ER PT J AU Thakur, A Jun, JH Gerena, CEVGEV Zayas, B Rawat, DS Malhotra, SV AF Thakur, Anuj Jun, Jung Ho Gerena, Christian E. Velez Gerena E. Velez Zayas, Beatriz Rawat, Diwan S. Malhotra, Sanjay V. TI Synthesis and anticancer activity of C-5-curcuminoids SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Thakur, Anuj; Rawat, Diwan S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Jun, Jung Ho; Malhotra, Sanjay V.] Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. [Gerena, Christian E. Velez Gerena E. Velez; Zayas, Beatriz] Univ Metropolitana, Sch Environm Affairs, San Juan, PR 00928 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 105-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618404765 ER PT J AU Urasa, IT Lash, TB Mavura, WJ Kimaro, A AF Urasa, Isai T. Lash, Tiffani B. Mavura, Ward J. Kimaro, Anael TI Developing a bioreactor for water defluoridation: A university-community partnership SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Urasa, Isai T.; Kimaro, Anael] Hampton Univ, Dept Chem, Hampton, VA 23668 USA. [Lash, Tiffani B.] NIH, Off Director, Bethesda, MD 20892 USA. [Mavura, Ward J.] Egerton Univ, Dept Chem, Njoro, Nakuru, Kenya. EM isai.urasa@hamptonu.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 118-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618403589 ER PT J AU Nalysnyk, L Papapetropoulos, S Rotella, P Simeone, JC Alter, KE Esquenazi, A AF Nalysnyk, Luba Papapetropoulos, Spyridon Rotella, Philip Simeone, Jason C. Alter, Katharine E. Esquenazi, Alberto TI OnabotulinumtoxinA muscle injection patterns in adult spasticity: a systematic literature review SO BMC NEUROLOGY LA English DT Review DE Botulinum toxin; OnabotulinumtoxinA; Spasticity; Muscles; Injection patterns ID TOXIN TYPE-A; UPPER-LIMB SPASTICITY; INTRAMUSCULAR BOTULINUM TOXIN; CHRONIC HEMIPARETIC PATIENTS; UPPER EXTREMITY SPASTICITY; PLACEBO-CONTROLLED TRIAL; ELBOW FLEXOR SPASTICITY; TRAUMATIC BRAIN-INJURY; STIFF-KNEE GAIT; DOUBLE-BLIND AB Background: OnabotulinumtoxinA has demonstrated significant benefit in adult focal spasticity. This study reviews the injection patterns (i.e., muscle distribution, dosing) of onabotulinumtoxinA for treatment of adult spasticity, as reported in published studies. Methods: A systematic review of clinical trials and observational studies published between 1990 and 2011 reporting data on muscles injected with onabotulinumtoxinA in adult patients treated for any cause of spasticity. Results: 28 randomized, 5 nonrandomized, and 37 single-arm studies evaluating 2,163 adult patients were included. The most frequently injected upper-limb muscles were flexor carpi radialis (64.0% of patients), flexor carpi ulnaris (59.1%), flexor digitorum superficialis (57.2%), flexor digitorum profundus (52.5%), and biceps brachii (38.8%). The most frequently injected lower-limb muscles were the gastrocnemius (66.1% of patients), soleus (54.7%), and tibialis posterior (50.5%). The overall dose range reported was 5-200 U for upper-limb muscles and 10-400 U for lower-limb muscles. Conclusions: The reviewed evidence indicates that the muscles most frequently injected with onabotulinumtoxinA in adults with spasticity were the wrist, elbow, and finger flexors and the ankle plantar flexors. OnabotulinumtoxinA was injected over a broad range of doses per muscle among the studies included in this review, but individual practitioners should be mindful of local regulatory approvals and regulations. C1 [Nalysnyk, Luba] United BioSource Corp, Epidemiol & Database Analyt, Lexington, MA USA. [Papapetropoulos, Spyridon] Allergan Pharmaceut Inc, Neurosciences, Med Affairs, Irvine, CA USA. [Rotella, Philip; Simeone, Jason C.] Evidera, Hlth Econ & Epidemiol, Lexington, MA USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Baltimore, MD USA. [Alter, Katharine E.] NIH, Bethesda, MD 20892 USA. [Esquenazi, Alberto] MossRehab & Albert Einstein Med Ctr, Gait & Mot Anal Lab, Elkins Pk, PA USA. RP Nalysnyk, L (reprint author), United BioSource Corp, Epidemiol & Database Analyt, Lexington, MA USA. EM lnalysnyk@aol.com FU Allergan, Inc. FX The authors thank Allergan, Inc., for funding Imprint Publication Science, New York, NY, to provide editorial support in the preparation and styling of this manuscript. NR 89 TC 10 Z9 10 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD SEP 8 PY 2013 VL 13 AR 118 DI 10.1186/1471-2377-13-118 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 222AZ UT WOS:000324703500001 PM 24011236 ER PT J AU Wang, Y Starling, AP Haug, LS Eggesbo, M Becher, G Thomsen, C Travlos, G King, D Hoppin, JA Rogan, WJ Longnecker, MP AF Wang, Yan Starling, Anne P. Haug, Line S. Eggesbo, Merete Becher, Georg Thomsen, Cathrine Travlos, Gregory King, Debra Hoppin, Jane A. Rogan, Walter J. Longnecker, Matthew P. TI Association between Perfluoroalkyl substances and thyroid stimulating hormone among pregnant women: a cross-sectional study SO ENVIRONMENTAL HEALTH LA English DT Article DE Perfluorinated alkyl substances; Thyroid stimulating hormone; Pregnant women; The Norwegian Mother and child cohort study; MoBa ID PERFLUORINATED COMPOUNDS; PERFLUOROOCTANE SULFONATE; NORWEGIAN MOTHER; CHILD COHORT; EXPOSURE; FETAL; THYROXINE; GESTATION; HEALTH; RAT AB Background: Perfluoroalkyl substances (PFASs) are a group of highly persistent chemicals that are widespread contaminants in wildlife and humans. Exposure to PFAS affects thyroid homeostasis in experimental animals and possibly in humans. The objective of this study was to examine the association between plasma concentrations of PFASs and thyroid stimulating hormone (TSH) among pregnant women. Methods: A total of 903 pregnant women who enrolled in the Norwegian Mother and Child Cohort Study from 2003 to 2004 were studied. Concentrations of thirteen PFASs and TSH were measured in plasma samples collected around the 18th week of gestation. Linear regression models were used to evaluate associations between PFASs and TSH. Results: Among the thirteen PFASs, seven were detected in more than 60% of samples and perfluorooctane sulfonate (PFOS) had the highest concentrations (median, 12.8 ng/mL; inter-quartile range [IQR], 10.1 - 16.5 ng/mL). The median TSH concentration was 3.5 (IQR, 2.4 - 4.8) mu IU/mL. Pregnant women with higher PFOS had higher TSH levels. After adjustment, with each 1 ng/mL increase in PFOS concentration, there was a 0.8% (95% confidence interval: 0.1%, 1.6%) rise in TSH. The odds ratio of having an abnormally high TSH, however, was not increased, and other PFASs were unrelated to TSH. Conclusions: Our results suggest an association between PFOS and TSH in pregnant women that is small and may be of no clinical significance. C1 [Wang, Yan; Starling, Anne P.; Travlos, Gregory; King, Debra; Hoppin, Jane A.; Rogan, Walter J.; Longnecker, Matthew P.] Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Durham, NC USA. [Starling, Anne P.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Haug, Line S.; Becher, Georg; Thomsen, Cathrine] Norwegian Inst Publ Hlth, Dept Environm Med, Oslo, Norway. [Eggesbo, Merete] Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, Oslo, Norway. [Becher, Georg] Univ Oslo, Dept Chem, Oslo, Norway. RP Wang, Y (reprint author), Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Durham, NC USA. EM wangy13@niehs.nih.gov RI Rogan, Walter/I-6034-2012; OI Rogan, Walter/0000-0002-9302-0160; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU Intramural Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); National Institute of Environmental Health Sciences [1-F30-ES022126-01]; Norwegian Ministry of Health; Ministry of Education and Research, NIH/NIEHS [N01-ES-85433]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This study was supported in part by the Intramural Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). Ms. Starling was supported by an extramural award (1-F30-ES022126-01) from the National Institute of Environmental Health Sciences. The Norwegian Mother and Child Cohort Study was supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (Contract No. N01-ES-85433), NIH/NINDS (Grant No. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (Grant No. 151918/S10). We are grateful to all the participating families in Norway who take part in this ongoing cohort study. NR 48 TC 12 Z9 12 U1 4 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD SEP 8 PY 2013 VL 12 AR 76 DI 10.1186/1476-069X-12-76 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 219PQ UT WOS:000324520500001 PM 24010716 ER PT J AU Kreimer, AR Campbell, CMP Lin, HY Fulp, W Papenfuss, MR Abrahamsen, M Hildesheim, A Villa, LL Salmeron, JJ Lazcano-Ponce, E Giuliano, AR AF Kreimer, Aimee R. Campbell, Christine M. Pierce Lin, Hui-Yi Fulp, William Papenfuss, Mary R. Abrahamsen, Martha Hildesheim, Allan Villa, Luisa L. Salmeron, Jorge J. Lazcano-Ponce, Eduardo Giuliano, Anna R. TI Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study SO LANCET LA English DT Article ID SQUAMOUS-CELL CARCINOMA; UNITED-STATES; HPV INFECTION; RISK-FACTOR; OROPHARYNGEAL CANCER; TOBACCO-SMOKE; YOUNG MEN; PREVALENCE; PERSISTENCE; HEAD AB Background Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men. Methods To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method. Findings 1626 men aged 18-73 years and with a median follow-up of 12.7 months (IQR 12.1-14.7) were included in the analysis. During the first 12 months of follow-up, 4.4% (95% CI 3.5-5.6; n=115 incident infections) of men acquired an incident oral HPV infection, 1.7% (1.2-2.5; n=53 incident infections) an oral oncogenic HPV infection, and 0.6% (0.3-1.1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6.9 months (95 % CI 6.2-9.3; n=45 cleared infections) for any HPV, 6.3 months (6.0-9.9; n=18 cleared infections) for oncogenic HPV, and 7.3 months (6.0-not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits. Interpretation Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts. C1 [Kreimer, Aimee R.; Hildesheim, Allan] NCI, NIH, Bethesda, MD 20892 USA. [Campbell, Christine M. Pierce; Lin, Hui-Yi; Fulp, William; Papenfuss, Mary R.; Abrahamsen, Martha; Giuliano, Anna R.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, Dept Radiol & Basic Oncol, Sao Paulo, Brazil. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, HPV Inst, Sao Paulo, Brazil. [Salmeron, Jorge J.] Inst Mexicano Seguro Social, Cuernavaca, Morelos, Mexico. [Lazcano-Ponce, Eduardo] Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. RP Kreimer, AR (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,RM 6-E104, Bethesda, MD 20892 USA. EM kreimera@mail.nih.gov RI Papilomavirus, Inct/I-2406-2013; USP, Oncologia/F-9053-2014; Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015; OI Hildesheim, Allan/0000-0003-0257-2363; Pierce Campbell, Christine/0000-0002-0233-4894 FU US National Cancer Institute; Merck Sharp Dohme FX US National Cancer Institute, Merck Sharp & Dohme. NR 31 TC 73 Z9 73 U1 0 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 7 PY 2013 VL 382 IS 9895 BP 877 EP 887 DI 10.1016/S0140-6736(13)60809-0 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 215WE UT WOS:000324240700029 PM 23827089 ER PT J AU Sacco, RL Smith, SC Holmes, D Shurin, S Brawley, O Cazap, E Glass, R Komajda, M Koroshetz, W Mayer-Davis, E Mbanya, JC Sledge, G Varmus, H AF Sacco, R. L. Smith, S. C. Holmes, D. Shurin, S. Brawley, O. Cazap, E. Glass, R. Komajda, M. Koroshetz, W. Mayer-Davis, E. Mbanya, J. C. Sledge, G. Varmus, H. TI Accelerating progress on non-communicable diseases SO LANCET LA English DT Editorial Material ID CRISIS C1 [Sacco, R. L.] Amer Heart Assoc, Dallas, TX 75231 USA. [Smith, S. C.] World Heart Federat, Geneva, Switzerland. [Holmes, D.] Amer Coll Cardiol, Washington, DC USA. [Shurin, S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Glass, R.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Koroshetz, W.] NINDS, NIH, Bethesda, MD 20892 USA. [Varmus, H.] NCI, NIH, Bethesda, MD 20892 USA. [Brawley, O.] Amer Canc Soc, Atlanta, GA 30329 USA. [Cazap, E.] Union Int Canc Control, Geneva, Switzerland. [Komajda, M.] European Soc Cardiol, Sophia Antipolis, France. [Mayer-Davis, E.] Amer Diabet Assoc, Alexandria, VA USA. [Mbanya, J. C.] Int Diabet Federat, Brussels, Belgium. [Sledge, G.] Amer Soc Clin Oncol, Alexandria, VA USA. RP Sacco, RL (reprint author), Amer Heart Assoc, Dallas, TX 75231 USA. EM rsacco@med.miami.edu NR 12 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 7 PY 2013 VL 382 IS 9895 BP E4 EP E5 DI 10.1016/S0140-6736(11)61477-3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 215WE UT WOS:000324240700001 PM 21933747 ER PT J AU Ma, S Hockings, C Anwari, K Kratina, T Fennell, S Lazarou, M Ryan, MT Kluck, RM Dewson, G AF Ma, Stephen Hockings, Colin Anwari, Khatira Kratina, Tobias Fennell, Stephanie Lazarou, Michael Ryan, Michael T. Kluck, Ruth M. Dewson, Grant TI Assembly of the Bak Apoptotic Pore A CRITICAL ROLE FOR THE BAK PROTEIN alpha 6 HELIX IN THE MULTIMERIZATION OF HOMODIMERS DURING APOPTOSIS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OUTER-MEMBRANE PROTEINS; CYTOCHROME-C; MITOCHONDRIAL APOPTOSIS; CONFORMATIONAL-CHANGES; PROAPOPTOTIC BAX; BH3 DOMAIN; CELL-DEATH; NATIVE ELECTROPHORESIS; OLIGOMERIZES BAK; ACTIVATION AB Bak and Bax are the essential effectors of the intrinsic pathway of apoptosis. Following an apoptotic stimulus, both undergo significant changes in conformation that facilitates their self-association to form pores in the mitochondrial outer membrane. However, the molecular structures of Bak and Bax oligomeric pores remain elusive. To characterize how Bak forms pores during apoptosis, we investigated its oligomerization under native conditions using blue native PAGE. We report that, in a healthy cell, inactive Bak is either monomeric or in a large complex involving VDAC2. Following an apoptotic stimulus, activated Bak forms BH3:groove homodimers that represent the basic stable oligomeric unit. These dimers multimerize to higher-order oligomers via a labile interface independent of both the BH3 domain and groove. Linkage of the alpha 6:alpha 6 interface is sufficient to stabilize higher-order Bak oligomers on native PAGE, suggesting an important role in the Bak oligomeric pore. Mutagenesis of the alpha 6 helix disrupted apoptotic function because a chimera of Bak with the alpha 6 derived from Bcl-2 could be activated by truncated Bid (tBid) and could form BH3:groove homodimers but could not form high molecular weight oligomers or mediate cell death. An alpha 6 peptide could block Bak function but did so upstream of dimerization, potentially implicating alpha 6 as a site for activation by BH3-only proteins. Our examination of native Bak oligomers indicates that the Bak apoptotic pore forms by the multimerization of BH3:groove homodimers and reveals that Bak alpha 6 is not only important for Bak oligomerization and function but may also be involved in how Bak is activated by BH3-only proteins. C1 [Ma, Stephen; Hockings, Colin; Anwari, Khatira; Kratina, Tobias; Fennell, Stephanie; Kluck, Ruth M.; Dewson, Grant] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia. [Ma, Stephen; Hockings, Colin; Kratina, Tobias; Fennell, Stephanie; Kluck, Ruth M.; Dewson, Grant] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia. [Lazarou, Michael] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Ryan, Michael T.] La Trobe Univ, Dept Biochem, La Trobe Inst Mol Sci, Melbourne, Vic 3086, Australia. RP Dewson, G (reprint author), Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3052, Australia. EM dewson@wehi.edu.au RI Kluck, Ruth/C-8413-2013; dewson, grant/C-7646-2013 OI Kluck, Ruth/0000-0002-7101-1925; dewson, grant/0000-0003-4251-8898 FU Victorian State Government Operational Infrastructure Support; Australian Government National Health and Medical Research Council Independent Research Institutes Support Scheme FX This work was supported by Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Support Scheme. NR 53 TC 31 Z9 31 U1 1 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 SEP 6 PY 2013 VL 288 IS 36 BP 26027 EP 26038 DI 10.1074/jbc.M113.490094 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302RT UT WOS:000330623300033 PM 23893415 ER PT J AU Rys-Sikora, KE Ketchum, CJ Star, RA AF Rys-Sikora, Krystyna E. Ketchum, Christian J. Star, Robert A. CA Kidney Res Natl Dialogue KRND TI Kidney Research National Dialogue Overview and Commentary SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article AB The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) asked the scientific community to formulate and prioritize research objectives to improve understanding of kidney function and disease. The Kidney Research National Dialogue welcomed all interested parties to submit, discuss, and prioritize ideas via an interactive website. More than 1600 participants posted approximately 300 ideas and assigned them to 12 topic areas (AKI, CKD, diabetic nephropathy, National Kidney Disease Education Program/translation, ESRD/dialysis, GN/inflammation, hypertension, normal biology/development/physiology, polycystic kidney disease, training, transplantation, other). This commentary provides an overview of the NIDDK's first experience with web-based strategic planning and addresses the broader issues of open access and cloud-sourcing technologies to capture input from a large, heterogeneous group of contributors. Discussions and findings for each topic will be published as separate, forthcoming commentaries. A final commentary will present cross-cutting themes and concluding remarks. The hope is that this series of commentaries constitutes a cohesive, integrated vision of future research opportunities to be pursued by the kidney research community and supported by the NIDDK. C1 [Rys-Sikora, Krystyna E.; Ketchum, Christian J.; Star, Robert A.; Kidney Res Natl Dialogue KRND] NIDDK, NIH, Bethesda, MD 20892 USA. RP Rys-Sikora, KE (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM Ryssikok@niddk.nih.gov NR 0 TC 6 Z9 6 U1 1 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD SEP 6 PY 2013 VL 8 IS 9 BP 1599 EP 1602 DI 10.2215/CJN.03590413 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 235GR UT WOS:000325705500020 PM 23788616 ER PT J AU Breyer, MD Coffman, TM Flessner, MF Fried, LF Harris, RC Ketchum, CJ Kretzler, M Nelson, RG Sedor, JR Susztak, K AF Breyer, Matthew D. Coffman, Thomas M. Flessner, Michael F. Fried, Linda F. Harris, Raymond C. Ketchum, Christian J. Kretzler, Matthias Nelson, Robert G. Sedor, John R. Susztak, Katalin CA KRND TI Diabetic Nephropathy: A National Dialogue SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID COMPLICATIONS; RISK AB The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue (KRND) asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease. Several high-priority objectives for diabetic nephropathy were identified in data and sample collection, hypothesis generation, hypothesis testing, and translation promotion. The lack of readily available human samples linked to comprehensive phenotypic, clinical, and demographic data remains a significant obstacle. With data and biological samples in place, several possibilities exist for using new technologies to develop hypotheses. Testing novel disease mechanisms with state-of-the-art tools should continue to be the foundation of the investigative community. Research must be translated to improve diagnosis and treatment of people. The objectives identified by the KRND provide the research community with future opportunities for improving the prevention, diagnosis, and treatment of diabetic nephropathy. C1 [Ketchum, Christian J.] NIDDK, NIH, Bethesda, MD 20892 USA. [Breyer, Matthew D.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Ketchum, CJ (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM chrisketchum@nih.gov FU NIDDK NIH HHS [P30 DK020572] NR 5 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD SEP 6 PY 2013 VL 8 IS 9 BP 1603 EP 1605 DI 10.2215/CJN.03640413 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 235GR UT WOS:000325705500021 PM 23788618 ER PT J AU Bonventre, JV Basile, D Liu, KD McKay, D Molitoris, BA Nath, KA Nickolas, TL Okusa, MD Palevsky, PM Schnellmann, R Rys-Sikora, K Kimmel, PL Star, RA AF Bonventre, Joseph V. Basile, David Liu, Kathleen D. McKay, Dianne Molitoris, Bruce A. Nath, Karl A. Nickolas, Thomas L. Okusa, Mark D. Palevsky, Paul M. Schnellmann, Rick Rys-Sikora, Krystyna Kimmel, Paul L. Star, Robert A. CA KRND TI AKI: A Path Forward SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE KIDNEY INJURY AB The Kidney Research National Dialogue, supported by the National Institute of Diabetes and Digestive and Kidney Diseases, asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease. High-priority objectives for AKI were identified, including enhancing training and collaborative opportunities, improving phenotyping and development of clinical tools, expanding our understanding of the pathophysiology and interaction between injury and reparative processes, and identifying determinants of long-term outcomes. Research in animal models must be translated to improve diagnosis and treatment of patients. The objectives identified by the Kidney Research National Dialogue provide the research community with future opportunities for improving the prevention, diagnosis, and treatment of people with AKI. C1 [Palevsky, Paul M.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Boulevard, Bethesda, MD 20892 USA. EM kimmelp@extra.niddk.nih.gov OI Palevsky, Paul/0000-0002-7334-5400 FU NIDDK NIH HHS [R01 DK072381, R01 DK063114, R01 DK062324, R01 DK091136, R37 DK039773] NR 3 TC 16 Z9 16 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD SEP 6 PY 2013 VL 8 IS 9 BP 1606 EP 1608 DI 10.2215/CJN.06040613 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 235GR UT WOS:000325705500022 PM 23868899 ER PT J AU Lu, Y Wang, WM Wang, JC Yang, CZ Mao, HM Fu, XL Wu, YL Cai, JP Han, JY Xu, ZG Zhuang, ZP Liu, ZM Hu, H Chen, BG AF Lu, Ying Wang, Weimin Wang, Junchen Yang, Chunzhang Mao, Huiming Fu, Xuelian Wu, Yanling Cai, Jingping Han, Junyi Xu, Zengguang Zhuang, Zhengping Liu, Zhongmin Hu, Hai Chen, Bingguan TI Overexpression of Arginine Transporter CAT-1 Is Associated with Accumulation of L-Arginine and Cell Growth in Human Colorectal Cancer Tissue SO PLOS ONE LA English DT Article ID NITRIC-OXIDE; ARGININOSUCCINATE SYNTHETASE; IN-VITRO; PROGRESSION; DEIMINASE; DISEASE; DEPRIVATION; POLYAMINES; CITRULLINE; CHEMOPREVENTION AB We previously showed that L-arginine (Arg) accumulates in colorectal cancer tissues. The aim of this study was to investigate the mechanism by which Arg accumulates and determine its biological significance. The concentration of Arg and Citrulline (Cit) in sera and tumor tissues from colorectal cancer (CRC) patients was analyzed by high-performance liquid chromatography (HPLC). The expression of Arg transporters was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis of tissue microarray. We also transfected the colon cancer cell line HCT-116 with siRNA specific for the Arg transporter CAT-1 and measured the induction of apoptosis by flow cytometry and cell proliferation by MTT assay. Consistent with our previous results, serum Arg and Cit concentrations in colorectal cancer patients were significantly lower than those in normal volunteers, while Arg and Cit concentrations in colorectal cancer tissues were significantly higher than in matched adjacent normal colon tissues. Quantitative RT-PCR showed that the CAT-1 gene was highly overexpressed in 70.5% of colorectal cancer tissue samples relative to adjacent normal colon tissues in all 122 patients with colorectal cancer. Immunohistochemical analysis of tissue microarray confirmed that the expression of CAT-1 was higher in all 25 colorectal cancer tissues tested. CAT-1 siRNA significantly induced apoptosis of HCT-116 cells and subsequently inhibited cell growth by 20-50%. Our findings indicate that accumulation of L-Arg and Cit and cell growth in colorectal cancer tissues is associated with over-expression of the Arg transporter gene CAT-1. Our results may be useful for the development of molecular diagnostic tools and targeted therapy for colorectal cancer. C1 [Lu, Ying; Wang, Junchen; Mao, Huiming; Fu, Xuelian; Wu, Yanling; Han, Junyi; Xu, Zengguang; Liu, Zhongmin; Hu, Hai; Chen, Bingguan] Tongji Univ, Clin Translat Med Res Ctr, Shanghai East Hosp, Sch Med, Shanghai 200092, Peoples R China. [Wang, Weimin; Cai, Jingping] Second Mil Med Univ, Changzheng Hosp, Dept Surg, Shanghai, Peoples R China. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hu, H (reprint author), Tongji Univ, Clin Translat Med Res Ctr, Shanghai East Hosp, Sch Med, Shanghai 200092, Peoples R China. EM huhailc@sina.com; chen.bingguan@seimc.com.cn FU National Natural Science Foundation of China [81172157] FX This research was supported by grants from the National Natural Science Foundation of China (81172157) to Bingguan Chen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 4 Z9 5 U1 2 U2 10 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 SEP 6 PY 2013 VL 8 IS 9 AR e73866 DI 10.1371/journal.pone.0073866 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 224BO UT WOS:000324856500063 PM 24040099 ER PT J AU Yoo, MH Carlson, BA Gladyshev, VN Hatfield, DL AF Yoo, Min-Hyuk Carlson, Bradley A. Gladyshev, Vadim N. Hatfield, Dolph L. TI Abrogated Thioredoxin System Causes Increased Sensitivity to TNF-alpha-Induced Apoptosis via Enrichment of p-ERK 1/2 in the Nucleus SO PLOS ONE LA English DT Article ID SIGNAL-REGULATED KINASE; NF-KAPPA-B; MAMMALIAN THIOREDOXIN; REDOX HOMEOSTASIS; CANCER-THERAPY; BREAST-CANCER; REDUCTASE; PROTEIN; CELLS; ACTIVATION AB Thioredoxin (Trx) and thioredoxin reductase 1 (TR1) are among the major redox regulators in mammalian cells and have a wide variety of roles, including removal of intracellular reactive oxygen species (ROS) and prevention of cell death. Tumor necrosis factor-alpha (TNF-alpha) induces cancer cell death. Although ROS have been proposed to participate in this process, the role of the thioredoxin system in TNF-alpha stimulated cell death remains unclear. We investigated the possibility that the thioredoxin system protects against TNF-alpha-induced cancer cell death by examining whether TR1/Trx1 status controls TNF-alpha-induced apoptosis in EMT6 murine breast cancer cells. TR1-deficient cells were more sensitive to TNF-alpha than control cells. Increased sensitivity to TNF-alpha was most pronounced in Trx1-deficient cells. TNF-alpha-induced nuclear localization of phosphorylated ERK 1/2 (p-ERK 1/2) correlated with increased apoptosis in TR1- and Trx1-deficient cells, suggesting a pro-apoptotic role for nuclear p-ERK 1/2 in TNF-alpha-induced apoptosis. In addition, phosphoinositide 3-kinase (PI3K) inhibition dramatically reduced TNF-alpha-stimulated apoptosis and nuclear localization of p-ERK 1/2. In contrast, inhibition of ROS, MEK, JNK, or p38 did not significantly alter p-ERK 1/2 localization or apoptosis in TR1- and Trx1-deficient cells compared to control cells. Further, NF-kappa B p65 localization was not changed in TR1- and Trx1-deficient cells in response to TNF-alpha relative to control cells. Our data suggest that the thioredoxin system plays a critical role in protecting against TNF-alpha-induced apoptosis by regulating the levels of nuclear p-ERK 1/2 in a PI3K-dependent manner. C1 [Yoo, Min-Hyuk; Carlson, Bradley A.; Hatfield, Dolph L.] NIH, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA USA. RP Hatfield, DL (reprint author), NIH, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health FX This work was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health (DLH) and by National Institutes of Health grants (VNG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 6 Z9 10 U1 0 U2 10 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 SEP 6 PY 2013 VL 8 IS 9 AR UNSP e71427 DI 10.1371/journal.pone.0071427 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 224BO UT WOS:000324856500006 PM 24039713 ER PT J AU Green, JA Yang, J Grati, M Kachar, B Bhat, MA AF Green, James A. Yang, Jun Grati, M'hamed Kachar, Bechara Bhat, Manzoor A. TI Whirlin, a cytoskeletal scaffolding protein, stabilizes the paranodal region and axonal cytoskeleton in myelinated axons SO BMC NEUROSCIENCE LA English DT Article DE Myelinated axons; Axonal domains; Paranodal domain; Axonal cytoskeleton; Whirlin ID CENTRAL-NERVOUS-SYSTEM; GLIAL INTERACTIONS; MYOSIN-XVA; JUNCTIONS; ORGANIZATION; NEUROFASCIN; STEREOCILIA; DOMAINS; REQUIRES; DIFFERENTIATION AB Background: Myelinated axons are organized into distinct subcellular and molecular regions. Without proper organization, electrical nerve conduction is delayed, resulting in detrimental physiological outcomes. One such region is the paranode where axo-glial septate junctions act as a molecular fence to separate the sodium (Na+) channel-enriched node from the potassium (K+) channel-enriched juxtaparanode. A significant lack of knowledge remains as to cytoskeletal proteins which stabilize paranodal domains and underlying cytoskeleton. Whirlin (Whrn) is a PDZ domain-containing cytoskeletal scaffold whose absence in humans results in Usher Syndromes or variable deafness-blindness syndromes. Mutant Whirlin (Whrn) mouse model studies have linked such behavioral deficits to improper localization of critical transmembrane protein complexes in the ear and eye. Until now, no reports exist about the function of Whrn in myelinated axons. Results: RT-PCR and immunoblot analyses revealed expression of Whrn mRNA and Whrn full-length protein, respectively, in several stages of central and peripheral nervous system development. Comparing wild-type mice to Whrn knockout (Whrn(-/-)) mice, we observed no significant differences in the expression of standard axonal domain markers by immunoblot analysis but observed and quantified a novel paranodal compaction phenotype in 4 to 8 week-old Whrn(-/-) nerves. The paranodal compaction phenotype and associated cytoskeletal disruption was observed in Whrn(-/-) mutant sciatic nerves and spinal cord fibers from early (2 week-old) to late (1 year-old) stages of development. Light and electron microscopic analyses of Whrn knockout mice reveal bead-like swellings in cerebellar Purkinje axons containing mitochondria and vesicles by both. These data suggest that Whrn plays a role in proper cytoskeletal organization in myelinated axons. Conclusions: Domain organization in myelinated axons remains a complex developmental process. Here we demonstrate that loss of Whrn disrupts proper axonal domain organization. Whrn likely contributes to the stabilization of paranodal myelin loops and axonal cytoskeleton through yet unconfirmed cytoskeletal proteins. Paranodal abnormalities are consistently observed throughout development (2 wk-1 yr) and similar between central and peripheral nervous systems. In conclusion, our observations suggest that Whrn is not required for the organization of axonal domains, but once organized, Whrn acts as a cytoskeletal linker to ensure proper paranodal compaction and stabilization of the axonal cytoskeleton in myelinated axons. C1 [Green, James A.; Bhat, Manzoor A.] Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Yang, Jun] Univ Utah, Moran Eye Ctr & Neurobiol & Anat, Salt Lake City, UT 84132 USA. [Grati, M'hamed; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Bhat, Manzoor A.] Univ Texas San Antonio, Sch Med, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. RP Bhat, MA (reprint author), Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. EM bhatm@uthscsa.edu FU NIH-NCI [P30 CA54174]; NIH-NIA [P30 AG013319]; NIH [GM63074, GM063074-07S1]; UNC-CH Medical Scientist Training Program [T32 GM008719]; [NIH-NIA P01AG19316] FX We are grateful to Thomas Friedman for generously sharing antibodies and reagents. We thank Alaine Pribisko for conducting the electrophysiology on sciatic nerves. We thank Barbara Hunter in the UTHSCSA electron microscopy core for her help in preparing the tissues for TEM. We thank Courtney Thaxton for comments on the manuscript and helpful discussions. We thank Vladimir Ghukasyan (UNC at Chapel Hill, NC) and Exing Wang (UTHSCSA, San Antonio, TX) for help with microscopy. The confocal microscopy cores were supported by Grants: NIH-NCI P30 CA54174 (San Antonio Cancer Institute), NIH-NIA P30 AG013319 (Nathan Shock Center) and (NIH-NIA P01AG19316). This work was supported by NIH grants GM63074 (MAB), GM063074-07S1 (JRG/MAB), and UNC-CH Medical Scientist Training Program Grant T32 GM008719 (JRG). NR 31 TC 10 Z9 10 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD SEP 6 PY 2013 VL 14 AR 96 DI 10.1186/1471-2202-14-96 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 214MC UT WOS:000324136500002 PM 24011083 ER PT J AU Moss, B AF Moss, Bernard TI Reflections on the early development of poxvirus vectors SO VACCINE LA English DT Article DE Recombinant vaccines; Vaccinia virus; Vaccine vectors; Recombinant DNA; DNA cloning ID RECOMBINANT VACCINIA VIRUS; GENETICALLY-ENGINEERED POXVIRUSES; BACTERIAL ARTIFICIAL CHROMOSOME; PRIME-BOOST IMMUNIZATION; THYMIDINE KINASE GENE; HERPES-SIMPLEX-VIRUS; OPEN READING FRAME; ESCHERICHIA-COLI; INFLUENZA-VIRUS; HEPATITIS-B AB Poxvirus expression vectors were described in 1982 and quickly became widely used for vaccine development as well as research in numerous fields. Advantages of the vectors include simple construction, ability to accommodate large amounts of foreign DNA and high expression levels. Numerous poxvirus-based veterinary vaccines are currently in use and many others are in human clinical trials. The early reports of poxvirus vectors paved the way for and stimulated the development of other viral vectors and recombinant DNA vaccines. Published by Elsevier Ltd. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS [ZIA AI000416-29] NR 59 TC 14 Z9 14 U1 0 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 6 PY 2013 VL 31 IS 39 SI SI BP 4220 EP 4222 DI 10.1016/j.vaccine.2013.03.042 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 218SN UT WOS:000324452900002 PM 23583893 ER PT J AU Reich, NG Shrestha, S King, AA Rohani, P Lessler, J Kalayanarooj, S Yoon, IK Gibbons, RV Burke, DS Cummings, DAT AF Reich, Nicholas G. Shrestha, Sourya King, Aaron A. Rohani, Pejman Lessler, Justin Kalayanarooj, Siripen Yoon, In-Kyu Gibbons, Robert V. Burke, Donald S. Cummings, Derek A. T. TI Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE dengue; infectious disease modelling; cross-protection; time-series models ID ANTIBODY-DEPENDENT ENHANCEMENT; HEMORRHAGIC-FEVER; VIRUS SEROTYPES; IMMUNOLOGICAL DETERMINANTS; CONCURRENT INFECTIONS; ACQUIRED-IMMUNITY; TRANSMISSION; BANGKOK; MODELS; NEUTRALIZATION AB Dengue, a mosquito-borne virus of humans, infects over 50 million people annually. Infection with any of the four dengue serotypes induces protective immunity to that serotype, but does not confer long-term protection against infection by other serotypes. The immunological interactions between serotypes are of central importance in understanding epidemiological dynamics and anticipating the impact of dengue vaccines. We analysed a 38-year time series with 12 197 serotyped dengue infections from a hospital in Bangkok, Thailand. Using novel mechanistic models to represent different hypothesized immune interactions between serotypes, we found strong evidence that infection with dengue provides substantial short-term cross-protection against other serotypes (approx. 1-3 years). This is the first quantitative evidence that short-term cross-protection exists since human experimental infection studies performed in the 1950s. These findings will impact strategies for designing dengue vaccine studies, future multi-strain modelling efforts, and our understanding of evolutionary pressures in multi-strain disease systems. C1 [Reich, Nicholas G.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01002 USA. [Reich, Nicholas G.; Lessler, Justin; Cummings, Derek A. T.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Shrestha, Sourya; King, Aaron A.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Shrestha, Sourya; King, Aaron A.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [King, Aaron A.; Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kalayanarooj, Siripen] Queen Sirikit Natl Inst Child Hlth, Bangkok, Thailand. [Yoon, In-Kyu; Gibbons, Robert V.] Armed Forces Res Inst Med Sci, Dept Virol, Bangkok 10400, Thailand. [Burke, Donald S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. RP Reich, NG (reprint author), Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01002 USA. EM nick@schoolph.umass.edu RI King, Aaron/B-8092-2012; OI King, Aaron/0000-0001-6159-3207; Shrestha, Sourya/0000-0002-6106-6834; Lessler, Justin/0000-0002-9741-8109; /0000-0002-5704-8094 FU National Institute of General Medical Sciences [R01GM090204, 1U54GM088491-0109]; Bill and Melinda Gates Foundation Vaccine Modeling Initiative; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Oceanic and Atmospheric Administration [NA08NOS4730321] FX N.G.R., D.S.D. and D.A.T.C. were supported by the National Institute of General Medical Sciences (Award no. R01GM090204 and Award no. 1U54GM088491-0109). D.A.T.C. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. D.A.T.C., D.S.B. and P.R. were supported by a grant from the Bill and Melinda Gates Foundation Vaccine Modeling Initiative. A.A.K. and P.R. acknowledge the support of the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. A.A.K. was also supported by the National Oceanic and Atmospheric Administration (grant no. NA08NOS4730321). NR 47 TC 53 Z9 53 U1 3 U2 40 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD SEP 6 PY 2013 VL 10 IS 86 AR 20130414 DI 10.1098/rsif.2013.0414 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 180RX UT WOS:000321614300009 PM 23825116 ER PT J AU Shrestha, S Foxman, B Dawid, S Aiello, AE Davis, BM Berus, J Rohani, P AF Shrestha, Sourya Foxman, Betsy Dawid, Suzanne Aiello, Allison E. Davis, Brian M. Berus, Joshua Rohani, Pejman TI Time and dose-dependent risk of pneumococcal pneumonia following influenza: a model for within-host interaction between influenza and Streptococcus pneumoniae SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE influenza-pneumococcal interaction; within-host model; influenza; pneumococcus; mathematical model ID ACTIVATING-FACTOR RECEPTOR; HONG KONG INFLUENZA; VIRUS-INFECTION; BACTERIAL PNEUMONIA; STAPHYLOCOCCUS-AUREUS; ALVEOLAR MACROPHAGES; INCREASED SUSCEPTIBILITY; PULMONARY INFECTION; PANDEMIC INFLUENZA; VIRULENCE FACTORS AB A significant fraction of seasonal and in particular pandemic influenza deaths are attributed to secondary bacterial infections. In animal models, influenza virus predisposes hosts to severe infection with both Streptococcus pneumoniae and Staphylococcus aureus. Despite its importance, the mechanistic nature of the interaction between influenza and pneumococci, its dependence on the timing and sequence of infections as well as the clinical and epidemiological consequences remain unclear. We explore an immune-mediated model of the viral-bacterial interaction that quantifies the timing and the intensity of the interaction. Taking advantage of the wealth of knowledge gained from animal models, and the quantitative understanding of the kinetics of pathogen-specific immunological dynamics, we formulate a mathematical model for immune-mediated interaction between influenza virus and S. pneumoniae in the lungs. We use the model to examine the pathogenic effect of inoculum size and timing of pneumococcal invasion relative to influenza infection, as well as the efficacy of antivirals in preventing severe pneumococcal disease. We find that our model is able to capture the key features of the interaction observed in animal experiments. The model predicts that introduction of pneumococcal bacteria during a 4-6 day window following influenza infection results in invasive pneumonia at significantly lower inoculum size than in hosts not infected with influenza. Furthermore, we find that antiviral treatment administered later than 4 days after influenza infection was not able to prevent invasive pneumococcal disease. This work provides a quantitative framework to study interactions between influenza and pneumococci and has the potential to accurately quantify the interactions. Such quantitative understanding can form a basis for effective clinical care, public health policies and pandemic preparedness. C1 [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Shrestha, Sourya; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Berus, Joshua] Univ Michigan, Undergrad Res Opportun Program, Ann Arbor, MI 48109 USA. [Foxman, Betsy; Aiello, Allison E.; Davis, Brian M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Aiello, Allison E.; Davis, Brian M.] Univ Michigan, Sch Publ Hlth, Ctr Social Epidemiol & Populat, Ann Arbor, MI 48109 USA. [Dawid, Suzanne] Univ Michigan, Sch Med, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shrestha, S (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM sourya@umich.edu RI Foxman, Betsy/E-1836-2015; OI Berus, Joshua/0000-0003-0473-125X; Shrestha, Sourya/0000-0002-6106-6834; Foxman, Betsy/0000-0001-6682-238X FU Pfizer, Inc.; Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation; RAPIDD Program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Undergraduate Research Opportunity Program, University of Michigan FX This study was supported in part through an investigator-initiated research grant from Pfizer, Inc. P.R. received support from the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation and the RAPIDD Program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. J.B. was supported by an Undergraduate Research Opportunity Program, University of Michigan. The authors are grateful to Andreas Handel, the King and Rohani laboratories and Suzanne Bradley for comments. NR 70 TC 6 Z9 7 U1 1 U2 28 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD SEP 6 PY 2013 VL 10 IS 86 AR 20130233 DI 10.1098/rsif.2013.0233 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 180RX UT WOS:000321614300001 PM 23825111 ER PT J AU Yu, HC Sloan, JL Scharer, G Brebner, A Quintana, AM Achilly, NP Manoli, I Coughlin, CR Geiger, EA Schneck, U Watkins, D Suormala, T Van Hove, JLK Fowler, B Baumgartner, MR Rosenblatt, DS Venditti, CP Shaikh, TH AF Yu, Hung-Chun Sloan, Jennifer L. Scharer, Gunter Brebner, Alison Quintana, Anita M. Achilly, Nathan P. Manoli, Irini Coughlin, Curtis R., II Geiger, Elizabeth A. Schneck, Una Watkins, David Suormala, Terttu Van Hove, Johan L. K. Fowler, Brian Baumgartner, Matthias R. Rosenblatt, David S. Venditti, Charles P. Shaikh, Tamim H. TI An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID VITAMIN-B-12 METABOLISM; METHYLMALONIC ACIDURIA; CELL-FUNCTION; HCF-1; IDENTIFICATION; ASSOCIATION; PROTEIN; EXPRESSION; PROMOTERS; COMPLEX AB Derivatives of vitamin B-12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype. C1 [Yu, Hung-Chun; Scharer, Gunter; Quintana, Anita M.; Coughlin, Curtis R., II; Geiger, Elizabeth A.; Schneck, Una; Van Hove, Johan L. K.; Shaikh, Tamim H.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Sloan, Jennifer L.; Achilly, Nathan P.; Manoli, Irini; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Scharer, Gunter; Coughlin, Curtis R., II; Van Hove, Johan L. K.; Shaikh, Tamim H.] Univ Colorado, Sch Med, Genet Sect, Aurora, CO 80045 USA. [Scharer, Gunter; Shaikh, Tamim H.] Univ Colorado, Sch Med, Colorado Intellectual & Dev Disabil Res Ctr, Aurora, CO 80045 USA. [Brebner, Alison; Watkins, David; Rosenblatt, David S.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Suormala, Terttu; Fowler, Brian; Baumgartner, Matthias R.] Univ Childrens Hosp, Div Metab, CH-8032 Zurich, Switzerland. [Suormala, Terttu; Fowler, Brian; Baumgartner, Matthias R.] Univ Childrens Hosp, Childrens Res Ctr, CH-8032 Zurich, Switzerland. [Baumgartner, Matthias R.] Univ Zurich, Zurich Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland. RP Shaikh, TH (reprint author), Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. EM tamim.shaikh@ucdenver.edu OI Manoli, Irini/0000-0003-1543-2941; Coughlin II, Curtis/0000-0002-3545-7903; Baumgartner, Matthias R./0000-0002-9270-0826; Yu, Hung-Chun/0000-0002-4980-8508 FU National Institutes of Health grant [GM081519]; Colorado Intellectual and Developmental Disabilities Research Center; Pediatrics Student Research Program at Children's Hospital Colorado; Intramural Research Program of the National Human Genome Research Institute; Canadian Institutes of Health Research [CIHR-M08-15078]; Swiss National Science Foundation [31003A_138521]; [T32MH015442] FX We are grateful to Renata Gallagher, Janet Thomas, Laura Pickler, and Cynthia Freehauf for their input and advice on the clinical aspects of this project and for their contribution to the care of affected individuals, to Leah Ladores for biochemical and complementation analysis, and to the referring physicians. This work was supported in part by a National Institutes of Health grant (GM081519) to T.H.S. and funds and services from the Colorado Intellectual and Developmental Disabilities Research Center. A.Q. was supported by a grant for postdoctoral research training (T32MH015442), and U.S. was supported by the 2012 Pediatrics Student Research Program at Children's Hospital Colorado. J.L.S., N.P.A., I.M., and C.P.V. were supported by the Intramural Research Program of the National Human Genome Research Institute. D.S.R. was supported by an operating grant from the Canadian Institutes of Health Research (CIHR-M08-15078). M.R.B and B.F. were supported by a grant from the Swiss National Science Foundation (31003A_138521). NR 36 TC 33 Z9 34 U1 0 U2 7 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 SEP 5 PY 2013 VL 93 IS 3 BP 506 EP 514 DI 10.1016/j.ajhg.2013.07.022 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 297QB UT WOS:000330268900009 PM 24011988 ER PT J AU Franceschini, N Fox, E Zhang, Z Edwards, TL Nalls, MA Sung, YJ Tayo, BO Sun, YV Gottesman, O Adeyemo, A Johnson, AD Young, JH Rice, K Duan, Q Chen, F Li, Y Tang, H Fornage, M Keene, KL Andrews, JS Smith, JA Fau, JD Guangfa, Z Guo, W Liu, Y Murray, SS Musani, SK Srinivasan, S Edwards, DRV Wang, H Becker, LC Bovet, P Bochud, M Broecke, U Burnier, M Carty, C Chasman, DI Ehret, G Chen, WM Chen, G Chen, W Ding, J Dreisbach, AW Evans, MK Guo, X Garcia, ME Jensen, R Keller, ME Lettre, G Lotay, V Martin, LW Moore, JH Morrison, AC Mosley, TH Ogunniyi, A Palmas, W Papanicolaou, G Penman, A Polak, JF Ridker, PM Salako, B Singleton, AB Shriner, D Taylor, KD Vasan, R Wiggins, K Williams, SM Yanek, LR Zhao, W Zonderman, AB Becker, DM Berenson, G Boerwinkle, E Bottinger, E Cushman, M Eaton, C Nyberg, F Heiss, G Hirschhron, JN Howard, VJ Karczewsk, KJ Lanktree, MB Liu, K Liu, YM Loos, R Margolis, K Snyder, M Psaty, BM Schork, NJ Weir, DR Rotimi, CN Sale, MM Harris, T Kardia, SLR Hunt, SC Arnett, D Redline, S Cooper, RS Risch, NJ Rao, DC Rotter, JI Chakravarti, A Reiner, AP Levy, D Keating, BJ Zhu, XO AF Franceschini, Nora Fox, Ervin Zhang, Zhaogong Edwards, Todd L. Nalls, Michael A. Sung, Yun Ju Tayo, Bamidele O. Sun, Yan V. Gottesman, Omri Adeyemo, Adebawole Johnson, Andrew D. Young, J. Hunter Rice, Ken Duan, Qing Chen, Fang Li, Yun Tang, Hua Fornage, Myriam Keene, Keith L. Andrews, Jeanette S. Smith, Jennifer A. Fau, Jessica D. Guangfa, Zhang Guo, Wei Liu, Yu Murray, Sarah S. Musani, Solomon K. Srinivasan, Sathanur Edwards, Digna R. Velez Wang, Heming Becker, Lewis C. Bovet, Pascal Bochud, Murielle Broecke, Ulrich Burnier, Michel Carty, Cara Chasman, Daniel I. Ehret, Georg Chen, Wei-Min Chen, Guanjie Chen, Wei Ding, Jingzhong Dreisbach, Albert W. Evans, Michele K. Guo, Xiuqing Garcia, Melissa E. Jensen, Rich Keller, Margaux E. Lettre, Guillaume Lotay, Vaneet Martin, Lisa W. Moore, Jason H. Morrison, Alanna C. Mosley, Thomas H. Ogunniyi, Adesola Palmas, Walter Papanicolaou, George Penman, Alan Polak, Joseph F. Ridker, Paul M. Salako, Babatunde Singleton, Andrew B. Shriner, Daniel Taylor, Kent D. Vasan, Ramachandran Wiggins, Kerni Williams, Scott M. Yanek, Lisa R. Zhao, Wei Zonderman, Alan B. Becker, Diane M. Berenson, Gerald Boerwinkle, Eric Bottinger, Erwin Cushman, Mary Eaton, Charles Nyberg, Fredrik Heiss, Gerardo Hirschhron, Joel N. Howard, Virginia J. Karczewsk, Konrad J. Lanktree, Matthew B. Liu, Kiang Liu, Yongmei Loos, Ruth Margolis, Karen Snyder, Michael Psaty, Bruce M. Schork, Nicholas J. Weir, David R. Rotimi, Charles N. Sale, Michele M. Harris, Tamara Kardia, Sharon L. R. Hunt, Steven C. Arnett, Donna Redline, Susan Cooper, Richard S. Risch, Neil J. Rao, D. C. Rotter, Jerome I. Chakravarti, Aravinda Reiner, Alex P. Levy, Daniel Keating, Brendan J. Zhu, Xiaofeng CA Asian Genetic Epidemiology Network TI Genome-wide Association Analysis of Blood-Pressure Traits in African-Ancestry Individuals Reveals Common Associated Genes in African and Non-African Populations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; INCIDENT HYPERTENSION; COMPLEX TRAITS; EAST ASIANS; LOCI; VARIANTS; RISK; METAANALYSIS; ANNOTATION AB High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 x 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability. C1 [Franceschini, Nora; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Musani, Solomon K.; Dreisbach, Albert W.; Mosley, Thomas H.; Penman, Alan] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39126 USA. [Zhang, Zhaogong; Guo, Wei; Wang, Heming; Zhu, Xiaofeng] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Zhang, Zhaogong] Heilongjiang Univ, Sch Comp Sci & Technol, Harbin 150080, Peoples R China. [Edwards, Todd L.; Williams, Scott M.] Vanderbilt Univ, Dept Med, Vanderbilt Epidemiol Ctr, Ctr Human Genet Res, Nashville, TN 37212 USA. [Sung, Yun Ju; Rao, D. C.] Natl Inst Aging, Natl Inst Hlth, Neurogenet Lab, Bethesda, MD 20892 USA. [Tayo, Bamidele O.; Cooper, Richard S.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Sun, Yan V.] Loyola Univ Chicago Stritch, Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Gottesman, Omri; Lotay, Vaneet; Bottinger, Erwin; Loos, Ruth] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Adeyemo, Adebawole; Chen, Guanjie; Shriner, Daniel; Rotimi, Charles N.] Charles Bronfman Inst Personalized Med, Mt Sinai Sch Med, New York, NY 10029 USA. [Johnson, Andrew D.; Levy, Daniel] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Young, J. Hunter; Yanek, Lisa R.; Becker, Diane M.] Natl Heart Lung & Blood Inst, Ctr Populat Studies, Framingham, MA 01702 USA. [Rice, Ken] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Duan, Qing] Univ Washington, Dept Biostat, Seattle, WA 98101 USA. [Chen, Fang; Chen, Wei-Min] Univ N Carolina, Bioinformat & Computat Biol Program, Chapel Hill, NC 27599 USA. [Li, Yun] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Tang, Hua; Karczewsk, Konrad J.; Snyder, Michael] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Fornage, Myriam] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Keene, Keith L.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA. [Andrews, Jeanette S.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Wake Forest Sch Med, Dept Biostat Sci Publ Hlth Sci, Winston Salem, NC 27157 USA. [Fau, Jessica D.; Weir, David R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Guangfa, Zhang; Schork, Nicholas J.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA. [Liu, Yu] Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Murray, Sarah S.; Srinivasan, Sathanur; Chen, Wei; Berenson, Gerald] Scripps Res Inst, La Jolla, CA 92037 USA. [Edwards, Digna R. Velez] Case Western Reserve Univ, Ctr Prote & Bioinformat, Cleveland, OH 44106 USA. [Becker, Lewis C.] Tulane Univ, Tulane Ctr Cardiovasc Hlth, New Orleans, LA 70112 USA. [Bovet, Pascal; Bochud, Murielle] Vanderbilt Univ, Dept Obstet & Gynecol, Vanderbilt Epidemiol Ctr, Ctr Human Genet Res, Nashville, TN 37212 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. Univ Lausanne Hosp, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland. [Bovet, Pascal] Minist Hlth, Victoria, Seychelles. [Broecke, Ulrich] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Burnier, Michel] Univ Lausanne Hosp, Serv Nephrol & Hypertens, CH-1010 Lausanne, Switzerland. [Carty, Cara] Univ Lausanne Hosp, Serv Nephrol & Hypertens, CH-1010 Lausanne, Switzerland. [Chasman, Daniel I.; Ridker, Paul M.] Fred Hutchinson Canc Res Ctr, Dept Biostat & Biomath, Seattle, WA 98109 USA. [Ehret, Georg] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ehret, Georg; Chakravarti, Aravinda] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland. [Ding, Jingzhong] Johns Hopkins Univ, Sch Med, McKusickNathans Inst Genet Med, Ctr Complex Dis Gen, Baltimore, MD 21205 USA. [Evans, Michele K.] Wake Forest Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. [Guo, Xiuqing; Taylor, Kent D.; Rotter, Jerome I.] Natl Inst Aging, Natl Inst Hlth, Hlth Dispar Unit, Bethesda, MD 20892 USA. [Garcia, Melissa E.] Inst Med Genet, Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Jensen, Rich; Wiggins, Kerni; Psaty, Bruce M.] Natl Inst Aging, Intramural Res Program, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Keller, Margaux E.] Univ Washington, Dept Med, Cardiovascular Hlth Res Unit, Epidemiol & Hlth Serv, Seattle, WA 98101 USA. [Lettre, Guillaume] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Moore, Jason H.] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Moore, Jason H.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Morrison, Alanna C.; Salako, Babatunde; Boerwinkle, Eric] George Washington Univ, Cardiovasc Inst, Washington, DC 20037 USA. [Ogunniyi, Adesola] Dartmouth Coll, Geisel Sch Med, Dept Genet, Inst Quantitat Biomed Sci, Hanover, NH 03756 USA. [Palmas, Walter] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Inst Quantitat Biomed Sci, Hanover, NH 03756 USA. [Papanicolaou, George] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Polak, Joseph F.] Univ Ibadan, Dept Med, Ibadan, Oyo, Nigeria. [Vasan, Ramachandran] Columbia Univ, Dept Med, New York, NY 10032 USA. [Zonderman, Alan B.] NHLBI, NIH, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Cushman, Mary] Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA. [Eaton, Charles] Boston Univ, Sch Med, Boston, MA 02118 USA. [Nyberg, Fredrik] NIA, NIH, Lab Personal & Cognit, Bethesda, MD 20892 USA. [Hirschhron, Joel N.] Univ Vermont, Coll Med, Burlington, VT 05446 USA. Brown Univ, Alpert Med Sch, Dept Family Med & Epidemiol, Providence, RI 02912 USA. Global Epidemiol AstraZeneca Res & Dev, SE-43183 Molndal, Sweden. [Hirschhron, Joel N.] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02141 USA. [Hirschhron, Joel N.] MIT, Cambridge, MA 02141 USA. [Hirschhron, Joel N.] Boston Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Hirschhron, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Howard, Virginia J.; Arnett, Donna] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Lanktree, Matthew B.] Univ Western Ontario, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada. [Liu, Kiang] Northwestern Univ Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent Publ Hlth Sci, Winston Salem, NC 27157 USA. [Margolis, Karen] Hennepin Cty Med Ctr, Div Clin Epidemiol, Minneapolis, MN 55415 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Sale, Michele M.] Univ Virginia Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Harris, Tamara] Natl Inst Aging, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hunt, Steven C.] Univ Utah, Cardiovasc Genet, Salt Lake City, UT 84132 USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Risch, Neil J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA. [Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci, Seattle, WA 98109 USA. [Levy, Daniel] Framingham Heart Study Natl Heart Lung & Blood In, Framingham, MA 01702 USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Keating, Brendan J.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM noraf@unc.edu; xiaofeng.zhu@case.edu RI Singleton, Andrew/C-3010-2009; Bovet, Pascal/F-4477-2011; Bochud, Murielle/A-3981-2010; Johnson, Andrew/G-6520-2013; OI Smith, Jennifer/0000-0002-3575-5468; Martin, Lisa Warsinger/0000-0003-4352-0914; Ramachandran, Vasan/0000-0001-7357-5970; Adeyemo, Adebowale/0000-0002-3105-3231; Zonderman, Alan B/0000-0002-6523-4778; Bovet, Pascal/0000-0002-0242-4259; Bochud, Murielle/0000-0002-5727-0218; Lanktree, Matthew/0000-0002-5750-6286 FU NCATS NIH HHS [UL1 TR000124]; NHGRI NIH HHS [R01 HG003054]; NHLBI NIH HHS [R01 HL105756]; NIA NIH HHS [U01 AG009740]; NIDDK NIH HHS [P30 DK063491]; NIGMS NIH HHS [P20 GM103534]; NIMHD NIH HHS [P20 MD006899] NR 41 TC 51 Z9 52 U1 3 U2 27 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 SEP 5 PY 2013 VL 93 IS 3 BP 545 EP 554 DI 10.1016/j.ajhg.2013.07.010 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 297QB UT WOS:000330268900014 PM 23972371 ER PT J AU Saha, RN Dudek, SM AF Saha, R. N. Dudek, S. M. TI SPLITTING HARES AND TORTOISES: A CLASSIFICATION OF NEURONAL IMMEDIATE EARLY GENE TRANSCRIPTION BASED ON POISED RNA POLYMERASE II SO NEUROSCIENCE LA English DT Review DE RNA polymerase II; transcription; immediate early genes; neuronal activity; arc; plasticity ID LONG-TERM POTENTIATION; NERVE GROWTH-FACTOR; C-FOS PROTEIN(S); LATE-PHASE; PROTO-ONCOGENE; HIPPOCAMPAL-NEURONS; CRITICAL PERIOD; IN-VITRO; POL-II; EXPRESSION AB Immediate early transcription is an integral part of the neuronal response to environmental stimulation and serves many brain processes including development, learning, triggers of programmed cell death, and reaction to injury and drugs. Following a stimulus, neurons express a select few genes within a short period of time without undergoing de novo protein translation. Referred to as the 'gateway to genetic response', these immediate early genes (IEGs) are either expressed within a few minutes of stimulation or later within the hour. In neuronal IEGs that are expressed rapidly, productive elongation in response to neuronal activity is jump-started by constitutive transcription initiation together with RNA polymerase II stalling in the vicinity of the promoter. IEGs expressed later in the hour do not depend on this mechanism. On the basis of this Polymerase II poising, we propose that the immediate early genes can be grouped in two distinct classes: the rapid and the delayed IEGs. The possible biological relevance of these classes in neurons is discussed. Published by Elsevier Ltd. on behalf of IBRO. C1 [Saha, R. N.; Dudek, S. M.] NIEHS, Synapt & Dev Plast Grp, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), NIEHS, Synapt & Dev Plast Grp, Neurobiol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov RI Saha, Ramendra/C-7000-2014; OI Saha, Ramendra/0000-0002-5494-2584; Dudek, Serena M./0000-0003-4094-8368 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES100221] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES100221). NR 68 TC 8 Z9 8 U1 0 U2 5 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 SEP 5 PY 2013 VL 247 BP 175 EP 181 DI 10.1016/j.neuroscience.2013.04.064 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 298OX UT WOS:000330335100017 PM 23711585 ER PT J AU Byakika-Tusiime, J Polley, EC Oyugi, JH Bangsberg, DR AF Byakika-Tusiime, Jayne Polley, Eric C. Oyugi, Jessica H. Bangsberg, David R. TI Free HIV Antiretroviral Therapy Enhances Adherence among Individuals on Stable Treatment: Implications for Potential Shortfalls in Free Antiretroviral Therapy SO PLOS ONE LA English DT Article ID MARGINAL STRUCTURAL MODELS; BARRIERS; EPIDEMIOLOGY; KAMPALA; UGANDA; ADULTS; HAART; TIME AB Objective: To estimate the population-level causal effect of source of payment for HIV medication on treatment adherence using Marginal Structural Models. Methods: Data were obtained from an observational cohort of 76 HIV-infected individuals with at least 24 weeks of antiretroviral therapy treatment from 2002 to 2007 in Kampala, Uganda. Adherence was the primary outcome and it was measured using the 30-day visual analogue scale. Marginal structural models (MSM) were used to estimate the effect of source of payment for HIV medication on adherence, adjusting for confounding by income, duration on antiretroviral therapy (ART), timing of visit, prior adherence, prior CD4(+) T cell count and prior plasma HIV RNA. Traditional association models were also examined and the results compared. Results: Free HIV treatment was associated with a 3.8% improvement in adherence in the marginal structural model, while the traditional statistical models showed a 3.1-3.3% improvement in adherence associated with free HIV treatment. Conclusion: Removing a financial barrier to treatment with ART by providing free HIV treatment appears to significantly improve adherence to antiretroviral therapy. With sufficient information on confounders, MSMs can be used to make robust inferences about causal effects in epidemiologic research. C1 [Byakika-Tusiime, Jayne] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Dept Epidemiol & Biostat, Kampala, Uganda. [Polley, Eric C.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Oyugi, Jessica H.] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Bangsberg, David R.] Massachusetts Gen Hosp Global Hlth, Dept Med, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. RP Byakika-Tusiime, J (reprint author), Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Dept Epidemiol & Biostat, Kampala, Uganda. EM tusjayne@hotmail.com FU National Institutes of Health [NIMH RO-154907, NIMH RO-3 66654, NIAAA R-21 014784, NIMH K-24 87227]; Fogarty AIDS International Training and Research Program/University of California, Berkeley [1D43 TW00003] FX This work was supported partly by the National Institutes of Health (NIMH RO-154907, NIMH RO-3 66654, NIAAA R-21 014784, NIMH K-24 87227) and the Fogarty AIDS International Training and Research Program/University of California, Berkeley (1D43 TW00003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 1 Z9 1 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2013 VL 8 IS 9 AR e70375 DI 10.1371/journal.pone.0070375 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600005 PM 24039704 ER PT J AU de Mendizabal, NV Hutmacher, MM Troconiz, IF Goni, J Villoslada, P Bagnato, F Bies, RR AF de Mendizabal, Nieves Velez Hutmacher, Matthew M. Troconiz, Inaki F. Goni, Joaquin Villoslada, Pablo Bagnato, Francesca Bies, Robert R. TI Predicting Relapsing-Remitting Dynamics in Multiple Sclerosis Using Discrete Distribution Models: A Population Approach SO PLOS ONE LA English DT Article ID ENHANCING LESION COUNTS; CLINICAL-TRIALS; POISSON REGRESSION; MRI; EVOLUTION; MS AB Background: Relapsing-remitting dynamics are a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). A clinical relapse in MS reflects an acute focal inflammatory event in the central nervous system that affects signal conduction by damaging myelinated axons. Those events are evident in T1-weighted post-contrast magnetic resonance imaging (MRI) as contrast enhancing lesions (CEL). CEL dynamics are considered unpredictable and are characterized by high intra- and interpatient variability. Here, a population approach (nonlinear mixed-effects models) was applied to analyse of CEL progression, aiming to propose a model that adequately captures CEL dynamics. Methods and Findings: We explored several discrete distribution models to CEL counts observed in nine MS patients undergoing a monthly MRI for 48 months. All patients were enrolled in the study free of immunosuppressive drugs, except for intravenous methylprednisolone or oral prednisone taper for a clinical relapse. Analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2. Although several models were able to adequately characterize the observed CEL dynamics, the negative binomial distribution model had the best predictive ability. Significant improvements in fitting were observed when the CEL counts from previous months were incorporated to predict the current month's CEL count. The predictive capacity of the model was validated using a second cohort of fourteen patients who underwent monthly MRIs during 6-months. This analysis also identified and quantified the effect of steroids for the relapse treatment. Conclusions: The model was able to characterize the observed relapsing-remitting CEL dynamic and to quantify the interpatient variability. Moreover, the nature of the effect of steroid treatment suggested that this therapy helps resolve older CELs yet does not affect newly appearing active lesions in that month. This model could be used for design of future longitudinal studies and clinical trials, as well as for the evaluation of new therapies. C1 [de Mendizabal, Nieves Velez; Bies, Robert R.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [de Mendizabal, Nieves Velez; Bies, Robert R.] Indiana Clin & Translat Sci Inst CTSI, Indianapolis, IN USA. [Hutmacher, Matthew M.] Ann Arbor Pharmacometr Grp A2PG, Ann Arbor, MI USA. [Troconiz, Inaki F.] Univ Navarra, Sch Pharm, Dept Pharm & Pharmaceut Technol, E-31080 Pamplona, Spain. [Goni, Joaquin] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Villoslada, Pablo] Hosp Clin Barcelona, Inst Biomed Res August Pi Sunyer IDIBAPS, Ctr Neuroimmunol, Barcelona, Spain. [Bagnato, Francesca] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD USA. [Bagnato, Francesca] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP de Mendizabal, NV (reprint author), Indiana Univ Sch Med, Indianapolis, IN 46202 USA. EM nvelezde@iupui.edu OI Villoslada, Pablo/0000-0002-8735-6119 FU Eli Lilly and Company through Indiana Clinical and Translational Sciences Institute (CTSI) FX NVM and RRB were supported through Eli Lilly and Company through the Indiana Clinical and Translational Sciences Institute (CTSI). FB contribution to this work was sustained by the intramural program of the NINDS NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 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 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2013 VL 8 IS 9 AR e73361 DI 10.1371/journal.pone.0073361 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600067 ER PT J AU Saldana, SM Lee, HH Lowery, FJ Khotskaya, YB Xia, WY Zhang, CY Chang, SS Chou, CK Steeg, PS Yu, DH Hung, MC AF Saldana, Sandra M. Lee, Heng-Huan Lowery, Frank J. Khotskaya, Yekaterina B. Xia, Weiya Zhang, Chenyu Chang, Shih-Shin Chou, Chao-Kai Steeg, Patricia S. Yu, Dihua Hung, Mien-Chie TI Inhibition of Type I Insulin-Like Growth Factor Receptor Signaling Attenuates the Development of Breast Cancer Brain Metastasis SO PLOS ONE LA English DT Article ID FACTOR BINDING PROTEIN-3; CYCLOLIGNAN PPP; IGF-I; TRASTUZUMAB RESISTANCE; TYROSINE KINASE; CELL-GROWTH; MOUSE MODEL; PATHWAY; ACTIVATION; EXPRESSION AB Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system. C1 [Saldana, Sandra M.; Lee, Heng-Huan; Lowery, Frank J.; Khotskaya, Yekaterina B.; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Yu, Dihua; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Saldana, Sandra M.; Lee, Heng-Huan; Lowery, Frank J.; Chang, Shih-Shin; Chou, Chao-Kai; Yu, Dihua; Hung, Mien-Chie] Univ Texas Houston, Grad Sch Biomed Sci, Canc Biol Program, Houston, TX 77030 USA. [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Chou, Chao-Kai; Hung, Mien-Chie] China Med Univ, Grad Inst Canc Biol, Taichung, Taiwan. [Chou, Chao-Kai; Hung, Mien-Chie] China Med Univ, Ctr Mol Med, Taichung, Taiwan. [Hung, Mien-Chie] Asia Univ, Dept Biotechnol, Taichung, Taiwan. RP Hung, MC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. EM mhung@mdanderson.org OI Lowery, Frank/0000-0002-4620-5293 FU U.S. Department of Defense (DOD) Breast Cancer Research Program, Center of Excellence (COE) [W81 XWH-062-0033]; National Institutes of Health [CA109311, CA099031, CCSG CA16672]; Susan G. Komen for the Cure; University of Texas MD Anderson-China Medical University; Hospital Sister Institution Fund; Cancer Research Center of Excellence (Taiwan) [DOH102-TD-C-111-005]; Program for Stem Cell and Regenerative Medicine Frontier Research (Taiwan) [NSC101-2321-B-039-001]; International Research-Intensive Centers of Excellence in Taiwan (Taiwan) [NSC102-2911-I-002-303]; Center for Biological Pathways; Patel Memorial Breast Cancer Endowment Fund; GSBS; DOD CDMR-BCRP [W81XWH-10-1-0749]; DOD [W81XWH-10-BCRP-POSTDOC] FX This study was supported, in whole or in part, by the U.S. Department of Defense (DOD) Breast Cancer Research Program, Center of Excellence (COE) grant W81 XWH-062-0033 (P.S., D.Y, M-C.H), National Institutes of Health (CA109311, CA099031, and CCSG CA16672), Susan G. Komen for the Cure, The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M.-C. Hung), Cancer Research Center of Excellence (DOH102-TD-C-111-005, Taiwan), Program for Stem Cell and Regenerative Medicine Frontier Research (NSC101-2321-B-039-001, Taiwan), International Research-Intensive Centers of Excellence in Taiwan (NSC102-2911-I-002-303, Taiwan), Center for Biological Pathways, and Patel Memorial Breast Cancer Endowment Fund. FJL was supported by the Isaiah J. Fidler Graduate Fellowship in Cancer Metastasis from GSBS. YBK was supported by DOD CDMR-BCRP Postdoctoral Fellowship (W81XWH-10-1-0749). CZ was supported by DOD Postdoctoral Fellowship (W81XWH-10-BCRP-POSTDOC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 16 Z9 16 U1 1 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 SEP 5 PY 2013 VL 8 IS 9 AR e73406 DI 10.1371/journal.pone.0073406 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600073 PM 24039934 ER PT J AU Taylor, CM Golding, J Hibbeln, J Emond, AM AF Taylor, Caroline M. Golding, Jean Hibbeln, Joseph Emond, Alan M. TI Environmental Factors Predicting Blood Lead Levels in Pregnant Women in the UK: The ALSPAC Study SO PLOS ONE LA English DT Article ID UMBILICAL-CORD BLOOD; PORT PIRIE COHORT; ESSENTIAL ELEMENTS; EARLY-CHILDHOOD; SWEDISH WOMEN; HEAVY-METALS; EXPOSURE; MERCURY; DIET; ORGANOCHLORINES AB Background: Lead is a widespread environmental toxin. The behaviour and academic performance of children can be adversely affected even at low blood lead levels (BLL) of 5-10 mu g/dl. An important contribution to the infant's lead load is provided by maternal transfer during pregnancy. Objectives: Our aim was to determine BLL in a large cohort of pregnant women in the UK and to identify the factors that contribute to BLL in pregnant women. Methods: Pregnant women resident in the Avon area of the UK were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) in 1991-1992. Whole blood samples were collected at median gestational age of 11 weeks and analysed by inductively coupled plasma dynamic reaction cell mass spectrometry (n = 4285). Self-completion postal questionnaires were used to collect data during pregnancy on lifestyle, diet and other environmental exposures. Statistical analysis was carried out with SPSS v19. Results: The mean +/- SD BLL was 3.67 +/- 1.47 (median 3.41, range 0.41-19.14) mu g/dl. Higher educational qualification was found to be one of the strongest independent predictor of BLL in an adjusted backwards stepwise logistic regression to predict maternal BLL <5 or >= 5 mu g/dl (odds ratio 1.26, 95% confidence interval 1.12-1.42; p<0.001). Other predictive factors included cigarette smoking, alcohol and coffee drinking, and heating the home with a coal fire, with some evidence for iron and calcium intake having protective effects. Conclusion: The mean BLL in this group of pregnant women is higher than has been found in similar populations in developed countries. The finding that high education attainment was independently associated with higher BLL was unexpected and currently unexplained. Reduction in maternal lead levels can best be undertaken by reducing intake of the social drugs cigarettes, alcohol and caffeine, although further investigation of the effect of calcium on lead levels is needed. C1 [Taylor, Caroline M.; Golding, Jean; Emond, Alan M.] Univ Bristol, Sch Social & Community Med, Ctr Child & Adolescent Hlth, Bristol, Avon, England. [Hibbeln, Joseph] NIAAA, NIH, Rockville, MD 20852 USA. RP Taylor, CM (reprint author), Univ Bristol, Sch Social & Community Med, Ctr Child & Adolescent Hlth, Bristol, Avon, England. EM caroline.m.taylor@bristol.ac.uk OI Taylor, Caroline/0000-0001-8347-5092; Golding, Jean/0000-0003-2826-3307 FU Wellcome Trust [092731]; NOAA; Daphne Jackson Trust Fellowship; University of Bristol FX The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. The assays of the maternal blood samples were carried out at the Centres for Disease Control with funding from NOAA. C. M. Taylor was supported by a Daphne Jackson Trust Fellowship sponsored by the University of Bristol. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 20 Z9 21 U1 1 U2 14 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 SEP 5 PY 2013 VL 8 IS 9 AR e72371 DI 10.1371/journal.pone.0072371 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600024 PM 24039753 ER PT J AU Zheng, YL Li, CY Hu, YF Cao, L Wang, H Li, B Lu, XH Bao, L Luo, HY Shukla, V Amin, ND Pant, HC AF Zheng, Ya-Li Li, Congyu Hu, Ya-Fang Cao, Li Wang, Hui Li, Bo Lu, Xiao-Hua Bao, Li Luo, Hong-Yan Shukla, Varsha Amin, Niranjana D. Pant, Harish C. TI Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR EXPRESSION; GENE-TRANSCRIPTION; ACTIVATOR P35; TAU HYPERPHOSPHORYLATION; ALZHEIMERS-DISEASE; ANTIDIABETIC DRUGS; DIABETES-MELLITUS; PPAR-GAMMA; NEURODEGENERATION; PHOSPHORYLATION AB Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG) results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4-12 hrs), however was detectable in the long exposure in HG cells (24 hrs and 48 hrs). Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5) with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes. C1 [Zheng, Ya-Li; Cao, Li; Wang, Hui; Li, Bo; Lu, Xiao-Hua; Bao, Li; Luo, Hong-Yan] Ningxia Peoples Hosp, Dept Nephrol, Yinchuan, Ningxia Provinc, Peoples R China. [Li, Congyu] Pharmerit North Amer, Bethesda, MD USA. [Shukla, Varsha; Amin, Niranjana D.; Pant, Harish C.] NINDS, Neurochem Lab, Bethesda, MD USA. [Hu, Ya-Fang] Southern Med Univ, Nanfang Hosp, Dept Neurol, Guangzhou, Guangdong, Peoples R China. RP Zheng, YL (reprint author), Ningxia Peoples Hosp, Dept Nephrol, Yinchuan, Ningxia Provinc, Peoples R China. EM yalinew@yahoo.com FU National Natural Science Foundation of China [81060066]; Natural Science Foundation of Ningxia Province [NZ10162]; Department of Science and Technology of Ningxia Province [KGX-19-10-16, 2011ZYH169]; NIH; NINDS/NIH FX This work was supported by the following grant sponsors: National Natural Science Foundation of China (grant No. 81060066, http://isisdemo.nsfc.gov.cn/miniiris/miniiris.asp), Natural Science Foundation of Ningxia Province (grant No. NZ10162), Department of Science and Technology of Ningxia Province (grant No. KGX-19-10-16 and 2011ZYH169), and NIH intramural funds (a collaboration with NINDS/NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 0 Z9 1 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2013 VL 8 IS 9 AR e63332 DI 10.1371/journal.pone.0063332 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600002 PM 24039692 ER PT J AU Venable, RM Luo, Y Gawrisch, K Roux, B Pastor, RW AF Venable, Richard M. Luo, Yun Gawrisch, Klaus Roux, Benoit Pastor, Richard W. TI Simulations of Anionic Lipid Membranes: Development of Interaction-Specific Ion Parameters and Validation Using NMR Data SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS; FORCE-FIELD; COMPUTER-SIMULATION; POTENTIAL FUNCTIONS; BILAYERS; INTERFACES; CHARMM; AREA; NACL; H-2 AB Overbinding of ions to lipid head groups is a potentially serious artifact in simulations of charged lipid bilayers. In this study, the Lennard-Jones radii in the CHARMM force field for interactions of Na+ and lipid oxygen atoms of carboxyl, phosphate, and ester groups were revised to match osmotic pressure data on sodium acetate and electrophoresis data on palmitoyloleoyl phosphatidylcholine (POPC) vesicles. The new parameters were then validated by successfully reproducing previously published experimental NMR deuterium order parameters for dimyristoyl phosphatidylglycerol (DMPG) and newly obtained values for palmitoyloleoyl phosphatidylserine (POPS). Although the increases in Lennard-Jones diameters are only 0.02-0.12 angstrom, they are sufficient of reduce Na+ binding, and thereby increase surface areas per lipid by 5-10% compared with the unmodified parameters. C1 [Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Luo, Yun] Argonne Natl Lab, Argonne Leadership Comp Facil, Argonne, IL 60439 USA. [Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Roux, Benoit] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Early Science Postdoctoral Fellowship for Blue Gene/Q of ALCF; Intramural Research Program of the NIH, National Heart, Lung and Blood Institute FX We thank Stuart McLaughlin and Wonpil Im for helpful discussions. The osmotic pressure and effective charge calculations were carried out on the IBM Blue Gene/P cluster Intrepid of the Argonne Leadership Computing Facility (ALCF). Dr. Luo's research was supported by the Early Science Postdoctoral Fellowship for Blue Gene/Q of ALCF. This research was also supported in part by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster). NR 40 TC 35 Z9 35 U1 1 U2 30 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 SEP 5 PY 2013 VL 117 IS 35 BP 10183 EP 10192 DI 10.1021/jp401512z PG 10 WC Chemistry, Physical SC Chemistry GA 240VX UT WOS:000326126900013 PM 23924441 ER PT J AU Rothman, SM Herdener, N Frankola, KA Mughal, MR Mattson, MP AF Rothman, Sarah M. Herdener, Nathan Frankola, Kathryn A. Mughal, Mohamed R. Mattson, Mark P. TI Chronic mild sleep restriction accentuates contextual memory impairments, and accumulations of cortical A beta and pTau in a mouse model of Alzheimer's disease SO BRAIN RESEARCH LA English DT Article DE Alzheimer's disease; Sleep restriction; Glucocorticoids; Amyloid; Morris water maze; Fear conditioning ID PRECURSOR PROTEIN; WATER MAZE; DEPRIVATION; NEUROGENESIS; PERFORMANCE; STRESS; COST; MICE; RAT AB Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid beta-peptide (A beta) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6 h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both A beta and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical A beta and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD. Published by Elsevier B.V. C1 [Rothman, Sarah M.; Herdener, Nathan; Frankola, Kathryn A.; Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Mughal, Mohamed R.] Army Inst Publ Hlth, US Army Publ Hlth Command, Aberdeen Proving Ground, MD 21010 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. The authors wish to thank Ernest Dabney for assistance with retro-orbital bleeding techniques and Catherine Crews for assistance with maintenance for the in vivo portion of the study. NR 29 TC 24 Z9 24 U1 3 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 5 PY 2013 VL 1529 BP 200 EP 208 DI 10.1016/j.brainres.2013.07.010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 221KQ UT WOS:000324658200020 PM 23856323 ER PT J AU Shaboltas, AV Skochilov, RV Brown, LB Elharrar, VN Kozlov, AP Hoffman, IF AF Shaboltas, Alla V. Skochilov, Roman V. Brown, Lillian B. Elharrar, Vanessa N. Kozlov, Andrei P. Hoffman, Irving F. TI The feasibility of an intensive case management program for injection drug users on antiretroviral therapy in St. Petersburg, Russia SO HARM REDUCTION JOURNAL LA English DT Article DE Injection drug users; Russia; HIV/AIDS; Antiretroviral therapy; Case management ID SUBSTANCE-ABUSE TREATMENT; MENTAL-ILLNESS; HIV; ADHERENCE; INDIVIDUALS; IMPACT; CARE; ENHANCEMENT; PREVALENCE; NALTREXONE AB Background: The majority of HIV-infected individuals requiring antiretroviral therapy (ART) in Russia are Injection Drug Users (IDU). Substitution therapy used as part of a comprehensive harm reduction program is unavailable in Russia. Past data shows that only 16% of IDU receiving substance abuse treatment completed the course without relapse, and only 40% of IDU on ART remained on treatment at 6 months. Our goal was to determine if it was feasible to improve these historic outcomes by adding intensive case management (ICM) to the substance abuse and ART treatment programs for IDU. Methods: IDU starting ART and able to involve a "supporter" who would assist in their treatment plan were enrolled. ICM included opiate detoxification, bi-monthly contact and counseling with the case, weekly group sessions, monthly contact with the "supporter" and home visits as needed. Full follow-up (FFU) was 8 months. Stata v10 (College Station, TX) was used for all analysis. Descriptive statistics were calculated for all baseline demographic variables, baseline and follow-up CD4 count, and viral load. Median baseline and follow-up CD4 counts and RNA levels were compared using the Kruskal-Wallis test. The proportion of participants with RNA < 1000 copies mL at baseline and follow-up was compared using Fisher's Exact test. McNemar's test for paired proportions was used to compare the change in proportion of participants with RNA < 1000 copies mL from baseline to follow-up. Results: Between November 2007 and December 2008, 60 IDU were enrolled. 34 (56.7%) were male. 54/60 (90.0%) remained in FFU. Overall, 31/60 (52%) were active IDU at enrollment and 27 (45%) were active at their last follow-up visit. 40/60 (66.7%) attended all of their ART clinic visits, 13/60 (21.7%) missed one or more visit but remained on ART, and 7/60 (11.7%) stopped ART before the end of FFU. Overall, 39/53 (74%) had a final 6-8 month HIV RNA viral load (VL) < 1000 copies/mL. Conclusions: Despite no substitution therapy to assist IDU in substance abuse and ART treatment programs, ICM was feasible, and the retention and adherence of IDU on ART in St. Petersburg could be greatly enhanced by adding ICM to the existing treatment programs. C1 [Shaboltas, Alla V.; Skochilov, Roman V.] St Petersburg St Univ, St Petersburg, Russia. [Brown, Lillian B.; Hoffman, Irving F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Elharrar, Vanessa N.] NIAID, NIH, Bethesda, MD 20892 USA. [Shaboltas, Alla V.; Skochilov, Roman V.; Kozlov, Andrei P.] Biomed Ctr, St Petersburg, Russia. RP Shaboltas, AV (reprint author), St Petersburg St Univ, Univ Skaya Nab 7-9, St Petersburg, Russia. EM alla.shaboltas@gmail.com RI Skochilov, Roman/H-6541-2013; Kozlov, Andrei/H-2117-2016 OI Skochilov, Roman/0000-0001-6046-7655; Kozlov, Andrei/0000-0003-4611-1534 FU NIMH NIH HHS [F30 MH085431] NR 38 TC 2 Z9 3 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7517 J9 HARM REDUCT J JI Harm Reduct. J. PD SEP 5 PY 2013 VL 10 AR 15 DI 10.1186/1477-7517-10-15 PG 8 WC Substance Abuse SC Substance Abuse GA 216FH UT WOS:000324266900001 PM 24006958 ER PT J AU Proctor, EK Landsverk, J Baumann, AA Mittman, BS Aarons, GA Brownson, RC Glisson, C Chambers, D AF Proctor, Enola K. Landsverk, John Baumann, Ana A. Mittman, Brian S. Aarons, Gregory A. Brownson, Ross C. Glisson, Charles Chambers, David TI The implementation research institute: training mental health implementation researchers in the United States SO IMPLEMENTATION SCIENCE LA English DT Article DE Dissemination research; Implementation research; Training; Translational research ID COMORBIDITY SURVEY REPLICATION; KNOWLEDGE TRANSLATION; DISSEMINATION; SCIENCE; STRATEGIES; DISORDERS; FRAMEWORK; TRAINEES; SERVICES; QUALITY AB Background: The Implementation Research Institute (IRI) provides two years of training in mental health implementation science for 10 new fellows each year. The IRI is supported by a National Institute of Mental Health (NIMH) R25 grant and the Department of Veterans Affairs (VA). Fellows attend two annual week-long trainings at Washington University in St. Louis. Training is provided through a rigorous curriculum, local and national mentoring, a 'learning site visit' to a federally funded implementation research project, pilot research, and grant writing. Methods: This paper describes the rationale, components, outcomes to date, and participant experiences with IRI. Results: IRI outcomes include 31 newly trained implementation researchers, their new grant proposals, contributions to other national dissemination and implementation research training, and publications in implementation science authored by the Core Faculty and fellows. Former fellows have obtained independent research funding in implementation science and are beginning to serve as mentors for more junior investigators. Conclusions: Based on the number of implementation research grant proposals and papers produced by fellows to date, the IRI is proving successful in preparing new researchers who can inform the process of making evidence-based mental healthcare more available through real-world settings of care and who are advancing the field of implementation science. C1 [Proctor, Enola K.; Baumann, Ana A.] Washington Univ, George Warren Brown Sch Social Work, Ctr Mental Hlth Serv Res, St Louis, MO 63130 USA. [Landsverk, John] San Diego Childrens Hosp, Child & Adolescent Serv Res Ctr, San Diego, CA USA. [Mittman, Brian S.] VA Greater Los Angeles Healthcare Syst, Sepulveda, CA USA. [Aarons, Gregory A.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Brownson, Ross C.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Glisson, Charles] Univ Tennessee, Childrens Mental Hlth Serv Res Ctr, Knoxville, TN USA. [Chambers, David] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Proctor, EK (reprint author), Washington Univ, George Warren Brown Sch Social Work, Ctr Mental Hlth Serv Res, 1 Brookings Dr Campus,Box 1196, St Louis, MO 63130 USA. EM ekp@wustl.edu OI Baumann, Ana/0000-0002-4523-0147; Mittman, Brian/0000-0003-3589-9178 FU National Institute of Mental Health through the Center for Mental Health Services Research [NIMH P30 MH068579]; National Institute of Mental Health through the Implementation Research Institute [NIMH R25 MH080916]; US Department of Veterans Affairs Quality Enhancement Research Initiative (QUERI) FX Preparation of this paper was supported by the National Institute of Mental Health through the Center for Mental Health Services Research (NIMH P30 MH068579) and the Implementation Research Institute (NIMH R25 MH080916) and the US Department of Veterans Affairs Quality Enhancement Research Initiative (QUERI). We gratefully acknowledge learning site hosts who make invaluable contribution to IRI training; administrative support from the Brown School, Washington University in St. Louis; and the volunteer research assistants who contribute to the Institute's success. NR 30 TC 11 Z9 11 U1 4 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD SEP 5 PY 2013 VL 8 AR 105 DI 10.1186/1748-5908-8-105 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 214JQ UT WOS:000324129400001 PM 24007290 ER PT J AU Juarez-Mendez, S Zentella-Dehesa, A Villegas-Ruiz, V Perez-Gonzalez, OA Salcedo, M Lopez-Romero, R Roman-Basaure, E Lazos-Ochoa, M de Oca-Fuentes, VEM Vazquez-Ortiz, G Moreno, J AF Juarez-Mendez, Sergio Zentella-Dehesa, Alejandro Villegas-Ruiz, Vanessa Alberto Perez-Gonzalez, Oscar Salcedo, Mauricio Lopez-Romero, Ricardo Roman-Basaure, Edgar Lazos-Ochoa, Minerva Eden Montes de Oca-Fuentes, Victor Vazquez-Ortiz, Guelaguetza Moreno, Jose TI Splice variants of zinc finger protein 695 mRNA associated to ovarian cancer SO JOURNAL OF OVARIAN RESEARCH LA English DT Article DE Ovarian cancer; Alternative mRNA splicing; ZNF695 ID ENDOTHELIAL GROWTH-FACTOR; GENE-EXPRESSION PROFILES; CELL-LINES; TRANSCRIPTIONAL ACTIVITY; CARCINOMA; TUMORS; REPRESSION; INVASION; RECEPTOR; EXON AB Background: Studies of alternative mRNA splicing (AS) in health and disease have yet to yield the complete picture of protein diversity and its role in physiology and pathology. Some forms of cancer appear to be associated to certain alternative mRNA splice variants, but their role in the cancer development and outcome is unclear. Methods: We examined AS profiles by means of whole genome exon expression microarrays (Affymetrix GeneChip 1.0) in ovarian tumors and ovarian cancer-derived cell lines, compared to healthy ovarian tissue. Alternatively spliced genes expressed predominantly in ovarian tumors and cell lines were confirmed by RT-PCR. Results: Among several significantly overexpressed AS genes in malignant ovarian tumors and ovarian cancer cell lines, the most significant one was that of the zinc finger protein ZNF695, with two previously unknown mRNA splice variants identified in ovarian tumors and cell lines. The identity of ZNF695 AS variants was confirmed by cloning and sequencing of the amplicons obtained from ovarian cancer tissue and cell lines. Conclusions: Alternative ZNF695 mRNA splicing could be a marker of ovarian cancer with possible implications on its pathogenesis. C1 [Juarez-Mendez, Sergio; Alberto Perez-Gonzalez, Oscar] Natl Inst Pediat, Res Dept, Expt Oncol Lab, Mexico City, DF, Mexico. [Moreno, Jose] La Salle Univ, Mexican Fac Med, Mexico City, DF, Mexico. [Zentella-Dehesa, Alejandro] Univ Nacl Autonoma Mexico, Biomed Res Inst, Genom Med & Environm Toxicol Dept, Mexico City, DF, Mexico. [Zentella-Dehesa, Alejandro; Eden Montes de Oca-Fuentes, Victor] Natl Inst Med Sci & Nutr Salvador Zubiran, Unit Biochem, Mexico City, DF, Mexico. [Villegas-Ruiz, Vanessa; Salcedo, Mauricio; Lopez-Romero, Ricardo; Vazquez-Ortiz, Guelaguetza] IMSS, Natl Med Ctr Siglo XXI, Med Res Unit Oncol Dis, Genom Oncol Lab,Oncol Hosp, Mexico City, DF, Mexico. [Lazos-Ochoa, Minerva] Univ Nacl Autonoma Mexico, Gen Hosp Mexico OD, Fac Med, Mexico City, DF, Mexico. [Roman-Basaure, Edgar] Gen Hosp Mexico OD, Dept Oncol, Mexico City, DF, Mexico. [Vazquez-Ortiz, Guelaguetza] NIDDK, Mammalian Genet Sect, NIH, Bethesda, MD 20892 USA. RP Vazquez-Ortiz, G (reprint author), IMSS, Natl Med Ctr Siglo XXI, Med Res Unit Oncol Dis, Genom Oncol Lab,Oncol Hosp, Mexico City, DF, Mexico. EM vazquezortizg@niiddk.nih.gov; jmoreno49@gmail.com RI Moreno, Jose/C-7319-2016 OI Moreno, Jose/0000-0002-8887-6087 FU SEP-CONACyT Mexico [61742]; National Council of Science and Technology (CONACyT); IMSS FX This work was supported in part by a Basic Science grant 61742 form SEP-CONACyT Mexico. Sergio Juarez-Mendez was financially supported by a scholarship provided by the National Council of Science and Technology (CONACyT) and IMSS. This work constitutes a partial fulfillment of the graduate program in PhD Biological Science of National Autonomous University of Mexico (UNAM) of Sergio Juarez-Mendez. We finally thank Dr. Carlos Perez-Plasencia, Faculty of Superior Studies, Ixtacala, UNAM for critical review of the manuscript and Dr. Laura Diaz-Cueto, Research Unit on Reproductive Medicine, Instituto Mexicano del Seguro Social (IMSS) for kindly providing cell lines. NR 47 TC 4 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-2215 J9 J OVARIAN RES JI J. Ovarian Res. PD SEP 5 PY 2013 VL 6 AR UNSP 61 DI 10.1186/1757-2215-6-61 PG 10 WC Reproductive Biology SC Reproductive Biology GA 218XB UT WOS:000324464900001 PM 24007497 ER PT J AU McWilliams, A Tammemagi, MC Mayo, JR Roberts, H Liu, G Soghrati, K Yasufuku, K Martel, S Laberge, F Gingras, M Atkar-Khattra, S Berg, CD Evans, K Finley, R Yee, J English, J Nasute, P Goffin, J Puksa, S Stewart, L Tsai, S Johnston, MR Manos, D Nicholas, G Goss, GD Seely, JM Amjadi, K Tremblay, A Burrowes, P MacEachern, P Bhatia, R Tsao, MS Lam, S AF McWilliams, Annette Tammemagi, Martin C. Mayo, John R. Roberts, Heidi Liu, Geoffrey Soghrati, Kam Yasufuku, Kazuhiro Martel, Simon Laberge, Francis Gingras, Michel Atkar-Khattra, Sukhinder Berg, Christine D. Evans, Ken Finley, Richard Yee, John English., John Nasute, Paola Goffin, John Puksa, Serge Stewart, Lori Tsai, Scott Johnston, Michael R. Manos, Daria Nicholas, Garth Goss, Glenwood D. Seely, Jean M. Amjadi, Kayvan Tremblay, Alain Burrowes, Paul MacEachern, Paul Bhatia, Rick Tsao, Ming-Sound Lam, Stephen TI Probability of Cancer in Pulmonary Nodules Detected on First Screening CT SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LUNG-CANCER; PERIFISSURAL NODULES; FLEISCHNER-SOCIETY; TRIAL; MALIGNANCY; MANAGEMENT; RECOMMENDATIONS; TOMOGRAPHY; VALIDATION; STATEMENT AB BACKGROUND Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up. METHODS We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer. RESULTS In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set. CONCLUSIONS Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. C1 [McWilliams, Annette; Mayo, John R.; Evans, Ken; Finley, Richard; Yee, John; English., John; Lam, Stephen] Vancouver Gen Hosp, Vancouver, BC, Canada. [McWilliams, Annette; Atkar-Khattra, Sukhinder; Lam, Stephen] British Columbia Canc Agcy, Vancouver, BC V5Z 1L3, Canada. [Tammemagi, Martin C.] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Roberts, Heidi; Liu, Geoffrey; Soghrati, Kam; Yasufuku, Kazuhiro; Tsao, Ming-Sound] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Roberts, Heidi; Liu, Geoffrey; Soghrati, Kam; Yasufuku, Kazuhiro; Tsao, Ming-Sound] Toronto Gen Hosp, Toronto, ON, Canada. [Goffin, John; Puksa, Serge; Stewart, Lori; Tsao, Ming-Sound] Juravinski Hosp, Hamilton, ON, Canada. [Goffin, John; Puksa, Serge; Stewart, Lori; Tsai, Scott] Ctr Canc, Hamilton, ON, Canada. [Nicholas, Garth; Goss, Glenwood D.; Seely, Jean M.; Amjadi, Kayvan] Ottawa Hosp, Ctr Canc, Ottawa, ON, Canada. [Martel, Simon; Laberge, Francis; Gingras, Michel] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Johnston, Michael R.; Manos, Daria] Dalhousie Univ, Halifax, NS, Canada. [Tremblay, Alain; Burrowes, Paul; MacEachern, Paul] Univ Calgary, Calgary, AB, Canada. [Bhatia, Rick] Mem Univ Newfoundland, St John, NF, Canada. [Berg, Christine D.] NCI, NIH, Bethesda, MD 20892 USA. [Nasute, Paola] Hosp Univ Austral, Buenos Aires, DF, Argentina. RP McWilliams, A (reprint author), British Columbia Canc Agcy, Dept Integrat Oncol, 601 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. RI Tremblay, Alain/F-3163-2011; Berg , Christine/K-1047-2014 OI Tremblay, Alain/0000-0002-0025-7426; FU Terry Fox Research Institute FX Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660. NR 31 TC 177 Z9 186 U1 9 U2 44 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 5 PY 2013 VL 369 IS 10 BP 910 EP 919 DI 10.1056/NEJMoa1214726 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 211KV UT WOS:000323906900008 PM 24004118 ER PT J AU Aberle, DR DeMello, S Berg, CD Black, WC Brewer, B Church, TR Clingan, KL Duan, F Fagerstrom, RM Gareen, IF Gatsonis, CA Gierada, DS Jain, A Jones, GC Mahon, I Marcus, PM Rathmell, JM Sicks, J AF Aberle, Denise R. DeMello, Sarah Berg, Christine D. Black, William C. Brewer, Brenda Church, Timothy R. Clingan, Kathy L. Duan, Fenghai Fagerstrom, Richard M. Gareen, Ilana F. Gatsonis, Constantine A. Gierada, David S. Jain, Amanda Jones, Gordon C. Mahon, Irene Marcus, Pamela M. Rathmell, Joshua M. Sicks, JoRean CA Natl Lung Screening Trial Res Team TI Results of the Two Incidence Screenings in the National Lung Screening Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CANCER; DESIGN AB BACKGROUND The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. C1 [Aberle, Denise R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90024 USA. [DeMello, Sarah; Duan, Fenghai; Gareen, Ilana F.; Gatsonis, Constantine A.; Jain, Amanda; Sicks, JoRean] Brown Univ, Biostat Ctr, ACRIN, Providence, RI USA. [Berg, Christine D.; Fagerstrom, Richard M.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Marcus, Pamela M.] NCI, Hlth Serv & Econ Appl Res Grp, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Brewer, Brenda; Clingan, Kathy L.] Westat Corp, Rockville, MD USA. [Jones, Gordon C.; Rathmell, Joshua M.] Informat Management Serv Inc, Rockville, MD USA. [Black, William C.] Dartmouth Med Sch, Dept Radiol, Lebanon, NH USA. [Church, Timothy R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Gierada, David S.] Washington Univ, Sch Med, Dept Radiol, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Mahon, Irene] ACRIN, Philadelphia, PA USA. RP Aberle, DR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, 924 West Wood Blvd,Suite 420, Los Angeles, CA 90024 USA. EM daberle@mednet.ucla.edu RI Gareen, Ilana/I-2816-2014; Duan, Fenghai/J-3709-2014; Berg , Christine/K-1047-2014; OI Gareen, Ilana/0000-0002-0457-5595; Duan, Fenghai/0000-0002-5084-0070; Blevins, Meridith/0000-0002-3861-9859; Church, Timothy R./0000-0003-3292-5035; fishman, elliot/0000-0002-2567-1658; Aberle, Denise/0000-0002-8858-3401 FU National Cancer Institute FX Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385. NR 20 TC 127 Z9 132 U1 4 U2 53 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 5 PY 2013 VL 369 IS 10 BP 920 EP 931 DI 10.1056/NEJMoa1208962 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 211KV UT WOS:000323906900009 PM 24004119 ER PT J AU Liu, SH Zhang, Y Moayeri, M Liu, J Crown, D Fattah, RJ Wein, AN Yu, ZX Finkel, T Leppla, SH AF Liu, Shihui Zhang, Yi Moayeri, Mahtab Liu, Jie Crown, Devorah Fattah, Rasem J. Wein, Alexander N. Yu, Zu-Xi Finkel, Toren Leppla, Stephen H. TI Key tissue targets responsible for anthrax-toxin-induced lethality SO NATURE LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; BACILLUS-ANTHRACIS; CRE-RECOMBINASE; INHALATIONAL ANTHRAX; CELLULAR RECEPTOR; KINASE-KINASE; IN-VIVO; CELLS; MOUSE; MICE AB Bacillus anthracis, the causative agent of anthrax disease, is lethal owing to the actions of two exotoxins: anthrax lethal toxin (LT) and oedema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type-specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type-specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occurs through damage to distinct cell types; whereas targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Notably, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not seem to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems. C1 [Liu, Shihui; Zhang, Yi; Moayeri, Mahtab; Crown, Devorah; Fattah, Rasem J.; Wein, Alexander N.; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Liu, Jie; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Liu, SH (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shliu@niaid.nih.gov; sleppla@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health FX This research was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, National Institutes of Health. We thank L. Feigenbaum and the staff at SAIC/NCI Frederick for generation of the founder CMG2 transgenic mice. We thank A. Kulkarni, B. Hall, B. Klaunberg, S. Anderson, I. Sastalla, C. Leysath and C. Bachran for discussions, and D. Despres for help with echocardiography. NR 44 TC 43 Z9 44 U1 2 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 5 PY 2013 VL 501 IS 7465 BP 63 EP + DI 10.1038/nature12510 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211ER UT WOS:000323888300032 PM 23995686 ER PT J AU Kim, HF Hikosaka, O AF Kim, Hyoung F. Hikosaka, Okihide TI Distinct Basal Ganglia Circuits Controlling Behaviors Guided by Flexible and Stable Values SO NEURON LA English DT Article ID SACCADIC EYE-MOVEMENTS; PARKINSONS-DISEASE; CAUDATE-NUCLEUS; ORBITOFRONTAL CORTEX; RHESUS-MONKEY; HUNTINGTONS-DISEASE; STRIATAL NEURONS; HABIT FORMATION; INFORMATION; RESPONSES AB Choosing valuable objects is critical for survival, but their values may change flexibly or remain stable. Therefore, animals should be able to update the object values flexibly by recent experiences and retain them stably by long-term experiences. However, it is unclear how the brain encodes the two conflicting forms of values and controls behavior accordingly. We found that distinct circuits of the primate caudate nucleus control behavior selectively in the flexible and stable value conditions. Single caudate neurons encoded the values of visual objects in a regionally distinct manner: flexible value coding in the caudate head and stable value coding in the caudate tail. Monkeys adapted in both conditions by looking at objects with higher values. Importantly, inactivation of each caudate subregion disrupted the high-low value discrimination selectively in the flexible or stable context. This parallel complementary mechanism enables animals to choose valuable objects in both flexible and stable conditions. C1 [Kim, Hyoung F.; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Kim, HF (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hyoung.f.kim@gmail.com FU Intramural Research Program at the National Institutes of Health, National Eye Institute FX We thank M. Yasuda, S. Yamamoto, A. Ghazizadeh, I. Monosov, and E. Bromberg-Martin for discussions and D. Parker, B. Nagy, M.K. Smith, G.Tansey, J.W. McClurkin, A.M. Nichols, T.W. Ruffner, and A.V. Hays for technical assistance. This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. NR 51 TC 27 Z9 27 U1 1 U2 13 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 SEP 4 PY 2013 VL 79 IS 5 BP 1001 EP 1010 DI 10.1016/j.neuron.2013.06.044 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 297QD UT WOS:000330269100016 PM 23954031 ER PT J AU Glass, RI AF Glass, Roger I. TI What the United States Has to Gain From Global Health Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM glassr@mail.nih.gov NR 5 TC 1 Z9 1 U1 1 U2 4 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 SEP 4 PY 2013 VL 310 IS 9 BP 903 EP 904 DI 10.1001/jama.2013.276558 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 211DT UT WOS:000323885700014 PM 24002270 ER PT J AU Drgonova, J Jacobsson, JA Han, JC Yanovski, JA Fredriksson, R Marcus, C Schioth, HB Uhl, GR AF Drgonova, Jana Jacobsson, Josefin A. Han, Joan C. Yanovski, Jack A. Fredriksson, Robert Marcus, Claude Schioth, Helgi B. Uhl, George R. TI Involvement of the Neutral Amino Acid Transporter SLC6A15 and Leucine in Obesity-Related Phenotypes SO PLOS ONE LA English DT Article ID DIET-INDUCED OBESITY; GENOME-WIDE ASSOCIATION; REGULATES FOOD-INTAKE; HIGH-PROTEIN DIET; INSULIN-RESISTANCE; ORPHAN TRANSPORTERS; V7-3 SLC6A15; ENERGY; MICE; HYPOTHALAMUS AB Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes. C1 [Drgonova, Jana; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, IRP, Baltimore, MD USA. [Jacobsson, Josefin A.; Fredriksson, Robert; Schioth, Helgi B.] Uppsala Univ, Unit Funct Pharmacol, Dept Neurosci, Uppsala, Sweden. [Han, Joan C.; Yanovski, Jack A.] NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, IRP,NIH,CRC 10, Bethesda, MD USA. [Marcus, Claude] Karolinska Inst, Div Pediat, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, NIH, IRP, Baltimore, MD USA. EM guhl@intra.nida.nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/DHHS); National Institute on Minority and Health Disparities (NIMHD), National Institutes of Health (NIH); Department of Health and Human Services; Swedish Medical Research foundation; Swedish Research Council; Novo Nordisk Foundation FX Financial support came from the Intramural Research Programs of the National Institute on Drug Abuse, the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/DHHS), supplementary funding from National Institute on Minority and Health Disparities (NIMHD), National Institutes of Health (NIH) (to JY), Department of Health and Human Services, the Swedish Medical Research foundation, Swedish Research Council and the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 11 Z9 11 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 4 PY 2013 VL 8 IS 9 AR UNSP e68245 DI 10.1371/journal.pone.0068245 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219OE UT WOS:000324515600003 PM 24023709 ER PT J AU Razzaghian, HR Forsberg, LA Prakash, KR Przerada, S Paprocka, H Zywicka, A Westerman, MP Pedersen, NL O'Hanlon, TP Rider, LG Miller, FW Srutek, E Jankowski, M Zegarski, W Piotrowski, A Absher, D Dumanski, JP AF Razzaghian, Hamid Reza Forsberg, Lars A. Prakash, Kancherla Reddy Przerada, Szymon Paprocka, Hanna Zywicka, Anna Westerman, Maxwell P. Pedersen, Nancy L. O'Hanlon, Terrance P. Rider, Lisa G. Miller, Frederick W. Srutek, Ewa Jankowski, Michal Zegarski, Wojciech Piotrowski, Arkadiusz Absher, Devin Dumanski, Jan P. TI Post-Zygotic and Inter-Individual Structural Genetic Variation in a Presumptive Enhancer Element of the Locus between the IL10R beta and IFNAR1 Genes SO PLOS ONE LA English DT Article ID COPY-NUMBER-VARIATION; SOMATIC MOSAICISM; TANDEM REPEATS; HUMAN GENOME; TRANSCRIPTION FACTORS; HUMAN TISSUES; INS VNTR; MECHANISMS; DNA; CANCER AB Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in similar to 24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10R beta, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer. C1 [Razzaghian, Hamid Reza; Forsberg, Lars A.; Prakash, Kancherla Reddy; Przerada, Szymon; Paprocka, Hanna; Zywicka, Anna; Dumanski, Jan P.] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Westerman, Maxwell P.] Mt Sinai Hosp Med Ctr, Chicago, IL USA. [Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [O'Hanlon, Terrance P.; Rider, Lisa G.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, Bethesda, MD USA. [Srutek, Ewa; Jankowski, Michal; Zegarski, Wojciech] Nicholas Copernicus Univ, Surg Oncol Clin, Coll Med, Ctr Oncol, Bydgoszcz, Poland. [Piotrowski, Arkadiusz] Med Univ Gdansk, Dept Biol & Pharmaceut Bot, Gdansk, Poland. [Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, MD USA. RP Dumanski, JP (reprint author), Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. EM jan.dumanski@igp.uu.se RI Piotrowski, Arkadiusz/A-5484-2010; Zegarski , Wojciech/H-7199-2014; OI Piotrowski, Arkadiusz/0000-0002-0823-0607; Miller, Frederick/0000-0003-2831-9593 FU Ellison Medical Foundation; Swedish Cancer Society; Swedish Research Council; Swedish Heart-Lung Foundation; Science for Life Laboratory-Uppsala; Foundation for Polish Science [FOCUS 4/2008, FOCUS 4/08/2009]; Uppsala University; Uppsala University Hospital; Swedish Research Council [80576801, 70374401]; National Institute of Environmental Health Sciences; National Institute of Health, Bethesda, Maryland, United States of America; NIH [AG 04563, AG10175] FX This study was sponsored by grants from the Ellison Medical Foundation (JPD and DA), the Swedish Cancer Society, the Swedish Research Council, Swedish Heart-Lung Foundation, and the Science for Life Laboratory-Uppsala (JPD). AP acknowledges FOCUS 4/2008 and FOCUS 4/08/2009 grants from the Foundation for Polish Science. Genotyping was performed in part by the SNP&SEQ Technology Platform, which is supported by Uppsala University, Uppsala University Hospital, the Science for Life Laboratory-Uppsala, and the Swedish Research Council (contracts 80576801 and 70374401). This study was also supported in part by the intramural research program of the National Institute of Environmental Health Sciences, the National Institute of Health, Bethesda, Maryland, United States of America. SATSA study is supported in part by grants from the NIH (AG 04563, AG10175) and the Swedish Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 1 Z9 1 U1 2 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 SEP 4 PY 2013 VL 8 IS 9 AR e67752 DI 10.1371/journal.pone.0067752 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219OE UT WOS:000324515600001 PM 24023707 ER PT J AU Robert, MA Okamoto, K Lloyd, AL Gould, F AF Robert, Michael A. Okamoto, Kenichi Lloyd, Alun L. Gould, Fred TI A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Deterministic Model SO PLOS ONE LA English DT Article ID AEDES-AEGYPTI DIPTERA; LETHAL GENETIC SYSTEM; THEORETICAL-ANALYSIS; DENGUE TRANSMISSION; STERILE MALES; HUMAN BLOOD; MOSQUITO; POPULATIONS; CULICIDAE; RELEASE AB Genetic approaches for controlling disease vectors have aimed either to reduce wild-type populations or to replace wildtype populations with insects that cannot transmit pathogens. Here, we propose a Reduce and Replace (R&R) strategy in which released insects have both female-killing and anti-pathogen genes. We develop a mathematical model to numerically explore release strategies involving an R&R strain of the dengue vector Aedes aegypti. We show that repeated R&R releases may lead to a temporary decrease in mosquito population density and, in the absence of fitness costs associated with the anti-pathogen gene, a long-term decrease in competent vector population density. We find that R&R releases more rapidly reduce the transient and long-term competent vector densities than female-killing releases alone. We show that releases including R&R females lead to greater reduction in competent vector density than male-only releases. The magnitude of reduction in total and competent vectors depends upon the release ratio, release duration, and whether females are included in releases. Even when the anti-pathogen allele has a fitness cost, R&R releases lead to greater reduction in competent vectors than female-killing releases during the release period; however, continued releases are needed to maintain low density of competent vectors long-term. We discuss the results of the model as motivation for more detailed studies of R&R strategies. C1 [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Okamoto, Kenichi; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Robert, MA (reprint author), N Carolina State Univ, Dept Math, Box 8205, Raleigh, NC 27695 USA. EM marober5@ncsu.edu RI Lloyd, Alun/H-4944-2012 FU National Institutes of Health (NIH) [R01AI091980]; Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative; University of Pretoria North Carolina State University Strategic Collaboration Seed Grant FX This work is funded in part by National Institutes of Health (NIH) grant R01AI091980, a grant to the Regents of the University of California from the Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative. This work is also funded in part by a University of Pretoria North Carolina State University Strategic Collaboration Seed Grant (to A. L. Lloyd). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 14 Z9 15 U1 1 U2 14 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 SEP 4 PY 2013 VL 8 IS 9 AR e73233 DI 10.1371/journal.pone.0073233 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219OE UT WOS:000324515600081 PM 24023839 ER PT J AU Fan, RZ Lee, AN Lu, ZH Liu, AY Troendle, JF Mills, JL AF Fan, Ruzong Lee, Annie Lu, Zhaohui Liu, Aiyi Troendle, James F. Mills, James L. TI Association analysis of complex diseases using triads, parent-child dyads and singleton monads SO BMC GENETICS LA English DT Article DE Association mapping of complex diseases; Likelihood ratio tests; Transmission disequilibrium tests ID TRANSMISSION DISEQUILIBRIUM TEST; GENETIC ASSOCIATION; RELATIVE RISKS; CANDIDATE-GENE; DESIGNS; INDIVIDUALS; POPULATION; FAMILY; LINKAGE AB Background: Triad families are routinely used to test association between genetic variants and complex diseases. Triad studies are important and popular since they are robust in terms of being less prone to false positives due to population structure. In practice, one may collect not only complete triads, but also incomplete families such as dyads (affected child with one parent) and singleton monads (affected child without parents). Since there is a lack of convenient algorithms and software to analyze the incomplete data, dyads and monads are usually discarded. This may lead to loss of power and insufficient utilization of genetic information in a study. Results: We develop likelihood-based statistical models and likelihood ratio tests to test for association between complex diseases and genetic markers by using combinations of full triads, parent-child dyads, and affected singleton monads for a unified analysis. A likelihood is calculated directly to facilitate the data analysis without imputation and to avoid computational complexity. This makes it easy to implement the models and to explain the results. Conclusion: By simulation studies, we show that the proposed models and tests are very robust in terms of accurately controlling type I error evaluations, and are powerful by empirical power evaluations. The methods are applied to test for association between transforming growth factor alpha (TGFA) gene and cleft palate in an Irish study. C1 [Fan, Ruzong; Lu, Zhaohui; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Lee, Annie] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Troendle, James F.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,MSC 7510, Rockville, MD 20852 USA. EM fanr@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland, USA FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland, USA. We thank Dr. Carter for sending us the cleft palate data to facilitate our analysis. Two anonymous reviewers and the editor, Dr Zuoheng Wang, provided very good and insightful comments for us to improve the manuscript. NR 24 TC 0 Z9 0 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD SEP 4 PY 2013 VL 14 AR 78 DI 10.1186/1471-2156-14-78 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 214NQ UT WOS:000324141000002 PM 24007308 ER PT J AU Hughey, CC Ma, LL James, FD Bracy, DP Wang, ZZ Wasserman, DH Rottman, JN Hittel, DS Shearer, J AF Hughey, Curtis C. Ma, Lianli James, Freyja D. Bracy, Deanna P. Wang, Zhizhang Wasserman, David H. Rottman, Jeffrey N. Hittel, Dustin S. Shearer, Jane TI Mesenchymal stem cell transplantation for the infarcted heart: therapeutic potential for insulin resistance beyond the heart SO CARDIOVASCULAR DIABETOLOGY LA English DT Article DE Diabetes; Glucose uptake; Isotopic tracer; Mitochondria; Myocardial infarction ID ACUTE MYOCARDIAL-INFARCTION; ACID-BINDING PROTEIN; FAILING HEART; STROMAL CELLS; FATTY-ACID; CARDIOVASCULAR-DISEASE; FUNCTIONAL IMPROVEMENT; UNCOUPLING PROTEINS; ENERGY-METABOLISM; CARDIAC-FUNCTION AB Background: This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance. Methods: C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[C-14] deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers. Results: MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding. Conclusions: These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action. C1 [Hughey, Curtis C.; Hittel, Dustin S.; Shearer, Jane] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. [Ma, Lianli; Wang, Zhizhang; Wasserman, David H.; Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37240 USA. [James, Freyja D.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37240 USA. [Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37232 USA. [Hittel, Dustin S.; Shearer, Jane] Univ Calgary, Fac Kinesiol, Calgary, AB T2N 1N4, Canada. RP Hughey, CC (reprint author), Univ Calgary, Fac Med, Dept Biochem & Mol Biol, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada. EM cchughey@ucalgary.ca FU Canadian Institutes of Health Research (CIHR); Killam Trusts; MitoCanada; National Institutes of Health Grant (NIH) [DK-054902] FX The authors thank the Vanderbilt University Analytical Resources Core for measuring plasma insulin concentrations. This work was supported by Canadian Institutes of Health Research (CIHR) (C.C. Hughey, J. Shearer), the Killam Trusts (C.C. Hughey), MitoCanada (J. Shearer) and the National Institutes of Health Grant (NIH) DK-054902 (D.H. Wasserman) and DK-59637 (Vanderbilt University Mouse Metabolic Phenotyping Center). NR 70 TC 7 Z9 8 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2840 J9 CARDIOVASC DIABETOL JI Cardiovasc. Diabetol. PD SEP 4 PY 2013 VL 12 AR 128 DI 10.1186/1475-2840-12-128 PG 14 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism SC Cardiovascular System & Cardiology; Endocrinology & Metabolism GA 219OF UT WOS:000324515700001 PM 24007410 ER PT J AU Das, I Park, JM Shin, JH Jeon, SK Lorenzi, H Linden, DJ Worley, PF Reeves, RH AF Das, Ishita Park, Joo-Min Shin, Jung H. Jeon, Soo Kyeong Lorenzi, Hernan Linden, David J. Worley, Paul F. Reeves, Roger H. TI Hedgehog Agonist Therapy Corrects Structural and Cognitive Deficits in a Down Syndrome Mouse Model SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TS65DN MOUSE; SONIC HEDGEHOG; CEREBELLAR PHENOTYPES; SYNDROME MICE; PROLIFERATION; IMPAIRMENT; LTD; NEURONS; NEUROGENESIS; EXCITABILITY AB Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus. We show that a single treatment of newborn mice with the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults. Further, SAG treatment at birth rescued phenotypes associated with hippocampal deficits that occur in untreated adult Ts65Dn mice. This treatment resulted in behavioral improvements and normalized performance in the Morris water maze task for learning and memory. SAG treatment also produced physiological effects and partially rescued both N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity and NMDA/AMPA receptor ratio, physiological measures associated with memory. These outcomes confirm an important role for the hedgehog pathway in cerebellar development and raise the possibility for its direct influence in hippocampal function. The positive results from this approach suggest a possible direction for therapeutic intervention to improve cognitive function for this population. C1 [Das, Ishita; Lorenzi, Hernan; Reeves, Roger H.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. [Das, Ishita; Lorenzi, Hernan; Reeves, Roger H.] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD 21205 USA. [Park, Joo-Min; Jeon, Soo Kyeong; Linden, David J.; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Park, Joo-Min] Jeju Natl Univ, Sch Med, Dept Physiol, Cheju 690756, South Korea. [Shin, Jung H.] NIH, Inst Alcohol Abuse & Alcoholism, Rockville, MD 20857 USA. RP Reeves, RH (reprint author), Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. EM rreeves@jhmi.edu FU Down Syndrome Research and Treatment Foundation; Research Down Syndrome; National Institute of Child Health and Human Development [R01 HD38384]; National Institute on Alcohol Abuse and Alcoholism at the NIH; National Institute of Mental Health [MH51106]; National Institute of Neurological Diseases and Stroke [R01 NS39156] FX This work was supported by the Down Syndrome Research and Treatment Foundation, Research Down Syndrome, and R01 HD38384 from the National Institute of Child Health and Human Development (R.H.R.); the intramural programs of National Institute on Alcohol Abuse and Alcoholism at the NIH (J.H.S.); MH51106 from the National Institute of Mental Health (D.J.L.); and R01 NS39156 from the National Institute of Neurological Diseases and Stroke (P.F.W.). The information presented does not necessarily reflect the opinions of the funding agencies. NR 49 TC 24 Z9 25 U1 2 U2 10 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 SEP 4 PY 2013 VL 5 IS 201 AR 201ra120 DI 10.1126/scitranslmed.3005983 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 214WJ UT WOS:000324167800008 PM 24005160 ER PT J AU Major, EO Douek, DC AF Major, Eugene O. Douek, Daniel C. TI Risk factors for rare diseases can be risky to define PML and natalizumab SO NEUROLOGY LA English DT Editorial Material ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY C1 [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov NR 9 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 3 PY 2013 VL 81 IS 10 BP 858 EP 859 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EF UT WOS:000330767400004 PM 23925759 ER PT J AU Gelber, RP Ross, GW Petrovitch, H Masaki, KH Launer, LJ White, LR AF Gelber, Rebecca P. Ross, G. Webster Petrovitch, Helen Masaki, Kamal H. Launer, Lenore J. White, Lon R. TI Antihypertensive medication use and risk of cognitive impairment The Honolulu-Asia Aging Study SO NEUROLOGY LA English DT Article ID MIDLIFE BLOOD-PRESSURE; ALZHEIMER-DISEASE; DOUBLE-BLIND; PROSPECTIVE COHORT; INCIDENT DEMENTIA; ELDERLY-MEN; MOUSE MODEL; OLDER; HYPERTENSION; ASSOCIATION AB Objective: To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men. Methods: The Honolulu-Asia Aging Study is a prospective, community-based cohort study of Japanese American men conducted in Honolulu, Hawaii. We examined 2,197 participants (mean age 77 years at cohort entry, 1991-1993, followed through September 2010) with hypertension and without dementia or cognitive impairment at baseline, who provided information on medication use. Cognitive function was assessed at 7 standardized examinations using the Cognitive Abilities Screening Instrument (CASI). Cognitive impairment was defined as a CASI score <74. Results: A total of 854 men developed cognitive impairment (median follow-up, 5.8 years). beta-Blocker use as the sole antihypertensive drug at baseline was consistently associated with a lower risk of cognitive impairment (incidence rate ratio [IRR] 0.69; 95% confidence interval [CI] 0.50-0.94), as compared with men not taking any antihypertensive medications, adjusting for multiple potential confounders. The use of diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, or vasodilators alone was not significantly associated with cognitive impairment. Results were similar excluding those with cardiovascular disease or <1 year of follow-up, and additionally adjusting for pulse pressure, heart rate, baseline and midlife systolic blood pressure, and midlife antihypertensive treatment (IRR 0.65; 95% CI 0.45-0.94). The association between beta-blocker use and cognitive impairment was stronger among men with diabetes, men aged >75 years, and those with pulse pressure >= 70 mm Hg. Conclusions: beta-blocker use is associated with a lower risk of developing cognitive impairment in elderly Japanese American men. C1 [Gelber, Rebecca P.; Ross, G. Webster; Petrovitch, Helen] VA Pacific Islands Hlth Care Syst, Honolulu, HI 96819 USA. [Ross, G. Webster; Petrovitch, Helen; White, Lon R.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Masaki, Kamal H.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Masaki, Kamal H.] Kuakini Med Ctr, Honolulu, HI USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Gelber, RP (reprint author), VA Pacific Islands Hlth Care Syst, Honolulu, HI 96819 USA. EM rebecca.gelber@va.gov FU National Institute on Aging [N01-AG-4-2149, UO1 AG017155, UO1 AG019349]; Intramural Research Program, NIA; National Heart, Lung, and Blood Institute [N01-HC-05102]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs FX Supported by a contract (N01-AG-4-2149) and grant (UO1 AG017155, UO1 AG019349) from the National Institute on Aging, the Intramural Research Program, NIA, a contract (N01-HC-05102) from the National Heart, Lung, and Blood Institute, and by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The information contained in this article does not necessarily reflect the position or the policy of the United States Government, and no official endorsement should be inferred. NR 34 TC 23 Z9 25 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 3 PY 2013 VL 81 IS 10 BP 888 EP 895 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EF UT WOS:000330767400011 PM 23911753 ER PT J AU Nussinov, R Ma, BY Tsai, CJ Csermely, P AF Nussinov, Ruth Ma, Buyong Tsai, Chung-Jung Csermely, Peter TI Allosteric Conformational Barcodes Direct Signaling in the Cell SO STRUCTURE LA English DT Review ID DISEASE-CAUSING MUTATION; STRUCTURAL BASIS; DRUG DISCOVERY; TRANSDUCTION PATHWAYS; MOLECULAR-MECHANISM; ENERGY LANDSCAPES; POPULATION SHIFT; COP9 SIGNALOSOME; FOLDING FUNNELS; BETA-ARRESTIN AB The cellular network is highly interconnected. Pathways merge and diverge. They proceed through shared proteins and may change directions. How are cellular pathways controlled and their directions decided, coded, and read? These questions become particularly acute when we consider that a small number of pathways, such as signaling pathways that regulate cell fates, cell proliferation, and cell death in development, are extensively exploited. This review focuses on these signaling questions from the structural standpoint and discusses the literature in this light. All co-occurring allosteric events (including posttranslational modifications, pathogen binding, and gain-of-function mutations) collectively tag the protein functional site with a unique barcode. The barcode shape is read by an interacting molecule, which transmits the signal. A conformational barcode provides an intracellular address label, which selectively favors binding to one partner and quenches binding to others, and, in this way, determines the pathway direction, and, eventually, the cell's response and fate. C1 [Nussinov, Ruth; Ma, Buyong; Tsai, Chung-Jung] NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Csermely, Peter] Semmelweis Univ, Dept Med Chem, H-1094 Budapest, Hungary. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. EM nussinor@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Hungarian National Science Foundation [OTKA K83314]; EU [TAMOP-4.2.2/B-10/1-2010-0013]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are grateful to one of our reviewers, who provided a broad, insightful overview of our review, uniquely capturing its significance to the structural and signaling biology community and its implications to the field. We have incorporated it in the Conclusions with only minor modifications. 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. It was also supported by research grants from the Hungarian National Science Foundation (OTKA K83314) and by the EU (TAMOP-4.2.2/B-10/1-2010-0013). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 97 TC 28 Z9 28 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD SEP 3 PY 2013 VL 21 IS 9 BP 1509 EP 1521 DI 10.1016/j.str.2013.06.002 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 297PY UT WOS:000330268600007 PM 24010710 ER PT J AU Montelione, GT Nilges, M Bax, A Guntert, P Herrmann, T Richardson, JS Schwieters, CD Vranken, WF Vuister, GW Wishart, DS Berman, HM Kleywegt, GJ Markley, JL AF Montelione, Gaetano T. Nilges, Michael Bax, Ad Guentert, Peter Herrmann, Torsten Richardson, Jane S. Schwieters, Charles D. Vranken, Wim F. Vuister, Geerten W. Wishart, David S. Berman, Helen M. Kleywegt, Gerard J. Markley, John L. TI Recommendations of the wwPDB NMR Validation Task Force SO STRUCTURE LA English DT Article ID PROTEIN DATA-BANK; STRUCTURE ENSEMBLES; CHEMICAL-SHIFTS; PRECISION; PREDICTION; QUALITY; TOOL; CRYSTALLOGRAPHY; REFINEMENT; RESTRAINTS AB As methods for analysis of biomolecular structure and dynamics using nuclear magnetic resonance spectroscopy (NMR) continue to advance, the resulting 3D structures, chemical shifts, and other NMR data are broadly impacting biology, chemistry, and medicine. Structure model assessment is a critical area of NMR methods development, and is an essential component of the process of making these structures accessible and useful to the wider scientific community. For these reasons, the Worldwide Protein Data Bank (wwPDB) has convened an NMR Validation Task Force (NMR-VTF) to work with wwPDB partners in developing metrics and policies for biomolecular NMR data harvesting, structure representation, and structure quality assessment. This paper summarizes the recommendations of the NMR-VTF, and lays the groundwork for future work in developing standards and metrics for biomolecular NMR structure quality assessment. C1 [Montelione, Gaetano T.] Rutgers State Univ, Ctr Adv Biotechnol & Med, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Montelione, Gaetano T.] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Biochem & Mol Biol, Piscataway, NJ 08854 USA. [Berman, Helen M.] Rutgers State Univ, Ctr Integrat Prote Res, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Nilges, Michael] Inst Pasteur, Dept Biol Struct & Chim, Unite Bioinformat Struct, F-75015 Paris, France. [Nilges, Michael] Ctr Natl Rech Sci, Unite Mixte Rech 3258, F-75015 Paris, France. [Bax, Ad] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NCI, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Guentert, Peter] Goethe Univ Frankfurt, Ctr Biomol Magnet Resonance, Inst Biophys Chem, D-60438 Frankfurt, Germany. [Guentert, Peter] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany. [Herrmann, Torsten] Ecole Normale Super Lyon, Ctr Resonance Magnet Nucl Tres Hauts Champs, F-69100 Villeurbanne, France. [Herrmann, Torsten] Ctr Natl Rech Sci, Inst Sci Analyt, Unite Mixte Rech 5280, F-69100 Villeurbanne, France. [Richardson, Jane S.] Duke Univ, Dept Biochem, Durham, NC 27710 USA. [Vranken, Wim F.] Vlaams Inst Biotechnol, Dept Struct Biol, B-1050 Brussels, Belgium. [Vranken, Wim F.] Vrije Univ Brussel, B-1050 Brussels, Belgium. [Vuister, Geerten W.] Univ Leicester, Dept Biochem, Lancaster LE1 9HN, England. [Wishart, David S.] Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2E8, Canada. [Wishart, David S.] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E8, Canada. [Kleywegt, Gerard J.] European Bioinformat Inst, European Mol Biol Lab, Protein Data Bank Europe, Cambridge CB10 1SD, England. [Markley, John L.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. RP Montelione, GT (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. EM guy@cabm.rutgers.edu RI Guntert, Peter/L-5577-2013; Herrmann, Torsten/B-9978-2008; Nilges, Michael/E-4803-2011; Vranken, Wim/J-5051-2016; Fachbereich14, Dekanat/C-8553-2015 OI Guntert, Peter/0000-0002-2911-7574; Wishart, David S/0000-0002-3207-2434; Kleywegt, Gerard J./0000-0002-4670-0331; Herrmann, Torsten/0000-0003-2115-4781; Nilges, Michael/0000-0002-1451-8092; Vranken, Wim/0000-0001-7470-4324; FU Pasteur Institute and NIGMS Protein Structure Initiative grant [U54 GM094597]; NIH Intramural Research Program of the NIDDK; NIH Intramural Research Program of the CIT; BBSRC grants [BB/J007471/1, BB/J007897/1]; NIH [R01-GM073930]; Brussels Institute for Research and Innovation (Innoviris) grant [BB2B 2010-1-12] FX We thank the following people for participation in the discussions of the wwPDB NMR-VTF and for their comments on these recommendations: J. Aramini, J. Block, R.A. Byrd, A. Gutmanas, P.M.S. Hendrickx, Y.P. Huang, N. Kobayashi, C. Lawson, H. Nakamura, R.J. Read, A. Rosato, D. Snyder, R. Tejero, E.L. Ulrich, and J. Westbrook. Support for this work was provided by members of the Worldwide PDB: RCSB PDB (NSF DBI 0829586); PDBe (Wellcome Trust 075968 and 088944; BBSRC BB/E007511/1); PDBj (NBDC-JST); BMRB (NLM NIH P41 LM05799); and The Pasteur Institute and NIGMS Protein Structure Initiative grant U54 GM094597 (to G.T.M.). Funding was also provided by NIH Intramural Research Programs of the NIDDK and CIT (to A.B. and C.S.), BBSRC grants BB/J007471/1 and BB/J007897/1 (to G.J.K. and G.W.V., respectively), NIH grant R01-GM073930 (to J.S.R.), and Brussels Institute for Research and Innovation (Innoviris) grant BB2B 2010-1-12 (to W.F.V.). NR 54 TC 48 Z9 48 U1 0 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD SEP 3 PY 2013 VL 21 IS 9 BP 1563 EP 1570 DI 10.1016/j.str.2013.07.021 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 297PY UT WOS:000330268600012 PM 24010715 ER PT J AU Abascal-Palacios, G Schindler, C Rojas, AL Bonifacino, JS Hierro, A AF Abascal-Palacios, Guillermo Schindler, Christina Rojas, Adriana L. Bonifacino, Juan S. Hierro, Aitor TI Structural Basis for the Interaction of the Golgi-Associated Retrograde Protein Complex with the t-SNARE Syntaxin 6 SO STRUCTURE LA English DT Article ID SYNAPTIC VESICLE FUSION; 3-DIMENSIONAL STRUCTURE; GARP COMPLEX; CONFORMATIONAL SWITCH; TETHERING FACTORS; TERMINAL DOMAIN; SUBUNIT; TLG1P; SIMILARITY; ENDOSOMES AB The Golgi-Associated Retrograde Protein (GARP) complex is a tethering factor involved in the fusion of endosome-derived transport vesicles to the trans-Golgi network through interaction with components of the Syntaxin 6/Syntaxin 16/Vti1a/VAMP4 SNARE complex. The mechanisms by which GARP and other tethering factors engage the SNARE fusion machinery are poorly understood. Herein, we report the structural basis for the interaction of the human Ang2 subunit of GARP with the Syntaxin 6 and the closely related Syntaxin 10. The crystal structure of the Syntaxin 6 Habc domain in complex with a peptide from the N terminus of Ang2 shows a binding mode in which a dityrosine motif of Ang2 interacts with a highly conserved groove in Syntaxin 6. Structure-based mutational analyses validate the crystal structure and support the phylogenetic conservation of this interaction. C1 [Abascal-Palacios, Guillermo; Rojas, Adriana L.; Hierro, Aitor] CIC bioGUNE, Struct Biol Unit, Derio 48160, Spain. [Schindler, Christina; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Hierro, Aitor] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov; ahierro@cicbiogune.es RI Rojas, Adriana/G-2403-2011; Hierro, Aitor/F-9998-2011; OI Rojas, Adriana/0000-0002-7358-3505; Hierro, Aitor/0000-0002-7721-1581; Bonifacino, Juan S./0000-0002-5673-6370 FU Carlos III Health Institute grant [PI11/00121]; Basque Government grant [PI2011-26]; National Institute of Child Health and Human Development; Basque Government [BFI08.53] FX We thank A. Muga (University of the Basque Country) for help with ITC experiments and A. Vidaurrazaga for technical assistance. This study made use of the Proteomics Platform at CIC bioGUNE, member of CIBERehd and ProteoRed-ISCIII and the European Synchrotron Radiation Facility (Grenoble) under the Block Allocation Group MX1283/MX1420. This research was supported by Carlos III Health Institute grant PI11/00121, Basque Government grant PI2011-26 (to A.H.), and the intramural program of the National Institute of Child Health and Human Development (to J.S.B.). G.A.-P. has been supported by a fellowship from the Basque Government (BFI08.53). NR 37 TC 6 Z9 7 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD SEP 3 PY 2013 VL 21 IS 9 BP 1698 EP 1706 DI 10.1016/j.str.2013.06.025 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 297PY UT WOS:000330268600025 PM 23932592 ER PT J AU Reitman, ML AF Reitman, Marc L. TI FGF21 Mimetic Shows Therapeutic Promise SO CELL METABOLISM LA English DT Editorial Material ID GAMMA AB FGF21 is a protein withmultiple metabolic actions, currently a bright star beckoning on the metabolic disease therapeutic horizon. Gaich et al. (2013) present the first clinical efficacy trial for an FGF21 mimetic, finding robust lipid-lowering effects, some reduction in body weight, but surprisingly modest effects on glucose homeostasis. C1 NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU Intramural NIH HHS [ZIA DK075062-01] NR 15 TC 16 Z9 17 U1 1 U2 4 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 SEP 3 PY 2013 VL 18 IS 3 BP 307 EP 309 DI 10.1016/j.cmet.2013.08.014 PG 3 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UG UT WOS:000326267300003 PM 24011067 ER PT J AU Azzam, G Wang, XT Bell, D Murphy, ME AF Azzam, Gregory Wang, Xuting Bell, Douglas Murphy, Maureen E. TI CSF1 Is a Novel p53 Target Gene Whose Protein Product Functions in a Feed-Forward Manner to Suppress Apoptosis and Enhance p53-Mediated Growth Arrest SO PLOS ONE LA English DT Article ID CODON 72 POLYMORPHISM; STIMULATING FACTOR-I; DNA-DAMAGE; REGULATORY ELEMENTS; RECEPTOR EXPRESSION; ULCERATIVE-COLITIS; R72P POLYMORPHISM; BREAST-CANCER; MICE; BINDING AB The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radioresistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types. C1 [Azzam, Gregory; Murphy, Maureen E.] Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, Philadelphia, PA USA. [Wang, Xuting; Bell, Douglas] NIEHS, Mol Genet Lab, Intramural Res Program, NIH, Res Triangle Pk, NC 27709 USA. RP Murphy, ME (reprint author), Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, Philadelphia, PA USA. EM mmurphy@wistar.org OI Wang, Xuting/0000-0001-6781-8008 FU National Institute of Environmental Health Sciences-National Institutes of Health [Z01ES100475, Z01ES065079] FX This work was funded in part by the Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health (projects: Z01ES100475 and Z01ES065079). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 6 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 3 PY 2013 VL 8 IS 9 AR e74297 DI 10.1371/journal.pone.0074297 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217DY UT WOS:000324338200104 PM 24019961 ER PT J AU Coggill, P Eberhardt, RY Finn, RD Chang, YY Jaroszewski, L Godzik, A Das, D Xu, QP Axelrod, HL Aravind, L Murzin, AG Bateman, A AF Coggill, Penelope Eberhardt, Ruth Y. Finn, Robert D. Chang, Yuanyuan Jaroszewski, Lukasz Godzik, Adam Das, Debanu Xu, Qingping Axelrod, Herbert L. Aravind, L. Murzin, Alexey G. Bateman, Alex TI Two Pfam protein families characterized by a crystal structure of protein lpg2210 from Legionella pneumophila SO BMC BIOINFORMATICS LA English DT Article DE Domain of unknown function; Protein family; Protein structure; DUF4424; YARHG domain; Sequence analysis ID GENOMICS; IDENTIFICATION AB Background: Every genome contains a large number of uncharacterized proteins that may encode entirely novel biological systems. Many of these uncharacterized proteins fall into related sequence families. By applying sequence and structural analysis we hope to provide insight into novel biology. Results: We analyze a previously uncharacterized Pfam protein family called DUF4424 [ Pfam: PF14415]. The recently solved three-dimensional structure of the protein lpg2210 from Legionella pneumophila provides the first structural information pertaining to this family. This protein additionally includes the first representative structure of another Pfam family called the YARHG domain [Pfam:PF13308]. The Pfam family DUF4424 adopts a 19-stranded beta-sandwich fold that shows similarity to the N-terminal domain of leukotriene A-4 hydrolase. The YARHG domain forms an all-helical domain at the C-terminus. Structure analysis allows us to recognize distant similarities between the DUF4424 domain and individual domains of M1 aminopeptidases and tricorn proteases, which form massive proteasome-like capsids in both archaea and bacteria. Conclusions: Based on our analyses we hypothesize that the DUF4424 domain may have a role in forming large, multi-component enzyme complexes. We suggest that the YARGH domain may play a role in binding a moiety in proximity with peptidoglycan, such as a hydrophobic outer membrane lipid or lipopolysaccharide. C1 [Coggill, Penelope; Eberhardt, Ruth Y.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Coggill, Penelope; Eberhardt, Ruth Y.; Bateman, Alex] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Finn, Robert D.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Chang, Yuanyuan; Jaroszewski, Lukasz; Godzik, Adam] Sanford Burnham Med Res Inst, Program Bioinformat & Syst Biol, La Jolla, CA 92037 USA. [Chang, Yuanyuan; Jaroszewski, Lukasz; Godzik, Adam; Das, Debanu; Xu, Qingping; Axelrod, Herbert L.] SLAC Natl Accelerator Lab, Joint Ctr Struct Genom, Menlo Pk, CA 94025 USA. [Das, Debanu; Xu, Qingping; Axelrod, Herbert L.] SLAC Natl Accelerator Lab, Stanford Synchrotron Radiat Lightsource, Menlo Pk, CA 94025 USA. [Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Murzin, Alexey G.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. RP Coggill, P (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, Cambs, England. EM pcc@sanger.ac.uk RI Godzik, Adam/A-7279-2009; OI Godzik, Adam/0000-0002-2425-852X; Eberhardt, Ruth/0000-0001-6152-1369; Finn, Robert/0000-0001-8626-2148; Bateman, Alex/0000-0002-6982-4660 FU Wellcome Trust [WT077044/Z/05/Z]; Howard Hughes Medical Institute; National Library of Medicine, USA; NIH [R01GM101457]; National Institutes of Health from the NIGMS Protein Structure Initiative [U54 GM094586]; National Science Foundation [IIS-0646708, IIS-1153617]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]; UK Medical Research Council [MC_U105192716] FX Wellcome Trust (grant numbers WT077044/Z/05/Z); Howard Hughes Medical Institute; Work by LA is supported by the intramural funds of the National Library of Medicine, USA.; NIH (R01GM101457); This work was supported in part by National Institutes of Health Grant U54 GM094586 from the NIGMS Protein Structure Initiative to the Joint Center for Structural Genomics. The DUF annotation jamboree was supported by National Science Foundation (IIS-0646708 and IIS-1153617); Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource, a Directorate of SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the U.S. Department of Energy Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). Work by AGM was supported by the UK Medical Research Council [MC_U105192716]. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NCRR or NIH. NR 14 TC 0 Z9 0 U1 0 U2 2 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 SEP 3 PY 2013 VL 14 AR 265 DI 10.1186/1471-2105-14-265 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 221TQ UT WOS:000324682800001 PM 24004689 ER PT J AU Nichols, HB Baird, DD DeRoo, LA Kissling, GE Sandler, DP AF Nichols, H. B. Baird, D. D. DeRoo, L. A. Kissling, G. E. Sandler, D. P. TI Tubal ligation in relation to menopausal symptoms and breast cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; hot flashes; menopause; tubal ligation ID STERILIZATION; HYSTERECTOMY; WOMEN; OOPHORECTOMY; COHORT AB Background: Local inflammation after tubal ligation may affect ovarian function and breast cancer risk. Methods: We analysed tubal ligation, menopausal characteristics, and breast cancer risk in the Sister Study cohort (N=50 884 women). Results: Tubal ligation was associated with hot flashes (hazard ratio (HR) 1.09; 95% confidence interval (CI): 1.06-1.12) but not menopausal age (HR 0.99; 95% CI: 0.96-1.02). Tubal ligation did not have an impact on breast cancer overall (HR 0.95; 95% CI: 0.85-1.06), but had a suggested inverse relation with oestrogen receptor+/progesterone receptor+ invasive tumours (HR 0.84; 95% CI: 0.70-1.01), possibly because of subsequent hysterectomy/bilateral oophorectomy. Conclusion: Tubal ligation does not influence overall breast cancer risk. C1 [Nichols, H. B.; Baird, D. D.; DeRoo, L. A.; Sandler, D. P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Kissling, G. E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Nichols, HB (reprint author), NIEHS, Epidemiol Branch, POB 12233,111 TW Alexander Dr,MD A3-05, Res Triangle Pk, NC 27709 USA. EM nicholshb@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Preliminary data were presented at the 36th annual meeting of the American Society of Preventive Oncology, 3-6 March 2012, Washington, DC, USA. The authors appreciate the helpful comments of Drs Matthew Longnecker and Allen Wilcox. NR 17 TC 4 Z9 4 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 3 PY 2013 VL 109 IS 5 BP 1291 EP 1295 DI 10.1038/bjc.2013.433 PG 5 WC Oncology SC Oncology GA 214WP UT WOS:000324168500027 PM 23922107 ER PT J AU Lai, GY Weinstein, SJ Albanes, D Taylor, PR McGlynn, KA Virtamo, J Sinha, R Freedman, ND AF Lai, G. Y. Weinstein, S. J. Albanes, D. Taylor, P. R. McGlynn, K. A. Virtamo, J. Sinha, R. Freedman, N. D. TI The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers SO BRITISH JOURNAL OF CANCER LA English DT Article DE liver cancer; chronic liver disease; coffee preparation; filtered coffee; boiled coffee; prospective cohort ID GAMMA-GLUTAMYL-TRANSFERASE; IMPAIRED GLUCOSE-TOLERANCE; TYPE-2 DIABETES-MELLITUS; HEPATOCELLULAR-CARCINOMA; DITERPENES CAFESTOL; CHLOROGENIC ACID; CAFFEINE CONSUMPTION; COMPONENTS KAHWEOL; METABOLIC SYNDROME; RISK-FACTORS AB Background: Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. Methods: We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27 037 Finnish male smokers, aged 50-69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. Results: Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73-0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48-0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee. Conclusion: These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered. C1 [Lai, G. Y.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Lai, G. Y.; Weinstein, S. J.; Albanes, D.; Sinha, R.; Freedman, N. D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Taylor, P. R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McGlynn, K. A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Lai, GY (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, 9609 Med Ctr Dr,Room 2W136 MSC 9712, Bethesda, MD 20892 USA. EM laigy@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services and US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004). The sponsor reviewed and approved final submission but had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation of the manuscript. NR 54 TC 18 Z9 19 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 3 PY 2013 VL 109 IS 5 BP 1344 EP 1351 DI 10.1038/bjc.2013.405 PG 8 WC Oncology SC Oncology GA 214WP UT WOS:000324168500034 PM 23880821 ER PT J AU Dominianni, C Huang, WY Berndt, S Hayes, RB Ahn, J AF Dominianni, C. Huang, W-Y Berndt, S. Hayes, R. B. Ahn, J. TI Prospective study of the relationship between coffee and tea with colorectal cancer risk: The PLCO Cancer Screening Trial SO BRITISH JOURNAL OF CANCER LA English DT Article DE coffee; tea; colorectal cancer; prospective; PLCO ID GREEN TEA; PROSPECTIVE COHORT; COLON-CANCER; BLACK TEA; POOLED ANALYSIS; RECTAL-CANCER; CONSUMPTION; CELLS; WOMEN; JAPAN AB Background: Coffee and tea are commonly consumed and carry potential anticancer components that could reduce the risk of colorectal cancer; however, their relationships with colorectal cancer risk remain inconsistent. Methods: A prospective analysis was carried out to examine the relationships of coffee and tea intake with colorectal cancer risk in 57 398 men and women in the intervention arm of the National Cancer Institute-Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, a national screening study that limits differential detection biases. Coffee and tea intakes were assessed by food frequency questionnaire. Results: Six hundred and eighty-one incident colorectal cancer cases were ascertained during a median follow-up of 11.4 years. Greater coffee intake was not associated with risk of colorectal cancer (relative risk (RR)=1.08, 95% confidence interval (CI)=0.79-1.48, P-trend=0.23). Stratifying by cancer site (P-heterogeneity=0.48) or stage (P-heterogeneity=0.83) did not alter the relationship. Associations remained unchanged in subsets of participants for either caffeinated or decaffeinated coffee or when stratifying by several colorectal cancer risk factors. Similarly, greater tea intake was not associated with colorectal cancer risk overall (RR=0.77, 95% CI=0.55-1.09, P-trend=0.17) or by cancer site (P-heterogeneity=0.14) or stage (P-heterogeneity=0.60). These associations were not modified by several colorectal cancer risk factors. Conclusion: The findings of this study do not provide evidence to suggest that drinking coffee or tea is beneficial in protecting against colorectal cancer. C1 [Dominianni, C.; Hayes, R. B.; Ahn, J.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY 10016 USA. [Dominianni, C.; Hayes, R. B.; Ahn, J.] NYU, Inst Canc, New York, NY 10016 USA. [Huang, W-Y; Berndt, S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Dominianni, C (reprint author), NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, 650 1st Ave, New York, NY 10016 USA. EM cb1748@nyumc.org OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [R03 CA159414]; AACR Career Development Award [R01CA159036]; Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics FX We thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Centre investigators and staff of the PLCO Cancer Screening Trial, Tom Riley and Staff, Information Management Services Inc., Barbara O'Brien and staff and Westat Inc. Most importantly, we acknowledge the study participants for their contributions to making this study possible. This work was supported by National Cancer Institute R03 CA159414, AACR Career Development Award, R01CA159036 and by the Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 47 TC 9 Z9 10 U1 4 U2 39 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 SEP 3 PY 2013 VL 109 IS 5 BP 1352 EP 1359 DI 10.1038/bjc.2013.434 PG 8 WC Oncology SC Oncology GA 214WP UT WOS:000324168500035 PM 23907431 ER PT J AU Dar, NA Islami, F Bhat, GA Shah, IA Makhdoomi, MA Iqbal, B Rafiq, R Lone, MM Abnet, CC Boffetta, P AF Dar, N. A. Islami, F. Bhat, G. A. Shah, I. A. Makhdoomi, M. A. Iqbal, B. Rafiq, R. Lone, M. M. Abnet, C. C. Boffetta, P. TI Poor oral hygiene and risk of esophageal squamous cell carcinoma in Kashmir SO BRITISH JOURNAL OF CANCER LA English DT Article DE esophageal cancer; oral health; dental hygiene; tooth loss; Kashmir ID TOOTH LOSS; GASTROINTESTINAL-TRACT; ENDOGENOUS FORMATION; PERIODONTAL-DISEASE; NORTHEASTERN IRAN; GASTRIC CANCERS; POPULATION; COHORT; HEALTH; DYSPLASIA AB Background: Several studies have suggested an association between poor oral health and esophageal squamous cell carcinoma (ESCC). We conducted a case-control study in Kashmir, a region with relatively high incidence of ESCC in north India, to investigate the association between oral hygiene and ESCC risk. Methods: We recruited 703 histologically confirmed ESCC cases, and 1664 controls individually matched to the cases for age, sex, and district of residence. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: We found an inverse association between teeth cleaning and ESCC risk. As compared with never cleaning teeth, the OR (95% CI) was 0.41 (0.28-0.62) for cleaning less than daily and 0.44 (0.25-0.77) for cleaning at least once a day (P for trend=0.026) in models adjusted for multiple potential confounders, including several indicators of socioeconomic status. This association persisted after we limited our analyses to never tobacco users. The inverse association between cleaning teeth and ESCC was stronger with using brushes than with using sticks/fingers. We also found an association between the number of decayed, filled, and missing teeth and ESCC risk, but the trend of the associations was not statistically significant. Avoiding solid food and cold beverages because of teeth and oral problems were also associated with ESCC risk. Conclusion: We found an association between poor oral hygiene indicators and ESCC risk, supporting the previous studies that showed the same associations. C1 [Dar, N. A.; Bhat, G. A.; Shah, I. A.; Makhdoomi, M. A.; Iqbal, B.; Rafiq, R.] Univ Kashmir, Dept Biochem, Hazratbal Srinagar 190006, JK, India. [Dar, N. A.; Islami, F.; Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Dar, N. A.; Islami, F.; Boffetta, P.] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY 10029 USA. [Islami, F.] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran 14117, Iran. [Lone, M. M.] SK Inst Med Sci, Dept Radiat Oncol, Srinagar 190011, India. [Abnet, C. C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Boffetta, P.] Int Prevent Res Inst, F-69006 Lyon, France. RP Dar, NA (reprint author), Univ Kashmir, Dept Biochem, Hazratbal Srinagar 190006, JK, India. EM nazirramzan@gmail.com RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Extramural grant of Indian Council of Medical Research (ICMR), New Delhi, under IRIS ID [5/13/37/2007/-NCD-III]; fellowship (American Cancer Society international fellowships for beginning investigators (ACSBI)) from the Union for International Cancer Control (UICC) FX This study was supported by Extramural grant of Indian Council of Medical Research (ICMR), New Delhi, under IRIS ID 5/13/37/2007/-NCD-III. NAD was supported by a fellowship (American Cancer Society international fellowships for beginning investigators (ACSBI)) from the Union for International Cancer Control (UICC). NR 30 TC 18 Z9 19 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 3 PY 2013 VL 109 IS 5 BP 1367 EP 1372 DI 10.1038/bjc.2013.437 PG 6 WC Oncology SC Oncology GA 214WP UT WOS:000324168500037 PM 23900216 ER PT J AU Pletcher, MJ Sibley, CT Pignone, M Vittinghoff, E Greenland, P AF Pletcher, Mark J. Sibley, Christopher T. Pignone, Michael Vittinghoff, Eric Greenland, Philip TI Interpretation of the Coronary Artery Calcium Score in Combination With Conventional Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA) SO CIRCULATION LA English DT Article DE calcium; coronary disease; epidemiology; imaging; medical ID ULTRAFAST COMPUTED-TOMOGRAPHY; HEART-DISEASE PREDICTION; ALL-CAUSE MORTALITY; YOUNG-ADULTS; ASYMPTOMATIC INDIVIDUALS; ETHNIC-GROUPS; CALCIFICATION; PREVALENCE; EVENTS; IMPACT AB Background The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established. Methods and Results We analyzed CAC scores and CHD risk factor measurements from 6757 black, Chinese, Hispanic, and white men and women aged 45 to 84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was associated with age, sex, race/ethnicity, and all conventional CHD risk factors. Multivariable models using these factors predicted the presence of CAC (C statistic=0.789) and degree of elevation (16% of variation explained) and can be used to update a pretest CHD risk estimate, such as the 10-year Framingham Risk Score, that is based on an individual's conventional risk factors. In scenarios in which a high CAC score is expected, a moderately elevated CAC score of 50 is reassuring (eg, reducing risk from 10% to 6% in a healthy older white man), but when a low/zero CAC score is expected, even with identical pretest CHD risk, the same CAC score of 50 may be alarmingly high (eg, increasing risk from 10% to 20% in a middle-aged black woman with multiple risk factors). Both the magnitude and direction of the shift in risk varied markedly with pretest CHD risk and with the pattern of risk factors. Conclusions Knowledge of what CAC score to expect for an individual patient, based on their conventional risk factors, may help clinicians decide when to order a CAC test and how to interpret the results. C1 [Pletcher, Mark J.; Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [Pletcher, Mark J.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94107 USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Pignone, Michael] Univ N Carolina, Chapel Hill, NC USA. [Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Pletcher, MJ (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM mpletcher@epi.ucsf.edu OI Pignone, Michael/0000-0002-6657-7342 FU National Heart, Lung, and Blood Institute [R21HL112256, N01-HC-95159, N01-HC-95169]; National Center for Research Resources [UL1-RR-024156, UL1-RR-025005]; National Institutes of Health Clinical Center FX Drs Pletcher, Pignone, and Greenland were supported by a grant from the National Heart, Lung, and Blood Institute (R21HL112256). MESA was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-RR-024156 and UL1-RR-025005 from the National Center for Research Resources. Dr Sibley was supported by the intramural research program of the National Institutes of Health Clinical Center. NR 32 TC 25 Z9 25 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 3 PY 2013 VL 128 IS 10 BP 1076 EP 1084 DI 10.1161/CIRCULATIONAHA.113.002598 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 210GY UT WOS:000323820200012 PM 23884352 ER PT J AU Jiang, ZH Cowell, RM Nakazawa, K AF Jiang, Zhihong Cowell, Rita M. Nakazawa, Kazu TI Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Review DE animal model; fast-spiking neurons; GABA neuron; NMDA receptors; oxidative stress; PGC-1 alpha; social isolation ID RECEPTOR-GAMMA COACTIVATOR-1-ALPHA; FAST-SPIKING INTERNEURONS; MONKEY PREFRONTAL CORTEX; ACTIVITY-DEPENDENT REGULATION; DECREASED GLUTATHIONE LEVELS; SELECTIVE VISUAL-ATTENTION; ANTIOXIDANT DEFENSE SYSTEM; ACTIVATED PROTEIN-KINASE; NEURON AXON TERMINALS; OXIDATIVE STRESS AB Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons (PVIs) vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model in which NMDA receptors (NMDARs) are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010). We have since revealed that this social isolation induced effect is caused by impairments in the antioxidant defense capacity in the PVIs in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1 alpha, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al., 2013). Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of PVIs. C1 [Jiang, Zhihong; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Bethesda, MD 20892 USA. [Cowell, Rita M.] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. RP Jiang, ZH (reprint author), NIMH, 35 Convent Dr,Bldg 35,Room 1C915, Bethesda, MD 20892 USA. EM zhihongjiang@mail.nih.gov; nakazawk@mail.nih.gov RI Cowell, Rita/J-5083-2013; Nakazawa, Kazutoshi/J-6195-2015 OI Cowell, Rita/0000-0001-5814-9412; Nakazawa, Kazutoshi/0000-0001-5699-9093 FU NIMH; [K01M11077955-05] FX This research was supported by the Intramural Research Programs of the NIMH, and K01M11077955-05 (RMC). NR 301 TC 28 Z9 28 U1 6 U2 37 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD SEP 3 PY 2013 VL 7 AR 116 DI 10.3389/fnbeh.2013.00116 PG 18 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 210GN UT WOS:000323818700001 PM 24027504 ER PT J AU Britton, KA Massaro, JM Murabito, JM Kreger, BE Hoffmann, U Fox, CS AF Britton, Kathryn A. Massaro, Joseph M. Murabito, Joanne M. Kreger, Bernard E. Hoffmann, Udo Fox, Caroline S. TI Body Fat Distribution, Incident Cardiovascular Disease, Cancer, and All-Cause Mortality SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE body fat distribution; cancer; cardiovascular disease; obesity; visceral fat ID VISCERAL ADIPOSE-TISSUE; PERICARDIAL FAT; ABDOMINAL FAT; RISK-FACTORS; ASSOCIATION; OBESITY; INFLAMMATION; BURDEN; MEN AB Objectives The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. Background The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. Methods Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. Results Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. Conclusions Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat. (C) 2013 by the American College of Cardiology Foundation C1 [Britton, Kathryn A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Britton, Kathryn A.; Murabito, Joanne M.; Kreger, Bernard E.; Fox, Caroline S.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Murabito, Joanne M.; Kreger, Bernard E.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. RP Fox, CS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Heart, Lung, and Blood Institute [K12 HL083786] FX Division of Endocrinology, Metabolism and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Dr. Britton was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. All other authors have reported that they have no relationships relevant to the content of this paper to disclose. NR 17 TC 102 Z9 108 U1 5 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 3 PY 2013 VL 62 IS 10 BP 921 EP 925 DI 10.1016/j.jacc.2013.06.027 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 211IO UT WOS:000323900300012 PM 23850922 ER PT J AU Gupte, R Muse, GW Chinenov, Y Adelman, K Rogatsky, I AF Gupte, Rebecca Muse, Ginger W. Chinenov, Yurii Adelman, Karen Rogatsky, Inez TI Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE initiation and elongation; transcriptional repression; NELF and P-TEFb complex; inflammation ID RNA-POLYMERASE-II; NF-KAPPA-B; P-TEFB; INFLAMMATORY RESPONSE; ELONGATION; EXPRESSION; CELLS; PHOSPHORYLATION; COFACTOR; NELF AB Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-kappa B and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR: GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle. C1 [Gupte, Rebecca; Rogatsky, Inez] Weill Cornell Grad Sch Med Sci, Grad Program Biochem Cell & Mol Biol, New York, NY 10021 USA. [Rogatsky, Inez] Weill Cornell Grad Sch Med Sci, Grad Program Immunol & Microbial Pathogenesis, New York, NY 10021 USA. [Gupte, Rebecca; Chinenov, Yurii; Rogatsky, Inez] Hosp Special Surg, New York, NY 10021 USA. [Muse, Ginger W.; Adelman, Karen] NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Rogatsky, I (reprint author), Weill Cornell Grad Sch Med Sci, Grad Program Biochem Cell & Mol Biol, New York, NY 10021 USA. EM rogatskyi@hss.edu FU Tow Foundation; National Institutes of Health; American Heart Association [11SDG5160006]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES101987] FX We thank M. Coppo, M. Sacta, D. Rollins, and L. Ivashkiv for insightful discussion and the Tow Foundation support to the Hospital for Special Surgery Genomics Center. This work was supported by grants from the National Institutes of Health (to I.R.), by American Heart Association Grant 11SDG5160006 (to Y.C.), and by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences Grant Z01 ES101987 (to K.A.). NR 41 TC 18 Z9 18 U1 0 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 SEP 3 PY 2013 VL 110 IS 36 BP 14616 EP 14621 DI 10.1073/pnas.1309898110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211DY UT WOS:000323886200037 PM 23950223 ER PT J AU Varadarajan, J McWilliams, MJ Hughes, SH AF Varadarajan, Janani McWilliams, Mary Jane Hughes, Stephen H. TI Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE strand transfer inhibitor; chromosomal rearrangements; integrase inhibitors ID STRAND TRANSFER INHIBITOR; TRANSFER-RNA CLEAVAGE; PRIMER BINDING-SITE; IN-VIVO; RETROVIRAL INTEGRATION; DNA; MUTATIONS; SEQUENCES; REPLICATION; RESISTANCE AB Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3' processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, similar to 10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen. C1 [Varadarajan, Janani; McWilliams, Mary Jane; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX We thank Dr. Daria Hazuda, who generously provided the RAL used in the experiments; Dr. Eric Freed, Ms. Sherimay Ablan and Dr. Angelica Martins for generously providing the PBMCs, IL-2, and PHA-P; Dr. Barry Johnson for helping with the HIV-1 intasome model in Fig. S1; Ms. Andrea Ferris for constructing the pSICO-LZF plasmid and providing cells for the experiments; Mr. Richard Frederickson for help with figures; and Ms. Teresa Burdette for help with the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 31 TC 8 Z9 8 U1 0 U2 5 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 SEP 3 PY 2013 VL 110 IS 36 BP 14747 EP 14752 DI 10.1073/pnas.1305066110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211DY UT WOS:000323886200059 PM 23959861 ER PT J AU Depoy, L Daut, R Brigman, JL MacPherson, K Crowley, N Gunduz-Cinar, O Pickens, CL Cinar, R Saksida, LM Kunos, G Lovinger, DM Bussey, TJ Camp, MC Holmes, A AF DePoy, Lauren Daut, Rachel Brigman, Jonathan L. MacPherson, Kathryn Crowley, Nicole Gunduz-Cinar, Ozge Pickens, Charles L. Cinar, Resat Saksida, Lisa M. Kunos, George Lovinger, David M. Bussey, Timothy J. Camp, Marguerite C. Holmes, Andrew TI Chronic alcohol produces neuroadaptations to prime dorsal striatal learning SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cannabinoid; abuse; touchscreen; PFC; dependence ID INTERMITTENT ETHANOL EXPOSURE; DRUG-ADDICTION; SYNAPTIC PLASTICITY; CB1 RECEPTORS; STRAIN DIFFERENCES; DRINKING BEHAVIOR; GENE-EXPRESSION; C57BL/6J MICE; RATS; DISCRIMINATION AB Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism. C1 [DePoy, Lauren; Daut, Rachel; Brigman, Jonathan L.; MacPherson, Kathryn; Gunduz-Cinar, Ozge; Pickens, Charles L.; Camp, Marguerite C.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20814 USA. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, MRC, Cambridge CB2 3EB, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Ctr, Cambridge CB2 3EB, England. [Cinar, Resat; Kunos, George] NIAAA, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. [Crowley, Nicole; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20814 USA. EM Andrew.Holmes@mail.nih.gov RI Brigman, Jonathan/O-4978-2016; Bussey, Timothy/M-2758-2016; Saksida, Lisa/M-2753-2016; Gunduz Cinar, Ozge/E-5756-2010; OI Bussey, Timothy/0000-0001-7518-4041; Saksida, Lisa/0000-0002-8416-8171; Gunduz Cinar, Ozge/0000-0002-3826-8905; CINAR, RESAT/0000-0002-8597-7253 FU National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX We thank Bianca Noronha, Aaron Plitt, and Benita Hurd for excellent technical assistance. This research was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 67 TC 67 Z9 67 U1 0 U2 37 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 SEP 3 PY 2013 VL 110 IS 36 BP 14783 EP 14788 DI 10.1073/pnas.1308198110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211DY UT WOS:000323886200065 PM 23959891 ER PT J AU Gotts, SJ Jo, HJ Wallace, GL Saad, ZS Cox, RW Martin, A AF Gotts, Stephen J. Jo, Hang Joon Wallace, Gregory L. Saad, Ziad S. Cox, Robert W. Martin, Alex TI Two distinct forms of functional lateralization in the human brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE specialization; asymmetry; intelligence; segregation; circuit ID AUTISM SPECTRUM DISORDERS; HEMISPHERIC-SPECIALIZATION; CEREBRAL HEMISPHERES; NEURAL BASIS; LANGUAGE; ORGANIZATION; ATTENTION; NETWORKS; CORTEX; CONNECTIVITY AB The hemispheric lateralization of certain faculties in the human brain has long been held to be beneficial for functioning. However, quantitative relationships between the degree of lateralization in particular brain regions and the level of functioning have yet to be established. Here we demonstrate that two distinct forms of functional lateralization are present in the left vs. the right cerebral hemisphere, with the left hemisphere showing a preference to interact more exclusively with itself, particularly for cortical regions involved in language and fine motor coordination. In contrast, right-hemisphere cortical regions involved in visuospatial and attentional processing interact in a more integrative fashion with both hemispheres. The degree of lateralization present in these distinct systems selectively predicted behavioral measures of verbal and visuospatial ability, providing direct evidence that lateralization is associated with enhanced cognitive ability. C1 [Gotts, Stephen J.; Wallace, Gregory L.; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Jo, Hang Joon; Saad, Ziad S.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Jo, HJ (reprint author), NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. EM hangjoon.jo@nih.gov RI JO, HANG JOON/D-1775-2011; OI JO, HANG JOON/0000-0002-9180-3831; Wallace, Gregory/0000-0003-0329-5054 FU National Institute of Mental Health, National Institutes of Health, Division of Intramural Research FX We thank Allen Braun, Kyle Simmons, Kelly Barnes, and Dale Stevens for helpful discussions; Gang Chen for advice on statistics; and Eunice Dixon, Ian Eisenberg, Lydia Milbury, Shawn Milleville, Briana Robustelli, and Henry Tessler for aid in data collection. This study was supported by the National Institute of Mental Health, National Institutes of Health, Division of Intramural Research, and it was conducted under National Institutes of Health Clinical Study Protocol 10-M-0027 (ClinicalTrials.gov ID NCT01031407). NR 67 TC 52 Z9 53 U1 5 U2 55 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 SEP 3 PY 2013 VL 110 IS 36 BP E3435 EP E3444 DI 10.1073/pnas.1302581110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211DY UT WOS:000323886200012 PM 23959883 ER PT J AU Li, MF Silberberg, SD Swartz, KJ AF Li, Mufeng Silberberg, Shai D. Swartz, Kenton J. TI Subtype-specific control of P2X receptor channel signaling by ATP and Mg2+ SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE magnesium ATP; magnesium regulation ID ION-CHANNEL; FUNCTIONAL-PROPERTIES; EXTRACELLULAR ATP; MOLECULAR PHYSIOLOGY; STABILITY-CONSTANTS; PURINERGIC RECEPTOR; DIVALENT-CATIONS; SENSORY NEURONS; KNOCKOUT MICE; CELLS AB The identity and forms of activating ligands for ion channels are fundamental to their physiological roles in rapid electrical signaling. P2X receptor channels are ATP-activated cation channels that serve important roles in sensory signaling and inflammation, yet the active forms of the nucleotide are unknown. In physiological solutions, ATP is ionized and primarily found in complex with Mg2+. Here we investigated the active forms of ATP and found that the action of MgATP(2-) and ATP(4-) differs between subtypes of P2X receptors. The slowly desensitizing P2X2 receptor can be activated by free ATP, but MgATP(2-) promotes opening with very low efficacy. In contrast, both free ATP and MgATP(2-) robustly open the rapidly desensitizing P2X3 subtype. A further distinction between these two subtypes is the ability of Mg2+ to regulate P2X3 through a distinct allosteric mechanism. Importantly, heteromeric P2X2/3 channels present in sensory neurons exhibit a hybrid phenotype, characterized by robust activation by MgATP(2-) and weak regulation by Mg2+. These results reveal the existence of two classes of homomeric P2X receptors with differential sensitivity to MgATP(2-) and regulation by Mg2+, and demonstrate that both restraining mechanisms can be disengaged in heteromeric channels to form fast and sensitive ATP signaling pathways in sensory neurons. C1 [Li, Mufeng; Silberberg, Shai D.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Li, MF (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM mufeng_li@nih.gov; kenton.swartz@nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); NIH [NS070954] FX We thank Joe Mindell, Miguel Holmgren, Jeff Diamond, Dmitriy Krepkiy, Jeet Kalia, Gilman Toombes, and other members of the K.J.S. laboratory for helpful discussions. We thank Pin Liu and Bruce Bean for graciously teaching us how to prepare DRG neurons. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH) (K.J.S.), and NIH Pathway to Independence Award NS070954 (to M.L.). NR 57 TC 14 Z9 14 U1 0 U2 5 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 SEP 3 PY 2013 VL 110 IS 36 BP E3455 EP E3463 DI 10.1073/pnas.1308088110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211DY UT WOS:000323886200014 PM 23959888 ER PT J AU Maerkens, A Kley, RA Olive, M Theis, V van der Ven, PFM Reimann, J Milting, H Schreiner, A Uszkoreit, J Eisenacher, M Barkovits, K Guttsches, AK Tonillo, J Kuhlmann, K Meyer, HE Schroder, R Tegenthoff, M Furst, DO Muller, T Goldfarb, LG Vorgerd, M Marcus, K AF Maerkens, A. Kley, R. A. Olive, M. Theis, V. van der Ven, P. F. M. Reimann, J. Milting, H. Schreiner, A. Uszkoreit, J. Eisenacher, M. Barkovits, K. Guettsches, A. K. Tonillo, J. Kuhlmann, K. Meyer, H. E. Schroeder, R. Tegenthoff, M. Fuerst, D. O. Mueller, T. Goldfarb, L. G. Vorgerd, M. Marcus, K. TI Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy SO JOURNAL OF PROTEOMICS LA English DT Article DE Myofibrillar myopathy; Desminopathy; Filaminopathy; Laser microdissection; Mass spectrometry; Parallel reaction monitoring ID INCLUSION-BODY MYOSITIS; BOX-BINDING-PROTEIN; ALPHA-B-CRYSTALLIN; MYOFIBRILLAR MYOPATHY; FILAMIN-C; SKELETAL-MUSCLE; IN-VITRO; MUTATIONS; EXPRESSION; AUTOPHAGY AB Desminopathy is a subtype of myofibrillar myopathy caused by desmin mutations and characterized by protein aggregates accumulating in muscle fibers. The aim of this study was to assess the protein composition of these aggregates. Aggregates and intact myofiber sections were obtained from skeletal muscle biopsies of five desminopathy patients by laser microdissection and analyzed by a label-free spectral count-based proteomic approach. We identified 397 proteins with 22 showing significantly higher spectral indices in aggregates (ratio >1.8, p <0.05). Fifteen of these proteins not previously reported as specific aggregate components provide new insights regarding pathomechanisms of desminopathy. Results of proteomic analysis were supported by immunolocalization studies and parallel reaction monitoring. Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy. Comparison of the proteomic results in desminopathy with our previous analysis of aggregate composition in filaminopathy, another myofibrillar myopathy subtype, allows to determine subtype-specific proteomic profile that facilitates identification of the specific disorder. Biological significance Our proteomic analysis provides essential new insights in the composition of pathological protein aggregates in skeletal muscle fibers of desminopathy patients. The results contribute to a better understanding of pathomechanisms in myofibrillar myopathies and provide the basis for hypothesis-driven studies. The detection of specific proteomic profiles in different myofibrillar myopathy subtypes indicates that proteomic analysis may become a useful tool in differential diagnosis of protein aggregate myopathies. This article is part of a Special Issue entitled: From Genome to Proteome: Open Innovations. (C) 2013 Elsevier B.V. All rights reserved. C1 [Maerkens, A.; Kley, R. A.; Theis, V.; Schreiner, A.; Guettsches, A. K.; Tegenthoff, M.; Vorgerd, M.] Ruhr Univ Bochum, Neuromuscular Ctr Ruhrgebiet, Univ Hosp Bergmannsheil, Dept Neurol, Bochum, Germany. [Maerkens, A.; Theis, V.; Mueller, T.; Marcus, K.] Ruhr Univ Bochum, Dept Funct Prote, Med Proteom Ctr, Bochum, Germany. [Olive, M.] IDIBELL Hosp Univ Bellvitge, Inst Neuropathol, Dept Pathol, Neuromuscular Unit,Dept Neurol, Barcelona, Spain. [Olive, M.] CIBERNED, Barcelona, Spain. [van der Ven, P. F. M.; Fuerst, D. O.] Univ Bonn, Inst Cell Biol, Bonn, Germany. [Reimann, J.] Univ Hosp Bonn, Dept Neurol, Bonn, Germany. [Milting, H.] Ruhr Univ Bochum, Erich & Hanna Klessmann Inst Cardiovasc Res & Dev, Clin Thorac & Cardiovasc Surg, Heart & Diabet Ctr NRW, Bad Oeynhausen, Germany. [Uszkoreit, J.; Eisenacher, M.; Barkovits, K.; Tonillo, J.; Kuhlmann, K.; Meyer, H. E.] Ruhr Univ Bochum, Dept Med Prote Bioanalyt, Med Proteom Ctr, Bochum, Germany. [Schroeder, R.] Univ Hosp Erlangen, Inst Neuropathol, Erlangen, Germany. [Goldfarb, L. G.] NIH, Bethesda, MD 20892 USA. RP Marcus, K (reprint author), Ruhr Univ Bochum, Dept Funct Prote, Med Proteom Ctr, Univ Str 150, Bochum, Germany. EM katrin.marcus@rub.de RI Eisenacher, Martin/J-8044-2014; Schroder, Rolf/B-2774-2011; OI Eisenacher, Martin/0000-0003-2687-7444; Olive, Montse/0000-0001-5727-0165 FU Ruhr-University Bochum [FoRUM F680-2009, F599R-2008, F755-2012]; German Research Foundation [KL 2487/1-1, FOR1228, FOR1352]; Heimer Foundation; Intramural Program of the National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA FX This research was supported by grants from the Ruhr-University Bochum (FoRUM F680-2009, F599R-2008 and F755-2012), the German Research Foundation (KL 2487/1-1, FOR1228 and FOR1352), and the Heimer Foundation. This work was supported in part by the Intramural Program of the National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. We thank the patients for participation in this study. NR 51 TC 20 Z9 20 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD SEP 2 PY 2013 VL 90 SI SI BP 14 EP 27 DI 10.1016/j.jprot.2013.04.026 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 218SH UT WOS:000324452300003 PM 23639843 ER PT J AU Ren, XF Graham, JC Jing, LC Mikheev, AM Gao, Y Lew, JP Xie, H Kim, AS Shang, X Friedman, C Vail, G Fang, MZ Bromberg, Y Zarbl, H AF Ren, Xuefeng Graham, Jessica C. Jing, Lichen Mikheev, Andrei M. Gao, Yuan Lew, Jenny Pan Xie, Hong Kim, Andrea S. Shang, Xiuling Friedman, Cynthia Vail, Graham Fang, Ming Zhu Bromberg, Yana Zarbl, Helmut TI Mapping of Mcs30, a New Mammary Carcinoma Susceptibility Quantitative Trait Locus (QTL30) on Rat Chromosome 12: Identification of Fry as a Candidate Mcs Gene SO PLOS ONE LA English DT Article ID BREAST-CANCER SUSCEPTIBILITY; RADIATION HYBRID MAP; PHOSPHORYLATION SITES; NORWAY RAT; PCR ASSAY; PROTEIN; SEQUENCE; LINKAGE; GENOME; EXPRESSION AB Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of similar to 8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression. C1 [Ren, Xuefeng; Shang, Xiuling] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Ren, Xuefeng] Anim Ctr, Guangdong Med Lab, Foshan, Guangdong, Peoples R China. [Graham, Jessica C.; Vail, Graham; Zarbl, Helmut] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ 07103 USA. [Graham, Jessica C.; Zarbl, Helmut] Rutgers State Univ, Joint Grad Program Toxicol, Piscataway, NJ 07102 USA. [Graham, Jessica C.; Zarbl, Helmut] Univ Med & Dent New Jersey, Piscataway, NJ 07103 USA. [Fang, Ming Zhu; Zarbl, Helmut] Univ Med & Dent New Jersey, NIEHS Ctr Environm Exposures & Dis, Piscataway, NJ 07103 USA. [Fang, Ming Zhu; Zarbl, Helmut] Rutgers State Univ, Piscataway, NJ 07102 USA. [Bromberg, Yana] Rutgers State Univ, Dept Biochem & Microbiol, Piscataway, NJ 07102 USA. [Zarbl, Helmut] Canc Inst New Jersey, New Brunswick, NJ USA. [Ren, Xuefeng; Jing, Lichen; Mikheev, Andrei M.; Gao, Yuan; Lew, Jenny Pan; Xie, Hong; Kim, Andrea S.; Friedman, Cynthia; Zarbl, Helmut] FHCRC, Seattle, WA USA. [Ren, Xuefeng; Zarbl, Helmut] Univ Washington, NIEHS Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. [Ren, Xuefeng; Zarbl, Helmut] Univ Washington, Dept Environm & Occupat Hlth, Seattle, WA 98195 USA. RP Zarbl, H (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ 07103 USA. EM zarbl@eohsi.rutgers.edu OI Bromberg, Yana/0000-0002-8351-0844 FU Public Health Services; National Cancer Institute [NCI RO1CA77222]; NIEHS [NIEHS P30ES007033, P30ES005022]; NIEHS sponsored Toxicogenomics Research Consortium [NIEHS U19ES011387]; New Jersey Commission on Cancer Research [09-1962-CCR-EO]; University at Buffalo; Natural Science Foundation of China [81272904] FX This research was supported by a Public Health Services Grants from the National Cancer Institute, Grant #: NCI RO1CA77222, NIEHS sponsored Center Grant #'s: NIEHS P30ES007033 and P30ES005022, the NIEHS sponsored Toxicogenomics Research Consortium, Grant #: NIEHS U19ES011387 and a fellowship to Jessica Graham from the New Jersey Commission on Cancer Research, Award #: 09-1962-CCR-EO. XR is currently supported by startup fund provided by University at Buffalo, and Natural Science Foundation of China (81272904). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 2 PY 2013 VL 8 IS 9 AR e70930 DI 10.1371/journal.pone.0070930 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215VH UT WOS:000324238400005 PM 24023717 ER PT J AU Yi, JS Wu, XF Chung, AH Chen, JK Kapoor, TM Hammer, JA AF Yi, Jason Wu, Xufeng Chung, Andrew H. Chen, James K. Kapoor, Tarun M. Hammer, John A. TI Centrosome repositioning in T cells is biphasic and driven by microtubule end-on capture-shrinkage SO JOURNAL OF CELL BIOLOGY LA English DT Article ID IMMUNOLOGICAL SYNAPSE; ORGANIZING CENTER; CYTOSKELETAL POLARIZATION; CYTOPLASMIC DYNEIN; CORTICAL DYNEIN; IMMUNE SYNAPSE; PULLING FORCES; ACTIVATION; PROTEINS; DYNAMICS AB T cells rapidly reposition their centrosome to the center of the immunological synapse (IS) to drive polarized secretion in the direction of the bound target cell. Using an optical trap for spatial and temporal control over target presentation, we show that centrosome repositioning in Jurkat T cells exhibited kinetically distinct polarization and docking phases and required calcium flux and signaling through both the T cell receptor and integrin to be robust. In "frustrated" conjugates where the centrosome is stuck behind the nucleus, the center of the IS invaginated dramatically to approach the centrosome. Consistently, imaging of microtubules during normal repositioning revealed a microtubule end-on capture-shrinkage mechanism operating at the center of the IS. In agreement with this mechanism, centrosome repositioning was impaired by inhibiting microtubule depolymerization or dynein. We conclude that dynein drives centrosome repositioning in T cells via microtubule end-on capture-shrinkage operating at the center of the IS and not cortical sliding at the IS periphery, as previously thought. C1 [Yi, Jason; Wu, Xufeng; Hammer, John A.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Chung, Andrew H.; Chen, James K.] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA. [Kapoor, Tarun M.] Rockefeller Univ, Lab Chem & Cell Biol, New York, NY 10065 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov RI Chen, James/G-9972-2011 OI Chen, James/0000-0002-9220-8436 FU National Institutes of Health/National Cancer Institute [R01 CA136574]; National Institutes of Health/National Institute of General Medical Sciences [RO1 GM65933] FX J.K. Chen gratefully acknowledges support from the National Institutes of Health/National Cancer Institute (R01 CA136574). T.M. Kapoor gratefully acknowledges support from the National Institutes of Health/National Institute of General Medical Sciences (RO1 GM65933). NR 33 TC 40 Z9 40 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 2 PY 2013 VL 202 IS 5 BP 779 EP 792 DI 10.1083/jcb.201301004 PG 14 WC Cell Biology SC Cell Biology GA 210YE UT WOS:000323870500007 PM 23979719 ER PT J AU Taguchi, Y Hohsfield, LA Hollister, JR Baron, GS AF Taguchi, Yuzuru Hohsfield, Lindsay A. Hollister, Jason R. Baron, Gerald S. TI Effects of FlAsH/Tetracysteine (TC) Tag on PrP Proteolysis and PrPres Formation by TC-Scanning SO CHEMBIOCHEM LA English DT Article DE biarsenical; fluorescent probes; prion; protein interactions; protein structure ID CELLULAR PRION PROTEIN; AMYLOID-BETA OLIGOMERS; N-TERMINAL CLEAVAGE; ALPHA-CLEAVAGE; NEUROBLASTOMA-CELLS; SCRAPIE ISOFORM; CULTURED-CELLS; AMINO-TERMINUS; NORMAL BRAIN; SITE AB Protein-protein interactions associated with proteolytic processing and aggregation are integral to normal and pathological aspects of prion protein (PrP) biology. Characterization of these interactions requires the identification of amino acid residues involved. The FlAsH/tetracysteine (FlAsH/TC) tag is a small fluorescent tag amenable to insertion at internal sites in proteins. In this study, we used serial FlAsH/TC insertions (TC-scanning) as a probe to characterize sites of protein-protein interaction between PrP and other molecules. To explore this application in the context of substrate-protease interactions, we analyzed the effect of FlAsH/TC insertions on proteolysis of cellular prion protein (PrPsen) in in vitro reactions and generation of the C1 metabolic fragment of PrPsen in live neuroblastoma cells. The influence of FlAsH/TC insertion was evaluated by TC-scanning across the cleavage sites of each protease. The results showed that FlAsH/TC inhibited protease cleavage only within limited ranges of the cleavage sites, which varied from about one to six residues in width, depending on the protease, providing an estimate of the PrP residues interacting with each protease. TC-scanning was also used to probe a different type of protein-protein interaction: the conformational conversion of FlAsH-PrPsen to the prion disease-associated isoform, PrPres. PrP constructs with FlAsH/TC insertions at residues 90-96 but not 97-101 were converted to FlAsH-PrPres, identifying a boundary separating loosely versus compactly folded regions of PrPres. Our observations demonstrate that TC-scanning with the FlAsH/TC tag can be a versatile method for probing protein-protein interactions and folding processes. C1 [Taguchi, Yuzuru; Hohsfield, Lindsay A.; Hollister, Jason R.; Baron, Gerald S.] NIAID, Rocky Mt Labs, NIH, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Taguchi, Y (reprint author), Univ Calgary, Fac Vet Med, Dept Comparat Biol & Expt Med, Calgary, AB T2N 4Z6, Canada. EM yzrtgch@gmail.com; lindsay.hohsfield@i-med.ac.at; gbaron@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors thank Aaron Hasenkrug for assistance with the TC-scanning constructs. We thank Motohiro Hoiruchi for the gift of mAb132 antibody. R24, R30, and R20 antibodies were generous gifts from Byron Caughey. We also thank Lynne Raymond, Greg Raymond, and Danielle Offerdahl for technical assistance. We are grateful to Byron Caughey, Lara Taubner, and Roger Moore for critical reading of the manuscript. NR 88 TC 0 Z9 0 U1 0 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 2 PY 2013 VL 14 IS 13 BP 1597 EP 1610 DI 10.1002/cbic.201300255 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 206SJ UT WOS:000323542500016 PM 23943295 ER PT J AU Browne, S AF Browne, Sarah TI THYMOMA, ANTICYTOKINE AUTOANTIBODIES, AND IMMUNODEFICIENCY SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE anticytokine autoantibodies; immunodeficiency C1 [Browne, Sarah] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2013 VL 8 SU 1 MA GS2.2 BP 5 EP 5 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AM1QS UT WOS:000339623500006 ER PT J AU Hodes, R AF Hodes, Richard TI CELLULAR CROSS-TALK IN THE DEVELOPMENT OF THE THYMIC ENVIRONMENT SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE thymus; crosstalk; NFkB C1 [Hodes, Richard] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2013 VL 8 SU 1 MA GS2.3 BP 5 EP 6 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AM1QS UT WOS:000339623500007 ER PT J AU Keijzers, M Rennspies, D Pujari, S Hamid, MAA Hochstenbag, M Kurz, A Speel, E Haugg, A Buck, C De Baets, M Zur Hausen, A AF Keijzers, Marlies Rennspies, Dorit Pujari, S. Hamid, M. A. Abdul Hochstenbag, Monique Kurz, Anna Speel, ErnstJan Haugg, A. Buck, C. De Baets, Marc Zur Hausen, Axel TI DETECTION OF HUMAN POLYOMAVIRUS 7 IN HUMAN THYMIC EPITHELIAL TUMORS SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE thymoma; Human Polyomavirus 7 C1 [Keijzers, Marlies; Rennspies, Dorit; Pujari, S.; Hamid, M. A. Abdul; Hochstenbag, Monique; Speel, ErnstJan; Haugg, A.; De Baets, Marc; Zur Hausen, Axel] Maastricht Univ, Med Ctr, Maastricht, Netherlands. [Kurz, Anna] Univ Hosp Aachen, Dept Internal Med 4, Aachen, Germany. [Buck, C.] NCI, Lab Cellular Oncol, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2013 VL 8 SU 1 MA O1.4 BP 17 EP 18 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AM1QS UT WOS:000339623500018 ER PT J AU Calzone, KA Jenkins, J Culp, S Bonham, VL Badzek, L AF Calzone, Kathleen A. Jenkins, Jean Culp, Stacey Bonham, Vence L., Jr. Badzek, Laurie TI National nursing workforce survey of nursing attitudes, knowledge and practice in genomics SO PERSONALIZED MEDICINE LA English DT Article DE genetics; genomics; nurses; nursing; nursing practice; survey ID GENETICS; MEDICINE AB Aim: Genomics has the potential to improve personalized healthcare. Nurses are vital to the utilization of genomics in practice. This study assessed nursing attitudes, receptivity, confidence, competency, knowledge and practice in genomics to inform education efforts. Materials & methods: Cross-sectional study of registered nurses who completed an online Genetic/Genomic Nursing Practice Survey posted on a national nursing organization website. Results: A total of 619 registered nurses participated. The largest proportion of education level were nurses with a baccalaureate degree (39%). Most (67.5%) considered genomics very important to nursing practice. However, 57% reported their genomic knowledge base to be poor or fair. The mean total knowledge score correct response rate was 75%. Yet 60% incorrectly answered that diabetes and heart disease are caused by a single gene variant. Most (64%) had never heard of the Essential Nursing Competencies and Curricula Guidelines in Genomics. Higher academic education or post licensure genetic education increased family history collection in practice. Conclusion: Most nurses are inadequately prepared to translate genomic information into personalized healthcare. Targeted genomic education is needed to assure optimal workforce preparation for genomics practice integration. C1 [Calzone, Kathleen A.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Jenkins, Jean] NHGRI, NIH, Bethesda, MD 20892 USA. [Culp, Stacey; Badzek, Laurie] W Virginia Univ, Sch Nursing, Morgantown, WV 26506 USA. [Bonham, Vence L., Jr.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Badzek, Laurie] ANA Ctr Eth & Human Rights, Silver Spring, MD 20910 USA. RP Calzone, KA (reprint author), NCI, NIH, Ctr Canc Res, Genet Branch, 37 Convent Dr,Bldg 37,Room 2068,MSC 4256, Bethesda, MD 20892 USA. EM calzonek@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; National Human Genome Research Institute; West Virginia University School of Nursing; American Nurses Association FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and National Human Genome Research Institute as well as West Virginia University School of Nursing and the American Nurses Association. 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 21 TC 7 Z9 7 U1 2 U2 6 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PD SEP PY 2013 VL 10 IS 7 BP 719 EP 728 DI 10.2217/PME.13.64 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AI8PX UT WOS:000337184100013 ER PT J AU Hachiya, A Reeve, AB Marchand, B Michailidis, E Ong, YT Kirby, KA Leslie, MD Oka, S Kodama, EN Rohan, LC Mitsuya, H Parniak, MA Sarafianos, SG AF Hachiya, Atsuko Reeve, Aaron B. Marchand, Bruno Michailidis, Eleftherios Ong, Yee Tsuey Kirby, Karen A. Leslie, Maxwell D. Oka, Shinichi Kodama, Eiichi N. Rohan, Lisa C. Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI Evaluation of Combinations of 4 '-Ethynyl-2-Fluoro-2 '-Deoxyadenosine with Clinically Used Antiretroviral Drugs SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LUNG-TRANSPLANT RECIPIENTS; INVASIVE FUNGAL-INFECTIONS; EPITHELIAL LINING FLUID; POPULATION PHARMACOKINETICS; VORICONAZOLE; PROPHYLAXIS; EFFICACY AB Drug combination studies of 4 '-ethynyl-2-fluoro-2 '-deoxyadenosine (EFdA) with FDA-approved drugs were evaluated by two different methods, MacSynergy II and CalcuSyn. Most of the combinations, including the combination of the two adenosine analogs EFdA and tenofovir, were essentially additive, without substantial antagonism or synergism. The combination of EFdA and rilpivirine showed apparent synergism. These studies provide information that may be useful for the design of EFdA combination regimens for initial and salvage therapy assessment. C1 [Hachiya, Atsuko; Marchand, Bruno; Michailidis, Eleftherios; Ong, Yee Tsuey; Kirby, Karen A.; Leslie, Maxwell D.; Sarafianos, Stefan G.] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Christopher Bond Life Sci Ctr, Columbia, MO 65212 USA. [Hachiya, Atsuko; Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. [Reeve, Aaron B.; Parniak, Michael A.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Kodama, Eiichi N.] Tohoku Univ, Tohoku Med Megabank Org, Div Emerging Infect Dis, Sendai, Miyagi 980, Japan. [Rohan, Lisa C.] Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. [Rohan, Lisa C.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol & Infect Dis, Kumamoto, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, Columbia, MO USA. RP Sarafianos, SG (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Christopher Bond Life Sci Ctr, Columbia, MO 65212 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Sarafianos, Stefan G/0000-0002-5840-154X; Kirby, Karen A./0000-0003-2468-4796 NR 17 TC 5 Z9 5 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2013 VL 57 IS 9 BP 4554 EP 4583 DI 10.1128/AAC.00283-13 PG 37 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AH7IW UT WOS:000336307700001 PM 23796932 ER PT J AU Djousse, L Benkeser, D Arnold, A Kizer, JR Zieman, SJ Lemaitre, RN Tracy, RP Gottdiener, JS Mozaffarian, D Siscovick, DS Mukamal, KJ Ix, JH AF Djousse, Luc Benkeser, David Arnold, Alice Kizer, Jorge R. Zieman, Susan J. Lemaitre, Rozenn N. Tracy, Russell P. Gottdiener, John S. Mozaffarian, Dariush Siscovick, David S. Mukamal, Kenneth J. Ix, Joachim H. TI Plasma Free Fatty Acids and Risk of Heart Failure The Cardiovascular Health Study SO CIRCULATION-HEART FAILURE LA English DT Article DE epidemiology; fatty acids; nonesterified; heart failure; nutrition ID INSULIN-RESISTANCE; ENDOTHELIAL-CELLS; UNITED-STATES; DISEASE; MORTALITY; HYPERTENSION; ELEVATION; CARDIOMYOPATHY; VASODILATION; FIBRILLATION AB Background Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF). Methods and Results To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6%-19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09-1.23]). Conclusions A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention. C1 [Djousse, Luc] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02120 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Dept Med, Boston, MA 02120 USA. [Mukamal, Kenneth J.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Benkeser, David; Arnold, Alice] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lemaitre, Rozenn N.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Div Cardiol, New York, NY USA. [Zieman, Susan J.] NIA, Bethesda, MD 20892 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. [Gottdiener, John S.] Univ Maryland, Med Ctr, Div Cardiol, Baltimore, MD 21201 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. RP Djousse, L (reprint author), Brigham & Womens Hosp, Div Aging, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM ldjousse@rics.bwh.harvard.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL-094555, HL080295, HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01HC35129, N01HC45133]; National Institute of Neurological Disorders and Stroke; National Institute on Aging [AG-023629] FX This work was supported by R01 HL-094555 from the National Heart, Lung, and Blood Institute (NHLBI) and by contracts HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01HC35129, N01HC45133, and grant HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by AG-023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org. NR 47 TC 17 Z9 17 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD SEP PY 2013 VL 6 IS 5 BP 964 EP 969 DI 10.1161/CIRCHEARTFAILURE.113.000521 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AG2GO UT WOS:000335234500015 PM 23926204 ER PT J AU Miller, FG AF Miller, Franklin G. TI THE STATEVILLE PENITENTIARY MALARIA EXPERIMENTS a case study in retrospective ethical assessment SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID CHALLENGE; PRISONERS; NUREMBERG; HISTORY AB During World War II, malaria research was conducted in prisons. A notable example was the experiments at Stateville Penitentiary in Illinois, in which prisoner-subjects were infected with malaria for the purpose of testing the safety and efficacy of novel anti-malaria drugs. Over time, commentators have shifted from viewing the malaria research at Stateville as a model of ethical clinical research to seeing the experiments as paradigmatic of abusive human experimentation. This essay undertakes a retrospective ethical assessment of the Stateville malaria research during the 1940s in light of basic ethical principles and the Nuremberg Code, as well as contemporary malaria research. In addition to its historical interest, this case study provides a rich context for addressing basic issues of research ethics, including the voluntariness of consent, the justification of risks, and the exploitation of vulnerable subjects. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Intramural Research Program of the Clinical Center, NIH FX The opinions expressed are those of the author and do not reflect the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. This research was supported by the Intramural Research Program of the Clinical Center, NIH. NR 39 TC 2 Z9 2 U1 2 U2 6 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 FAL PY 2013 VL 56 IS 4 BP 548 EP 567 PG 20 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA AG0FO UT WOS:000335091500005 PM 24769747 ER PT J AU Abraham, NG Zeldin, DC Sodhi, K Silvis, AM Favero, G Rezzani, R Fabrizio, RL Lee, C Shapiro, J Schwartzman, ML AF Abraham, Nader G. Zeldin, Darryl C. Sodhi, Komal Silvis, Anne M. Favero, Gaia Rezzani, Rita Fabrizio, Rodella Luigi Lee, Craig Shapiro, Joseph Schwartzman, Michal L. TI CYP2J2 Targeting to Endothelial Cells Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High Fat Diet by Reprogramming Adipocyte Phenotype SO HYPERTENSION LA English DT Meeting Abstract CT American-Heart-Association High Blood Pressure Research Scientific Sessions CY SEP 11-14, 2013 CL New Orleans, LA SP Amer Heart Assoc DE AMPK; blood pressure; PPAR C1 [Abraham, Nader G.] Marshall Univ, Joan C Edwards Sch Med, Dept Med, Huntington, WV USA. [Zeldin, Darryl C.; Lee, Craig] NIEHS, Div Intramural Rsch, NIH, Rsch Triangle Pk, NC USA. [Sodhi, Komal; Silvis, Anne M.] Marshall Univ, Dept Surg, Joan C Edwards Sch Med, Huntington, WV USA. [Favero, Gaia; Rezzani, Rita; Fabrizio, Rodella Luigi] Univ Brescia, Div Anat & Physiopathol, Dept Clin & Expt Sci, Brescia, Italy. [Shapiro, Joseph] Marshall Univ, Dept Med, Joan C Edwards Sch Med, Huntington, WI USA. [Schwartzman, Michal L.] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2013 VL 62 IS 3 SU S MA 34 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB9QM UT WOS:000332130700035 ER PT J AU Cao, J Peterson, SJ Favero, G Rezzani, R Fabrizio, RL Schwartzman, ML Zeldin, DC Shapiro, J Abraham, NG AF Cao, Jian Peterson, Stephen J. Favero, Gaia Rezzani, Rita Fabrizio, Rodella Luigi Schwartzman, Michal L. Zeldin, Darryl C. Shapiro, Joseph Abraham, Nader G. TI EET Agonist Improves Cardiac Energy Metabolism and Heart Function by Regulating Fatty Acid Oxidation and Oxidative Stress in Infarcted Myocardium SO HYPERTENSION LA English DT Meeting Abstract CT American-Heart-Association High Blood Pressure Research Scientific Sessions CY SEP 11-14, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Myocardium; Oxidative Stress; echocardiography C1 [Cao, Jian] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Cardiol 1, Beijing, Peoples R China. [Peterson, Stephen J.] New York Methodist Weill Cornell Med Coll, Dept Med, New York, NY USA. [Favero, Gaia; Rezzani, Rita; Fabrizio, Rodella Luigi] Univ Brescia, Div Anat & Physiopathol, Dept Clin & Expt Sci, Brescia, Italy. [Schwartzman, Michal L.] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. [Zeldin, Darryl C.] NIEHS, LRB, Rsch Triangle Pk, NC USA. [Shapiro, Joseph; Abraham, Nader G.] Marshall Univ, Joan C Edwards Sch Med, Dept Med, Huntington, WV USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2013 VL 62 IS 3 SU S MA 374 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB9QM UT WOS:000332130700287 ER PT J AU Uchida, N Evans, ME Hsieh, MM Bonifacino, AC Krouse, AE Metzger, ME Sellers, SE Dunbar, CE Donahue, RE Tisdale, JF AF Uchida, Naoya Evans, Molly E. Hsieh, Matthew M. Bonifacino, Aylin C. Krouse, Allen E. Metzger, Mark E. Sellers, Stephanie E. Dunbar, Cynthia E. Donahue, Robert E. Tisdale, John F. TI Integration-specific In Vitro Evaluation of Lentivirally Transduced Rhesus CD34(+) Cells Correlates With In Vivo Vector Copy Number SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE CD34(+) cells; hematopoietic stem cell transplantation; large animal model; lentiviral vector ID GENE-THERAPY; HEMATOPOIETIC-CELLS; IMMUNODEFICIENCY; EXPRESSION; TRANSCRIPTION; ACTIVATION; INSULATOR; SCID-X1; DISEASE; DESIGN AB Hematopoietic stem cell (HSC) gene therapy using integrating vectors has a potential leukemogenic risk due to insertional mutagenesis. To reduce this risk, a limitation of <= 2 average vector copy number (VCN) per cell is generally accepted. We developed an assay for VCN among transduced CD34(+) cells that reliably predicts in vivo VCN in 16 rhesus recipients of CD34(+) cells transduced with a green fluorescent protein (GFP) (or yellow fluorescent protein (YFP))-encoding lentiviral vector. Using GFP (or YFP)-specific probe/primers by real-time PCR, VCN among transduced CD34(+) cells had no correlation with VCN among granulocytes or lymphocytes in vivo assayed 6 months post-transplantation. This was a likely result of residual plasmids present in the vector preparation. We then designed self-inactivating long terminal repeat (SIN-LTR)-specific probe/primers, which detect only integrated provirus. Evaluation with SIN-LTR probe/primers resulted in a positive correlation of VCN among transduced CD34(+) cells with granulocytes and lymphocytes in vivo. The transduced CD34(+) cells had higher VCN (25.1 +/- 5.6) as compared with granulocytes (2.8 +/- 1) and lymphocytes (2.4 +/- 0.7). In summary, an integrated provirus-specific real-time PCR system demonstrated nine-to tenfold higher VCN in transduced CD34+ cells in vitro, as compared with VCN in vivo. Therefore, the restriction of <= 2 VCN before infusion might unnecessarily limit gene transfer efficacy. C1 [Uchida, Naoya; Evans, Molly E.; Hsieh, Matthew M.; Tisdale, John F.] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD 20892 USA. [Bonifacino, Aylin C.; Krouse, Allen E.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. [Sellers, Stephanie E.; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health. We thank the animal care staff and technicians at 5 Research Court for their excellent care and handling of the animals. The authors declared no conflict of interest. NR 28 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD SEP PY 2013 VL 2 AR e122 DI 10.1038/mtna.2013.49 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC4CF UT WOS:000332467500005 PM 24045711 ER PT J AU Endres, T Hofer, F Goldbach-Mansky, R Hoffman, H Blank, N Krause, K Rietschel, C Horneff, G Lohse, P Kummerle-Deschner, J AF Endres, T. Hofer, F. Goldbach-Mansky, R. Hoffman, H. Blank, N. Krause, K. Rietschel, C. Horneff, G. Lohse, P. Kuemmerle-Deschner, J. TI NLRP3-Variants with little Penetrance SO ZEITSCHRIFT FUR RHEUMATOLOGIE LA German DT Meeting Abstract C1 [Endres, T.; Hofer, F.; Kuemmerle-Deschner, J.] Univ Klinikum Tubingen, Klin Kinder & Jugendmed, Tubingen, Germany. [Goldbach-Mansky, R.] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Hoffman, H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Blank, N.] Univ Klinikum Heidelberg, Med Klin 5, Sekt Rheumatol, Heidelberg, Germany. [Krause, K.] Charite, Klin Dermatol, Allergie Ctr Charite, D-13353 Berlin, Germany. [Rietschel, C.] Clementine Hosp Frankfurt, Kinderklin, Frankfurt, Germany. [Horneff, G.] Asklepios Klin Sankt Augustin, Zentrum Allgemeine Padiatrie & Neonatol, St Augustin, Germany. [Lohse, P.] Lab Blessing & Partner, Mol Genet, Singen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-1855 EI 1435-1250 J9 Z RHEUMATOL JI Z. Rheumatol. PD SEP PY 2013 VL 72 SU 2 BP 137 EP 137 PG 1 WC Rheumatology SC Rheumatology GA AB3RY UT WOS:000331709100270 ER PT J AU Kretschmer, D Hanzelmann, D Wang, JM Otto, M Peschel, A AF Kretschmer, D. Hanzelmann, D. Wang, J. M. Otto, M. Peschel, A. TI In vivo role of the mFPR2 receptor in S. aureus infection SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) e V / Annual Meeting of the German-Society-for-Infectious-Diseases (DGI) e V CY SEP 22-25, 2013 CL Univ Rostock, Rostock, GERMANY SP German Soc Hyg & Microbiol e V, German Soc Infect Dis e V, SIEMENS HO Univ Rostock C1 [Wang, J. M.] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD 21701 USA. [Otto, M.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 EI 1618-0607 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2013 VL 303 SU 1 BP 49 EP 49 PG 1 WC Microbiology; Virology SC Microbiology; Virology GA AB0QQ UT WOS:000331497600166 ER PT J AU Kretschmer, D Hanzelmann, D Nikola, N Rautenberg, M Linke, D Otto, M Peschel, A AF Kretschmer, D. Hanzelmann, D. Nikola, N. Rautenberg, M. Linke, D. Otto, M. Peschel, A. TI Influence of truncation of staphylococcal b-type phenol-soluble modulins on the activation of the human formyl-peptide receptors SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) e V / Annual Meeting of the German-Society-for-Infectious-Diseases (DGI) e V CY SEP 22-25, 2013 CL Univ Rostock, Rostock, GERMANY SP German Soc Hyg & Microbiol e V, German Soc Infect Dis e V, SIEMENS HO Univ Rostock C1 [Kretschmer, D.; Hanzelmann, D.; Nikola, N.; Peschel, A.] Inst Med Mikrobiol & Hyg, Sekt Zellulare & Mol Mikrobiol, Tubingen, Germany. [Rautenberg, M.] Inst Med Mikrobiol & Hyg, Tubingen, Germany. [Linke, D.] Max Planck Inst Entwicklungsbiol, Abt Prot Evolut, D-72076 Tubingen, Germany. [Otto, M.; Peschel, A.] NIH, Pathogen Mol Genet Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 EI 1618-0607 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2013 VL 303 SU 1 BP 56 EP 57 PG 2 WC Microbiology; Virology SC Microbiology; Virology GA AB0QQ UT WOS:000331497600191 ER PT J AU Masse, LC Perna, F Agurs-Collins, T Chriqui, JF AF Masse, Louise C. Perna, Frank Agurs-Collins, Tanya Chriqui, Jamie F. TI Change in School Nutrition-Related Laws From 2003 to 2008: Evidence From the School Nutrition-Environment State Policy Classification System SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID BODY-MASS INDEX; SWEETENED BEVERAGES; COMPETITIVE FOOD; HEALTH POLICIES; OBESITY; IMPLEMENTATION; AVAILABILITY; ADOLESCENTS; STUDENTS; ENERGY AB Objectives. We examined state laws affecting the school food environment and changes in these laws between 2003 to 2008. Methods. We used the Westlaw legal database to identify state-codified laws, with scoring derived from the updated School Nutrition-Environment State Policy Classification System, obtained from the Classification of Laws Associated With School Students Web site. Results. States significantly changed their school nutrition laws from 2003 to 2008, and many increased the stringency of the laws targeting competitive foods (snacks and entrees sold in competition with the school meal) and beverages sold in school and for in-school fundraising. Many states enacted laws that mandated the establishment of a coordinating or advisory wellness team or council. Stronger laws were enacted for elementary grades. We found tremendous variability in the strength of the laws and plenty of room for improvement. Conclusions. State law governing school nutrition policies significantly changed from 2003 to 2008, primarily affecting the competitive food environment in schools. The extent to which changes in school nutrition laws will lead to desired health outcomes is an area for additional research. C1 [Masse, Louise C.] Univ British Columbia, Sch Populat & Publ Hlth, Dept Pediat, Vancouver, BC V6H 3V4, Canada. [Perna, Frank; Agurs-Collins, Tanya] NCI, Hlth Behav Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chriqui, Jamie F.] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL USA. RP Masse, LC (reprint author), Univ British Columbia, Sch Populat & Publ Hlth, Dept Pediat, F508-4480 Oak S, Vancouver, BC V6H 3V4, Canada. EM lmasse@cfri.ubc.ca FU Michael Smith Foundation for Health Research; Child and the Family Research Institute; Sunny Hill Foundation; National Cancer Institute FX Louise C. Masse received salary support from the Michael Smith Foundation for Health Research (senior scholar award), the Child and the Family Research Institute (level 2 investigator scientist award), and the Sunny Hill Foundation. She and Jamie F. Chriqui received support from the National Cancer Institute to prepare this article. NR 42 TC 9 Z9 9 U1 4 U2 17 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2013 VL 103 IS 9 BP 1597 EP 1603 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3NB UT WOS:000330998200031 PM 23327259 ER PT J AU Cottler, LB McCloskey, DJ Aguilar-Gaxiola, S Bennett, NM Strelnick, H Dwyer-White, M Collyar, DE Ajinkya, S Seifer, SD O'Leary, CC Striley, CW Evanoff, B AF Cottler, Linda B. McCloskey, Donna Jo Aguilar-Gaxiola, Sergio Bennett, Nancy M. Strelnick, Hal Dwyer-White, Molly Collyar, Deborah E. Ajinkya, Shaun Seifer, Sarena D. O'Leary, Catina Callahan Striley, Catherine W. Evanoff, Bradley TI Community Needs, Concerns, and Perceptions About Health Research: Findings From the Clinical and Translational Science Award Sentinel Network SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID AFRICAN-AMERICANS; RACE; PARTICIPATION; RECRUITMENT; MINORITIES; TUSKEGEE; WORKERS; TRIALS AB Objectives. We used results generated from the first study of the National Institutes of Health Sentinel Network to understand health concerns and perceptions of research among underrepresented groups such as women, the elderly, racial/ethnic groups, and rural populations. Methods. Investigators at 5 Sentinel Network sites and 2 community-focused national organizations developed a common assessment tool used by community health workers to assess research perceptions, health concerns, and conditions. Results. Among 5979 individuals assessed, the top 5 health concerns were hypertension, diabetes, cancer, weight, and heart problems; hypertension was the most common self-reported condition. Levels of interest in research participation ranged from 70.1% among those in the "other" racial/ethnic category to 91.0% among African Americans. Overall, African Americans were more likely than members of other racial/ethnic groups to be interested in studies requiring blood samples (82.6%), genetic samples (76.9%), or medical records (77.2%); staying overnight in a hospital (70.5%); and use of medical equipment (75.4%). Conclusions. Top health concerns were consistent across geographic areas. African Americans reported more willingness to participate in research even if it required blood samples or genetic testing. C1 [Cottler, Linda B.; Striley, Catherine W.] Univ Florida, Coll Publ Hlth & Hlth Profess, Gainesville, FL 32610 USA. [Cottler, Linda B.; Striley, Catherine W.] Univ Florida, Coll Med, Gainesville, FL 32610 USA. [McCloskey, Donna Jo] NINR, NIH, Bethesda, MD 20892 USA. [Aguilar-Gaxiola, Sergio] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. [Bennett, Nancy M.] Univ Rochester, Ctr Community Hlth, Rochester, NY USA. [Strelnick, Hal] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Dwyer-White, Molly] Univ Michigan, Michigan Inst Clin & Hlth Res, Ann Arbor, MI 48109 USA. [Collyar, Deborah E.] Patient Advocates Res, San Francisco, CA USA. [Ajinkya, Shaun] Univ Cent Florida, Orlando, FL 32816 USA. [Seifer, Sarena D.] Community Campus Partnerships Hlth, Seattle, WA USA. [O'Leary, Catina Callahan] Hlth Literacy Missouri, St Louis, MO USA. [Evanoff, Bradley] Washington Univ, Sch Med, St Louis, MO USA. RP Cottler, LB (reprint author), Univ Florida, Dept Epidemiol, 1225 Ctr Dr,Room 3107,POB 100231, Gainesville, FL 32610 USA. EM lbcottler@ufl.edu OI Striley, Catherine Woodstock/0000-0003-2973-7842; Evanoff, Bradley A./0000-0003-0085-333X FU National Center for Research Resources; National Center for Advancing Translational Sciences (NCATS) through the Clinical and Translational Science Awards Program [NCRR UL1 RR024992-03S2, NCRR 2 UL1 RR024146-06, NCRR UL1RR024986, NCRR UL1RR025750, P60MD00514, NCRR UL1RR024992-03S3, NCRR UL1RR024992-05S1, NCRR UL1RR029890] FX This project was supported by federal funds from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) through the Clinical and Translational Science Awards Program (grants NCRR UL1 RR024992-03S2, NCRR 2 UL1 RR024146-06, NCRR UL1RR024986, NCRR UL1RR025750, P60MD00514, NCRR UL1RR024992-03S3, NCRR UL1RR024992-05S1, and NCRR UL1RR029890). NR 42 TC 11 Z9 11 U1 3 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2013 VL 103 IS 9 BP 1685 EP 1692 DI 10.2105/AJPH.2012.300941 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3NB UT WOS:000330998200042 PM 23409875 ER PT J AU Choyke, P Kurdziel, KA Mena, E Lindenberg, ML AF Choyke, Peter Kurdziel, Karen A. Mena, Esther Lindenberg, Maria L. TI Meeting the challenges of PET-based molecular imaging in cancer SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE cancer; FLT; fluorodeoxyglucose; fluoro-L-thymidine; ionizing radiation; medical costs; molecular imaging; PET; positron emission tomography; regulations; single-photon emission-computed tomography; SPECT ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC PROSTATE-CANCER; BREAST-CANCER; COLORECTAL-CARCINOMA; MEMBRANE ANTIGEN; BRAIN-TUMORS; THERAPY; 16-BETA-F-18-FLUORO-5-ALPHA-DIHYDROTESTOSTERONE; PHARMACOKINETICS; HETEROGENEITY AB As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent. C1 [Choyke, Peter; Kurdziel, Karen A.; Mena, Esther; Lindenberg, Maria L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Choyke, P (reprint author), NCI, Mol Imaging Program, Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. EM pchoyke@nih.gov NR 39 TC 1 Z9 1 U1 1 U2 6 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD SEP PY 2013 VL 13 IS 7 BP 671 EP 680 DI 10.1586/14737159.2013.835568 PG 10 WC Pathology SC Pathology GA AA7PH UT WOS:000331288900010 PM 24063395 ER PT J AU Yang, XP Amar, MJ Vaisman, B Bocharov, AV Vishnyakova, TG Freeman, LA Kurlander, RJ Patterson, AP Becker, LC Remaley, AT AF Yang, Xiao-Ping Amar, Marcelo J. Vaisman, Boris Bocharov, Alexander V. Vishnyakova, Tatyana G. Freeman, Lita A. Kurlander, Roger J. Patterson, Amy P. Becker, Lewis C. Remaley, Alan T. TI Scavenger receptor-BI is a receptor for lipoprotein(a) SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lipoprotein receptors; atherosclerosis; apolipoprotein(a); oxidized lipids; selective uptake ID LOW-DENSITY-LIPOPROTEIN; CHOLESTERYL ESTER; ENDOTHELIAL-CELLS; SR-BI; GENE; ATHEROSCLEROSIS; EXPRESSION; LP(A); HDL; OVEREXPRESSION AB Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that binds a variety of lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL), but lipoprotein(a) [Lp(a)] has not been investigated as a possible ligand. Stable cell lines (HEK293 and HeLa) expressing human SR-BI were incubated with protein-or lipid-labeled Lp(a) to investigate SR-BI-dependent Lp(a) cell association. SR-BI expression enhanced the association of both I-125- and Alexa Fluor-labeled protein from Lp(a). By confocal microscopy, SR-BI was also found to promote the internalization of fluorescent lipids (BODIPY-cholesteryl ester (CE)- and DiI-labeled) from Lp(a), and by immunocytochemistry the cellular internalization of apolipoprotein(a) and apolipoprotein B. When dual-labeled (H-3-cholesteryl ether, I-125-protein) Lp(a) was added to cells expressing SR-BI, there was a greater relative increase in lipid uptake over protein, indicating that SR-BI mediates selective lipid uptake from Lp(a). Compared with C57BL/6 control mice, transgenic mice overexpressing human SR-BI in liver were found to have increased plasma clearance of H-3-CE-Lp(a), whereas mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice had decreased plasma clearance (fractional catabolic rate: 0.63 +/- 0.08/day, 1.64 +/- 0.62/day, and 4.64 +/- 0.40/day for Sr-b1-KO, C57BL/6, and human scavenger receptor class B type I transgenic mice, respectively).jlr We conclude that Lp(a) is a novel ligand for SR-BI and that SR-BI mediates selective uptake of Lp(a)associated lipids. C1 [Yang, Xiao-Ping; Becker, Lewis C.] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Amar, Marcelo J.; Vaisman, Boris; Freeman, Lita A.; Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Bocharov, Alexander V.; Vishnyakova, Tatyana G.; Patterson, Amy P.] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Kurlander, Roger J.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov FU National Heart, Lung, and Blood Institute [HL-72518, HL-59684, HL-65608] FX This work was supported by grants HL-72518 (L.C.B.), HL-59684 (L.C.B.), and HL-65608 (L.C.B.) from the National Heart, Lung, and Blood Institute and intramural research funding of National Heart, Lung, and Blood Institute (A.T.R.). NR 34 TC 22 Z9 22 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD SEP PY 2013 VL 54 IS 9 BP 2450 EP 2457 DI 10.1194/jlr.M038877 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 301LK UT WOS:000330533600015 PM 23812625 ER PT J AU Dowling, TC Wang, ES Ferrucci, L Sorkin, JD AF Dowling, Thomas C. Wang, En-Shih Ferrucci, Luigi Sorkin, John D. TI Glomerular Filtration Rate Equations Overestimate Creatinine Clearance in Older Individuals Enrolled in the Baltimore Longitudinal Study on Aging: Impact on Renal Drug Dosing SO PHARMACOTHERAPY LA English DT Article DE GFR; glomerular filtration rate; creatinine clearance; geriatrics; BLSA; drug safety ID COCKCROFT-GAULT EQUATIONS; IMPAIRED KIDNEY-FUNCTION; SERUM CREATININE; ELDERLY-PATIENTS; DISEASE FORMULA; DIET; DABIGATRAN; ADULTS; RECOMMENDATIONS; ADJUSTMENTS AB OBJECTIVES To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS A total of 269 men and women with a mean +/- SD age of 81 +/- 6 years, mean serum creatinine concentration (S-cr) of 1.1 +/- 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mCl(cr)) of 53 +/- 13 ml/minute. MEASUREMENTS AND MAIN RESULTS Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mCl(cr). Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mCl(cr). The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean +/- SD 34 +/- 20% and 22 +/- 15%, respectively, p<0.001) and mCl(cr) (29 +/- 47% and 18 +/- 40%, respectively, p<0.001). Rounding low S-cr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 +/- 10 ml/minute) that were significantly lower than mCl(cr) (56 +/- 12 ml/minute, p<0.001) and CG (56 +/- 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mCl(cr) and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low S-cr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed. C1 [Dowling, Thomas C.; Wang, En-Shih] Univ Maryland, Dept Pharm Practice & Sci, Sch Pharm, Baltimore, MD 21201 USA. [Ferrucci, Luigi] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. [Sorkin, John D.] GRECC, Baltimore VA Med Ctr, Baltimore, MD USA. [Sorkin, John D.] Univ Maryland, Sch Med, Baltimore VA Med Ctr, Div Gerontol & Geriatr,Dept Med, Baltimore, MD 21201 USA. RP Dowling, TC (reprint author), Univ Maryland, Dept Pharm Practice & Sci, 20 N Pine St,PH N413, Baltimore, MD 21201 USA. EM tdowling@rx.umaryland.edu RI Dowling, Thomas/D-2147-2013 OI Dowling, Thomas/0000-0003-3214-9283 FU National Institutes of Health [P30 AG028747-07]; Baltimore Veterans Administration Geriatric Research Education and Clinical Center FX This work was supported by the National Institutes of Health grant P30 AG028747-07 and the Baltimore Veterans Administration Geriatric Research Education and Clinical Center. NR 50 TC 22 Z9 23 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD SEP PY 2013 VL 33 IS 9 BP 912 EP 921 DI 10.1002/phar.1282 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AA5MJ UT WOS:000331143200006 PM 23625813 ER PT J AU Ballester, LY Wang, ZF Shandilya, S Miettinen, M Burger, PC Eberhart, CG Rodriguez, FJ Raabe, E Nazarian, J Warren, K Quezado, MM AF Ballester, Leomar Y. Wang, Zengfeng Shandilya, Shaefali Miettinen, Markku Burger, Peter C. Eberhart, Charles G. Rodriguez, Fausto J. Raabe, Eric Nazarian, Javad Warren, Katherine Quezado, Martha M. TI Morphologic Characteristics and Immunohistochemical Profile of Diffuse Intrinsic Pontine Gliomas SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE DIPG; gliomas; brain tumor; brainstem; pontine; pediatric glioma ID BRAIN-STEM GLIOMAS; GENE AMPLIFICATION; MALIGNANT GLIOMAS; RECEPTOR GENE; EXPRESSION; MUTATIONS; CHILDREN; CELL; GLIOBLASTOMA; SUBGROUPS AB Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years. We built multitissue arrays with 24 postmortem DIPG samples and analyzed the morphology and expression of several proteins (p53, EGFR, GFAP, MIB1, BMI1, beta-catenin, p16, Nanog, Nestin, OCT4, OLIG2, SOX2) with the goal of identifying potential treatment targets and improving our understanding of the biology of these tumors. The majority of DIPGs were high-grade gliomas (22), with 18 cases having features of glioblastoma (World Health Organization [WHO] grade IV) and 4 cases with high-grade features consistent with anaplastic astrocytoma (WHO grade III). One case was low grade (WHO grade II), and 1 case showed intermediate features between a grade II and grade III glioma (low mitotic rate but increased cellularity and cell atypia), being difficult to grade precisely. The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). Our results suggest that dys-regulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment. C1 [Ballester, Leomar Y.; Wang, Zengfeng; Miettinen, Markku; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Shandilya, Shaefali; Warren, Katherine] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Burger, Peter C.; Eberhart, Charles G.; Rodriguez, Fausto J.; Raabe, Eric] Johns Hopkins Univ Hosp, Dept Pathol, Div Neuropathol, Baltimore, MD 21287 USA. [Nazarian, Javad] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. RP Quezado, MM (reprint author), NCI, Pathol Lab, NIH, Bldg 10-2B50,10 Ctr Dr, Bethesda, MD 20892 USA. EM quezadom@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 14 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2013 VL 37 IS 9 BP 1357 EP 1364 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 299XU UT WOS:000330429800008 PM 24076776 ER PT J AU Alimchandani, M Lai, JP Aung, PP Khangura, S Kamal, N Gallin, JI Holland, SM Malech, HL Heller, T Miettinen, M Quezado, MM AF Alimchandani, Meghna Lai, Jin-Ping Phyu Phyu Aung Khangura, Sajneet Kamal, Natasha Gallin, John I. Holland, Steven M. Malech, Harry L. Heller, Theo Miettinen, Markku Quezado, Martha M. TI Gastrointestinal Histopathology in Chronic Granulomatous Disease A Study of 87 Patients SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE chronic granulomatous disease; granulomas; colitis; pigmented macrophages; eosinophilia; inflammatory bowel disease; gastrointestinal tract ID INFLAMMATORY-BOWEL-DISEASE; FEATURES; COLITIS; MANIFESTATIONS; COMPLICATIONS; INVOLVEMENT; CHILDHOOD; REGISTRY; CGD AB Gastrointestinal (GI) involvement in chronic granulomatous disease (CGD), a rare genetic immunodeficiency, mimics other inflammatory bowel diseases. We report GI pathology from 87 CGD patients seen at the NIH Clinical Center, with vague to severe clinical symptoms, in whom biopsies (313) had been evaluated (esophagus [23], stomach [71], small bowel [52] including duodenum [39], ileum [12], and jejunum [1], and colon [167]). Additionally reviewed was GI tissue from 15 autopsies. In our patient cohort, the mean age was 22 years (age range, 3 to 44 y; 2:1 male to female ratio). There were pathologic changes in 83/87 (95%) patients; with colon being the most commonly involved site and esophagus the least. There were microgranulomas in 53/87 (61%), pigmented macrophages in 64/87 (74%), tissue eosinophilia in 31/87 (36%), and chronic and/or acute inflammation in 57/87 (66%) patients. A subset of patients had villous shortening in the duodenum (8/39) and ileum (5/12). We identify microgranulomas in 76/167 (46%) colon, 12/52 (23%) small bowel, and 4/71 (6%) gastric biopsies; pigmented macrophages in 109/167 (65%) colon and 7/52 (13%) small bowel biopsies and 14/15 autopsies; chronic and/or acute inflammation in 97/167 (58%) colon, 13/52 (25%) small bowel, 42/71 (59%) gastric, and 5/23 (22%) esophageal biopsies; tissue eosinophilia in 43/167 (26%) colon, 7/52 (13%) small bowel, and 2/71 (3%) gastric biopsies. Only 4/87 (5%) patients had normal histology. No infectious etiology was identified in the majority of inflammatory lesions. We found that mild to severe GI pathology was common in CGD. In addition, microgranulomas, pigmented macrophages, and eosinophilia are not associated with acute (neutrophilic) inflammation. C1 [Alimchandani, Meghna; Lai, Jin-Ping; Phyu Phyu Aung; Miettinen, Markku; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Khangura, Sajneet; Kamal, Natasha; Heller, Theo] NIDDK, NIH, Bethesda, MD 20892 USA. [Gallin, John I.] NCI, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.; Malech, Harry L.] NIAID, NIH, Bethesda, MD 20892 USA. RP Quezado, MM (reprint author), NCI, Pathol Lab, NIH, 10 Ctr Dr Bldg 10-2B50, Bethesda, MD 20892 USA. EM quezadom@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 24 TC 14 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2013 VL 37 IS 9 BP 1365 EP 1372 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 299XU UT WOS:000330429800009 PM 23887163 ER PT J AU Merkel, TJ Perera, PY Lee, GM Verma, A Hiroi, T Yokote, H Waldmann, TA Perera, LP AF Merkel, Tod J. Perera, Pin-Yu Lee, Gloria M. Verma, Anita Hiroi, Toyoko Yokote, Hiroyuki Waldmann, Thomas A. Perera, Liyanage P. TI Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE anthrax; vaccines; protective antigen; vaccinia; IL-15; bioluminescence ID BACILLUS-ANTHRACIS; DNA VACCINE; MODEL; DISSEMINATION; CHALLENGE; RABBITS; TOXIN; ELECTROPORATION; DISEASE; SPORES AB An intense effort has been launched to develop improved anthrax vaccines that confer rapid, long lasting protection preferably with an extended stability profile amenable for stockpiling. Protective antigen (PA)-based vaccines are most favored as immune responses directed against PA are singularly protective, although the actual protective mechanism remains to be unraveled. Herein we show that contrary to the prevailing view, an efficacious PA-based vaccine confers protection against inhalation anthrax by preventing the establishment of a toxin-releasing systemic infection. Equally importantly, antibodies measured by the in vitro lethal toxin neutralization activity assay (TNA) that is considered as a reliable correlate of protection, especially for PA protein-based vaccines adjuvanted with aluminum salts appear to be not absolutely essential for this protective immune response. C1 [Merkel, Tod J.; Lee, Gloria M.; Verma, Anita] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Perera, Pin-Yu] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Hiroi, Toyoko] NIA, Lymphocyte Differentiat Sect, Baltimore, MD 21224 USA. [Yokote, Hiroyuki] Chemoserotherapeut Res Inst, Kumamoto, Japan. [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Perera, LP (reprint author), NCI, Metab Branch, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH; Trans-NIH/FDA Intramural Biodefense Program; Biodefense and Emerging Infections Research Resources Repository (BEI Resources, NIAID) FX This work was in part supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH and by a 3-y competitive research funding award to L.P.P from the Trans-NIH/FDA Intramural Biodefense Program. We gratefully acknowledge the receipt of reagents from the Biodefense and Emerging Infections Research Resources Repository (BEI Resources, NIAID) for this study. We also express our gratitude to Drs Anne Boyer and John Barr at the CDC for assistance with LF measurements in the rabbit sera. NR 26 TC 2 Z9 2 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD SEP PY 2013 VL 9 IS 9 BP 1841 EP 1848 DI 10.4161/hv.25337 PG 8 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 298AJ UT WOS:000330295900011 PM 23787486 ER PT J AU de Witt, P Maartens, DJ Uldrick, TS Sissolak, G AF de Witt, Pieter Maartens, Deborah J. Uldrick, Thomas S. Sissolak, Gerhard TI Treatment Outcomes in AIDS-Related Diffuse Large B-cell Lymphoma in the Setting Roll Out of Combination Antiretroviral Therapy in South Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE diffuse large B-cell lymphoma; AIDS-related lymphoma; South Africa; AIDS-related lymphoma risk score ID NON-HODGKINS-LYMPHOMA; HUMAN-IMMUNODEFICIENCY-VIRUS; PROGNOSTIC-FACTORS; CHEMOTHERAPY; RITUXIMAB; TRIAL; MANAGEMENT; CHOP; CYCLOPHOSPHAMIDE; PREVALENCE AB Background: Long-term survival for patients with AIDS-related diffuse large B-cell lymphoma (DLBCL) is feasible in settings with available combination antiretroviral therapy (cART). However, given limited oncology resources, outcomes for AIDS-associated DLBCL in South Africa are unknown. Methods: We performed a retrospective analysis of survival in patients with newly diagnosed AIDS-related DLBCL treated at a tertiary teaching hospital in Cape Town, South Africa, with cyclophosphamide, doxorubicin, vincristine, and oral prednisone (CHOP) or CHOP-like chemotherapy (January 2004 until December 2010). HIV-related and lymphoma-related prognostic factors were evaluated. Results: Thirty-six patients evaluated; median age 37.3 years, 52.8% men, and 61.1% black South Africans. Median CD4 count 184 cells per microliter (in 27.8% this was < 100 cells/mu L), 80% high risk according to the age-adjusted International Prognostic Index. Concurrent Mycobacterium tuberculosis in 25%. Two-year overall survival (OS) was 40.5% (median OS 10.5 months, 95% confidence interval: 6.5 to 31.8). Eastern Cooperative Oncology Group performance status of 2 or more (25.4% vs 50.0%, P = 0.01) and poor response to cART (18.0% vs 53.9%, P = 0.03) predicted inferior 2-year OS. No difference in 2-year OS was demonstrated in patients coinfected with M. tuberculosis (P = 0.87). Conclusions: Two-year OS for patients with AIDS-related DLBCL treated with CHOP like regimens and cART is comparable to that seen in the United States and Europe. Important factors effecting OS in AIDS-related DLBCL in South Africa include performance status at presentation and response to cART. Patients with comorbid M. tuberculosis or hepatitis B seropositivity seem to tolerate CHOP in our setting. Additional improvements in outcomes are likely possible. C1 [de Witt, Pieter; Sissolak, Gerhard] Univ Stellenbosch, Dept Internal Med, Cape Town, South Africa. [Maartens, Deborah J.] Univ Stellenbosch, Dept Anat Pathol, Cape Town, South Africa. [Maartens, Deborah J.] Univ Stellenbosch, NHLS, Cape Town, South Africa. [Maartens, Deborah J.] Univ Stellenbosch, Fac Hlth Sci, Tygerberg Acad Hosp, Cape Town, South Africa. [Uldrick, Thomas S.] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Sissolak, G (reprint author), Dept Med, Div Clin Hematol, POB 19063, ZA-7505 Cape Town, South Africa. EM sissolak1@telkomsa.net FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 39 TC 4 Z9 4 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD SEP 1 PY 2013 VL 64 IS 1 BP 66 EP 73 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300GE UT WOS:000330451600013 PM 23797692 ER PT J AU Freidlin, B Sun, ZX Gray, R Korn, EL AF Freidlin, Boris Sun, Zhuoxin Gray, Robert Korn, Edward L. TI Phase III Clinical Trials That Integrate Treatment and Biomarker Evaluation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; DESIGNS; FLUOROURACIL; PANITUMUMAB; LEUCOVORIN; ERLOTINIB C1 [Freidlin, Boris; Korn, Edward L.] NCI, Bethesda, MD 20852 USA. [Sun, Zhuoxin; Gray, Robert] Eastern Cooperat Oncol Grp, Boston, MA USA. [Sun, Zhuoxin; Gray, Robert] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN 8129, Bethesda, MD 20852 USA. EM freidlinb@ctep.nci.nih.gov FU National Institutes of Health [CA023318] FX Supported in part by Grant No. CA023318 from the National Institutes of Health. NR 16 TC 19 Z9 19 U1 1 U2 7 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 SEP 1 PY 2013 VL 31 IS 25 BP 3158 EP 3161 DI 10.1200/JCO.2012.48.3826 PG 4 WC Oncology SC Oncology GA 301OC UT WOS:000330540600018 PM 23569306 ER PT J AU Graf-Myles, J Farmer, C Thurm, A Royster, C Kahn, P Soskey, L Rothschild, L Swedo, S AF Graf-Myles, Jennifer Farmer, Cristan Thurm, Audrey Royster, Caitlin Kahn, Phoebe Soskey, Laura Rothschild, Leah Swedo, Susan TI Dietary Adequacy of Children with Autism Compared with Controls and the Impact of Restricted Diet SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE autism; diet; nutrition; healthy eating index; gluten-free; casein-free ID TYPICALLY DEVELOPING-CHILDREN; HEALTHY EATING INDEX-2005; VITAMIN-A-DEFICIENCY; SPECTRUM DISORDERS; FOOD SELECTIVITY; PRESCHOOL-CHILDREN; NUTRIENT INTAKE; YOUNG-CHILDREN; BEHAVIORS; NUTRITION AB Objective: Children with autism (AUT) may consume a restricted diet relative to typical peers, whether due to therapeutic measures or sensory sensitivities. The objective of this study was to compare children with AUT with both typically developing (TYP) and developmentally delayed children on nutrient and food group intake and overall diet quality and to evaluate the impact of diet restriction. Methods: Three-day food records and interview information were analyzed from 69 children with AUT, 14 children with developmental delay, and 37 TYP children, drawn from a larger longitudinal study. Results: Children with AUT did not differ significantly from children with other developmental delays on any dietary measures. Although there were differences in the average intake of some nutrients between AUT and typical controls, only calcium and dairy were also less likely to be consumed in adequate amounts by the AUT group. Intentional diet restriction accounted for most of the differences between AUT and typical controls. On average, all groups had inadequate fiber, vitamin D, and vegetable intake. Inadequate intake of folate, grains, and dairy was noted for the AUT subgroup with intentional diet restrictions. Children in the AUT group not following a restricted diet received significantly worse Healthy Eating Index-2005 scores than those following a restricted diet and typical controls. These differences were not nutritionally significant. Conclusions: When evaluating nutritional adequacy of children with AUT, special consideration should be given to calcium, folate, dairy, and grains. Diets of all children with AUT should be evaluated for idiosyncratic deficiencies because of unique dietary patterns. C1 [Graf-Myles, Jennifer; Royster, Caitlin] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Farmer, Cristan; Thurm, Audrey; Kahn, Phoebe; Soskey, Laura; Rothschild, Leah; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Graf-Myles, J (reprint author), NIH, Dept Nutr, Room B2-2426,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM mylesjg@cc.nih.gov FU National Institute of Mental Health of the National Institutes of Health [NCT00298246, 06-M-0102] FX This work was supported by the Intramural Program of the National Institute of Mental Health of the National Institutes of Health, NCT00298246, 06-M-0102. NR 43 TC 11 Z9 11 U1 12 U2 63 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD SEP PY 2013 VL 34 IS 7 BP 449 EP 459 PG 11 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 298XW UT WOS:000330359000001 PM 24042076 ER PT J AU Berry-Kravis, E Hessl, D Abbeduto, L Reiss, AL Beckel-Mitchener, A Urv, TK AF Berry-Kravis, Elizabeth Hessl, David Abbeduto, Leonard Reiss, Allan L. Beckel-Mitchener, Andrea Urv, Tiina K. CA Outcome Measures Working Grp TI Outcome Measures for Clinical Trials in Fragile X Syndrome SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE fragile X syndrome; clinical trials; outcome measures; intellectual disability ID AUTISM SPECTRUM DISORDER; ABERRANT BEHAVIOR CHECKLIST; DOWN-SYNDROME; WORKING-MEMORY; EXPRESSIVE LANGUAGE; MENTAL-RETARDATION; DOUBLE-BLIND; DEVELOPMENTAL-DISABILITIES; REPETITIVE BEHAVIOR; ATTENTION DEFICITS AB Objective: Progress in basic neuroscience has led to identification of molecular targets for treatment in fragile X syndrome (FXS) and other neurodevelopmental disorders; however, there is a gap in translation to targeted therapies in humans. One major obstacle to the demonstration of efficacy in human trials has been the lack of generally accepted endpoints to assess improvement in function in individuals with FXS. To address this problem, the National Institutes of Health convened a meeting of leading scientists and clinicians with the goal of identifying and standardizing outcome measures for use as potential endpoints in clinical trials in FXS. Methods: Participants in the meeting included FXS experts, experts in the design and implementation of clinical trials and measure development, and representatives from advocacy groups, industry, and federal agencies. Results: The group generated recommendations for optimal outcome measures in cognitive, behavioral, and biomarker/medical domains, including additional testing and validation of existing measures and development of new measures in areas of need. Although no one endpoint or set of endpoints could be identified that met all criteria as an optimal measure, recommendations are presented in this report. Conclusion: The report is expected to guide the selection of measures in clinical trials and lead to the use of a more consistent battery of measures across trials. Furthermore, this will help to direct research toward gaps in the development of validated FXS-specific outcome measures and to assist with interpretation of clinical trial data by creating templates for measurement of treatment efficacy. C1 [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Pediat, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Hessl, David; Abbeduto, Leonard] Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Hessl, David; Abbeduto, Leonard] Univ Calif Davis, Med Ctr, MIND Inst, Sacramento, CA 95817 USA. [Reiss, Allan L.] Stanford Univ, Sch Med, Ctr Interdisciplinary Brain Sci Res, Stanford, CA 94305 USA. [Reiss, Allan L.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Reiss, Allan L.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. [Reiss, Allan L.] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Beckel-Mitchener, Andrea] NIMH, NIH, Bethesda, MD 20892 USA. [Urv, Tiina K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Berry-Kravis, E (reprint author), Rush Univ, Med Ctr, 1725 West Harrison,Suite 718, Chicago, IL 60612 USA. EM elizabeth_m_berry-kravis@rush.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Rare Disease Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke FX The Fragile X Outcome Measures Working Group meeting was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Office of Rare Disease Research, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. The authors thank Dr. Shaguna Mathur for her assistance with manuscript formatting and submission. NR 124 TC 40 Z9 40 U1 8 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD SEP PY 2013 VL 34 IS 7 BP 508 EP 522 PG 15 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 298XW UT WOS:000330359000008 PM 24042082 ER PT J AU Hadimani, MB MacDonough, MT Ghatak, A Strecker, TE Lopez, R Sriram, M Nguyen, BL Hall, JJ Kessler, RJ Shirali, AR Liu, L Garner, CM Pettit, GR Hame, E Chaplin, DJ Mason, RP Trawick, ML Pinney, KG AF Hadimani, Mallinath B. MacDonough, Matthew T. Ghatak, Anjan Strecker, Tracy E. Lopez, Ramona Sriram, Madhavi Nguyen, Benson L. Hall, John J. Kessler, Raymond J. Shirali, Anupama R. Liu, Li Garner, Charles M. Pettit, George R. Hame, Ernest Chaplin, David J. Mason, Ralph P. Trawick, Mary Lynn Pinney, Kevin G. TI Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID TUBULIN POLYMERIZATION INHIBITOR; POTENT ANTITUBULIN AGENTS; BREAST-CANCER CELLS; ANTICANCER AGENTS; ANTINEOPLASTIC AGENTS; ANTIMITOTIC AGENTS; BIOLOGICAL EVALUATION; ANALOGS; COLCHICINE; BINDING AB The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI(50) = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 mu M) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCUD mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer. C1 [Hadimani, Mallinath B.; MacDonough, Matthew T.; Ghatak, Anjan; Strecker, Tracy E.; Sriram, Madhavi; Hall, John J.; Kessler, Raymond J.; Shirali, Anupama R.; Garner, Charles M.; Trawick, Mary Lynn; Pinney, Kevin G.] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA. [Lopez, Ramona; Liu, Li; Mason, Ralph P.] Univ Texas SW Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA. [Pettit, George R.] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. [Hame, Ernest] NCI, NIH, Frederick Natl Lab Canc Res, Dev Therapeut Program,Div Canc Treatment & Diag,S, Frederick, MD 21702 USA. [Chaplin, David J.] Oxigene Inc, San Francisco, CA 94080 USA. RP Pinney, KG (reprint author), Baylor Univ, Dept Chem & Biochem, One Bear Pl 97348, Waco, TX 76798 USA. EM Kevin_Pinney@baylor.edu RI Mason, Ralph/C-8472-2012; Liu, LI/B-6912-2013; OI Mason, Ralph/0000-0001-7517-3721; Liu, LI/0000-0002-9731-6145; Pinney, Kevin/0000-0003-1262-8631; Garner, Charles/0000-0002-3043-3240 FU Cancer Prevention and Research Institute of Texas [CPRIT] [RP100406]; Oxigene, Inc.; Welch Foundation [AA-1278]; National Cancer Institute [5R01CA140674]; NCI [U24 CAI26608]; Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant [IP30 CA142543]; Department of Radiology; NIH Shared Instrumentation Grant [S10 RR031859] FX The authors are grateful to the Cancer Prevention and Research Institute of Texas [CPRIT (RP100406), to K.G.P. and M.L.T.], Oxigene, Inc. (to K.G.P. and M.L.T), the Welch Foundation (grant no. AA-1278 to K.G.P.), the Baylor University Research Committee (URC grant to K.G.P.), and the National Cancer Institute Award Number 5R01CA140674 (to K.G.P. and M.L.T. with subcontract to R.P.M.) for their financial support of this project. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors also thank Dr. A. Ramirez (Mass Spectrometry Core Facility, Baylor University) and Dr. J. Karban and Dr. M. Nemec (Director) for use of the shared Molecular Biosciences Center at Baylor University. Imaging was facilitated with the assistance of the Southwestern Small Animal Imaging Resource (SW-SAIRP), which is supported in part by NCI U24 CAI26608, the Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant, IP30 CA142543, and the Department of Radiology. We are grateful to Professor). Hill (Cardiology, UTSW) for providing access to the Vevo 2100, which was acquired thanks to the NIH Shared Instrumentation Grant S10 RR031859. NR 53 TC 22 Z9 23 U1 0 U2 19 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 SEP PY 2013 VL 76 IS 9 BP 1668 EP 1678 DI 10.1021/np400374w PG 11 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 298NS UT WOS:000330331200021 PM 24016002 ER PT J AU Malfatti, E Olive, M Taratuto, AL Richard, P Brochier, G Bitoun, M Gueneau, L Laforet, P Stojkovic, T Maisonobe, T Monges, S Lubieniecki, F Vasquez, G Streichenberger, N Lacene, E Saccoliti, M Prudhon, B Alexianu, M Figarella-Branger, D Schessl, J Bonnemann, C Eymard, B Fardeau, M Bonne, G Romero, NB AF Malfatti, Edoardo Olive, Montse Taratuto, Ana Lia Richard, Pascale Brochier, Guy Bitoun, Marc Gueneau, Lucie Laforet, Pascal Stojkovic, Tanya Maisonobe, Thierry Monges, Soledad Lubieniecki, Fabiana Vasquez, Gabriel Streichenberger, Nathalie Lacene, Emmanuelle Saccoliti, Maria Prudhon, Bernard Alexianu, Marilena Figarella-Branger, Dominique Schessl, Joachim Bonnemann, Carsten Eymard, Bruno Fardeau, Michel Bonne, Gisele Romero, Norma Beatriz TI Skeletal Muscle Biopsy Analysis in Reducing Body Myopathy and Other FHL1-Related Disorders SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Congenital myopathies with protein aggregates; FHL1; FHL1-related myopathies; Protein surplus myopathies; Reducing bodies ID LIM DOMAIN; FHL1; MUTATIONS; ISOFORM; GENE; CYTOSKELETON; PROTEIN-1; FEATURES; NUCLEUS; BODIES AB FHL1 mutations have been associated with various disorders that include reducing body myopathy (RBM), Emery-Dreifuss-like muscular dystrophy, isolated hypertrophic cardiomyopathy, and some overlapping conditions. We report a detailed histochemical, immunohistochemical, electron microscopic, and immunoelectron microscopic analyses of muscle biopsies from 18 patients carrying mutations in FHL1: 14 RBM patients (Group 1), 3 Emery-Dreifuss muscular dystrophy patients (Group 2), and 1 patient with hypertrophic cardiomyopathy and muscular hypertrophy (Group 2). Group 1 muscle biopsies consistently showed RBs associated with cytoplasmic bodies. The RBs showed prominent FHL1 immunoreactivity whereas desmin, alpha B-crystallin, and myotilin immunoreactivity surrounded RBs. By electron microscopy, RBs were composed of electron-dense tubulofilamentous material that seemed to spread progressively between the myofibrils and around myonuclei. By immunoelectron microscopy, FHL1 protein was found exclusively inside RBs. Group 2 biopsies showed mild dystrophic abnormalities without RBs; only minor nonspecific myofibrillar abnormalities were observed under electron microscopy. Molecular analysis revealed missense mutations in the second FHL1 LIM domain in Group 1 patients and ins/del or missense mutations within the fourth FHL1 LIM domain in Group 2 patients. Our findings expand the morphologic features of RBM, clearly demonstrate the localization of FHL1 in RBs, and further illustrate major morphologic differences among different FHL1-related myopathies. C1 [Olive, Montse; Brochier, Guy; Lacene, Emmanuelle; Fardeau, Michel; Romero, Norma Beatriz] Grp Hosp Univ La Pitie Salpetriere, Inst Myol, Unite Morphol Neuromusculaire, Paris, France. [Malfatti, Edoardo] Univ Siena, Dept Neurol Neurosurg & Behav Sci, I-53100 Siena, Italy. [Malfatti, Edoardo; Bitoun, Marc; Gueneau, Lucie; Prudhon, Bernard; Bonne, Gisele; Romero, Norma Beatriz] INSERM, Paris, France. [Malfatti, Edoardo; Bitoun, Marc; Gueneau, Lucie; Prudhon, Bernard; Bonne, Gisele; Romero, Norma Beatriz] Univ Paris 06, Inst Myol, Paris, France. [Malfatti, Edoardo; Laforet, Pascal; Stojkovic, Tanya; Eymard, Bruno; Romero, Norma Beatriz] Ctr Reference Pathol Neuromusculaire Paris Est, Inst Myol, Paris, France. [Olive, Montse] Bellvitge Hosp, IDIBELL, Inst Neuropathol, Barcelona, Spain. [Taratuto, Ana Lia; Monges, Soledad; Lubieniecki, Fabiana; Vasquez, Gabriel; Saccoliti, Maria] Hosp Nacl Pediat JP Garrahan, Buenos Aires, DF, Argentina. [Taratuto, Ana Lia; Monges, Soledad; Lubieniecki, Fabiana; Vasquez, Gabriel; Saccoliti, Maria] FLENI, Inst Invest Neurol, Buenos Aires, DF, Argentina. [Richard, Pascale; Brochier, Guy] GHU La Pitie Salpetriere, AP HP, UF Cardiogenet & Myogenet, Serv Biochim Metabol, Paris, France. [Maisonobe, Thierry] AP HP, Dept Clin Neurophysiol, Paris, France. [Streichenberger, Nathalie] Univ Lyon 1, Hosp Civils Lyon, Ctr Pathol Est, F-69365 Lyon, France. [Figarella-Branger, Dominique] CHU Timone, Aix Marseille Univ, AP HM, Neurooncol Team, Marseille, France. [Figarella-Branger, Dominique] Aix Marseille Univ, INSERM, Marseille, France. [Schessl, Joachim] Univ Munich, Dept Neurol, Friedrich Baur Inst, D-80539 Munich, Germany. [Bonnemann, Carsten] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA. RP Romero, NB (reprint author), GHU La Pitie Salpetriere, INSERM, Inst Myol, UMR 974, Paris, France. EM nb.romero@institut-myologie.org RI Bonne, Gisele/G-3121-2013; OI Olive, Montse/0000-0001-5727-0165 FU Institut National de la Sante et de la Recherche Medicale; Association Francaise contre les Myopathies; Association Institut de Myologie; Agence Nationale de la Recherche FX This work was supported by the Institut National de la Sante et de la Recherche Medicale, the Association Francaise contre les Myopathies, the Association Institut de Myologie, and the Agence Nationale de la Recherche. NR 19 TC 13 Z9 13 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD SEP PY 2013 VL 72 IS 9 BP 833 EP 845 PG 13 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 299GO UT WOS:000330384300004 PM 23965743 ER PT J AU Brown, ER Kincheloe, J Breen, N Olson, JL Portnoy, B Lee, SJC AF Brown, E. Richard Kincheloe, Jennifer Breen, Nancy Olson, Jean L. Portnoy, Barry Lee, Simon J. Craddock TI States' Use of Local Population Health Data: Comparing the Behavioral Risk Factor Surveillance System and Independent State Health Surveys SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Article DE Behavioral Risk Factor Surveillance System; community health needs assessment; health care reform; health surveys; independent state health surveys; population health surveillance; state health surveys ID CARE AB Objectives: To identify and compare key features of independent comprehensive state health surveys (SHS) with those of the Behavioral Risk Factor Surveillance System (BRFSS) for addressing the need for statewide and local population health data. Methods: We developed inclusion criteria, systematically collected information about federal and SHS that met these criteria, and obtained supplemental information from SHS leaders. Results: We identified comprehensive independent SHS in 11 states and BRFSS surveys in all 50 states. The independent SHS meet important statewide and local data needs, filling 3 key health data gaps in the BRFSS: lack of adequate data on special populations such as children, lack of data on specific localities, and limited depth and scope of health topics surveyed on key issues such as health insurance coverage. Unlike BRFSS, independent SHS have limited comparability with each other. Conclusions: The BRFSS and independent SHS each meet some key state and local data needs but result in data gaps and inefficient use of resources. Surveys could more effectively and efficiently meet future needs for comparable data to monitor health care reform and address health disparities if they were coordinated across states and at the national, state, and local levels. C1 [Brown, E. Richard; Kincheloe, Jennifer] Univ Calif Los Angeles, Ctr Hlth Policy Res, Los Angeles, CA USA. [Brown, E. Richard] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Breen, Nancy] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Olson, Jean L.] NHLBI, Epidemiol Branch, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Portnoy, Barry] NIH, Off Dis Prevent, Off Director, Bethesda, MD 20892 USA. [Lee, Simon J. Craddock] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Lee, Simon J. Craddock] Univ Texas SW Med Ctr Dallas, Program Populat Sci & Canc Control, Dallas, TX USA. RP Breen, N (reprint author), NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM breenn@mail.nih.gov OI Lee, Simon J. Craddock/0000-0001-6345-1237 NR 15 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD SEP-OCT PY 2013 VL 19 IS 5 BP 444 EP 450 DI 10.1097/PHH.0b013e3182751cfb PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 300DU UT WOS:000330445400012 PM 23295408 ER PT J AU Abbatiello, SE Mani, DR Schilling, B MacLean, B Zimmerman, LJ Feng, XD Cusack, MP Sedransk, N Hall, SC Addona, T Allen, S Dodder, NG Ghosh, M Held, JM Hedrick, V Inerowicz, HD Jackson, A Keshishian, H Kim, JW Lyssand, JS Riley, CP Rudnick, P Sadowski, P Shaddox, K Smith, D Tomazela, D Wahlander, A Waldemarson, S Whitwell, CA You, J Zhang, SC Kinsinger, CR Mesri, M Rodriguez, H Borchers, CH Buck, C Fisher, SJ Gibson, BW Liebler, D MacCoss, M Neubert, TA Paulovich, A Regnier, F Skates, SJ Tempst, P Wang, M Carr, SA AF Abbatiello, Susan E. Mani, D. R. Schilling, Birgit MacLean, Brendan Zimmerman, Lisa J. Feng, Xingdong Cusack, Michael P. Sedransk, Nell Hall, Steven C. Addona, Terri Allen, Simon Dodder, Nathan G. Ghosh, Mousumi Held, Jason M. Hedrick, Victoria Inerowicz, H. Dorota Jackson, Angela Keshishian, Hasmik Kim, Jong Won Lyssand, John S. Riley, C. Paige Rudnick, Paul Sadowski, Pawel Shaddox, Kent Smith, Derek Tomazela, Daniela Wahlander, Asa Waldemarson, Sofia Whitwell, Corbin A. You, Jinsam Zhang, Shucha Kinsinger, Christopher R. Mesri, Mehdi Rodriguez, Henry Borchers, Christoph H. Buck, Charles Fisher, Susan J. Gibson, Bradford W. Liebler, Daniel MacCoss, Michael Neubert, Thomas A. Paulovich, Amanda Regnier, Fred Skates, Steven J. Tempst, Paul Wang, Mu Carr, Steven A. TI Design, Implementation and Multisite Evaluation of a System Suitability Protocol for the Quantitative Assessment of Instrument Performance in Liquid Chromatography-Multiple Reaction Monitoring-MS (LC-MRM-MS) SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID TANDEM MASS-SPECTROMETRY; PEPTIDE IMMUNOAFFINITY ENRICHMENT; ABSOLUTE QUANTIFICATION; TARGETED PROTEOMICS; ISOTOPE-DILUTION; QUALITY-CONTROL; PROTEINS; PLASMA; LC/MS/MS; ASSAYS AB Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM-MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LCSID- MRM-MS platforms for routine use, with pass/ fail criteria for system suitability performance measures defined as peak area coefficient of variation < 0.15, peak width coefficient of variation < 0.15, standard deviation of RT < 0.15 min (9 s), and the RT drift < 0.5min (30 s). The deleterious effect of a marginally performing LC-SID-MRM-MS system on the limit of quantification (LOQ) in targeted quantitative assays illustrates the use and need for a SSP to establish robust and reliable system performance. Use of a SSP helps to ensure that analyte quantification measurements can be replicated with good precision within and across multiple laboratories and should facilitate more widespread use of MRM-MS technology by the basic biomedical and clinical laboratory research communities. C1 [Abbatiello, Susan E.; Mani, D. R.; Addona, Terri; Keshishian, Hasmik; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Schilling, Birgit; Cusack, Michael P.; Held, Jason M.; Gibson, Bradford W.] Buck Inst Res Aging, Novato, CA 94945 USA. [MacLean, Brendan; Tomazela, Daniela; MacCoss, Michael] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Zimmerman, Lisa J.; Shaddox, Kent; Whitwell, Corbin A.; Liebler, Daniel] Vanderbilt Univ, Nashville, TN 37232 USA. [Feng, Xingdong; Sedransk, Nell] Natl Inst Stat Sci, Res Triangle Pk, NC 27709 USA. [Hall, Steven C.; Allen, Simon; Fisher, Susan J.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Dodder, Nathan G.; Rudnick, Paul] NIST, Gaithersburg, MD 20899 USA. [Ghosh, Mousumi; Tempst, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Hedrick, Victoria; Inerowicz, H. Dorota; Riley, C. Paige; Buck, Charles; Regnier, Fred] Purdue Univ, W Lafayette, IN 47907 USA. [Jackson, Angela; Smith, Derek; Borchers, Christoph H.] Univ Victoria, Genome BC Prote Ctr, Victoria, BC V8Z 7X8, Canada. [Kim, Jong Won; You, Jinsam; Wang, Mu] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Lyssand, John S.; Sadowski, Pawel; Wahlander, Asa; Waldemarson, Sofia; Neubert, Thomas A.] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA. [Lyssand, John S.; Sadowski, Pawel; Wahlander, Asa; Waldemarson, Sofia; Neubert, Thomas A.] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Zhang, Shucha; Paulovich, Amanda] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. [Skates, Steven J.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Abbatiello, SE (reprint author), Broad Inst MIT & Harvard, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM susana@broad.mit.edu RI Dodder, Nathan/C-7971-2015; OI Dodder, Nathan/0000-0001-5913-1767; Tempst, Paul/0000-0002-6680-3987; Held, Jason/0000-0001-8024-2736; Liebler, Daniel/0000-0002-7873-3031 FU National Cancer Institute [U24 CA126476, U24 126477, U24 126480, U24 CA126485, U24 126479]; National Institute of Standards and Technology [70NANB9H9001]; NCRR [S10 RR0021222]; National Institute of Statistical Sciences FX This work was supported by grants from the National Cancer Institute (U24 CA126476, U24 126477, U24 126480, U24 CA126485, and U24 126479), part of NCI Clinical Proteomic Technologies for Cancer (http://proteomics.cancer.gov) initiative. A component of this initiative is the Clinical Proteomic Technology Assessment for Cancer (CPTAC) Network and teams, which include the Broad Institute of MIT and Harvard (with the Fred Hutchinson Cancer Research Center, Massachusetts General Hospital, the University of North Carolina at Chapel Hill, the University of Victoria and the Plasma Proteome Institute), Memorial Sloan-Kettering Cancer Center (with the Skirball Institute at New York University), Purdue University (with Monarch Life Sciences, Indiana University, Indiana University-Purdue University Indianapolis and the Hoosier Oncology Group), University of California, San Francisco (with the Buck Institute for Age Research, Lawrence Berkeley National Laboratory, and the University of Texas M. D. Anderson Cancer Center), and Vanderbilt University School of Medicine (with the University of Texas M. D. Anderson Cancer Center, the University of Washington, and the University of Arizona). The UCSF CPTAC team gratefully acknowledges the support of the Canary Foundation for providing funds to purchase a 4000 QTRAP mass spectrometer. The Vanderbilt CPTAC team was additionally supported by Cooperative Agreement No. 70NANB9H9001 from the National Institute of Standards and Technology. BWG acknowledges instrumentation to the Buck Institute from an NCRR Shared Instrumentation grant S10 RR0021222. The NCI CPTAC also supported the work by the National Institute of Statistical Sciences. NR 35 TC 41 Z9 43 U1 0 U2 27 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD SEP PY 2013 VL 12 IS 9 BP 2623 EP 2639 DI 10.1074/mcp.M112.027078 PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 301MM UT WOS:000330536400019 PM 23689285 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Defining "Term" Pregnancy: Recommendations From the Defining "Term" Pregnancy Workgroup EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material ID POSTTERM PREGNANCY; NEONATAL OUTCOMES; DELIVERY C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD SEP PY 2013 VL 68 IS 9 BP 611 EP 612 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301DM UT WOS:000330513000002 ER PT J AU Manolio, TA Chisholm, RL Ozenberger, B Roden, DM Williams, MS Wilson, R Bick, D Bottinger, EP Brilliant, MH Eng, C Frazer, KA Korf, B Ledbetter, DH Lupski, JR Marsh, C Mrazek, D Murray, MF O'Donnell, PH Rader, DJ Relling, MV Shuldiner, AR Valle, D Weinshilboum, R Green, ED Ginsburg, GS AF Manolio, Teri A. Chisholm, Rex L. Ozenberger, Brad Roden, Dan M. Williams, Marc S. Wilson, Richard Bick, David Bottinger, Erwin P. Brilliant, Murray H. Eng, Charis Frazer, Kelly A. Korf, Bruce Ledbetter, David H. Lupski, James R. Marsh, Clay Mrazek, David Murray, Michael F. O'Donnell, Peter H. Rader, Daniel J. Relling, Mary V. Shuldiner, Alan R. Valle, David Weinshilboum, Richard Green, Eric D. Ginsburg, Geoffrey S. TI Implementing Genomic Medicine in the Clinic: The Future Is Here EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Manolio, Teri A.; Ozenberger, Brad; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chisholm, Rex L.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. [Williams, Marc S.] Intermt Healthcare, Clin Genet Inst, Salt Lake City, UT USA. [Williams, Marc S.; Ledbetter, David H.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Weinshilboum, Richard] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. [Bick, David] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA. [Bottinger, Erwin P.] Mt Sinai Sch Med, Charles Bronfman Inst Personalized Med, New York, NY USA. [Brilliant, Murray H.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI USA. [Eng, Charis] Cleveland Clin, Lerner Res Inst, Genom Med Inst, Cleveland, OH 44106 USA. [Frazer, Kelly A.] Univ Calif San Diego, Dept Pediat, Div Genome Informat Sci, La Jolla, CA 92093 USA. [Korf, Bruce] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Marsh, Clay] Ohio State Univ, Med Ctr, Ctr Personalized Hlth Care, Columbus, OH 43210 USA. [Mrazek, David] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Murray, Michael F.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [O'Donnell, Peter H.] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Relling, Mary V.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Valle, David] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Weinshilboum, Richard] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA. [Ginsburg, Geoffrey S.] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA. [Ginsburg, Geoffrey S.] Duke Univ, Ctr Personalized Med, Durham, NC USA. RP Manolio, TA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD SEP PY 2013 VL 68 IS 9 BP 621 EP 623 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301DM UT WOS:000330513000007 ER PT J AU Luhn, P Dallal, CM Weiss, JM Black, A Huang, WY Lacey, JV Hayes, RB Stanczyk, FZ Wentzensen, N Brinton, LA AF Luhn, Patricia Dallal, Cher M. Weiss, Jocelyn M. Black, Amanda Huang, Wen-Yi Lacey, James V., Jr. Hayes, Richard B. Stanczyk, Frank Z. Wentzensen, Nicolas Brinton, Louise A. TI Circulating Adipokine Levels and Endometrial Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Luhn, Patricia; Dallal, Cher M.; Black, Amanda; Huang, Wen-Yi; Wentzensen, Nicolas; Brinton, Louise A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Luhn, Patricia; Dallal, Cher M.] Natl Canc Inst, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD USA. [Weiss, Jocelyn M.] Mt Sinai Adolescent Hlth Ctr, New York, NY USA. Beckman Res Inst City Hope, Duarte, CA USA. [Hayes, Richard B.] NYU Langone Med Ctr, Dept Populat Hlth, New York, NY USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA USA. RP Luhn, P (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD SEP PY 2013 VL 68 IS 9 BP 632 EP 633 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301DM UT WOS:000330513000013 ER PT J AU Silver, RM Parker, CB Reddy, UM Goldenberg, R Coustan, D Dudley, DJ Saade, GR Stoll, B Koch, MA Conway, D Bukowski, R Hogue, CJR Pinar, H Moore, J Willinger, M Branch, DW AF Silver, Robert M. Parker, Corette B. Reddy, Uma M. Goldenberg, Robert Coustan, Donald Dudley, Donald J. Saade, George R. Stoll, Barbara Koch, Matthew A. Conway, Deborah Bukowski, Radek Hogue, Carol J. Rowland Pinar, Halit Moore, Janet Willinger, Marian Branch, D. Ware TI Antiphospholipid Antibodies in Stillbirth SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID FETAL LOSS; ANTICARDIOLIPIN ANTIBODIES; PREGNANCY; DEATH; WOMEN; ASSOCIATION; EXPERIENCE; UPDATE; APS AB OBJECTIVE: To compare antiphospholipid antibodies in deliveries with and without stillbirth using a multicenter, population-based case-control study of stillbirths and live births. METHODS: Maternal sera were assayed for immunoglobulin (Ig)G and IgM anticardiolipin and anti-beta 2-glyco-protein-I antibodies. Assays were performed in 582 stillbirth deliveries and 1,547 live birth deliveries. RESULTS: Elevated levels of IgG anticardiolipin and IgG anti-beta 2-glycoprotein-I antibodies were associated with an approximate threefold increased odds of stillbirth (crude odds ratio [OR] 3.43, 95% confidence interval [CI] 1.79-6.60, 3.8% compared with 1.1% and OR 3.17, 95% CI 1.30-7.72, (1.9% compared with 0.6%, respectively) when all deliveries with stillbirth were compared with all deliveries with live birth. When the subset of stillbirths not associated with fetal anomalies or obstetric complications was compared with term live births, elevated IgG anticardiolipin antibodies were associated with stillbirth (5.0% compared with 1.0%; OR 5.30, 95% CI, 2.39-11.76; IgG anti-b2-glycoprotein-I antibodies (1.9% compared with 0.6%) had an OR of 3.00 (95% CI 1.01-8.90) and IgM anticardiolipin antibodies (6.0% compared with 3.0%) had an OR of 2.03 (95% CI 1.09-3.76). Elevated levels of anticardiolipin and anti-beta 2-glycoprotein-I antibodies were associated with a threefold to fivefold increased odds of stillbirth. CONCLUSIONS: Our data support consideration of testing for antiphospholipid antibodies in cases of otherwise unexplained stillbirth. C1 [Silver, Robert M.] Univ Utah, Sch Med, Salt Lake City, UT 84132 USA. RTI Int, Res Triangle Pk, NC USA. NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Emory Univ, Sch Med, Atlanta, GA USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. RP Silver, RM (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, 30 North 1900 East,Room 2B308, Salt Lake City, UT 84132 USA. EM bsilver@hsc.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HD045953]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Brown University, Providence, Rhode Island [U10-HD045925]; Eunice Kennedy Shriver National Institute of Child Health and Human Development Emory University, Atlanta, Georgia [U10-HD045952]; Eunice Kennedy Shriver National Institute of Child Health and Human Development University of Texas Medical Branch at Galveston, Galveston, Texas [U10-HDO45955]; Eunice Kennedy Shriver National Institute of Child Health and Human Development University of Texas Health Sciences Center at San Antonio, San Antonio, Texas [U10-HD045944]; University of Utah Health Sciences Center, Salt Lake City, Utah; RTI International, Research Triangle Park, North Carolina [U01-HD045954] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10-HD045953 Brown University, Providence, Rhode Island; U10-HD045925 Emory University, Atlanta, Georgia; U10-HD045952 University of Texas Medical Branch at Galveston, Galveston, Texas; U10-HDO45955 University of Texas Health Sciences Center at San Antonio, San Antonio, Texas; U10-HD045944 University of Utah Health Sciences Center, Salt Lake City, Utah; and U01-HD045954 RTI International, Research Triangle Park, North Carolina. NR 24 TC 16 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2013 VL 122 IS 3 BP 641 EP 657 DI 10.1097/AOG.0b013e3182a1060e PG 17 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300DJ UT WOS:000330444300022 PM 23921873 ER PT J AU Viana, LM Seyyedi, M Brewer, CC Zalewski, C DiGiovanna, JJ Tamura, D Totonchy, M Kraemer, KH Nadol, JB AF Viana, Lucas M. Seyyedi, Mohammad Brewer, Carmen C. Zalewski, Christopher DiGiovanna, John J. Tamura, Deborah Totonchy, Mariam Kraemer, Kenneth H. Nadol, Joseph B., Jr. TI Histopathology of the Inner Ear in Patients With Xeroderma Pigmentosum and Neurologic Degeneration SO OTOLOGY & NEUROTOLOGY LA English DT Article DE DNA repair; Sensorineural hearing loss; Temporal bone histopathology; Xeroderma pigmentosum ID DNA-REPAIR; COCKAYNE-SYNDROME; SUN SENSITIVITY; DEAFNESS; DISEASE; ABNORMALITIES AB Introduction: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet-induced neoplasms and premature aging of sun-exposed tissue. Approximately 25% of XP patients in the United States have neurologic abnormalities including progressive sensorineural hearing loss (SNHL). Objective: To describe the temporal bone histopathology in 2 individuals with XP (XPA and XPD) with neurologic degeneration and to discuss the possible causes of deafness in these patients. Methods: Temporal bones were removed at autopsy and studied using light microscopy. Results: In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared with age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa's ganglion in the case with XPA. Conclusion: Two cases of XP with neurologic degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis, and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells. C1 [Viana, Lucas M.; Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Viana, Lucas M.; Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Viana, Lucas M.] Univ Brasilia, Fac Hlth Sci, BR-70910900 Brasilia, DF, Brazil. [Brewer, Carmen C.; Zalewski, Christopher] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Bethesda, MD USA. [DiGiovanna, John J.; Tamura, Deborah; Totonchy, Mariam; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Totonchy, Mariam] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. RP Viana, LM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 4th Floor,243 Charles St, Boston, MA 02114 USA. EM lucasmvianaorl@gmail.com FU Center for Cancer Research, National Cancer Institute; National Institute on Deafness and Other Communication Disorders (NIDCD); Clinical Research Training Program; National Institutes of Health; Pfizer Inc; NIDCD [5U24DC011968] FX This research was supported by the Intramural Research Programs of the Center for Cancer Research, National Cancer Institute (D. T., J. J. D., M. T., and K. H. K.), the National Institute on Deafness and Other Communication Disorders (NIDCD) (C. Z. and C. C. B.), the Clinical Research Training Program (M. B. T.), a public-private partnership supported jointly by the National Institutes of Health and Pfizer Inc (via a grant to the Foundation for National Institutes of Health from Pfizer Inc.), and NIDCD grant no. 5U24DC011968 (J. B. N). NR 22 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2013 VL 34 IS 7 BP 1230 EP 1236 PG 7 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 301HI UT WOS:000330523000023 PM 23928520 ER PT J AU Cohen-Wolkowiez, M Sampson, M Bloom, BT Arrieta, A Wynn, JL Martz, K Harper, B Kearns, GL Capparelli, EV Siegel, D Benjamin, DK Smith, PB AF Cohen-Wolkowiez, Michael Sampson, Mario Bloom, Barry T. Arrieta, Antonio Wynn, James L. Martz, Karen Harper, Barrie Kearns, Gregory L. Capparelli, Edmund V. Siegel, David Benjamin, Daniel K., Jr. Smith, P. Brian CA Best Pharmaceuticals Children Act TI Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples From Premature Infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE neonate; drug; pharmacokinetics; metronidazole; dried blood spots ID NECROTIZING ENTEROCOLITIS; INTRAVENOUS METRONIDAZOLE; SUSCEPTIBILITY AB Background: Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. Methods: We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants <= 32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. Results: Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 x (postmenstrual age/30)(2.45) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. Conclusion: Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing. C1 [Cohen-Wolkowiez, Michael; Benjamin, Daniel K., Jr.; Smith, P. Brian] Duke Univ, Dept Pediat, Durham, NC 27715 USA. [Cohen-Wolkowiez, Michael; Sampson, Mario; Harper, Barrie; Benjamin, Daniel K., Jr.; Smith, P. Brian] Duke Clin Res Inst, Durham, NC USA. [Bloom, Barry T.] Wichita Med Res & Educ Fdn, Wichita, KS USA. [Arrieta, Antonio] CHOC, Div Infect Dis, Orange, CA USA. [Wynn, James L.] Vanderbilt Univ, Med Ctr, Dept Pediat, Div Neonatal Perinatal Med, Nashville, TN 37232 USA. [Martz, Karen] EMES Corp, Rockville, MD USA. [Kearns, Gregory L.] Univ Missouri, Sch Med, Dept Pediat, Kansas City, MO 64108 USA. [Kearns, Gregory L.] Childrens Mercy Hosp, Div Pediat Pharmacol & Therapeut Innovat, Kansas City, MO 64108 USA. [Capparelli, Edmund V.] Univ Calif San Diego, Dept Pediat Pharmacol, San Diego, CA 92103 USA. [Siegel, David] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Cohen-Wolkowiez, M (reprint author), Duke Univ, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM michael.cohenwolkowiez@duke.edu RI Smith, Phillip/I-5565-2014; OI Paul, Ian/0000-0002-6344-8609 FU US government from the National Institutes of Health/National Institute of General Medical Sciences [HHSN267200700051C, DHHS-1R18AE000028-01, T32GM086330]; Best Pharmaceuticals for Children Act; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Thrasher Research Foundation; Astellas Pharma US; AstraZeneca; UCB Pharma; CV Therapeutics Inc. FX This work was supported by US government contract HHSN267200700051C (PI: D. K. B.), DHHS-1R18AE000028-01 (PI: P. B. S.), T32GM086330 (M. S.) from the National Institutes of Health/National Institute of General Medical Sciences, the Best Pharmaceuticals for Children Act and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.; M.C.-W. receives support from the nonprofit organization Thrasher Research Foundation (www.thrasherresearch.org) and from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). D. K. B. has received research grants from Astellas Pharma US, AstraZeneca and UCB Pharma; he has also served as a consultant for Astellas Pharma US, Biosynexus, Cubist Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, Merck & Co., Pfizer and The Medicines Company. P. B. S. has received a research grant from CV Therapeutics Inc.; he has also served as consultant for Astellas Pharma US, CV Therapeutics Inc., Johnson & Johnson, Pangen, Biostystems Inc. and Pfizer. The authors have no other funding or conflicts of interest to disclose. NR 22 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2013 VL 32 IS 9 BP 956 EP 961 DI 10.1097/INF.0b013e3182947cf8 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 301IH UT WOS:000330525500014 PM 23587979 ER PT J AU Maring, J Croarkin, E Morgan, S Plack, M AF Maring, Joyce Croarkin, Earllaine Morgan, Sylvia Plack, Margaret TI Perceived Effectiveness and Barriers to Physical Therapy Services for Families and Children With Friedreich Ataxia SO PEDIATRIC PHYSICAL THERAPY LA English DT Article DE child; disabled child/psychology; exercise therapy; family health; Friedreich ataxia; parents; patient(family) preference; physical therapy; professional-family relations ID EXERCISE TRAINING-PROGRAM; HEALTH-CARE; MULTIPLE-SCLEROSIS; DIABETES-MELLITUS; REPEAT EXPANSION; PARENTS; GUIDELINES; DISEASES; FATIGUE; STRESS AB Purpose: To describe the frequency, type, and perceived effectiveness of physical therapy interventions for children with Friedreich ataxia (FA); identify barriers to therapy; and solicit advice from parents. Method: Parents of 30 children with FA participated in semistructured interviews. Qualitative and quantitative methods were used to analyze the data. Results: Sixty-seven percent of children received direct physical therapy service. Stretching and strengthening exercises were used most frequently, and their perceived usefulness increased as the children aged. Seventy-three percent received home exercise programs; 9% implemented these consistently. External barriers included a lack of expert providers and limited reimbursement. Internal barriers included limited time and energy, lack of awareness of services, and children's preferences not to be treated differently. Parents advised therapists to become experts, advocates, and use approaches based on family and child preferences. Conclusions: Outcomes provide a starting point for developing further research, education, and effective interventions for children with FA. C1 [Maring, Joyce; Morgan, Sylvia; Plack, Margaret] George Washington Univ, Dept Phys Therapy & Hlth Care Serv, Washington, DC USA. [Croarkin, Earllaine] NIH, Phys Therapy Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Maring, J (reprint author), 900 23rd St NW 6145, Washington, DC 20037 USA. EM maringj@gwu.edu FU Intramural NIH HHS [Z99 CL999999] NR 44 TC 0 Z9 1 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD FAL PY 2013 VL 25 IS 3 BP 305 EP 313 DI 10.1097/PEP.0b013e31828ed7cb PG 9 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA 300FW UT WOS:000330450800014 PM 23685741 ER PT J AU Yeung, J Apopa, PL Vesci, J Stolla, M Rai, G Simeonov, A Jadhav, A Fernandez-Perez, P Maloney, DJ Boutaud, O Holman, TR Holinstat, M AF Yeung, Jennifer Apopa, Patrick L. Vesci, Joanne Stolla, Moritz Rai, Ganesha Simeonov, Anton Jadhav, Ajit Fernandez-Perez, Pilar Maloney, David J. Boutaud, Olivier Holman, Theodore R. Holinstat, Michael TI 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Platelet activation; 12-lipoxygenase; eicosanoids; aggregation; thrombosis ID SELECTIVE INHIBITORS; THROMBUS FORMATION; ARACHIDONIC-ACID; MELANOMA-CELLS; LIPOXYGENASE; ACTIVATION; RECEPTOR; AGGREGATION; ASPIRIN; BINDING AB Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation. C1 [Yeung, Jennifer; Apopa, Patrick L.; Vesci, Joanne; Stolla, Moritz; Fernandez-Perez, Pilar; Holinstat, Michael] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA. [Yeung, Jennifer; Apopa, Patrick L.; Vesci, Joanne; Stolla, Moritz; Fernandez-Perez, Pilar; Holinstat, Michael] Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Philadelphia, PA 19107 USA. [Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.] Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, Rockville, MD USA. [Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Boutaud, Olivier] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. RP Holinstat, M (reprint author), Thomas Jefferson Univ, Dept Med, Cardeza Fdn Hematol Res, 1020 Locust St,Suite 394,Jefferson Alumni Hall, Philadelphia, PA 19107 USA. EM michael.holinstat@jefferson.edu FU NHLBI NIH HHS [HL081009, HL089457, K99 HL089457, P50 HL081009, R00 HL089457, R01 HL114405]; NIGMS NIH HHS [R01 GM105671]; NIMH NIH HHS [MH081283, R03 MH081283] NR 51 TC 16 Z9 16 U1 0 U2 7 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 SEP PY 2013 VL 110 IS 3 BP 569 EP 581 DI 10.1160/TH13-01-0014 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 297QW UT WOS:000330271000023 PM 23784669 ER PT J AU Dumitrescu, L Carty, CL Franceschini, N Hindorff, LA Cole, SA Buzkova, P Schumacher, FR Eaton, CB Goodloe, RJ Duggan, DJ Haessler, J Cochran, B Henderson, BE Cheng, I Johnson, KC Carlson, CS Love, SA Brown-Gentry, K Nato, AQ Quibrera, M Anderson, G Shohet, RV Ambite, JL Wilkens, LR Le Marchand, L Haiman, CA Buyske, S Kooperberg, C North, KE Fornage, M Crawford, DC AF Dumitrescu, Logan Carty, Cara L. Franceschini, Nora Hindorff, Lucia A. Cole, Shelley A. Buzkova, Petra Schumacher, Fredrick R. Eaton, Charles B. Goodloe, Robert J. Duggan, David J. Haessler, Jeff Cochran, Barbara Henderson, Brian E. Cheng, Iona Johnson, Karen C. Carlson, Chris S. Love, Shelly-Ann Brown-Gentry, Kristin Nato, Alejandro Q., Jr. Quibrera, Miguel Anderson, Garnet Shohet, Ralph V. Ambite, Jose Luis Wilkens, Lynne R. Le Marchand, Loic Haiman, Christopher A. Buyske, Steven Kooperberg, Charles North, Kari E. Fornage, Myriam Crawford, Dana C. TI Post-Genome-Wide Association Study Challenges for Lipid Traits: Describing Age as a Modifier of Gene-Lipid Associations in the Population Architecture Using Genomics and Epidemiology (PAGE) Study SO ANNALS OF HUMAN GENETICS LA English DT Article DE PAGE; modifier; age; lipids; genetic association ID SERUM-CHOLESTEROL LEVELS; DESIGN; RISK; MENOPAUSE; ATHEROSCLEROSIS; LIPOPROTEINS; METAANALYSIS; ENVIRONMENT; GENERATION; PHENOTYPES AB Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: < 50 or >= 50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant P-het values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (P-het < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (P-het = 1.74E-03, I-2 = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes. C1 [Dumitrescu, Logan; Goodloe, Robert J.; Brown-Gentry, Kristin; Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Carty, Cara L.; Haessler, Jeff; Carlson, Chris S.; Anderson, Garnet; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Franceschini, Nora; Love, Shelly-Ann; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Cole, Shelley A.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Schumacher, Fredrick R.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Duggan, David J.] Translat Genom Res Inst, Phoenix, AZ USA. [Cochran, Barbara] Baylor Coll Med, Houston, TX 77030 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Nato, Alejandro Q., Jr.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Quibrera, Miguel] Univ N Carolina, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Crawford, DC (reprint author), Vanderbilt Univ, Ctr Human Genet Res, 2215 Garland Ave,519 Light Hall, Nashville, TN 37232 USA. EM crawford@chgr.mc.vanderbilt.edu RI Nato, Alejandro/J-3880-2016; OI Nato, Alejandro/0000-0002-8745-9046; Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI); CALiCo [U01HG004803]; EAGLE [U01HG004798]; MEC [U01HG004802]; WHI [U01HG004790]; Coordinating Center [U01HG004801]; EAGLE through NHGRI PAGE program [U01HG004798-01]; Johns Hopkins University under federal contract from National Heart, Lung, and Blood Institute (NHLBI) [N01-HV-48195]; CDC; MEC through NHGRI PAGE program [U01HG004802]; MEC through National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; Epidemiology of putative genetic variants: The Women's Health Initiative through NHGRI PAGE program [U01HG004790]; NHLBI; NIH; U.S. Department of Health and Human Services [N01WH22110, 24152,, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 4210726, 42129-32, 44221]; Genetic Epidemiology of CALiCo program through NHGRI PAGE program [U01HG004803]; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, HL080295]; National Institutes of Health, NHLBI [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205]; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; National Institutes of Mental Health; [HHSN268201200036C]; [N01-HC-85239]; [N01-HC-85079]; [N01-HC-85086]; [N01-HC-35129]; [N01 HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133] FX The PAGE program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org.; The data and materials included in this report result from a collaboration between the following studies: EAGLE is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). Genotyping services for select NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from National Heart, Lung, and Blood Institute (NHLBI). The study participants derive from the NHANES, and these studies are supported by the CDC. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC.; The MEC study characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758).; Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the NHLBI; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 4210726, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Short%20List.pdf.; Funding support for the Genetic Epidemiology of CALiCo program was provided through the NHGRI PAGE program (U01HG004803 and its NHGRI ARRA supplement). The following studies contributed to this manuscript and are funded by the following agencies: The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The CARDIA study is supported by the following National Institutes of Health, NHLBI contracts: N01-HC-95095; N01-HC-48047; N01-HC-48048; N01-HC-48049; N01-HC-48050; N01-HC-45134; N01-HC-05187; and N01-HC-45205. The CHS is supported by contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging.; Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. NR 33 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 EI 1469-1809 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2013 VL 77 BP 416 EP 425 DI 10.1111/ahg.12027 PN 5 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 296GZ UT WOS:000330174500006 PM 23808484 ER PT J AU Shi, Y Xia, Z Zhang, JJ Best, R Wu, CJ Ponder, JW Ren, PY AF Shi, Yue Xia, Zhen Zhang, Jiajing Best, Robert Wu, Chuanjie Ponder, Jay W. Ren, Pengyu TI Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; FREE-ENERGY CALCULATIONS; INITIO QUANTUM-CHEMISTRY; MAGNETIC-RESONANCE RELAXATION; PANCREATIC TRYPSIN-INHIBITOR; CRYSTAL-STRUCTURE PREDICTION; CLASSICAL DRUDE OSCILLATOR; HISTOGRAM ANALYSIS METHOD; N-15 NMR RELAXATION; PARTICLE MESH EWALD AB Development of the AMOEBA (atomic multipole optimized energetics for biomolecular simulation) force field for proteins is presented. The current version (AMOEBA-2013) utilizes permanent electrostatic multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chemical and physical environments. The atomic multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mechanical calculations via a consistent and extensible protocol. Molecular polarizability is modeled via a Thole-style damped interactive induction model based upon distributed atomic polarizabilities. Inter- and intramolecular polarization is treated in a consistent fashion via the Thole model. The intramolecular polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were determined by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Molecular dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in solution. Overall the calculated conformational free energies and J-coupling constants are consistent with PDB statistics and experimental NMR results, respectively. In addition, the experimental crystal structures of a number of proteins are well maintained during molecular dynamics (MD) simulation. While further calculations are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and solution environments. C1 [Shi, Yue; Xia, Zhen; Zhang, Jiajing; Ren, Pengyu] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Best, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Wu, Chuanjie; Ponder, Jay W.] Washington Univ, Dept Chem, St Louis, MO 63130 USA. RP Ren, PY (reprint author), Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. EM pren@mail.utexas.edu RI Xia, Zhen/B-3391-2014 FU National Institute of General Medical Sciences [R01GM079686, R01GM106137]; Robert A. Welch Foundation [F-1691]; National Science Foundation [NSF CHE-1152823] FX The authors are grateful to the support by the National Institute of General Medical Sciences (R01GM079686 and R01GM106137) and Robert A. Welch Foundation (F-1691). J.W.P. wishes to acknowledge support from National Science Foundation awards NSF CHE-1152823. NR 139 TC 126 Z9 127 U1 11 U2 87 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD SEP PY 2013 VL 9 IS 9 BP 4046 EP 4063 DI 10.1021/ct4003702 PG 18 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 295DM UT WOS:000330096800021 PM 24163642 ER PT J AU Branduardi, D Faraldo-Gomez, JD AF Branduardi, Davide Faraldo-Gomez, Jose D. TI String Method for Calculation of Minimum Free-Energy Paths in Cartesian Space in Freely Tumbling Systems SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS; CONFORMATIONAL-CHANGES; REACTION COORDINATE; SIMULATION; FORCE; METADYNAMICS; EFFICIENT; DISTRIBUTIONS; LANDSCAPE; SURFACES AB The string method is a molecular-simulation technique that aims to calculate the minimum free-energy path of a chemical reaction or conformational transition, in the space of a predefined set of reaction coordinates that is typically highly dimensional. Any descriptor may be used as a reaction coordinate, but arguably the Cartesian coordinates of the atoms involved are the most unprejudiced and intuitive choice. Cartesian coordinates, however, present a nontrivial problem, in that they are not invariant to rigid-body molecular rotations and translations, which ideally ought to be unrestricted in the simulations. To overcome this difficulty, we reformulate the framework of the string method to integrate an on-the-fly structural-alignment algorithm. This approach, referred to as SOMA (String method with Optimal Molecular Alignment), enables the use of Cartesian reaction coordinates in freely tumbling molecular systems. In addition, this scheme permits the dissection of the free-energy change along the most probable path into individual atomic contributions, thus revealing the dominant mechanism of the simulated process. This detailed analysis also provides a physically meaningful criterion to coarse-grain the representation of the path. To demonstrate the accuracy of the method, we analyze the isomerization of the alanine dipeptide in a vacuum and the chair-to-inverted-chair transition of beta-D mannose in explicit water. Notwithstanding the simplicity of these systems, the SOMA approach reveals novel insights into the atomic mechanism of these isomerizations. In both cases, we find that the dynamics and the energetics of the isomerization process are controlled by interactions involving only a handful of atoms in each molecule. Consistent with this result, we show that a coarse-grained SOMA calculation defined in terms of these subsets of atoms yields near-identical minimum free-energy paths and committor distributions to those obtained via a highly dimensional string. C1 [Branduardi, Davide; Faraldo-Gomez, Jose D.] Max Planck Inst Biophys, Theoret Mol Biophys Grp, DE-60438 Frankfurt, Germany. RP Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM davide.branduardi@biophys.mpg.de; jose.faraldo@biophys.mpg.de RI Faraldo-Gomez, Jose/H-7127-2016 FU Intramural NIH HHS [Z99 HL999999] NR 60 TC 8 Z9 8 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD SEP PY 2013 VL 9 IS 9 BP 4140 EP 4154 DI 10.1021/ct400469w PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 295DM UT WOS:000330096800029 PM 24729762 ER PT J AU Wright, JD Sargsyan, K Wu, XW Brooks, BR Lim, C AF Wright, Jon D. Sargsyan, Karen Wu, Xiongwu Brooks, Bernard R. Lim, Carmay TI Protein-Protein Docking Using EMAP in CHARMM and Support Vector Machine: Application to Ab/Ag Complexes SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-SURFACE RECOGNITION; SIDE-CHAIN FLEXIBILITY; CAPRI EXPERIMENT; LIGAND DOCKING; ENERGY MINIMIZATION; GEOMETRIC FIT; NORMAL-MODES; PREDICTIONS; PROGRESS; BINDING AB In this work, we have (i) evaluated the ability of the EMAP method implemented in the CHARMM program to generate the correct conformation of Ab/Ag complex structures and (ii) developed a support vector machine (SVM) classifier to detect native conformations among the thousands of refined Ab/Ag configurations using the individual components of the binding free energy based on a thermodynamic cycle as input features in training the SVM. Tests on 24 Ab/Ag complexes from the protein-protein docking benchmark version 3.0 showed that based on CAPRI evaluation criteria, EMAP could generate medium-quality native conformations in each case. Furthermore, the SVM classifier could rank medium/high-quality native conformations mostly in the top six among the thousands of refined Ab/Ag configurations. Thus, Ab-Ag docking can be performed using different levels of protein representations, from grid-based (EMAP) to polar hydrogen (united-atom) to all-atom representation within the same program. The scripts used and the trained SVM are available at the www.charmm.org forum script repository. C1 [Wright, Jon D.; Sargsyan, Karen; Lim, Carmay] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Wright, Jon D.] Acad Sinica, Genom Res Inst, Taipei 115, Taiwan. [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Lim, Carmay] Natl Tsinghua Univ, Dept Chem, Hsinchu 300, Taiwan. RP Lim, C (reprint author), Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. EM carmay@gate.sinica.edu.tw RI Lim, Carmay/H-5949-2011; Lim, Carmay/N-9648-2015 OI Lim, Carmay/0000-0001-9077-7769; Lim, Carmay/0000-0001-9077-7769 FU National Science Council; Academia Sinica, Taiwan; National Institutes of Health (NIH) [Z01 HL001027-30] FX This work was supported by research grants from the National Science Council and Academia Sinica, Taiwan. Software development efforts by X.W. and B.R.B. were supported by the National Institutes of Health (NIH) intramural research program (Z01 HL001027-30). NR 79 TC 1 Z9 1 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD SEP PY 2013 VL 9 IS 9 BP 4186 EP 4194 DI 10.1021/ct400508s PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 295DM UT WOS:000330096800033 PM 26592408 ER PT J AU Freidlin, B Abrams, JS Korn, EL AF Freidlin, Boris Abrams, Jeffrey S. Korn, Edward L. TI New challenges for comparative effectiveness in oncology: choice of primary end points for randomized clinical trials SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Review DE quality of life; screening trials; surrogate end points ID METASTATIC BREAST-CANCER; PROGRESSION-FREE SURVIVAL; EFFECTIVE SUBSEQUENT THERAPIES; DOXORUBICIN PLUS DOCETAXEL; STEM-CELL TRANSPLANTATION; WHOLE-BRAIN RADIOTHERAPY; PHASE-III TRIAL; SOLID TUMORS; ADJUVANT TREATMENT; COLORECTAL-CANCER AB Recent advances have led to a steady improvement in cancer treatments. The increasing number of therapeutic options and the corresponding improvement in outcomes pose a number of challenges for comparative effectiveness research in oncology. This review is focused on the choice of primary end points and their interpretation in randomized clinical trials that are designed to inform patients and clinicians on the relative benefits of cancer therapies. We discuss end points that directly measure clinical benefit as well as end points that are thought to be surrogates for clinical benefit. Particular attention is given to the issues associated with the use of overall survival as the primary end point in randomized clinical trials. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 82 TC 1 Z9 1 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD SEP PY 2013 VL 2 IS 5 BP 469 EP 481 DI 10.2217/cer.13.50 PG 13 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 297DX UT WOS:000330236700017 PM 24236744 ER PT J AU Attene-Ramos, MS Huang, RL Sakamuru, S Witt, KL Beeson, GC Shou, L Schnellmann, RG Beeson, CC Tice, RR Austin, CP Xia, MH AF Attene-Ramos, Matias S. Huang, Ruili Sakamuru, Srilatha Witt, Kristine L. Beeson, Gyda C. Shou, Louie Schnellmann, Rick G. Beeson, Craig C. Tice, Raymond R. Austin, Christopher P. Xia, Menghang TI Systematic Study of Mitochondria! Toxicity of Environmental Chemicals Using Quantitative High Throughput Screening SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ANTIBACTERIAL AGENT FENTICHLOR; RAT LIVER MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; STAPHYLOCOCCUS-AUREUS; HEPG2 CELLS; IN-VIVO; MEMBRANE; RESPIRATION; BIOGENESIS; APOPTOSIS AB A goal of the Tox21 program is to transit toxicity testing from traditional in vivo models to in vitro assays that assess how chemicals affect cellular responses and toxicity pathways. A critical contribution of the NIH Chemical Genomics center (NCGC) to the Tox21 program is the implementation of a quantitative high throughput screening (qHTS) approach, using cell-and biochemical-based assays to generate toxicological profiles for thousands of environmental compounds. Here, we evaluated the effect of chemical compounds on mitochondrial membrane potential in HepG2 cells by screening a library of 1,408 compounds provided by the National Toxicology Program (NTP) in a qHTS platform. Compounds were screened over 14 concentrations, and results showed that 91 and 88 compounds disrupted mitochondrial membrane potential after treatment for 1 or 5 h, respectively. Seventy-six compounds active at both time points were clustered by structural similarity, producing 11 clusters and 23 singletons. Thirty-eight compounds covering most of the active chemical space were more extensively evaluated. Thirty-six of the 38 compounds were confirmed to disrupt mitochondrial membrane potential using a fluorescence plate reader, and 35 were confirmed using a high content imaging approach. Among the 38 compounds, 4 and 6 induced LDH release, a measure of cytotoxicity, at 1 or S h, respectively. Compounds were further assessed for mechanism of action (MOA) by measuring changes in oxygen consumption rate, which enabled the identification of 20 compounds as uncouplers. This comprehensive approach allows for the evaluation of thousands of environmental chemicals for mitochondrial toxicity and identification of possible MOAs. C1 [Attene-Ramos, Matias S.; Huang, Ruili; Sakamuru, Srilatha; Shou, Louie; Austin, Christopher P.; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Witt, Kristine L.; Tice, Raymond R.] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Beeson, Gyda C.; Schnellmann, Rick G.; Beeson, Craig C.] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Beeson, Craig C.] MitoHealth, Charleston, SC 29403 USA. RP Xia, MH (reprint author), NIH, Natl Ctr Adv Translat Sci, Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU National Institute of Environmental Health Sciences/National Toxicology Program [IAG Y3-ES-7020-01]; NIEHS [2R44ES019378-02] FX This work was supported through an interagency agreement (IAG #Y3-ES-7020-01) from the National Institute of Environmental Health Sciences/National Toxicology Program to the National Center for Advancing Translational Sciences, National Institutes of Health and the NIEHS 2R44ES019378-02 grant (CB). NR 54 TC 10 Z9 10 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2013 VL 26 IS 9 BP 1323 EP 1332 DI 10.1021/tx4001754 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 295DA UT WOS:000330095600004 PM 23895456 ER PT J AU Lewis, JP Stephens, SH Horenstein, RB O'Connell, JR Ryan, K Peer, CJ Figg, WD Spencer, SD Pacanowski, MA Mitchell, BD Shuldiner, AR AF Lewis, J. P. Stephens, S. H. Horenstein, R. B. O'Connell, J. R. Ryan, K. Peer, C. J. Figg, W. D. Spencer, S. D. Pacanowski, M. A. Mitchell, B. D. Shuldiner, A. R. TI The CYP2C19*17 variant is not independently associated with clopidogrel response SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Clopidogrel; drug metabolism; poor; CYP2C19-related; linkage disequilibrium; pharmacogenetics; platelets ID 2C19-ASTERISK-17 ALLELIC VARIANT; CORONARY STENT PLACEMENT; TREATED PATIENTS; ANTIPLATELET TREATMENT; CARDIOVASCULAR EVENTS; PLATELET-AGGREGATION; CLINICAL-EFFICACY; BLEEDING EVENTS; POLYMORPHISMS; THROMBOSIS AB SummaryBackground Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. Objective We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). Patients/Methods We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5 '-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure. Results The CYP2C19*2 and CYP2C19*17 variants were in LD (|D '| = 1.0; r(2) = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (beta = -5.24, P = 3.0 x 10(-9) and beta = -5.36, P = 3.3 x 10(-14), respectively) and posttreatment ADP-stimulated platelet aggregation (beta = 7.55, P = 2.9 x 10(-16) and beta = 7.51, P = 7.0 x 10(-15), respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (beta = 1.57, P = 0.04 and beta = -1.98, P = 0.01, respectively) but not after (beta = 0.40, P = 0.59 and beta = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. Conclusions Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant. C1 [Lewis, J. P.; Stephens, S. H.; Horenstein, R. B.; O'Connell, J. R.; Ryan, K.; Mitchell, B. D.; Shuldiner, A. R.] Univ Maryland, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Lewis, J. P.; Stephens, S. H.; Horenstein, R. B.; O'Connell, J. R.; Ryan, K.; Mitchell, B. D.; Shuldiner, A. R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Peer, C. J.; Figg, W. D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Spencer, S. D.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Pacanowski, M. A.] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. [Shuldiner, A. R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Shuldiner, AR (reprint author), Univ Maryland, Sch Med, 685 West Baltimore St,Rm 379, Baltimore, MD 21201 USA. EM ashuldin@medicine.umaryland.edu RI Figg Sr, William/M-2411-2016; OI Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health [NIH U01 GM074518, U01 HL105198, U01 HL084756, U01 GM074492, R01074730, K23 GM102678, GM074518-05S1]; Mid-Atlantic Nutrition and Obesity Center [P30 DK072488]; University of Maryland General Clinical Research Center [M01 RR16500]; Baltimore Veterans Administration Geriatric Research and Education Clinical Center FX This study was supported by National Institutes of Health grants NIH U01 GM074518, U01 HL105198, U01 HL084756, U01 GM074492, R01074730, and K23 GM102678, GM074518-05S1, the Mid-Atlantic Nutrition and Obesity Center (P30 DK072488), the University of Maryland General Clinical Research Center (M01 RR16500), and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center. NR 23 TC 20 Z9 22 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD SEP PY 2013 VL 11 IS 9 BP 1640 EP 1646 DI 10.1111/jth.12342 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 216UU UT WOS:000324311400002 PM 23809542 ER PT J AU Pancioli, AM Adeoye, O Schmit, PA Khoury, J Levine, SR Tomsick, TA Sucharew, H Brooks, CE Crocco, TJ Gutmann, L Hemmen, TM Kasner, SE Kleindorfer, D Knight, WA Martini, S McKinney, JS Meurer, WJ Meyer, BC Schneider, A Scott, PA Starkman, S Warach, S Broderick, JP AF Pancioli, Arthur M. Adeoye, Opeolu Schmit, Pamela A. Khoury, Jane Levine, Steven R. Tomsick, Thomas A. Sucharew, Heidi Brooks, Claudette E. Crocco, Todd J. Gutmann, Laurie Hemmen, Thomas M. Kasner, Scott E. Kleindorfer, Dawn Knight, William A. Martini, Sharyl McKinney, James S. Meurer, William J. Meyer, Brett C. Schneider, Alexander Scott, Phillip A. Starkman, Sidney Warach, Steven Broderick, Joseph P. CA CLEAR-ER Investigators TI Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke-Enhanced Regimen Stroke Trial SO STROKE LA English DT Article DE clinical trial; eptifibatide; ischemic stroke; tissue plasminogen activator ID RANDOMIZED-TRIAL; RT-PA; TIROFIBAN AB Background and Purpose In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial. Methods CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score 1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression. Results Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS 1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52). Conclusions The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen. C1 [Pancioli, Arthur M.; Adeoye, Opeolu; Schmit, Pamela A.; Tomsick, Thomas A.; Kleindorfer, Dawn; Knight, William A.; Martini, Sharyl; Broderick, Joseph P.] Univ Cincinnati, Inst Neurosci, Cincinnati, OH 45267 USA. [Pancioli, Arthur M.; Adeoye, Opeolu; Schmit, Pamela A.; Knight, William A.] Univ Cincinnati, Dept Emergency Med, Cincinnati, OH 45267 USA. [Adeoye, Opeolu; Knight, William A.] Univ Cincinnati, Dept Neurosurg, Cincinnati, OH 45267 USA. [Tomsick, Thomas A.] Univ Cincinnati, Dept Radiol, Cincinnati, OH 45267 USA. [Kleindorfer, Dawn; Martini, Sharyl; Broderick, Joseph P.] Univ Cincinnati, Dept Neurol, Cincinnati, OH 45267 USA. [Khoury, Jane; Sucharew, Heidi] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Levine, Steven R.] SUNY Downstate Stroke Ctr, Dept Neurol, Brooklyn, NY USA. [Levine, Steven R.] SUNY Downstate Stroke Ctr, Dept Emergency Med, Brooklyn, NY USA. [Levine, Steven R.] Med Ctr, Brooklyn, NY USA. [Levine, Steven R.] King Cty Hosp Ctr, Brooklyn, NY USA. [Brooks, Claudette E.; Gutmann, Laurie] W Virginia Univ, Dept Neurol, Morgantown, WV 26506 USA. [Crocco, Todd J.] W Virginia Univ, Dept Emergency Med, Morgantown, WV 26506 USA. [Hemmen, Thomas M.; Meyer, Brett C.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Kasner, Scott E.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [McKinney, James S.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, New Brunswick, NJ 08903 USA. [Meurer, William J.; Scott, Phillip A.] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. [Meurer, William J.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Schneider, Alexander] Mission Hosp, Asheville, NC USA. [Starkman, Sidney] Univ Calif Los Angeles, Dept Emergency Med, Los Angeles, CA USA. [Starkman, Sidney] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Warach, Steven] NINDS, Bethesda, MD 20892 USA. RP Pancioli, AM (reprint author), Univ Cincinnati, Coll Med, Dept Emergency Med, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM Arthur.Pancioli@uc.edu RI Demchuk, Andrew/E-1103-2012; Sucharew, Heidi/M-4338-2015; Khoury, Jane/O-2068-2015 OI Demchuk, Andrew/0000-0002-4930-7789; FU National Institutes of Health [P50 NS044283] FX This work was supported by National Institutes of Health grant P50 NS044283. NR 11 TC 27 Z9 27 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD SEP PY 2013 VL 44 IS 9 BP 2381 EP 2387 DI 10.1161/STROKEAHA.113.001059 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OP UT WOS:000329982500018 PM 23887841 ER PT J AU Wintermark, M Albers, GW Broderick, JP Demchuk, AM Fiebach, JB Fiehler, J Grotta, JC Houser, G Jovin, TG Lees, KR Lev, MH Liebeskind, DS Luby, M Muir, KW Parsons, MW von Kummer, R Wardlaw, JM Wu, O Yoo, AJ Alexandrov, AV Alger, JR Aviv, RI Bammer, R Baron, JC Calamante, F Campbell, BCV Carpenter, TC Christensen, S Copen, WA Derdeyn, CP Haley, C Khatri, P Kudo, K Lansberg, MG Latour, LL Lee, TY Leigh, R Lin, WL Lyden, P Mair, G Menon, BK Michel, P Mikulik, R Nogueira, RG Ostergaard, L Pedraza, S Riedel, CH Rowley, HA Sanelli, PC Sasaki, M Saver, JL Schaefer, PW Schellinger, PD Tsivgoulis, G Wechsler, LR White, PM Zaharchuk, G Zaidat, OO Davis, SM Donnan, GA Furlan, AJ Hacke, W Kang, DW Kidwell, C Thijs, VN Thomalla, G Warach, SJ AF Wintermark, Max Albers, Gregory W. Broderick, Joseph P. Demchuk, Andrew M. Fiebach, Jochen B. Fiehler, Jens Grotta, James C. Houser, Gary Jovin, Tudor G. Lees, Kennedy R. Lev, Michael H. Liebeskind, David S. Luby, Marie Muir, Keith W. Parsons, Mark W. von Kummer, Ruediger Wardlaw, Joanna M. Wu, Ona Yoo, Albert J. Alexandrov, Andrei V. Alger, Jeffry R. Aviv, Richard I. Bammer, Roland Baron, Jean-Claude Calamante, Fernando Campbell, Bruce C. V. Carpenter, Trevor C. Christensen, Soren Copen, William A. Derdeyn, Colin P. Haley, Clarke, Jr. Khatri, Pooja Kudo, Kohsuke Lansberg, Maarten G. Latour, Lawrence L. Lee, Ting-Yim Leigh, Richard Lin, Weili Lyden, Patrick Mair, Grant Menon, Bijoy K. Michel, Patrik Mikulik, Robert Nogueira, Raul G. Ostergaard, Leif Pedraza, Salvador Riedel, Christian H. Rowley, Howard A. Sanelli, Pina C. Sasaki, Makoto Saver, Jeffrey L. Schaefer, Pamela W. Schellinger, Peter D. Tsivgoulis, Georgios Wechsler, Lawrence R. White, Philip M. Zaharchuk, Greg Zaidat, Osama O. Davis, Stephen M. Donnan, Geoffrey A. Furlan, Anthony J. Hacke, Werner Kang, Dong-Wha Kidwell, Chelsea Thijs, Vincent N. Thomalla, Goetz Warach, Steven J. CA Storke Imageing Res STIR Imaging Virtual Int Stroke Trials Archive TI Acute Stroke Imaging Research Roadmap II SO STROKE LA English DT Article DE angiography; clinical trial; computed tomography; consensus; imaging; magnetic resonance imaging; stroke; thrombolysis ID ACUTE ISCHEMIC-STROKE; MIDDLE CEREBRAL-ARTERY; TISSUE-PLASMINOGEN-ACTIVATOR; BRAIN-BARRIER DISRUPTION; INTRAVENOUS THROMBOLYSIS; HEMORRHAGIC TRANSFORMATION; INTRACEREBRAL HEMORRHAGE; CT ANGIOGRAPHY; PERFUSION; MRI C1 Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Wintermark, Max] CHU Vaudois, Dept Radiol, CH-1011 Lausanne, Switzerland. [Albers, Gregory W.; Bammer, Roland; Christensen, Soren; Lansberg, Maarten G.; Zaharchuk, Greg] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA. [Broderick, Joseph P.; Khatri, Pooja] Univ Cincinnati, Dept Neurol, Inst Neurosci, Cincinnati, OH USA. [Demchuk, Andrew M.] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Demchuk, Andrew M.] Univ Calgary, Dept Radiol, Hotchkiss Brain Inst, Calgary, AB, Canada. [Menon, Bijoy K.] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary Stroke Program, Calgary, AB, Canada. [Menon, Bijoy K.] Univ Calgary, Dept Radiol, Hotchkiss Brain Inst, Calgary Stroke Program, Calgary, AB, Canada. [Fiebach, Jochen B.] Charite, Ctr Stroke Res Berlin, Acad Neuroradiol, Dept Neurol, D-13353 Berlin, Germany. [Fiehler, Jens; Tsivgoulis, Georgios] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Grotta, James C.] Univ Texas Hlth Sci Ctr Houston, Dept Neurol, Houston, TX 77030 USA. [Houser, Gary] Stroke Grp, Centennial, CO USA. [Jovin, Tudor G.] Univ Pittsburgh, Dept Neurol, Med Ctr, Stroke Inst, Pittsburgh, PA 15260 USA. [Jovin, Tudor G.] UPMC, Ctr Neuroendovasc Therapy, Pittsburgh, PA USA. [Lees, Kennedy R.] Univ Glasgow, Western Infirm, Inst Cardiovasc & Med Sci, Dept Med & Therapeut, Glasgow G11 6NT, Lanark, Scotland. [Lev, Michael H.; Wu, Ona; Yoo, Albert J.; Copen, William A.; Schaefer, Pamela W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Liebeskind, David S.; Alger, Jeffry R.; Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Stroke Ctr, Los Angeles, CA 90024 USA. [Luby, Marie; Latour, Lawrence L.] NINDS, Stroke Diagnost & Therapeut Sect, Bethesda, MD 20892 USA. [Luby, Marie; Latour, Lawrence L.] NIH, Bethesda, MD 20892 USA. [Muir, Keith W.] Univ Glasgow, So Gen Hosp, Dept Neurol, Inst Neurosci & Psychol, Glasgow, Lanark, Scotland. [Parsons, Mark W.] Univ Newcastle, Hunter Med Res Inst, John Hunter Hosp, Dept Neurol, Callaghan, NSW 2308, Australia. [von Kummer, Ruediger] Tech Univ Dresden, Dept Neuroradiol, D-01062 Dresden, Germany. [von Kummer, Ruediger] Tech Univ Dresden, Dresden Univ, Stroke Ctr, Univ Hosp Carl Gustav Carus, D-01062 Dresden, Germany. [Wardlaw, Joanna M.; Carpenter, Trevor C.] Univ Edinburgh, Dept Clin Neurosci, Brain Res Imaging Ctr, Div Neuroimaging Sci,Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Alexandrov, Andrei V.] Univ Alabama Hosp & Clin, Comprehens Stroke Ctr, Dept Neurol, Birmingham, AL USA. [Aviv, Richard I.] Univ Toronto, Dept Med Imaging, Toronto, ON, Canada. [Aviv, Richard I.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Baron, Jean-Claude] Sorbonne Paris Cite, INSERM, U894, Paris, France. [Baron, Jean-Claude] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. [Calamante, Fernando; Donnan, Geoffrey A.] Florey Inst Neurosci & Mental Hlth, Dept Med, Melbourne, Vic, Australia. [Campbell, Bruce C. V.; Davis, Stephen M.] Univ Melbourne, Royal Melbourne Hosp, Melbourne Brain Ctr, Dept Med, Parkville, Vic, Australia. [Campbell, Bruce C. V.; Davis, Stephen M.] Univ Melbourne, Royal Melbourne Hosp, Melbourne Brain Ctr, Dept Neurol, Parkville, Vic, Australia. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Kudo, Kohsuke] Hokkaido Univ Hosp, Dept Diagnost Radiol, Sapporo, Hokkaido 060, Japan. [Lee, Ting-Yim] Univ Western Ontario, Dept Med Imaging, London, ON, Canada. [Leigh, Richard] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Lin, Weili] Univ N Carolina, Biomed Res Imaging Ctr, Chapel Hill, NC USA. [Lin, Weili] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Lin, Weili] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Lyden, Patrick] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Mair, Grant] Western Gen Hosp, Dept Neuroradiol, Div Neuroimaging Sci, Edinburgh EH4 2XU, Midlothian, Scotland. [Michel, Patrik] Univ Lausanne, CHU Vaudois, Dept Neurol, Lausanne, Switzerland. [Mikulik, Robert] St Annes Hosp, Int Clin Res Ctr, Dept Neurol, Brno, Czech Republic. [Nogueira, Raul G.] Emory Univ, Sch Med, Dept Neurol, Marcus Stroke & Neurosci Ctr,Grady Mem Hosp, Atlanta, GA 30322 USA. [Ostergaard, Leif] Aarhus Univ Hosp, Dept Neurol, Ctr Funct Integrat Neurosci, DK-8000 Aarhus, Denmark. [Pedraza, Salvador] Univ Hosp Dr Josep Trueta, IDIBGI, IDI, Dept Radiol, Girona, Spain. [Riedel, Christian H.] Univ Kiel, Dept Neuroradiol, Kiel, Germany. [Rowley, Howard A.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Sanelli, Pina C.] NewYork Presbyterian Hosp, Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Sasaki, Makoto] Iwate Med Univ, Inst Biomed Sci, Dept Radiol, Yahaba, Iwate, Japan. [Schellinger, Peter D.] Johannes Wesling Klinikum Minden, Dept Neurol, Minden, Germany. [Tsivgoulis, Georgios] Univ Alabama Birmingham, Dept Neurol, Comprehens Stroke Ctr, Birmingham, AL 35294 USA. [Tsivgoulis, Georgios] Univ Athens, Sch Med, Dept Neurol 2, GR-11527 Athens, Greece. [Wechsler, Lawrence R.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [White, Philip M.] Newcastle Univ, Inst Ageing & Hlth, Dept Neuroradiol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Froedtert Hosp, Milwaukee, WI USA. [Furlan, Anthony J.] Case Western Reserve Univ, Dept Neurol, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Hacke, Werner] Heidelberg Univ, Dept Neurol, Heidelberg, Germany. [Kang, Dong-Wha] Univ Ulsan, Dept Neurol, Asan Med Ctr, Coll Med, Seoul, South Korea. [Kidwell, Chelsea] Georgetown Univ, Dept Neurol, Washington, DC USA. [Kidwell, Chelsea] Georgetown Univ, Stroke Ctr, Washington, DC USA. [Thijs, Vincent N.] Catholic Univ Louvain VIB, Neurobiol Lab, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Thijs, Vincent N.] Catholic Univ Louvain VIB, Leuven Res Inst Neurosci & Dis, B-3000 Louvain, Belgium. [Thijs, Vincent N.] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium. [Warach, Steven J.] Seton UT SW Clin Res Inst Austin, Austin, TX USA. [Warach, Steven J.] UT Southwestern Med Ctr, Dept Neurol & Neurotherapeut, Austin, TX USA. [Wintermark, Max] Univ Virginia, Dept Radiol, Div Neuroradiol, Charlottesville, VA USA. RP Wintermark, M (reprint author), UVA, Dept Radiol, Div Neuroradiol, Charlottesville, VA USA. EM Max.Wintermark@gmail.com RI Lee, Ting-Yim/M-1721-2013; Parsons, Mark/G-3750-2014; Davis, Stephen/L-5260-2013; Demchuk, Andrew/E-1103-2012; Thijs, Vincent/C-3647-2009; Muir, Keith/A-7670-2011; Ostergaard, Leif/A-9281-2008; Michel, Patrik/Q-2275-2016 OI Fiebach, Jochen B./0000-0002-7936-6958; Campbell, Bruce/0000-0003-3632-9433; Derdeyn, Colin/0000-0002-5932-2683; Donnan, Geoffrey/0000-0001-6324-3403; baron, jean-claude/0000-0002-5264-2588; Leigh, Richard/0000-0002-8285-1815; Alexandrov, Andrei V/0000-0001-8871-1023; Saver, Jeffrey/0000-0001-9141-2251; Wintermark, Max/0000-0002-6726-3951; Davis, Stephen/0000-0003-0962-2300; Demchuk, Andrew/0000-0002-4930-7789; Thijs, Vincent/0000-0002-6614-8417; Muir, Keith/0000-0001-9535-022X; Ostergaard, Leif/0000-0003-2930-6997; Michel, Patrik/0000-0003-4954-7579 FU Bayer; GE Healthcare; Philips Healthcare; Siemens Healthcare; Bracco; Toshiba; Vital Images FX Stroke Imaging Research (STIR) efforts were supported by generous grants from Bayer, GE Healthcare, Philips Healthcare, Siemens Healthcare, Bracco, Toshiba, and Vital Images. NR 79 TC 62 Z9 63 U1 2 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD SEP PY 2013 VL 44 IS 9 BP 2628 EP 2639 DI 10.1161/STROKEAHA.113.002015 PG 12 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OP UT WOS:000329982500063 PM 23860298 ER PT J AU Hopping, G Kellock, J Caughey, B Daggett, V AF Hopping, Gene Kellock, Jackson Caughey, Byron Daggett, Valerie TI Designed Trpzip-3 beta-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Alzheimer's disease; Trpzip; transthyretin; ANS fluorescence; computational docking ID ALZHEIMERS-DISEASE; TRANSTHYRETIN; PROTEIN; POTENT; AMYLOIDOGENESIS; FLUORESCENCE; TOXICITY; DOCKING; HADDOCK; BINDING AB The trpzip peptides are small, monomeric, and extremely stable beta-hairpins that have become valuable tools for studying protein folding. Here, we show that trpzip-3 inhibits aggregation in two very different amyloid systems: transthyretin and A beta(1-42). Interestingly, Trp -> Leu mutations renders the peptide ineffective against transthyretin, but A beta inhibition remains. Computational docking was used to predict the interactions between trpzip-3 and transthyretin, suggesting that inhibition occurs via binding to the outer region of the thyroxine-binding site, which is supported by dye displacement experiments. C1 [Hopping, Gene; Kellock, Jackson; Daggett, Valerie] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Daggett, V (reprint author), Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. EM daggett@u.washington.edu FU W. H. Coulter Foundation Translational Research Partnership Program; National Science Foundation [CBET-0966977]; Coins for Alzheimer's Research Trust; Intramural Research Program of the NIAID FX This work was funded by the W. H. Coulter Foundation Translational Research Partnership Program (to V.D.), a grant from the National Science Foundation (CBET-0966977 to V.D.), the Coins for Alzheimer's Research Trust (to V.D.), and the Intramural Research Program of the NIAID (to B.C.). NR 28 TC 13 Z9 14 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD SEP PY 2013 VL 4 IS 9 BP 824 EP 828 DI 10.1021/ml300478w PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 294BE UT WOS:000330016600007 PM 24900756 ER PT J AU Johnson, SL Finigan, N Bradshaw, C Haynie, D Cheng, T AF Johnson, Sarah Lindstrom Finigan, Nadine Bradshaw, Catherine Haynie, Denise Cheng, Tina TI Urban African American Parents' Messages About Violence SO JOURNAL OF ADOLESCENT RESEARCH LA English DT Article DE community; neighborhood issues; violence; parenting; African Americans ID CHILDREN; ADOLESCENTS; BEHAVIORS; MOTHERS; YOUTH; RISK; CONSEQUENCES; AGGRESSION; DISCIPLINE; PREVENTION AB Family socialization, which includes parental control and support, plays an important role in reducing the likelihood of adolescent involvement in conflict. This study examined the strategies that urban parents living in neighborhoods with high crime rates suggest to help their adolescent children avoid or deescalate conflict. Data came from 48 African American parent/adolescent dyads recruited through the youths' middle school. Dyads responded to three video-taped scenarios depicting youth in potential conflict situations. Qualitative methods were used to identify 11 strategies parents suggested to help youth avoid or deescalate conflict. Although the majority of parents advocated for nonviolent solutions, these same parents described situations in which their child may need to use violence. These findings have important implications for family-focused violence prevention programs. C1 [Johnson, Sarah Lindstrom] Johns Hopkins Sch Med, Dept Gen Pediat & Adolescent Med, Baltimore, MD 21287 USA. [Johnson, Sarah Lindstrom; Cheng, Tina] Johns Hopkins Sch Med, Baltimore, MD 21287 USA. [Finigan, Nadine] Univ Maryland, Sch Social Work, Ruth Young Ctr Children & Families, Baltimore, MD 21201 USA. [Bradshaw, Catherine] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Haynie, Denise] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Rockville, MD USA. RP Johnson, SL (reprint author), Johns Hopkins Sch Med, 200 N Wolfe St, Baltimore, MD 21287 USA. EM slj@jhmi.edu OI Haynie, Denise/0000-0002-8270-6079 NR 37 TC 7 Z9 7 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0743-5584 EI 1552-6895 J9 J ADOLESCENT RES JI J. Adolesc. Res. PD SEP PY 2013 VL 28 IS 5 BP 511 EP 534 DI 10.1177/0743558412447859 PG 24 WC Psychology, Developmental SC Psychology GA 287WU UT WOS:000329573800001 ER PT J AU Marcum, CS AF Marcum, Christopher Steven TI Age Differences in Daily Social Activities SO RESEARCH ON AGING LA English DT Article DE aging; social interaction; time use; social activities; leisure ID OLDER-PEOPLE; PHYSICAL-ACTIVITY; UNITED-STATES; LEISURE-TIME; LATE-LIFE; NETWORKS; RETIREMENT; SUPPORT; HEALTH; ADULTS AB The extent to which older and younger people do different activities when they are with others and when they are alone is examined in this article. I leverage interpersonal data in combination with information on activities from the American Time Use Survey to shed light on the long held finding that older people have less social contact than younger people. The results show that, net of intervening factors, age is associated with declines in time spent with others for virtually all types of time use. However, the variety of activities that older and younger people do also differs. Using leisure activities to probe this finding reveals that, when older people spend time with others it tends to be during activities that are sui generis social activities such as attending partiesbut that this is not necessarily the case for younger people. The literature on time use and aging is discussed in light of these findings and a new hypothesis on agency in the life course is proposed. C1 [Marcum, Christopher Steven] RAND Corp, Natl Inst Aging, Santa Monica, CA 90407 USA. RP Marcum, CS (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90407 USA. EM cmarcum@uci.edu OI Marcum, Christopher/0000-0002-0899-6143 FU NIA NIH HHS [T32 AG000244] NR 71 TC 8 Z9 8 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0164-0275 EI 1552-7573 J9 RES AGING JI Res. Aging PD SEP PY 2013 VL 35 IS 5 BP 612 EP 640 DI 10.1177/0164027512453468 PG 29 WC Gerontology SC Geriatrics & Gerontology GA 287WX UT WOS:000329574100006 PM 25190898 ER PT J AU Carson, AP Badon, SE Zhao, L Lewis, CE Biggs, ML Golden, SH Pankow, JS Fox, CS Vimalananda, VG Kuller, LH De Chavez, PD Carnethon, MR AF Carson, A. P. Badon, S. E. Zhao, L. Lewis, C. E. Biggs, M. L. Golden, S. H. Pankow, J. S. Fox, C. S. Vimalananda, V. G. Kuller, L. H. De Chavez, P. D. Carnethon, M. R. TI Does the association of diabetes with mortality vary by sex? Results from a pooled cohort analysis SO DIABETOLOGIA LA English DT Meeting Abstract CT 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 23-27, 2013 CL Barcelona, SPAIN SP European Assoc Study Diabet C1 [Carson, A. P.; Lewis, C. E.] Univ Alabama Birmingham, Birmingham, AL USA. [Badon, S. E.; Zhao, L.; De Chavez, P. D.; Carnethon, M. R.] Northwestern Univ, Chicago, IL 60611 USA. [Biggs, M. L.] Univ Washington, Seattle, WA 98195 USA. [Golden, S. H.] Johns Hopkins Univ, Baltimore, MD USA. [Pankow, J. S.] Univ Minnesota, Minneapolis, MN USA. [Fox, C. S.] NHLBI, Bethesda, MD 20892 USA. [Vimalananda, V. G.] Boston Univ, Boston, MA 02215 USA. [Kuller, L. H.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2013 VL 56 SU 1 MA 447 BP S187 EP S187 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 282TQ UT WOS:000329196901106 ER PT J AU Mercader, JM Voichita, C Donato, M Sanchez, F Bonas, S Tarca, AL Draghici, S Torrents, D AF Mercader, J. M. Voichita, C. Donato, M. Sanchez, F. Bonas, S. Tarca, A. L. Draghici, S. Torrents, D. TI Novel gene-bases and pathway analysis GWAS methods for the identification of new candidate genes and pathways for type 2 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract CT 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 23-27, 2013 CL Barcelona, SPAIN SP European Assoc Study Diabet C1 [Mercader, J. M.; Sanchez, F.; Bonas, S.; Torrents, D.] Barcelona Supercomp Ctr, Joint IRB BSC Program Computat Biol, Barcelona, Spain. [Voichita, C.; Donato, M.; Tarca, A. L.; Draghici, S.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Tarca, A. L.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Tarca, A. L.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Draghici, S.] Wayne State Univ, Dept Clin & Translat Sci, Detroit, MI USA. [Torrents, D.] ICREA, Barcelona, Spain. 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 SU 1 MA 370 BP S157 EP S157 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 282TQ UT WOS:000329196901029 ER PT J AU Moreno-Villegas, Z Ramos-Alvarez, I Sanz, R Portal-Nunez, S Gonzalez, N Jensen, RT AF Moreno-Villegas, Z. Ramos-Alvarez, I. Sanz, R. Portal-Nunez, S. Gonzalez, N. Jensen, R. T. TI Bombesin receptor subtype-3: expression/function/role in cell signalling pathway and glucose transport, in adipose tissue from human and animal model SO DIABETOLOGIA LA English DT Meeting Abstract CT 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 23-27, 2013 CL Barcelona, SPAIN SP European Assoc Study Diabet C1 [Moreno-Villegas, Z.; Ramos-Alvarez, I.; Sanz, R.; Portal-Nunez, S.; Gonzalez, N.] IIS Fdn Jimenez Diaz CIBERDEM, Madrid, Spain. [Jensen, R. T.] NIH, Bethesda, MD 20892 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 SU 1 MA 822 BP S328 EP S329 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 282TQ UT WOS:000329196902019 ER PT J AU Williams, AJK Lampasona, V Schlosser, M Mueller, PW Pittman, D Winter, WE Wyatt, R Akolkar, B Bingley, PJ Achenbach, P AF Williams, A. J. K. Lampasona, V. Schlosser, M. Mueller, P. W. Pittman, D. Winter, W. E. Wyatt, R. Akolkar, B. Bingley, P. J. Achenbach, P. TI N-terminally truncated GAD discriminates progression in GAD antibody positive relatives of patients with type 1 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract CT 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 23-27, 2013 CL Barcelona, SPAIN SP European Assoc Study Diabet C1 [Williams, A. J. K.; Wyatt, R.; Bingley, P. J.] Univ Bristol, Sch Clin Sci, Bristol BS8 1TH, Avon, England. [Lampasona, V.] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy. [Schlosser, M.] Ernst Moritz Arndt Univ Greifswald, Dept Med Biochem & Mol Biol, Karlsburg, Germany. [Mueller, P. W.] Ctr Dis Control & Prevent, Mol Risk Assessment Lab, Atlanta, GA USA. [Pittman, D.; Winter, W. E.] Univ Florida, Dept Pathol, Gainesville, FL 32611 USA. [Akolkar, B.] NIDDK, Div Diabet Endocrinol & Metab, Bethesda, MD 20892 USA. [Achenbach, P.] Helmholtz Ctr Munich, Diabet Res Inst, Neuherberg, Germany. RI Achenbach, Peter/M-9867-2014 OI Achenbach, Peter/0000-0001-6720-2684 NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2013 VL 56 SU 1 MA 25 BP S17 EP S17 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 282TQ UT WOS:000329196900026 ER PT J AU Boca, SM Bravo, HC Caffo, B Leek, JT Parmigiani, G AF Boca, Simina M. Bravo, Hector Ceorrada Caffo, Brian Leek, Jeffrey T. Parmigiani, Giovanni TI A Decision-Theory Approach to Interpretable Set Analysis for High-Dimensional Data SO BIOMETRICS LA English DT Article DE Atomic false discovery rate; Gene-sets; Hypothesis testing; Set-level inference ID FALSE DISCOVERY RATE; GENE-EXPRESSION; ENRICHMENT ANALYSIS; MICROARRAY DATA; EXTENSIONS; TESTS; RATES; FMRI AB A key problem in high-dimensional significance analysis is to find pre-defined sets that show enrichment for a statistical signal of interest; the classic example is the enrichment of gene sets for differentially expressed genes. Here, we propose a new decision-theory approach to the analysis of gene sets which focuses on estimating the fraction of non-null variables in a set. We introduce the idea of atoms, non-overlapping sets based on the original pre-defined set annotations. Our approach focuses on finding the union of atoms that minimizes a weighted average of the number of false discoveries and missed discoveries. We introduce a new false discovery rate for sets, called the atomic false discovery rate (afdr), and prove that the optimal estimator in our decision-theory framework is to threshold the afdr. These results provide a coherent and interpretable framework for the analysis of sets that addresses the key issues of overlapping annotations and difficulty in interpreting p values in both competitive and self-contained tests. We illustrate our method and compare it to a popular existing method using simulated examples, as well as gene-set and brain ROI data analyses. C1 [Boca, Simina M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bravo, Hector Ceorrada] Univ Maryland, College Pk, MD 20742 USA. [Caffo, Brian; Leek, Jeffrey T.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Boca, SM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM jleek@jhsph.edu OI Leek, Jeffrey/0000-0002-2873-2671; Corrada Bravo, Hector/0000-0002-1255-4444 FU NIH [3T32GM074906-04S1]; Johns Hopkins Sommer Scholar Program; Intramural Program of the NIH FX We would like to thank Rafael Irizarry, Luigi Marchionni, and John Storey for helpful discussions and sharing of code and data, as well as the referee and editors for their constructive comments. This research was supported by the NIH grant 3T32GM074906-04S1, the Johns Hopkins Sommer Scholar Program, and the Intramural Program of the NIH. NR 37 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD SEP PY 2013 VL 69 IS 3 BP 614 EP 623 DI 10.1111/biom.12060 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 283ZO UT WOS:000329285700009 PM 23909925 ER PT J AU Leung, DHY Small, DS Qin, J Zhu, M AF Leung, Denis Heng-Yan Small, Dylan S. Qin, Jing Zhu, Min TI Shrinkage Empirical Likelihood Estimator in Longitudinal Analysis with Time-Dependent Covariates-Application to Modeling the Health of Filipino Children SO BIOMETRICS LA English DT Article DE Empirical likelihood; Estimating functions; Generalized estimating equations; Longitudinal data ID ESTIMATING EQUATIONS; GENERALIZED-METHOD; MOMENTS; INFERENCE; SELECTION; CHOICE AB The method of generalized estimating equations (GEE) is a popular tool for analysing longitudinal (panel) data. Often, the covariates collected are time-dependent in nature, for example, age, relapse status, monthly income. When using GEE to analyse longitudinal data with time-dependent covariates, crucial assumptions about the covariates are necessary for valid inferences to be drawn. When those assumptions do not hold or cannot be verified, Pepe and Anderson (1994, Communications in Statistics, Simulations and Computation 23, 939-951) advocated using an independence working correlation assumption in the GEE model as a robust approach. However, using GEE with the independence correlation assumption may lead to significant efficiency loss (Fitzmaurice, 1995, Biometrics 51, 309-317). In this article, we propose a method that extracts additional information from the estimating equations that are excluded by the independence assumption. The method always includes the estimating equations under the independence assumption and the contribution from the remaining estimating equations is weighted according to the likelihood of each equation being a consistent estimating equation and the information it carries. We apply the method to a longitudinal study of the health of a group of Filipino children. C1 [Leung, Denis Heng-Yan] Singapore Management Univ, Sch Econ, Singapore 178902, Singapore. [Small, Dylan S.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. [Zhu, Min] Queensland Univ Technol, Sch Econ & Finance, Brisbane, Qld 4001, Australia. RP Leung, DHY (reprint author), Singapore Management Univ, Sch Econ, Singapore 178902, Singapore. EM denisleung@smu.edu.sg RI LEUNG, Denis Heng Yan/D-1439-2009 FU Research Center at Singapore Management University FX We thank the referees and the Associate Editor for the detailed and insightful comments, that have led to a greatly improved version of this paper. Denis Leung, Dylan Small and Min Zhu were partially supported by the Research Center at Singapore Management University. NR 31 TC 1 Z9 1 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD SEP PY 2013 VL 69 IS 3 BP 624 EP 632 DI 10.1111/biom.12039 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 283ZO UT WOS:000329285700010 PM 23845158 ER PT J AU Palmer, ND Musani, SK Yerges-Armstrong, LM Feitosa, MF Bielak, LF Hernaez, R Kahali, B Carr, JJ Harris, TB Jhun, MA Kardia, SLR Langefeld, CD Mosley, TH Norris, JM Smith, AV Taylor, HA Wagenknecht, LE Liu, JK Borecki, IB Peyser, PA Speliotes, EK AF Palmer, Nicholette D. Musani, Solomon K. Yerges-Armstrong, Laura M. Feitosa, Mary F. Bielak, Lawrence F. Hernaez, Ruben Kahali, Bratati Carr, J. Jeffrey Harris, Tamara B. Jhun, Min A. Kardia, Sharon L. R. Langefeld, Carl D. Mosley, Thomas H., Jr. Norris, Jill M. Smith, Albert V. Taylor, Herman A. Wagenknecht, Lynne E. Liu, Jiankang Borecki, Ingrid B. Peyser, Patricia A. Speliotes, Elizabeth K. TI Characterization of European Ancestry Nonalcoholic Fatty Liver Disease-Associated Variants in Individuals of African and Hispanic Descent SO HEPATOLOGY LA English DT Article ID TYPE-2 DIABETES RISK; HEPATIC STEATOSIS; DIAGNOSTIC-ACCURACY; INSULIN-RESISTANCE; NATURAL-HISTORY; P446L VARIANT; VISCERAL FAT; PNPLA3; FAMILY; POPULATION AB Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n=3,124) and one Hispanic American (n=849) cohorts. All analyses controlled for variation in age, age(2), gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2), respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P<0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Conclusion: Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries. (Hepatology 2013;53:966-975) C1 [Palmer, Nicholette D.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA. [Musani, Solomon K.; Mosley, Thomas H., Jr.; Taylor, Herman A.] Univ Mississippi, Dept Med, Jackson, MS 39216 USA. [Yerges-Armstrong, Laura M.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Dept Genet, St Louis, MO 63110 USA. [Bielak, Lawrence F.; Jhun, Min A.; Kardia, Sharon L. R.; Peyser, Patricia A.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Hernaez, Ruben] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Carr, J. Jeffrey] Wake Forest Sch Med, Dept Radiol Sci, Winston Salem, NC USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Langefeld, Carl D.; Wagenknecht, Lynne E.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Norris, Jill M.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Liu, Jiankang] Univ Mississippi, Jackson Heart Study, Jackson, MS 39216 USA. RP Speliotes, EK (reprint author), Univ Michigan, 6520 MSRBI,SPC 5682,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM espeliot@med.umich.edu RI Hernaez, Ruben/C-4039-2014; Carr, John/A-1938-2012; Smith, Albert/K-5150-2015; Feitosa, Mary/K-8044-2012 OI Hernaez, Ruben/0000-0002-1518-4020; Carr, John/0000-0002-4398-8237; Smith, Albert/0000-0003-1942-5845; Feitosa, Mary/0000-0002-0933-2410 FU National Heart Lung and Blood Institute; National Center on Minority Health and Health Disparities [N01-HC95170, N01-HC95171, N01-HC95172]; National Heart, Lung and Blood Institute [5R01HL060944, 5R01HL061019, 5R01HL060919, 5R01HL060894, 5R01HL061210, 5R01HL08770003]; National Institutes of Health from National Heart, Lung, Blood Institute [HL085571, HL087660, HL100245]; National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK075681]; Department of Internal Medicine at the University of Michigan; Mid-Atlantic Nutrition Obesity Research Center from the National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK072488]; American Diabetes Association Mentor-Based Postdoctoral Fellowship Program [7-07-MN-08]; Doris Duke Charitable Foundation [2012067] FX Support for the Jackson Heart Study was provided by the National Heart Lung and Blood Institute and the National Center on Minority Health and Health Disparities grants N01-HC95170, N01-HC95171, and N01-HC95172. Support for the Insulin Resistance Atherosclerosis Family Study was provided by the National Heart, Lung and Blood Institute grants 5R01HL060944, 5R01HL061019, 5R01HL060919, 5R01HL060894, and 5R01HL061210. Support for the Genetic Epidemiology Network of Arteriopathy was provided by the National Institutes of Health, grant numbers HL085571, HL087660, and HL100245 from National Heart, Lung, Blood Institute. Support for the Family Heart Study was provided by the National Heart, Lung and Blood Institute grant 5R01HL08770003 and by the National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01DK075681. IRASFS genotyping was carried out with funds from the Department of Internal Medicine at the University of Michigan. Analysis was partially supported by the Mid-Atlantic Nutrition Obesity Research Center (P30 DK072488) from the National Institute of Diabetes and Digestive and Kidney Diseases. In addition, we thank the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK081350, to N.D.P.), the American Diabetes Association Mentor-Based Postdoctoral Fellowship Program (7-07-MN-08, RH), the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK080145 to E. K. S. and B. K.), the Doris Duke Charitable Foundation (Grant 2012067, to E. K. S. and B. K.), the Department of Internal Medicine and Biological Sciences Scholars Program at the University of Michigan (to E. K. S. and B.K.). NR 32 TC 32 Z9 32 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2013 VL 58 IS 3 BP 966 EP 975 DI 10.1002/hep.26440 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 283YX UT WOS:000329284000018 PM 23564467 ER PT J AU Marquardt, JU Fischer, K Baus, K Kashyap, A Ma, SY Krupp, M Linke, M Teufel, A Zechner, U Strand, D Thorgeirsson, SS Galle, PR Strand, S AF Marquardt, Jens U. Fischer, Kerstin Baus, Katharina Kashyap, Anubha Ma, Shengyun Krupp, Markus Linke, Matthias Teufel, Andreas Zechner, Ulrich Strand, Dennis Thorgeirsson, Snorri S. Galle, Peter R. Strand, Susanne TI Sirtuin-6-Dependent Genetic and Epigenetic Alterations Are Associated With Poor Clinical Outcome in Hepatocellular Carcinoma Patients SO HEPATOLOGY LA English DT Article ID COMPARATIVE FUNCTIONAL GENOMICS; HISTONE DEACETYLASE SIRT6; FACTOR-KAPPA-B; CANCER DEVELOPMENT; CARCINOGENESIS; EXPRESSION; INITIATION; FIBROSIS; MODELS; MICE AB Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer). Conclusion: Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients. (Hepatology 2013;53:1054-1064) C1 [Marquardt, Jens U.; Fischer, Kerstin; Baus, Katharina; Kashyap, Anubha; Ma, Shengyun; Krupp, Markus; Teufel, Andreas; Strand, Dennis; Galle, Peter R.; Strand, Susanne] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Internal Med 1, D-55131 Mainz, Germany. [Linke, Matthias; Zechner, Ulrich] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Human Genet, D-55131 Mainz, Germany. [Marquardt, Jens U.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Strand, S (reprint author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Internal Med 1, Obere Zahlbacherstr 63, D-55131 Mainz, Germany. EM sstrand@uni-mainz.de RI Zechner, Ulrich/G-2116-2010 FU "Inneruniversitare Forschungsforderung Stufe," Johannes Gutenberg University, Mainz; Forschungszentrum Immunologie, Imaging Core Facility, Johannes Gutenberg University, Mainz FX This study was supported by grants from the "Inneruniversitare Forschungsforderung Stufe 1," Johannes Gutenberg University, Mainz (to S.S.) and in part by the Forschungszentrum Immunologie, Imaging Core Facility, Johannes Gutenberg University, Mainz (to D.S.). NR 40 TC 36 Z9 40 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 2013 VL 58 IS 3 BP 1054 EP 1064 DI 10.1002/hep.26413 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 283YX UT WOS:000329284000026 PM 23526469 ER PT J AU Fernandes, AM Fero, K Driever, W Burgess, HA AF Fernandes, Antonio M. Fero, Kandice Driever, Wolfgang Burgess, Harold A. TI Enlightening the brain: Linking deep brain photoreception with behavior and physiology SO BIOESSAYS LA English DT Article DE behavior; deep brain photoreceptors; melanopsin; neurohormones; zebrafish ID CONTACTING NEURONS; LOCOMOTOR-ACTIVITY; PINEAL ORGAN; LIGHT; MELANOPSIN; ZEBRAFISH; EVOLUTION; CELLS; FISH; ADAPTATION AB Vertebrates respond to light with more than just their eyes. In this article, we speculate on the intriguing possibility that a link remains between non-visual opsins and neurohormonal systems that control neuronal circuit formation and activity in mammals. Historically, the retina and pineal gland were considered the only significant light-sensing tissues in vertebrates. However over the last century, evidence has accumulated arguing that extra-ocular tissues in vertebrates influence behavior through non-image-forming photoreception. One such class of extra-ocular light detectors are the long mysterious deep brain photoreceptors. Here, we review recent findings on the cellular identity and the function of deep brain photoreceptors controlling behavior and physiology in zebrafish, and discuss their implications. C1 [Fernandes, Antonio M.; Driever, Wolfgang] Univ Freiburg, Dev Biol Unit, Fac Biol, D-79106 Freiburg, Germany. [Fernandes, Antonio M.; Driever, Wolfgang] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79106 Freiburg, Germany. [Fero, Kandice; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. RP Burgess, HA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD USA. EM miguel.fernandes@biologie.uni-freiburg.de; haroldburgess@mail.nih.gov RI Burgess, Harold/B-8474-2015 OI Burgess, Harold/0000-0003-1966-7801 FU Intramural Research Program of the National Institute of Child Health and Human Development; EU ZF-HEALTH Program; DFG Centre for Biological Signalling Studies [EXC 294] FX We thank Marc Norman and Aristides B. Arrenberg for their comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (H. A. B.) and the EU ZF-HEALTH Program and DFG Centre for Biological Signalling Studies EXC 294 (W.D.). NR 33 TC 6 Z9 6 U1 4 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD SEP PY 2013 VL 35 IS 9 BP 775 EP 779 DI 10.1002/bies.201300034 PG 5 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 263FX UT WOS:000327793500006 PM 23712321 ER PT J AU Wolf, YI Koonin, EV AF Wolf, Yuri I. Koonin, Eugene V. TI Genome reduction as the dominant mode of evolution SO BIOESSAYS LA English DT Article DE ancestral reconstruction; archaea; genome complexification; genome reduction; horizontal gene transfer; orthologs ID HORIZONTAL GENE-TRANSFER; BACTERIAL PATHOGENS; EUKARYOTIC GENOMES; PHYLETIC PATTERNS; COMPLEXITY; ARCHAEA; LIKELIHOOD; DIVERSITY; SYMBIONTS; ANCESTOR AB A common belief is that evolution generally proceeds towards greater complexity at both the organismal and the genomic level, numerous examples of reductive evolution of parasites and symbionts notwithstanding. However, recent evolutionary reconstructions challenge this notion. Two notable examples are the reconstruction of the complex archaeal ancestor and the intron-rich ancestor of eukaryotes. In both cases, evolution in most of the lineages was apparently dominated by extensive loss of genes and introns, respectively. These and many other cases of reductive evolution are consistent with a general model composed of two distinct evolutionary phases: the short, explosive, innovation phase that leads to an abrupt increase in genome complexity, followed by a much longer reductive phase, which encompasses either a neutral ratchet of genetic material loss or adaptive genome streamlining. Quantitatively, the evolution of genomes appears to be dominated by reduction and simplification, punctuated by episodes of complexification. C1 [Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MA USA. RP Wolf, YI (reprint author), NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MA USA. EM wolf@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The authors' research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 90 TC 65 Z9 65 U1 5 U2 48 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD SEP PY 2013 VL 35 IS 9 BP 829 EP 837 DI 10.1002/bies.201300037 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 263FX UT WOS:000327793500013 PM 23801028 ER PT J AU Morris, CR Kim, HY Wood, J Porter, JB Klings, ES Trachtenberg, FL Sweeters, N Olivieri, NF Kwiatkowski, JL Virzi, L Singer, ST Taher, A Neufeld, EJ Thompson, AA Sachdev, V Larkin, S Suh, JH Kuypers, FA Vichinsky, EP AF Morris, Claudia R. Kim, Hae-Young Wood, John Porter, John B. Klings, Elizabeth S. Trachtenberg, Felicia L. Sweeters, Nancy Olivieri, Nancy F. Kwiatkowski, Janet L. Virzi, Lisa Singer, Sylvia T. Taher, Ali Neufeld, Ellis J. Thompson, Alexis A. Sachdev, Vandana Larkin, Sandra Suh, Jung H. Kuypers, Frans A. Vichinsky, Elliott P. CA Thalassemia Clinical Res Network TI Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension SO HAEMATOLOGICA LA English DT Article ID SICKLE-CELL-DISEASE; BETA-THALASSEMIA; HEART-FAILURE; NITRIC-OXIDE; ARTERIAL-HYPERTENSION; ARGININE BIOAVAILABILITY; HYPERCOAGULABLE STATE; PLATELET ACTIVATION; ORAL SILDENAFIL; TASK-FORCE AB Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with beta-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0+/-0.7 versus 2.6+/-0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (rho=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with beta-thalassemia. C1 [Morris, Claudia R.] Emory Univ, Sch Med, Emory Childrens Ctr Dev Lung Biol, Dept Pediat,Div Emergency Med, Atlanta, GA 30322 USA. [Kim, Hae-Young; Trachtenberg, Felicia L.; Virzi, Lisa] New England Res Inst, Watertown, MA 02172 USA. [Wood, John] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Porter, John B.] UCL, London, England. [Klings, Elizabeth S.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Sweeters, Nancy; Singer, Sylvia T.; Vichinsky, Elliott P.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Olivieri, Nancy F.] Toronto Gen Hosp, Toronto, ON, Canada. [Kwiatkowski, Janet L.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Taher, Ali] Amer Univ Beirut, Beirut, Lebanon. [Neufeld, Ellis J.] Childrens Hosp, Boston, MA 02115 USA. [Thompson, Alexis A.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Sachdev, Vandana] NHLBI, Cardiovasc & Pulm Med Branch, Bethesda, MD 20892 USA. [Larkin, Sandra; Suh, Jung H.; Kuypers, Frans A.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. RP Morris, CR (reprint author), Emory Univ, Sch Med, Emory Childrens Ctr Dev Lung Biol, Dept Pediat,Div Emergency Med, Atlanta, GA 30322 USA. EM claudiamorris@comcast.net OI Porter, John/0000-0003-3000-9359 FU NIH-NHLBI [U01 HL065238NIH, U01-HL65232, NIH/NCRR UL1-RR-024134, U04-HL72291]; FDA [1R0FD003534-03]; Intramural Research Program of the NIH; NHLBI; NIH-NHLBI, Harvard Catalyst CTSC [U-01RR025758, U01-HL65233, ULIRR024431-014, U04-HL65244, CTSC UL1-RR024996, U01-HL65238] FX This work was supported by the NIH-NHLBI cooperative agreement U01 HL065238NIH grant. This research was also supported in part by FDA grant 1R0FD003534-03 (to CRM), the Intramural Research Program of the NIH, NHLBI and by the following NIH-NHLBI cooperative agreements: U01-HL65232 and NIH/NCRR UL1-RR-024134 to the Children's Hospital of Philadelphia, U04-HL72291 and by Harvard Catalyst CTSC U-01RR025758 to the Children's Hospital, Boston, U01-HL65233 to the University Health Network Toronto General Hospital, ULIRR024431-014 to the Children's Hospital & Research Center Oakland, U04-HL65244 and CTSC UL1-RR024996 to Weill Medical College of Cornell University, and U01-HL65238 to New England Research Institutes. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI. NR 54 TC 10 Z9 10 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD SEP PY 2013 VL 98 IS 9 BP 1359 EP 1367 DI 10.3324/haematol.2012.082065 PG 9 WC Hematology SC Hematology GA 273NR UT WOS:000328542500017 PM 23585527 ER PT J AU Ampofo, WK Baylor, N Cobey, S Cox, NJ Daves, S Edwards, S Ferguson, N Grohmann, G Hay, A Katz, J Kullabutr, K Lambert, L Levandowski, R Mishra, AC Monto, A Siqueira, M Tashiro, M Waddell, AL Wairagkar, N Wood, J Zambon, M Zhang, WQ AF Ampofo, William K. Baylor, Norman Cobey, Sarah Cox, Nancy J. Daves, Sharon Edwards, Steven Ferguson, Neil Grohmann, Gary Hay, Alan Katz, Jacqueline Kullabutr, Kornnika Lambert, Linda Levandowski, Roland Mishra, A. C. Monto, Arnold Siqueira, Marilda Tashiro, Masato Waddell, Anthony L. Wairagkar, Niteen Wood, John Zambon, Maria Zhang, Wenqing CA WHO Writing Grp TI Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14-16 June 2010 SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE influenza vaccine viruses; vaccine virus selection; WHO recommendations C1 [Ampofo, William K.] Natl Influenza Ctr, Accra, Ghana. [Baylor, Norman] Food & Drug Adm, Rockville, MA USA. [Cobey, Sarah] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cox, Nancy J.; Katz, Jacqueline] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Daves, Sharon] NAMRU 3, Cairo, Egypt. [Edwards, Steven] Network Expertise Anim Influenzas OFFLU Steering, Hereford, England. [Ferguson, Neil] Imperial Coll Sch Med St Marys, London, England. [Grohmann, Gary] Therapeut Goods Adm Labs, Symonston, Australia. [Hay, Alan] Natl Inst Med Res, London NW7 1AA, England. [Kullabutr, Kornnika] Minist Publ Hlth, Nonthaburi, Thailand. [Lambert, Linda] NIH, Bethesda, MD 20892 USA. [Mishra, A. C.] Natl Influenza Ctr, Pune, Maharashtra, India. [Monto, Arnold] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Siqueira, Marilda] Inst Oswaldo Cruz, BR-20001 Rio De Janeiro, Brazil. [Tashiro, Masato] WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Wairagkar, Niteen; Zhang, Wenqing] WHO, CH-1211 Geneva, Switzerland. [Wood, John] NIBSC, Potters Bar, Herts, England. [Zambon, Maria] Hlth Protect Agcy, London, England. RP Zhang, WQ (reprint author), WHO, CH-1211 Geneva, Switzerland. EM zhangw@who.int RI Ferguson, Neil/B-8578-2008 OI Ferguson, Neil/0000-0002-1154-8093 NR 2 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2013 VL 7 SU 2 SI SI BP 52 EP 53 DI 10.1111/irv.12081 PG 2 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 265KE UT WOS:000327949400008 PM 24034484 ER PT J AU Charu, V Simonsen, L Lustig, R Steiner, C Viboud, C AF Charu, Vivek Simonsen, Lone Lustig, Roger Steiner, Claudia Viboud, Cecile TI Mortality burden of the 2009-10 influenza pandemic in the United States: improving the timeliness of influenza severity estimates using inpatient mortality records SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Age patterns; influenza; influenza-related mortality; pandemic influenza; years of life lost ID RESPIRATORY SYNCYTIAL VIRUS; SEASONAL INFLUENZA; LIFE LOST; A H1N1; HOSPITALIZATIONS; IMPACT; EPIDEMIOLOGY; DISEASE AB Background Delays in the release of national vital statistics hinder timely assessment of influenza severity, especially during pandemics. Inpatient mortality records could provide timelier estimates of influenza-associated mortality. Methods We compiled weekly age-specific deaths for various causes from US State Inpatient Databases (1990-2010) and national vital statistics (1990-2009). We calculated influenza-attributable excess deaths by season based on Poisson regression models driven by indicators of respiratory virus activity, seasonality, and temporal trends. Results Extrapolations of excess mortality from inpatient data fell within 11% and 17% of vital statistics estimates for pandemic and seasonal influenza, respectively, with high year-to-year correlation (Spearman's rho=087-090, P<0001, n=19). We attribute 14800 excess respiratory and cardiac deaths (95% CI: 10000-19650) to pandemic influenza activity during April 2009-April 2010, 79% of which occurred in people under 65years. Conclusions Modeling inpatient mortality records provides useful estimates of influenza severity in advance of national vital statistics release, capturing both the magnitude and the age distribution of pandemic and epidemic deaths. We provide the first age- and cause-specific estimates of the 2009 pandemic mortality burden using traditional excess mortality' methods, confirming the unusual burden of this virus in young populations. Our inpatient-based approach could help monitor mortality trends in other infectious diseases. C1 [Charu, Vivek; Simonsen, Lone; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Charu, Vivek] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. [Lustig, Roger] Sage Analyt, Bethesda, MD USA. [Steiner, Claudia] Agcy Healthcare Res & Qual, Rockville, MD USA. RP Charu, V (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM charuvn@mail.nih.gov; viboudc@mail.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 FU in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; International Influenza Unit, Office of Global Affairs, Department of Health and Human Services; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security FX We thank Richard Jordan at the Agency for Healthcare Quality and Research (AHRQ) for his help in data extraction. This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). This work was supported by the in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, which is funded by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services. L.S. acknowledges support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security. Part of the information contained in this manuscript was presented at the International Conference on Emerging Infectious Diseases (Atlanta, GA USA; March 2012). The authors do not have commercial or other associations that might pose a conflict of interest. NR 24 TC 7 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2013 VL 7 IS 5 BP 863 EP 871 DI 10.1111/irv.12096 PG 9 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 268IE UT WOS:000328162800016 PM 23419002 ER PT J AU Byrd-Bredbenner, C Berning, J Martin-Biggers, J Quick, V AF Byrd-Bredbenner, Carol Berning, Jacqueline Martin-Biggers, Jennifer Quick, Virginia TI Food Safety in Home Kitchens: A Synthesis of the Literature SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE food safety; food handling; foodborne illness; consumers; risky ID YERSINIA-ENTEROCOLITICA INFECTIONS; COLI O157-H7 INFECTIONS; MIDDLE SCHOOL STUDENTS; MEXICAN-STYLE CHEESE; UNITED-STATES; HANDLING PRACTICES; FOODBORNE ILLNESS; YOUNG-ADULTS; DOMESTIC ENVIRONMENT; HIGH-RISK AB Although foodborne illness is preventable, more than 56,000 people per year become ill in the U.S., creating high economic costs, loss of productivity and reduced quality of life for many. Experts agree that the home is the primary location where foodborne outbreaks occur; however, many consumers do not believe the home to be a risky place. Health care professionals need to be aware of consumers' food safety attitudes and behaviors in the home and deliver tailored food safety interventions that are theory-based. Thus, the purpose of this paper is to synthesize/summarize the food safety literature by examining the following: consumers' perceptions and attitudes towards food safety and their susceptibility to foodborne illness in the home, work, and school; common risky food safety practices and barriers to handling food safely; and the application of theory-based food safety interventions. Findings will help healthcare professionals become more aware of consumers' food safety attitudes and behaviors and serve to inform future food safety interventions. C1 [Byrd-Bredbenner, Carol; Martin-Biggers, Jennifer] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08901 USA. [Berning, Jacqueline] Univ Colorado, Dept Biol, Colorado Springs, CO 80918 USA. [Quick, Virginia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Byrd-Bredbenner, C (reprint author), Rutgers State Univ, Dept Nutr Sci, 26 Nichol Ave,211 Davison Hall, New Brunswick, NJ 08901 USA. EM bredbenner@aesop.rutgers.edu; jberning@uccs.edu; jmartin@aesop.rutgers.edu; quickvm@mail.nih.gov RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Martin-Biggers, Jennifer/0000-0001-8857-6386; Quick, Virginia/0000-0002-4338-963X FU ConAgra; Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Training Award FX This research was supported by ConAgra and in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Training Award. NR 179 TC 23 Z9 23 U1 0 U2 36 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD SEP PY 2013 VL 10 IS 9 BP 4060 EP 4085 DI 10.3390/ijerph10094060 PG 26 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 274QD UT WOS:000328620200017 PM 24002725 ER PT J AU Panda, AC Grammatikakis, I Yoon, JH Abdelmohsen, K AF Panda, Amaresh C. Grammatikakis, Ioannis Yoon, Je-Hyun Abdelmohsen, Kotb TI Posttranscriptional Regulation of Insulin Family Ligands and Receptors SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE glucose homeostasis; insulin-like growth factor; insulin-like growth factor receptor; RNA-binding protein; micro RNA; long noncoding RNA; mRNA decay; mRNA translation; insulin signaling; alternative splicing IRES ID GROWTH-FACTOR-I; RNA-BINDING PROTEIN; SQUAMOUS-CELL CARCINOMA; NEURONAL ELAV PROTEINS; RIBOSOME ENTRY SEGMENT; MESSENGER-RNA; SKELETAL-MUSCLE; POLYPYRIMIDINE-TRACT; MYOTONIC-DYSTROPHY; PANCREATIC-ISLETS AB Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and their receptors are posttranscriptionally controlled by three major groups of regulators; (i) alternative splicing regulatory factors; (ii) turnover and translation regulator RNA-binding proteins (TTR-RBPs); and (iii) non-coding RNAs including miRNAs and long non-coding RNAs (lncRNAs). In this review, we discuss the influence of these regulators on alternative splicing, mRNA stability and translation. Due to the pathological impacts of insulin system, we also discussed the possibilities of discovering new potential regulators which will improve understanding of insulin system and associated diseases. C1 [Panda, Amaresh C.; Grammatikakis, Ioannis; Yoon, Je-Hyun; Abdelmohsen, Kotb] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM amaresh.panda@nih.gov; yannis.grammatikakis@nih.gov; je-hyun.yoon@nih.gov; abdelmohsenk@mail.nih.gov OI PANDA, AMARESH/0000-0003-3189-8995 FU NIA-IRP, NIH FX PA, IG, JY and KA were supported by the NIA-IRP, NIH. Our apologies to all colleagues whose work could not be included due to space constraints. NR 152 TC 2 Z9 4 U1 0 U2 16 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD SEP PY 2013 VL 14 IS 9 BP 19202 EP 19229 DI 10.3390/ijms140919202 PG 28 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 274RN UT WOS:000328623900104 PM 24051403 ER PT J AU Legare, F Moumjid-Ferdjaoui, N Drolet, R Stacey, D Harter, M Bastian, H Beaulieu, MD Borduas, F Charles, C Coulter, A Desroches, S Friedrich, G Gafni, A Graham, ID Labrecque, M LeBlanc, A Legare, J Politi, M Sargeant, J Thomson, R AF Legare, France Moumjid-Ferdjaoui, Nora Drolet, Renee Stacey, Dawn Haerter, Martin Bastian, Hilda Beaulieu, Marie-Dominique Borduas, Francine Charles, Cathy Coulter, Angela Desroches, Sophie Friedrich, Gwendolyn Gafni, Amiram Graham, Ian D. Labrecque, Michel LeBlanc, Annie Legare, Jean Politi, Mary Sargeant, Joan Thomson, Richard TI Core Competencies for Shared Decision Making Training Programs: Insights From an International, Interdisciplinary Working Group SO JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS LA English DT Article DE shared decision making; education; patient-centered care; implementation science; theory; risk communication ID RANDOMIZED CONTROLLED-TRIAL; CLINICAL-PRACTICE; RISK COMMUNICATION; MEDICAL ENCOUNTER; PRIMARY-CARE; CALL CENTER; SUPPORT; MODEL; INTERVENTIONS; PROFESSIONALS AB Shared decision making is now making inroads in health care professionals' continuing education curriculum, but there is no consensus on what core competencies are required by clinicians for effectively involving patients in health-related decisions. Ready-made programs for training clinicians in shared decision making are in high demand, but existing programs vary widely in their theoretical foundations, length, and content. An international, interdisciplinary group of 25 individuals met in 2012 to discuss theoretical approaches to making health-related decisions, compare notes on existing programs, take stock of stakeholders concerns, and deliberate on core competencies. This article summarizes the results of those discussions. Some participants believed that existing models already provide a sufficient conceptual basis for developing and implementing shared decision making competency-based training programs on a wide scale. Others argued that this would be premature as there is still no consensus on the definition of shared decision making or sufficient evidence to recommend specific competencies for implementing shared decision making. However, all participants agreed that there were 2 broad types of competencies that clinicians need for implementing shared decision making: relational competencies and risk communication competencies. Further multidisciplinary research could broaden and deepen our understanding of core competencies for shared decision making training. C1 [Legare, France; Drolet, Renee; Desroches, Sophie; Labrecque, Michel] Hop St Francois Assise, CHUQ Res Ctr, Quebec City, PQ G1L 3L5, Canada. [Moumjid-Ferdjaoui, Nora] Univ Lyon 1, CNRS, Ctr Leon Berard, GATE,UMR 5824, F-69008 Lyon, France. [Stacey, Dawn; Graham, Ian D.] Univ Ottawa, Fac Hlth Sci, Sch Nursing, Ottawa, ON K1H 8M5, Canada. [Stacey, Dawn; Graham, Ian D.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON K1H 8M5, Canada. [Haerter, Martin] Univ Med Ctr Hamburg Eppendorf, Dept Med Psychol, D-20246 Hamburg, Germany. [Bastian, Hilda] NIH, PubMed Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Beaulieu, Marie-Dominique] Hop Hotel Dieu, Ctr Rech CHUM, Dept Med Familiale, Montreal, PQ H2W 1T8, Canada. [Borduas, Francine] Univ Laval, Fac Med, Continuing Profess Dev Off, Ste Foy, PQ G1K 7P4, Canada. [Charles, Cathy; Gafni, Amiram] McMaster Univ, Ctr Hlth Econ & Policy Anal, Dept Clin Epidemiol & Biostat, Hamilton, ON L8N 3Z5, Canada. [Coulter, Angela] Univ Oxford, Dept Publ Hlth, Informed Med Decis Fdn UK, Oxford OX3 7LF, England. [Friedrich, Gwendolyn] Pathways Hlth Solut, Regina, SK S4S 6K1, Canada. [LeBlanc, Annie] Mayo Clin, Dept Hlth Serv Res, Div Hlth Care Policy Res, Coll Med,Knowledge & Evaluat Res KER Unit, Rochester, MN 55905 USA. [Legare, Jean] Canadian Arthrit Patient Alliance, Neuville, PQ G0A 2RD, Canada. [Politi, Mary] Washington Univ, Dept Surg, Div Publ Hlth Sci, Sch Med, St Louis, MO 63112 USA. [Sargeant, Joan] Dalhousie Univ, Fac Med, Div Med Educ Res & Evaluat, Halifax, NS B3H 4H7, Canada. [Thomson, Richard] Newcastle Univ, Epidemiol & Publ Hlth Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. RP Legare, F (reprint author), Hop St Francois Assise, Ctr Hosp Univ Quebec, 10 Rue Espinay, Quebec City, PQ G1L 3L5, Canada. EM France.legare@mfa.ulaval.ca OI Coulter, Angela/0000-0002-6308-8375; Politi, Mary/0000-0001-9103-6495; Graham, Ian D/0000-0002-3669-1216; Bastian, Hilda/0000-0001-8544-7386 FU Canadian Institutes of Health Research [201102KRD-248672-KTB-CFBA-19158]; Rhone-Alps Region FX This meeting was funded by a grant from the Canadian Institutes of Health Research (201102KRD-248672-KTB-CFBA-19158). Professor Nora Moumjid gratefully acknowledges the Rhone-Alps Region for the grant Explora Pro that she received for her sabbatical (2011-2012) at the CHUQ Research Centre, Hopital St-Francois D'Assise. NR 41 TC 14 Z9 14 U1 1 U2 10 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 0894-1912 EI 1554-558X J9 J CONTIN EDUC HEALTH JI J. Contin. Educ. Health Prof. PD SEP PY 2013 VL 33 IS 4 BP 267 EP 273 DI 10.1002/chp.21197 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 274DC UT WOS:000328584300008 PM 24347105 ER PT J AU Simon, N Simon, R AF Simon, Noah Simon, Richard TI Adaptive enrichment designs for clinical trials SO BIOSTATISTICS LA English DT Article DE Adaptive clinical trials; Biomarker; Cutpoint; Enrichment ID CANCER; SUBPOPULATIONS; EFFICIENCY; SUBSET AB Modern medicine has graduated from broad spectrum treatments to targeted therapeutics. New drugs recognize the recently discovered heterogeneity of many diseases previously considered to be fairly homogeneous. These treatments attack specific genetic pathways which are only dysregulated in some smaller subset of patients with the disease. Often this subset is only rudimentarily understood until well into large-scale clinical trials. As such, standard practice has been to enroll a broad range of patients and run post hoc subset analysis to determine those who may particularly benefit. This unnecessarily exposes many patients to hazardous side effects, and may vastly decrease the efficiency of the trial (especially if only a small subset of patients benefit). In this manuscript, we propose a class of adaptive enrichment designs that allow the eligibility criteria of a trial to be adaptively updated during the trial, restricting entry to patients likely to benefit from the new treatment. We show that our designs both preserve the type 1 error, and in a variety of cases provide a substantial increase in power. C1 [Simon, Noah] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, N (reprint author), Stanford Univ, Dept Stat, Stanford, CA 94305 USA. EM nsimon@stanford.edu FU Ric Weiland endowed fellowship FX R.S. is an employee of the National Institutes of Health. N.S. is partially supported by a Ric Weiland endowed fellowship. NR 22 TC 21 Z9 21 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD SEP PY 2013 VL 14 IS 4 BP 613 EP 625 DI 10.1093/biostatistics/kxt010 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 269ZZ UT WOS:000328285800001 PM 23525452 ER PT J AU Sampson, JN Chatterjee, N Carroll, RJ Muller, S AF Sampson, Joshua N. Chatterjee, Nilanjan Carroll, Raymond J. Mueller, Samuel TI Controlling the local false discovery rate in the adaptive Lasso SO BIOSTATISTICS LA English DT Article DE Adaptive Lasso; Local false discovery rate; Smoothing parameter; Variable selection ID GENOME-WIDE ASSOCIATION; REGRESSION SHRINKAGE; ORACLE PROPERTIES; SELECTION AB The Lasso shrinkage procedure achieved its popularity, in part, by its tendency to shrink estimated coefficients to zero, and its ability to serve as a variable selection procedure. Using data-adaptive weights, the adaptive Lasso modified the original procedure to increase the penalty terms for those variables estimated to be less important by ordinary least squares. Although this modified procedure attained the oracle properties, the resulting models tend to include a large number of "false positives" in practice. Here, we adapt the concept of local false discovery rates (lFDRs) so that it applies to the sequence, lambda(n), of smoothing parameters for the adaptive Lasso. We define the lFDR for a given lambda(n) to be the probability that the variable added to the model by decreasing lambda(n) to lambda(n) - delta is not associated with the outcome, where delta is a small value. We derive the relationship between the lFDR and lambda(n), show lFDR = 1 for traditional smoothing parameters, and show how to select lambda(n) so as to achieve a desired lFDR. We compare the smoothing parameters chosen to achieve a specified lFDR and those chosen to achieve the oracle properties, as well as their resulting estimates for model coefficients, with both simulation and an example from a genetic study of prostate specific antigen. C1 [Sampson, Joshua N.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Mueller, Samuel] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. RP Sampson, JN (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8038, Rockville, MD 20852 USA. EM joshua.sampson@nih.gov RI Mueller, Samuel/D-4850-2009 OI Mueller, Samuel/0000-0002-3087-8127 FU Intramural Research Program of the NCI; NHLBI [RO1-HL091172-01]; Australian Research Council [DP110101998]; National Cancer Institute [R37-CA057030]; King Abdullah University of Science and Technology (KAUST) [KUS-CI-016-04] FX Sampson's and Chatterjee's research was supported by the Intramural Research Program of the NCI. Chatterjee's research was supported by a gene-environment initiative grant from the NHLBI (RO1-HL091172-01). Muller's research was supported by a grant from the Australian Research Council (DP110101998). Carroll's research was supported by a grant from the National Cancer Institute (R37-CA057030). Carroll was also supported by Award Number KUS-CI-016-04, made by King Abdullah University of Science and Technology (KAUST). NR 23 TC 3 Z9 3 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD SEP PY 2013 VL 14 IS 4 BP 653 EP 666 DI 10.1093/biostatistics/kxt008 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 269ZZ UT WOS:000328285800004 PM 23575212 ER PT J AU Fay, MP Brittain, EH Proschan, MA AF Fay, Michael P. Brittain, Erica H. Proschan, Michael A. TI Pointwise confidence intervals for a survival distribution with small samples or heavy censoring SO BIOSTATISTICS LA English DT Article DE Clopper-Pearson confidence interval; Exact confidence interval; Kaplan-Meier estimator; Median survival; Non-parametric methods; Survival analysis ID PROBABILITIES; QUANTILES; ESTIMATOR; DESIGN AB We propose a beta product confidence procedure (BPCP) that is a non-parametric confidence procedure for the survival curve at a fixed time for right-censored data assuming independent censoring. In such situations, the Kaplan-Meier estimator is typically used with an asymptotic confidence interval (CI) that can have coverage problems when the number of observed failures is not large, and/or when testing the latter parts of the curve where there are few remaining subjects at risk. The BPCP guarantees central coverage (i.e. ensures that both one-sided error rates are no more than half of the total nominal rate) when there is no censoring (in which case it reduces to the Clopper-Pearson interval) or when there is progressive type II censoring (i.e. when censoring only occurs immediately after failures on fixed proportions of the remaining individuals). For general independent censoring, simulations show that the BPCP maintains central coverage in many situations where competing methods can have very substantial error rate inflation for the lower limit. The BPCP gives asymptotically correct coverage and is asymptotically equivalent to the CI on the Kaplan-Meier estimator using Greenwood's variance. The BPCP may be inverted to create confidence procedures for a quantile of the underlying survival distribution. Because the BPCP is easy to implement, offers protection in settings when other methods fail, and essentially matches other methods when they succeed, it should be the method of choice. C1 [Fay, Michael P.; Brittain, Erica H.; Proschan, Michael A.] NIAID, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 6700B Rockledge Dr MSC 7630, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 NR 23 TC 4 Z9 4 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD SEP PY 2013 VL 14 IS 4 BP 723 EP 736 DI 10.1093/biostatistics/kxt016 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 269ZZ UT WOS:000328285800009 PM 23632624 ER PT J AU Rao, CV Patlolla, JMR Qian, L Zhang, YT Brewer, M Mohammed, A Desai, D Amin, S Lightfoot, S Kopelovich, L AF Rao, Chinthalapally V. Patlolla, Jagan Mohan R. Qian, Li Zhang, Yuting Brewer, Misty Mohammed, Altaf Desai, Dhimant Amin, Shantu Lightfoot, Stan Kopelovich, Levy TI Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice SO NEOPLASIA LA English DT Article ID TUMOR-SUPPRESSOR FUNCTION; MUTANT P53; WILD-TYPE; CANCER-CELLS; P53-STABILIZING AGENT; CIGARETTE-SMOKE; K-RAS; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; INDUCTION; APOPTOSIS AB Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 mu mol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation. C1 [Rao, Chinthalapally V.; Patlolla, Jagan Mohan R.; Qian, Li; Zhang, Yuting; Brewer, Misty; Mohammed, Altaf] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Hematol Oncol Sect,Dept Med,Peggy & Charles Steph, Oklahoma City, OK 73104 USA. [Desai, Dhimant; Amin, Shantu] Penn State Hershey Coll Med, Dept Pharmacol, Hershey, PA USA. [Lightfoot, Stan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Lightfoot, Stan] VA Hosp, Oklahoma City, OK USA. [Kopelovich, Levy] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU Kerley-Cade Endowed Chair; [NIH/NCI-NO2-CB-81013-74]; [NIH/NCI-CN-53300] FX This work was supported by NIH/NCI-NO2-CB-81013-74, NIH/NCI-CN-53300, and the Kerley-Cade Endowed Chair. NR 45 TC 9 Z9 9 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 EI 1476-5586 J9 NEOPLASIA JI Neoplasia PD SEP PY 2013 VL 15 IS 9 BP 1018 EP 1027 DI 10.1593/neo.131256 PG 10 WC Oncology SC Oncology GA 267YR UT WOS:000328134800003 PM 24027427 ER PT J AU Dowell, SF Sejvar, JJ Riek, L Vandemaele, KAH Lamunu, M Kuesel, AC Schmutzhard, E Matuja, W Bunga, S Foltz, J Nutman, TB Winkler, AS Mbonye, AK AF Dowell, Scott F. Sejvar, James J. Riek, Lul Vandemaele, Katelijn A. H. Lamunu, Margaret Kuesel, Annette C. Schmutzhard, Erich Matuja, William Bunga, Sudhir Foltz, Jennifer Nutman, Thomas B. Winkler, Andrea S. Mbonye, Anthony K. TI Nodding Syndrome SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CLINICAL-CHARACTERISTICS; ONCHOCERCA-VOLVULUS; EPILEPTIC SEIZURES; SYDENHAMS CHOREA; SOUTHERN SUDAN; WEST UGANDA; FOLLOW-UP; CLASSIFICATION; METAANALYSIS; ASSOCIATION AB An epidemic illness characterized by head nodding associated with onchocerciasis has been described in eastern Africa since the early 1960s; we summarize published reports and recent studies. Onset of nodding occurs in previously healthy 5-15-year-old children and is often triggered by eating or cold temperatures and accompanied by cognitive impairment. Its incidence has increased in Uganda and South Sudan over the past 10 years. Four case control studies identified modest and inconsistent associations. There were nonspecific lesions seen by magnetic resonance imaging, no cerebrospinal fluid inflammation, and markedly abnormal electroencephalography results. Nodding episodes are atonic seizures. Testing has failed to demonstrate associations with trypanosomiasis, cysticercosis, loiasis, lymphatic filariasis, cerebral malaria, measles, prion disease, or novel pathogens; or deficiencies of folate, cobalamin, pyridoxine, retinol, or zinc; or toxicity from mercury, copper, or homocysteine. There is a consistent enigmatic association with onchocerciasis detected by skin snip or serologic analysis. Nodding syndrome is an unexplained epidemic epilepsy. C1 [Dowell, Scott F.; Sejvar, James J.; Bunga, Sudhir; Foltz, Jennifer] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Riek, Lul] Minist Hlth, Juba, Sudan. [Vandemaele, Katelijn A. H.; Lamunu, Margaret; Kuesel, Annette C.] World Hlth Org, Geneva, Switzerland. [Schmutzhard, Erich] Univ Innsbruck, A-6020 Innsbruck, Austria. [Matuja, William] Muhimbili Univ, Dar Es Salaam, Tanzania. [Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. [Winkler, Andrea S.] Tech Univ Munich, D-80290 Munich, Germany. [Mbonye, Anthony K.] Minist Hlth, Kampala, Uganda. [Mbonye, Anthony K.] Makerere Univ, Kampala, Uganda. RP Dowell, SF (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop D69, Atlanta, GA 30333 USA. EM sfd2@cdc.gov OI Kuesel, Annette C./0000-0002-1696-1784 NR 40 TC 26 Z9 26 U1 1 U2 16 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2013 VL 19 IS 9 BP 1374 EP 1384 DI 10.3201/eid1909.130401 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268MB UT WOS:000328173800003 PM 23965548 ER PT J AU Mombouli, JV Bitsindou, P Elion, DOA Grolla, A Feldmann, H Niama, FR Parra, HJ Munster, VJ AF Mombouli, Jean-Vivien Bitsindou, Patrick Elion, Darrel O. A. Grolla, Allen Feldmann, Heinz Niama, Fabien R. Parra, Henri-Joseph Munster, Vincent J. TI Chikungunya Virus Infection, Brazzaville, Republic of Congo, 2011 SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID AEDES-ALBOPICTUS; CENTRAL-AFRICA; DENGUE VIRUS; GABON; PCR C1 [Mombouli, Jean-Vivien; Elion, Darrel O. A.; Niama, Fabien R.; Parra, Henri-Joseph] Lab Natl Sante Publ, Brazzaville, Congo. [Mombouli, Jean-Vivien; Niama, Fabien R.] Univ Marien Ngouabi, Brazzaville, Congo. [Bitsindou, Patrick] Delegat Gen Rech Sci & Technol, Brazzaville, Congo. [Grolla, Allen] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Feldmann, Heinz; Munster, Vincent J.] NIH, Hamilton, MT USA. RP Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 NR 10 TC 12 Z9 12 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD SEP PY 2013 VL 19 IS 9 BP 1542 EP 1543 DI 10.3201/eid1909.130451 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268MB UT WOS:000328173800034 PM 23968609 ER PT J AU Karpova, T Kent, RS Kim, MJ Mueller, F Stasevich, T Mazza, D McNally, J AF Karpova, Tatiana Kent, R. S. Kim, Min J. Mueller, F. Stasevich, T. Mazza, D. McNally, J. TI Single-cell in vivo analysis reveals that relocation of the yeast CUP1 locus to the nuclear pore is associated with its mRNA release SO YEAST LA English DT Meeting Abstract CT 26th International Conference on Yeast Genetics and Molecular Biology CY AUG 29-SEP 03, 2013 CL Frankfurt Main, GERMANY SP Wiley Blackwell, Lesaffre, Singer Instruments, Federat European Microbiol Soc, Sci Res & Dev GmbH, VAAM, Cluster Excellence Frankfurt, Carlsberg Lab, Butalco, SFB 902, DSM, ARTES C1 [Karpova, Tatiana; Kent, R. S.; Kim, Min J.; McNally, J.] NCI, NIH, Bethesda, MD 20892 USA. [Stasevich, T.] Osaka Univ, Suita, Osaka 565, Japan. [Mazza, D.] Ist Sci Osped, Milan, Italy. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0749-503X EI 1097-0061 J9 YEAST JI Yeast PD SEP PY 2013 VL 30 SU 1 BP 109 EP 109 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 265CN UT WOS:000327927400172 ER PT J AU Huang, L Midthune, D Krapcho, M Zou, ZH Horner, MJ Feuer, EJ AF Huang, Lan Midthune, Douglas Krapcho, Martin Zou, Zhaohui Horner, Marie-Joseph Feuer, Eric J. TI Adjusting for reporting delay in cancer incidence when combining different sets of cancer registries SO BIOMETRICAL JOURNAL LA English DT Article DE Adjusted cancer incidence; Delay models; Delay adjustment factor; Reporting delay; SEER ID AIDS INCIDENCE; REGRESSION; RATES; SURVEILLANCE; TRENDS AB Cancer registries collect cancer incidence data that can be used to calculate incidence rates in a population and track changes over time. For incidence rates to be accurate, it is critical that diagnosed cases be reported in a timely manner. Registries typically allow a fixed amount of time (e.g. two years) for diagnosed cases to be reported before releasing the initial case counts for a particular diagnosis year. Inevitably, however, additional cases are reported after the initial counts are released; these extra cases are included in subsequent releases that become more complete over time, while incidence rates based on earlier releases will underestimate the true rates. Statistical methods have been developed to estimate the distribution of reporting delay (the amount of time until a diagnosed case is reported) and to correct incidence rates for underestimation due to reporting delay. Since the observed reporting delays must be less than the length of time the registry has been collecting data, most methods estimate a truncated delay distribution. These methods can be applied to a group of registries that began collecting data in the same diagnosis year. In this paper, we extend the methods to two groups of registries that began collecting data in two different diagnosis years (so that the delay distributions are truncated at different times). We apply the proposed method to data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program, a consortium of U.S. cancer registries that includes nine registries with data collection beginning in 1981 and four registries with data collection beginning in 1992. We use the method to obtain delay-adjusted incidence rates for melanoma, liver cancer, and Hodgkin lymphoma. C1 [Huang, Lan] FDA CDER, Silver Spring, MD 20993 USA. [Midthune, Douglas; Feuer, Eric J.] NCI, NIH, Rockville, MD 20850 USA. [Krapcho, Martin; Zou, Zhaohui] Informat Management Serv Inc, Calverton, MD 20705 USA. [Horner, Marie-Joseph] Univ N Carolina, Dept Epidemiol, UNC Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Feuer, EJ (reprint author), NCI, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM feuerr@mail.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD SEP PY 2013 VL 55 IS 5 BP 755 EP 770 DI 10.1002/bimj.201100191 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 263OC UT WOS:000327816900008 PM 23873707 ER PT J AU Amarnath, S AF Amarnath, Shoba TI c-Rel in GVHD biology: A missing link SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE c-Rel; GVHD; GVL; Transplantation ID VERSUS-HOST-DISEASE; REGULATORY T-CELLS; ROR-GAMMA-T; NF-KAPPA-B; LYMPHOCYTE-PROLIFERATION; TRANSCRIPTION; EXPRESSION; TARGET; TRANSPLANTATION; PREVENTION AB Graft-versus-host disease (GVHD) is a major complication associated with allogeneic bone marrow transplantation (BMT). Recent advances in the treatment of lymphoid malignancies with BMT include exploring mechanisms that can inhibit GVHD while maintaining graft-versus-leukemic (GVL) effects. In this issue of the European Journal of Immunology, Yu et al. [Eur. J. Immunol. 2013.43: 2327-2337] demonstrate efficient separation of GVHD and GVL by abrogating c-Rel in T cells. Intrinsic c-Rel deficiency in T cells resulted in complete protection against GVHD in both major and minor histocompatibility mismatched murine models of BMT. Protection against GVHD was associated with a decreased presence of Th1 and Th17 cells with a concomitant increase in Treg-cell numbers. Interestingly, an intrinsic defect of c-Rel also resulted in decreased expression of the Th1-associated chemokine receptor CXCR3. Finally, the absence of c-Rel maintained GVL effects with significant tumor clearance in murine recipients. These data suggest that specific targeting of the T-cell-specific transcription factor c-Rel can inhibit GVHD while maintaining GVL effects. C1 NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Amarnath, S (reprint author), NCI, NIH, Expt Transplantat & Immunol Branch, 10 Ctr Dr,Room 3E-3224, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 30 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2013 VL 43 IS 9 BP 2255 EP 2258 DI 10.1002/eji.201343924 PG 4 WC Immunology SC Immunology GA 263OZ UT WOS:000327819200005 PM 24037677 ER PT J AU Linowes, BA Ligons, DL Nam, AS Hong, C Keller, HR Tai, X Luckey, MA Park, JH AF Linowes, Brett A. Ligons, Davinna L. Nam, Anna S. Hong, Changwan Keller, Hilary R. Tai, Xuguang Luckey, Megan A. Park, Jung-Hyun TI Pim1 permits generation and survival of CD4(+) T cells in the absence of gamma c cytokine receptor signaling SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Apoptosis; Cytokines; Homeostasis; Thymopoiesis ID CHAIN-DEFICIENT MICE; LYMPHOID DEVELOPMENT; THYMOCYTE DEVELOPMENT; NEGATIVE SELECTION; POSITIVE SELECTION; LINEAGE FATE; BCL-2; DIFFERENTIATION; APOPTOSIS; PROMOTES AB gamma-chain (c) cytokine receptor signaling is required for the development of all lymphocytes. Why c signaling plays such an essential role is not fully understood, but induction of the serine/threonine kinase Pim1 is considered a major downstream event of c as Pim1 prevents apoptosis and increases metabolic activity. Consequently, we asked whether Pim1 overexpression would suffice to restore lymphocyte development in c-deficient mice. By analyzing Pim1-transgenic c-deficient mice (Pim1(Tg)c(KO)), we show that Pim1 promoted T-cell development and survival in the absence of c. Interestingly, such effects were largely limited to CD4(+) lineage T cells as CD4(+) T-cell numbers improved to near normal levels but CD8(+) T cells remained severely lymphopenic. Notably, Pim1 over-expression failed to promote development and survival of any T-lineage cells other than T cells, as we observed complete lack of , NKT, FoxP3(+) T regulatory cells and TCR-(+) CD8 IELs in Pim1(Tg)c(KO) mice. Collectively, these results uncover distinct requirements for c signaling between CD4(+) T cells and all other T-lineage cells, and they identify Pim1 as a novel effector molecule sufficient to drive CD4(+) T-cell development and survival in the absence of c cytokine receptor signaling. C1 [Linowes, Brett A.; Ligons, Davinna L.; Nam, Anna S.; Hong, Changwan; Keller, Hilary R.; Tai, Xuguang; Luckey, Megan A.; Park, Jung-Hyun] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. [Linowes, Brett A.] Boston Univ, Sch Med, Div Grad Med Sci, Boston, MA 02118 USA. [Nam, Anna S.] Univ Missouri, Sch Med, Columbia, MO USA. [Nam, Anna S.] NIH, Howard Hughes Med Inst, Res Scholars Program, Chevy Chase, MD USA. RP Park, JH (reprint author), NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU US National Institutes of Health, National Cancer Institute; Center for Cancer Research FX We are grateful to Dr. A. Singer and Dr. R. Etzensperger for critical review of the manuscript. This study was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 48 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2013 VL 43 IS 9 BP 2283 EP 2294 DI 10.1002/eji.201242686 PG 12 WC Immunology SC Immunology GA 263OZ UT WOS:000327819200009 PM 23712827 ER PT J AU Tjomsland, V Ellegard, R Kjolhede, P Wodlin, NB Hinkula, J Lifson, JD Larsson, M AF Tjomsland, Veronica Ellegard, Rada Kjolhede, Preben Wodlin, Ninni Borendal Hinkula, Jorma Lifson, Jeffrey D. Larsson, Marie TI Blocking of integrins inhibits HIV-1 infection of human cervical mucosa immune cells with free and complement-opsonized virions SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD4(+) T cells; Complement system; DCs; HIV; Integrins ID SIMIAN IMMUNODEFICIENCY VIRUS; DENDRITIC CELLS; T-CELLS; CERVICOVAGINAL TISSUE; SEXUAL TRANSMISSION; ENHANCES INFECTION; LANGERHANS CELLS; EARLY EVENTS; EX-VIVO; RECEPTORS AB The initial interaction between HIV-1 and the host occurs at the mucosa during sexual intercourse. In cervical mucosa, HIV-1 exists both as free and opsonized virions and this might influence initial infection. We used cervical explants to study HIV-1 transmission, the effects of opsonization on infectivity, and how infection can be prevented. Complement opsonization enhanced HIV-1 infection of dendritic cells (DCs) compared with that by free HIV-1, but this increased infection was not observed with CD4(+) T cells. Blockage of the 4-, 7-, and 1-integrins significantly inhibited HIV-1 infection of both DCs and CD4(+) T cells. We found a greater impairment of HIV-1 infection in DCs for complement-opsonized virions compared with that of free virions when M/2- and 4-integrins were blocked. Blocking the C-type lectin receptor macrophage mannose receptor (MMR) inhibited infection of emigrating DCs but had no effect on CD4(+) T-cell infection. We show that blocking of integrins decreases the HIV-1 infection of both mucosal DCs and CD4(+) T cells emigrating from the cervical tissues. These findings may provide the basis of novel microbicidal strategies that may help limit or prevent initial infection of the cervical mucosa, thereby reducing or averting systemic HIV-1 infection. C1 [Tjomsland, Veronica; Ellegard, Rada; Hinkula, Jorma; Larsson, Marie] Linkoping Univ, Dept Clin & Expt Med, Div Mol Virol, S-58185 Linkoping, Sweden. [Kjolhede, Preben; Wodlin, Ninni Borendal] Linkoping Univ, Dept Clin & Expt Med, Div Gynecol, S-58185 Linkoping, Sweden. [Lifson, Jeffrey D.] NCI, SAIC Fredrick, Frederick, MD 21701 USA. RP Larsson, M (reprint author), Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. EM marie.larsson@liu.se OI Hinkula, Jorma/0000-0003-1908-5609 FU Swedish Research Council; Swedish, Physicians Against AIDS research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University hospital research Fund; C ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [AI52731] FX We thank the Biological Products Core of the AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, MD, USA for providing infectious and AT-2 inactivated HIV-1. This work was supported by grants through: Marie Larsson: AI52731, The Swedish Research Council, The Swedish, Physicians Against AIDS research Foundation, The Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linkoping University hospital research Fund, C ALF, and The Swedish Society of Medicine, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E (J.L.). NR 40 TC 7 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2013 VL 43 IS 9 BP 2361 EP 2372 DI 10.1002/eji.201243257 PG 12 WC Immunology SC Immunology GA 263OZ UT WOS:000327819200016 PM 23686382 ER PT J AU Ephrem, A Epstein, AL Stephens, GL Thornton, AM Glass, D Shevach, EM AF Ephrem, Amal Epstein, Alan L. Stephens, Geoffrey L. Thornton, Angela M. Glass, Deborah Shevach, Ethan M. TI Modulation of Treg cells/T effector function by GITR signaling is context-dependent SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Glucocorticoid-induced tumor necrosis factor-related receptor (GITR); Inflammatory bowel disease; Treg cell; T effector cells ID REGULATORY T-CELLS; INDUCED TNF RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; TUMOR-IMMUNITY; IN-VIVO; MICE; ACTIVATION; EXPANSION; COSTIMULATION; ENGAGEMENT AB Treg cells express high levels of the glucocorticoid-induced tumor necrosis factor-related receptor (GITR), while resting conventional T (Tconv) cells express low levels that are increased upon activation. Manipulation of GITR/GITR-Ligand (GITR-L) interactions results in enhancement of immune responses, but it remains unclear whether this enhancement is secondary to costimulation of Tconv cells or to reversal of Treg-cell-mediated suppression. Here, we used a nondepleting Fc-GITR-L and combinations of WT and GITR KO Treg cells and Tconv cells to reexamine the effects of GITR stimulation on each subpopulation in both unmanipulated mice and mice with inflammatory bowel disease. Treatment of mice with Fc-GITR-L resulted in significant expansion of Treg cells and a modest expansion of Tconv cells. When RAG KO mice were reconstituted with Tconv cells alone, GITR-L resulted in Tconv-cell expansion and severe inflammatory bowel disease. The protective effect of Treg cells was lost in the presence of Fc-GITR-L, secondary to death of the Treg cells. When RAG KO mice were reconstituted with Treg cells alone, the transferred cells expanded normally, and Fc-GITR-L treatment resulted in a loss of Foxp3 expression, but the ex-Treg cells did not cause any pathology. The effects of GITR activation are complex and depend on the host environment and the activation state of the Treg cells and T effector cells. C1 [Ephrem, Amal; Stephens, Geoffrey L.; Thornton, Angela M.; Glass, Deborah; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Epstein, Alan L.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM eshevach@Niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX These studies were supported by funds from the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 33 TC 24 Z9 27 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2013 VL 43 IS 9 BP 2421 EP 2429 DI 10.1002/eji.201343451 PG 9 WC Immunology SC Immunology GA 263OZ UT WOS:000327819200021 PM 23722868 ER PT J AU Brenner, RA Taneja, GS Schroeder, TJ Trumble, AC Moyer, PM Louis, GMB AF Brenner, Ruth A. Taneja, Gitanjali S. Schroeder, Thomas J. Trumble, Ann C. Moyer, Patricia M. Louis, Germaine M. Buck TI Unintentional injuries among youth with developmental disabilities in the United States, 2006-2007 SO INTERNATIONAL JOURNAL OF INJURY CONTROL AND SAFETY PROMOTION LA English DT Article DE injury; developmental disability; learning disability ID US CHILDREN; NONFATAL INJURIES; INCREASED RISK; PREVALENCE; IMPACT; CHILDHOOD; DISORDER; PARENTS; HEALTH AB We examined unintentional injury among youth with and without developmental disabilities. Our nationally representative sample included 6369 injured youth, aged 0-17 years, who were seen in one of the 63 US hospital emergency rooms that participated in the National Electronic Injury Surveillance System - All Injury Program (NEISS-AIP) in 2006-2007. Parents or guardians of injured youth were interviewed by telephone after the hospital visit to ascertain disability status. Denominator data were obtained from the National Health Interview Survey. Leading causes of injury were comparable for youth with and without disability. Injury rates (per 100 youth per year) were also comparable [10.4; 95% confidence interval (CI) 7.8, 13.0 and 10.5; 95% CI 8.2, 12.9, for youth with and without disability, respectively]. When examined by specific disability, the rate ratio for youth with learning disabilities versus youth without learning disability was 1.57 (95% CI 1.04, 2.10), which may represent a subgroup for targeted interventions. C1 [Brenner, Ruth A.; Taneja, Gitanjali S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, Rockville, MD 20852 USA. [Schroeder, Thomas J.] US Consumer Prod Safety Commiss, Bethesda, MD 20814 USA. [Trumble, Ann C.; Moyer, Patricia M.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Brenner, RA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, 6100 Execut Blvd,Suite 3A01, Rockville, MD 20852 USA. EM Brennerr@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural NIH HHS; NICHD NIH HHS [Y01 HD006001, Y01 HD006001-02] NR 27 TC 6 Z9 6 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1745-7300 EI 1745-7319 J9 INT J INJ CONTROL SA JI Int. J. Inj. Control Saf. Promot. PD SEP 1 PY 2013 VL 20 IS 3 BP 259 EP 265 DI 10.1080/17457300.2012.696662 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 264WS UT WOS:000327912300008 PM 22757768 ER PT J AU Fredericks, WJ McGarvey, T Wang, HY Zheng, YM Fredericks, NJ Yin, HK Wang, LP Hsiao, W Lee, R Weiss, JS Nickerson, ML Kruth, HS Rauscher, FJ Malkowicz, SB AF Fredericks, William J. McGarvey, Terry Wang, Huiyi Zheng, Yongmu Fredericks, Nathaniel J. Yin, Hankun Wang, Li-Ping Hsiao, Wayland Lee, Rob Weiss, Jayne S. Nickerson, Michael L. Kruth, Howard S. Rauscher, Frank J., III Malkowicz, S. Bruce TI The TERE1 Protein Interacts With Mitochondrial TBL2: Regulation of Trans-Membrane Potential, ROS/RNS and SXR Target Genes SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE TERE1; TBL2; MITOCHONDRIA; LIPID METABOLISM; ROS; SXR TARGET GENES ID BREAST-CANCER CELLS; CARCINOMA-CELLS; NITRIC-OXIDE; BLADDER; UBIAD1; CHOLESTEROL; VITAMIN-K-2; ACTIVATION; RECEPTOR; INHIBITION AB We originally discovered TERE1 as a potential tumor suppressor protein based upon reduced expression in bladder and prostate cancer specimens and growth inhibition of tumor cell lines/xenografts upon ectopic expression. Analysis of TERE1 (aka UBIAD1) has shown it is a prenyltransferase enzyme in the natural bio-synthetic pathways for both vitamin K-2 and COQ10 production and exhibits multiple subcellular localizations including mitochondria, endoplasmic reticulum, and golgi. Vitamin K-2 is involved in mitochondrial electron transport, SXR nuclear hormone receptor signaling and redox cycling: together these functions may form the basis for tumor suppressor function. To gain further insight into mechanisms of growth suppression and enzymatic regulation of TERE1 we isolated TERE1 associated proteins and identified the WD40 repeat, mitochondrial protein TBL2. We examined whether disease specific mutations in TERE1 affected interactions with TBL2 and the role of each protein in altering mitochondrial function, ROS/RNS production and SXR target gene regulation. Biochemical binding assays demonstrated a direct, high affinity interaction between TERE1 and TBL2 proteins; TERE1 was localized to both mitochondrial and non-mitochondrial membranes whereas TBL2 was predominantly mitochondrial; multiple independent single amino acid substitutions in TERE1 which cause a human hereditary corneal disease reduced binding to TBL2 strongly suggesting the relevance of this interaction. Ectopic TERE1 expression elevated mitochondrial trans-membrane potential, oxidative stress, NO production, and activated SXR targets. A TERE1-TBL2 complex likely functions in oxidative/nitrosative stress, lipid metabolism, and SXR signaling pathways in its role as a tumor suppressor. J. Cell. Biochem. 114: 2170-2187, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Fredericks, William J.; Wang, Huiyi; Zheng, Yongmu; Fredericks, Nathaniel J.; Yin, Hankun; Malkowicz, S. Bruce] Univ Penn, Dept Surg, Div Urol, Philadelphia, PA 19104 USA. [Fredericks, William J.; Wang, Huiyi; Zheng, Yongmu; Fredericks, Nathaniel J.; Yin, Hankun; Lee, Rob; Malkowicz, S. Bruce] Vet Affairs Med Ctr Philadelphia, Philadelphia, PA 19104 USA. [McGarvey, Terry] Kirksville Osteopath Med Sch, Dept Anat, Kirksville, MO 63501 USA. [Wang, Li-Ping] Univ Penn, Med Ctr, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hsiao, Wayland] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [Lee, Rob] Univ Penn, Dept Otorhinolaryngol, Philadelphia, PA 19104 USA. [Weiss, Jayne S.] Louisiana State Univ, Dept Ophthalmol, New Orleans, LA USA. [Weiss, Jayne S.] Louisiana State Univ, Ctr Eye, New Orleans, LA 70112 USA. [Nickerson, Michael L.] NCI, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. [Kruth, Howard S.] NIH, Sect Expt Atherosclerosis, Bethesda, MD 20892 USA. [Rauscher, Frank J., III] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Fredericks, WJ (reprint author), VA Med Ctr Philadelphia, Res Bldg 21,Room A418,Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM wjfredericks@verizon.net OI Lee, Robert/0000-0001-5826-6686 FU Veterans Affairs Merit Review; Innisfree Foundation of Bryn Mawr, PA; Castleman Family Fund FX Grant sponsor: Veterans Affairs Merit Review; Grant sponsor: The Innisfree Foundation of Bryn Mawr, PA; Grant sponsor: The Castleman Family Fund. NR 50 TC 11 Z9 11 U1 0 U2 9 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 SEP PY 2013 VL 114 IS 9 BP 2170 EP 2187 DI 10.1002/jcb.24567 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 261YA UT WOS:000327699500024 PM 23564352 ER PT J AU Piao, HL Kuan, CT Chandramohan, V Keir, ST Pegram, CN Bao, XH Mansson, JE Pastan, IH Bigner, DD AF Piao, Hailan Kuan, Chien-Tsun Chandramohan, Vidya Keir, Stephen T. Pegram, Charles N. Bao, Xuhui Mansson, Jan-Eric Pastan, Ira H. Bigner, Darell D. TI Affinity-matured recombinant immunotoxin targeting gangliosides 3 '-isoLM1 and 3 ', 6 '-isoLD1 on malignant gliomas SO MABS LA English DT Article DE ganglioside; recombinant immunotoxin; single-chain variable fragment; glioblastoma; affinity maturation ID SINGLE-CHAIN IMMUNOTOXIN; IN-VITRO; MONOCLONAL-ANTIBODIES; TUMORS; BRAIN; EXPRESSION; GROWTH; GD3; MENINGITIS; XENOGRAFTS AB About 60 percent of glioblastomas highly express the gangliosides 3-isoLM1 and 3,6-isoLD1 on the cell surface, providing ideal targets for brain tumor immunotherapy. A novel recombinant immunotoxin, DmAb14m-(scFv)-PE38KDEL (DmAb14m-IT), specific for the gangliosides 3-isoLM1 and 3,6-isoLD1, was constructed with improved affinity and increased cytotoxicity for immunotherapeutic targeting of glioblastoma. We isolated an scFv parental clone from a previously established murine hybridoma, DmAb14, that is specific to both 3-isoLM1 and 3,6-isoLD1. We then performed in vitro affinity maturation by CDR hotspot random mutagenesis. The binding affinity and specificity of affinity-matured DmAb14m-IT were measured by surface-plasmon resonance, flow cytometry, and immunohistochemical analysis. In vitro cytotoxicity of DmAb14m-IT was measured by protein synthesis inhibition and cell death assays in human cell lines expressing gangliosides 3-isoLM1 and 3,6-isoLD1 (D54MG and D336MG) and xenograft-derived cells (D2224MG). As a result, the K-D of DmAb14m-IT for gangliosides 3-isoLM1 and 3,6-isoLD1 was 2.6 x 10(-9)M. Also, DmAb14m-IT showed a significantly higher internalization rate in cells expressing 3-isoLM1 and 3,6-isoLD1. The DmAb14m-IT IC50 was 80 ng/mL (1194 pM) on the D54MG cell line, 5 ng/ml (75 pM) on the D336MG cell line, and 0.5 ng/ml (7.5 pM) on the D2224MG xenograft-derived cells. There was no cytotoxicity on ganglioside-negative HEK293 cells. Immunohistochemical analysis confirmed the specific apparent affinity of DmAb14m-IT with 3-isoLM1 and 3,6-isoLD1. In conclusion, DmAb14m-IT showed specific binding affinity, a significantly high internalization rate, and selective cytotoxicity on glioma cell lines and xenograft-derived cells expressing 3-isoLM1 and 3,6-isoLD1, thereby displaying robust therapeutic potential for testing the antitumor efficacy of DmAb14m-IT at the preclinical level and eventually in the clinical setting. C1 [Piao, Hailan; Kuan, Chien-Tsun; Chandramohan, Vidya; Keir, Stephen T.; Pegram, Charles N.; Bao, Xuhui; Bigner, Darell D.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27705 USA. [Piao, Hailan; Kuan, Chien-Tsun; Chandramohan, Vidya; Keir, Stephen T.; Pegram, Charles N.; Bao, Xuhui; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Bao, Xuhui] Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200433, Peoples R China. [Mansson, Jan-Eric] Univ Gothenburg, Sahlgren Univ Hosp Molndal, Sahlgren Acad, Inst Neurosci & Physiol,Dept Psychiat & Neurochem, Molndal, Sweden. [Pastan, Ira H.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bigner, DD (reprint author), Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27705 USA. EM darell.bigner@duke.edu FU NIH, NINDS [P50 NS020023]; NIH, NCI SPORE [P50 CA108786]; NIH, NCI [R37 CA 011898] FX Thanks are due to Dr Carol J Wikstrand of the Department of Microbiology at the Saba University School of Medicine for the established DmAb14 hybridoma, as well as to Dr Michael Zalutsky of the Medical Physics Program and Biomedical Engineering at Duke University, for radio-labeling the DmAb14m-IT. We also thank Scott Szafranski and Ling Wang for technical support. This work was supported by the following NIH grants: NINDS grant P50 NS020023, NCI SPORE grant P50 CA108786, and NCI Merit Award grant R37 CA 011898. NR 33 TC 3 Z9 4 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD SEP 1 PY 2013 VL 5 IS 5 BP 748 EP 762 DI 10.4161/mabs.25860 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 260PS UT WOS:000327607400017 PM 23924792 ER PT J AU Barak, B Shvarts-Serebro, I Modai, S Gilam, A Okun, E Michaelson, DM Mattson, MP Shomron, N Ashery, U AF Barak, B. Shvarts-Serebro, I. Modai, S. Gilam, A. Okun, E. Michaelson, D. M. Mattson, M. P. Shomron, N. Ashery, U. TI Opposing actions of environmental enrichment and Alzheimer's disease on the expression of hippocampal microRNAs in mouse models SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; enriched environment; hippocampus; microRNA; synaptic plasticity; tomosyn ID LONG-TERM POTENTIATION; NEUROTROPHIC FACTOR; A-BETA; SYNAPTIC PLASTICITY; TRANSGENIC MICE; ALPHA-SYNUCLEIN; SPATIAL MEMORY; NEUROTRANSMITTER RELEASE; COGNITIVE IMPAIRMENT; SYNAPTOPHYSIN LEVELS AB Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although there are no drugs that modify the disease process, exposure to an enriched environment (EE) can slow the disease progression. Here, we characterize the effects of AD and EE on the post-transcriptional regulators, microRNAs (miRNAs), which may contribute to the detrimental and beneficial effects of AD and EE, respectively, on synaptic plasticity-related proteins and AD pathology. We found for the first time miRNAs that were inversely regulated in AD and EE, and may affect synaptic proteins and modulators, molecular factors associated with AD pathology, and survival and neuroprotective factors. MiRNAs that were upregulated only in 3xTgAD mice model of AD compared with their control mice were localized to synapses, predicted to downregulate essential synaptic proteins and are highly associated with regulating apoptosis, AD-associated processes and axon guidance. Studying the progressive change in miRNAs modulation during aging of 3xTgAD mice, we identified miRNAs that were regulated in earlier stages of AD, suggesting them as potential AD biomarkers. Last, we characterized AD- and EE-related effects in the mouse hippocampus on tomosyn protein levels, an inhibitor of the synaptic transmission machinery. While EE reduced tomosyn levels, tomosyn levels were increased in old 3xTgAD mice, suggesting a role for tomosyn in the impairment of synaptic transmission in AD. Interestingly, we found that miR-325 regulates the expression levels of tomosyn as demonstrated by a luciferase reporter assay, and that miR-325 was downregulated in AD and upregulated following EE. These findings improve our understanding of the molecular and cellular processes in AD pathology, following EE, and the interplay between the two processes, and open new avenues for the studies of understanding and controlling AD. C1 [Barak, B.; Shvarts-Serebro, I.; Michaelson, D. M.; Ashery, U.] Tel Aviv Univ, Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Barak, B.; Shvarts-Serebro, I.; Michaelson, D. M.; Shomron, N.; Ashery, U.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Modai, S.; Gilam, A.; Shomron, N.] Tel Aviv Univ, Sackler Fac Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. [Okun, E.] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. [Okun, E.] Bar Ilan Univ, Gonda Goldschmidt Multidisciplinary Brain Res Ctr, Ramat Gan, Israel. [Mattson, M. P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ashery, U (reprint author), Tel Aviv Univ, Fac Life Sci, Dept Neurobiol, Sherman Bldg Room 719, IL-69978 Tel Aviv, Israel. EM uria@post.tau.ac.il RI okun, eitan/K-1314-2016 OI okun, eitan/0000-0001-8474-1487 FU Intramural Research Program of the National Institute on Aging, NIH; Israel Science Foundation [1211/07, 730/11]; BSF [2009279]; Boehringer Ingelheim Fonds; Israel Cancer Association; Wolfson Family Charitable Fund; Claire and Amedee Maratier Institute for the Study of Blindness and Visual Disorders; I-CORE Program of the Planning and Budgeting Committee, The Israel Science Foundation [41/11] FX We would like to thank Mr Shahar Alon for comments on the manuscript and Dr Haim Belinson, Professor Gideon Rechavi and Mr Dan Dominissini for technical help. This research was supported, in part, by the Intramural Research Program of the National Institute on Aging, NIH, the Israel Science Foundation (Grant no. 1211/07 and 730/11; UA) and the BSF (Grant no. 2009279; UA) and by travel grant from Boehringer Ingelheim Fonds (awarded to Dr Boaz Barak). The Shomron laboratory is supported by the Israel Cancer Association; Wolfson Family Charitable Fund; Claire and Amedee Maratier Institute for the Study of Blindness and Visual Disorders; I-CORE Program of the Planning and Budgeting Committee, The Israel Science Foundation (grant number 41/11). NR 117 TC 17 Z9 17 U1 1 U2 4 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 SEP PY 2013 VL 3 AR e304 DI 10.1038/tp.2013.77 PG 13 WC Psychiatry SC Psychiatry GA 258PX UT WOS:000327472300007 PM 24022509 ER PT J AU Mercken, EM Majounie, E Ding, JH Guo, R Kim, J Bernier, M Mattison, J Cookson, MR Gorospe, M de Cabo, R Abdelmohsen, K AF Mercken, Evi M. Majounie, Elisa Ding, Jinhui Guo, Rong Kim, Jiyoung Bernier, Michel Mattison, Julie Cookson, Mark R. Gorospe, Myriam de Cabo, Rafael Abdelmohsen, Kotb TI Age-associated miRNA Alterations in Skeletal Muscle from Rhesus Monkeys reversed by caloric restriction SO AGING-US LA English DT Article DE gene expression; posttranscriptional gene regulation; muscle aging; muscle diseases ID GENE-EXPRESSION; MICRORNA EXPRESSION; TRANSCRIPTION FACTORS; IV COLLAGEN; CANCER; SENESCENCE; SARCOPENIA; IMPACT; MICE; INFLAMMATION AB The levels of microRNAs (miRNAs) are altered under different conditions such as cancer, senescence, and aging. Here, we have identified differentially expressed miRNAs in skeletal muscle from young and old rhesus monkeys using RNA sequencing. In old muscle, several miRNAs were upregulated, including miR-451, miR-144, miR-18a and miR-15a, while a few miRNAs were downregulated, including miR-181a and miR-181b. A number of novel miRNAs were also identified, particularly in old muscle. We also examined the impact of caloric restriction (CR) on miRNA abundance by reverse transcription (RT) followed by real-time, quantitative (q)PCR analysis and found that CR rescued the levels of miR-181b and chr1:205580546, and also dampened the age-induced increase in miR-451 and miR-144 levels. Our results reveal that there are changes in expression of known and novel miRNAs with skeletal muscle aging and that CR may reverse some of these changes to a younger phenotype. C1 [Mercken, Evi M.; Bernier, Michel; Mattison, Julie; de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Majounie, Elisa; Ding, Jinhui; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Guo, Rong; Kim, Jiyoung; Gorospe, Myriam; Abdelmohsen, Kotb] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institute on Aging, Intramural Research Program, National Institutes of Health FX This research was supported in full by the National Institute on Aging, Intramural Research Program, National Institutes of Health. We thank N Noren Hooten (NIA, NIH) for helpful advice. We appreciate the animal care staff and technicians at the NIH Animal Center and the Oregon National Primate Research Center. NR 53 TC 31 Z9 31 U1 0 U2 9 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 SEP PY 2013 VL 5 IS 9 BP 692 EP 703 PG 12 WC Cell Biology SC Cell Biology GA 258RN UT WOS:000327476500008 PM 24036467 ER PT J AU Akilzhanova, A Nurkina, Z Momynaliev, K Ramanculov, E Zhumadilov, Z Rakhypbekov, T Hayashida, N Nakashima, M Takamura, N AF Akilzhanova, Ainur Nurkina, Zhannur Momynaliev, Kuvat Ramanculov, Erlan Zhumadilov, Zhaxybai Rakhypbekov, Tolebay Hayashida, Naomi Nakashima, Masahiro Takamura, Noboru TI Genetic Profile and Determinants of Homocysteine Levels in Kazakhstan Patients with Breast Cancer SO ANTICANCER RESEARCH LA English DT Article DE Breast cancer; folate; homocysteine; MTHFR; FTO; polymorphism; Kazakhstan ID METHYLENETETRAHYDROFOLATE-REDUCTASE POLYMORPHISM; DIETARY-FOLATE INTAKE; ONE-CARBON METABOLISM; MTHFR POLYMORPHISMS; C677T POLYMORPHISM; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; CHINESE POPULATION; DNA METHYLATION; HDL-CHOLESTEROL; NO ASSOCIATION AB Aim: To analyze associations between homocysteine level, MTHFR and FTO rs1477196 polymorphisms and folate status in patients with breast cancer (BC) in order to clarify determinants of hyperhomocysteinemia. Patients and Methods: The study included 315 BC cases and 604 controls. Results: The MTHFRC677T genotype was associated with an increased incidence of BC [Odds ratio (OR)=1.71; 95% Confidential interval (CI)=1.21-2.43]. The MTHFR A1298C genotype was associated with a decreased risk of BC [OR=0.68; 95% CI: 0.49-0.95]. The homocysteine level was not associated with either MTHFR C677T or A1298C, nor with FTO rs1477196, but was inversely correlated with folate status in cancer cases (p<0.0001) and tended to be higher in patients with the MTHFR 677TT genotype. The folate level (p<0.0005) was an independent predictor of hyper-homocysteinemia in patients with BC. Conclusion: These results suggest an important role of homocysteine in breast tumorigenesis. Further studies are warranted to investigate how combined MTHFR genotypes exert their effects on cancer susceptibility. C1 [Akilzhanova, Ainur; Hayashida, Naomi; Nakashima, Masahiro; Takamura, Noboru] Nagasaki Univ, Atom Bomb Dis Inst, Dept Global Hlth Med & Welf, Nagasaki 8528523, Japan. [Akilzhanova, Ainur; Nurkina, Zhannur; Zhumadilov, Zhaxybai] Nazarbayev Univ, Ctr Life Sci, Dept Genom & Personalised Med, Astana, Kazakhstan. [Akilzhanova, Ainur; Momynaliev, Kuvat; Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. [Rakhypbekov, Tolebay] Semey State Med Univ, Ctr Oncol, Semey, Kazakhstan. RP Takamura, N (reprint author), Nagasaki Univ, Atom Bomb Dis Inst, Dept Global Hlth Med & Welf, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. EM takamura@nagasaki-u.ac.jp FU Japan Society for the Promotion of Science FX The Authors express their gratitude to all the study participants. They are thankful to Dr. I. Shtephanov, Dr. Z. Zhumatova, and Dr. G. Akilzhanova for their help in sample collection. This study was supported by a Grant-in-Aid from the Japan Society for the Promotion of Science. NR 56 TC 8 Z9 8 U1 1 U2 7 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD SEP PY 2013 VL 33 IS 9 BP 4049 EP 4059 PG 11 WC Oncology SC Oncology GA 253AY UT WOS:000327055200072 PM 24023349 ER PT J AU Ierano, C Chakraborty, AR Nicolae, A Bahr, JC Zhan, ZR Pittaluga, S Bates, SE Robey, RW AF Ierano, Caterina Chakraborty, Arup R. Nicolae, Alina Bahr, Julian C. Zhan, Zhirong Pittaluga, Stefania Bates, Susan E. Robey, Robert W. TI Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors SO CELL CYCLE LA English DT Article ID T-CELL LYMPHOMA; PROAPOPTOTIC GENE BAX; MICROSATELLITE INSTABILITY; DEPSIPEPTIDE FR901228; THERAPEUTIC ACTIVITIES; FRAMESHIFT MUTATIONS; LEUKEMIA-CELLS; CANCER-THERAPY; OPEN-LABEL; PHASE-I C1 [Ierano, Caterina; Chakraborty, Arup R.; Bahr, Julian C.; Zhan, Zhirong; Bates, Susan E.; Robey, Robert W.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Nicolae, Alina; Pittaluga, Stefania] NCI, Lab Pathol, Bethesda, MD 20892 USA. RP Robey, RW (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI Ierano, Caterina/K-1676-2016 OI Ierano, Caterina/0000-0003-3138-1873 FU CRADA; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.; This work was supported in part by a CRADA between the NCI and Celgene Corporation. NR 57 TC 8 Z9 8 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2013 VL 12 IS 17 BP 2829 EP 2838 PG 10 WC Cell Biology SC Cell Biology GA 258CJ UT WOS:000327436300021 PM 23966164 ER PT J AU Wang, NY Meng, F Chen, L Madhavan, S Clarke, R Hoffman, EP Xuan, JH Wang, Y AF Wang, Niya Meng, Fan Chen, Li Madhavan, Subha Clarke, Robert Hoffman, Eric P. Xuan, Jianhua Wang, Yue TI The CAM Software for Nonnegative Blind Source Separation in R-Java SO JOURNAL OF MACHINE LEARNING RESEARCH LA English DT Article DE convex analysis of mixtures; blind source separation; affinity propagation clustering; compartment modeling; information-based model selection ID MATRIX FACTORIZATION; DYNAMIC CONTRAST AB We describe a R-Java CAM (convex analysis of mixtures) package that provides comprehensive analytic functions and a graphic user interface (GUI) for blindly separating mixed nonnegative sources. This open-source multiplatform software implements recent and classic algorithms in the literature including Chan et al. (2008), Wang et al. (2010), Chen et al. (2011a) and Chen et al. (2011b). The CAM package offers several attractive features: (1) instead of using proprietary MATLAB, its analytic functions are written in R, which makes the codes more portable and easier to modify; (2) besides producing and plotting results in R, it also provides a Java GUI for automatic progress update and convenient visual monitoring; (3) multi-thread interactions between the R and Java modules are driven and integrated by a Java GUI, assuring that the whole CAM software runs responsively; (4) the package offers a simple mechanism to allow others to plug-in additional R-functions. C1 [Wang, Niya; Meng, Fan; Xuan, Jianhua; Wang, Yue] Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Chen, Li] NCI, Pediat Oncol Branch, NIH, Gaithersburg, MD 20850 USA. [Madhavan, Subha] Georgetown Univ, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [Clarke, Robert] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Hoffman, Eric P.] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. RP Wang, NY (reprint author), Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. EM WANGNY@VT.EDU; MENGFAN@VT.EDU; CHENL14@MAIL.NIH.GOV; SM696@GEORGETOWN.EDU; CLARKER@GEORGETOWN.EDU; EHOFFMAN@CNMCRESEARCH.ORG; XUAN@VT.EDU; YUEWANG@VT.EDU RI Clarke, Robert/A-6485-2008 OI Clarke, Robert/0000-0002-9278-0854 FU US National Institutes of Health [CA109872, CA 100970, NS29525] FX We have developed a R-Java CAM package for blindly separating mixed nonnegative sources. The open-source cross-platform software is easy-to-use and effective, validated in several real-world applications leading to plausible scientific discoveries. The software is freely downloadable from http://mloss.org/software/view/437/. We intend to maintain and support this package in the future. This work was supported in part by the US National Institutes of Health under Grants CA109872, CA 100970, and NS29525. We thank T.H. Chan, F.Y. Wang, Y. Zhu, and D.J. Miller for technical discussions. NR 12 TC 3 Z9 3 U1 0 U2 1 PU MICROTOME PUBL PI BROOKLINE PA 31 GIBBS ST, BROOKLINE, MA 02446 USA SN 1532-4435 J9 J MACH LEARN RES JI J. Mach. Learn. Res. PD SEP PY 2013 VL 14 BP 2899 EP 2903 PG 5 WC Automation & Control Systems; Computer Science, Artificial Intelligence SC Automation & Control Systems; Computer Science GA 252LW UT WOS:000327007400013 ER PT J AU Di, X Zhang, GF Zhang, YQ Takeda, K Rosado, LAR Zhang, BL AF Di, Xu Zhang, Guofeng Zhang, Yaqin Takeda, Kazuyo Rosado, Leslie A. Rivera Zhang, Baolin TI Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5 SO ONCOTARGET LA English DT Article DE TRAIL resistance; basal autophagosomes; death receptors; cell surface expression ID TUMOR-NECROSIS-FACTOR; PANCREATIC DUCTAL ADENOCARCINOMA; INDUCED APOPTOSIS; CROSS-PRESENTATION; OVARIAN-CANCER; LIGAND TRAIL; LUNG-CANCER; PHASE-I; INHIBITION; SURVIVAL AB TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. We have previously shown that deficiency of DR4 and DR5 on the surface membrane is a critical mechanism of cancer cell resistance to the recombinant human TRAIL and its receptor agonistic antibodies, which are being evaluated clinically for treating cancers. In certain cancer cells, DR4 and DR5 were found to be mislocalized in intracellular compartments yet to be characterized. Here, we report a novel role of autophagy in the regulation of dynamics of TRAIL death receptors. We first assessed basal levels of autophagosomes in a panel of 11 breast cancer cell lines using complementary approaches (LC3 immunoblotting, RFP-LC3 fluorescence microscopy, and electron microscopy). We found high levels of basal autophagosomes in TRAIL resistant breast cancer cell lines (e.g. BT474 and AU565) and relevant mouse xenograft models under nutrition-rich conditions. Notably, DR4 and DR5 co-localized with LC3-II in the autophagosomes of TRAIL-resistant cells. Disruption of basal autophagosomes successfully restored the surface expression of the death receptors which was accompanied by sensitization of TRAIL-resistant cells to TRAIL induced apoptosis. By contrast, TRAIL-sensitive cell lines (MDA-MB-231) are characterized by high levels of surface DR4/DR5 and an absence of basal autophagosomes. Inhibition of lysosomal activity induced an accumulation of autophagosomes and a decrease in surface DR4 and DR5, and the cells became less sensitive to TRAIL-induced apoptosis. These findings demonstrate a novel role for the basal autophagosomes in the regulation of TRAIL death receptors. Further studies are warranted to explore the possibility of using autophagosome markers such as LC3-II/LC3-I ratios for prediction of tumor resistance to TRAIL related therapies. The results also provide a rationale for future non-clinical and clinical studies testing TRAIL agonists in combination with agents that directly inhibit autophagosome assembly. C1 [Di, Xu; Zhang, Yaqin; Rosado, Leslie A. Rivera; Zhang, Baolin] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Takeda, Kazuyo] US FDA, Confocal Microscopy Core Facil, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Zhang, BL (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM Baolin.Zhang@fda.hhs.gov FU FDA Critical Path Initiative FX This work was supported by the FDA Critical Path Initiative funding. NR 62 TC 25 Z9 27 U1 0 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 SEP PY 2013 VL 4 IS 9 BP 1349 EP 1364 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 257QJ UT WOS:000327400300007 PM 23988408 ER PT J AU Hoenen, T Groseth, A Callison, J Takada, A Feldmann, H AF Hoenen, Thomas Groseth, Allison Callison, Julie Takada, Ayato Feldmann, Heinz TI A novel Ebola virus expressing luciferase allows for rapid and quantitative testing of antivirals SO ANTIVIRAL RESEARCH LA English DT Article DE Ebola virus; Luciferase; Firefly; Reverse genetics; Antiviral screening; High-throughput screening ID POSTEXPOSURE PROTECTION; RNA INTERFERENCE; IDENTIFICATION; ASSAYS; REPLICATION; VALIDATION; CHALLENGE; LIGHT AB Ebola virus (EBOV) causes a severe hemorrhagic fever with case fatality rates of up to 90%, for which no antiviral therapies are available. Antiviral screening is hampered by the fact that development of cytopathic effect, the easiest means to detect infection with wild-type EBOV, is relatively slow. To overcome this problem we generated a recombinant EBOV carrying a luciferase reporter. Using this virus we show that EBOV entry is rapid, with viral protein expression detectable within 2 h after infection. Further, luminescence-based assays were developed to allow highly sensitive titer determination within 48 h. As a proof-of-concept for its utility in antiviral screening we used this virus to assess neutralizing antibodies and siRNAs, with significantly faster screening times than currently available wild-type or recombinant viruses. The availability of this recombinant virus will allow for more rapid and quantitative evaluation of antivirals against EBOV, as well as the study of details of the EBOV life cycle. Published by Elsevier B.V. C1 [Hoenen, Thomas; Groseth, Allison; Callison, Julie; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Sapporo, Hokkaido 060, Japan. RP Hoenen, T (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM thomas.hoenen@nih.gov; feldmannh@mail.nih.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 20 TC 17 Z9 17 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD SEP PY 2013 VL 99 IS 3 BP 207 EP 213 DI 10.1016/j.antivira1.2013.05.017 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 253RZ UT WOS:000327108300002 PM 23751367 ER PT J AU Georgiev, IS Joyce, MG Zhou, TQ Kwong, PD AF Georgiev, Ivelin S. Joyce, M. Gordon Zhou, Tongqing Kwong, Peter D. TI Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE antibody template; B-cell ontogeny; gp120 envelope glycoprotein; HIV-1 vaccine; structure-based design ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODY; ENVELOPE GLYCOPROTEIN TRIMER; HUMAN MONOCLONAL-ANTIBODY; HIV-1 ENV TRIMERS; B-CELL RESPONSES; CD4 BINDING-SITE; STRUCTURAL BASIS; GP120 CORE; IMMUNOGEN DESIGN AB Purpose of reviewThe HIV-1 site of binding for the CD4 receptor has long attracted attention as a potential supersite of vulnerability to antibody-mediated neutralization. We review recent findings related to effective CD4-binding site antibodies isolated from HIV-1-infected individuals and discuss implications for immunogen design.Recent findingsHighly effective CD4-binding site antibodies such as antibody VRC01 have the ability to neutralize over 90% of circulating HIV-1 strains. Sequence and structural analysis of these antibodies from over half a dozen HIV-1-infected donors reveals remarkable similarity in their ontogenies and their modes of recognition, all of which involve mimicry of CD4 receptor by antibody-heavy chain. Meanwhile, other effective CD4-binding site neutralizers such as antibody CH103 have been shown to utilize a different mode of recognition, with next-generation sequencing of both virus and antibody suggesting co-evolution to drive the development of antibody-neutralization breadth.SummaryThe nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. Although barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site antibodies. C1 [Georgiev, Ivelin S.; Joyce, M. Gordon; Zhou, Tongqing; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 85 TC 14 Z9 14 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2013 VL 8 IS 5 BP 382 EP 392 DI 10.1097/COH.0b013e328363a90e PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 248US UT WOS:000326730500004 PM 23924998 ER PT J AU Mofenson, LM AF Mofenson, Lynne M. TI Prevention of mother-to-child HIV transmission: can we meet the goal of global elimination of new pediatric infections? SO CURRENT OPINION IN HIV AND AIDS LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; PERINATAL TRANSMISSION; UNITED-STATES; GENERATION; HEALTH; ZIDOVUDINE; BORN C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Rockville, MD 20852 USA. RP Mofenson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. EM LM65D@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 NR 32 TC 3 Z9 3 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD SEP PY 2013 VL 8 IS 5 BP 443 EP 446 DI 10.1097/COH.0b013e328363d280 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 248US UT WOS:000326730500011 PM 23872612 ER PT J AU Anthony, SJ Epstein, JH Murray, KA Navarrete-Macias, I Zambrana-Torrelio, CM Solovyov, A Ojeda-Flores, R Arrigo, NC Islam, A Khan, SA Hosseini, P Bogich, TL Olival, KJ Sanchez-Leon, MD Karesh, WB Goldstein, T Luby, SP Morse, SS Mazet, JAK Daszak, P Lipkin, WI AF Anthony, Simon J. Epstein, Jonathan H. Murray, Kris A. Navarrete-Macias, Isamara Zambrana-Torrelio, Carlos M. Solovyov, Alexander Ojeda-Flores, Rafael Arrigo, Nicole C. Islam, Ariful Khan, Shahneaz Ali Hosseini, Parviez Bogich, Tiffany L. Olival, Kevin J. Sanchez-Leon, Maria D. Karesh, William B. Goldstein, Tracey Luby, Stephen P. Morse, Stephen S. Mazet, Jonna A. K. Daszak, Peter Lipkin, W. Ian TI A Strategy To Estimate Unknown Viral Diversity in Mammals SO MBIO LA English DT Article ID CONSENSUS PRIMER PCR; NIPAH VIRUS; HUMAN CYTOMEGALOVIRUS; INFECTIOUS-DISEASES; SPECIES RICHNESS; TIOMAN-VIRUS; FRUIT BATS; RECOMBINATION; DISCOVERY; OUTBREAK AB The majority of emerging zoonoses originate in wildlife, and many are caused by viruses. However, there are no rigorous estimates of total viral diversity (here termed "virodiversity") for any wildlife species, despite the utility of this to future surveillance and control of emerging zoonoses. In this case study, we repeatedly sampled a mammalian wildlife host known to harbor emerging zoonotic pathogens (the Indian Flying Fox, Pteropus giganteus) and used PCR with degenerate viral family-level primers to discover and analyze the occurrence patterns of 55 viruses from nine viral families. We then adapted statistical techniques used to estimate biodiversity in vertebrates and plants and estimated the total viral richness of these nine families in P. giganteus to be 58 viruses. Our analyses demonstrate proof-of-concept of a strategy for estimating viral richness and provide the first statistically supported estimate of the number of undiscovered viruses in a mammalian host. We used a simple extrapolation to estimate that there are a minimum of 320,000 mammalian viruses awaiting discovery within these nine families, assuming all species harbor a similar number of viruses, with minimal turnover between host species. We estimate the cost of discovering these viruses to be similar to$ 6.3 billion (or similar to$ 1.4 billion for 85% of the total diversity), which if annualized over a 10-year study time frame would represent a small fraction of the cost of many pandemic zoonoses. IMPORTANCE Recent years have seen a dramatic increase in viral discovery efforts. However, most lack rigorous systematic design, which limits our ability to understand viral diversity and its ecological drivers and reduces their value to public health intervention. Here, we present a new framework for the discovery of novel viruses in wildlife and use it to make the first-ever estimate of the number of viruses that exist in a mammalian host. As pathogens continue to emerge from wildlife, this estimate allows us to put preliminary bounds around the potential size of the total zoonotic pool and facilitates a better understanding of where best to allocate resources for the subsequent discovery of global viral diversity. C1 [Anthony, Simon J.; Navarrete-Macias, Isamara; Solovyov, Alexander; Arrigo, Nicole C.; Sanchez-Leon, Maria D.; Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10027 USA. [Anthony, Simon J.; Epstein, Jonathan H.; Murray, Kris A.; Zambrana-Torrelio, Carlos M.; Islam, Ariful; Hosseini, Parviez; Olival, Kevin J.; Sanchez-Leon, Maria D.; Karesh, William B.; Daszak, Peter] EcoHlth Alliance, New York, NY USA. [Ojeda-Flores, Rafael] Univ Nacl Autonoma Mexico, Fac Med Vet & Zootecn, Mexico City 04510, DF, Mexico. [Khan, Shahneaz Ali] Chittagong Vet & Anim Sci Univ, Chittagong, Bangladesh. [Bogich, Tiffany L.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Bogich, Tiffany L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Goldstein, Tracey; Morse, Stephen S.; Mazet, Jonna A. K.] Univ Calif Davis, Hlth Inst & Wildlife Hlth Ctr 1, Davis, CA 95616 USA. [Luby, Stephen P.] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Morse, Stephen S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Anthony, SJ (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10027 USA. EM sja2127@columbia.edu; daszak@ecohealthalliance.org OI Luby, Stephen/0000-0001-5385-899X FU United States Agency for International Development (USAID) [GHN-A-OO-09-00010-00]; NIAID [R01-AI079231]; NIH/NSF Ecology and Evolution of Infectious Diseases award from the Fogarty International Center [R01TW005869, K08AI067549, NIH-AI57158] FX Weacknowledge funding from the United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT project, cooperative agreement number GHN-A-OO-09-00010-00, an NIAID nonbiodefense Emerging Infectious Disease Research Opportunities award (R01-AI079231 [P.D.]), an NIH/NSF Ecology and Evolution of Infectious Diseases award from the Fogarty International Center (R01TW005869 [P.D.]), K08AI067549 (J.H.E.), and NIH-AI57158 (W.I.L.). NR 64 TC 56 Z9 56 U1 2 U2 59 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2013 VL 4 IS 5 AR e00598-13 DI 10.1128/mBio.00598-13 PG 15 WC Microbiology SC Microbiology GA 250UQ UT WOS:000326881800020 PM 24003179 ER PT J AU Hall, MD Knowles, NJ Wadsworth, J Rambaut, A Woolhouse, MEJ AF Hall, Matthew D. Knowles, Nick J. Wadsworth, Jemma Rambaut, Andrew Woolhouse, Mark E. J. TI Reconstructing Geographical Movements and Host Species Transitions of Foot-and-Mouth Disease Virus Serotype SAT 2 SO MBIO LA English DT Article ID SUB-SAHARAN AFRICA; IMPALA AEPYCEROS-MELAMPUS; KRUGER-NATIONAL-PARK; SOUTH-AFRICA; MOLECULAR EPIDEMIOLOGY; POPULATION-DYNAMICS; ADAMAWA PROVINCE; MIDDLE-EAST; EVOLUTION; EGYPT AB Of the three foot-and-mouth-disease virus SAT serotypes mainly confined to sub-Saharan Africa, SAT 2 is the strain most often recorded in domestic animals and has caused outbreaks in North Africa and the Middle East six times in the last 25 years, with three apparently separate events occurring in 2012. This study updates the picture of SAT 2 phylogenetics by using all available sequences for the VP1 section of the genome available at the time of writing and uses phylogeographic methods to trace the origin of all outbreaks occurring north of the Sahara since 1990 and identify patterns of spread among countries of endemicity. Transitions between different host species are also enumerated. Outbreaks in North Africa appear to have origins in countries immediately south of the Sahara, whereas those in the Middle East are more often from East Africa. The results of the analysis of spread within sub-Saharan Africa are consistent with it being driven by relatively short-distance movements of animals across national borders, and the analysis of host species transitions supports the role of the African buffalo (Syncerus caffer) as an important natural reservoir. IMPORTANCE Foot-and-mouth disease virus is a livestock pathogen of major economic importance, with seven distinct serotypes occurring globally. The SAT 2 serotype, endemic in sub-Saharan Africa, has caused a number of outbreaks in North Africa and the Middle East during the last decades, including three separate incidents in 2012. A comprehensive analysis of all available RNA sequences for SAT 2 has not been published for some years. In this work, we performed this analysis using all previously published sequences and 49 newly determined examples. We also used phylogenetic methods to infer the source country for all outbreaks occurring outside sub-Saharan Africa since 1990 and to reconstruct the spread of viral lineages between countries where it is endemic and movements between different host species. C1 [Hall, Matthew D.; Rambaut, Andrew; Woolhouse, Mark E. J.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Hall, Matthew D.; Rambaut, Andrew; Woolhouse, Mark E. J.] Univ Edinburgh, Ctr Immu Infect & Evolut, Edinburgh, Midlothian, Scotland. [Knowles, Nick J.; Wadsworth, Jemma] Pirbright Inst, Surrey, England. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Hall, MD (reprint author), Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. EM m.d.hall@sms.ed.ac.uk RI Institute, Pirbright/K-4476-2014; OI Rambaut, Andrew/0000-0003-4337-3707 FU Department for Environment; Food and Rural Affairs (Defra). United Kingdom [SE2939, SE2940] FX M.D.H.was supported by a Ph.D.studentship from the Scottish Government-funded EPIC program.N.J.K.and J.W.were supported by funding from the Department for Environment. Food and Rural Affairs (Defra). United Kingdom (contract no.SE2939 and SE2940). NR 37 TC 13 Z9 13 U1 2 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2013 VL 4 IS 5 AR e00591-13 DI 10.1128/mBio.00591-13 PG 10 WC Microbiology SC Microbiology GA 250UQ UT WOS:000326881800018 PM 24149511 ER PT J AU Kobayashi, SD DeLeo, FR AF Kobayashi, Scott D. DeLeo, Frank R. TI Staphylococcus aureus Protein A Promotes Immune Suppression SO MBIO LA English DT Editorial Material ID UNITED-STATES; INFECTIONS; VACCINE; SUPERANTIGEN AB Staphylococcus aureus is a prominent cause of human infections worldwide and is notorious for its ability to acquire resistance to antibiotics. Methicillin-resistant S. aureus (MRSA), in particular, is endemic in hospitals and is the most frequent cause of community-associated bacterial infections in the United States. Inasmuch as treatment options for severe MRSA infections are limited, there is need for a vaccine that protects against such infections. However, recent efforts to generate a staphylococcal vaccine have met with little success in human clinical trials. These failures are somewhat puzzling, since the vaccine antigens tested promote opsonophagocytosis in vitro and confer protection in animal infection models. One possibility is that the pathogen inhibits (and/or fails to elicit) the development of protective immunity in humans. Indeed, S. aureus produces numerous molecules that can potentially promote immune evasion, including protein A (SpA), an immunoglobulin (Ig)-binding protein present on the bacterial surface and freely secreted into the extracellular environment. SpA binds the Fc region of antibody and the Fab regions of the B-cell receptor, processes that are known to block opsonophagocytosis and cause B-cell death in vitro. In a recent study, Falugi et al. [F. Falugi, H. K. Kim, D. M. Missiakas, and O. Schneewind, mBio 4(5): e00575-13, 2013] showed that vaccination with spa mutant S. aureus strains lacking antibody Fc-and/or Fab-binding capacity protects against subsequent challenge with the USA300 epidemic strain. The findings provide strong support for the idea that SpA promotes S. aureus immune evasion in vivo and form the foundation for a new approach in our efforts to develop a vaccine that prevents severe S. aureus infections. C1 [Kobayashi, Scott D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural NIH HHS NR 18 TC 10 Z9 10 U1 0 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2013 VL 4 IS 5 AR e00764-13 DI 10.1128/mBio.00764-13 PG 3 WC Microbiology SC Microbiology GA 250UQ UT WOS:000326881800038 PM 24085782 ER PT J AU Shannon, JG Hasenkrug, AM Dorward, DW Nair, V Carmody, AB Hinnebusch, BJ AF Shannon, Jeffrey G. Hasenkrug, Aaron M. Dorward, David W. Nair, Vinod Carmody, Aaron B. Hinnebusch, B. Joseph TI Yersinia pestis Subverts the Dermal Neutrophil Response in a Mouse Model of Bubonic Plague SO MBIO LA English DT Article ID III SECRETION SYSTEM; PASTEURELLA-PESTIS; PERITONEAL-MACROPHAGES; DENDRITIC CELLS; LYMPH-NODES; IN-VIVO; PATHOGENESIS; INFECTION; VIRULENCE; PHAGOCYTES AB The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host's innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of bubonic plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.) Y. pestis infection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressing Y. pestis, and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d. Y. pestis infection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early in Y. pestis infection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination of Y. pestis from the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response to Y. pestis in the dermis and that the virulence plasmid pCD1 is important for the evasion of this response. IMPORTANCE Yersinia pestis remains a public health concern today because of sporadic plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since bubonic plague pathogenesis is initiated by the introduction of Y. pestis into the skin, we sought to characterize the response of the host's innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating that Y. pestis is unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated with Y. pestis strains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cells in vivo. C1 [Shannon, Jeffrey G.; Hasenkrug, Aaron M.; Hinnebusch, B. Joseph] Natl Inst Allergy & Infect Dis, Lab Zoonot Pathogens, NIH, Hamilton, MT USA. [Dorward, David W.; Nair, Vinod; Carmody, Aaron B.] Natl Inst Allergy & Infect Dis, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Shannon, JG (reprint author), Natl Inst Allergy & Infect Dis, Lab Zoonot Pathogens, NIH, Hamilton, MT USA. EM jshannon@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 38 TC 6 Z9 9 U1 3 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2013 VL 4 IS 5 AR e00170-13 DI 10.1128/mBio.00170-13 PG 10 WC Microbiology SC Microbiology GA 250UQ UT WOS:000326881800001 PM 23982068 ER PT J AU Holly, AC Melzer, D Pilling, LC Fellows, AC Tanaka, T Ferrucci, L Harries, LW AF Holly, Alice C. Melzer, David Pilling, Luke C. Fellows, Alexander C. Tanaka, Toshiko Ferrucci, Luigi Harries, Lorna W. TI Changes in splicing factor expression are associated with advancing age in man SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Ageing; Splicing; SRSF; hnRNP; Human ID DNA-DAMAGE RESPONSE; CELLULAR SENESCENCE; AGING PRIMATES; HUMAN-DISEASE; IN-VIVO; RNA; MESSENGER; CELLS; ACCUMULATION; DISCOVERY AB Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression. We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis. Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts. We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Holly, Alice C.; Fellows, Alexander C.; Harries, Lorna W.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Melzer, David; Pilling, Luke C.] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Harries, LW (reprint author), Exeter Med Sch, Inst Biomed & Clin Sci, Barrack Rd, Exeter EX2 5DW, Devon, England. EM L.W.Harries@exeter.ac.uk RI Harries, Lorna/D-2241-2014; OI Pilling, Luke/0000-0002-3332-8454; Melzer, David/0000-0002-0170-3838 FU National Institute on Ageing; University of Exeter Medical School FX This work was supported by the intramural program of the National Institute on Ageing and Internal Funds of the University of Exeter Medical School. NR 50 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD SEP PY 2013 VL 134 IS 9 BP 356 EP 366 DI 10.1016/j.mad.2013.05.006 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 254MQ UT WOS:000327170200002 PM 23747814 ER PT J AU Kissling, GE Grogan, DW Drake, JW AF Kissling, Grace E. Grogan, Dennis W. Drake, John W. TI Confounders of mutation-rate estimators: Selection and phenotypic lag in Thermus thermophilus SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Differential growth rates; Fluctuation test; Mutation rate; Phenotypic lag ID AZOTOBACTER-VINELANDII; YEAST; DNA AB In a recent description of the rate and character of spontaneous mutation in the hyperthermophilic bacterium Thermus thermophilus, the mutation rate was observed to be substantially lower than seen in several mesophiles. Subsequently, a report appeared indicating that this bacterium maintains an average of about 4.5 genomes per cell. This number of genomes might result in a segregation lag for the expression of a recessive mutation and might therefore lead to an underestimate of the rate of mutation. Here we describe some kinds of problems that may arise when estimating mutation rates and outline ways to adjust the rates accordingly. The emphasis is mainly on differential rates of growth of mutants versus their parents and on various kinds of phenotypic lag. We then apply these methods to the T. thermophilus data and conclude that there is as yet no reliable impact on a previously described rate. Published by Elsevier B.V. C1 [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Grogan, Dennis W.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. [Drake, John W.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Mol Genet Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM drake@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01ES065016] FX This research was supported by funds allocated to project number Z01ES065016 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 18 TC 2 Z9 2 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD SEP PY 2013 VL 749 IS 1-2 BP 16 EP 20 DI 10.1016/j.mrfmmm.2013.07.006 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 253SG UT WOS:000327109000004 PM 23916418 ER PT J AU Mehta, PJ Alexander, JL Sen, HN AF Mehta, Preema J. Alexander, Janet L. Sen, H. Nida TI Pediatric uveitis: new and future treatments SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Review DE biologic agents; immunosuppressive therapy; juvenile idiopathic arthritis; pediatric uveitis; uveitis ID JUVENILE IDIOPATHIC ARTHRITIS; REFRACTORY UVEITIS; NONINFECTIOUS UVEITIS; RHEUMATOID-ARTHRITIS; INTRAVITREAL IMPLANT; OCULAR COMPLICATIONS; POSTERIOR UVEITIS; CHILDHOOD UVEITIS; ANTERIOR UVEITIS; CYCLOSPORINE-A AB Purpose of reviewPediatric uveitis is relatively uncommon, accounting for only 5-10% of all patients with uveitis. However, owing to high prevalence of complications and devastating outcomes, its lifetime burden can be significant.Recent findingsImmunomodulatory therapy has been associated with better outcomes in noninfectious pediatric uveitis. However, effective treatments are limited by medication-related complications, including multiorgan toxicities and systemic side effects.SummaryWe review the current therapies available to treat pediatric uveitis, discuss novel and future therapies, and provide clinical recommendations utilizing these new agents. The consideration for treatment regimens in noninfectious pediatric uveitis is multifactorial. Understanding past, present, and future technology will aid in treatment of a complex and refractory disease. C1 [Mehta, Preema J.] NEI, NIH, Bethesda, MD 20892 USA. [Alexander, Janet L.] Childrens Natl Med Ctr, Bethesda, MD USA. [Sen, H. Nida] NEI, Uveitis & Ocular Immunol Fellowship Program, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10 Rm 10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 64 TC 6 Z9 7 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD SEP PY 2013 VL 24 IS 5 BP 453 EP 462 DI 10.1097/ICU.0b013e3283641ede PG 10 WC Ophthalmology SC Ophthalmology GA 247BR UT WOS:000326589100012 PM 23872814 ER PT J AU Bates, SE Chakraborty, AR Basseville, A Luchenko, VL Frye, R Zhan, Z Piekarz, RL Robey, RW AF Bates, S. E. Chakraborty, A. R. Basseville, A. Luchenko, V. L. Frye, R. Zhan, Z. Piekarz, R. L. Robey, R. W. TI How to overcome resistance to HDAC inhibitors? SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Bates, S. E.; Chakraborty, A. R.; Basseville, A.; Luchenko, V. L.; Frye, R.; Zhan, Z.; Robey, R. W.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Piekarz, R. L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 142 BP S33 EP S33 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843600114 ER PT J AU Cremolini, C Loupakis, F Antoniotti, C Bergamo, F Tonini, G Buonadonna, A Valsuani, C Chiara, S Lucchesi, S Falcone, A AF Cremolini, C. Loupakis, F. Antoniotti, C. Bergamo, F. Tonini, G. Buonadonna, A. Valsuani, C. Chiara, S. Lucchesi, S. Falcone, A. TI Assessing tumor response beyond RECIST criteria: early tumor shrinkage (ETS) and deepness of response (DpR) in phase III TRIBE trial by the GONO group SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Cremolini, C.; Loupakis, F.; Antoniotti, C.; Falcone, A.] Osped Santa Chiara, UO Oncol Med 2, Pisa, Italy. [Bergamo, F.] Ist Oncol Veneto IRCCS, Padua, Italy. [Tonini, G.] Univ Campus Biomed, Rome, Italy. [Buonadonna, A.] Ist Nazl Tumori, Aviano, Italy. [Valsuani, C.] Osped Versilia, Viareggio, Italy. [Chiara, S.] Natl Canc Inst, Genoa, Italy. [Lucchesi, S.] USL 5 Pontedera, Oncol Med, Pontedera, Italy. RI Bergamo, Francesca/G-3134-2014 OI Bergamo, Francesca/0000-0002-8795-4653 NR 0 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 2180 BP S491 EP S491 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843603236 ER PT J AU Doroshow, J AF Doroshow, J. TI Impact of biomarkers on the value of crossover designs in cancer clinical trials SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Doroshow, J.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 172 BP S40 EP S40 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843600141 ER PT J AU Geiger, TR Bai, L Hu, Y Walker, RC Webster, JD Gatti, DM Simpson, RM Churchill, GA de Villena, FPM Hunter, KW AF Geiger, T. R. Bai, L. Hu, Y. Walker, R. C. Webster, J. D. Gatti, D. M. Simpson, R. M. Churchill, G. A. de Villena, F. Pardo Manuel Hunter, K. W. TI Genome-wide identification of stromal metastasis regulators in breast cancer mouse models (Winner of ECCO/EJC Young Investigator's Award) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Geiger, T. R.; Bai, L.; Walker, R. C.; Webster, J. D.; Simpson, R. M.; Hunter, K. W.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Hu, Y.] NCI, Lab Populat Genet, Bethesda, MD 20892 USA. [Gatti, D. M.; Churchill, G. A.] Jackson Lab, Bar Harbor, ME 04609 USA. [de Villena, F. Pardo Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 503 BP S97 EP S98 PG 2 WC Oncology SC Oncology GA 250HY UT WOS:000326843600347 ER PT J AU Grimley, P Apostle, K Henson, DE Anderson, WF AF Grimley, P. Apostle, K. Henson, D. E. Anderson, W. F. TI Age-related heterogeneity of ovarian epithelial carcinomas in a nationwide population (USA) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Grimley, P.; Apostle, K.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Henson, D. E.] George Washington Univ, Inst Canc, Washington, DC USA. [Anderson, W. F.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 3006 BP S714 EP S714 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843604312 ER PT J AU Le, D Gilliam, AW Picozzi, V Greten, T Crocenzi, T Springett, G Morse, M Zeh, H Brockstedt, D Jaffee, E AF Le, D. Gilliam, A. Wang Picozzi, V. Greten, T. Crocenzi, T. Springett, G. Morse, M. Zeh, H. Brockstedt, D. Jaffee, E. TI Safety, efficacy, and immune analyses of a phase 2, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Le, D.; Jaffee, E.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Gilliam, A. Wang] Washington Univ, St Louis, MO USA. [Picozzi, V.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Greten, T.] NCI, Bethesda, MD 20892 USA. [Crocenzi, T.] Providence Med Grp, Portland, OR USA. [Springett, G.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Morse, M.] Duke Univ, Med Ctr, Durham, NC USA. [Zeh, H.] Univ Pittsburgh, Pittsburgh, PA USA. [Brockstedt, D.] Aduro Biotech Inc, Immunol & Oncol, Berkeley, CA USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 0 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 2590 BP S616 EP S616 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843604028 ER PT J AU Lombaert, I Abrams, S Hoffman, M AF Lombaert, I. Abrams, S. Hoffman, M. TI Kit plus progenitor cells regenerate the branching architecture of salivary glands SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Lombaert, I.; Abrams, S.; Hoffman, M.] Nidcr, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 397 BP S90 EP S90 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843600331 ER PT J AU McShane, CM Murray, LJ Landgren, O Engels, EA Anderson, LA AF McShane, C. M. Murray, L. J. Landgren, O. Engels, E. A. Anderson, L. A. TI Exposure to common community acquired infections associated with increased risk of multiple myeloma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [McShane, C. M.; Murray, L. J.; Anderson, L. A.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Landgren, O.] NCI, Multiple Myeloma Sect, Bethesda, MD 20892 USA. [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 3610 BP S839 EP S840 PG 2 WC Oncology SC Oncology GA 250HY UT WOS:000326843605256 ER PT J AU McShane, CM Murray, LJ Engels, EA Anderson, LA AF McShane, C. M. Murray, L. J. Engels, E. A. Anderson, L. A. TI Common community acquired infections and risk of lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia: A population based study SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [McShane, C. M.; Murray, L. J.; Anderson, L. A.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 3611 BP S840 EP S840 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843605257 ER PT J AU McShane, CM Murray, LJ Landgren, O O'Rorke, MA Korde, N Kunzmann, AT Ismail, MR Anderson, LA AF McShane, C. M. Murray, L. J. Landgren, O. O'Rorke, M. A. Korde, N. Kunzmann, A. T. Ismail, M. R. Anderson, L. A. TI Prior autoimmune disease and risk of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma: A systematic review and meta-analysis of the literature SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [McShane, C. M.; Murray, L. J.; O'Rorke, M. A.; Kunzmann, A. T.; Anderson, L. A.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Landgren, O.; Korde, N.] NCI, Multiple Myeloma Sect, Bethesda, MD 20892 USA. [Ismail, M. R.] Univ Malaya, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 3606 BP S838 EP S838 PG 1 WC Oncology SC Oncology GA 250HY UT WOS:000326843605252 ER PT J AU Stamatakis, L Singer, EA Siddiqui, MM Shuch, B Nix, JW Friend, JC Shih, JH Choyke, PL Linehan, WM Srinivasan, R AF Stamatakis, L. Singer, E. A. Siddiqui, M. M. Shuch, B. Nix, J. W. Friend, J. C. Shih, J. H. Choyke, P. L. Linehan, W. M. Srinivasan, R. TI Phase II trial of bevacizumab and erlotinib in patients with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Cancer Congress 2013 - 17th ECCO / 38th ESMO / 32nd ESTRO CY SEP 27-OCT 01, 2013 CL Amsterdam, NETHERLANDS SP European Conf Clin Oncol, European Soc Therapeut Radiol & Oncol, European Soc Med Oncol, European Soc Surg Oncol, European Assoc Canc Res, European Oncol Nursing Soc, European Soc Paediat Oncol C1 [Stamatakis, L.; Singer, E. A.; Siddiqui, M. M.; Shuch, B.; Nix, J. W.; Friend, J. C.; Linehan, W. M.; Srinivasan, R.] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. [Shih, J. H.] NCI, NIH, Biometr Res Branch, Bethesda, MD 20892 USA. [Choyke, P. L.] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 2 MA 2753 BP S659 EP S660 PG 2 WC Oncology SC Oncology GA 250HY UT WOS:000326843604156 ER PT J AU Wu, CO Tian, X AF Wu, Colin O. Tian, Xin TI Nonparametric Estimation of Conditional Distributions and Rank-Tracking Probabilities With Time-Varying Transformation Models in Longitudinal Studies SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Conditional distribution function; Longitudinal data; Proportional odds model; Tracking ability Two-step smoothing method ID CARDIOVASCULAR-DISEASE; QUANTILE REGRESSION; COEFFICIENT MODELS; RISK-FACTORS; GROWTH; CHILDHOOD; HEALTH; GIRLS AB An objective of longitudinal analysis is to estimate the conditional distributions of an outcome variable through a regression model. The approaches based on modeling the conditional means are not appropriate for this task when the conditional distributions are skewed or cannot be approximated by a normal distribution through a known transformation. We study a class of time-varying transformation models and a two-step smoothing method for the estimation of the conditional distribution functions. Based on our models, we propose a rank-tracking probability and a rank-tracking probability ratio to measure the strength of tracking ability of an outcome variable at two different time points. Our models and estimation method can be applied to a wide range of scientific objectives that cannot be evaluated by the conditional mean-based models. We derive the asymptotic properties for the two-step local polynomial estimators of the conditional distribution functions. Finite sample properties of our procedures are investigated through a simulation study. Application of our models and estimation method is demonstrated through an epidemiological study of childhood growth and blood pressure. Supplementary materials for this article are available online. C1 [Wu, Colin O.; Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. EM wuc@nhlbi.nih.gov; tianx@nhlbi.nih.gov FU National Heart, Lung and Blood Institute [NO1-HC-55023-26, U01-HL48941-44] FX The National Growth and Health Study was supported by contracts NO1-HC-55023-26 and grants U01-HL48941-44 from the National Heart, Lung and Blood Institute. NR 18 TC 1 Z9 1 U1 0 U2 4 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD SEP PY 2013 VL 108 IS 503 BP 971 EP 982 DI 10.1080/01621459.2013.808949 PG 12 WC Statistics & Probability SC Mathematics GA 236GA UT WOS:000325782300020 ER PT J AU van Wijngaarden, E Thurston, SW Myers, GJ Strain, JJ Weiss, B Zarcone, T Watson, GE Zareba, G McSorley, EM Mulhern, MS Yeates, AJ Henderson, J Gedeon, J Shamlaye, CF Davidson, PW AF van Wijngaarden, E. Thurston, S. W. Myers, G. J. Strain, J. J. Weiss, B. Zarcone, T. Watson, G. E. Zareba, G. McSorley, E. M. Mulhern, M. S. Yeates, A. J. Henderson, J. Gedeon, J. Shamlaye, C. F. Davidson, P. W. TI Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles Child Development Study SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Methyl mercury; Prenatal exposure; Child development ID POLYUNSATURATED FATTY-ACIDS; IN-UTERO EXPOSURE; FISH CONSUMPTION; METHYLMERCURY EXPOSURE; FOLLOW-UP; COHORT; OUTCOMES; NUTRITION; METAANALYSIS; PREGNANCY AB Background: Fish are important sources of protein and contain a variety of nutrients, such as n-3 long-chain polyunsaturated fatty acids (PUFA), essential for normal brain development. Nevertheless, all fish also contain methyl mercury (MeHg), a known neurotoxicant in adequate dosage. Our studies of the Seychelles Child Development Study (SCDS) Main Cohort enrolled in 1989-1990 (n = 779) have found no consistent pattern of adverse MeHg effects at exposures achieved by daily fish consumption. Rather, we have observed evidence of improved performance on some cognitive endpoints as prenatal MeHg exposure increases in the range studied. These observations cannot be related to MeHg and may reflect the role of unmeasured covariates such as essential nutrients present in fish. To determine if these associations persist into young adulthood, we examined the relationship between prenatal MeHg exposure, recent PUFA exposure and subjects' neurodevelopment and behavior at 19 years of age. Methods: We examined 533 participants using the following test battery: the Profile of Mood States Bipolar (POMS-Bi); Finger Tapping; Kaufman Brief Intelligence Test (K-BIT); measures of Fine Motor Control and Complex Perceptual Motor Control; and Visual Spatial Contrast Sensitivity. We collected the following covariates: maternal IQ family life course stressors, socioeconomic status, and subjects' recent postnatal MeHg, sex, and computer use. Primary analyses (based on N = 392-475) examined covariate-adjusted associations in multiple linear regression models with prenatal MeHg as the primary exposure measure. Secondary analyses additionally adjusted for total n-6 and fish-related n-3 PUFA measured in the subjects' serum at the 19-year examination. Results: Study participants had a mean prenatal MeHg exposure of 6.9 ppm, and a mean recent postnatal exposure of 10.3 ppm. There were no adverse associations between prenatal MeHg and any of the measured endpoints. For recent postnatal MeHg exposure, however, adverse associations were observed for Finger Tapping (non-dominant hand) among women and for the K-BIT Matrices for both sexes, with or without adjustment for PUFA. Conclusion: Our findings continue to provide no evidence for an adverse effect of prenatal MeHg exposure on development in a cohort that consumes fish daily. Observations for postnatal MeHg exposure will need to be confirmed using more comprehensive exposure measures. (C) 2013 Elsevier Inc. All rights reserved. C1 [van Wijngaarden, E.; Thurston, S. W.; Myers, G. J.; Weiss, B.; Watson, G. E.; Zareba, G.; Davidson, P. W.] Univ Rochester, Sch Med & Dent, Rochester, NY 14642 USA. [Strain, J. J.; McSorley, E. M.; Mulhern, M. S.; Yeates, A. J.] Univ Ulster, Coleraine BT52 1SA, Londonderry, North Ireland. [Zarcone, T.] NIAAA, Bethesda, MD USA. [Henderson, J.; Gedeon, J.; Shamlaye, C. F.] Minist Hlth, Victoria, Seychelles. RP van Wijngaarden, E (reprint author), Univ Rochester, Dept Publ Hlth Sci, Sch Med & Dent, 265 Crittenden Blvd,CU 420644, Rochester, NY 14642 USA. EM edwin_van_wijngaarden@urmc.rochester.edu OI McSorley, Emeir/0000-0003-1861-3991; Mulhern, Maria S/0000-0002-2212-3744; Yeates, Alison/0000-0002-2393-1663 FU US National Institute of Environmental Health Sciences, National Institutes of Health [5-RO1-ES008442, P30-ES01247]; Government of the Republic of Seychelles FX This research was supported by grants 5-RO1-ES008442 and P30-ES01247 from the US National Institute of Environmental Health Sciences, National Institutes of Health and by the Government of the Republic of Seychelles. NR 39 TC 11 Z9 11 U1 3 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2013 VL 39 BP 19 EP 25 DI 10.1016/j.ntt.2013.06.003 PG 7 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 246SE UT WOS:000326558600003 PM 23770126 ER PT J AU Kiss, JE Cable, RG Brambilla, D Simone, G Mast, AE Spencer, BR Stone, M Tobler, LH AF Kiss, J. E. Cable, R. G. Brambilla, D. Simone, G. Mast, A. E. Spencer, B. R. Stone, M. Tobler, L. H. TI Hemoglobin Recovery after Blood Donation and the Effects of Iron Supplementation: The Hemoglobin and Iron Recovery Study (HEIRS) SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. [Cable, R. G.] Amer Red Cross, Farmington, CT USA. [Brambilla, D.] RTI, Rockville, MD USA. [Spencer, B. R.] Amer Red Cross, Dedham, MA USA. [Simone, G.] NHLBI, Bethesda, MD 20892 USA. [Mast, A. E.] BloodCtr Wisconsin, Milwaukee, WI USA. [Stone, M.; Tobler, L. H.] Blood Syst Res Inst, San Francisco, CA USA. EM jkiss@itxm.org NR 0 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 14A EP 15A PG 2 WC Hematology SC Hematology GA 218CA UT WOS:000324409000006 ER PT J AU Panch, SR Yau, YC Kang, E Malech, H Leitman, SF AF Panch, S. R. Yau, Y. C. Kang, E. Malech, H. Leitman, S. F. TI Hematopoietic Progenitor Cell (HPC) Mobilization in Patients with Chronic Granulomatous Disease (CGD) and Severe Combined Immunodeficiency SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Yau, Y. C.; Leitman, S. F.] NIH, CC, Bethesda, MD 20892 USA. [Panch, S. R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kang, E.; Malech, H.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. EM sandhya.panch@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 22A EP 23A PG 2 WC Hematology SC Hematology GA 218CA UT WOS:000324409000025 ER PT J AU Panch, SR Yau, YC Sweigart, TS Diggs, K Leitman, SF AF Panch, S. R. Yau, Y. C. Sweigart, T. S. Diggs, K. Leitman, S. F. TI Initial Serum Ferritin Predicts Number of Therapeutic Phlebotomies to Iron Depletion in Secondary Iron Overload (IO) SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Yau, Y. C.; Sweigart, T. S.; Diggs, K.; Leitman, S. F.] NIH, CC, Bethesda, MD 20892 USA. [Panch, S. R.] NHLBI, Bethesda, MD 20892 USA. EM sandhya.panch@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 24A EP 24A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000028 ER PT J AU Spencer, BR Wright, DJ Simone, G Mast, AE Kleinman, S Kiss, JE Benjamin, RJ Busch, MP Cable, RG AF Spencer, B. R. Wright, D. J. Simone, G. Mast, A. E. Kleinman, S. Kiss, J. E. Benjamin, R. J. Busch, M. P. Cable, R. G. TI Limited Impact on Donor Iron Status from Longer Donation Intervals and Higher Male Donor Hemoglobin Cutoff: Results of Simulation Models Using REDS-II Data SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Spencer, B. R.; Cable, R. G.] Amer Red Cross, Dedham, MA USA. [Wright, D. J.] WESTAT Corp, Rockville, MD 20850 USA. [Simone, G.] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Mast, A. E.] BloodCtr Wisconsin, Milwaukee, WI USA. [Kleinman, S.] AABB, Bethesda, MD USA. [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. [Benjamin, R. J.] Amer Red Cross, Holland Labs, Rockville, MD USA. [Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. EM bryan.spencer@redcross.org NR 0 TC 1 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 35A EP 35A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000053 ER PT J AU Williams, JD Dixon, M Robertson, GF Bravo, MD Williams, RC Leparc, GF Caglioti, S Williamson, PC AF Williams, J. Dunn Dixon, M. Robertson, G. F. Bravo, M. D. Williams, R. C. Leparc, G. F. Caglioti, S. Williamson, P. C. TI Evaluation of Blood Donor Ferritin Testing SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Williams, J. Dunn; Dixon, M.; Robertson, G. F.; Leparc, G. F.; Caglioti, S.; Williamson, P. C.] Creat Testing Solut, Phoenix, AZ USA. [Williams, R. C.] NIH, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Bravo, M. D.] Blood Syst Inc, Scottsdale, AZ USA. EM jdunnwilliams@mycts.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 107A EP 107A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000227 ER PT J AU Cable, RG Brambilla, D Simone, G Kiss, JE AF Cable, R. G. Brambilla, D. Simone, G. Kiss, J. E. TI Predictors of Venous Hemoglobin (Hb) in the Week Following Whole Blood Donation SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Cable, R. G.] Amer Red Cross, Farmington, CT USA. [Brambilla, D.] RTI Int, Rockville, MD USA. [Simone, G.] NHLBI, Bethesda, MD 20892 USA. [Kiss, J. E.] Inst Transfus Med, Pittsburgh, PA USA. EM Ritchard.Cable@redcross.org 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 108A EP 108A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000230 ER PT J AU Chen, Q Ardinski, SC Lam, K Huvard, MJ Schmid, P Flegel, WA AF Chen, Q. Ardinski, S. C. Lam, K. Huvard, M. J. Schmid, P. Flegel, W. A. TI Full Length Nucleotide Sequence of SLC44A2 Alleles Encoding Human Neutrophil Antigen-3 (HNA-3) in African Americans and Caucasians SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Chen, Q.; Ardinski, S. C.; Lam, K.; Huvard, M. J.; Schmid, P.; Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Chen, Q.] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. EM qngchen@gmail.com 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 128A EP 128A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000282 ER PT J AU Chen, Q Xiao, J Liu, Z Flegel, WA AF Chen, Q. Xiao, J. Liu, Z. Flegel, W. A. TI Genotype Frequency of Human Neutrophil Antigen-3 (HNA-3) Polymorphism in the Han Population of Jiangsu Province, China SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Chen, Q.; Xiao, J.] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. [Liu, Z.] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu, Peoples R China. [Liu, Z.] Peking Union Med Coll, Chengdu, Peoples R China. [Flegel, W. A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM qngchen@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 130A EP 130A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000287 ER PT J AU Rujirojindakul, P Flegel, WA AF Rujirojindakul, P. Flegel, W. A. TI Applying Molecular Immunohematology to Regularly Transfused Thalassemic Patients in Thailand SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Rujirojindakul, P.] Prince Songkla Univ, Hat Yai, Thailand. [Flegel, W. A.] NIH, Bethesda, MD 20892 USA. EM rupairay@hotmail.com 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 160A EP 160A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000364 ER PT J AU Scott, MK Sheldon, SL Flegel, WA AF Scott, M. K. Sheldon, S. L. Flegel, W. A. TI Prospective Observational Study on the Efficacy of Excluding High Titer ABO Antibodies in Preventing Hemolysis due to Plasma Incompatible Plateletpheresis Transfusions SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Scott, M. K.; Sheldon, S. L.; Flegel, W. A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM MaScott@lifebridgehealth.org 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 190A EP 191A PG 2 WC Hematology SC Hematology GA 218CA UT WOS:000324409000442 ER PT J AU Pelton, SB Flegel, WA Byrne, KM AF Pelton, S. B. Flegel, W. A. Byrne, K. M. TI Development of an Audit Toolkit Utilizing Tracer Methodology which Incorporates AABB, CAP, and TJC Standards for Blood Centers and Hospital Blood Banks SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Pelton, S. B.; Flegel, W. A.; Byrne, K. M.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM sbpelton@gmail.com 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 268A EP 269A PG 2 WC Hematology SC Hematology GA 218CA UT WOS:000324409000637 ER PT J AU Newman-Gerhardt, S Muiruri, S Muchiri, E Peters, CJ Morrill, J Lucas, AH King, CH Kazura, J LaBeaud, AD AF Newman-Gerhardt, Shoshana Muiruri, Samuel Muchiri, Eric Peters, Clarence J. Morrill, John Lucas, Alexander H. King, Charles H. Kazura, James LaBeaud, Angelle Desiree TI Short Report: Potential for Autoimmune Pathogenesis of Rift Valley Fever Virus Retinitis SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID NORTHEASTERN KENYA; SAUDI-ARABIA; OUTBREAK; BUNYAVIRIDAE; PHLEBOVIRUS; ILLNESS AB Rift Valley Fever (RVF) is a significant threat to human health because it can progress to retinitis, encephalitis, and hemorrhagic fever. The timing of onset of Rift Valley Fever virus (RVFV) retinitis suggests an autoimmune origin. To determine whether RVFV retinitis is associated with increased levels of IgG against retinal tissue, we measured and compared levels of IgG against healthy human eye tissue by immunohistochemical analysis. We found that serum samples from RVFV-exposed Kenyans with retinitis (n = 8) were slightly more likely to have antibodies against retinal tissue than control populations, but the correlation was not statistically significant. Further investigation into the possible immune pathogenesis of RVFV retinitis could lead to improved therapies to prevent or treat this severe complication. C1 [Newman-Gerhardt, Shoshana] NIH, Bethesda, MD 20892 USA. [Muiruri, Samuel] Minist Hlth, Div Vector Borne & Neglected Trop Dis, Nairobi, Kenya. [Muchiri, Eric] Minist Publ Hlth & Sanitat, Div Vector Borne & Neglected Trop Dis, Nairobi, Kenya. [Peters, Clarence J.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Morrill, John] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Lucas, Alexander H.; LaBeaud, Angelle Desiree] Childrens Hosp, Oakland Res Inst, Ctr Immunobiol & Vaccine Dev, Oakland, CA 94609 USA. [King, Charles H.; Kazura, James] Case Western Reserve Univ, Ctr Global Hlth, Cleveland, OH 44106 USA. RP Newman-Gerhardt, S (reprint author), NIH, Bldg 29B,Room 2c17,29 Lincoln Way, Bethesda, MD 20892 USA. EM snhypheng@gmail.com; muiruri1001@yahoo.com; ericmmuchiri@gmail.com; cjpeters@utmb.edu; jcmorril@utmb.edu; alucas@chori.org; chk@case.edu; jxk14@po.cwru.edu; alabeaud@chori.org FU National Institutes of Health grant [U54AI057160]; Midwest Regional Center of Excellence Program Project Award; International Collaborations in Infectious Disease Research ICIDR Biodefense Supplement grant [U01AI45473]; Robert E. Shope International Fellowship in Infectious Diseases; Center for Immunobiology and Vaccine Development at Children's Hospital Oakland Research Institute FX This study was supported by the National Institutes of Health grant U54AI057160; the Midwest Regional Center of Excellence Program Project Award, International Collaborations in Infectious Disease Research ICIDR Biodefense Supplement grant U01AI45473, the Robert E. Shope International Fellowship in Infectious Diseases, and the Center for Immunobiology and Vaccine Development at Children's Hospital Oakland Research Institute. NR 18 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD SEP PY 2013 VL 89 IS 3 BP 495 EP 497 DI 10.4269/ajtmh.12-0562 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 240XB UT WOS:000326129900016 PM 23918215 ER PT J AU Martinez, L Arman, A Haveman, N Lundgren, A Cabrera, L Evans, CA Pelly, TF Saito, M Callacondo, D Oberhelman, R Collazo, G Carnero, AM Gilman, RH AF Martinez, Leonardo Arman, Alyssa Haveman, Nathan Lundgren, Ashley Cabrera, Lilia Evans, Carlton A. Pelly, Tom F. Saito, Mayuko Callacondo, David Oberhelman, Richard Collazo, Gisela Carnero, Andres M. Gilman, Robert H. TI Changes in Tuberculin Skin Test Positivity Over 20 Years in Periurban Shantytowns in Lima, Peru SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID MICROSCOPIC-OBSERVATION; REACTIVITY; DIAGNOSIS; POPULATION; PREVALENCE; INFECTION; METAANALYSIS; VACCINATION; INDICATOR; OUTCOMES AB A cross-sectional, community-based study was performed in 2012 with 428 residents of periurban shanty-towns in Lima, Peru to study risk factors for and changes in latent tuberculosis infection in age-stratified groups compared with our data from the same region in 1990 (N = 219) and 2005 (N = 103). Tuberculin skin test positivity in these communities was highly prevalent at 52% overall, increased with age (P < 0.01) and was similar to 2005 (53%) and 1990 (48%). From 1990 to 2012, the prevalence of tuberculin positivity decreased in 5-14 and 15-24 year old groups (to 17% and 34%, respectively, both P < 0.05). However, this may be explained by cessation of Bacille Calmette-Guerin revaccination during this period, because Bacille Calmette-Guerin revaccination doubled tuberculin positivity. Over the same 22-year period, tuberculin positivity in the >= 25 year old group remained high (71%, P = 0.3), suggesting that prevalent latent tuberculosis infection persists in the adult population despite improving medical care and socioeconomic development in this region. C1 [Martinez, Leonardo; Oberhelman, Richard] Tulane Univ, Sch Publ Hlth & Trop Med, Global Community Hlth & Behav Sci, New Orleans, LA USA. [Arman, Alyssa; Haveman, Nathan] Calif State Univ Fullerton, San Diego, CA USA. [Lundgren, Ashley] Weill Cornell Med Coll, New York, NY USA. [Cabrera, Lilia] Asociac Benef PRISMA, Lima, Peru. [Evans, Carlton A.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis & Immun, Wellcome Trust Ctr Clin Trop Med, London, England. [Pelly, Tom F.] Univ Peruana Cayetano Heredia, IFHAD Innovat Hlth & Dev, Lima, Peru. [Saito, Mayuko] Univ Calif San Diego, San Diego, CA 92103 USA. [Callacondo, David] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Collazo, Gisela] Tulane Univ, New Orleans, LA 70118 USA. [Carnero, Andres M.] Univ Peruana Cayetano Heredia, Postgrad Sch, Lima, Peru. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ, Dept Int Hlth, Baltimore, MD USA. RP Gilman, RH (reprint author), Johns Hopkins Sch Publ Hlth, Dept Int Hlth, 615 N Wolfe St,Room 3501, Baltimore, MD 21205 USA. EM lmartin7@tulane.edu; lyssiejoy@gmail.com; n.eight.h@gmail.com; ashley.diana@gmail.com; lilia_deviaje@yahoo.com; carlton.evans@ifhad.org; tompelly@doctors.org.uk; msaitop@gmail.com; david.callacondo@upch.pe; oberhel@tulane.edu; gcollazo@tulane.edu; andrescarnero@gmail.com; rgilman@jhsph.edu OI Carnero, Andres/0000-0002-9372-0378; Evans, Carlton/0000-0002-6873-5447 FU Tulane-Xavier Minority Health International Research Training (MHIRT) Program; National Institutes of Health [T37 MD001424]; IFHAD: Innovation For Health And Development; RG-ER; NIH [RO1 HD059005]; Wellcome Trust FX LM and GC were supported through the Tulane-Xavier Minority Health International Research Training (MHIRT) Program, funded by a training grant from the National Institutes of Health (T37 MD001424). CAE, TFP, and the 2005 study were supported by IFHAD: Innovation For Health And Development and The Wellcome Trust. This study was funded in part by the anonymous RG-ER fund and NIH RO1 HD059005. NR 48 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD SEP PY 2013 VL 89 IS 3 BP 507 EP 515 DI 10.4269/ajtmh.13-0005 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 240XB UT WOS:000326129900019 PM 23878185 ER PT J AU Cressey, TR Best, BM Achalapong, J Stek, A Wang, JJ Chotivanich, N Yuthavisuthi, P Suriyachai, P Prommas, S Shapiro, DE Watts, DH Smith, E Capparelli, E Kreitchmann, R Mirochnick, M AF Cressey, Tim R. Best, Brookie M. Achalapong, Jullapong Stek, Alice Wang, Jiajia Chotivanich, Nantasak Yuthavisuthi, Prapap Suriyachai, Pornnapa Prommas, Sinart Shapiro, David E. Watts, D. Heather Smith, Elizabeth Capparelli, Edmund Kreitchmann, Regis Mirochnick, Mark CA IMPAACT P1026S Team TI Reduced indinavir exposure during pregnancy SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE antiretrovirals; HIV; pregnancy; prevention of mother-to-child transmission ID INFECTED THAI PATIENTS; RITONAVIR; PHARMACOKINETICS; LOPINAVIR; WOMEN; ANTIRETROVIRALS; EFFICACY; REGIMEN AB AimTo describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. MethodsIMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9gml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1gml(-1), the suggested minimum target. ResultsTwenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12h) and C-max during the second trimester and post-partum (ante:post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12h) and C-max ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. ConclusionIndinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and approximate to 30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100mg twice daily may be preferable to ensure adequate drug concentrations. C1 [Cressey, Tim R.] Chiang Mai Univ, Program HIV Prevent & Treatment IRD URI 174, Dept Med Technol, Fac Associated Med Sci, Chiang Mai 50000, Thailand. [Cressey, Tim R.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cressey, Tim R.] IRD, UMI PHPT 174, Marseille, France. [Best, Brookie M.; Capparelli, Edmund] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Best, Brookie M.; Capparelli, Edmund] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Achalapong, Jullapong] Chiang Rai Prachanukroh Hosp, Chiang Rai, Thailand. [Stek, Alice] Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Wang, Jiajia; Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Chotivanich, Nantasak] Chonburi Hosp, Chon Buri, Thailand. [Yuthavisuthi, Prapap] Prapokklao Hosp, Chanthaburi, Thailand. [Suriyachai, Pornnapa] Phayao Hosp, Phayao, Thailand. [Prommas, Sinart] Bhumibol Adulyadej Hosp, Bangkok, Thailand. [Watts, D. Heather] NICHD, Bethesda, MD USA. [Smith, Elizabeth] NIAID, Bethesda, MD 20892 USA. [Kreitchmann, Regis] Santa Casa de Misericordia Porto Alegre, Porto Alegre, RS, Brazil. [Mirochnick, Mark] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Cressey, TR (reprint author), Fac Associated Med Sci, Dept Med Technol, Program HIV Prevent & Treatment PHPT IRD174, 6th Floor,110 Inthawaroros Rd, Muang Chiang Mai 50200, Thailand. EM tim.cressey@phpt.org FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health; National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG) [1 U01 AI068616]; IMPAACT Group; National Institute of Allergy and Infectious Diseases (NIAID); NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-DK-9001/HHSN267200800001C] FX The authors wish to thank thewomen who participated in the protocol and the staff of the participating IMPAACT centres. Team/Site Investigators: Study Team: Elizabeth Hawkins, D. Heather Watts, Sandra K. Burchett, Francesca Aweeka, Steve Rossi, Michael Basar, Kathleen Kaiser, Emily Barr, Kenneth D. Braun, Jr, Jennifer Bryant, Kathleen A. Medvik, and Amy Jennings. Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand (#8352): Patcharee Kantipong, Jullapong Achalapong, Kannikar Saisawat, Chulapong Chanta, Kanchana Preedisripipat, Supaporn Utsaha, Chaniporn Yodsuwan, Pollawat Thongsuk and Yupawan Thaweesombat. ChonburiHospital, Chonburi, Thailand (#8356): Chureeratana Bowonwatanuwong, Nantasak Chotivanich, Suchat Hongsiriwon, Ladda Argadamnuy, Donyapattra Ekkomonrat, Prakit Yothipitak, Duangporn Wiwattanasorn, Somrat Matchua, Suluck Soontaros and Kessarin Chaisiri. Bhumibol Adulyadej Hospital, Bangkok, Thailand (#8355): Sinart Prommas, Prapaisri Layangool, Jutarat Mekmallika, Sommai Tratong, Ladda Ruluk, Titima Taweewattanapan and Marina Thitathan. Prapokklao Hospital (#8354): PrapapYuthavisuthi, Chaiwat Ngampiyaskul, Ubon Chanasit, Wanna Chamjamrat, Pathanee Teirsonsern, Nuttupassasorn Tungtongcha and Pisut Greetanukroh. Phayao Hospital, Phayao, Thailand, (#8353): Guttiga Halue, Wirawan Rasri, Pornnapa Suriyachai, Pornchai Techakunakorn, Kunlaya Jansook, Chutima Ruklao, Khanungnit Thungkham, Borwornluck Changlor and Wanpen Mooninta. PHPT-IRD174, Chiang Mai (#8351): Marc Lallemant, Gonzague Jourdain, Nicole Ngo-Giang-Huong, Pra-ornsuda Sukrakanchana, Kanchana Than-in-at, Nusara Krapunpongsakul, Renoo Wongsrisai, Patcharaporn Krueduangkam, Janjira Thonglo, Ruethai Wongchai, Tiwacha Thimakam, Purivis Chart, Yardpiroon Taworn, Pimpinun Punyati, Worathip Sripaoraya and Suriyan Tanasri. 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) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [AI068632]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9001/ HHSN267200800001C). NR 21 TC 11 Z9 11 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0306-5251 EI 1365-2125 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD SEP PY 2013 VL 76 IS 3 SI SI BP 475 EP 483 DI 10.1111/bcp.12078 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 242MF UT WOS:000326245400016 PM 23305215 ER PT J AU Jukic, AM AF Jukic, Anne Marie TI Length of human pregnancies can vary naturally by 5 weeks SO BRITISH JOURNAL OF HOSPITAL MEDICINE LA English DT News Item C1 NIEHS, Durham, NC USA. RP Jukic, AM (reprint author), NIEHS, Durham, NC USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU MA HEALTHCARE LTD PI LONDON PA ST JUDES CHURCH, DULWICH ROAD, LONDON SE24 0PB, ENGLAND SN 1750-8460 EI 1759-7390 J9 BRIT J HOSP MED JI Br. J. Hosp. Med. PD SEP PY 2013 VL 74 IS 9 BP 491 EP 491 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 243GH UT WOS:000326304400009 ER PT J AU Christian, B Chattopadhyay, A Kingman, A Boroumand, S Adams, A Garcia, I AF Christian, B. Chattopadhyay, A. Kingman, A. Boroumand, S. Adams, A. Garcia, I. TI Oral health care services utilisation in the adult US population: Medical Expenditure Panel Survey 2006 SO COMMUNITY DENTAL HEALTH LA English DT Article DE health services research; utilization; dental health services; epidemiologic factors; healthcare disparities ID DENTAL-CARE; UNITED-STATES; INTERVIEW SURVEY; INSURANCE; VISITS; RACE/ETHNICITY; COVERAGE; CHILDREN; PAYMENT; ACCESS AB Objectives: To estimate the proportion of dental visits and to explore determinants of oral health care service (OHCS) utilisation among US civilian non-institutionalised adults. Methods: Cross-sectional data from the 2006 Medical Expenditure Panel Survey (MEPS) were used to analyse adults' self-reported dental visits across potential risk factors (n=22,721). MEPS uses a complex sample design including stratification, clustering, multiple stages of selection, and disproportionate sampling. These survey design complexities were taken into account for analysis in this study. The analysis was performed in SAS 9.2 and used chi-square tests and binary logistic regression. Results: MEPS (2006) represented approximately 222 million non-institutionalised US adults. 42% (weighted) of this population reported a dental visit in the past 12 months. Dental visit numbers were observed to increase with age, with the 55-64-year-olds approximately 44% more likely than the 18-24-year olds to have visited the dentist in the past year. Hispanics were 48% less likely to report a dental visit compared to Non-Hispanic Whites. Respondents with public-or no-dental insurance were less likely to report a dental visit than persons with private dental coverage. Conclusions: Under half the US adult civilian non-institutionalised population reported a dental visit during 2006. To help address utilisation disparities, creative initiatives and systemic approaches aimed at groups currently utilising OHCS less often could be an important step towards oral health equity. C1 [Christian, B.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, McCaughey Ctr, Parkville, Vic 3052, Australia. [Chattopadhyay, A.; Boroumand, S.; Adams, A.; Garcia, I.] NIDCR, Off Sci Policy & Anal, NIH, Bethesda, MD USA. [Kingman, A.] NIDCR, Clin Res Ctr, NIH, Bethesda, MD USA. RP Christian, B (reprint author), Univ Melbourne, Melbourne Sch Populat & Global Hlth, McCaughey Ctr, Jack Brockhoff Child Hlth & Wellbeing Program, Level 5,207 Bouverie St, Parkville, Vic 3052, Australia. EM bradley.christian@unimelb.edu.au OI Christian, Bradley/0000-0001-5072-3512 FU National Institute of Dental and Craniofacial Research, Bethesda, MD, US FX This study was supported by the National Institute of Dental and Craniofacial Research, Bethesda, MD, US. We thank Dr Richard Manski and Ms Tina Stiller for their input to this study. NR 31 TC 5 Z9 5 U1 0 U2 9 PU F D I WORLD DENTAL PRESS LTD PI LOWESTOFT PA 5 BATTERY GREEN RD, LOWESTOFT NR32 1 DE, SUFFOLK, ENGLAND SN 0265-539X J9 COMMUNITY DENT HLTH JI Community Dent. Health PD SEP PY 2013 VL 30 IS 3 BP 161 EP 167 DI 10.1922/CDH_3096Christian07 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 238SJ UT WOS:000325968700008 PM 24151790 ER PT J AU Kodish, E Fins, JJ Braddock, C Cohn, F Dubler, NN Danis, M Derse, AR Pearlman, RA Smith, M Tarzian, A Youngner, S Kuczewski, MG AF Kodish, Eric Fins, Joseph J. Braddock, Clarence, III Cohn, Felicia Dubler, Nancy Neveloff Danis, Marion Derse, Arthur R. Pearlman, Robert A. Smith, Martin Tarzian, Anita Youngner, Stuart Kuczewski, Mark G. TI Quality Attestation for Clinical Ethics Consultants: A Two-Step Model from the American Society for Bioethics and Humanities SO HASTINGS CENTER REPORT LA English DT Article ID STANDARDS AB Clinical ethics consultation is largely outside the scope of regulation and oversight, despite its importance. For decades, the bioethics community has been unable to reach a consensus on whether there should be accountability in this work, as there is for other clinical activities that influence the care of patients. The American Society for Bioethics and Humanities, the primary society of bioethicists and scholars in the medical humanities and the organizational home for individuals who perform CEC in the United States, has initiated a two-step quality attestation process as a means to assess clinical ethics consultants and help identify individuals who are qualified to perform this role. This article describes the process. C1 [Kodish, Eric] Cleveland Clin, Cleveland, OH 53226 USA. [Fins, Joseph J.] Weill Cornell Med Coll, Div Med Eth, New York, NY 98195 USA. [Braddock, Clarence, III] Stanford Sch Med, Ctr Med Eth, Ctr Med Educ Res & Innovat, Stanford, CA USA. [Braddock, Clarence, III] Stanford Sch Med, Div Gen Internal Med, Dept Med, Stanford, CA 21201 USA. [Cohn, Felicia] Kaiser Permanente Orange Cty, Anaheim, CA 21201 USA. [Dubler, Nancy Neveloff] New York City Hlth & Hosp Corp, Albert Einstein Coll Med, New York, NY 44106 USA. [Dubler, Nancy Neveloff] NYU Langone Med Ctr, New York, NY USA. [Danis, Marion] Natl Inst Hlth, Sect Eth & Hlth Policy, Dept Bioeth, NIH Clin Ctr, Bethesda, MD USA. [Derse, Arthur R.] Med Coll Wisconsin, Inst Hlth & Soc, Ctr Bioeth & Med Humanities, Milwaukee, WI USA. [Pearlman, Robert A.] Univ Washington, Seattle, WA USA. [Smith, Martin] Cleveland Clin, Dept Bioeth, Ctr Eth Humanities & Spiritual Care, Cleveland, OH USA. [Tarzian, Anita] Univ Maryland, Sch Nursing, Baltimore, MD USA. [Tarzian, Anita] Univ Maryland, Sch Law, Maryland Hlth Care Eth Comm Network, Baltimore, MD USA. [Youngner, Stuart] Case Western Reserve Univ, Dept Bioeth, Cleveland, OH USA. [Kuczewski, Mark G.] Loyola Univ Chicago, Div Hlth Sci, Neiswanger Inst Bioeth & Hlth Policy, Chicago, IL USA. FU Josiah H. Macy Foundation FX ASBH acknowledges major funding from the Josiah H. Macy Foundation as well as the contributions of the authors and their institutions to this publication. NR 44 TC 27 Z9 27 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP PY 2013 VL 43 IS 5 BP 26 EP 36 DI 10.1002/hast.198 PG 11 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 242LI UT WOS:000326243000015 PM 24092588 ER PT J AU Brody, H Miller, FG AF Brody, Howard Miller, Franklin G. TI The Research-Clinical Practice Distinction, Learning Health Systems, and Relationships SO HASTINGS CENTER REPORT LA English DT Article ID RESEARCH ETHICS; INVESTIGATOR; TENSION; CARE AB A special report of The Hastings Center and the Association of American Medical Colleges addressed the ethical oversight of learning health systems, which seek to combine high-quality patient care with routine data collection aimed at improving patient outcomes. The report contained two position papers, authored by a number of distinguished bioethicists, and several commentaries. The position papers urged two changes. First, they urged a rethinking of our approach to the regulation of human subjects research, so as to make it easier in the future for learning health systems to function well. Second, they argued that the rethinking required dispensing with a strict distinction between research and therapy, which has been a major tenet of bioethics since the Belmont Report, which explicated basic ethical principles governing human subjects research.We fully support the objectives of the authors, and we agree that the learning health system is an important advance that serves patients well. Unnecessary regulatory burden ought not impede this progress. We disagree, however, that the best way to bring about these needed changes in the regulatory environment is to reject the basic distinction between research and treatment. Unfortunately, we find the arguments in favor of that strategy to be, in places, reminiscent of what we take to be basic conceptual errors that hampered the ethical understanding of human subjects research prior to adoption of the Belmont Report.To see why one need not reject the research-treatment distinction in order to promote learning health systems, we first investigate in some detail the arguments offered for eliminating the distinction. We next turn to an issue not addressed by those authors, namely, the relationship between the physician or investigator and the patient or subject, to illustrate why the distinction is important and what is lost if it is jettisoned. C1 [Brody, Howard] Univ Texas Med Branch, Galveston, TX 77555 USA. [Brody, Howard] Univ Texas Med Branch, Inst Med Humanities, Galveston, TX 77555 USA. [Miller, Franklin G.] Natl Inst Hlth, Ctr Clin, Dept Bioeth, Bethesda, MD USA. RP Brody, H (reprint author), Univ Texas Med Branch, Galveston, TX 77555 USA. NR 17 TC 8 Z9 8 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP PY 2013 VL 43 IS 5 BP 41 EP 47 DI 10.1002/hast.199 PG 7 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 242LI UT WOS:000326243000018 PM 24092591 ER PT J AU Schmidt, SP Jokinen, MP Law, JM Pandiri, AR Weddle, DL Wolf, JC Sills, RC AF Schmidt, S. P. Jokinen, M. P. Law, J. M. Pandiri, A. R. Weddle, D. L. Wolf, J. C. Sills, R. C. TI Environmental Pathobiology and Global Opportunities SO VETERINARY PATHOLOGY LA English DT Editorial Material C1 [Schmidt, S. P.] Pfizer Inc, DSRD, Groton, CT 06340 USA. [Jokinen, M. P.] Integrated Lab Sci Inc, Res Triangle Pk, NC USA. [Law, J. M.] N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. [Pandiri, A. R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Weddle, D. L.] Xenometr LLC, Stilwell, KS USA. [Wolf, J. C.] Expt Pathol Labs Inc, Sterling, VA USA. [Sills, R. C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Schmidt, SP (reprint author), Pfizer Inc, DSRD, Groton, CT 06340 USA. EM stephen.p.schmidt@pfizer.com NR 5 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD SEP PY 2013 VL 50 IS 5 BP 733 EP 734 DI 10.1177/0300985813485098 PG 2 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 245PI UT WOS:000326475500001 PM 24014610 ER PT J AU Pniewska, E Sokolowska, MM Kacprzak, D Pawliczak, R AF Pniewska, E. Sokolowska, M. M. Kacprzak, D. Pawliczak, R. TI Lipopolysaccharide, Der p1 but not Fel d1 induce expression of selected phospholipases A(2) ( PLA(2)s) in peripheral blood mononuclear cells of asthmatics SO ALLERGY LA English DT Meeting Abstract CT World Allergy and Asthma Congress of the European-Academy-of-Allergy-and-Clinical-Immunology and World-Allergy-Organization CY JUN 22-26, 2013 CL Milan, ITALY SP European Acad Allergy & Clin Immunol, World Allergy Org C1 [Pniewska, E.; Sokolowska, M. M.; Kacprzak, D.; Pawliczak, R.] Med Univ Lodz, Dept Immunopathol, Lodz, Poland. [Sokolowska, M. M.] NIH, Bethesda, MD 20892 USA. RI Pawliczak, Rafal/S-9649-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD SEP PY 2013 VL 68 SU 97 SI SI BP 225 EP 225 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 227VH UT WOS:000325142901278 ER PT J AU Yende, S Alvarez, K Loehr, L Folsom, AR Newman, AB Weissfeld, LA Wunderink, RG Kritchevsky, SB Mukamal, KJ London, SJ Harris, TB Bauer, DC Angus, DC AF Yende, Sachin Alvarez, Karina Loehr, Laura Folsom, Aaron R. Newman, Anne B. Weissfeld, Lisa A. Wunderink, Richard G. Kritchevsky, Stephen B. Mukamal, Kenneth J. London, Stephanie J. Harris, Tamara B. Bauer, Doug C. Angus, Derek C. CA Atherosclerosis Risk Communities Cardiovasc Hlth Study Hlth Aging Body Composition Study TI Epidemiology and Long-term Clinical and Biologic Risk Factors for Pneumonia in Community-Dwelling Older Americans Analysis of Three Cohorts SO CHEST LA English DT Article ID C-REACTIVE-PROTEIN; STREPTOCOCCUS-PNEUMONIAE; ACQUIRED PNEUMONIA; UNITED-STATES; BREAST-CANCER; SEVERE SEPSIS; MORTALITY; STATINS; HOSPITALIZATIONS; DISEASE AB Background: Preventing pneumonia requires better understanding of incidence, mortality, and long-term clinical and biologic risk factors, particularly in younger individuals. Methods: This was a cohort study in three population-based cohorts of community-dwelling individuals. A derivation cohort (n=16,260) was used to determine incidence and survival and develop a risk prediction model. The prediction model was validated in two cohorts (n=8,495). The primary outcome was 10-year risk of pneumonia hospitalization. Results: The crude and age-adjusted incidences of pneumonia were 6.71 and 9.43 cases/1,000 person-years (10-year risk was 6.15%). The 30-day and 1-year mortality were 16.5% and 31.5%. Although age was the most important risk factor (range of crude incidence rates, 1.69-39.13 cases/1,000 person-years for each 5-year increment from 45-85 years), 38% of pneumonia cases occurred in adults<65 years of age. The 30-day and 1-year mortality were 12.5% and 25.7% in those<65 years of age. Although most comorbidities were associated with higher risk of pneumonia, reduced lung function was the most important risk factor (relative risk=6.61 for severe reduction based on FEV1 by spirometry). A clinical risk prediction model based on age, smoking, and lung function predicted 10-year risk (area under curve [AUC]=0.77 and Hosmer-Lemeshow [HL] C statistic=0.12). Model discrimination and calibration were similar in the internal validation cohort (AUC=0.77; HL C statistic, 0.65) but lower in the external validation cohort (AUC=0.62; HL C statistic, 0.45). The model also calibrated well in blacks and younger adults. C-reactive protein and IL-6 were associated with higher pneumonia risk but did not improve model performance. Conclusions: Pneumonia hospitalization is common and associated with high mortality, even in younger healthy adults. Long-term risk of pneumonia can be predicted in community-dwelling adults with a simple clinical risk prediction model. C1 [Yende, Sachin; Alvarez, Karina; Weissfeld, Lisa A.; Angus, Derek C.] Univ Pittsburgh, Clin Res Invest & Syst Modeling Acute Illness CRI, Pittsburgh, PA 15261 USA. [Yende, Sachin; Angus, Derek C.] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15261 USA. [Alvarez, Karina; Weissfeld, Lisa A.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Loehr, Laura] Univ N Carolina, Dept Epidemiol, UNC Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Wunderink, Richard G.] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bauer, Doug C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Doug C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Yende, S (reprint author), Univ Pittsburgh, 606D Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM yendes@upmc.edu RI Newman, Anne/C-6408-2013; Angus, Derek/E-9671-2012; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781; London, Stephanie/0000-0003-4911-5290; Wunderink, Richard/0000-0002-8527-4195 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, H01-HC-85086, HL080295]; National Institute on Aging (NIA) [AG-023629]; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01-NR012459]; National Institutes of Health [K23GM083215]; Intramural Research Program of the National Institute of Environmental Health Sciences; Intramural Research Program of the NIA; National Institute of Neurological Disorders and Stroke FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) [Contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022]. This research was supported by NHLBI [Contracts HHSN268201200036C, HHSN268200800007C, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, H01-HC-85086 and Grant HL080295], with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided by the National Institute on Aging (NIA) [Grant AG-023629]. A full list of principal Cardiovascular Health Study investigators and institutions can be found at CHS-NHLBI. org. The Health, Aging, and Body Composition Study is supported by NIA [Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, and R01-NR012459]. This study was in part funded by National Institutes of Health [Grant K23GM083215 to Dr Yende] and Intramural Research Programs of the National Institute of Environmental Health Sciences and NIA. NR 37 TC 14 Z9 15 U1 2 U2 5 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 EI 1931-3543 J9 CHEST JI Chest PD SEP PY 2013 VL 144 IS 3 BP 1008 EP 1017 DI 10.1378/chest.12-2818 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 241JC UT WOS:000326161700040 PM 23744106 ER PT J AU Duma, D Cidlowski, JA AF Duma, Danielle Cidlowski, John A. TI Glucocorticoids, sex and life and death SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Duma, Danielle; Cidlowski, John A.] NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2013 VL 31 IS 5 BP 818 EP 818 PG 1 WC Rheumatology SC Rheumatology GA 243ZI UT WOS:000326356500031 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Capillary array waveguide amplified fluorescence detector for mHealth SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Microfabrication; Microfluidics; CMOS; Fluorescence; Mobile phone; Smartphone ID STAPHYLOCOCCAL-ENTEROTOXIN-B; GLOBAL HEALTH; FOOD SAMPLES; CELL-PHONE; BIOSENSOR; IMMUNOSENSOR; CARE; PLATFORM; IMMUNOASSAY; ANALYTES AB Mobile health (mHealth) analytical technologies are potentially useful for carrying out modern medical diagnostics in resource-poor settings. Effective mHealth devices for underserved populations need to be simple, low cost, and portable. Although cell phone cameras have been used for biodetection, their sensitivity is a limiting factor because currently it is too low to be effective for many mHealth applications, which depend on detection of weak fluorescent signals. To improve the sensitivity of portable phones, a capillary tube array was developed to amplify fluorescence signals using their waveguide properties. An array configured with 36 capillary tubes was demonstrated to have a similar to 100x increase in sensitivity, lowering the limit of detection (LOD) of mobile phones from 1000 nM to 10 nM for fluorescein. To confirm that the amplification was due to waveguide behavior, we coated the external surfaces of the capillaries with silver. The silver coating interfered with the waveguide behavior and diminished the fluorescence signal, thereby proving that the waveguide behavior was the main mechanism for enhancing optical sensitivity. The optical configuration described here is novel in several ways. First, the use of capillaries waveguide properties to improve detection of weak florescence signal is new. Second we describe here a three dimensional illumination system, while conventional angular laser waveguide illumination is spot (or line), which is functionally one-dimensional illumination, can illuminate only a single capillary or a single column (when a line generator is used) of capillaries and thus inherently limits the multiplexing capability of detection. The planar illumination demonstrated in this work enables illumination of a two dimensional capillary array (e.g., x columns and y rows of capillaries). In addition, the waveguide light propagation via the capillary wall provides a third dimension for illumination along the axis of the capillaries. Such an array can potentially be used for sensitive analysis of multiple fluorescent detection assays simultaneously. The simple phone based capillary array approach presented in this paper is capable of amplifying weak fluorescent signals thereby improving the sensitivity of optical detectors based on mobile phones. This may allow sensitive biological assays to be measured with low sensitivity detectors and may make mHealth practical for many diagnostics applications, especially in resource-poor and global health settings. Published by Elsevier B.V. C1 [Balsam, Joshua; Rasooly, Avraham] US FDA, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Div Canc Biol, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), US FDA, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 53 TC 7 Z9 7 U1 6 U2 43 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD SEP PY 2013 VL 186 BP 711 EP 717 DI 10.1016/j.snb.2013.06.030 PG 7 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 215PU UT WOS:000324223600095 PM 24039345 ER PT J AU Belle, SH Berk, PD Courcoulas, AP Engel, S Flum, DR Gourash, W Horlick, M Hsu, JY Khandelwal, S Mitchell, JE O'Rourke, RW Pories, W Schrope, B Wolfe, B AF Belle, Steven H. Berk, Paul D. Courcoulas, Anita P. Engel, Scott Flum, David R. Gourash, William Horlick, Mary Hsu, Jesse Y. Khandelwal, Saurabh Mitchell, James E. O'Rourke, Robert W. Pories, Walter Schrope, Beth Wolfe, Bruce CA LABS Consortium Weight Change TI Reporting weight change: standardized reporting accounting for baseline weight SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Article DE Obesity; Bariatric surgery; Weight change ID LONGITUDINAL ASSESSMENT; BARIATRIC SURGERY; SAFETY AB Background: Although it is recognized that a standardized approach to reporting weight change is essential to meaningful comparisons among cohorts and across studies, consensus is lacking. This study aimed to propose a method of reporting weight change that would allow meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS). Methods: Relationships among several measures of weight change are described. Results from an observational, longitudinal cohort study of adults undergoing bariatric surgery and from simulation studies are used to illustrate the proposed method. Results: Baseline weight is a critical parameter when assessing weight change. Men undergoing a bariatric procedure other than gastric bypass or adjustable band tended to have greater weight loss 12 months after surgery than men undergoing gastric bypass when not accounting for baseline weight, but the opposite was found when results were adjusted for baseline weight. Simulation results show that with relatively modest sample sizes, the adjusted weight loss was significantly different between the 2 groups of men. Conclusion: A consistent metric for reporting weight loss after bariatric surgery is essential to interpret outcomes across studies and among subgroups. The baseline weight adjusted percent of weight loss (A%WL) uses a standard population (e.g., the LABS cohort) to account for differences between cohorts with respect to baseline weight, and its use can change the interpretation of results compared with an unadjusted measure. (c) 2013 American Society for Metabolic and Bariatric Surgery. All rights reserved. C1 [Belle, Steven H.; Hsu, Jesse Y.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Berk, Paul D.] Columbia Univ, Med Ctr, Dept Med, New York, NY USA. [Courcoulas, Anita P.; Gourash, William] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA 15261 USA. [Engel, Scott; Mitchell, James E.] Univ N Dakota, Sch Hlth & Sci, Dept Neurosci, Neuropsychiat Res Inst, Fargo, ND USA. [Flum, David R.; Khandelwal, Saurabh] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Horlick, Mary] NIDDK, Bethesda, MD USA. [O'Rourke, Robert W.; Wolfe, Bruce] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Pories, Walter] E Carolina Univ, Dept Surg, Greenville, NC USA. [Schrope, Beth] Columbia Univ, Med Ctr, Dept Surg, New York, NY USA. RP Belle, SH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Epidemiol Data Ctr, 130 DeSoto St,127 Parran Hall, Pittsburgh, PA 15261 USA. EM belle@edc.pitt.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DCC-U01-DK066557, U01-DK66667, UL1-RR024996, U01-DK66568, M01RR-00037, U01-DK66471, U01-DK66526, U01-DK66585, UL1-RR024153, U01-DK66555]; Cornell University Medical Center CTSC [UL1-RR024996]; CTRC [M01RR-00037, UL1-RR024153] FX This clinical study was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant numbers: DCC-U01-DK066557; Columbia-U01-DK66667 (in collaboration with Cornell University Medical Center CTSC, Grant UL1-RR024996); University of Washington-U01-DK66568 (in collaboration with CTRC, Grant M01RR-00037); Neuropsychiatric Research Institute-U01-DK66471; East Carolina University-U01-DK66526; University of Pittsburgh Medical Center-U01-DK66585 (in collaboration with CTRC, Grant UL1-RR024153); Oregon Health & Science University-U01-DK66555. NR 16 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD SEP-OCT PY 2013 VL 9 IS 5 BP 782 EP 789 DI 10.1016/j.soard.2012.11.006 PG 8 WC Surgery SC Surgery GA 236GG UT WOS:000325782900038 PM 23337770 ER PT J AU Brohl, AS Song, JY Lieberman, R Gause, B AF Brohl, Andrew S. Song, Joo Y. Lieberman, Ron Gause, Barry TI Synchronous Indolent Primary Gastrointestinal Lymphomas Managed Successfully With Conservative Measures SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE follicular lymphoma; extranodal marginal zone lymphoma; MALT; Helicobacter pylori ID GASTRIC MALT LYMPHOMA; HELICOBACTER-PYLORI ERADICATION; DUODENAL FOLLICULAR LYMPHOMA; B-CELL LYMPHOMA; TISSUE; IMMUNOGLOBULIN; TRANSLOCATION; TRACT; INFECTION; PATIENT AB We report the case of a 65-year-old man who presented with epigastric pain and guaic-positive stool. Upper and lower endoscopy revealed abnormalities in the gastric antrum and terminal ileum. Biopsy of these sites revealed histologically and immunophenotypically distinct lymphomas: gastric extranodal marginal zone lymphoma in the background of Helicobacter pylori infection and follicular lymphoma of the terminal ileum. After treatment with an H. pylori eradication regimen, repeat endoscopy showed resolution of the gastric extranodal marginal zone lymphoma and persistence of the ileal follicular lymphoma. Interestingly, molecular studies performed on the biopsy specimens revealed a common IgH rearrangement, suggesting a common precursor cell responsible for these two malignant processes. We present this unique case with a review of the literature, highlighting treatment principles for these two subtypes of indolent gastrointestinal non-Hodgkin lymphoma. C1 [Brohl, Andrew S.; Lieberman, Ron] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Song, Joo Y.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Gause, Barry] SAIC Frederick, Frederick, MD USA. RP Brohl, AS (reprint author), NCI, Med Oncol Branch, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM andrew.brohl@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 28 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD SEP-OCT PY 2013 VL 20 IS 5 BP 549 EP 553 DI 10.1097/MJT.0b013e3182246a6a PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219XB UT WOS:000324543900015 PM 22020085 ER PT J AU Nath, A Tyler, KL AF Nath, Avindra Tyler, Kenneth L. TI Novel Approaches and Challenges to Treatment of Central Nervous System Viral Infections SO ANNALS OF NEUROLOGY LA English DT Article ID WEST-NILE-VIRUS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HERPES-SIMPLEX ENCEPHALITIS; HUMAN-IMMUNODEFICIENCY-VIRUS; STEM-CELL TRANSPLANTATION; CD8(+) T-CELLS; CONJUGATED MORPHOLINO OLIGOMERS; HUMANIZED MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED TRIAL; NECROSIS FACTOR THERAPY AB Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available, including candidate thiazolide and pyrazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antiviral agents and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T lymphocytes has been used in humans and may provide an effective therapy for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. Ann Neurol 2013;74:412-422 C1 [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Tyler, Kenneth L.] Univ Colorado, Dept Neurol, Sch Med, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado, Dept Microbiol, Sch Med, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado, Dept Med, Sch Med, Aurora, CO USA. [Tyler, Kenneth L.] Denver Vet Adm Med Ctr, Neurol Serv, Denver, CO USA. RP Tyler, KL (reprint author), Univ Colorado, Sch Med, Neurol Mailstop B-182,Res Complex 2,12700 East 19, Aurora, CO 80045 USA. EM ken.tyler@ucdenver.edu FU NIAID NIH HHS [R21 AI101064]; NINDS NIH HHS [R01 NS076512] NR 122 TC 11 Z9 11 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2013 VL 74 IS 3 BP 412 EP 422 DI 10.1002/ana.23988 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 232BJ UT WOS:000325463100018 PM 23913580 ER PT J AU Chang, RL Wood, AW Huang, MT Xie, JG Cui, XX Reuhl, KR Boyd, DR Lin, Y Shih, WJ Balani, SK Yagi, H Jerina, DM Conney, AH AF Chang, Richard L. Wood, Alexander W. Huang, Mou Tuan Xie, Jian Guo Cui, Xiao Xing Reuhl, Kenneth R. Boyd, D. R. Lin, Yong Shih, Weichung Joe Balani, Suresh K. Yagi, Haruhiko Jerina, Donald M. Conney, Allan H. TI Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene SO CARCINOGENESIS LA English DT Article ID RECONSTITUTED CYTOCHROME-P-450 SYSTEM; POLYCYCLIC AROMATIC-HYDROCARBONS; MURINE TUMOR-MODELS; RAT-LIVER ENZYMES; DIOL-EPOXIDES; NEWBORN MICE; STEREOSELECTIVE METABOLISM; MAMMALIAN-CELLS; MOUSE SKIN; NITROGEN HETEROCYCLE AB Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3 beta,4 alpha-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3 alpha,4 beta-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice. C1 [Chang, Richard L.; Huang, Mou Tuan; Xie, Jian Guo; Cui, Xiao Xing; Conney, Allan H.] Rutgers State Univ, Susan Lehman Cullman Lab Canc Res, Dept Biol Chem, Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA. [Wood, Alexander W.] Hoffmann La Roche Inc, Roche Res Ctr, Nutley, NJ 07110 USA. [Reuhl, Kenneth R.] Ernest Mario Sch Pharm, Dept Pharmacol & Toxicol, Piscataway, NJ 08854 USA. [Boyd, D. R.; Balani, Suresh K.; Yagi, Haruhiko; Jerina, Donald M.] NIDDK, NIH, Bethesda, MD 20892 USA. [Lin, Yong; Shih, Weichung Joe] Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Lin, Yong; Shih, Weichung Joe] Univ Med & Dent New Jersey, Sch Publ Hlth, Dept Biostat, New Brunswick, NJ 08901 USA. [Conney, Allan H.] Guangdong Univ Technol, Allan H Conney Lab Anticanc Res, Guangzhou 510006, Guangdong, Peoples R China. RP Conney, AH (reprint author), Rutgers State Univ, Susan Lehman Cullman Lab Canc Res, Dept Biol Chem, Ernest Mario Sch Pharm, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM aconney@pharmacy.rutgers.edu FU Hoffmann-La Roche Inc.; Department of Chemical Biology at Rutgers; National Institutes of Health [CA49765, ES005022] FX Hoffmann-La Roche Inc.; Department of Chemical Biology at Rutgers; National Institutes of Health (CA49765, ES005022). NR 59 TC 3 Z9 3 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2013 VL 34 IS 9 BP 2184 EP 2191 DI 10.1093/carcin/bgt164 PG 8 WC Oncology SC Oncology GA 233ED UT WOS:000325547900027 PM 23671133 ER PT J AU Gidding, SS Liu, K Colangelo, LA Cook, NL Goff, DC Glasser, SP Gardin, JM Lima, JAC AF Gidding, Samuel S. Liu, Kiang Colangelo, Laura A. Cook, Nakela L. Goff, David C. Glasser, Stephen P. Gardin, Julius M. Lima, Joao A. C. TI Longitudinal Determinants of Left Ventricular Mass and Geometry The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE blood pressure; echocardiography; left ventricular mass; obesity; risk assessment ID SYSTOLIC BLOOD-PRESSURE; ECHOCARDIOGRAPHY; HYPERTROPHY; AMERICAN; OUTCOMES; WOMEN; MEN AB Background The purpose of this study was to identify determinants of 20-year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Methods and Results We studied 2426 black and white men and women (54.7% white) aged 43 to 55 years with cardiovascular risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, sex, race, body mass index, change in body mass index, mean arterial blood pressure, change in mean blood pressure, heart rate, change in heart rate, tobacco use, presence of diabetes mellitus, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased, whereas prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m(2.7) were year 5 LVM, year 5 and change in body mass index, year 5 and change in mean arterial pressure, year 5 and change in heart rate, baseline diabetes mellitus, and year 5 tobacco and alcohol use (overall r(2)=0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in body mass index, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes mellitus (overall r(2)=0.11). Conclusions Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult cardiovascular risk traits and change in these traits predicted change in LV mass/geometry. C1 [Gidding, Samuel S.] Alfred I DuPont Hosp Children, Nemours Cardiac Ctr, Wilmington, DE 19803 USA. [Liu, Kiang; Colangelo, Laura A.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Cook, Nakela L.] NHLBI, Bethesda, MD 20892 USA. [Goff, David C.] Univ Colorado, Denver, CO 80202 USA. [Glasser, Stephen P.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Gardin, Julius M.] Hackensack Univ Med Ctr, Dept Med, Hackensack, NJ USA. [Lima, Joao A. C.] Johns Hopkins Univ Hosp, Dept Med, Baltimore, MD USA. RP Gidding, SS (reprint author), Alfred I DuPont Hosp Children, Nemours Cardiac Ctr, Wilmington, DE 19803 USA. EM sgidding@nemours.org OI Glasser, Stephen/0000-0001-9620-6406 FU CARDIA [N01-HC-48047-N01-HC-48050, N01-HC-95095]; Echocardiography reading centers [N01-HC-45134, NIH NHLBI-HC-09-09] FX CARDIA is funded by the CARDIA contract (N01-HC-48047-N01-HC-48050 and N01-HC-95095) and a subcontract with the Echocardiography reading centers at year 5 (N01-HC-45134) and at year 25 (NIH NHLBI-HC-09-09). NR 20 TC 31 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD SEP PY 2013 VL 6 IS 5 BP 769 EP 775 DI 10.1161/CIRCIMAGING.112.000450 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 219RQ UT WOS:000324526900024 PM 23922005 ER PT J AU Navarro, VJ Bonkovsky, HL Hwang, SI Vega, M Barnhart, H Serrano, J AF Navarro, Victor J. Bonkovsky, Herbert L. Hwang, Sun-Il Vega, Maricruz Barnhart, Huiman Serrano, Jose TI Catechins in Dietary Supplements and Hepatotoxicity SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Green tea extract; Hepatotoxin; Contamination; EGCG; Hepatocellular jaundice ID GALLATE EGCG PREPARATIONS; INDUCED LIVER-INJURY; TEA CAMELLIA-SINENSIS; GREEN TEA; EPIGALLOCATECHIN GALLATE; UNITED-STATES; SAFETY; HEPATITIS; TOXICITY; EXTRACTS AB Background Many herbal dietary supplements (HDS) contain green tea extract (GTE) and its component catechins, although their presence may not always be indicated on the product label. Purpose Because GTE and catechins have been implicated in human hepatotoxicity in several case reports, our objective was to determine whether catechins were present in HDS that were implicated in hepatotoxicity, even if not identified among the labeled ingredients, and whether these compounds could be associated with liver injury. Methods We assayed 97 HDS implicated in human hepatotoxicity for catechins. Results We found that 29 of 73 HDS (39.7 %) that did not identify GTE or any of its component catechins on their label contained catechins. Among patients with confirmed hepatotoxicity, there was no statistically significant association between the presence of catechin or the dose consumed and liver injury causality score, severity, or pattern of liver injury. Catechin levels tended to be highest in products used for weight loss, although catechin concentrations were low in most products. Conclusions Many HDS commonly contain catechins that are implicated in hepatotoxicity, although their presence may not be indicated on the product label. Although our results did not establish an association between GTE or catechins with hepatotoxicity, they highlight some of the many complexities and uncertainties that surround the attribution of drug-induced liver injury (DILI) to HDS. C1 [Navarro, Victor J.; Vega, Maricruz] Albert Einstein Med Ctr, Div Hepatol, Philadelphia, PA 19141 USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, LBP Ctr, Charlotte, NC 28236 USA. [Hwang, Sun-Il] Carolinas Med Ctr, Cannon Res Ctr, Charlotte, NC 28203 USA. [Barnhart, Huiman] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Duke Clin Res Inst, Durham, NC USA. [Serrano, Jose] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. RP Navarro, VJ (reprint author), Albert Einstein Med Ctr, Div Hepatol, 5401 Old York Rd,Suite 505, Philadelphia, PA 19141 USA. EM NavarroV@einstein.edu; Herbert.Bonkovsky@carolinashealthcare.org; sunil.hwang@carolinashealthcare.org; VegaMari@einstein.edu; huiman.barnhart@duke.edu; SerranoJ@extra.niddk.nih.gov OI Hwang, Sunil/0000-0003-0600-3694 FU NIDDK, NIH FX This study was supported by the NIDDK, NIH. See website for a complete list of DILIN funding sources, DILIN sites, investigators, co-investigators, coordinators, and staff https://dilin.dcri.duke.edu/publications-1. NR 29 TC 31 Z9 31 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD SEP PY 2013 VL 58 IS 9 BP 2682 EP 2690 DI 10.1007/s10620-013-2687-9 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 215YE UT WOS:000324246300054 PM 23625293 ER PT J AU Liu, LY Fox, CS North, TE Goessling, W AF Liu, Leah Y. Fox, Caroline S. North, Trista E. Goessling, Wolfram TI Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development SO DISEASE MODELS & MECHANISMS LA English DT Article ID NONALCOHOLIC FATTY LIVER; GENOME-WIDE ASSOCIATION; HEREDITARY FRUCTOSE INTOLERANCE; HEPATIC STEATOSIS; SUSCEPTIBILITY; ACETAMINOPHEN; VARIANTS; DISEASE; DISRUPTION; PROMOTER AB Genome-wide association studies (GWAS) have revealed numerous associations between many phenotypes and gene candidates. Frequently, however, further elucidation of gene function has not been achieved. A recent GWAS identified 69 candidate genes associated with elevated liver enzyme concentrations, which are clinical markers of liver disease. To investigate the role of these genes in liver homeostasis, we narrowed down this list to 12 genes based on zebrafish orthology, zebrafish liver expression and disease correlation. To assess the function of gene candidates during liver development, we assayed hepatic progenitors at 48 hours post fertilization (hpf) and hepatocytes at 72 hpf using in situ hybridization following morpholino knockdown in zebrafish embryos. Knockdown of three genes (pnpla3, pklr and mapk10) decreased expression of hepatic progenitor cells, whereas knockdown of eight genes (pnpla3, cpn1, trib1, fads2, slc2a2, pklr, mapk10 and samm50) decreased cell-specific hepatocyte expression. We then induced liver injury in zebrafish embryos using acetaminophen exposure and observed changes in liver toxicity incidence in morphants. Prioritization of GWAS candidates and morpholino knockdown expedites the study of newly identified genes impacting liver development and represents a feasible method for initial assessment of candidate genes to instruct further mechanistic analyses. Our analysis can be extended to GWAS for additional disease-associated phenotypes. C1 [Liu, Leah Y.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA 01702 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [North, Trista E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [North, Trista E.; Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. [Goessling, Wolfram] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. RP Goessling, W (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. EM wgoessling@partners.org OI Goessling, Wolfram/0000-0001-9972-1569 FU Harvard Stem Cell Institute; National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK090311]; National Science Foundation FX This work was supported by a seed grant from the Harvard Stem Cell Institute and the National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK090311 (to W.G.). L.Y.L. was supported by the National Science Foundation. NR 33 TC 6 Z9 6 U1 2 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD SEP PY 2013 VL 6 IS 5 BP 1271 EP 1278 DI 10.1242/dmm.011726 PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 236IV UT WOS:000325789600022 PM 23813869 ER PT J AU Zhang, XZ Beckles, GL Chou, CF Saaddine, JB Wilson, MR Lee, PP Parvathy, N Ryskulova, A Geiss, LS AF Zhang, Xinzhi Beckles, Gloria L. Chou, Chiu-Fang Saaddine, Jinan B. Wilson, M. Roy Lee, Paul P. Parvathy, Nair Ryskulova, Asel Geiss, Linda S. TI Socioeconomic Disparity in Use of Eye Care Services Among US Adults With Age-Related Eye Diseases National Health Interview Survey, 2002 and 2008 SO JAMA OPHTHALMOLOGY LA English DT Article ID BLUE MOUNTAINS EYE; VISUAL IMPAIRMENT; UNITED-STATES; OLDER-ADULTS; MACULAR DEGENERATION; SOCIAL DETERMINANTS; 2020 VISION; PREVALENCE; PEOPLE; RISK AB IMPORTANCE Individuals with age-related eye disease (ARED) need to use eye care services for detection, assessment, and care at regular intervals. OBJECTIVE To explore the association between socioeconomic position (SEP) and use of eye care services among US adults with self-reported ARED during 2002 and 2008. DESIGN Data were from the National Health Interview Survey 2002 and 2008. We used multiple logistic regression to estimate predictive margins, controlling for other factors, and we used the slope index of inequality to measure the relationship between SEP and use of eye care services across the entire distributions of poverty-income ratio (PIR) and educational attainment. SETTING A cross-sectional, nationally representative sample of adults, with prevalence estimates weighted to represent the civilian, noninstitutionalized US population. PARTICIPANTS The sample included US participants in the 2002 (n = 3586) and the 2008 (n = 3104) National Health Interview Survey who were at least 40 years old and reported any ARED (age-related macular degeneration, cataract, diabetic retinopathy, or glaucoma). MAIN OUTCOMES AND MEASURES Use of eye care services; SEP was measured by the PIR and educational attainment. RESULTS In 2002, persons with ARED and a PIR of less than 1.50 were significantly less likely than those with a PIR of at least 5 to report visiting an eye care provider (62.7% vs 80.1%; P < .001) or undergoing a dilated eye examination in the past 12 months (64.3% vs 80.4%; P < .001), after adjustment for other factors. Similarly, persons with less than a high school education were less likely than those with at least a college education to report a visit to an eye care provider (62.9% vs 80.8%; P < .001) or dilated eye examination (64.8% vs 81.4%; P < .001). In 2002, the slope index of inequality showed statistically significant differences for eye care provider visits across the levels of education (24.4; P = .006), and in 2008, it showed a significant difference for eye care provider visits across the levels of educational attainment (25.2; P = .049) and PIR (21.8; P = .01). CONCLUSIONS AND RELEVANCE Significant differences in the use of eye care services by SEP persist among US adults with eye diseases. C1 [Zhang, Xinzhi; Wilson, M. Roy] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Beckles, Gloria L.; Chou, Chiu-Fang; Saaddine, Jinan B.; Parvathy, Nair; Geiss, Linda S.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Lee, Paul P.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Ryskulova, Asel] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Zhang, XZ (reprint author), Natl Inst Minor Hlth & Hlth Dispar, Div Data Management & Sci Reporting, NIH, 6707 Democracy Blvd,Ste 800, Bethesda, MD 20892 USA. EM xinzhi.zhang@nih.gov FU National Center for Health Statistics, Centers for Disease Control and Prevention FX This study was supported by the National Center for Health Statistics, Centers for Disease Control and Prevention. NR 52 TC 12 Z9 12 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD SEP PY 2013 VL 131 IS 9 BP 1198 EP 1206 DI 10.1001/jamaophthalmol.2013.4694 PG 9 WC Ophthalmology SC Ophthalmology GA 232HC UT WOS:000325482400012 PM 23868137 ER EF