FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Wang, YQ Gildersleeve, JC Basu, A Zimmt, MB AF Wang, Yaqi Gildersleeve, Jeffrey C. Basu, Amit Zimmt, Matthew B. TI Photo- and Biophysical Studies of Lectin-Conjugated Fluorescent Nanoparticles Reduced Sensitivity in High Density Assays SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID DOPED SILICA NANOPARTICLES; CONCANAVALIN-A; BIOCONJUGATED NANOPARTICLES; ANGSTROM RESOLUTION; SERUM ANTIBODIES; QUANTUM DOTS; MICROARRAY; PHOTOSTABILITY; AGGREGATION; RECOGNITION AB Lectin-conjugated, fluorescent silica nanoparticles (fNP) have been developed for carbohydrate-based histopathology evaluations of epithelial tissue biopsies The fNP platform was selected for its enhanced emissive brightness compared to direct dye labeling Carbohydrate microarray studies were performed to compare the carbohydrate selectivity of the mannose-recognizing lectin Concanavalin A (ConA) before and after conjugation to fluorescent silica nanoparticles (ConA-fNP) These studies revealed surprisingly low emission intensities upon staining with ConA-fNP compared to those with biotin-ConA/Cy3-streptavidin staining A series of photophysical and biophysical characterizations of the fNP and ConA-fNP conjugates were performed to probe the low sensitivity from fNP in the microarray assays Up to 1200 fluorescein (FL) and 80 tetramethylrhodamine (TR) dye molecules were incorporated into 46 nm diameter fNP, yielding emissive brightness values 400 and 35 times larger than the individual dye molecules, respectively ConA lectin conjugated to carboxylic acid surface-modified nanoparticles covers 15-30% of the fNP surface The CD spectra and mannose substrate selectivity of ConA conjugated to the fNP differed slightly compared to that of soluble ConA Although, the high emissive brightness of fNP enhances detection sensitivity for samples with low analyte densities, large fNP diameters limit fNP recruitment and binding to samples with high analyte densities The high analyte density and nearly two-dimensional target format of carbohydrate microarrays make probe size a critical parameter In this application, fNP labels afford minimal sensitivity advantage compared to direct dye labeling C1 [Wang, Yaqi; Basu, Amit; Zimmt, Matthew B.] Brown Univ, Dept Chem, Providence, RI 02912 USA. [Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Zimmt, MB (reprint author), Brown Univ, Dept Chem, Providence, RI 02912 USA. RI Gildersleeve, Jeffrey/N-3392-2014 FU NIH NCI; Brown University; Chemistry Department; National Science Foundation [CHE0616474] FX This research was supported, in part by the Intramural Research Program of the NIH NCI (J C G) by a Brown University Seed Fund Award (A B), by a Chemistry Department Seed Fund Award (A B, M Z), by a Brown University Wernig Fellowship (Y W) and by the National Science Foundation (CHE0616474) NR 60 TC 9 Z9 9 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD NOV 18 PY 2010 VL 114 IS 45 BP 14487 EP 14494 DI 10.1021/jp101854m PG 8 WC Chemistry, Physical SC Chemistry GA 677US UT WOS:000284018000045 PM 20496897 ER PT J AU Daffis, S Szretter, KJ Schriewer, J Li, JQ Youn, S Errett, J Lin, TY Schneller, S Zust, R Dong, HP Thiel, V Sen, GC Fensterl, V Klimstra, WB Pierson, TC Buller, RM Gale, M Shi, PY Diamond, MS AF Daffis, Stephane Szretter, Kristy J. Schriewer, Jill Li, Jianqing Youn, Soonjeon Errett, John Lin, Tsai-Yu Schneller, Stewart Zust, Roland Dong, Hongping Thiel, Volker Sen, Ganes C. Fensterl, Volker Klimstra, William B. Pierson, Theodore C. Buller, R. Mark Gale, Michael, Jr. Shi, Pei-Yong Diamond, Michael S. TI 2 '-O methylation of the viral mRNA cap evades host restriction by IFIT family members SO NATURE LA English DT Article ID NILE-VIRUS-INFECTION; PROTEINS; GENES; METHYLTRANSFERASE; TRANSLATION; IDENTIFICATION; INITIATION; INDUCTION; PROTECTS; ALPHA AB Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2'-O positions of the 5' guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability(1), the function of 2'-O methylation has remained uncertain since its discovery 35 years ago(2-4). Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2'-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2'-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2'-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2'-O methylation of the 5' cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2'-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells. C1 [Daffis, Stephane; Szretter, Kristy J.; Youn, Soonjeon; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Li, Jianqing; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Buller, R. Mark; Gale, Michael, Jr.; Shi, Pei-Yong; Diamond, Michael S.] Midw Reg Ctr Biodef & Emerging Infect Dis Res, St Louis, MO 63104 USA. [Schriewer, Jill; Buller, R. Mark] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, St Louis, MO 63104 USA. [Errett, John; Gale, Michael, Jr.] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA. [Lin, Tsai-Yu; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Schneller, Stewart] Auburn Univ, Dept Chem & Biochem, Auburn, AL 36849 USA. [Zust, Roland; Thiel, Volker] Kantonal Hosp St Gallen, Inst Immunobiol, CH-9007 St Gallen, Switzerland. [Thiel, Volker] Univ Zurich, Vetsuisse Fac, CH-8006 Zurich, Switzerland. [Dong, Hongping; Shi, Pei-Yong] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA. [Sen, Ganes C.; Fensterl, Volker] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44195 USA. [Klimstra, William B.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. [Buller, R. Mark; Gale, Michael, Jr.; Shi, Pei-Yong; Diamond, Michael S.] Pacific NW Reg Ctr Biodef & Emerging Infect Dis R, St Louis, MO 63104 USA. [Buller, R. Mark; Gale, Michael, Jr.; Shi, Pei-Yong; Diamond, Michael S.] NE Reg Ctr Biodef & Emerging Infect Dis Res, St Louis, MO 63104 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu RI Lin, Tsai-Yu/B-8873-2016; OI Lin, Tsai-Yu/0000-0002-8076-1584; Gale, Michael/0000-0002-6332-7436; Szretter, Kristy/0000-0003-0391-2307 FU National Institutes of Health [U54 AI081680, U19 AI083019, R01 AI074973, R01 AI56540, U54 AI057160, U54 AI057158, R01 CA068782]; Swiss National Science Foundation [3100A0-118425/1]; Novartis Foundation FX This work was supported by National Institutes of Health grants U54 AI081680, U19 AI083019 and R01 AI074973 (to M.G. and M.S.D.), R01 AI56540 (to S.S.), U54 AI057160 (to R.M.B.) and U54 AI057158 (to P.Y.S.), R01 CA068782 (to G.C.S.) the Swiss National Science Foundation, 3100A0-118425/1, and the Novartis Foundation (to V.T. and R.Z.). We thank H. Virgin and B. Moss for reading the manuscript. NR 25 TC 241 Z9 252 U1 3 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD NOV 18 PY 2010 VL 468 IS 7322 BP 452 EP 456 DI 10.1038/nature09489 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 681KP UT WOS:000284313100046 PM 21085181 ER PT J AU Lambert, LC Fauci, AS AF Lambert, Linda C. Fauci, Anthony S. TI CURRENT CONCEPTS Influenza Vaccines for the Future SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; RESEARCH-AND-DEVELOPMENT; PANDEMIC INFLUENZA; MF59-ADJUVANTED INFLUENZA; ANTIBODY-RESPONSE; UNITED-STATES; DNA VACCINES; A VIRUSES; IMMUNOGENICITY; SAFETY C1 [Lambert, Linda C.] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Fauci, Anthony S.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. RP Lambert, LC (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM lclambert@mail.nih.gov NR 64 TC 151 Z9 164 U1 7 U2 34 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 NOV 18 PY 2010 VL 363 IS 21 BP 2036 EP 2044 DI 10.1056/NEJMra1002842 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 681KC UT WOS:000284310000008 PM 21083388 ER PT J AU Aumakhan, B Hardick, A Quinn, TC Laeyendecker, O Gange, SJ Beyrer, C Cox, C Anastos, K Cohen, M Greenblatt, RM Merenstein, DJ Minkoff, H Nowicki, M Gaydos, CA AF Aumakhan, Bulbulgul Hardick, Andrew Quinn, Thomas C. Laeyendecker, Oliver Gange, Stephen J. Beyrer, Chris Cox, Christopher Anastos, Kathryn Cohen, Mardge Greenblatt, Ruth M. Merenstein, Daniel J. Minkoff, Howard Nowicki, Marek Gaydos, Charlotte A. TI Genital herpes evaluation by quantitative TaqMan PCR: correlating single detection and quantity of HSV-2 DNA in cervicovaginal lavage fluids with cross-sectional and longitudinal clinical data SO VIROLOGY JOURNAL LA English DT Article ID POLYMERASE-CHAIN-REACTION; SIMPLEX-VIRUS TYPE-2; WOMENS INTERAGENCY HIV; INFECTION; TRACT; SUPPRESSION; ACYCLOVIR; CULTURE; SAMPLES; ASSAY AB Objective: To evaluate the utility of a single quantitative PCR (qPCR) measurement of HSV (HSV-1&2) DNA in cervicovaginal lavage (CVL) specimens collected from women with predominantly chronic HSV-2 infection in assessing genital HSV shedding and the clinical course of genital herpes (GH) within a cohort with semiannual schedule of follow up and collection of specimens. Methods: Two previously described methods used for detection of HSV DNA in mucocutaneous swab samples were adapted for quantification of HSV DNA in CVLs. Single CVL specimens from 509 women were tested. Presence and quantity of CVL HSV DNA were explored in relation to observed cross-sectional and longitudinal clinical data. Results: The PCR assay was sensitive and reproducible with a limit of quantification of similar to 50 copies per milliliter of CVL. Overall, 7% of the samples were positive for HSV-2 DNA with median log(10) HSV-2 DNA copy number of 3.9 (IQR: 2.6-5.7). No HSV-1 was detected. Presence and quantity of HSV-2 DNA in CVL directly correlated with the clinical signs and symptoms of presence of active symptomatic disease with frequent recurrences. Conclusion: Single qPCR measurement of HSV DNA in CVL fluids of women with chronic HSV-2 infection provided useful information for assessing GH in the setting of infrequent sampling of specimens. Observed positive correlation of the presence and quantity of HSV-2 DNA with the presence of active and more severe course of HSV-2 infection may have clinical significance in the evaluation and management of HSV-2 infected patients. C1 [Aumakhan, Bulbulgul; Gange, Stephen J.; Beyrer, Chris; Cox, Christopher] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hardick, Andrew; Quinn, Thomas C.; Laeyendecker, Oliver; Gaydos, Charlotte A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Cohen, Mardge] Cook Cty Med Ctr, Chicago, IL USA. [Merenstein, Daniel J.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Minkoff, Howard] Maimonides Hosp, Brooklyn, NY 11219 USA. [Minkoff, Howard] SUNY Downstate, Brooklyn, NY USA. [Nowicki, Marek] Univ So Calif, Los Angeles, CA USA. RP Aumakhan, B (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. EM an_bulbul@yahoo.com RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Gange, Stephen/0000-0001-7842-512X FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131] FX Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 36 TC 9 Z9 9 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD NOV 18 PY 2010 VL 7 AR 328 DI 10.1186/1743-422X-7-328 PG 8 WC Virology SC Virology GA 693QV UT WOS:000285240600001 PM 21087488 ER PT J AU Simeon, FG Wendahl, MT Pike, VW AF Simeon, Fabrice G. Wendahl, Matthew T. Pike, Victor W. TI The [F-18]2-fluoro-1,3-thiazolyl moiety-an easily-accessible structural motif for prospective molecular imaging radiotracers SO TETRAHEDRON LETTERS LA English DT Article DE Radiofluorination; 1,3-Thiazole; Microwave-assisted synthesis ID POSITRON-EMISSION-TOMOGRAPHY; DIARYLIODONIUM-SALTS; F-18; FLUORINATION; ANTAGONIST; CONVERSION; FLUORIDES; CHEMISTRY; ION AB 2-Fluoro-1,3-thiazoles were rapidly and efficiently labeled with no-carrier-added fluorine-18 (t(1/2) = 109.7 min) by treatment of readily prepared 2-halo precursors with cyclotron-produced [F-18]fluoride ion. The [F-18]2-fluoro-1,3-thiazolyl moiety constitutes a new and easily-labeled structural motif for prospective molecular imaging radiotracers. Published by Elsevier Ltd. C1 [Simeon, Fabrice G.; Wendahl, Matthew T.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Simeon, FG (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM simeonf@mail.nih.gov FU National Institutes of Health (NIMH) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIMH). NR 38 TC 6 Z9 6 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD NOV 17 PY 2010 VL 51 IS 46 BP 6034 EP 6036 DI 10.1016/j.tetlet.2010.09.037 PG 3 WC Chemistry, Organic SC Chemistry GA 677FX UT WOS:000283975600019 PM 21057601 ER PT J AU Hickman, AB James, JA Barabas, O Pasternak, C Ton-Hoang, B Chandler, M Sommer, S Dyda, F AF Hickman, Alison Burgess James, Jeffrey A. Barabas, Orsolya Pasternak, Cecile Ton-Hoang, Bao Chandler, Michael Sommer, Suzanne Dyda, Fred TI DNA recognition and the precleavage state during single-stranded DNA transposition in D. radiodurans SO EMBO JOURNAL LA English DT Article DE Deinococcus; insertion sequence; IS; mobile element; transposition ID DEINOCOCCUS-RADIODURANS; CRYSTAL-STRUCTURE; INSERTION SPECIFICITY; CONJUGATIVE RELAXASE; HELICOBACTER-PYLORI; DIFFRACTION DATA; BINDING; REPAIR; CLEAVAGE; COMPLEX AB Bacterial insertion sequences (ISs) from the IS200/IS605 family encode the smallest known DNA transposases and mobilize through single-stranded DNA transposition. Transposition by one particular family member, ISDra2 from Deinococcus radiodurans, is dramatically stimulated upon massive gamma irradiation. We have determined the crystal structures of four ISDra2 transposase/IS end complexes; combined with in vivo activity assays and fluorescence anisotropy binding measurements, these have revealed the molecular basis of strand discrimination and transposase action. The structures also show that previously established structural rules of target site recognition that allow different specific sequences to be targeted are only partially conserved among family members. Furthermore, we have captured a fully assembled active site including the scissile phosphate bound by a divalent metal ion cofactor (Cd(2+)) that supports DNA cleavage. Finally, the observed active site rearrangements when the transposase binds a metal ion in which it is inactive provide a clear rationale for metal ion specificity. C1 [Hickman, Alison Burgess; James, Jeffrey A.; Barabas, Orsolya; Dyda, Fred] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Pasternak, Cecile; Sommer, Suzanne] Univ Paris 11, Inst Genet & Microbiol, CNRS, LRC CEA 42V,UMR 8621, F-91405 Orsay, France. [Ton-Hoang, Bao; Chandler, Michael] CNRS, Lab Microbiol & Genet Mol, Toulouse, France. RP Dyda, F (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov RI Barabas, Orsolya/F-3961-2012; OI Barabas, Orsolya/0000-0002-2873-5872; Chandler, Michael/0000-0002-0292-6662 FU National Institute of Diabetes, Digestive, and Kidney Diseases of the National Institutes of Health; Centre National de la Recherche Scientifique (France); ANR; US. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; European contract [LSHM-CT-2005-019023] FX We thank A Bailone for fruitful discussions and G Coste for expert technical assistance. This work was supported by the Intramural Program of the National Institute of Diabetes, Digestive, and Kidney Diseases of the National Institutes of Health (FD), the Centre National de la Recherche Scientifique (France, MC and SS), European contract LSHM-CT-2005-019023 (MC), and ANR grant Mobigen (MC and SS). Some data were collected at the Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory. Use of the APS was supported by the US. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. NR 41 TC 22 Z9 22 U1 0 U2 4 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 NOV 17 PY 2010 VL 29 IS 22 BP 3840 EP 3852 DI 10.1038/emboj.2010.241 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695SB UT WOS:000285391800010 PM 20890269 ER PT J AU Zapata, A Minney, VL Shippenberg, TS AF Zapata, Agustin Minney, Vicki L. Shippenberg, Toni S. TI Shift from Goal-Directed to Habitual Cocaine Seeking after Prolonged Experience in Rats SO JOURNAL OF NEUROSCIENCE LA English DT Article ID COMPULSIVE DRUG-SEEKING; DORSAL STRIATUM; BASAL GANGLIA; REINFORCER DEVALUATION; MEMORY-SYSTEMS; ADDICTION; BEHAVIOR; DOPAMINE; INACTIVATION; LESIONS AB The development of drug-seeking habits is implicated in the transition from recreational drug use to addiction. Using a drug seeking/taking chained schedule of intravenous cocaine self-administration and reward devaluation methods in rats, the present studies examined whether drug seeking that is initially goal-directed becomes habitual after prolonged drug seeking and taking. Devaluation of the outcome of the drug seeking link (i.e., the drug taking link of the chained schedule) by extinction significantly decreased drug seeking indicating that behavior is goal-directed rather than habitual. With, however, more prolonged drug experience, animals transitioned to habitual cocaine seeking. Thus, in these animals, cocaine seeking was insensitive to outcome devaluation. Moreover, when the dorsolateral striatum, an area implicated in habit learning, was transiently inactivated, outcome devaluation was effective in decreasing drug seeking indicating that responding was no longer habitual but had reverted to control by the goal-directed system. These studies provide direct evidence that cocaine seeking becomes habitual with prolonged drug experience and describe a rodent model with which to study the neural mechanisms underlying the transition from goal-directed to habitual drug seeking. C1 [Zapata, Agustin; Minney, Vicki L.; Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Zapata, A (reprint author), NIDA, Integrat Neurosci Sect, NIH, Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. EM Azapata@mail.nih.gov FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This work was supported by funding from the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 45 TC 96 Z9 99 U1 2 U2 18 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 17 PY 2010 VL 30 IS 46 BP 15457 EP 15463 DI 10.1523/JNEUROSCI.4072-10.2010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 681XU UT WOS:000284358500012 PM 21084602 ER PT J AU Torborg, CL Nakashiba, T Tonegawa, S McBain, CJ AF Torborg, Christine L. Nakashiba, Toshiaki Tonegawa, Susumu McBain, Chris J. TI Control of CA3 Output by Feedforward Inhibition Despite Developmental Changes in the Excitation-Inhibition Balance SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MOSSY FIBER SYNAPSES; LONG-TERM DEPRESSION; HIPPOCAMPAL INTERNEURONS; SYNAPTIC-TRANSMISSION; PYRAMIDAL NEURONS; RAT HIPPOCAMPUS; CELLS; INNERVATION; PLASTICITY; DISCHARGE AB In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, glutamatergic mossy fiber (MF) synapses onto CA3 pyramidal cells (PCs) provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrate in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitate to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input can facilitate or depress in response to short trains of activity. Transgenic mice lacking the feedback inhibitory loop continue to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition is not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABA(A) receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings. C1 [Torborg, Christine L.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Dev Neurobiol, Bethesda, MD 20892 USA. [Nakashiba, Toshiaki; Tonegawa, Susumu] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Nakashiba, Toshiaki; Tonegawa, Susumu] MIT, RIKEN MIT Ctr Neural Circuit Genet, Cambridge, MA 02139 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Dev Neurobiol, Bldg 35, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov FU National Institute of Child Health and Human Development; Pharmacology Research Associate (PRAT) fellowship; National Institutes of Health [R01-MH078821, P50-MH58880] FX This study was supported by National Institute of Child Health and Human Development intramural funding to C.J.M., a Pharmacology Research Associate (PRAT) fellowship to C.L.T., and National Institutes of Health Grants R01-MH078821 and P50-MH58880 to S.T. We thank Brian Jeffries for providing technical support and Ken Pelkey for comments on the manuscript. NR 36 TC 28 Z9 28 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 17 PY 2010 VL 30 IS 46 BP 15628 EP 15637 DI 10.1523/JNEUROSCI.3099-10.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 681XU UT WOS:000284358500028 PM 21084618 ER PT J AU Gurnev, PA Harries, D Parsegian, VA Bezrukov, SM AF Gurnev, Philip A. Harries, Daniel Parsegian, V. Adrian Bezrukov, Sergey M. TI Osmotic stress regulates the strength and kinetics of sugar binding to the maltoporin channel SO JOURNAL OF PHYSICS-CONDENSED MATTER LA English DT Article ID BACTERIOPHAGE-LAMBDA RECEPTOR; OUTER-MEMBRANE PERMEABILITY; ESCHERICHIA-COLI; INCLUSION COMPLEXES; STRUCTURAL BASIS; TRANSPORT; TRANSLOCATION; MOLECULE; PORINS; CYCLODEXTRINS AB We study the effect of osmotic stress, exerted by salts, on carbohydrate binding to the sugar-specific bacterial channel maltoporin. When the channel is reconstituted into planar lipid bilayers, single events of its occlusion by sugar are seen as transient interruptions in the flow of small ions. We find that, for most salts, changes in the free energy of maltoporin-sugar binding vary linearly with solution osmotic pressure. Such a change in binding with solution osmolarity indicates that for each salt a constant number of salt-excluding water molecules is released upon sugar-maltoporin association at all salt concentrations. We find that larger numbers of water molecules are released upon binding of the cyclic carbohydrate beta-cyclodextrin (CD) than upon binding of the corresponding linear homologue maltoheptaose (m7). Remarkably, the extent to which salts affect the binding constants and rates depends sensitively on the type of salt; dehydration in solutions of different anions corresponds to the Hofmeister series. In sodium sulfate solutions, CD and m7 respectively release about 120 and 35 salt-excluding water molecules; in sodium chloride solutions, 35 and 15 waters. No water release is observed with sodium bromide. Finally, by adding adamantane, known to form an inclusion complex with CD, we can infer that CD not only dehydrates but also undergoes a conformational change upon binding to the channel. As a practical outcome, our results also demonstrate how osmotic stress can improve single-molecule detection of different solutes using protein-based nanopores. C1 [Harries, Daniel] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Harries, Daniel] Hebrew Univ Jerusalem, Fritz Haber Res Ctr, IL-91904 Jerusalem, Israel. [Gurnev, Philip A.; Bezrukov, Sergey M.] NIH, Lab Phys & Struct Biol, Program Phys Biol, NICHD, Bethesda, MD 20892 USA. [Parsegian, V. Adrian] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. RP Harries, D (reprint author), Hebrew Univ Jerusalem, Inst Chem, Edmond J Safra Campus, IL-91904 Jerusalem, Israel. EM daniel@huji.ac.il RI Harries, Daniel/F-7016-2012 OI Harries, Daniel/0000-0002-3057-9485 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to Donald Rau for fruitful discussions. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 33 TC 9 Z9 9 U1 2 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0953-8984 J9 J PHYS-CONDENS MAT JI J. Phys.-Condes. Matter PD NOV 17 PY 2010 VL 22 IS 45 AR 454110 DI 10.1088/0953-8984/22/45/454110 PG 8 WC Physics, Condensed Matter SC Physics GA 673HZ UT WOS:000283651400012 PM 21339598 ER PT J AU French, B Joo, J Geller, NL Kimmel, SE Rosenberg, Y Anderson, JL Gage, BF Johnson, JA Ellenberg, JH AF French, Benjamin Joo, Jungnam Geller, Nancy L. Kimmel, Stephen E. Rosenberg, Yves Anderson, Jeffrey L. Gage, Brian F. Johnson, Julie A. Ellenberg, Jonas H. CA COAG Clarification Optimal Anticoa TI Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial SO TRIALS LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; ALPHA-ALLOCATION; WARFARIN; EFFICIENCY; PREDICT AB Background: There is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patient's genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants. Methods: The statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subject's genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in CYP2C9 and VKORC1; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information. Results: We determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either CYP2C9 or VKORC1 and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%. Conclusions: In a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention. C1 [French, Benjamin; Kimmel, Stephen E.; Ellenberg, Jonas H.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Joo, Jungnam; Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Rosenberg, Yves] NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD 20892 USA. [Anderson, Jeffrey L.] Intermt Med Ctr, JL Sorenson Heart & Lung Ctr, Murray, UT 84107 USA. [Gage, Brian F.] Washington Univ, Sch Med, Div Gen Med Sci, St Louis, MO 63110 USA. [Johnson, Julie A.] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. RP French, B (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, 423 Guardian Dr, Philadelphia, PA 19104 USA. EM bcfrench@upenn.edu FU National Heart, Lung and Blood Institute [N01 HV88210]; University of Pennsylvania FX We gratefully acknowledge the National Heart, Lung and Blood Institute (N01 HV88210) and the University of Pennsylvania for supporting this research, and two reviewers for comments that greatly improved the manuscript. NR 28 TC 54 Z9 54 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD NOV 17 PY 2010 VL 11 AR 108 DI 10.1186/1745-6215-11-108 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 692MN UT WOS:000285157000001 PM 21083927 ER PT J AU Millum, J Menikoff, J AF Millum, Joseph Menikoff, Jerry TI Streamlining Ethical Review SO ANNALS OF INTERNAL MEDICINE LA English DT Review AB The review system for human subjects research in the United States has been widely criticized in recent years for requirements that delay research without improving human subject protections. Any major reformulation of regulations may take some time to implement. However, current regulations often allow for streamlined ethics review that does not jeopardize-and may improve-protections for research participants. The authors discuss under-utilized options, including research that need not be classified as human subjects research, categories of studies that can be exempt from ethical review, studies that need only undergo expedited review by 1 institutional review board (IRB) member, and simplifying reviews of multicenter research by using the IRB of 1 institution. The authors speculate on multiple reasons for the underuse of these mechanisms and exhort IRBs and researchers to take advantage of these important opportunities to improve the review process. C1 [Millum, Joseph] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Off Human Res Protect, Rockville, MD USA. RP Millum, J (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM millumj@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 13 TC 16 Z9 16 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 16 PY 2010 VL 153 IS 10 BP 655 EP 657 DI 10.7326/0003-4819-153-10-201011160-00008 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 680ES UT WOS:000284215800018 PM 21079221 ER PT J AU Raben, N Schreiner, C Baum, R Takikita, S Xu, SG Xie, T Myerowitz, R Komatsu, M Van Der Meulen, JH Nagaraju, K Ralston, E Plotz, PH AF Raben, Nina Schreiner, Cynthia Baum, Rebecca Takikita, Shoichi Xu, Sengen Xie, Tao Myerowitz, Rachel Komatsu, Masaaki Van Der Meulen, Jack H. Nagaraju, Kanneboyina Ralston, Evelyn Plotz, Paul H. TI Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder-murine Pompe disease SO AUTOPHAGY LA English DT Article DE Pompe disease; lysosomal glycogen storage; myopathy; Atg7; enzyme replacement therapy ID ACID ALPHA-GLUCOSIDASE; SINGLE MUSCLE-FIBERS; SKELETAL-MUSCLE; MOUSE MODEL; CONSTITUTIVE AUTOPHAGY; TARGETED DISRUPTION; IN-VIVO; MICE; GLYCOGEN; CELLS AB Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alpha-glucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50-60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy. C1 [Raben, Nina; Schreiner, Cynthia; Baum, Rebecca; Takikita, Shoichi; Xu, Sengen; Xie, Tao; Myerowitz, Rachel; Plotz, Paul H.] NIAMSD, Arthritis & Rheumatism Branch, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Komatsu, Masaaki] Tokyo Metropolitan Inst Med Sci, Tokyo 113, Japan. [Van Der Meulen, Jack H.; Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. RP Raben, N (reprint author), NIAMSD, Arthritis & Rheumatism Branch, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov FU NIAMS of the NIH; NIH; Genzyme Corporation FX This research was supported by the Intramural Research Program of the NIAMS of the NIH. Dr. Takikita was supported in part by a CRADA between the NIH and Genzyme Corporation. NR 66 TC 62 Z9 65 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD NOV 16 PY 2010 VL 6 IS 8 BP 1078 EP 1089 DI 10.4161/auto.6.8.13378 PG 12 WC Cell Biology SC Cell Biology GA 680TU UT WOS:000284258900008 PM 20861693 ER PT J AU Narendra, DP Kane, LA Hauser, DN Fearnley, IM Youle, RJ AF Narendra, Derek P. Kane, Lesley A. Hauser, David N. Fearnley, Ian M. Youle, Richard J. TI p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both SO AUTOPHAGY LA English DT Article DE sequestration; PINK1; Parkinson disease; porin ID INCLUSION-BODY FORMATION; CELL-DEATH; DROSOPHILA-MELANOGASTER; SELECTIVE AUTOPHAGY; UBIQUITIN CHAINS; QUALITY-CONTROL; HUMAN PORIN; MUTATIONS; P62; ANTIBODIES AB Mitochondria sustain damage with aging, and the resulting mitochondrial dysfunction has been implicated in a number of diseases including Parkinson disease. We recently demonstrated that the E3 ubiquitin ligase Parkin, which is linked to recessive forms of parkinsonism, causes a dramatic increase in mitophagy and a change in mitochondrial distribution, following its translocation from the cytosol to mitochondria. Investigating how Parkin induces these changes may offer insight into the mechanisms that lead to the sequestration and elimination of damaged mitochondria. We report that following Parkin's translocation from the cytosol to mitochondria, Parkin (but not a pathogenic mutant) promotes the K63-linked polyubiquitination of mitochondrial substrate(s) and recruits the ubiquitin-and LC3-binding protein, p62/SQSTM1, to mitochondria. After its recruitment, p62/SQSTM1 mediates the aggregation of dysfunctional mitochondria through polymerization via its PB1 domain, in a manner analogous to its aggregation of polyubiquitinated proteins. Surprisingly and in contrast to what has been recently reported for ubiquitin-induced pexophagy and xenophagy, p62 appears to be dispensable for mitophagy. Similarly, mitochondrial-anchored ubiquitin is sufficient to recruit p62 and promote mitochondrial clustering, but does not promote mitophagy. Although VDAC1 (but not VDAC2) is ubiquitinated following mitochondrial depolarization, we find VDAC1 cannot fully account for the mitochondrial K63-linked ubiquitin immunoreactivity observed following depolarization, as it is also observed in VDAC1/3(-/-) mouse embryonic fibroblasts. Additionally, we find VDAC1 and VDAC3 are dispensable for the recruitment of p62, mitochondrial clustering and mitophagy. These results demonstrate that mitochondria are aggregated by p62, following its recruitment by Parkin in a VDAC1-independent manner. They also suggest that proteins other than p62 are likely required for mitophagy downstream of Parkin substrates other than VDAC1. C1 [Narendra, Derek P.; Kane, Lesley A.; Hauser, David N.; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Narendra, Derek P.; Fearnley, Ian M.] MRC, Mitochondrial Biol Unit, Cambridge, England. [Narendra, Derek P.] Natl Inst Hlth Oxford Cambridge Scholars Program, Oxford, England. [Hauser, David N.] Brown Univ NIH Neurosci Grad Partnership Program, Natl Inst Hlth, Providence, RI USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov RI Hauser, David/I-4933-2012 OI Hauser, David/0000-0002-9500-5255 FU Proteomics Group at the MRC-Mitochondrial Biology Unit; Youle lab FX We thank C. Smith for help with confocal microscopy, S. Smith for assistance with cell culture, S. Ding, K. Jayawardena for technical assistance with sample preparation and mass spectrometry. We thank J.E. Walker, J. Carroll, the Proteomics Group at the MRC-Mitochondrial Biology Unit, the Youle lab and W. Motley for support and discussions. We thank K. Tanaka and M. Komatsu for transformed p62+/+ and p62-/- MEFs; T. Johansen for EGFP-p62, EGFP-p62 D69A and EGFP-p62 Delta LIR constructs; V. Dixit for the Apu2 and Apu3 antibodies; and B. Turner and J. Atkin for the EGFP-SOD1 G93A construct. We also thank M. Komatsu and T. Johansen for a careful reading of the manuscript and their thoughtful comments. NR 50 TC 284 Z9 295 U1 4 U2 20 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD NOV 16 PY 2010 VL 6 IS 8 BP 1090 EP 1106 DI 10.4161/auto.6.8.13426 PG 17 WC Cell Biology SC Cell Biology GA 680TU UT WOS:000284258900009 PM 20890124 ER PT J AU Guan, LR Bebenek, K Kunkel, TA Greenberg, MM AF Guan, Lirui Bebenek, Katarzyna Kunkel, Thomas A. Greenberg, Marc M. TI Inhibition of Short Patch and Long Patch Base Excision Repair by an Oxidized Abasic Site SO BIOCHEMISTRY LA English DT Article ID DNA-POLYMERASE-BETA; CROSS-LINK FORMATION; DEOXYRIBOSE PHOSPHATE LYASE; ANTITUMOR ANTIBIOTICS; SELECTIVE GENERATION; REACTIVE METABOLITE; OXIDATIVE STRESS; IN-VITRO; MECHANISM; DAMAGE AB 5'-(2-Phosphoryl-1,4-dioxobutane) (DOB) is an oxidized abasic lesion that is produced by a variety of DNA damaging agents, including several antitumor antibiotics. DOB efficiently and irreversibly inhibits DNA polymerase beta, an essential base excision repair enzyme in mammalian cells. The generality of this mode of inhibition by DOB is supported by the inactivation of DNA polymerase lambda, which may serve as a possible backup for DNA polymerase beta during abasic site repair. Protein digests suggest that Lys72 and Lys84, which are present in the lyase active site of DNA polymerase beta, are modified by DOB. Monoaldehyde analogues of DOB substantiate the importance of the 1,4-dicarbonyl component of DOB for efficient inactivation of Pol beta and the contribution of a freely diffusible electrophile liberated from the inhibitor by the enzyme. Inhibition of DNA polymerase beta's lyase function is accompanied by inactivation of its DNA polymerase activity as well, which prevents long patch base excision repair of DOB. Overall, DOB is highly refractory to short patch and long patch base excision repair. Its recalcitrance to succumb to repair suggests that DOB is a significant source of the cytotoxicity of DNA damaging agents that produce it. C1 [Guan, Lirui; Greenberg, Marc M.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Bebenek, Katarzyna; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Greenberg, MM (reprint author), Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA. EM mgreenberg@jhu.edu RI Guan, Lirui/E-5611-2013 FU National Institute of General Medical Science [GM-063028]; Division of intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070] FX I:We are grateful for support of this research by the National Institute of General Medical Science (GM-063028). This work was supported in part by Project Z01 ES065070 to T.A.K. from the Division of intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 56 TC 14 Z9 14 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 16 PY 2010 VL 49 IS 45 BP 9904 EP 9910 DI 10.1021/bi101533a PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675MC UT WOS:000283833800027 PM 20961055 ER PT J AU Ma, WL Kantarjian, H Zhang, K Zhang, X Wang, XQ Chen, C Donahue, AC Zhang, Z Yeh, CH O'Brien, S Garcia-Manero, G Caporaso, N Landgren, O Albitar, M AF Ma, Wanlong Kantarjian, Hagop Zhang, Ke Zhang, Xi Wang, Xiuqiang Chen, Clifford Donahue, Amber C. Zhang, Zhong Yeh, Chen-Hsiung O'Brien, Susan Garcia-Manero, Guillermo Caporaso, Neil Landgren, Ola Albitar, Maher TI Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome SO BMC MEDICAL GENETICS LA English DT Article ID COLONY-STIMULATING FACTOR; ANEMIA; SURVIVAL AB Background: Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS. Methods: We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML), 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls. Results: The G/G genotype was significantly more common in MDS patients (47/187; 25.1%) than in controls (6/95; 6.3%) or in patients with other leukemias (101/813; 12.4%) (all P < 0.001). Individuals with the G/G genotype were more likely than those with other genotypes to have MDS (odd ratio = 4.98; 95% CI = 2.04-12.13). Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P = 0.03). Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02). Conclusions: These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy. C1 [Ma, Wanlong; Zhang, Ke; Zhang, Xi; Wang, Xiuqiang; Chen, Clifford; Donahue, Amber C.; Zhang, Zhong; Yeh, Chen-Hsiung; Albitar, Maher] Quest Diagnost Nichols Inst, Dept Hematol Oncol, San Juan Capistrano, CA USA. [Kantarjian, Hagop; O'Brien, Susan; Garcia-Manero, Guillermo] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, Ctr Canc Res, Natl Canc Inst Hlth, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, Natl Canc Inst Hlth, Bethesda, MD 20892 USA. RP Albitar, M (reprint author), Quest Diagnost Nichols Inst, Dept Hematol Oncol, San Juan Capistrano, CA USA. EM maheralbitar@gmail.com FU NCI NIH HHS [P30 CA016672] NR 18 TC 10 Z9 12 U1 0 U2 2 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 NOV 16 PY 2010 VL 11 AR 163 DI 10.1186/1471-2350-11-163 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 685NX UT WOS:000284636500001 PM 21078205 ER PT J AU Restifo, NP AF Restifo, Nicholas P. TI Can Antitumor Immunity Help to Explain "Oncogene Addiction"? SO CANCER CELL LA English DT Editorial Material ID CANCER; INHIBITION AB "Oncogene addiction" refers to the process of tumor cell death that can occur after inactivation of a single oncogene. In this issue of Cancer Cell, Rakhra et al. argue that complete tumor clearance after molecular targeted therapies requires a functioning immune system, pointing the way toward radically new combination therapies. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM restifo@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, ZIA BC010763-04] NR 9 TC 9 Z9 9 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD NOV 16 PY 2010 VL 18 IS 5 BP 403 EP 405 DI 10.1016/j.ccr.2010.11.002 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 685WK UT WOS:000284658600003 PM 21075303 ER PT J AU Marcus, GM Alonso, A Peralta, CA Lettre, G Vittinghoff, E Lubitz, SA Fox, ER Levitzky, YS Mehra, R Kerr, KF Deo, R Sotoodehnia, N Akylbekova, M Ellinor, PT Paltoo, DN Soliman, EZ Benjamin, EJ Heckbert, SR AF Marcus, Gregory M. Alonso, Alvaro Peralta, Carmen A. Lettre, Guillaume Vittinghoff, Eric Lubitz, Steven A. Fox, Ervin R. Levitzky, Yamini S. Mehra, Reena Kerr, Kathleen F. Deo, Rajat Sotoodehnia, Nona Akylbekova, Meggie Ellinor, Patrick T. Paltoo, Dina N. Soliman, Elsayed Z. Benjamin, Emelia J. Heckbert, Susan R. CA Candidate-Gene Assoc Resource CARe TI European Ancestry as a Risk Factor for Atrial Fibrillation in African Americans SO CIRCULATION LA English DT Article DE ancestry; African Americans; atrial fibrillation; genetics ID ATHEROSCLEROSIS RISK; HEART-FAILURE; UNITED-STATES; ADULTS; PREVALENCE; LOCUS; EPIDEMIOLOGY; HYPERTENSION; MANAGEMENT; INFERENCE AB Background-Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF. Methods and Results-We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results. Conclusions-European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative. (Circulation. 2010; 122: 2009-2015.) C1 [Marcus, Gregory M.] Univ Calif San Francisco, Div Cardiol, Electrophysiol Sect, San Francisco, CA 94143 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Ellinor, Patrick T.] Harvard Univ, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. [Lubitz, Steven A.] Harvard Univ, Brigham & Womens Hosp, Massachusetts Gen Hosp, Div Prevent Med,Med Sch, Boston, MA 02115 USA. [Fox, Ervin R.; Akylbekova, Meggie] Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS USA. [Levitzky, Yamini S.] Case Western Reserve Univ, Heart & Vasc Ctr, Div Cardiol, Cleveland, OH 44106 USA. [Mehra, Reena] Case Western Reserve Univ, Ctr Clin Invest, Cleveland, OH 44106 USA. [Mehra, Reena] Case Western Reserve Univ, Div Pulm Crit Care & Sleep Med, Cleveland, OH 44106 USA. [Kerr, Kathleen F.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Deo, Rajat] Univ Penn, Electrophysiol Sect, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Paltoo, Dina N.] Natl Heart Blood & Lung Inst, NIH, DHHS, Bethesda, MD USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Epidemiol Cardiol Res Ctr, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Div Cardiol & Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Dept Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Marcus, GM (reprint author), Univ Calif San Francisco, Div Cardiol, Electrophysiol Sect, 500 Parnassus Ave,MUE 434, San Francisco, CA 94143 USA. EM marcusg@medicine.ucsf.edu RI Alonso, Alvaro/A-4917-2010; Soliman, Elsayed/D-8124-2011; Kerr, Kathleen/A-2893-2013; OI Alonso, Alvaro/0000-0002-2225-8323; Soliman, Elsayed/0000-0001-5632-8150; Mehra, Reena/0000-0002-6222-2675; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute (NHLBI) [K23 HL079114]; National Center for Research Resources (NCRR), National Institutes of Health (NIH). [KL2 RR024130]; CARe [N01-HC-65226]; University of North Carolina at Chapel Hill [N01-HC-55015]; Baylor Medical College [N01-HC55016]; University of Mississippi Medical Center [N01-HC-55021]; University of Minnesota [N01-HC-55019, N01-HC-48048, N01-HC-95163, U01 HL053934]; Johns Hopkins University [N01-HC-55020, N01-HC-85081, N01 HC-15103, N01-HC-95162, N01-HC-95168, U01 HL064360, U01 HL053937]; University of Texas, Houston [N01-HC-55022]; University of North Carolina, Forsyth County [N01-HC-55018]; National Human Genome Research Institute [U01HG004402]; NIH [UL1RR025005, RC1-HL01056, DA027021, R01 HL088456, T32HL007575, HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; NIH/NHLBI [RC1-HL099452]; American Heart Association [09SDG2280087, 0530188N]; Wake Forest University [N01-HC-85080, N01-HC-45205, N01-HC-95165]; University of Pittsburgh [N01-HC-85082, U01 HL077813]; University of California, Davis [N01-HC-85083]; University of California, Irvine [N01-HC85084, N01-HC-45134, N01-HC-95100, U01 HL053916]; New England Medical Center [N01-HC-85085, N01-HC-95167]; University of Vermont [N01-HC-85086, N01-HC-95166]; Georgetown University [N01-HC-35129]; University of Wisconsin [N01-HC-75150]; Geisinger Clinic [N01-HC-45133]; University of Washington [N01 HC-55222, U01 HL080295, N01-HC-95159, N01-HC-85079]; Case Western Reserve University [NIH HL 46380, M01RR00080]; University of Illinois [N01-HB-72982, N01-HB-97062]; Howard University [N01-HB-72991, N01-HB-97061]; University of Miami [N01-HB-72992, N01-HB-97064]; Duke University [N01-HB-72993]; George Washington University [N01-HB-72994]; University of Tennessee [N01-HB-72995, N01-HB-97070]; Yale University [N01-HB-72996, N01-HB-97072]; Children's Hospital-Philadelphia [N01-HB-72997, N01-HB-97056]; University of Chicago [N01-HB-72998, N01-HB-97053]; Medical College of Georgia [N01-HB-73000, N01-HB-97060]; Washington University [N01-HB-73001, N01-HB-97071]; Jewish Hospital and Medical Center of Brooklyn [N01-HB-73002]; Trustees of Health and Hospitals of the City of Boston, Inc [N01-HB-73003]; Children's Hospital-Oakland [N01-HB-73004, N01-HB-97054]; University of Mississippi [N01-HB-73005, N01-HC-95171]; St Luke's Hospital-New York [N01-HB-73006]; Alta Bates-Herrick Hospital [N01-HB-97051]; Columbia University [N01-HB-97058, N01-HC-95161]; St Jude's Children's Research Hospital [N01-HB-97066]; State University of New York-Albany [N01-HB-97068, N01-HB-97069]; New England Research Institute [N01-HB-97073]; Interfaith Medical Center-Brooklyn [N01-HB-97085]; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; Northwestern University [N01-HC-48049, N01-HC-95164]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Harbor-UCLA Research and Education Institute [N01-HC-05187, N01-HC-95169]; Boston University [N01-HC-25195, R01HL092577-01A1, RO1 HL076784, R01 AG028321, 6R01-NS 17950, U01 HL053941]; Jackson State University; Tougaloo College; Regents of the University of California; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; Case Western University [U01 HL063463]; University of Arizona [U01 HL053938]; MedStar Research Institute [U01 HL063429]; Central Society of Clinical Research Career Development Award; [N01-HC-95170]; [N01-HC-95172]; [N01-HC-95160] FX We wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. We would like to thank Drs Richard S. Cooper and Philip L. De Jager for providing the Nigerian and European American Affymetrix 6.0 genotype data sets, as well as Dr Nick Patterson and Arti Tandon for curating the list of AIMs on the Affymetrix 6.0 genotyping platform.; This work was made possible by grant KL2 RR024130 (G. M. M.) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The CARe project (N01-HC-65226) involves 9 parent studies that contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology-Broad Institute to create this genotype/phenotype database for wide dissemination to the biomedical research community. ARIC: University of North Carolina at Chapel Hill (N01-HC-55015), Baylor Medical College (N01-HC55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022), University of North Carolina, Forsyth County (N01-HC-55018); R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This study was also supported by grant RC1-HL099452 from NIH/NHLBI and grant 09SDG2280087 from the American Heart Association. CHS: University of Washington (N01-HC-85079), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081), University of Pittsburgh (N01-HC-85082), University of California, Davis (N01-HC-85083), University of California, Irvine (N01-HC85084), New England Medical Center (N01-HC-85085), University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), Johns Hopkins University (N01 HC-15103), University of Wisconsin (N01-HC-75150), Geisinger Clinic (N01-HC-45133), University of Washington (N01 HC-55222, U01 HL080295). Cleveland Family Study: Case Western Reserve University (NIH HL 46380, M01RR00080). Cooperative Study of Sickle Cell Disease: University of Illinois (N01-HB-72982, N01-HB-97062), Howard University (N01-HB-72991, N01-HB-97061), University of Miami (N01-HB-72992, N01-HB-97064), Duke University (N01-HB-72993), George Washington University (N01-HB-72994), University of Tennessee (N01-HB-72995, N01-HB-97070), Yale University (N01-HB-72996, N01-HB-97072), Children's Hospital-Philadelphia (N01-HB-72997, N01-HB-97056), University of Chicago (N01-HB-72998, N01-HB-97053), Medical College of Georgia (N01-HB-73000, N01-HB-97060), Washington University (N01-HB-73001, N01-HB-97071), Jewish Hospital and Medical Center of Brooklyn (N01-HB-73002), Trustees of Health and Hospitals of the City of Boston, Inc, (N01-HB-73003), Children's Hospital-Oakland (N01-HB-73004, N01-HB-97054), University of Mississippi (N01-HB-73005), St Luke's Hospital-New York (N01-HB-73006), Alta Bates-Herrick Hospital (N01-HB-97051), Columbia University (N01-HB-97058), St Jude's Children's Research Hospital (N01-HB-97066), Research Foundation, State University of New York-Albany (N01-HB-97068, N01-HB-97069), New England Research Institute (N01-HB-97073), Interfaith Medical Center-Brooklyn (N01-HB-97085). Coronary Artery Risk in Young Adults: University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100).; Framingham Heart Study: Boston University (N0-HC-25195, R01HL092577-01A1, RO1 HL076784, R01 AG028321, 6R01-NS 17950). Jackson Heart Study: Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172). Multi-Ethnic Study of Atherosclerosis: University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205). Sleep Heart Health Study: Johns Hopkins University (U01 HL064360), Case Western University (U01 HL063463), University of California, Davis (U01 HL053916), University of Arizona (U01 HL053938), University of Minnesota (relocating in 2006 to University of Arizona; U01 HL053934), University of Pittsburgh (U01 HL077813), Boston University (U01 HL053941), MedStar Research Institute (U01 HL063429), Johns Hopkins University (U01 HL053937). This work was also supported by grants from the NIH: RC1-HL01056 to Drs Benjamin and Alonso, DA027021 to Dr Ellinor, and R01 HL088456 to Dr Sotoodehnia. Dr Lubitz is supported by a training grant in the Epidemiology of Cardiovascular Disease from the NIH (T32HL007575). Dr Mehra is supported by the following: NHLBI K23 HL079114, American Heart Association National Scientist Development Award 0530188N, and Central Society of Clinical Research Career Development Award. NR 41 TC 77 Z9 80 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD NOV 16 PY 2010 VL 122 IS 20 BP 2009 EP 2015 DI 10.1161/CIRCULATIONAHA.110.958306 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 680DS UT WOS:000284213200010 PM 21098467 ER PT J AU Alves, G Ogurtsov, AY Yu, YK AF Alves, Gelio Ogurtsov, Aleksey Y. Yu, Yi-Kuo TI RAId_aPS: MS/MS Analysis with Multiple Scoring Functions and Spectrum-Specific Statistics SO PLOS ONE LA English DT Article ID TANDEM MASS-SPECTRA; PEPTIDE IDENTIFICATION; PROTEIN IDENTIFICATIONS; IMPROVING SENSITIVITY; SEARCH; SPECTROMETRY; DATABASE; PROTEOMICS; CONFIDENCE; ALGORITHM AB Statistically meaningful comparison/combination of peptide identification results from various search methods is impeded by the lack of a universal statistical standard. Providing an E-value calibration protocol, we demonstrated earlier the feasibility of translating either the score or heuristic E-value reported by any method into the textbook-defined E-value, which may serve as the universal statistical standard. This protocol, although robust, may lose spectrum-specific statistics and might require a new calibration when changes in experimental setup occur. To mitigate these issues, we developed a new MS/MS search tool, RAId_aPS, that is able to provide spectrum-specific E-values for additive scoring functions. Given a selection of scoring functions out of RAId score, K-score, Hyperscore and XCorr, RAId_aPS generates the corresponding score histograms of all possible peptides using dynamic programming. Using these score histograms to assign E-values enables a calibration-free protocol for accurate significance assignment for each scoring function. RAId_aPS features four different modes: (i) compute the total number of possible peptides for a given molecular mass range, (ii) generate the score histogram given a MS/MS spectrum and a scoring function, (iii) reassign E-values for a list of candidate peptides given a MS/MS spectrum and the scoring functions chosen, and (iv) perform database searches using selected scoring functions. In modes (iii) and (iv), RAId_aPS is also capable of combining results from different scoring functions using spectrum-specific statistics. The web link is http://www.ncbi.nlm.nih.gov/ CBBresearch/Yu/raid_aps/index.html. Relevant binaries for Linux, Windows, and Mac OS X are available from the same page. C1 [Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Alves, G (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM yyu@ncbi.nlm.nih.gov FU National Library of Medicine of the National Institutes of Health/DHHS FX This work was supported by the Intramural Research Program of the National Library of Medicine of the National Institutes of Health/DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 8 Z9 8 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 16 PY 2010 VL 5 IS 11 AR e15438 DI 10.1371/journal.pone.0015438 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680TI UT WOS:000284257400022 PM 21103371 ER PT J AU Das, BB Dexheimer, TS Maddali, K Pommier, Y AF Das, Benu Brata Dexheimer, Thomas S. Maddali, Kasthuraiah Pommier, Yves TI Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA repair; ligase III; oxidative DNA damage; topoisomerase I; mitochondrial BER ID BASE EXCISION-REPAIR; SINGLE-STRAND BREAKS; COLI EXONUCLEASE-III; TOPOISOMERASE-I; SPINOCEREBELLAR ATAXIA; MAMMALIAN MITOCHONDRIA; AXONAL NEUROPATHY; OXIDATIVE DAMAGE; NUCLEAR-DNA; HUMAN-CELLS AB Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3'-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (Top1)-DNA covalent complexes. TDP1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolate and 3'-abasic sites, and exhibits 3'-nucleosidase activity indicating it may function as a general 3'-end-processing DNA repair enzyme. Here, using laser confocal microscopy, subcellular fractionation and biochemical analyses we demonstrate that a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. We also show that mitochondrial base excision repair depends on TDP1 activity and provide evidence that TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Together, our findings provide evidence for TDP1 as a novel mitochondrial enzyme. C1 [Das, Benu Brata; Dexheimer, Thomas S.; Maddali, Kasthuraiah; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX We thank Dr. Cornelius F. Boerkoel (Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada) for providing the TDP1+/+ and TDP1-/- primary MEFS cells. The NCI Intramural Program, Center for Cancer Research, National Cancer Institute, NIH, supported this work. NR 65 TC 56 Z9 57 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 16 PY 2010 VL 107 IS 46 BP 19790 EP 19795 DI 10.1073/pnas.1009814107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680UT UT WOS:000284261800037 PM 21041670 ER PT J AU Zhu, FQ Hummer, G AF Zhu, Fangqiang Hummer, Gerhard TI Pore opening and closing of a pentameric ligand-gated ion channel SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ELIC; nicotinic acetylcholine receptor; hydrophobic gate; conformational change; string method ID NICOTINIC ACETYLCHOLINE-RECEPTOR; MOLECULAR-DYNAMICS SIMULATIONS; X-RAY-STRUCTURE; STRING METHOD; CONDUCTION; STATE; PERMEATION; TRANSITION; GRAMICIDIN; HOMOLOG AB Nerve signaling in humans and chemical sensing in bacteria both rely on the controlled opening and closing of the ion-conducting pore in pentameric ligand-gated ion channels. With the help of a multiscale simulation approach that combines mixed elastic network model calculations with molecular dynamics simulations, we study the opening and closing of the pore in Gloeobacter violaceus channel GLIC at atomic resolution. In our simulations of the GLIC transmembrane domain, we first verify that the two endpoints of the transition are open and closed to sodium ion conduction, respectively. We then show that a two-stage tilting of the pore-lining helices induces cooperative drying and iris-like closing of the channel pore. From the free energy profile of the gating transition and from unrestrained simulations, we conclude that the pore of the isolated GLIC transmembrane domain closes spontaneously. The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening. C1 [Zhu, Fangqiang; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 33 TC 79 Z9 80 U1 3 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 16 PY 2010 VL 107 IS 46 BP 19814 EP 19819 DI 10.1073/pnas.1009313107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680UT UT WOS:000284261800041 PM 21041674 ER PT J AU Ross, JM Oberg, J Brene, S Coppotelli, G Terzioglu, M Pernold, K Goiny, M Sitnikov, R Kehr, J Trifunovic, A Larsson, NG Hoffer, BJ Olson, L AF Ross, Jaime M. Oberg, Johanna Brene, Stefan Coppotelli, Giuseppe Terzioglu, Mugen Pernold, Karin Goiny, Michel Sitnikov, Rouslan Kehr, Jan Trifunovic, Aleksandra Larsson, Nils-Goran Hoffer, Barry J. Olson, Lars TI High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mtDNA mutator mouse; proton magnetic resonance spectroscopy; in situ hybridization; COX/SDH enzyme histochemistry; HPLC ID MITOCHONDRIAL-DNA DELETIONS; CEREBROSPINAL-FLUID LACTATE; OXIDATIVE-PHOSPHORYLATION; POINT MUTATIONS; SKELETAL-MUSCLE; MUTATOR MICE; MOUSE; GLUCOSE; PROTEIN; AGE AB At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate. lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes. C1 [Ross, Jaime M.; Pernold, Karin; Olson, Lars] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. [Ross, Jaime M.; Hoffer, Barry J.] NIDA, NIH, Baltimore, MD 21224 USA. [Oberg, Johanna] Karolinska Inst, Div Radiol, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden. [Brene, Stefan] Karolinska Inst, Dept Neurobiol Hlth Sci & Soc, Expt Magnet Resonance Ctr, SE-17177 Stockholm, Sweden. [Coppotelli, Giuseppe] Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. [Terzioglu, Mugen; Larsson, Nils-Goran] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Goiny, Michel; Kehr, Jan] Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden. [Sitnikov, Rouslan] UCL, Inst Neurol, London WC1N 1PJ, England. [Trifunovic, Aleksandra] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50674 Cologne, Germany. [Larsson, Nils-Goran] Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden. RP Ross, JM (reprint author), Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. EM rossja@nida.nih.gov; Lars.Olson@ki.se RI Ross, Jaime/A-6893-2012 FU National Institute on Aging [AG04418]; National Institute on Drug Abuse; National Institutes of Health; Swedish Research Council; Swedish Brain Power; Swedish Brain Foundation; Karolinska Experimental Magnetic Resonance Center; Karolinska Institutet FX We thank Professor M. G. Masucci for support and the use of spectrophotometric equipment, E. Lindqvist and K. Lundstromer for technical assistance, and Dr. D. Marcellino for advice. This work was supported by the National Institute on Aging (AG04418), National Institute on Drug Abuse, National Institutes of Health-Karolinska Graduate Partnerships Program, Swedish Research Council, Swedish Brain Power, Swedish Brain Foundation, Karolinska Experimental Magnetic Resonance Center, and Karolinska Institutet Doctoral Funding. NR 51 TC 63 Z9 64 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 16 PY 2010 VL 107 IS 46 BP 20087 EP 20092 DI 10.1073/pnas.1008189107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680UT UT WOS:000284261800087 PM 21041631 ER PT J AU Juliano, JJ Porter, K Mwapasa, V Sem, R Rogers, WO Ariey, F Wongsrichanalai, C Read, A Meshnick, SR AF Juliano, Jonathan J. Porter, Kimberly Mwapasa, Victor Sem, Rithy Rogers, William O. Ariey, Frederic Wongsrichanalai, Chansuda Read, Andrew Meshnick, Steven R. TI Exposing malaria in-host diversity and estimating population diversity by capture-recapture using massively parallel pyrosequencing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Plasmodium falciparum; next generation sequencing ID PLASMODIUM-FALCIPARUM INFECTIONS; HETERODUPLEX TRACKING ASSAY; SPECIES-RICHNESS; DRUG-RESISTANCE; ANTIMALARIAL TRIALS; MOLECULAR EVOLUTION; PCR; PARASITES; RECOMBINATION; TRANSMISSION AB Malaria infections commonly contain multiple genetically distinct variants. Mathematical and animal models suggest that interactions among these variants have a profound impact on the emergence of drug resistance. However, methods currently used for quantifying parasite diversity in individual infections are insensitive to low-abundance variants and are not quantitative for variant population sizes. To more completely describe the in-host complexity and ecology of malaria infections, we used massively parallel pyrosequencing to characterize malaria parasite diversity in the infections of a group of patients. By individually sequencing single strands of DNA in a complex mixture, this technique can quantify uncommon variants in mixed infections. The in-host diversity revealed by this method far exceeded that described by currently recommended genotyping methods, with as many as sixfold more variants per infection. In addition, in paired pre- and posttreatment samples, we show a complex milieu of parasites, including variants likely up-selected and down-selected by drug therapy. As with all surveys of diversity, sampling limitations prevent full discovery and differences in sampling effort can confound comparisons among samples, hosts, and populations. Here, we used ecological approaches of species accumulation curves and capture-recapture to estimate the number of variants we failed to detect in the population, and show that these methods enable comparisons of diversity before and after treatment, as well as between malaria populations. The combination of ecological statistics and massively parallel pyrosequencing provides a powerful tool for studying the evolution of drug resistance and the in-host ecology of malaria infections. C1 [Juliano, Jonathan J.] Univ N Carolina, Sch Med, Div Infect Dis, Chapel Hill, NC 27514 USA. [Porter, Kimberly; Meshnick, Steven R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Mwapasa, Victor] Univ Malawi, Coll Med, Dept Community Hlth, Blantyre 3, Malawi. [Sem, Rithy] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Rogers, William O.; Wongsrichanalai, Chansuda] USN, Med Res Unit 2, Honolulu, HI 96860 USA. [Ariey, Frederic] Inst Pasteur Cambodge, Phnom Penh, Cambodia. [Read, Andrew] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Read, Andrew] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Read, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Juliano, JJ (reprint author), Univ N Carolina, Sch Med, Div Infect Dis, Chapel Hill, NC 27514 USA. EM jjuliano@med.unc.edu RI Valle, Ruben/A-7512-2013 FU National Institute of Allergy and Infectious Diseases (NIAID) [1R21AI076785, T32-AI070114-01]; National Center for Research Resources [KL2RR025746] FX We thank Xiaojun Guan for cluster computing support. We are also grateful to Dr. Socheat Duong and Dr. Sinuon Muth of the Cambodian National Malaria Control Program for their support. We thank Steve Taylor, Ian Hastings, and our anonymous reviewers for their thoughtful reviews. This project was funded by National Institute of Allergy and Infectious Diseases (NIAID) Grant 1R21AI076785, National Center for Research Resources Award KL2RR025746 (to J.J.J.), and National Research Service Award T32-AI070114-01 from NIAID (to K.P.). A.R. has benefited from discussion with members of the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 50 TC 48 Z9 49 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 16 PY 2010 VL 107 IS 46 BP 20138 EP 20143 DI 10.1073/pnas.1007068107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680UT UT WOS:000284261800096 PM 21041629 ER PT J AU Korzeniowski, MK Manjarres, IM Varnai, P Balla, T AF Korzeniowski, Marek K. Martin Manjarres, Isabel Varnai, Peter Balla, Tamas TI Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism SO SCIENCE SIGNALING LA English DT Article ID OPERATED CALCIUM-ENTRY; CRAC CHANNEL; ORAI CHANNELS; CA2+-DEPENDENT INACTIVATION; MOLECULAR DETERMINANTS; ENDOPLASMIC-RETICULUM; COILED-COIL; STIM1 GATES; CA2+ INFLUX; DEPLETION AB Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca(2+)) entry through plasma membrane Orai1 channels in response to decreased Ca(2+) concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca(2+) activation domain [Ca(2+) release-activated Ca(2+) (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]-a cytoplasmic region required for its activation of Orai1-inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding. C1 [Korzeniowski, Marek K.; Balla, Tamas] NICHHD, Sect Mol Signal Transduct, Program Dev Neurosci, Bethesda, MD 20892 USA. [Martin Manjarres, Isabel] Univ Valladolid, CSIC, Inst Biol & Genet Mol, Valladolid 47003, Spain. [Varnai, Peter] Semmelweis Univ, Fac Med, Dept Physiol, H-1094 Budapest, Hungary. RP Balla, T (reprint author), NICHHD, Sect Mol Signal Transduct, Program Dev Neurosci, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Korzeniowski, Marek/G-7214-2011; OI Balla, Tamas/0000-0002-9077-3335 FU NICHD, NIH; Hungarian Scientific Research fund (OTKA) [OTKA NF-68563]; Medical Research Council [ETT 440/2006]; Ministry of Science and Education of Spain FX This research was supported in part by the Intramural Research Program of the NICHD, NIH. P.V. was supported by the Hungarian Scientific Research fund (OTKA NF-68563) and the Medical Research Council (ETT 440/2006). I.M.M. was supported by a Fellowship from the Spanish Personnel Research Training Program from the Ministry of Science and Education of Spain. NR 44 TC 96 Z9 96 U1 3 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD NOV 16 PY 2010 VL 3 IS 148 AR ra82 DI 10.1126/scisignal.2001122 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 680VF UT WOS:000284263300001 PM 21081754 ER PT J AU Edlich, B Hogdal, LJ Rehermann, B Behrens, SE AF Edlich, Birgit Hogdal, Leah J. Rehermann, Barbara Behrens, Sven-Erik TI Dendritic cells transfected with Her2 antigen-encoding RNA replicons cross-prime CD8 T cells and protect mice against tumor challenge SO VACCINE LA English DT Article DE Cross-priming; Her2; RNA replicon ID VIRAL DIARRHEA VIRUS; MHC CLASS-I; BREAST-CANCER; B-CELLS; IMMUNITY; VACCINATION; VACCINES; IMMUNOTHERAPY; HER-2/NEU; MELANOMA AB Antigen-specific T cells can be induced by direct priming and cross-priming. To investigate cross-priming as a vaccination approach dendritic cells were transfected with cytopathogenic viral RNA-replicons that expressed domains of the tumor-associated Her2-antigen and injected into MHC-discordant mice that did not allow direct priming. Upon tumor challenge 75% of the vaccinated, but none of the mock-vaccinated mice remained tumor-free. The anti-tumor effect required T cells and correlated with the vigor of the cross-primed CD8 T cell response. Her2-specific antibodies were not detected. This study highlights the potential of T cell cross-priming in cancer immunotherapy. Published by Elsevier Ltd. C1 [Edlich, Birgit; Hogdal, Leah J.; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Edlich, Birgit; Behrens, Sven-Erik] Univ Halle Wittenberg, Sect Microbial Biotechnol, Fac Life Sci NFI, Inst Biochem & Biotechnol, D-06120 Halle, Germany. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov; sven.behrens@biochemtech.uni-halle.de FU Martin-Luther-University Halle-Wittenberg; NIDDK, NIH FX We thank Dr. E.M. Jaffee for the NT-2 cell line, Dr. K.L. Rock for the DC2.4 cell line and Dr. N. Tautz for the anti BVDV NS3 antibody. This study was supported by the Martin-Luther-University Halle-Wittenberg and the intramural research program of NIDDK, NIH. NR 52 TC 4 Z9 4 U1 0 U2 0 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 NOV 16 PY 2010 VL 28 IS 49 BP 7764 EP 7773 DI 10.1016/j.vaccine.2010.09.054 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 697PD UT WOS:000285526300009 PM 20887827 ER PT J AU Helzlsouer, KJ Gallicchio, L Weinstein, SJ AF Helzlsouer, Kathy J. Gallicchio, Lisa Weinstein, Stephanie J. TI RE: "OVERVIEW OF THE COHORT CONSORTIUM VITAMIN D POOLING PROJECT OF RARER CANCERS'' REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID 25-HYDROXYVITAMIN D; RISK C1 [Helzlsouer, Kathy J.; Gallicchio, Lisa] St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD 21202 USA. [Weinstein, Stephanie J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Helzlsouer, KJ (reprint author), St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD 21202 USA. EM khelzlsouer@mdmercy.com NR 7 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 15 PY 2010 VL 172 IS 10 BP 1211 EP 1212 DI 10.1093/aje/kwq302 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 676NH UT WOS:000283918700014 ER PT J AU Laje, G Morse, R Richter, W Ball, J Pao, M Smith, ACM AF Laje, Gonzalo Morse, Rebecca Richter, William Ball, Jonathan Pao, Maryland Smith, Ann C. M. TI Autism Spectrum Features in Smith-Magenis Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE del 17p11.2; RAI1; microdeletion syndrome; behavioral phenotype; social communication ID SYNDROME DEL 17P11.2; MALADAPTIVE BEHAVIOR; CHILDREN; MELATONIN; SLEEP; DELETION AB Smith-Magenis syndrome (SMS; OMIM 182290) is a neurodevelopmental disorder characterized by a well-defined pattern of anomalies. The majority of cases are due to a common deletion in chromosome 17p11.2 that includes the RAI1 gene. In children with SMS, autistic-like behaviors and symptoms start to emerge around 18 months of age. This study included 26 individuals (15 females and 11 males), with a confirmed deletion (del 17p11.2). Parents/caregivers were asked to complete the Social Responsiveness Scale (SRS) and the Social Communication Questionnaire (SCQ) both current and lifetime versions. The results suggest that 90% of the sample had SRS scores consistent with autism spectrum disorders. Moreover, females showed more impairment in total T-scores (P=0.02), in the social cognition (P=0.01) and autistic mannerisms (P=0.002) subscales. The SCQ scores are consistent to show that a majority of individuals may meet criteria for autism spectrum disorders at some point in their lifetime. These results suggest that SMS needs to be considered in the differential diagnosis of autism spectrum disorders but also that therapeutic interventions for autism are likely to benefit individuals with SMS. The mechanisms by which the deletion of RAI1 and contiguous genes cause psychopathology remain unknown but they provide a solid starting point for further studies of gene-brain-behavior interactions in SMS and autism spectrum disorders. Published 2010 Wiley-Liss, Inc.dagger C1 [Smith, Ann C. M.] NHGRI, Off Clin Director, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Pao, Maryland] NIH, Psychiat Consultat Liaison Serv, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Laje, Gonzalo] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Laje, Gonzalo; Morse, Rebecca] George Mason Univ, Fairfax, VA 22030 USA. RP Smith, ACM (reprint author), NHGRI, Off Clin Director, Div Intramural Res, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. EM acmsmith@mail.nih.gov FU National Institute of Mental Health; National Human Genome Research Institute; NIH; USDHHS FX Grant sponsor: Intramural Research Programs of the National Institute of Mental Health and the National Human Genome Research Institute, NIH, USDHHS. NR 26 TC 32 Z9 32 U1 2 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD NOV 15 PY 2010 VL 154C IS 4 SI SI BP 456 EP 462 DI 10.1002/ajmg.c.30275 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 677PV UT WOS:000284005200009 PM 20981775 ER PT J AU Laje, G Bernert, R Morse, R Pao, M Smith, ACM AF Laje, Gonzalo Bernert, Rebecca Morse, Rebecca Pao, Maryland Smith, Ann C. M. TI Pharmacological Treatment of Disruptive Behavior in Smith-Magenis Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE Smith-Magenis syndrome (SMS); treatment; pharmacology; genetics; pharmacogenomics; pharmacogenetics; autism; mental retardation; self-injurious behavior; aggression; sleep; melatonin ID SYNDROME DEL 17P11.2; BETA(1)-ADRENERGIC ANTAGONISTS; MALADAPTIVE BEHAVIOR; CIRCADIAN DISORDER; MELATONIN; SLEEP; CHILDREN; RHYTHM AB Smith-Magenis syndrome (SMS) is a complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2. Children and adults with SMS appear to have unique neurobehavioral problems that include: sleep disturbance, self-injurious and maladaptive behaviors, stereotypies, and sensory integration disorders. We gathered retrospective psychotropic use information from parents or other caregivers of 62 individuals with SMS who were asked about use of psychotropic medication from a list of commonly used psychiatric medications. For those drugs identified, respondents were asked to rate the experience with the particular medication using a likert-type scale. Drugs were grouped into seven main categories: (1) stimulants; (2) antidepressants; (3) antipsychotics; (4) sleep aides; (5) mood stabilizers; (6) alpha 2 agonists; and (7) benzodiazepines. Relative frequencies, means and standard deviations pertaining to age and medication effect were derived for each medication category. Six of the seven medication categories examined showed no meaningful deviations from the "no change" score. The benzodiazepine group showed a mild detrimental effect. There were no gender differences in efficacy. Use of psychotropic medication started early in life (mean age 5 years), particularly with sleep aides. Although no medication category was identified as efficacious in SMS, all the categories reported herein may be considered as an option for brief symptomatic relief. Published 2010 Wiley-Liss, Inc. C1 [Laje, Gonzalo] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Morse, Rebecca] George Mason Univ, Fairfax, VA 22030 USA. [Pao, Maryland] NIH, Psychiat Consultat Liaison Serv, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Smith, Ann C. M.] NHGRI, Off Clin Director, Div Intramural Res, Bethesda, MD 20892 USA. RP Laje, G (reprint author), NIMH, Intramural Res Program, NIH, 35 Convent Dr,Rm 1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov FU National Institute of Mental Health; National Human Genome Research Institute; USDHHS; NIMH FX Grant sponsor: The Intramural Research Programs of the National Institute of Mental Health; Grant sponsor: National Human Genome Research Institute; Grant sponsor: USDHHS. NR 18 TC 7 Z9 7 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD NOV 15 PY 2010 VL 154C IS 4 SI SI BP 463 EP 468 DI 10.1002/ajmg.c.30282 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 677PV UT WOS:000284005200010 PM 20981776 ER PT J AU Yao, XL Fredriksson, K Yu, ZX Xu, XL Raghavachari, N Keeran, KJ Zywicke, GJ Kwak, M Amar, MJA Remaley, AT Levine, SJ AF Yao, Xianglan Fredriksson, Karin Yu, Zu-Xi Xu, Xiuli Raghavachari, Nalini Keeran, Karen J. Zywicke, Gayle J. Kwak, Minjung Amar, Marcelo J. A. Remaley, Alan T. Levine, Stewart J. TI Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a Low-Density Lipoprotein Receptor-mediated Pathway SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE asthma; house dust mite; apolipoprotein E; LDL; receptor ID MIMETIC PEPTIDE; AIRWAY HYPERRESPONSIVENESS; ALTERNATIVE ACTIVATION; RESEARCH-PROGRAM; IN-VIVO; CELLS; INFLAMMATION; DISEASE; MACROPHAGES; ANTIGEN AB Rationale Distinct sets of corticosteroid unresponsive genes rnodulate disease severity in asthma Objectives To identify corticosteroid unresponsive genes that provide new insights into disease pathogenesis and asthma therapeutics Methods Experimental murine asthma was induced by nasal ad ministration of house dust mite for 5 days per week Dexamethasone and apolipoprotein E (apo E) mimetic peptides were administered via osmotic minipumps Measurements and Main Results Genome wide expression profiling of the lung transcriptome in a house dust mite-induced model of murine asthma identified increases in apo E mRNA levels that persisted despite corticosteroid treatment House dust mite-challenged apo E(-/-) mice displayed enhanced airway hyperreactivity and goblet cell hyperplasia, which could be rescued by administration of an apo E(130-149) mimetic peptide Administration of the apo E(130-149) mimetic peptide to house dust mite-challenged apo E(-/-) mice also inhibited eosinophilic airway inflammation IgE production, and the expression of Th2 and Th17 cytokines House dust mite-challenged low density lipoprotein receptor (LDLR) knockout mice displayed a similar phenotype as apo E(-/-) mice with enhanced airway hyperreactivity goblet cell hyperplasia and mum gene expression, but could not be rescued by the apo E(130-149) mimetic peptide, consistent with a LDLR dependent mechanism Conclusions These findings for the first time identify an apo E-LDLR pathway as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma Furthermore, our results demonstrate that strategies that activate the apo E-LDLR pathway, such as apo E mimetic peptides, might be developed into a novel treatment approach for patients with asthma C1 [Yao, Xianglan; Fredriksson, Karin; Xu, Xiuli; Raghavachari, Nalini; Amar, Marcelo J. A.; Remaley, Alan T.; Levine, Stewart J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Xu, Xiuli; Raghavachari, Nalini] NHLBI, Gene Express Core Facil, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Zywicke, Gayle J.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Kwak, Minjung] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. FU Division of Intramural Research National Heart Lung and Blood Institute National Institutes of Health; Light Microscopy Core Facility NHLBI FX Supported by the Division of Intramural Research National Heart Lung and Blood Institute National Institutes of Health; The authors are extremely appreciative of the staff of the National Heart Lung and Blood Institute (NHLBI) Laboratory of Animal Medicine and Surgery whose commitment professional advice and excellent technical support made this study possible They are very appreciative of the Pathology Core Facility NHLBI for their assistance with the histopathologic analyses The authors are most appreciative of the support provided by Dr Peter Munson from the Mathematical and Statistical Computing Lab Division of Computational Biosciences Center for Information Technology National Institutes of Health regarding the analysis of gene expression data The authors thank the Light Microscopy Core Facility NHLBI for their support They also thank Dr Myra Mandel for her assistance with assays and Hiren Bhakta Andrew Crouch and Milkesso Foge for their assistance with the performance of experiments The authors are most appreciative of Drs Joel Moss and Martha Vaughan for their helpful discussions and comments regarding the manuscript NR 45 TC 35 Z9 35 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD NOV 15 PY 2010 VL 182 IS 10 BP 1228 EP 1238 DI 10.1164/rccm.201002.0308OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 686DI UT WOS:000284676600006 PM 20622028 ER PT J AU Lardinois, OM Chatterjee, S Mason, RP Tomer, KB Deterding, LJ AF Lardinois, Olivier M. Chatterjee, Saurabh Mason, Ronald P. Tomer, Kenneth B. Deterding, Leesa J. TI Biotinylated Analogue of the Spin-Trap 5,5-Dimethyl-1-pyrroline-N-oxide for the Detection of Low-Abundance Protein Radicals by Mass Spectrometry SO ANALYTICAL CHEMISTRY LA English DT Letter ID CYTOCHROME-C PEROXIDASE; IDENTIFICATION; DERIVATIVES; SITE; EPR AB Protein radicals are implicated in oxidative stress and are associated with a wide range of diseases and disorders. In the present work, we describe the specific application of a newly synthesized nitrone spin trap, Bio-SS-DMPO, for the detection of these highly reactive species by mass spectrometry (MS). Bio-SS-DMPO is a biotinylated analogue of the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) that allows for specific capture of the protein(s)/peptide(s) labeled by the spin-trap on a (strept)avidin-bound solid matrix. The disulfide bond in the linker arm joining biotin to DMPO can be cleaved to release captured spin-adduct peptide from the solid matrix. This (strept)avidin-based affinity purification reduces the complexity of the samples prior to MS analyses, thereby facilitating the location of the sites of spin trap addition. In addition, the biotin moiety on the spin-trap can efficiently be probed with (strept)avidin-conjugated reporter. This offers an effective means to visualize the presence of DMPO-adducted proteins in intact cells. C1 [Tomer, Kenneth B.; Deterding, Leesa J.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Lardinois, Olivier M.; Chatterjee, Saurabh; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. EM deterdi2@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS [Z99 ES999999, Z01 ES050139-14, ZIA ES050150-14]; NIEHS NIH HHS [Z01 ES050139, Z01 ES050171] NR 15 TC 2 Z9 2 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD NOV 15 PY 2010 VL 82 IS 22 BP 9155 EP 9158 DI 10.1021/ac1023183 PG 4 WC Chemistry, Analytical SC Chemistry GA 678MQ UT WOS:000284080500006 PM 20957988 ER PT J AU Abraham, I Jain, S Wu, CP Khanfar, MA Kuang, YH Dai, CL Shi, Z Chen, XA Fu, LW Ambudkar, SV El Sayed, K Chen, ZS AF Abraham, Ioana Jain, Sandeep Wu, Chung-Pu Khanfar, Mohammad A. Kuang, Yehong Dai, Chun-Ling Shi, Zhi Chen, Xiang Fu, Liwu Ambudkar, Suresh V. El Sayed, Khalid Chen, Zhe-Sheng TI Marine sponge-derived sipholane triterpenoids reverse P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE ABC transporter; Chemosensitivity; P-glycoprotein; Sipholane triterpenoid; Multidrug resistance ID ACUTE MYELOID-LEUKEMIA; SOFT-TISSUE SARCOMAS; RANDOMIZED PHASE-II; CATALYTIC CYCLE; ATPASE ACTIVITY; IN-VITRO; INHIBITOR; CHEMOTHERAPY; COMBINATION; TRANSPORT AB Previously, we reported sipholenol A, a sipholane triterpenoid from the Red Sea sponge Callyspongia siphonella, as a potent reversal of multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). Through extensive screening of several related sipholane triterpenoids that have been isolated from the same sponge, we identified sipholenone E, sipholenol L and siphonellinol D as potent reversals of MDR in cancer cells. These compounds enhanced the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine and paclitaxel, and significantly reversed the MDR-phenotype in P-gp-overexpressing MDR cancer cells KB-C2 in a dose-dependent manner. Moreover, these three sipholanes had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MRP1 (ABCC1) or MRP7 (ABCC10) or breast cancer resistance protein (BCRP/ABCG2). All three sipholanes (IC(50) >50 mu M) were not toxic to all the cell lines that were used. [(3)H]-Paclitaxel accumulation and efflux studies demonstrated that all three triterpenoids time-dependently increased the intracellular accumulation of [[(3)H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. Sipholanes also inhibited calcein-AM transport from P-gp-overexpressing cells. The Western blot analysis revealed that these three triterpenoids did not alter the expression of P-gp. However, they stimulated P-gp ATPase activity in a concentration-dependent manner and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. In silk molecular docking aided the virtual identification of ligand binding sites of these compounds. In conclusion, sipholane triterpenoids efficiently inhibit the function of P-gp through direct interactions and may represent potential reversal agents for the treatment of MDR. (c) 2010 Elsevier Inc. All rights reserved. C1 [Abraham, Ioana; Kuang, Yehong; Dai, Chun-Ling; Shi, Zhi; Chen, Zhe-Sheng] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Jamaica, NY 11439 USA. [Jain, Sandeep; Khanfar, Mohammad A.; El Sayed, Khalid] NE Louisiana Univ, Dept Basic Pharmaceut Sci, Coll Pharm, Monroe, LA 71201 USA. [Wu, Chung-Pu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kuang, Yehong; Chen, Xiang] Cent S Univ, Dept Dermatol, Xiang Ya Hosp, Changsha 410008, Hunan, Peoples R China. [Dai, Chun-Ling; Shi, Zhi; Fu, Liwu] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, Guangzhou 510060, Guangdong, Peoples R China. RP Chen, ZS (reprint author), St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Jamaica, NY 11439 USA. EM Chenz@stjohns.edu FU St. John's University [579-1110]; Ray Biotech Co.; NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. Michael M. Gottesman (NCI, NIH, Bethesda, MD) for KB-3-1 and KB-V1 cells, Shin-ichi Akiyama (Kagoshima University, Japan) for KB-C2 and KB-CV60 cell lines. We thank Kakenshoyaku Co. (Japan) for providing cepharanthine. We thank Drs. Susan E. Bates and Robert W. Robey (NCI, NIH, Bethesda, MD) for providing Fumitremorgin (FTC), HEK293/pcDNA3 and HEK/ABCG2-R2 transfectant cells. We thank Dr. Gary D. Kruh (Cancer Center, University of Illinois at Chicago) for the HEK293 control and HEK/MRP7 transfectant cells. This work was supported by funds from St. John's University Seed Grant No. 579-1110, (Z.S. Chen) and research support from Ray Biotech Co. (Z.S. Chen) and C.-P.W. and S.V.A. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 52 TC 23 Z9 25 U1 0 U2 15 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 NOV 15 PY 2010 VL 80 IS 10 BP 1497 EP 1506 DI 10.1016/j.bcp.2010.08.001 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662YT UT WOS:000282850900005 PM 20696137 ER PT J AU Pistollato, F Abbadi, S Rampazzo, E Viola, G Della Puppa, A Cavallini, L Frasson, C Persano, L Panchision, DM Basso, G AF Pistollato, Francesca Abbadi, Sara Rampazzo, Elena Viola, Giampietro Della Puppa, Alessandro Cavallini, Lucia Frasson, Chiara Persano, Luca Panchision, David M. Basso, Giuseppe TI Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE 2-Deoxyglucose; Hypoxia; Hypoxia inducible factor-1 alpha; Prolyl hydroxylase 2; GBM differentiation ID MITOCHONDRIAL COMPLEX-III; CANCER-CELL METABOLISM; STEM-CELLS; INDUCIBLE FACTOR-1-ALPHA; HIF PATHWAY; IN-VITRO; 2-DEOXY-D-GLUCOSE; GLIOMA; GROWTH; HIF-1-ALPHA AB Glioblastoma multiforme (GBM) are highly proliferative brain tumors characterized by a hypoxic microenvironment which controls GBM stem cell maintenance. Tumor hypoxia promotes also elevated glycolytic rate; thus, limiting glucose metabolism is a potential approach to inhibit tumor growth. Here we investigate the effects mediated by 2-deoxyglucose (2-DG), a glucose analogue, on primary GBM-derived cells maintained under hypoxia. Our results indicate that hypoxia protects GBM cells from the apoptotic effect elicited by 2-DG, which raises succinate dehydrogenase activity thus promoting succinate level decrease. As a consequence hypoxia inducible factor-1 alpha (HIF-1 alpha) degradation occurs and this induces GBM cells to acquire a neuronal committed phenotype. By adding succinate these effects are reverted, as succinate stabilizes HIF-1 alpha and increases GBM stem cell fraction particularly under hypoxia, thus preserving the tumor stem cell niche. 2-DG inhibits anaerobic glycolysis altering GBM cell phenotype by forcing tumor cells into mitochondrial metabolism and by inducing differentiation. (c) 2010 Elsevier Inc. All rights reserved. C1 [Pistollato, Francesca; Abbadi, Sara; Rampazzo, Elena; Viola, Giampietro; Frasson, Chiara; Persano, Luca; Basso, Giuseppe] Univ Padua, Dept Pediat, Hematooncol Lab, I-35128 Padua, Italy. [Della Puppa, Alessandro] Univ Padua, Dept Neurosurg, I-35128 Padua, Italy. [Cavallini, Lucia] Univ Padua, Dept Biochem, I-35131 Padua, Italy. [Panchision, David M.] NIMH, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. RP Viola, G (reprint author), Univ Padua, Dept Pediat, Hematooncol Lab, Via Giustiniani 3, I-35128 Padua, Italy. EM giampietro.viola.1@unipd.it RI Viola, Giampietro/I-4095-2012; Persano, Luca/H-6416-2016; OI Viola, Giampietro/0000-0001-9329-165X; Persano, Luca/0000-0002-0050-3666; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Italian Association for the Fight against Neuroblastoma; Italian Association AIRC FX We thank Dr. Ahmed Mohyeldin for kindly providing the antibody for pPDH E1 alpha, Dr. Hugo Guerrero-Cazares and Dr. Martina Pigazzi for their suggestions on the manuscript and Dr. Alberto Burlina for kindly providing the Lactate Assay Kit. This work was supported by funds from the Italian Association for the Fight against Neuroblastoma (Pensiero Project) and the Italian Association AIRC (Interregional pediatric project grant). NR 63 TC 25 Z9 27 U1 0 U2 6 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 NOV 15 PY 2010 VL 80 IS 10 BP 1517 EP 1527 DI 10.1016/j.bcp.2010.08.003 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662YT UT WOS:000282850900007 PM 20705058 ER PT J AU Tanaka, N Zhang, XG Sugiyama, E Kono, H Horiuchi, A Nakajima, T Kanbe, H Tanaka, E Gonzalez, FJ Aoyama, T AF Tanaka, Naoki Zhang, Xiuguo Sugiyama, Eiko Kono, Hiroyuki Horiuchi, Akira Nakajima, Takero Kanbe, Hiroki Tanaka, Eiji Gonzalez, Frank J. Aoyama, Toshifumi TI Eicosapentaenoic acid improves hepatic steatosis independent of PPAR alpha activation through inhibition of SREBP-1 maturation in mice SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE beta-Oxidation; Fatty acid uptake; SCAP; S1P; Superoxide dismutase ID FATTY LIVER-DISEASE; RECEPTOR-ALPHA; FISH-OIL; NONALCOHOLIC STEATOHEPATITIS; GENE-EXPRESSION; PEROXISOME PROLIFERATORS; DOWN-REGULATION; HEART-DISEASE; MECHANISM; BINDING AB Eicosapentaenoic acid (EPA) in fish oil is known to improve hepatic steatosis. However, it remains unclear whether such action of EPA is actually caused by peroxisome proliferator-activated receptor alpha (PPAR alpha) activation. To explore the contribution of PPAR alpha to the effects of EPA itself, male wild-type and PPAR alpha-null mice were fed a saturated fat diet for 16 weeks, and highly (>98%)-purified EPA was administered in the last 12 weeks. Furthermore, the changes caused by EPA treatment were compared to those elicited by fenofibrate (FF), a typical PPAR alpha. activator. A saturated fat diet caused macrovesicular steatosis in both genotypes. However, EPA ameliorated steatosis only in wild-type mice without PPAR alpha activation, which was evidently different from numerous previous observations. Instead. EPA inhibited maturation of sterol-responsive element-binding protein (SREBP)-1 in the presence of PPAR alpha through down-regulation of SREBP cleavage-activating protein and site-1 protease. Additionally, EPA suppressed fatty acid uptake and promoted hydrolysis of intrahepatic triglycerides in a PPAR alpha-independent manner. These effects were distinct from those of fenofibrate. Although fenofibrate induced NAPDH oxidase and acyl-coenzyme A oxidase and significantly increased hepatic lipid peroxides. EPA caused PPAR alpha-dependent induction of superoxide dismutases, probably contributing to a decrease in the lipid peroxides. These results firstly demonstrate detailed mechanisms of steatosis-ameliorating effects of EPA without PPAR alpha activation and ensuing augmentation of hepatic oxidative stress. (c) 2010 Elsevier Inc. All rights reserved. C1 [Tanaka, Naoki; Zhang, Xiuguo; Nakajima, Takero; Kanbe, Hiroki; Aoyama, Toshifumi] Shinshu Univ, Dept Metab Regulat, Grad Sch Med, Matsumoto, Nagano 3908621, Japan. [Tanaka, Naoki; Tanaka, Eiji] Shinshu Univ, Dept Gastroenterol, Sch Med, Matsumoto, Nagano 3908621, Japan. [Sugiyama, Eiko] Nagano Prefectural Coll, Dept Nutr Sci, Nagano, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Dept Metab Regulat, Grad Sch Med, Asahi 3-1-1, Matsumoto, Nagano 3908621, Japan. EM tanakan@mail.nih.gov; eikoyoko@nagano-kentan.ac.jp NR 47 TC 34 Z9 37 U1 1 U2 11 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 NOV 15 PY 2010 VL 80 IS 10 BP 1601 EP 1612 DI 10.1016/j.bcp.2010.07.031 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 662YT UT WOS:000282850900016 PM 20691165 ER PT J AU Hooker, JM Kim, SW Reibel, AT Alexoff, D Xu, YW Shea, C AF Hooker, Jacob M. Kim, Sung Won Reibel, Achim T. Alexoff, David Xu, Youwen Shea, Colleen TI Evaluation of [C-11]metergoline as a PET radiotracer for 5HTR in nonhuman primates SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Metergoline; Carbon-11; PET; Serotonin; Altanserin ID 5-HT2A RECEPTORS; PHARMACOLOGICAL CHARACTERIZATION; SEROTONIN TRANSPORTER; METERGOLINE; RADIOLIGAND; VOLUNTEERS; BINDING; ANTAGONIST; DISORDER; LIGAND AB Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [C-11]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [C-11]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Hooker, Jacob M.; Kim, Sung Won; Reibel, Achim T.; Alexoff, David; Xu, Youwen; Shea, Colleen] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Hooker, Jacob M.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hooker, Jacob M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Kim, Sung Won] NIAAA, Rockville, MD 20892 USA. [Reibel, Achim T.] Johannes Gutenberg Univ Mainz, Mainz, Germany. RP Hooker, JM (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM hooker@nmr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708 FU U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-98CH10886]; NIH [1F32EB008320]; NIMH PDSP [HHSN-271-2008-00025-C] FX This work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the U.S. Department of Energy, supported by its Office of Biological and Environmental Research. J.M.H. was supported by an NIH Postdoctoral Fellowship (1F32EB008320) and through the Goldhaber Distinguished Fellowship program at BNL. The authors are grateful to Dr. Michael Schueller for cyclotron operation and the PET imaging team at BNL (Pauline Carter, Payton King, and Don Warner) for carrying out primate imaging experiments and to Dr. Joanna Fowler for scientific input. The receptor binding profile for metergoline was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. NR 37 TC 5 Z9 5 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 15 PY 2010 VL 18 IS 22 BP 7739 EP 7745 DI 10.1016/j.bmc.2010.04.039 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 673HK UT WOS:000283649900005 PM 20451398 ER PT J AU Zuliani, V Fantini, M Nigam, A Stables, JP Patel, MK Rivara, M AF Zuliani, Valentina Fantini, Marco Nigam, Aradhya Stables, James P. Patel, Manoj K. Rivara, Mirko TI Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Sodium channel blockers; Epilepsy; Seizure models; hNaV1.2 ID GATED SODIUM-CHANNELS; ANTIEPILEPTIC DRUGS; MOLECULAR DETERMINANTS; STATUS EPILEPTICUS; NA+ CHANNELS; EPILEPSY; 2,4(5)-DIARYLIMIDAZOLES; MECHANISMS; CURRENTS AB 2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNaV1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50) = 61.7 mg/kg; compound 13, ED(50) = 46.8 mg/kg, compound 17, ED(50) = 129.5 mg/kg and compound 20, ED(50) = 136.7 mg/kg). Protective indexes (PI = TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNaV1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs). (C) 2010 Elsevier Ltd. All rights reserved. C1 [Zuliani, Valentina; Fantini, Marco; Rivara, Mirko] Univ Parma, Dipartimento Farmaceut, I-43124 Parma, Italy. [Stables, James P.] NINDS, ASP Program, Rockville, MD 20852 USA. [Nigam, Aradhya; Patel, Manoj K.] Univ Virginia, Dept Anesthesiol, Charlottesville, VA 22908 USA. RP Zuliani, V (reprint author), Univ Parma, Dipartimento Farmaceut, Vle GP Usberti 27-A, I-43124 Parma, Italy. EM valentina.zuliani@unipr.it FU Italian MIUR; Siena Biotech S.p.A; National Institutes of Health NINDS [R21NS061069-02] FX Financial support from Italian MIUR, Siena Biotech S.p.A. and the National Institutes of Health NINDS R21NS061069-02 (M.K.P.) is gratefully acknowledged. We are grateful to the Centro Interdipartimentale Misure of the University of Parma for providing the NMR instrumentation. NR 28 TC 11 Z9 11 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 15 PY 2010 VL 18 IS 22 BP 7957 EP 7965 DI 10.1016/j.bmc.2010.09.029 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 673HK UT WOS:000283649900031 PM 20943396 ER PT J AU Kang, DW Kim, YS Lim, KS Kim, MS Pearce, LV Pavlyukovets, VA Tao, AK Lang-Kuhs, KA Blumberg, PM Lee, J AF Kang, Dong Wook Kim, Yong Soo Lim, Kwang Su Kim, Myeong Seop Pearce, Larry V. Pavlyukovets, Vladimir A. Tao, Andy K. Lang-Kuhs, Krystle A. Blumberg, Peter M. Lee, Jeewoo TI Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE TRPV1 agonist; TRPV1 antagonist; Halogenation; Resiniferatoxin; Capsaicinoid; Capsaicin ID HIGH-AFFINITY ANTAGONISTS; VANILLOID RECEPTOR TRPV1; POTENT; RESINIFERATOXIN; ANALOGS; ANALGESICS; CHANNEL; PAIN; MECHANISMS AB As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3-methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with K(i) (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6'-iodononivamide. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Kang, Dong Wook; Kim, Yong Soo; Lim, Kwang Su; Kim, Myeong Seop; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Pearce, Larry V.; Pavlyukovets, Vladimir A.; Tao, Andy K.; Lang-Kuhs, Krystle A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Korea Science and Engineering Foundation (KOSEF) [R11-2007-107-02001-0, R01-2007-000-20052-0]; National Institutes of Health, Center for Cancer Research, National Cancer Institute FX This research was supported by Grants R11-2007-107-02001-0 and R01-2007-000-20052-0 from the Korea Science and Engineering Foundation (KOSEF) and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. We thank numerous fellows in the laboratory for assistance with the bioassays. NR 25 TC 3 Z9 3 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 15 PY 2010 VL 18 IS 22 BP 8092 EP 8105 DI 10.1016/j.bmc.2010.09.001 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 673HK UT WOS:000283649900047 PM 20937561 ER PT J AU Iera, JA Jenkins, LMM Kajiyama, H Kopp, JB Appella, DH AF Iera, Jaclyn A. Jenkins, Lisa M. Miller Kajiyama, Hiroshi Kopp, Jeffrey B. Appella, Daniel H. TI Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Protein-protein interactions; Combinatorial library; High-throughput screening; Vpr ID VPR; INHIBITION; MOLECULES; ALDEHYDES; AFFINITY; DRUG AB Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction. Current chemical libraries, however, consist mostly of molecules designed to inhibit enzymes. In this manuscript, we report the synthesis and screening of a library based on an N-acylated polyamine (NAPA) scaffold that we designed to have specific molecular features necessary to inhibit protein-protein interactions. Screens of the library identified a member with favorable binding properties to the HIV viral protein R (Vpr), a regulatory protein from HIV, that is involved in numerous interactions with other proteins critical for viral replication. Published by Elsevier Ltd. C1 [Iera, Jaclyn A.; Kajiyama, Hiroshi; Kopp, Jeffrey B.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Iera, Jaclyn A.; Kajiyama, Hiroshi; Kopp, Jeffrey B.; Appella, Daniel H.] NIDDK, Kidney Dis Sect, NIH, DHHS, Bethesda, MD 20892 USA. [Jenkins, Lisa M. Miller] NCI, Cell Biol Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK; NCI; NIH FX The authors thank Dr. Ulrich Schubert for the supply of biotinylated Vpr. This research was supported by the Intramural Research Programs (IRPs) of NIDDK and NCI, and the Intramural AIDS Targeted Antiviral Program (IATAP) at NIH. NR 22 TC 6 Z9 6 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 15 PY 2010 VL 20 IS 22 BP 6500 EP 6503 DI 10.1016/j.bmcl.2010.09.054 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 665RJ UT WOS:000283052900032 PM 20932761 ER PT J AU Jiao, GS Kim, S Moayeri, M Cregar-Hernandez, L McKasson, L Margosiak, SA Leppla, SH Johnson, AT AF Jiao, Guan-Sheng Kim, Seongjin Moayeri, Mahtab Cregar-Hernandez, Lynne McKasson, Linda Margosiak, Stephen A. Leppla, Stephen H. Johnson, Alan T. TI Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Anthrax; Lethal factor; Inhibitor; Small molecule ID TOXIN; AGENT AB Sub-nanomolar small molecule inhibitors of anthrax lethal factor have been identified using SAR and Merck L915 (4) as a model compound. One of these compounds (16) provided 100% protection in a rat lethal toxin model of anthrax disease. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Jiao, Guan-Sheng; Kim, Seongjin; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Johnson, Alan T.] PanThera Biopharma LLC, Aiea, HI 96701 USA. [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Johnson, AT (reprint author), PanThera Biopharma LLC, Aiea, HI 96701 USA. EM ajohnson@pantherabio.com FU National Institutes of Health [R44 AI052587]; NIH, National Institute of Allergy and Infectious Diseases FX We thank Dr. Sherri Millis, Dr. Petr Kuzmic, and Devorah Crown for help with preliminary experiments. We also thank the National Institutes of Health for their support of this work with grant R44 AI052587. Animal studies were supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the NIH. NR 16 TC 14 Z9 16 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 15 PY 2010 VL 20 IS 22 BP 6850 EP 6853 DI 10.1016/j.bmcl.2010.08.058 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 665RJ UT WOS:000283052900106 PM 20864339 ER PT J AU Glynn, SA Prueitt, RL Ridnour, LA Boersma, BJ Dorsey, TM Wink, DA Goodman, JE Yfantis, HG Lee, DH Ambs, S AF Glynn, Sharon A. Prueitt, Robyn L. Ridnour, Lisa A. Boersma, Brenda J. Dorsey, Tiffany M. Wink, David A. Goodman, Julie E. Yfantis, Harris G. Lee, Dong H. Ambs, Stefan TI COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer SO BMC CANCER LA English DT Article ID ELEVATED CYCLOOXYGENASE-2 EXPRESSION; PROTEIN-KINASE-B; PROGNOSTIC-SIGNIFICANCE; CELECOXIB; ANGIOGENESIS; INHIBITOR; EXEMESTANE; CARCINOMA; RECEPTOR; TUMORS AB Background: Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Methods: Tumor COX-2, HER2 and estrogen receptor alpha (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. Results: COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Conclusions: Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype. C1 [Glynn, Sharon A.; Prueitt, Robyn L.; Boersma, Brenda J.; Dorsey, Tiffany M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.; Wink, David A.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20892 USA. [Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Pathol & Lab Med, Baltimore, MD USA. [Goodman, Julie E.] Gradient Corp, Cambridge, MA 02138 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Boersma, Brenda/A-9270-2009 OI Glynn, Sharon/0000-0003-1459-2580; Boersma, Brenda/0000-0002-8992-2735 FU NIH, National Cancer Institute, Center for Cancer Research; All-Ireland Cancer Consortium National Cancer Institute Cancer Prevention Fellowship; Health Research Board of Ireland FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We would like to thank Raymond Jones, Audrey Salabes, Leoni Leondaridis, Glennwood Trivers, Elise Bowman, and personnel at the University of Maryland and the Baltimore Veterans Administration, and the Surgery and Pathology Departments at the University of Maryland Medical Center, Baltimore Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital for their contributions. Sharon A. Glynn is a recipient of an All-Ireland Cancer Consortium National Cancer Institute Cancer Prevention Fellowship, sponsored in part by the Health Research Board of Ireland. NR 38 TC 26 Z9 27 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD NOV 15 PY 2010 VL 10 AR 626 DI 10.1186/1471-2407-10-626 PG 12 WC Oncology SC Oncology GA 686IC UT WOS:000284689000001 PM 21078168 ER PT J AU Fraga, LAD Lamb, EW Moreno, EC Chatterjee, M Dvorak, J Delcroix, M Sajid, M Caffrey, CR Davies, SJ AF de Oliveira Fraga, Lucia A. Lamb, Erika W. Moreno, Elizabeth C. Chatterjee, Mitali Dvorak, Jan Delcroix, Melaine Sajid, Mohammed Caffrey, Conor R. Davies, Stephen J. TI Rapid induction of IgE responses to a worm cysteine protease during murine pre-patent schistosome infection SO BMC IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MAJOR EGG ANTIGEN; CATHEPSIN-B; HUMAN RESISTANCE; IMMUNE-RESPONSE; MANSONI INFECTION; TYPE-2 RESPONSES; SURFACE-ANTIGEN; TH2 RESPONSES; CELL RESPONSE AB Background: During the pre-patent stage of infection, juvenile Schistosoma blood flukes co-opt signals from the adaptive immune system to facilitate parasite development, but the types of responses that are induced at this early stage of infection, and the parasite antigens they target, have not been characterized. Results: Through analysis of experimental pre-patent infections, we show that the S. mansoni cysteine protease SmCB1 is rapidly targeted by an antigen-specific IgE response. The induction of this response is independent of schistosome eggs as infection with male or female worms alone also induced SmCB1-specific IgE. We also show that the SmCB1-specific IgE response is dependent on cognate CD4(+) T cell help and IL-4, suggesting that prepatent Th2 responses provide T cell help for the SmCB1-specific IgE response. Finally, exposed human subjects also produced IgE against SmCB1. Conclusions: Our data demonstrate that, like eggs, schistosome worms also induce functional type 2 responses and that a parasite cysteine protease is an inducer of type 2 responses during the early stages of schistosome infection. C1 [de Oliveira Fraga, Lucia A.; Lamb, Erika W.; Chatterjee, Mitali; Davies, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [de Oliveira Fraga, Lucia A.] Univ Vale do Rio Doce UNIVALE, Governador Valadares, MG, Brazil. [Moreno, Elizabeth C.] FUNASA BH, Belo Horizonte, MG, Brazil. [Dvorak, Jan; Delcroix, Melaine; Sajid, Mohammed; Caffrey, Conor R.] Univ Calif San Francisco, Calif Inst Quantitat Biosci QB3, Sandler Ctr Basic Res Parasit Dis, San Francisco, CA 94158 USA. [Lamb, Erika W.] NIAID, NIH, LPD, Bethesda, MD 20892 USA. [Sajid, Mohammed] Leiden Univ Med Ctr, Leiden Malaria Res Grp, Afd Parasitol, NL-2333 ZA Leiden, Netherlands. RP Davies, SJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM sdavies@usuhs.mil RI Dvorak, Jan/I-3909-2012; OI MORENO, ELIZABETH/0000-0002-8434-2483 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [N01 AI30026, R01 AI066227]; CNPq [210320/2006-0] FX We thank Maria de Fatima da Silva, Marlucy Lima, Lilia Pires and Ivanete Santos for invaluable assistance with field studies and Sean Maynard for excellent technical assistance. S. mansoni-infected and non-infected B. glabrata snails were provided by Dr. Fred Lewis through National Institutes of Health/National Institute of Allergy and Infectious Diseases Contract N01 AI30026. Financial support was provided by NIH/NIAID grant R01 AI066227 (to SJD) and by CNPq fellowship 210320/2006-0 (to LAOF). NR 63 TC 11 Z9 11 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD NOV 15 PY 2010 VL 11 AR 56 DI 10.1186/1471-2172-11-56 PG 11 WC Immunology SC Immunology GA 686JO UT WOS:000284692800001 ER PT J AU Sobin, LH Compton, CC AF Sobin, Leslie H. Compton, Carolyn C. TI TNM Seventh Edition: What's New, What's Changed Communication From the International Union Against Cancer and the American Joint Committee on Cancer SO CANCER LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; TERM-FOLLOW-UP; CLASSIFICATION C1 [Sobin, Leslie H.] Int Union Canc TNM Prognost Factors Project, Geneva, Switzerland. [Compton, Carolyn C.] Amer Joint Comm Canc, Chicago, IL USA. [Compton, Carolyn C.] NCI, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. RP Sobin, LH (reprint author), UICC TNM Comm, 4280 Massachusetts Ave NW, Washington, DC 20016 USA. EM sobin@uicc.org NR 12 TC 190 Z9 193 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD NOV 15 PY 2010 VL 116 IS 22 BP 5336 EP 5339 DI 10.1002/cncr.25537 PG 4 WC Oncology SC Oncology GA 678CP UT WOS:000284047400026 PM 20665503 ER PT J AU Brown, VA Patel, KR Viskaduraki, M Crowell, JA Perloff, M Booth, TD Vasilinin, G Sen, A Schinas, AM Piccirilli, G Brown, K Steward, WP Gescher, AJ Brenner, DE AF Brown, Victoria A. Patel, Ketan R. Viskaduraki, Maria Crowell, James A. Perloff, Marjorie Booth, Tristan D. Vasilinin, Grygoriy Sen, Ananda Schinas, Anna Maria Piccirilli, Gianfranca Brown, Karen Steward, William P. Gescher, Andreas J. Brenner, Dean E. TI Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics, and Effect on the Insulin-like Growth Factor Axis SO CANCER RESEARCH LA English DT Article ID FACTOR-I; TRANS-RESVERATROL; COLORECTAL-CANCER; METABOLITES; RISK; RESTRICTION; MECHANISMS; RECEPTOR; CELLS AB Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P < 0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. Cancer Res; 70(22); 9003-11. (C) 2010 AACR. C1 [Gescher, Andreas J.] Univ Leicester, Dept Canc Studies & Mol Med, LRI,RKCSB, Canc Biomarkers & Prevent Grp, Leicester LE2 7LX, Leics, England. [Crowell, James A.; Perloff, Marjorie] NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. [Booth, Tristan D.; Piccirilli, Gianfranca] Pharmascience Inc, Montreal, PQ, Canada. [Vasilinin, Grygoriy; Schinas, Anna Maria] MDS Pharma Serv, Montreal, PQ, Canada. [Sen, Ananda] Univ Michigan, Sch Med, Dept Family Practice, Ann Arbor, MI 48109 USA. [Brenner, Dean E.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Brenner, Dean E.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Brenner, Dean E.] VA Med Ctr, Ann Arbor, MI USA. RP Gescher, AJ (reprint author), Univ Leicester, Dept Canc Studies & Mol Med, LRI,RKCSB, Canc Biomarkers & Prevent Grp, Leicester LE2 7LX, Leics, England. EM ag15@le.ac.uk FU National Cancer Institute [NCI-N01-CN-25025]; Cancer Research UK [C325/A6691]; UK Department of Health; Kutsche Family Memorial Endowment; Michigan Clinical Research Unit NIH [UL1RR024986] FX This study was funded by National Cancer Institute contract NCI-N01-CN-25025, programme grant C325/A6691 from Cancer Research UK, Experimental Cancer Medicine Centre grant from Cancer Research UK and the UK Department of Health to Leicester University, Kutsche Family Memorial Endowment, and Michigan Clinical Research Unit NIH grant UL1RR024986. NR 32 TC 210 Z9 213 U1 0 U2 21 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 NOV 15 PY 2010 VL 70 IS 22 BP 9003 EP 9011 DI 10.1158/0008-5472.CAN-10-2364 PG 9 WC Oncology SC Oncology GA 680DT UT WOS:000284213300006 PM 20935227 ER PT J AU Su, YR Meador, JA Calaf, GM De-Santis, LP Zhao, YL Bohr, VA Balajee, AS AF Su, Yanrong Meador, Jarah A. Calaf, Gloria M. De-Santis, Luca Proietti Zhao, Yongliang Bohr, Vilhelm A. Balajee, Adayabalam S. TI Human RecQL4 Helicase Plays Critical Roles in Prostate Carcinogenesis SO CANCER RESEARCH LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; COMPARATIVE GENOMIC HYBRIDIZATION; DNA-REPLICATION; GENE-EXPRESSION; CHROMOSOMAL INSTABILITY; SYNDROME PROTEIN; WERNER-SYNDROME; COPY NUMBER; CELL-LINES; CANCER AB Prostate cancer is the second leading cause of cancer-associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer-prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer cell lines. Increased RecQL4 expression was also detected in human prostate tumor tissues as a function of tumor grade with the highest expression level in metastatic tumor samples, suggesting that RecQL4 may be a potential prognostic factor for advanced stage of prostate cancer. Transient and stable suppression of RecQL4 by small interfering RNA and short hairpin RNA vectors drastically reduced the growth and survival of metastatic prostate cancer cells, indicating that RecQL4 is a prosurvival factor for prostate cancer cells. RecQL4 suppression led to increased poly(ADP-ribose) polymerase (PARP) synthesis and RecQL4-suppressed prostate cancer cells underwent an extensive apoptotic death in a PARP-1-dependent manner. Most notably, RecQL4 knockdown in metastatic prostate cancer cells drastically reduced their cell invasiveness in vitro and tumorigenicity in vivo, showing that RecQL4 is essential for prostate cancer promotion. Observation of a direct interaction of retinoblastoma (Rb) and E2F1 proteins with RecQL4 promoter suggests that Rb-E2F1 pathway may regulate RecQL4 expression. Collectively, our study shows that RecQL4 is an essential factor for prostate carcinogenesis. Cancer Res; 70(22); 9207-17. (C) 2010 AACR. C1 [Balajee, Adayabalam S.] Columbia Univ, Coll Phys & Surg, Ctr Radiol Res, Dept Radiat Oncol,Med Ctr, New York, NY 10032 USA. [De-Santis, Luca Proietti] Dept ABAC, Lab Mol Cytogenet & Mutagenesis, Vitterbo, Italy. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Balajee, AS (reprint author), Columbia Univ, Coll Phys & Surg, Ctr Radiol Res, Dept Radiat Oncol,Med Ctr, VC-11,Room 239,630 West,168th St, New York, NY 10032 USA. EM ab836@columbia.edu FU U.S. Department of Energy Office of Science Biological and Environmental Research [DE-FG02-05ER64055]; NIH National Cancer Institute [CA127120] FX U.S. Department of Energy Office of Science Biological and Environmental Research grant DE-FG02-05ER64055 (A. S. B.) and NIH National Cancer Institute grant CA127120 (Y.L.). NR 45 TC 22 Z9 22 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2010 VL 70 IS 22 BP 9207 EP 9217 DI 10.1158/0008-5472.CAN-10-1743 PG 11 WC Oncology SC Oncology GA 680DT UT WOS:000284213300026 PM 21045146 ER PT J AU Mondul, AM Weinstein, SJ Mannisto, S Snyder, K Horst, RL Virtamo, J Albanes, D AF Mondul, Alison M. Weinstein, Stephanie J. Mannisto, Satu Snyder, Kirk Horst, Ronald L. Virtamo, Jarmo Albanes, Demetrius TI Serum Vitamin D and Risk of Bladder Cancer SO CANCER RESEARCH LA English DT Article ID CIRCULATING 25-HYDROXYVITAMIN D; ADOLESCENTS; METABOLITES; POPULATION; COHORT AB Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1: 1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH) D; i.e., <25, 25 to <37.5, 37.5 to <50, >= 50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH) D was associated with a statistically significantly increased risk of bladder cancer (versus >= 50 nmol/L; <25 nmol/L: OR, 1.73; 95% CI, 1.03-2.91; 25 to <37.5 nmol/L: OR, 1.81; 95% CI, 1.05-3.14; 37.5 to <50 nmol/L: OR, 1.76; 95% CI, 1.02-3.02; P trend = 0.04). Similarly, increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (Q1 versus Q4: OR, 1.63; 95% CI, 0.96-2.75; P trend = 0.03). In this prospective study of male smokers, lower serum 25(OH) D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially nonsmokers and women. Cancer Res; 70(22); 9218-23. (C) 2010 AACR. C1 [Mondul, Alison M.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 21045 USA. [Mannisto, Satu; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Snyder, Kirk] Informat Management Serv Inc, Silver Spring, MD USA. [Horst, Ronald L.] Heartland Assays Inc, Ames, IA USA. RP Mondul, AM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Suite 320, Rockville, MD 21045 USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Osborne, Nicholas/N-4915-2015; OI Osborne, Nicholas/0000-0002-6700-2284; Mannisto, Satu/0000-0002-8668-3046; Mondul, Alison/0000-0002-8843-1416 FU National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX USPHS (contract numbers N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services, and Intramural Research Program of the National Cancer Institute. NR 28 TC 34 Z9 34 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2010 VL 70 IS 22 BP 9218 EP 9223 DI 10.1158/0008-5472.CAN-10-0985 PG 6 WC Oncology SC Oncology GA 680DT UT WOS:000284213300027 PM 20978193 ER PT J AU Koutros, S Freeman, LEB Berndt, SI Andreotti, G Lubin, JH Sandler, DP Hoppin, JA Yu, K Li, QZ Burdette, LA Yuenger, J Yeager, M Alavanja, MCR AF Koutros, Stella Freeman, Laura E. Beane Berndt, Sonja I. Andreotti, Gabriella Lubin, Jay H. Sandler, Dale P. Hoppin, Jane A. Yu, Kai Li, Qizhai Burdette, Laura A. Yuenger, Jeffrey Yeager, Meredith Alavanja, Michael C. R. TI Pesticide Use Modifies the Association Between Genetic Variants on Chromosome 8q24 and Prostate Cancer SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; AGRICULTURAL HEALTH; DNA-DAMAGE; RISK LOCUS; IN-VITRO; COLORECTAL-CANCER; MYC EXPRESSION; MULTIPLE LOCI; SUSCEPTIBILITY AB Genome-wide association studies have identified 8q24 region variants as risk factors for prostate cancer. In the Agricultural Health Study, a prospective study of licensed pesticide applicators, we observed increased prostate cancer risk with specific pesticide use among those with a family history of prostate cancer. Thus, we evaluated the interaction among pesticide use, 8q24 variants, and prostate cancer risk. The authors estimated odds ratios (OR) and 95% confidence intervals (95% CI) for interactions among 211 8q24 variants, 49 pesticides, and prostate cancer risk in 776 cases and 1,444 controls. The ORs for a previously identified variant, rs4242382, and prostate cancer increased significantly (P < 0.05) with exposure to the organophosphate insecticide fonofos, after correction for multiple testing, with per allele ORnonexposed of 1.17 (95% CI, 0.93-1.48), per allele ORlow of 1.30 (95% CI, 0.75-2.27), and per allele ORhigh of 4.46 (95% CI, 2.17-9.17; P-interaction = 0.002, adjusted P-interaction = 0.02). A similar effect modification was observed for three other organophosphate insecticides (coumaphos, terbufos, and phorate) and one pyrethroid insecticide (permethrin). Among ever users of fonofos, subjects with three or four risk alleles at rs7837328 and rs4242382 had approximately three times the risk of prostate cancer (OR, 3.14; 95% CI, 1.41-7.00) compared with subjects who had zero risk alleles and never used fonofos. We observed a significant interaction among variants on chromosome 8q24, pesticide use, and risk of prostate cancer. Insecticides, particularly organophosphates, were the strongest modifiers of risk, although the biological mechanism is unclear. This is the first report of effect modification between 8q24 and an environmental exposure on prostate cancer risk. Cancer Res; 70(22); 9224-33. (C) 2010 AACR. C1 [Koutros, Stella] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Sandler, Dale P.; Hoppin, Jane A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing, Peoples R China. [Burdette, Laura A.; Yuenger, Jeffrey; Yeager, Meredith] NCI, Core Genotyping Facil, Adv Technol Program, Frederick, MD 21701 USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM KoutrosS@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences [Z01ES049030] FX Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119) and National Institute of Environmental Health Sciences (Z01ES049030). We thank the participants in the Agricultural Health Study for their contributions in support of this research. NR 49 TC 24 Z9 25 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 NOV 15 PY 2010 VL 70 IS 22 BP 9224 EP 9233 DI 10.1158/0008-5472.CAN-10-1078 PG 10 WC Oncology SC Oncology GA 680DT UT WOS:000284213300028 PM 20978189 ER PT J AU Clark, AB Kunkel, TA AF Clark, Alan B. Kunkel, Thomas A. TI The importance of being DNA SO CELL CYCLE LA English DT Editorial Material ID POLYMERASES; CANCER C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES065070] NR 11 TC 6 Z9 6 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD NOV 15 PY 2010 VL 9 IS 22 BP 4422 EP 4424 DI 10.4161/cc.9.22.14052 PG 3 WC Cell Biology SC Cell Biology GA 690KD UT WOS:000285002800003 PM 21088478 ER PT J AU Daee, D Myung, K AF Daee, Danielle Myung, Kyungjae TI Small RFC subunits make a big difference SO CELL CYCLE LA English DT Editorial Material ID SISTER-CHROMATID COHESION; SACCHAROMYCES-CEREVISIAE; PCNA C1 [Daee, Danielle; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM kmyung@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD NOV 15 PY 2010 VL 9 IS 22 BP 4429 EP 4430 DI 10.4161/cc.9.22.13821 PG 2 WC Cell Biology SC Cell Biology GA 690KD UT WOS:000285002800008 PM 21088482 ER PT J AU Dilts, DM Cheng, SK Crites, JS Sandler, AB Doroshow, JH AF Dilts, David M. Cheng, Steven K. Crites, Joshua S. Sandler, Alan B. Doroshow, James H. TI Phase III Clinical Trial Development: A Process of Chutes and Ladders SO CLINICAL CANCER RESEARCH LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; CANCER; TIME AB Purpose: The Institute of Medicine report on cooperative groups and the National Cancer Institute (NCI) report from the Operational Efficiency Working Group both recommend changes to the processes for opening a clinical trial. This article provides evidence for the need for such changes by completing the first comprehensive review of all the time and steps required to open a phase III oncology clinical trial and discusses the effect of time to protocol activation on subject accrual. Methods: The Dilts and Sandler method was used at four cancer centers, two cooperative groups, and the NCI Cancer Therapy Evaluation Program. Accrual data were also collected. Results: Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than non-group trials (20.6%; P < 0.0001). Of the closed NCI Cancer Therapy Evaluation Program-approved phase III clinical trials from 2000 to 2007, 39.1% resulted in <21 accruals. Conclusions: The length, variability, and low accrual results demonstrate the need for the NCI clinical trials system to be reengineered. Improvements will be of only limited effectiveness if done in isolation; there is a need to return to the collaborative spirit with all parties creating an efficient and effective system. Recommendations put forth by the Institute of Medicine and Operational Efficiency Working Group reports, if implemented, will aid this renewal. Clin Cancer Res; 16(22); 5381-9. (C) 2010 AACR. C1 [Dilts, David M.; Cheng, Steven K.; Crites, Joshua S.; Sandler, Alan B.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Dilts, David M.; Cheng, Steven K.; Crites, Joshua S.; Sandler, Alan B.] Oregon Hlth & Sci Univ, Ctr Management Res Healthcare, Portland, OR 97239 USA. [Dilts, David M.; Cheng, Steven K.] Oregon Hlth & Sci Univ, Div Management, Sch Med, Portland, OR 97239 USA. [Sandler, Alan B.] Oregon Hlth & Sci Univ, Div Hematol Oncol, Sch Med, Portland, OR 97239 USA. [Crites, Joshua S.] Cleveland Clin, Dept Bioeth, Cleveland, OH 44106 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Dilts, DM (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, 3303 SW Bond Ave, Portland, OR 97239 USA. EM dilts@ohsu.edu FU NCI NIH HHS [U10 CA031946-24] NR 23 TC 38 Z9 38 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2010 VL 16 IS 22 BP 5381 EP 5389 DI 10.1158/1078-0432.CCR-10-1273 PG 9 WC Oncology SC Oncology GA 679PP UT WOS:000284173600003 PM 21062928 ER PT J AU Kinders, RJ Hollingshead, M Lawrence, S Ji, JP Tabb, B Bonner, WM Pommier, Y Rubinstein, L Evrard, YA Parchment, RE Tomaszewski, J Doroshow, JH AF Kinders, Robert J. Hollingshead, Melinda Lawrence, Scott Ji, Jiuping Tabb, Brian Bonner, William M. Pommier, Yves Rubinstein, Larry Evrard, Yvonne A. Parchment, Ralph E. Tomaszewski, Joseph Doroshow, James H. CA Natl Canc Inst Phase 0 Clinical Tr TI Development of a Validated Immunofluorescence Assay for gamma H2AX as a Pharmacodynamic Marker of Topoisomerase I Inhibitor Activity SO CLINICAL CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX PHOSPHORYLATION; ADP-RIBOSE POLYMERASE; PLUCKED HUMAN HAIR; CELL-CYCLE PHASE; 0 CLINICAL-TRIAL; DRUG DEVELOPMENT; CLEAVAGE COMPLEXES; DNA-DAMAGE; END-POINTS AB Purpose: Phosphorylated histone H2AX (gamma H2AX) serves as a biomarker for formation of DNA double-strand break repair complexes. A quantitative pharmacodynamic immunofluorescence assay for gamma H2AX was developed, validated, and tested in human tumor xenograft models with the use of clinically relevant procedures. Experimental Design: The gamma H2AX immunofluorescence assay uses a novel data quantitation and image processing algorithm to determine the extent of nuclear-specific gamma H2AX staining in tumor needle biopsies and hair follicles collected from mice bearing topotecan-responsive A375 xenografts. After method validation with the topoisomerase I (Top1) inhibitor topotecan, the assay was used to compare pharmacodynamic properties of three structurally related indenoisoquinoline Top1 inhibitors. Results: gamma H2AX response to topotecan was quantified over a 60-fold dose range (0.016-1.0 times the murine single-dose maximum tolerated dose), and significant pharmacodynamic response was measured at the mouse equivalent of the 1.5 mg/m(2) clinical dose as well as the lowest dose tested. Responses were within a time window amenable for biopsy collection in clinical trials. These studies enabled characterization of dose and time responses for three indenoisoquinolines, resulting in selection of two for clinical evaluation. gamma H2AX response to Top1 inhibitors in hair follicles was also observable above a minimal dose threshold. Conclusions: Our gamma H2AX assay is sufficiently accurate and sensitive to quantify gamma H2AX in tumor samples and will be used in correlative studies of two indenoisoquinolines in a phase I clinical trial at the National Cancer Institute. Data suggest that hair follicles may potentially serve as a surrogate tissue to evaluate tumor gamma H2AX response to Top1 inhibitors. Clin Cancer Res; 16(22); 5447-57. (C) 2010 AACR. C1 [Kinders, Robert J.] NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Lawrence, Scott; Tabb, Brian] NCI, Pathol Histotechnol Lab, Lab Anim Sci Program, Frederick, MD 21702 USA. [Hollingshead, Melinda] NCI, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21702 USA. [Bonner, William M.; Pommier, Yves; Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Rubinstein, Larry; Tomaszewski, Joseph; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kinders, RJ (reprint author), NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, Sci Applicat Int Corp Frederick Inc, POB B, Frederick, MD 21702 USA. EM kindersr@mail.nih.gov FU National Cancer Institute, NIH [N01-CO-12400]; Division of Cancer Treatment; Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. This research was supported in part by the Developmental Therapeutics Program of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 47 TC 46 Z9 47 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2010 VL 16 IS 22 BP 5447 EP 5457 DI 10.1158/1078-0432.CCR-09-3076 PG 11 WC Oncology SC Oncology GA 679PP UT WOS:000284173600009 PM 20924131 ER PT J AU Yao, HJ Brick, K Evrard, Y Xiao, TJ Camerini-Otero, RD Felsenfeld, G AF Yao, Hongjie Brick, Kevin Evrard, Yvonne Xiao, Tiaojiang Camerini-Otero, R. Daniel Felsenfeld, Gary TI Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA SO GENES & DEVELOPMENT LA English DT Article DE RNA-binding protein; noncoding RNA; CTCF; insulator function ID ENHANCER-BLOCKING ACTIVITY; ZINC-FINGER PROTEIN; CHROMATIN INSULATOR; HUMAN GENOME; GENE-EXPRESSION; H19/IGF2 LOCUS; H19 GENE; METHYLATION; COACTIVATOR; DROSOPHILA AB CCCTC-binding factor (CTCF) is a DNA-binding protein that plays important roles in chromatin organization, although the mechanism by which CTCF carries out these functions is not fully understood. Recent studies show that CTCF recruits the cohesin complex to insulator sites and that cohesin is required for insulator activity. Here we showed that the DEAD-box RNA helicase p68 (DDX5) and its associated noncoding RNA, steroid receptor RNA activator (SRA), form a complex with CTCF that is essential for insulator function. p68 was detected at CTCF sites in the IGF2/H19 imprinted control region (ICR) as well as other genomic CTCF sites. In vivo depletion of SRA or p68 reduced CTCF-mediated insulator activity at the IGF2/H19 ICR, increased levels of IGF2 expression, and increased interactions between the endodermal enhancer and IGF2 promoter. p68/SRA also interacts with members of the cohesin complex. Depletion of either p68 or SRA does not affect CTCF binding to its genomic sites, but does reduce cohesin binding. The results suggest that p68/SRA stabilizes the interaction of cohesin with CTCF by binding to both, and is required for proper insulator function. C1 [Yao, Hongjie; Evrard, Yvonne; Xiao, Tiaojiang; Felsenfeld, Gary] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Brick, Kevin; Camerini-Otero, R. Daniel] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov OI Brick, Kevin/0000-0002-9596-6400 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Drs. Frances Fuller-Pace and Zhi-Ren Liu for p68 constructs, Dr. Mitsuyoshi Nakao for luciferase constructs, Drs. Chunhui Hou and Ann Dean for the mouse CTCF shRNA construct, Dr. Marisa Bartolomei for MEF cells, and Drs. Chunhui Hou and Zhixiong Xu for suggestions in 3C experiments. We also acknowledge Drs. Keith Giles and Zhixiong Xu for their critical reading of the manuscript, and all other members of the Felsenfeld laboratory for helpful discussions. This work was supported by the intramural research program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 62 TC 104 Z9 109 U1 2 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD NOV 15 PY 2010 VL 24 IS 22 BP 2543 EP 2555 DI 10.1101/gad.1967810 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 680DJ UT WOS:000284212300008 PM 20966046 ER PT J AU Hurd, T Zhou, WB Jenkins, P Liu, CJ Swaroop, A Khanna, H Martens, J Hildebrandt, F Margolis, B AF Hurd, Toby Zhou, Weibin Jenkins, Paul Liu, Chia-Jen Swaroop, Anand Khanna, Hemant Martens, Jeffrey Hildebrandt, Friedhelm Margolis, Ben TI The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development SO HUMAN MOLECULAR GENETICS LA English DT Article ID INTRAFLAGELLAR TRANSPORT IFT; NORTH-AMERICAN COHORT; BARDET-BIEDL-SYNDROME; SENIOR-LOKEN-SYNDROME; PLANAR CELL POLARITY; LEFT-RIGHT AXIS; KIDNEY-DISEASE; PLASMA-MEMBRANE; CAENORHABDITIS-ELEGANS; RETINAL DEGENERATION AB Ciliopathies represent a growing group of human genetic diseases whose etiology lies in defects in ciliogenesis or ciliary function. Given the established entity of renal-retinal ciliopathies, we have been examining the role of cilia-localized proteins mutated in retinitis pigmentosa (RP) in regulating renal ciliogenesis or cilia-dependent signaling cascades. Specifically, this study examines the role of the RP2 gene product with an emphasis on renal and vertebrate development. We demonstrate that in renal epithelia, RP2 localizes to the primary cilium through dual acylation of the amino-terminus. We also show that RP2 forms a calcium- sensitive complex with the autosomal dominant polycystic kidney disease protein polycystin 2. Ablation of RP2 by shRNA promotes swelling of the cilia tip that may be a result of aberrant trafficking of polycystin 2 and other ciliary proteins. Morpholino-mediated repression of RP2 expression in zebrafish results in multiple developmental defects that have been previously associated with ciliary dysfunction, such as hydrocephalus, kidney cysts and situs inversus. Finally, we demonstrate that, in addition to our observed physical interaction between RP2 and polycystin 2, dual morpholino-mediated knockdown of polycystin 2 and RP2 results in enhanced situs inversus, indicating that these two genes also regulate a common developmental process. This work suggests that RP2 may be an important regulator of ciliary function through its association with polycystin 2 and provides evidence of a further link between retinal and renal cilia function. C1 [Hurd, Toby; Zhou, Weibin; Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Jenkins, Paul; Martens, Jeffrey] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Liu, Chia-Jen; Margolis, Ben] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Khanna, Hemant] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. RP Hurd, T (reprint author), Univ Michigan, Dept Pediat & Communicable Dis, 1150 W Med Ctr Dr,8220 MSRB 3, Ann Arbor, MI 48109 USA. EM twhurd@umich.edu OI Swaroop, Anand/0000-0002-1975-1141 FU PKD foundation [162G08a, 92a2f]; NIH [DC009606, DC009524, DK1069274, DK1068306, DK064614, DK084725]; NEI [EY007961]; Foundation Fighting Blindness FX This work was supported by grants from the PKD foundation (B.M.-162G08a), NIH (J.M.-DC009606; P.J.-DC009524; F.H.-DK1069274, DK1068306, DK064614; B.M.-DK084725), NEI (H.K.-EY007961 and intramural funds to A.S.) and The Foundation Fighting Blindness (H.K.). T.H. was supported by a fellowship from the PKD Foundation (92a2f). NR 58 TC 44 Z9 44 U1 0 U2 4 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 NOV 15 PY 2010 VL 19 IS 22 BP 4330 EP 4344 DI 10.1093/hmg/ddq355 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 673OT UT WOS:000283673500003 PM 20729296 ER PT J AU Shi, ZQ Dragin, N Miller, ML Stringer, KF Johansson, E Chen, J Uno, S Gonzalez, FJ Rubio, CA Nebert, DW AF Shi, Zhanquan Dragin, Nadine Miller, Marian L. Stringer, Keith F. Johansson, Elisabet Chen, Jing Uno, Shigeyuki Gonzalez, Frank J. Rubio, Carlos A. Nebert, Daniel W. TI Oral benzo[a]pyrene-induced cancer: two distinct types in different target organs depend on the mouse Cyp1 genotype SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE oral benzo[a]pyrene; CYP1 enzymes; Cyp1a1 gene; Cyp1b1 gene; adenocarcinoma of proximal small intestine; immunoglobulin-secreting tumor; squamous cell carcinoma of preputial gland duct; Xist gene; Rab30 oncogene; Nr0b2 tumor suppressor gene; nonagouti locus; Olfr genes ID POLYCYCLIC AROMATIC-HYDROCARBONS; LUNG-CANCER; METABOLIC-ACTIVATION; SUBCUTANEOUS TUMORS; MESSENGER-RNA; PANETH CELLS; AH LOCUS; MICE; EXPRESSION; RECEPTOR AB Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1 and CYP1B1) can both detoxify PAHs and activate them to cancer-causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within similar to 28 days, whereas Cyp1(+/+) wild-type mice remain healthy for >12 months on this regimen. In this study, male Cyp1(+/+) wild-type, Cyp1a1(-/-) and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) double-knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs-including proximal small intestine (PSI), liver and preputial gland duct (PGD)-were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(-/-) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(-/-) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD. Cyp1(+/+) and Cyp1b1(-/-) mice remained healthy with no remarkable abnormalities in any tissue examined. PSI adenocarcinomas exhibited striking upregulation of the Xist gene, suggesting epigenetic silencing of specific genes on the Y-chromosome; the Rab30 oncogene was upregulated; the Nr0b2 tumor suppressor gene was downregulated; paradoxical overexpression of numerous immunoglobulin kappa- and heavy-chain variable genes was found-although the adenocarcinoma showed no immunohistochemical evidence of being lymphatic in origin. This oral BaP mouse paradigm represents an example of "gene-environment interactions" in which the same exposure of carcinogen results in altered target organ and tumor type, as a function of just 1 or 2 globally absent genes. C1 [Shi, Zhanquan; Dragin, Nadine; Miller, Marian L.; Johansson, Elisabet; Chen, Jing; Uno, Shigeyuki; Nebert, Daniel W.] Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Shi, Zhanquan; Dragin, Nadine; Miller, Marian L.; Johansson, Elisabet; Chen, Jing; Uno, Shigeyuki; Nebert, Daniel W.] Univ Cincinnati, CEG, Cincinnati, OH 45267 USA. [Stringer, Keith F.] Cincinnati Childrens Hosp, Med Ctr, Dept Pathol, Cincinnati, OH USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rubio, Carlos A.] Karolinska Inst, Gastrointestinal & Liver Pathol Res Lab, Stockholm, Sweden. RP Nebert, DW (reprint author), Univ Cincinnati, Med Ctr, Dept Environm Hlth, POB 670056, Cincinnati, OH 45267 USA. EM dan.nebert@uc.edu FU NIH [R01 ES014403, P30 ES06096] FX Grant sponsor: NIH; Grant numbers: R01 ES014403, P30 ES06096 NR 68 TC 20 Z9 20 U1 1 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 15 PY 2010 VL 127 IS 10 BP 2334 EP 2350 DI 10.1002/ijc.25222 PG 17 WC Oncology SC Oncology GA 672DT UT WOS:000283563900010 PM 20127859 ER PT J AU Vissink, A Mitchell, JB Baum, BJ Limesand, KH Jensen, SB Fox, PC Elting, LS Langendijk, JA Coppes, RP Reyland, ME AF Vissink, Arjan Mitchell, James B. Baum, Bruce J. Limesand, Kirsten H. Jensen, Siri Beier Fox, Philip C. Elting, Linda S. Langendijk, Johannes A. Coppes, Robert P. Reyland, Mary E. TI CLINICAL MANAGEMENT OF SALIVARY GLAND HYPOFUNCTION AND XEROSTOMIA IN HEAD-AND-NECK CANCER PATIENTS: SUCCESSES AND BARRIERS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review DE Radiotherapy; Hyposalivation; Xerostomia; Prevention; Palliative care; Gene transfer; Stem cell therapy ID RADIATION-INDUCED XEROSTOMIA; PROPHYLACTIC PILOCARPINE TREATMENT; ADENOVIRAL-MEDIATED TRANSFER; INTENSITY-MODULATED PHOTON; INCREASED FLUID SECRETION; RAT SUBMANDIBULAR-GLAND; QUALITY-OF-LIFE; ORAL PILOCARPINE; PROTON THERAPY; DOUBLE-BLIND AB The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy. (C) 2010 Elsevier Inc. C1 [Reyland, Mary E.] Univ Colorado Denver, Sch Dent Med, Dept Craniofacial Biol, Aurora, CO 80220 USA. [Coppes, Robert P.] Univ Groningen, Univ Med Ctr Groningen, Sect Radiat & Stress Biol, Dept Cell Biol, Groningen, Netherlands. [Vissink, Arjan] Univ Groningen, Univ Med Ctr Groningen, Dept Oral & Maxillofacial Surg, Groningen, Netherlands. [Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Limesand, Kirsten H.] Univ Arizona, Dept Nutr Sci, Tucson, AZ USA. [Jensen, Siri Beier] Univ Copenhagen, Fac Hlth Sci, Inst Odontol, Dept Oral Med, Copenhagen, Denmark. [Fox, Philip C.] PC Fox Consulting, Spello, Italy. [Elting, Linda S.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Langendijk, Johannes A.; Coppes, Robert P.] Univ Groningen, Univ Med Ctr Groningen, Dept Radiat Oncol, Groningen, Netherlands. RP Reyland, ME (reprint author), Univ Colorado Denver, Sch Dent Med, Dept Craniofacial Biol, MS 8120,POB 6511, Aurora, CO 80220 USA. EM Mary.Reyland@UCDenver.edu RI Coppes, Robert P/B-4089-2008 OI Coppes, Robert P/0000-0001-5503-1064 FU National Institute of Dental and Craniofacial Research [R13 DE 19330]; National Cancer Institute; National Institutes of Health Office of Rare Diseases; University of Connecticut School of Dental Medicine; Carolinas Medical Center; Multinational Association of Supportive Care in Cancer; International Society of Oral Oncology; Endo Pharmaceuticals, Inc.; EUSA Pharma; Biovitrum and Helsinn Healthcare SA FX Funding for this conference was made possible in part by Award Number R13 DE 19330 from the National Institute of Dental and Craniofacial Research. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Partial funding was also provided by the National Cancer Institute, the National Institutes of Health Office of Rare Diseases, The University of Connecticut School of Dental Medicine, Carolinas Medical Center, The Multinational Association of Supportive Care in Cancer, and the International Society of Oral Oncology. This conference was also supported by unrestricted educational grant funds from Endo Pharmaceuticals, Inc. and from EUSA Pharma, and by funds from Biovitrum and Helsinn Healthcare SA. NR 73 TC 87 Z9 94 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2010 VL 78 IS 4 BP 983 EP 991 DI 10.1016/j.ijrobp.2010.06.052 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 677BC UT WOS:000283963100003 PM 20970030 ER PT J AU Milano, MT Okunieff, P Donatello, RS Mohile, NA Sul, J Walter, KA Korones, DN AF Milano, Michael T. Okunieff, Paul Donatello, Rosemary S. Mohile, Nimish A. Sul, Joohee Walter, Kevin A. Korones, David N. TI PATTERNS AND TIMING OF RECURRENCE AFTER TEMOZOLOMIDE-BASED CHEMORADIATION FOR GLIOBLASTOMA SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Glioblastoma; Radiation therapy; Patterns of recurrence ID PROMOTER METHYLATION STATUS; LIMITED-VOLUME IRRADIATION; MALIGNANT GLIOMA; RADIATION-THERAPY; INTERSTITIAL BRACHYTHERAPY; CONFORMAL RADIOTHERAPY; IN-VITRO; MULTIFORME; FAILURE; ASTROCYTOMAS AB Purpose: To determine recurrence patterns of glioblastoma treated with temozolomide-based chemoradiation. Methods: Pretreatment and serial posttreatment magnetic resonance imaging scans of 54 patients were retrospectively evaluated. Central recurrence (i.e., local progression) and the development of new (i.e., interval appearance of discrete enhancing lesion) in-field, marginal, and distant recurrences were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line (D(95)). Distant recurrences were defined as lesions completely outside D(95), marginal recurrences crossed D(95), and in-field recurrences were completely inside D(95). Results: At a median follow-up of 17 months, 39 of 54 (72%) patients developed recurrent glioblastoma. Among these 39 patients, central recurrence occurred in 80% (at a median of 7 months from diagnosis); new in-field recurrence developed in 33% (at a median of 14 months); marginal recurrences developed in 15% (at a median of 18 months); and distant recurrences developed in 20% (at a median of 11 months). The actuarial rates of central, new in-field, marginal, distant, and any new recurrences at 1-year were 46%, 15%, 3%, 14%, and 25% respectively, whereas at 2 years, the rates were 68%, 60%, 32%, 28%, and 66%, reflecting an increasing probability of new lesions developing at later time points. Ten patients developed subependymal recurrences, of whom 7 developed multiple subependymal lesions. .Conclusions: Whereas central recurrence of glioblastoma treated with radiation and temozolomide predominates and persists over time, new in-field, marginal, and distant recurrences commonly develop, particularly at later time points in patients with longer survival. (C) 2010 Elsevier Inc. C1 [Milano, Michael T.; Okunieff, Paul; Donatello, Rosemary S.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Mohile, Nimish A.; Sul, Joohee] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Walter, Kevin A.] Univ Rochester, Med Ctr, Dept Neurosurg, Rochester, NY 14642 USA. [Walter, Kevin A.; Korones, David N.] Univ Rochester, Med Ctr, Dept Med, Div Oncol, Rochester, NY 14642 USA. [Korones, David N.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Sul, Joohee] NCI, Rockville, MD USA. RP Milano, MT (reprint author), Univ Rochester, Med Ctr, Dept Radiat Oncol, 601 Elmwood Ave,Box 647, Rochester, NY 14642 USA. EM MTMilano@yahoo.com NR 39 TC 53 Z9 54 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2010 VL 78 IS 4 BP 1147 EP 1155 DI 10.1016/j.ijrobp.2009.09.018 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 677BC UT WOS:000283963100025 PM 20207495 ER PT J AU Spitzner, M Emons, G Kramer, F Gaedcke, J Rave-Frank, M Scharf, JG Burfeind, P Becker, H Beissbarth, T Ghadimi, BM Ried, T Grade, M AF Spitzner, Melanie Emons, Georg Kramer, Frank Gaedcke, Jochen Rave-Fraenk, Margret Scharf, Jens-Gerd Burfeind, Peter Becker, Heinz Beissbarth, Tim Ghadimi, B. Michael Ried, Thomas Grade, Marian TI A GENE EXPRESSION SIGNATURE FOR CHEMORADIOSENSITIVITY OF COLORECTAL CANCER CELLS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Colorectal cancer; chemoradiotherapy; response; resistance; gene expression profiling ID RECTAL-CANCER; RADIORESISTANCE FACTOR; CARCINOMA CELLS; RADIATION; PREDICTION; LINES; RADIOSENSITIVITY; CHEMORADIATION; INHIBITION; SURVIVIN AB Purpose: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need. Methods and Materials: To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 mu M of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines. Results: We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q < .05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. Conclusion: We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. (C) 2010 Elsevier Inc. C1 [Spitzner, Melanie; Emons, Georg; Gaedcke, Jochen; Becker, Heinz; Ghadimi, B. Michael; Grade, Marian] Univ Gottingen, Dept Gen & Visceral Surg, Gottingen, Germany. [Kramer, Frank; Beissbarth, Tim] Univ Gottingen, Dept Med Stat, Gottingen, Germany. [Rave-Fraenk, Margret] Univ Gottingen, Dept Radiotherapy & Radio Oncol, Gottingen, Germany. [Scharf, Jens-Gerd] Univ Gottingen, Dept Gastroenterol & Endocrinol, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Burfeind, Peter] Univ Gottingen, Inst Human Genet, D-3400 Gottingen, Germany. RP Grade, M (reprint author), Univ Gottingen, Dept Gen & Visceral Surg, Gottingen, Germany. EM mgrade@uni-goettingen.de RI Beissbarth, Tim/B-3129-2013 OI Beissbarth, Tim/0000-0001-6509-2143 FU Deutsche Forschungsgemeinschaft [KFO 179] FX Supported by the Deutsche Forschungsgemeinschaft (KFO 179). Melanie Spitzner and Georg Emons contributed equally to this work. NR 43 TC 30 Z9 32 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2010 VL 78 IS 4 BP 1184 EP 1192 DI 10.1016/j.ijrobp.2010.06.023 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 677BC UT WOS:000283963100030 PM 20970032 ER PT J AU Ryu, H Furuta, M Kirkpatrick, D Gygi, SP Azuma, Y AF Ryu, Hyunju Furuta, Maiko Kirkpatrick, Donald Gygi, Steven P. Azuma, Yoshiaki TI PIASy-dependent SUMOylation regulates DNA topoisomerase II alpha activity SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CHROMOSOME SEGREGATION; MITOTIC CHROMOSOMES; SUMO PATHWAY; MITOSIS; CONJUGATION; MECHANISM; PROTEIN; CELLS; DECATENATION; KINETOCHORES AB DNA topoisomerase II alpha (TopoII alpha) is an essential chromosome associated enzyme with activity implicated in the resolution of tangled DNA at centromeres before anaphase onset However, the regulatory mechanism of TopoII alpha activity is not understood Here, we show that PIASy mediated small ubiquitin like modifier 2/3 (SUMO2/3) modification of TopoII alpha strongly inhibits TopoII alpha decatenation activity Using mass spectrometry and biochemical analysis, we demonstrate that TopoII alpha is SUMOylated at lysine 660 (Lys660), a residue located in the DNA gate domain, where both DNA cleavage and religation take place Remarkably, loss of SUMOylation on Lys660 eliminates SUMOylation dependent inhibition of TopoII alpha, which indicates that Lys660 SUMOylation is critical for PIASy mediated inhibition of TopoII alpha activity Together, our findings provide evidence for the regulation of TopoII alpha activity on mitotic chromosomes by SUMOylation Therefore, we propose a novel mechanism for regulation of centromeric DNA catenation during mitosis by PIASy mediated SUMOylation of TopoII alpha C1 [Ryu, Hyunju; Azuma, Yoshiaki] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. [Furuta, Maiko] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Kirkpatrick, Donald; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Azuma, Y (reprint author), Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. OI Kirkpatrick, Donald/0000-0003-3091-2804 FU Japan Society for the Promotion of Science; Department of Molecular Biosciences at the University of Kansas; National Institutes of Health/National Center for Research Resources Center For Cancer Experimental Therapeutics at the Centers of Biomedical Research Excellence (CCET-COBRE) [P20 RR015563]; National Institutes of Health/National Institute of General Medical Sciences [3M80278, GM67945] FX M Furuta was supported as a Japan Society for the Promotion of Science Research Fellow in Biomedical and Behavioral Research at the National Institutes of Health This project was supported in part by a start up grant from the Department of Molecular Biosciences at the University of Kansas and National Institutes of Health/National Center for Research Resources Center For Cancer Experimental Therapeutics at the Centers of Biomedical Research Excellence (CCET-COBRE P20 RR015563) and is currently supported by National Institutes of Health/National Institute of General Medical Sciences grants 3M80278 and GM67945 (to S P Gygi) NR 45 TC 24 Z9 24 U1 0 U2 3 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 NOV 15 PY 2010 VL 191 IS 4 BP 783 EP 794 DI 10.1083/jcb.201004033 PG 12 WC Cell Biology SC Cell Biology GA 686YF UT WOS:000284737200012 PM 21079245 ER PT J AU Jain, L Gardner, ER Venitz, J Giaccone, G Houk, BE Figg, WD AF Jain, Lokesh Gardner, Erin R. Venitz, Juergen Giaccone, Giuseppe Houk, Brett E. Figg, William D. TI Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE PF-04928473; PF-04929113; Hsp90 inhibitors; SNX-2112; SNX-5422 ID INHIBITOR; HSP90 AB A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma. following administration of its prodrug, PF-04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 mu L volume of plasma sample. Chromatographic separation of PF-04928473 and PF-04972487 was achieved on a Phenomenex (R) Luna C18(2)(2.0mm x 50 mm, 5 mu m) column using a gradient elution method with mobile phase solvents: methanol containing 0.1% formic acid and 0.1% formic acid at a flow rate of 0.25 mL/min. Detection was performed in electrospray positive ionization mode, monitoring the ion transitions from m/z 465.1 -> 350.1 (PF-04928473) and m/z 447.0 -> 329.1 (PF-04972487). The retention times for PF-04928473 and PF-04972487 were 1.86 and 2.85 min, respectively. Calibration curves were generated in the range of 2-2000 ng/mL. The accuracy and precision ranged from 94.1 to 99.0% and 86.7 to 97.6%, respectively, which were calculated using quality control samples of three different concentrations analyzed in quintuplicate on four different days. Published by Elsevier B.V. C1 [Figg, William D.] NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Jain, Lokesh; Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Gardner, Erin R.] NCI, Clin Pharmacol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Jain, Lokesh; Venitz, Juergen; Figg, William D.] Virginia Commonwealth Univ, Dept Pharmaceut, Sch Pharm, Richmond, VA 23298 USA. [Houk, Brett E.] Pfizer Inc, Dept Clin Pharmacol, San Diego, CA 92121 USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research 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 HHSN261200800001E (ERG). This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 9 TC 1 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD NOV 15 PY 2010 VL 878 IS 30 BP 3187 EP 3192 DI 10.1016/j.jchromb.2010.09.017 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 686BR UT WOS:000284672300021 PM 20951100 ER PT J AU Kadam, Y Singh, K Marangoni, DG Ma, JH Aswal, VK Bahadur, P AF Kadam, Y. Singh, K. Marangoni, D. G. Ma, J. H. Aswal, V. K. Bahadur, P. TI Induced micellization and micellar transitions in aqueous solutions of non-linear block copolymer Tetronic (R) T904 SO JOURNAL OF COLLOID AND INTERFACE SCIENCE LA English DT Article DE Tetronic (R); SANS; Micellization; Block copolymers; Surfactants ID ANGLE NEUTRON-SCATTERING; SALT-INDUCED MICELLIZATION; POLY(OXYETHYLENE OXYPROPYLENE OXYETHYLENE); TRIBLOCK COPOLYMER; POLY(ETHYLENE OXIDE); AGGREGATION TRANSITIONS; BEHAVIOR; WATER; POLOXAMINE; PH AB Tetronics (R) (Poloxamines) are the least studied block copolymers with an X-shaped molecular geometry formed by four poly (propylene oxide, PPO) and poly (ethylene oxide, PEO) block chains, bonded to a central ethylenediamine group. Compared to their linear counterparts, the Pluronics, Tetronics (R) are novel, in that they posses superior physicochemical properties, and are relatively less studied. A complete understanding of their solution behavior under different solution conditions can make them competitive candidates for novel drug delivery systems. The micellization behavior and aqueous solution properties of Tetronic (R) T904 [(EO15PO17)(2)NCH2CH2N (PO17EO15)(2)] have been determined by cloud point, viscosity, dynamic light scattering (DLS), small-angle neutron scattering (SANS), and nuclear magnetic resonance (NMR) measurements. The copolymer formed spherical micelles at 30 degrees C with a core radius (R-c) of about 2.5 nm, a hard sphere radius (R-hs) of 5.2 nm and an aggregation number (N-agg) of 10. The effect of copolymer concentration, temperature, pH and salt on the micellar and phase behavior is examined. The copolymer has been found to exist in aggregated form only at higher pH values of >8. An increase in micelle size and aggregation has been observed for an increase in temperature and salt concentration, mainly due to the dehydration of the hydrated PEO shell. The added salts (NaCl, Na2SO4 and Na3PO4) induce micellization and favor the micellar transition at lower temperatures due to the "salting out effect"; the effect of anions follows the Hofmeister series (PO34- > SO42- > Cl). (C) 2010 Elsevier Inc. All rights reserved. C1 [Kadam, Y.; Bahadur, P.] VN S Gujarat Univ, Dept Chem, Surat 395007, India. [Singh, K.; Marangoni, D. G.] St FX Univ, Dept Chem, Antigonish, NS, Canada. [Ma, J. H.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Aswal, V. K.] Bhabha Atom Res Ctr, Div Solid State Phys, Bombay 400085, Maharashtra, India. RP Kadam, Y (reprint author), VN S Gujarat Univ, Dept Chem, Surat 395007, India. EM yogeshkadam2010@yahoo.com; ksingh@stfx.ca; gmarango@stfx.ca; jhma1980@yahoo.com.cn; vkaswal@barc.gov.in; pbahadur2002@yahoo.com RI Marangoni, Gerrard/G-3438-2011; OI Kadam, Yogesh/0000-0002-3522-4659; singh, kulbir/0000-0003-3152-1119 FU NSERC; StFX University; Atlantic Innovation Fund FX PB thanks St. Francis Xavier University, Antigonish, Canada for James Chair Visiting Professorship. DGM and KS thank NSERC (Discovery Grant, GM), StFX University, and the Atlantic Innovation Fund for financial support. NR 64 TC 20 Z9 20 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9797 J9 J COLLOID INTERF SCI JI J. Colloid Interface Sci. PD NOV 15 PY 2010 VL 351 IS 2 BP 449 EP 456 DI 10.1016/j.jcis.2010.07.046 PG 8 WC Chemistry, Physical SC Chemistry GA 661EH UT WOS:000282706100018 PM 20797723 ER PT J AU Gao, Q Jiang, Y Ma, TA Zhu, FL Gao, F Zhang, P Guo, C Wang, Q Wang, XY Ma, CH Zhang, Y Chen, WJ Zhang, LN AF Gao, Qi Jiang, Yang Ma, Tian Zhu, Faliang Gao, Fei Zhang, Pin Guo, Chun Wang, Qun Wang, Xiaoyan Ma, Chunhong Zhang, Yun Chen, Wanjun Zhang, Lining TI A Critical Function of Th17 Proinflammatory Cells in the Development of Atherosclerotic Plaque in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID APOLIPOPROTEIN E-DEFICIENT; REGULATORY T-CELLS; E KNOCKOUT MICE; INTERFERON-GAMMA; AGGRAVATES ATHEROSCLEROSIS; IL-17; INFLAMMATION; LINEAGE; DIFFERENTIATION; INTERLEUKIN-17 AB Considerable evidence supports that the CD4(+) T cell-mediated immune response contributes to the development of atherosclerotic plaque. However, the effects of Th17 cells on atherosclerosis are not thoroughly understood. In this study, we evaluated the production and function of Th17 and Th1 cells in atherosclerotic-susceptible ApoE(-/-) mice. We observed that the proportion of Th17 cells, as well as Th1, increased in atherosclerotic ApoE(-/-) mice compared with nonatherosclerotic wild-type littermates. In ApoE(-/-) mice with atherosclerosis, the expression of IL-17 and retinoic acid-related orphan receptor gamma t was substantially higher in the arterial wall with plaque than in the arterial wall without plaque. Increased Th17 cells were associated with the magnitude of atherosclerotic plaque in ApoE(-/-) mice. Importantly, treatment of ApoE(-/-) mice with neutralizing anti-IL-17 Ab dramatically inhibited the development of atherosclerotic plaque, whereas rIL-17 application significantly promoted the formation of atherosclerotic plaque. These data demonstrate that Th17 cells play a critical role in atherosclerotic plaque formation in mice, which may have implications in patients with atherosclerosis. The Journal of Immunology, 2010, 185: 5820-5827. C1 [Gao, Qi; Jiang, Yang; Ma, Tian; Zhu, Faliang; Guo, Chun; Wang, Qun; Wang, Xiaoyan; Ma, Chunhong; Zhang, Lining] Shandong Univ, Dept Immunol, Sch Med, Jinan 250012, Shandong, Peoples R China. [Gao, Fei; Zhang, Yun] Shandong Univ, Key Lab Cardiovasc Remodeling & Funct Res, Qilu Hosp, Jinan 250012, Shandong, Peoples R China. [Zhang, Pin; Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, LN (reprint author), Shandong Univ, Dept Immunol, Sch Med, 44 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China. EM wchen@dir.nidcr.nih.gov; immuno@sdu.edu.cn RI ma, chunhong/C-6043-2008 FU National "973" Program of China [2011CB503906]; National Natural Science Foundation of China [30628015, 30700729, 30872309]; National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by the National "973" Program of China (2011CB503906), National Natural Science Foundation of China (30628015, 30700729, and 30872309), and by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 41 TC 99 Z9 109 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2010 VL 185 IS 10 BP 5820 EP 5827 DI 10.4049/jimmunol.1000116 PG 8 WC Immunology SC Immunology GA 675RJ UT WOS:000283848000019 PM 20952673 ER PT J AU Duverger, A Carre, JM Jee, J Leppla, SH Cormet-Boyaka, E Tang, WJ Tome, D Boyaka, PN AF Duverger, Alexandra Carre, Jeanne-Marie Jee, Junbae Leppla, Stephen H. Cormet-Boyaka, Estelle Tang, Wei-Jen Tome, Daniel Boyaka, Prosper N. TI Contributions of Edema Factor and Protective Antigen to the Induction of Protective Immunity by Bacillus anthracis Edema Toxin as an Intranasal Adjuvant SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ADP-RIBOSYLTRANSFERASE ACTIVITY; HEAT-LABILE TOXIN; CHOLERA-TOXIN; ESCHERICHIA-COLI; FUSION PROTEIN; MUCOSAL IMMUNITY; DENDRITIC CELLS; LETHAL FACTOR; TUMOR-CELLS; IN-VIVO AB We have shown that intranasal coapplication of Bacillus anthracis protective Ag (PA) together with a B. anthracis edema factor (EF) mutant having reduced adenylate cyclase activity (i.e., EF-S414N) enhances anti-PA Ab responses, but also acts as a mucosal adjuvant for coadministered unrelated Ags. To elucidate the role of edema toxin (EdTx) components in its adjuvanticity, we examined how a PA mutant lacking the ability to bind EF (PA-U7) or another mutant that allows the cellular uptake of EF, but fails to efficiently mediate its translocation into the cytosol (PA-dFF), would affect EdTx-induced adaptive immunity. Native EdTx promotes costimulatory molecule expression by macrophages and B lymphocytes, and a broad spectrum of cytokine responses by cervical lymph node cells in vitro. These effects were reduced or abrogated when cells were treated with EF plus PA-dFF, or PA-U7 instead of PA. We also intranasally immunized groups of mice with a recombinant fusion protein of Yersinia pestis F1 and LcrV Ags (F1-V) together with EdTx variants consisting of wild-type or mutants PA and EF. Analysis of serum and mucosal Ab responses against F1-V or EdTx components (i.e., PA and EF) revealed no adjuvant activity in mice that received PA-U7 instead of PA. In contrast, coimmunization with PA-dFF enhanced serum Ab responses. Finally, immunization with native PA and an EF mutant lacking adenylate cyclase activity (EF-K346R) failed to enhance Ab responses. In summary, a fully functional PA and a minimum of adenylate cyclase activity are needed for EdTx to act as a mucosal adjuvant. The Journal of Immunology, 2010, 185: 5943-5952. C1 [Duverger, Alexandra; Carre, Jeanne-Marie; Jee, Junbae; Boyaka, Prosper N.] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA. [Boyaka, Prosper N.] Ohio State Univ, Ctr Microbial Interface Biol, Columbus, OH 43210 USA. [Carre, Jeanne-Marie; Tome, Daniel] AgroParis Tech, Lab Comportement Alimentaire, Paris, France. [Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Tang, Wei-Jen] Univ Chicago, Ben Inst Canc Res, Chicago, IL 60637 USA. RP Boyaka, PN (reprint author), Ohio State Univ, Dept Vet Biosci, VMAB Room 345,1900 Coffey Rd, Columbus, OH 43210 USA. EM boyaka.1@osu.edu RI Cormet-Boyaka, Estelle/H-5624-2011; OI Tang, Wei-Jen/0000-0002-8267-8995 FU National Institutes of Health [AI 43197] FX This work was supported by National Institutes of Health Grant AI 43197. NR 44 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 NOV 15 PY 2010 VL 185 IS 10 BP 5943 EP 5952 DI 10.4049/jimmunol.0902795 PG 10 WC Immunology SC Immunology GA 675RJ UT WOS:000283848000032 PM 20952678 ER PT J AU Khadra, A Tsai, S Santamaria, P Edelstein-Keshet, L AF Khadra, Anmar Tsai, Sue Santamaria, Pere Edelstein-Keshet, Leah TI On How Monospecific Memory-Like Autoregulatory CD8(+) T Cells Can Blunt Diabetogenic Autoimmunity: A Computational Approach SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NONOBESE DIABETIC MICE; AVIDITY MATURATION; RECEPTOR; POPULATION; PEPTIDE; COMPLEX AB We have recently shown that during progression to autoimmune diabetes in NOD mice, memory autoreactive regulatory CD8(+) T cells arising from low-avidity precursors can be expanded to therapeutic levels using nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHCs). Here we examine the dynamics of memory autoregulatory CD8(+) T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein(206-214), a prevalent beta cell autoantigen; their high-avidity counterparts (dominant effectors); and all other autoreactive non-islet-specific glucose-6-phosphatase catalytic subunit-related protein(206-214)-specific CD8(+) T cell specificities (subdominant effectors) in response to pMHC-coated nanoparticle (pMHC-nanoparticle) therapy. We combine experimental data with mathematical modeling to investigate the clonal competition dynamics of these T cell pools. To mimic the response diversity observed in NOD mice, we simulated many individual mice, using a wide range of parameters, and averaged the results as done experimentally. We find that under certain circumstances, pMHC-nanoparticle-induced expansion of autoregulatory CD8(+) T cells can effectively suppress the expansion of dominant and subdominant effectors simultaneously but, in some few cases, can lead to the substitution (or switching) of one effector population by another. The model supports the idea that disease suppression is based on the elimination of autoantigen-loaded APCs by the expanded autoregulatory CD8(+) T cells. The model also predicts that treatment strategies that operate by selectively inhibiting autoantigen-loaded APCs, such as the pMHC-nanoparticle approach, have the highest promise to blunt polyclonal, multiantigen-specific autoimmune responses in vivo without impairing systemic immunity. The Journal of Immunology, 2010, 185: 5962-5972. C1 [Tsai, Sue; Santamaria, Pere] Univ Calgary, Fac Med, Julia McFarlane Diabet Res Ctr, Dept Microbiol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Khadra, Anmar] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Edelstein-Keshet, Leah] Univ British Columbia, Dept Math, Inst Appl Math, Vancouver, BC, Canada. RP Santamaria, P (reprint author), Univ Calgary, Fac Med, Julia McFarlane Diabet Res Ctr, Dept Microbiol & Infect Dis, Calgary, AB T2N 4N1, Canada. EM psantama@ucalgary.ca FU Mathematics of Information Technology and Complex Systems Canada; Juvenile Diabetes Research Foundation; Alberta Innovates-Health Solutions; Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada FX This work was supported in part by the Mathematics of Information Technology and Complex Systems Canada and by the Juvenile Diabetes Research Foundation (to A. K.), a studentship from the Alberta Innovates-Health Solutions (to S. T.), the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Juvenile Diabetes Research Foundation (to P. S.), as well as the Natural Sciences and Engineering Research Council of Canada (to L.E.-K.). L.E.-K. has been a 2009-2010 Distinguished Scholar in Residence at the Peter Wall Institute of Advanced Studies, University of British Columbia. NR 23 TC 8 Z9 8 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 NOV 15 PY 2010 VL 185 IS 10 BP 5962 EP 5972 DI 10.4049/jimmunol.1001306 PG 11 WC Immunology SC Immunology GA 675RJ UT WOS:000283848000034 PM 20962260 ER PT J AU Yang, ZY Zhang, X Darrah, PA Mosser, DM AF Yang, Ziyan Zhang, Xia Darrah, Patricia A. Mosser, David M. TI The Regulation of Th1 Responses by the p38 MAPK SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; LEISHMANIA-DONOVANI INFECTION; IL-12 PRODUCTION; DENDRITIC CELLS; MESSENGER-RNA; INNATE RESISTANCE; ADAPTIVE IMMUNITY; PROTEIN-KINASES; GENE-EXPRESSION; T-CELLS AB IL-12 is a dimeric cytokine that is produced primarily by APCs. In this study we examined the role that the p38 MAPKs (MAPK/p38) play in regulating IL-12 production. We show that inhibition of p38 dramatically increased IL-12 production upon stimulation, while decreasing TNF-alpha. This reciprocal effect on these two cytokines following MAPK/p38 inhibition occurred in many different APCs, following a variety of different stimuli. IL-12 production was also increased in macrophages treated with small interfering RNA to limit p38 alpha expression, and in macrophages deficient in MKK3, a kinase upstream of p38. The increase in IL-12 production following MAPK/p38 inhibition appears to be due to enhanced IL-12 (p40) mRNA stability. We show that MAPK/p38 inhibition can promote Th1 immune responses and thereby enhance vaccine efficacy against leishmaniasis. In a mouse model of Leishmania major infection, vaccination with heat-killed L. major plus CpG and SB203580 elicited complete protection against infection compared with heat-killed L. major plus CpG without SB203580. Thus, this work suggests that MAPK/p38 inhibitors may be applied as adjuvants to bias immune responses and improve vaccinations against intracellular pathogens. The Journal of Immunology, 2010, 185: 6205-6213. C1 [Yang, Ziyan; Zhang, Xia; Mosser, David M.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Yang, Ziyan; Zhang, Xia; Mosser, David M.] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Darrah, Patricia A.] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mosser, DM (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, Room 3102,Biosci Res Bldg, College Pk, MD 20742 USA. EM dmosser@umd.edu RI Zhang, Xia/B-8152-2008; Mosser, David/I-6697-2016 OI Zhang, Xia/0000-0002-9040-1486; Mosser, David/0000-0002-9503-4187 FU National Institutes of Health [AI55576] FX This work was supported in part by National Institutes of Health Grant AI55576. NR 40 TC 25 Z9 26 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 NOV 15 PY 2010 VL 185 IS 10 BP 6205 EP 6213 DI 10.4049/jimmunol.1000243 PG 9 WC Immunology SC Immunology GA 675RJ UT WOS:000283848000059 PM 20937847 ER PT J AU Semnani, RT Mahapatra, L Dembele, B Konate, S Metenou, S Dolo, H Coulibaly, ME Soumaoro, L Coulibaly, SY Sanogo, D Doumbia, SS Diallo, AA Traore, SF Klion, A Nutman, TB Mahanty, S AF Semnani, Roshanak Tolouei Mahapatra, Lily Dembele, Benoit Konate, Siaka Metenou, Simon Dolo, Housseini Coulibaly, Michel E. Soumaoro, Lamine Coulibaly, Siaka Y. Sanogo, Dramane Doumbia, Salif Seriba Diallo, Abdallah A. Traore, Sekou F. Klion, Amy Nutman, Thomas B. Mahanty, Siddhartha TI Expanded Numbers of Circulating Myeloid Dendritic Cells in Patent Human Filarial Infection Reflect Lower CCR1 Expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR EXPRESSION; WHIM SYNDROME; MIGRATION; RECRUITMENT; RESPONSES; DISEASE; SURFACE AB APC dysfunction has been postulated to mediate some of the parasite-specific T cell unresponsiveness seen in patent filarial infection. We have shown that live microfilariae of Brugia malayi induce caspase-dependent apoptosis in human monocyte-derived dendritic cells (DCs) in vitro. This study addresses whether apoptosis observed in vitro extends to patent filarial infections in humans and is reflected in the number of circulating myeloid DCs (mDCs; CD11c(-) CD123(lo)) in peripheral blood of infected microfilaremic individuals. Utilizing flow cytometry to identify DC subpopulations (mDCs and plasmacytoid DCs [ pDCs]) based on expression of CD11c and CD123, we found a significant increase in numbers of circulating mDCs (CD11c(+) CD123(lo)) in filaria-infected individuals compared with uninfected controls from the same filaria-endemic region of Mali. Total numbers of pDCs, monocytes, and lymphocytes did not differ between the two groups. To investigate potential causes of differences in mDC numbers between the two groups, we assessed chemokine receptor expression on mDCs. Our data indicate that filaria-infected individuals had a lower percentage of circulating CCR1(+) mDCs and a higher percentage of circulating CCR5(+) mDCs and pDCs. Finally, live microfilariae of B. malayi were able to downregulate cell-surface expression of CCR1 on monocyte-derived DCs and diminish their calcium flux in response to stimulation by a CCR1 ligand. These findings suggest that microfilaria are capable of altering mDC migration through downregulation of expression of some chemokine receptors and their signaling functions. These observations have major implications for regulation of immune responses to these long-lived parasites. The Journal of Immunology, 2010, 185: 6364-6372. C1 [Semnani, Roshanak Tolouei; Mahapatra, Lily; Metenou, Simon; Klion, Amy; Nutman, Thomas B.; Mahanty, Siddhartha] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Dembele, Benoit; Konate, Siaka; Dolo, Housseini; Coulibaly, Michel E.; Soumaoro, Lamine; Coulibaly, Siaka Y.; Sanogo, Dramane; Doumbia, Salif Seriba; Diallo, Abdallah A.; Traore, Sekou F.] Univ Bamako, Fac Med Pharm & Odontostomatol, Filariasis Unit, Bamako, Mali. RP Semnani, RT (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. EM rsemnani@niaid.nih.gov; smahanty@niaid.nih.gov RI Metenou, Simon/C-1101-2013; OI Klion, Amy/0000-0002-4986-5326; Mahanty, Siddhartha/0000-0003-1068-0524 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 29 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD NOV 15 PY 2010 VL 185 IS 10 BP 6364 EP 6372 DI 10.4049/jimmunol.1001605 PG 9 WC Immunology SC Immunology GA 675RJ UT WOS:000283848000075 PM 20956349 ER PT J AU Kearney, M Maldarelli, F AF Kearney, Mary Maldarelli, Frank TI Current Status of Xenotropic Murine Leukemia Virus-Related Retrovirus in Chronic Fatigue Syndrome and Prostate Cancer: Reach for a Scorecard, Not a Prescription Pad SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID INFECTIOUS RETROVIRUS; CARCINOMA-CELLS; XMRV INFECTION; PREVALENCE; TUMORS; BLOOD C1 [Kearney, Mary; Maldarelli, Frank] NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. RP Maldarelli, F (reprint author), NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. EM fmalli@mail.nih.gov NR 29 TC 7 Z9 7 U1 0 U2 1 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 NOV 15 PY 2010 VL 202 IS 10 BP 1463 EP 1466 DI 10.1086/657169 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 665SY UT WOS:000283057000001 PM 20936981 ER PT J AU Ratsela, A Polis, M Dhlomo, S Emery, S Grandits, G Khabo, P Khanyile, T Komati, S Neaton, JD Naidoo, LCD Magongoa, D Qolohle, D Brodine, S Lane, HC Motumi, N Radebe, M Jamuna, A Oelofse, PJ Ngqakayi, S Siwisa, L Swanapoel, S Levin, J Rida, WN Morodi, T Leeuw, Y Hassim, S Malan, L Somarro, H Mokhathi, T Mokwena, N Coangae, N Khanyile, T Yokwana, Z Mabindla, B Manqola, G Maluleke, M Tseka, T Dlamini, J Ledwaba, L Maja, P Marumo, M Matchaba, U Mthethwa, J Sangweni, P Baseler, B Eckes, R Masur, H Grace, B Morgan, G Mcnay, L Metcalf, J Orsega, S Pau, A Tavel, J Zuckerman, J Simpson, S Highbarger, H Dewar, R DuChene, A Harrison, M Lifson, A AF Ratsela, Andrew Polis, Michael Dhlomo, Sibongiseni Emery, Sean Grandits, Greg Khabo, Paul Khanyile, Thandeka Komati, Stephanus Neaton, James D. Naidoo, Lionel Chris David Magongoa, Daphne Qolohle, Duma Brodine, S. Lane, H. C. Motumi, N. Radebe, M. Jamuna, A. Oelofse, P. J. Ngqakayi, S. Siwisa, L. Swanapoel, S. Levin, J. Rida, W. N. Morodi, T. Leeuw, Y. Hassim, S. Malan, L. Somarro, H. Mokhathi, T. Mokwena, N. Coangae, N. Khanyile, T. Yokwana, Z. Mabindla, B. Manqola, G. Maluleke, M. Tseka, T. Dlamini, J. Ledwaba, L. Maja, P. Marumo, M. Matchaba, U. Mthethwa, J. Sangweni, P. Baseler, B. Eckes, R. Masur, H. Grace, B. Morgan, G. Mcnay, L. Metcalf, J. Orsega, S. Pau, A. Tavel, J. Zuckerman, J. Simpson, S. Highbarger, H. Dewar, R. DuChene, A. Harrison, M. Lifson, A. TI A Randomized Factorial Trial Comparing 4 Treatment Regimens in Treatment-Naive HIV-Infected Persons with AIDS and/or a CD4 Cell Count < 200 Cells/mu L in South Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; RESOURCE-LIMITED SETTINGS; LACTIC-ACIDOSIS; EARLY MORTALITY; HIV-1-INFECTED PATIENTS; SEVERE HYPERLACTATEMIA; CLINICAL-TRIAL; 1ST YEAR; ADULTS; STAVUDINE AB Background. Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings. Methods. In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/mL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of A IDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events. Results. In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%). Conclusion. EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy. C1 [Polis, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Emery, Sean] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2052, Australia. [Grandits, Greg; Neaton, James D.; DuChene, A.; Harrison, M.; Lifson, A.] Univ Minnesota, Minneapolis, MN 55455 USA. [Hassim, S.; Malan, L.; Somarro, H.; Mokhathi, T.] Mil Hosp Site, Pretoria, South Africa. [Masur, H.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Polis, M (reprint author), NIAID, NIH, 6700B Rockledge Dr,Room 1118, Bethesda, MD 20892 USA. EM mpolis@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU US Department of Defense; US National Institutes of Health (NIH) through the National Institute of Allergy and Infectious Diseases (NIAID) FX Funding was provided by the US Department of Defense and the US National Institutes of Health (NIH) through the National Institute of Allergy and Infectious Diseases (NIAID). The South African Military Health Service and the US NIAID, NIH, signed a cooperative agreement to conduct this research project. NR 31 TC 24 Z9 24 U1 1 U2 4 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 NOV 15 PY 2010 VL 202 IS 10 BP 1529 EP 1537 DI 10.1086/656718 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 665SY UT WOS:000283057000011 ER PT J AU Muehlenbachs, A Fried, M McGready, R Harrington, WE Mutabingwa, TK Nosten, F Duffy, PE AF Muehlenbachs, Atis Fried, Michal McGready, Rose Harrington, Whitney E. Mutabingwa, Theonest K. Nosten, Francois Duffy, Patrick E. TI A Novel Histological Grading Scheme for Placental Malaria Applied in Areas of High and Low Malaria Transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; MASSIVE CHRONIC INTERVILLOSITIS; BIRTH-WEIGHT; PREGNANCY; INFECTION; WOMEN; HIV; IMPAIRMENT; TANZANIA; ARTESUNATE AB Background. Plasmodium falciparum-infected erythrocytes sequester in the placenta and elicit an inflammatory response that is harmful to both fetus and mother. Histologic measurements during placental malaria might provide surrogate end points for interventional trials, but existing histologic schemes capture limited complexity and are not consistently used among study sites. Methods. Using frozen-section histologic evaluation in Tanzania (high-transmission area), we established a novel grading scheme to separately quantify inflammation and pigment deposition during placental malaria (n = 102). To generalize this method, formalin-fixed, paraffin-embedded placental samples from Karen women in Thailand (low-transmission area) were selected from among women with documented antenatal parasitemia who were near term (n = 18). Results. In the Tanzanian cohort, the inflammation and pigment-deposition scores were independently associated with birth weight, and the inflammation score was associated with chemokine levels. In the smaller cohort from Thailand, both inflammation and pigment scores were associated with birth weight, and the pigment score had an inverse trend with the number of antenatal clinic visits. Conclusions. This semiquantitative pathological grading scheme is simple to implement and captures information that is associated with outcomes in Asia and Africa; therefore, it should facilitate the comparison and standardization of results among clinical trials across areas of differing endemicity. C1 [Duffy, Patrick E.] Univ Washington, NIAID, Lab Malaria Immunol & Vaccinol, Seattle Biomed Res Inst, Rockville, MD 20852 USA. [Muehlenbachs, Atis] Univ Washington, Dept Pathol, Rockville, MD 20852 USA. [Fried, Michal; Harrington, Whitney E.; Duffy, Patrick E.] Univ Washington, Dept Global Hlth, Rockville, MD 20852 USA. [Nosten, Francois; Duffy, Patrick E.] NIAID, Washington, DC USA. [McGready, Rose] Shoklo Malaria Res Inst, Mae Sot, Thailand. [Nosten, Francois] Mahidol Oxford Univ, Trop Med Res Program, Bangkok, Thailand. [Mutabingwa, Theonest K.] Natl Inst Med Res, Dar Es Salaam, Tanzania. [McGready, Rose; Nosten, Francois] Churchill Hosp, Ctr Trop Med & Vaccinol, Oxford OX3 7LJ, England. RP Duffy, PE (reprint author), Univ Washington, NIAID, Lab Malaria Immunol & Vaccinol, Seattle Biomed Res Inst, Twinbrook I 1111,5640 Fishers Ln, Rockville, MD 20852 USA. EM duffype@niaid.nih.gov OI Nosten, Francois/0000-0002-7951-0745; McGready, Rose/0000-0003-1621-3257 FU University of Washington House Staff Association; American Society of Tropical Medicine and Hygiene; PREMA-EU [ICA4-CT-2001-10012]; Wellcome Trust of Great Britain; Bill and Melinda Gates Foundation [29202]; National Institutes of Health [R01AI52059] FX This work was supported by a University of Washington House Staff Association grant, the Benjamin H. Kean Fellowship from the American Society of Tropical Medicine and Hygiene (to A. M.), and PREMA-EU (contract no. ICA4-CT-2001-10012). The Shoklo Malaria Research Unit is part of the Wellcome-Mahidol University-Oxford Tropical Medicine Research Program funded by the Wellcome Trust of Great Britain. The Mother Offspring Malaria Studies Project was supported by grants from the Bill and Melinda Gates Foundation (29202) and the National Institutes of Health (R01AI52059 to P.E.D.). NR 34 TC 24 Z9 24 U1 0 U2 1 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 NOV 15 PY 2010 VL 202 IS 10 BP 1608 EP 1616 DI 10.1086/656723 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 665SY UT WOS:000283057000021 PM 20929353 ER PT J AU Jiang, WZ Bibiana, B AF Jiang Wenzheng Bibiana, Bielekova TI Granule exocytosis pathway contributes to NK cells-mediated killing of autologous T cells in Multiple Sclerosis (MS) SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Jiang Wenzheng; Bibiana, Bielekova] NIH, 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 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 106 EP 106 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400304 ER PT J AU Justin, P SungPil, H Boyce, KL Bielekova, B AF Justin, Perry SungPil, Han Boyce, Kennedy Lucy Bielekova, Bibiana TI Opposing regulation between lymphoid tissue inducer cells and immunoregulatory CD56bright NK cells underlies therapeutic benefit of daclizumab in MS SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Justin, Perry; SungPil, Han; Boyce, Kennedy Lucy; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol 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 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 111 EP 112 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400320 ER PT J AU Polly, M AF Polly, Matzinger TI Conversations between tissues and T cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Polly, Matzinger] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 147 EP 147 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400417 ER PT J AU Jiang, WZ Bibiana, B AF Jiang Wenzheng Bibiana, Bielekova TI Immunoregulatory CD56bright NK cells kill autologous T cells through granzyme-K (and A) mediated induction of reactive oxygen species SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Jiang Wenzheng; Bibiana, Bielekova] NINDS, NIH, Neuroimmunol 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 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 167 EP 167 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400474 ER PT J AU Heather, A Nina, R Emilio, P Dwight, F Rashmi, R Derese, G Paul, P Svetlana, G Yi-Wen, C Ingrid, L Kanneboyina, N AF Heather M, Alger Nina, Raben Emilio, Pistilli Dwight, Francia Rashmi, Rawat Derese, Getnet Paul, Plotz Svetlana, Ghimbovschi Yi-Wen, Chen Ingrid, Lundberg Kanneboyina, Nagaraju TI The role of Tumor Necrosis Factor-alpha-Related Apoptosis Inducing Ligand (TRAIL) in mediating muscle fiber damage in myositis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Heather M, Alger; Dwight, Francia; Svetlana, Ghimbovschi; Yi-Wen, Chen; Kanneboyina, Nagaraju] Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. [Nina, Raben; Paul, Plotz] NIAMSD, NIH, Bethesda, MD 20892 USA. [Emilio, Pistilli] Univ Penn, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Rashmi, Rawat] US FDA, Silver Spring, MD USA. [Derese, Getnet] Johns Hopkins Univ, Baltimore, MD USA. [Ingrid, Lundberg] Karolinska Univ Hosp Solna, Dept Med, Rheumatol Unit, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 206 EP 206 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400585 ER PT J AU Jacqueline, Q Jaebong, H Jeeva, M Fuminori, H Grenye, O Li, XH Christopher, D Murali, C James, M Henry, M AF Jacqueline, Quandt Jaebong, Huh Jeeva, Munasinghe Fuminori, Hyodo Grenye, O'Malley Li Xinhui Christopher, Dharmaraj Murali, Cherukari James, Mitchell Henry, McFarland TI Oral administration of the nitroxide radical TEMPOL protects from disease in animal models of MS SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 10th Congress of the International-Society-of-Neuroimmunology (ISNI) CY OCT 26-30, 2010 CL Sitges, SPAIN SP Int Soc Neuroimmunol C1 [Jacqueline, Quandt] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Jaebong, Huh; Grenye, O'Malley; Li Xinhui; Henry, McFarland] NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Jeeva, Munasinghe] NIH, Mol Imaging Facil, Bethesda, MD 20892 USA. [Fuminori, Hyodo; Christopher, Dharmaraj; Murali, Cherukari; James, Mitchell] NIH, Radiat Oncol 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 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD NOV 15 PY 2010 VL 228 IS 1-2 SI SI BP 208 EP 208 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 673WH UT WOS:000283694400592 ER PT J AU McCormack, TJ Melis, C Colon, J Gay, EA Mike, A Karoly, R Lamb, PW Molteni, C Yakel, JL AF McCormack, Thomas J. Melis, Claudio Colon, Jose Gay, Elaine A. Mike, Arpad Karoly, Robert Lamb, Patricia W. Molteni, Carla Yakel, Jerrel L. TI Rapid desensitization of the rat alpha 7 nAChR is facilitated by the presence of a proline residue in the outer beta-sheet SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; INDUCED CONFORMATIONAL-CHANGES; CYS-LOOP RECEPTOR; AGONIST-BINDING; EXTRACELLULAR DOMAIN; HIPPOCAMPAL-NEURONS; ACH RECEPTORS; AMINO-ACIDS; LIGAND-BINDING; CHANNEL AB The rat alpha 7 nicotinic acetylcholine receptor (nAChR) has a proline residue near the middle of the beta 9 strand. The replacement of this proline residue at position 180 (P180) by either threonine (alpha 7-P180T) or serine (alpha 7-P180S) slowed the onset of desensitization dramatically, with half-times of similar to 930 and 700 ms, respectively, compared to 90 ms for the wild-type receptor. To investigate the importance of the hydroxyl group on the position 180 side-chains, the mutant receptors alpha 7-P180Y and alpha 7-P180F were studied and showed half-times of desensitization of 650 and 160 ms, respectively. While a position 180 side-chain OH group may contribute to the slow desensitization rates, alpha 7-P180S and alpha 7-P180V resulted in receptors with similar desensitization rates, suggesting that increased backbone to backbone H bonding expected in the absence of proline at position 180 would likely exert a great effect on desensitization. Single channel recordings indicated that for the alpha 7-P180T receptor there was a significantly reduced closed time without any change in single channel conductance (as compared to wild-type). Kinetic simulations indicated that all changes observed for the mutant channel behaviour were reproduced by decreasing the rate of desensitization, and increasing the microscopic affinity to resting receptors. Molecular dynamics (MD) simulations on a homology model were used to provide insight into likely H bond interactions within the outer beta-sheet that occur when the P180 residue is mutated. All mutations analysed increased about twofold the predicted number of H bonds between the residue at position 180 and the backbone of the beta 10 strand. Moreover, the alpha 7-P180T and alpha 7-P180S mutations also formed some intrastrand H bonds along the beta 9 strand, although H bonding of the OH groups of the threonine or serine side-chains was predicted to be infrequent. Our results indicate that rapid desensitization of the wild-type rat alpha 7 nAChR is facilitated by the presence of the proline residue within the beta 9 strand. C1 [McCormack, Thomas J.; Colon, Jose; Gay, Elaine A.; Lamb, Patricia W.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Melis, Claudio; Molteni, Carla] Kings Coll London, Dept Phys, London WC2R 2LS, England. [Melis, Claudio] Univ Cagliari, Dipartimento Fis, I-09124 Cagliari, Italy. [Mike, Arpad; Karoly, Robert] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, Budapest, Hungary. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov RI MELIS, CLAUDIO/J-1079-2016 OI MELIS, CLAUDIO/0000-0002-5768-8403 FU NIH; UK Engineering and Physical Sciences Research Council [EPSRC EP/F037457/1]; Hungarian Research Fund [NK 72959] FX This work was supported by the Intramural Research Program of the NIH. C.M. and C.M. thank the UK Engineering and Physical Sciences Research Council for Supercomputer Time (Grant: EPSRC EP/F037457/1). A.M. and R.K. were supported by Hungarian Research Fund NK 72959. NR 47 TC 11 Z9 11 U1 1 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD NOV 15 PY 2010 VL 588 IS 22 BP 4415 EP 4429 DI 10.1113/jphysiol.2010.195495 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 680ZM UT WOS:000284276000012 PM 20837638 ER PT J AU Collins, FS AF Collins, Francis S. TI Change, Change, Change: Heeding the Call SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material ID GILFORD-PROGERIA-SYNDROME C1 NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 15 PY 2010 VL 21 IS 22 BP 3793 EP 3794 DI 10.1091/mbc.E10-08-0726 PG 2 WC Cell Biology SC Cell Biology GA 680FC UT WOS:000284216800014 PM 21079014 ER PT J AU Ma, XF Jana, SS Conti, MA Kawamoto, S Claycomb, WC Adelstein, RS AF Ma, Xuefei Jana, Siddhartha S. Conti, Mary Anne Kawamoto, Sachiyo Claycomb, William C. Adelstein, Robert S. TI Ablation of Nonmuscle Myosin II-B and II-C Reveals a Role for Nonmuscle Myosin II in Cardiac Myocyte Karyokinesis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HEAVY-CHAIN GENE; CELL-ADHESION; CYTOKINESIS; ISOFORMS; MUSCLE; MICE; CARDIOMYOCYTES; INHIBITOR; MUTATIONS; REQUIRES AB Ablation of nonmuscle myosin (NM) II-A or NM II-B results in mouse embryonic lethality. Here, we report the results of ablating NM II-C as well as NM II-C/II-B together in mice. NM II-C ablated mice survive to adulthood and show no obvious defects compared with wild-type littermates. However, ablation of NM II-C in mice expressing only 12% of wild-type amounts of NM II-B results in a marked increase in cardiac myocyte hypertrophy compared with the NM II-B hypomorphic mice alone. In addition, these hearts develop interstitial fibrosis associated with diffuse N-cadherin and beta-catenin localization at the intercalated discs, where both NM II-B and II-C are normally concentrated. When both NM II-C and II-B are ablated the B-C-/B-C- cardiac myocytes show major defects in karyokinesis. More than 90% of B-C-/B-C- myocytes demonstrate defects in chromatid segregation and mitotic spindle formation accompanied by increased stability of microtubules and abnormal formation of multiple centrosomes. This requirement for NM II in karyokinesis is further demonstrated in the HL-1 cell line derived from mouse atrial myocytes, by using small interfering RNA knockdown of NM II or treatment with the myosin inhibitor blebbistatin. Our study shows that NM II is involved in regulating cardiac myocyte karyokinesis by affecting microtubule dynamics. C1 [Ma, Xuefei; Jana, Siddhartha S.; Conti, Mary Anne; Kawamoto, Sachiyo; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Claycomb, William C.] Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. RP Ma, XF (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM max@nhlbi.nih.gov OI Adelstein, Robert/0000-0002-8683-2144 NR 44 TC 43 Z9 45 U1 0 U2 9 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 15 PY 2010 VL 21 IS 22 BP 3952 EP 3962 DI 10.1091/mbc.E10-04-0293 PG 11 WC Cell Biology SC Cell Biology GA 680FC UT WOS:000284216800046 PM 20861308 ER PT J AU Obermann, M Vollrath, C de Greiff, A Gizewski, ER Diener, HC Hallett, M Maschke, M AF Obermann, Mark Vollrath, Clemens de Greiff, Armin Gizewski, Elke R. Diener, Hans-Christoph Hallett, Mark Maschke, Matthias TI Sensory Disinhibition on Passive Movement in Cervical Dystonia SO MOVEMENT DISORDERS LA English DT Article DE focal dystonia; cervical dystonia; fMRI; cortical disinhibition; somatosensory system ID PRIMARY SOMATOSENSORY CORTEX; FOCAL HAND DYSTONIA; SPASMODIC TORTICOLLIS; SPATIAL DISCRIMINATION; WRITERS CRAMP; MOTOR; ACTIVATION; ABNORMALITIES; INHIBITION; DISORDER AB The relevance of the sensory system in the pathophysiology of cervical dystonia (CD) has been discussed since the description of sensory tricks associated with this disorder. Our objective was to locate changes in somatosensory processing of patients with CD responding in a passive sensory task of body regions that are not affected by dystonic symptoms. We used functional magnetic resonance imaging (fMRI) in 17 patients with CD and 17 healthy controls performing a strictly passive 30-degree forearm movement task with the left arm. TSUI and TWSTRS rating scales were used for clinical assessment. All patients were treated with botulinum neurotoxin type A (BoNT-A; Dysport (R)). Patients with CD showed BOLD-signal increase in the contralateral primary and secondary sensory cortex, the cingulate cortex and cerebellum bilaterally compared to healthy controls. We found a strong positive correlation of this activation with BoNT-A dosage in the supplementary motor area (SMA) and a negative correlation with the TWSTRS in that same region. The observed sensory overactivation suggests a general disinhibition of the somatosensory system in CD as it was not limited to the motor-system or the direct neuronal representation of the affected dystonic musculature alone. (C) 2010 Movement Disorder Society C1 [Obermann, Mark; Vollrath, Clemens; Diener, Hans-Christoph; Maschke, Matthias] Univ Duisburg Essen, Dept Neurol, D-45122 Essen, Germany. [de Greiff, Armin; Gizewski, Elke R.] Univ Duisburg Essen, Dept Neuroradiol, D-45122 Essen, Germany. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Maschke, Matthias] Bruederkrankenhaus Trier, Dept Neurol & Neurophysiol, Trier, Germany. RP Obermann, M (reprint author), Univ Duisburg Essen, Dept Neurol, Hufelandstr 55, D-45122 Essen, Germany. EM mark.obermann@uni-due.de NR 33 TC 14 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD NOV 15 PY 2010 VL 25 IS 15 BP 2627 EP 2633 DI 10.1002/mds.23321 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 678FX UT WOS:000284060600021 PM 20725914 ER PT J AU Bigos, KL Weinberger, DR AF Bigos, Kristin L. Weinberger, Daniel R. TI Imaging genetics-days of future past SO NEUROIMAGE LA English DT Review ID GRAY-MATTER VOLUME; BIPOLAR DISORDER; HUMAN BRAIN; AMYGDALA ACTIVATION; 5-HTTLPR GENOTYPE; SCHIZOPHRENIA; RISK; POLYMORPHISM; METAANALYSIS; DEPRESSION AB Imaging genetics provides a unique tool with which to explore and evaluate the functional impact of brain-relevant genetic polymorphisms with the potential to understand their impact on behavior. Because statistical association with clinical diagnosis does not establish biological significance nor identify a mechanism of risk, imaging genetics is a uniquely valuable strategy for extending statistical evidence with biological data. Applications include identifying biologic mechanisms and pathways that mediate individual differences in complex behaviors and vulnerability to disease, and conversely identifying genes that contribute to functional variation in brain circuitry. Additionally, neuroimaging genetics can validate data that suggest an association with psychiatric illness as well as providing evidence of the mechanism of risk. This review also outlines several critical principles of imaging genetics including a rational approach to the selection of candidate genes, the selection of task paradigms that could be plausibly linked to the biology of the gene of interest, and careful control of non-genetic factors. The future of imaging genetics holds great promise for brain research and for biologic validation of genetic validation in CNS disorders, but a disciplined application of the basic principles outlined in this review is critical. Published by Elsevier Inc. C1 [Bigos, Kristin L.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Div Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Div Intramural Res Program, NIH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov NR 41 TC 51 Z9 55 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2010 VL 53 IS 3 BP 804 EP 809 DI 10.1016/j.neuroimage.2010.01.035 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 652VQ UT WOS:000282039300002 PM 20080192 ER PT J AU Marenco, S Radulescu, E AF Marenco, Stefano Radulescu, Eugenia TI Imaging genetics of structural brain connectivity and neural integrity markers SO NEUROIMAGE LA English DT Review DE Diffusion tensor imaging; Spectroscopy; Genes; Psychiatric disorders ID MAGNETIC-RESONANCE-SPECTROSCOPY; DORSOLATERAL PREFRONTAL CORTEX; WHITE-MATTER ARCHITECTURE; N-ACETYL-ASPARTATE; TRANSPORTER PROMOTER POLYMORPHISM; METABOTROPIC GLUTAMATE-RECEPTOR; CATECHOL-O-METHYLTRANSFERASE; BIPOLAR AFFECTIVE-DISORDER; ANXIETY-RELATED TRAITS; SUBJECT DIFFUSION DATA AB We review studies that have used diffusion imaging (DI) and magnetic resonance spectroscopy (MRS) to investigate genetic associations. A brief description of the measures obtainable with these methods and of some methodological and interpretability limitations is given. The usefulness of DI and MRS in defining intermediate phenotypes and in demonstrating the effects of common genetic variants known to increase risk for psychiatric manifestations on anatomical and metabolic phenotypes is reviewed. The main focus is on schizophrenia where the greatest amount of data has been collected. Moreover, we present an example coming from a different approach, where the genetic alteration is known (the deletion that causes Williams syndrome) and the DI phenotype can shed new light on the function of genes affected by the mutation. We conclude that, although these are still early days of this type of research and many findings remain controversial, both techniques can significantly contribute to the understanding of genetic effects in the brain and the pathophysiology of psychiatric disorders. Published by Elsevier Inc. C1 [Marenco, Stefano; Radulescu, Eugenia] NIMH, Unit Multimodal Imaging Genet, Clin Brain Disorders Branch, GCAP,IRP, Bethesda, MD 20892 USA. RP Marenco, S (reprint author), NIMH, Unit Multimodal Imaging Genet, Clin Brain Disorders Branch, GCAP,IRP, 10 Ctr Dr,Bldg 10,Room 3C103, Bethesda, MD 20892 USA. EM marencos@mail.nih.gov RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 FU NIMH IRP FX This work was entirely funded by the NIMH IRP. The authors have no conflicts of interest or relevant financial interests or affiliations to report. Thanks to Heike Tost, MD, PhD, and Daniel R. Weinberger, MD, for help in editing the manuscript. NR 141 TC 14 Z9 14 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2010 VL 53 IS 3 BP 848 EP 856 DI 10.1016/j.neuroimage.2009.11.030 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 652VQ UT WOS:000282039300007 PM 19932755 ER PT J AU Eisenberg, DP Jabbi, M Berman, KF AF Eisenberg, Daniel Paul Jabbi, Mbemba Berman, Karen Faith TI Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes SO NEUROIMAGE LA English DT Review ID CARDIO-FACIAL SYNDROME; SUPRAVALVULAR AORTIC-STENOSIS; CORPUS-CALLOSUM MORPHOLOGY; STRUCTURAL BRAIN ABNORMALITIES; HIPPOCAMPAL VOLUME REDUCTION; WHITE-MATTER ARCHITECTURE; CONGENITAL HEART-DISEASE; PRIMARY VISUAL-CORTEX; CHROMOSOME 22Q11.2; BEUREN-SYNDROME AB Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial syndrome (VCFS) and Williams syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems-level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful "bottom-up" approach to defining gene-brain relationships. Published by Elsevier Inc. C1 [Eisenberg, Daniel Paul; Jabbi, Mbemba; Berman, Karen Faith] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,NIH,Intramural R, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,NIH,Intramural R, 9000 Rockville Pike,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU National Institute of Mental Health, National Institutes of Health, Bethesda, MD [20892] FX This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892. All authors report no financial conflict of interest with regard to this manuscript. NR 207 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2010 VL 53 IS 3 BP 857 EP 869 DI 10.1016/j.neuroimage.2010.02.070 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 652VQ UT WOS:000282039300008 PM 20206275 ER PT J AU Lau, JYF Goldman, D Buzas, B Hodgkinson, C Leibenluft, E Nelson, E Sankin, L Pine, DS Ernst, M AF Lau, Jennifer Y. F. Goldman, David Buzas, Beata Hodgkinson, Colin Leibenluft, Ellen Nelson, Eric Sankin, Lindsey Pine, Daniel S. Ernst, Monique TI BDNF gene polymorphism (Val66Met) predicts amygdala and anterior hippocampus responses to emotional faces in anxious and depressed adolescents SO NEUROIMAGE LA English DT Article DE Brain Derived Neurotrophic Factor Gene; Adolescence; Anxiety; Depression; Medial temporal lobe; fMRI; Development ID SEROTONIN TRANSPORTER PROMOTER; GENERALIZED ANXIETY DISORDER; FACIAL EXPRESSIONS; MOOD DISORDERS; ENVIRONMENT INTERACTIONS; NEUROTROPHIC FACTOR; PREFRONTAL CORTEX; MAJOR DEPRESSION; CHILDREN; ASSOCIATION AB A polymorphism of the human Brain Derived Neurotrophic Factor (BDNF) gene that produces a valine-to-methionine substitution at codon 66 (Val66Met) is linked to adult anxiety and mood disorders, possibly through effects on brain circuitry function. Associations between BDNF gene variants and brain activity have not been explored in anxious and depressed adolescents. The current study investigated the association between BDNF genotype and amygdala-hippocampal responses to emotional stimuli in adolescents with anxiety disorders and/or major depressive disorder (MDD) and in healthy adolescents. Twenty-seven unmedicated patients with acutely-impairing current anxiety disorders and/or MOD and 31 healthy adolescents, matched on age, gender and IQ rated their fear of fearful, angry, neutral and happy facial expressions during collection of fMRI data on the amygdala and hippocampus. Left and right amygdala and hippocampal responses were analyzed using repeated-measures analyses of variance models, with diagnosis (patients, healthy) and genotype (Met-carriers, Val/Val homozygotes) as between-group factors and facial expression (fearful, angry, neutral, happy) as a within-subject factor. Significant effects of diagnosis and diagnosis-by-genotype interactions (Fs>4, p's<0.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. These data are first to demonstrate the contribution of BDNF gene variants to the neural correlates of adolescent anxiety and depression. Early "gene-brain" linkages may lay the foundation for longer-term patterns of neural dysfunction in affective disorders. (C) 2009 Elsevier Inc. All rights reserved. C1 [Lau, Jennifer Y. F.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Lau, Jennifer Y. F.; Leibenluft, Ellen; Nelson, Eric; Sankin, Lindsey; Pine, Daniel S.; Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Goldman, David; Hodgkinson, Colin] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Lau, JYF (reprint author), Dept Expt Psychol, S Parks Rd, Oxford OX1 4AU, England. EM jennifer.lau@psy.ox.ac.uk RI Hodgkinson, Colin/F-9899-2010; Nelson, Eric/B-8980-2008; Goldman, David/F-9772-2010 OI Nelson, Eric/0000-0002-3376-2453; Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z99 MH999999] NR 64 TC 51 Z9 51 U1 4 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2010 VL 53 IS 3 BP 952 EP 961 DI 10.1016/j.neuroimage.2009.11.026 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 652VQ UT WOS:000282039300018 PM 19931400 ER PT J AU Currier, JR Ngauy, V de Souza, MS Ratto-Kim, S Cox, JH Polonis, VR Earl, P Moss, B Peel, S Slike, B Sriplienchan, S Thongcharoen, P Paris, RM Robb, ML Kim, J Michael, NL Marovich, MA AF Currier, Jeffrey R. Ngauy, Viseth de Souza, Mark S. Ratto-Kim, Silvia Cox, Josephine H. Polonis, Victoria R. Earl, Patricia Moss, Bernard Peel, Sheila Slike, Bonnie Sriplienchan, Somchai Thongcharoen, Prasert Paris, Robert M. Robb, Merlin L. Kim, Jerome Michael, Nelson L. Marovich, Mary A. TI Phase I Safety and Immunogenicity Evaluation of MVA-CMDR, a Multigenic, Recombinant Modified Vaccinia Ankara-HIV-1 Vaccine Candidate SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; HIV-1 VACCINE; BOOST VACCINE; SMALLPOX VACCINATION; IMMUNE-RESPONSES; SUBTYPE-B; NYVAC-C; DNA; PRIME AB Background: We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand. Methodology/Principal Findings: MVA-CMDR or placebo was administered intra-muscularly (IM; 10(7) or 10(8) pfu) or intradermally (ID; 10(6) or 10(7) pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10: 2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFN gamma Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a Cr-51-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFN gamma Elispot of 78 SFC/10(6) PBMC at 10(8) pfu IM), but high in response rate (70% Cr-51-release positive; 90% Elispot positive; 100% ICS positive, at 10(8) pfu IM); (ii) predominantly HIV Env-specific CD4(+) T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 10(8) pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10(8) pfu IM). Conclusions/Significance: MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses. C1 [Currier, Jeffrey R.; Ratto-Kim, Silvia; Polonis, Victoria R.; Peel, Sheila; Slike, Bonnie; Robb, Merlin L.; Kim, Jerome; Michael, Nelson L.; Marovich, Mary A.] US Mil HIV Res Program, Rockville, MD USA. [Ngauy, Viseth; de Souza, Mark S.; Sriplienchan, Somchai; Paris, Robert M.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Cox, Josephine H.] Int AIDS Vaccine Initiat, New York, NY USA. [Earl, Patricia; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Thongcharoen, Prasert] Mahidol Univ, Bangkok 10700, Thailand. RP Currier, JR (reprint author), US Mil HIV Res Program, Rockville, MD USA. EM jcurrier@hivresearch.org FU U.S. Army Medical Research and Materiel Command [W81XWH-04-02-0005]; Henry M. Jackson Foundation for the Advancement of Military Medicine FX This work was supported by the U.S. Army Medical Research and Materiel Command and its Cooperative Agreement (W81XWH-04-02-0005) with the Henry M. Jackson Foundation for the Advancement of Military Medicine. The opinions expressed herein are those of the authors and do not represent the official position of the U. S. Army or Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 51 Z9 51 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 NOV 15 PY 2010 VL 5 IS 11 AR e13983 DI 10.1371/journal.pone.0013983 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680KW UT WOS:000284231800013 PM 21085591 ER PT J AU Jones, L Holmans, PA Hamshere, ML Harold, D Moskvina, V Ivanov, D Pocklington, A Abraham, R Hollingworth, P Sims, R Gerrish, A Pahwa, JS Jones, N Stretton, A Morgan, AR Lovestone, S Powell, J Proitsi, P Lupton, MK Brayne, C Rubinsztein, DC Gill, M Lawlor, B Lynch, A Morgan, K Brown, KS Passmore, PA Craig, D McGuinness, B Todd, S Holmes, C Mann, D Smith, AD Love, S Kehoe, PG Mead, S Fox, N Rossor, M Collinge, J Maier, W Jessen, F Schurmann, B van den Bussche, H Heuser, I Peters, O Kornhuber, J Wiltfang, J Dichgans, M Frolich, L Hampel, H Hull, M Rujescu, D Goate, AM Kauwe, JSK Cruchaga, C Nowotny, P Morris, JC Mayo, K Livingston, G Bass, NJ Gurling, H McQuillin, A Gwilliam, R Deloukas, P Al-Chalabi, A Shaw, CE Singleton, AB Guerreiro, R Muhleisen, TW Nothen, MM Moebus, S Jockel, KH Klopp, N Wichmann, HE Ruther, E Carrasquillo, MM Pankratz, VS Younkin, SG Hardy, J O'Donovan, MC Owen, MJ Williams, J AF Jones, Lesley Holmans, Peter A. Hamshere, Marian L. Harold, Denise Moskvina, Valentina Ivanov, Dobril Pocklington, Andrew Abraham, Richard Hollingworth, Paul Sims, Rebecca Gerrish, Amy Pahwa, Jaspreet Singh Jones, Nicola Stretton, Alexandra Morgan, Angharad R. Lovestone, Simon Powell, John Proitsi, Petroula Lupton, Michelle K. Brayne, Carol Rubinsztein, David C. Gill, Michael Lawlor, Brian Lynch, Aoibhinn Morgan, Kevin Brown, Kristelle S. Passmore, Peter A. Craig, David McGuinness, Bernadette Todd, Stephen Holmes, Clive Mann, David Smith, A. David Love, Seth Kehoe, Patrick G. Mead, Simon Fox, Nick Rossor, Martin Collinge, John Maier, Wolfgang Jessen, Frank Schuermann, Britta van den Bussche, Hendrik Heuser, Isabella Peters, Oliver Kornhuber, Johannes Wiltfang, Jens Dichgans, Martin Froelich, Lutz Hampel, Harald Huell, Michael Rujescu, Dan Goate, Alison M. Kauwe, John S. K. Cruchaga, Carlos Nowotny, Petra Morris, John C. Mayo, Kevin Livingston, Gill Bass, Nicholas J. Gurling, Hugh McQuillin, Andrew Gwilliam, Rhian Deloukas, Panos Al-Chalabi, Ammar Shaw, Christopher E. Singleton, Andrew B. Guerreiro, Rita Muehleisen, Thomas W. Noethen, Markus M. Moebus, Susanne Joeckel, Karl-Heinz Klopp, Norman Wichmann, H. -Erich Ruether, Eckhard Carrasquillo, Minerva M. Pankratz, V. Shane Younkin, Steven G. Hardy, John O'Donovan, Michael C. Owen, Michael J. Williams, Julie TI Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; APOLIPOPROTEIN-E; DEMENTIA; RISK; BETA; INFLAMMATION; POPULATION; MICROGLIA; PATHWAYS AB Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches. C1 [Jones, Lesley; Holmans, Peter A.; Hamshere, Marian L.; Harold, Denise; Moskvina, Valentina; Ivanov, Dobril; Pocklington, Andrew; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Pahwa, Jaspreet Singh; Jones, Nicola; Stretton, Alexandra; Morgan, Angharad R.; O'Donovan, Michael C.; Owen, Michael J.; Williams, Julie] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Ctr Neuropsychiat Genet & Genom,MRC, Cardiff, S Glam, Wales. [Lovestone, Simon] Kings Coll London, S London & Maudsley Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, London WC2R 2LS, England. [Powell, John; Proitsi, Petroula; Lupton, Michelle K.] Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England. [Brayne, Carol] Univ Cambridge, Inst Publ Hlth, Cambridge, England. [Rubinsztein, David C.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland. [Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn] Trinity Coll Dublin, Dublin, Ireland. [Morgan, Kevin; Brown, Kristelle S.] Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NG7 2RD, England. [Passmore, Peter A.; Craig, David; McGuinness, Bernadette; Todd, Stephen] Queens Univ Belfast, Ageing Grp, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland. [Holmes, Clive] Univ Southampton, Sch Med, Div Clin Neurosci, Southampton, Hants, England. [Mann, David] Univ Manchester, Greater Manchester Neurosci Ctr, Clin Neurosci Res Grp, Salford, Lancs, England. [Smith, A. David] Univ Oxford, John Radcliffe Hosp, Oxford Project Invest Memory & Ageing, Oxford OX3 9DU, England. [Love, Seth; Kehoe, Patrick G.] Univ Bristol, Frenchay Hosp, Inst Clin Neurosci, Dementia Res Grp, Bristol, Avon, England. [Mead, Simon; Collinge, John] UCL Inst Neurol, Dept Neurodegenerat Dis, MRC Prion Unit, London, England. [Fox, Nick; Rossor, Martin] UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, England. [Maier, Wolfgang; Jessen, Frank; Schuermann, Britta] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [van den Bussche, Hendrik; Heuser, Isabella; Peters, Oliver] Univ Med Ctr Hamburg Eppendorf, Inst Primary Med Care, Hamburg, Germany. [Kornhuber, Johannes] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, Erlangen, Germany. [Wiltfang, Jens] Univ Duisburg Essen, Dept Psychiat & Psychotherapy, Landschaftsverband Rheinland Hosp Essen, Essen, Germany. [Dichgans, Martin] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Klinikum Univ Munchen, Dept Neurol, Munich, Germany. [Froelich, Lutz] Univ Heidelberg, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Geriatr Psychiat, D-6800 Mannheim, Germany. [Hampel, Harald] Univ Dublin Trinity Coll, Sch Med, Discipline Psychiat, Dublin 2, Ireland. [Hampel, Harald] Univ Dublin Trinity Coll, Trinity Coll Inst Neurosci, Lab Neuroimaging & Biomarker Res, Dublin 2, Ireland. [Hampel, Harald; Rujescu, Dan] Univ Munich, Alzheimer Mem Ctr, Munich, Germany. [Hampel, Harald; Rujescu, Dan] Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, D-8000 Munich, Germany. [Huell, Michael] Univ Freiburg, Sch Med, Ctr Geriatr Med, Freiburg, Germany. [Huell, Michael] Univ Freiburg, Sch Med, Sect Gerontopsychiat & Neuropsychol, Freiburg, Germany. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Goate, Alison M.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Kauwe, John S. K.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew] UCL, Dept Mental Hlth Sci, London, England. [Gwilliam, Rhian; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Al-Chalabi, Ammar; Shaw, Christopher E.] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, MRC Ctr Neurodegenerat Res, London WC2R 2LS, England. [Singleton, Andrew B.; Guerreiro, Rita] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, D-5300 Bonn, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Moebus, Susanne] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Klopp, Norman; Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Ruether, Eckhard] Univ Gottingen, Dept Psychiat, Gottingen, Germany. [Wichmann, H. -Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Carrasquillo, Minerva M.; Younkin, Steven G.] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. [Pankratz, V. Shane] Mayo Clin & Mayo Fdn, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. RP Jones, L (reprint author), Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Ctr Neuropsychiat Genet & Genom,MRC, Cardiff, S Glam, Wales. EM owenmj@cf.ac.uk; williamsj@cf.ac.uk RI Singleton, Andrew/C-3010-2009; Kornhuber, Johannes/B-9613-2014; Fox, Nick/B-1319-2009; Holmans, Peter/F-4518-2015; Smith, Anthony/A-4233-2010; McQuillin, Andrew/C-1623-2008; Morris, John/A-1686-2012; Livingston, Gill/C-7081-2008; Al-Chalabi, Ammar/E-5361-2010; Rubinsztein, David/C-3472-2011; Mead, Simon/E-9414-2011; Hardy, John/C-2451-2009; Love, Seth/E-6545-2012; Jessen, Frank/E-7655-2012; Hull, Michael/F-2618-2012; Powell, John/G-4412-2011; Deloukas, Panos/B-2922-2013; Gurling, Hugh/A-5029-2010; Kauwe, John/B-2034-2009; OI Kornhuber, Johannes/0000-0002-8096-3987; Fox, Nick/0000-0002-6660-657X; Holmans, Peter/0000-0003-0870-9412; Smith, Anthony/0000-0002-1095-6722; McQuillin, Andrew/0000-0003-1567-2240; O'Donovan, Michael/0000-0001-7073-2379; Gill, Michael/0000-0003-0206-5337; Wiltfang, Jens/0000-0003-1492-5330; Harold, Denise/0000-0001-5195-0143; Al-Chalabi, Ammar/0000-0002-4924-7712; Mead, Simon/0000-0002-4326-1468; Powell, John/0000-0001-6124-439X; Deloukas, Panos/0000-0001-9251-070X; Kauwe, John/0000-0001-8641-2468; Ivanov, Dobril/0000-0001-6271-6301; Cruchaga, Carlos/0000-0002-0276-2899; Escott-Price, Valentina/0000-0003-1784-5483; Nothen, Markus/0000-0002-8770-2464; Todd, Stephen/0000-0002-2312-9195 FU Wellcome Trust; Medical Research Council (MRC, UK); Alzheimer's Research Trust (ART); Welsh Assembly Government; Alzheimer's Society; Ulster Garden Villages; Northern Ireland Research and Development Office; Royal College of Physicians-Dunhill Medical Trust; Trinity College group; Bristol Research into Alzheimer's and Care of the Elderly; Oxford Project to Investigate Memory and Ageing (OPTIMA) group; Motor Neurone Disease Association; MRC; US National Institutes of Health (NIH); Barnes Jewish Foundation; Charles and Joanne Knight Alzheimer's Research Initiative; NIH; Robert and Clarice Smith and Abigail Van Buren AD Research Program; UCL Hospital/UCL Biomedical Centre; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; BMBF; German National Genome Research Network; Munich Center of Health Sciences; National Institute on Aging (NIA); NIA, NIH, Department of Health and Human Services [Z01 AG000950-06]; University of Antwerp; Fund for Scientific Research-Flanders; Belgian Federal Science Policy Office [P6/43] FX Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC, UK), Alzheimer's Research Trust (ART) and the Welsh Assembly Government. ART supported sample collections at the Institute of Psychiatry, the South West Dementia Bank and the Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, Northern Ireland Research and Development Office and the Royal College of Physicians-Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing (OPTIMA) group. A. A-C. and C. E. S. thank the Motor Neurone Disease Association and MRC for support. D. C. R. is a Wellcome Trust Senior Clinical Research Fellow. Washington University was funded by US National Institutes of Health (NIH) grants, the Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. The Mayo GWAS was supported by NIH grants, the Robert and Clarice Smith and Abigail Van Buren AD Research Program, and the Palumbo Professorship in AD Research. Patient recruitment for the MRC Prion Unit/University College London Department of Neurodegenerative Disease collection was supported by the UCL Hospital/UCL Biomedical Centre. London and the South East Region (LASER)-AD was funded by Lundbeck. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The Kooperative gesundheitsforschung in der region Augsburg (KORA) F4 studies were financed by Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, BMBF, the German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (G. Schmidt, chairman) and BMBF. Coriell Cell Repositories is supported by the US National Institute of Neurological Disorders and Stroke and the Intramural Research Program (IRP) of the National Institute on Aging (NIA). Work on this sample was supported in part by the IRP of the NIA, NIH, Department of Health and Human Services; Z01 AG000950-06. The authors acknowledge use of DNA from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust, which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Antwerp site was supported by the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, the Special Research Fund of the University of Antwerp, the Fund for Scientific Research-Flanders, the Foundation for Alzheimer Research and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. K. S. is a postdoctoral fellow and K. B. a PhD fellow (Fund for Scientific Research-Flanders). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 142 Z9 143 U1 3 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 15 PY 2010 VL 5 IS 11 AR e13950 DI 10.1371/journal.pone.0013950 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 680KW UT WOS:000284231800004 PM 21085570 ER PT J AU Mashiach, E Schneidman-Duhovny, D Peri, A Shavit, Y Nussinov, R Wolfson, HJ AF Mashiach, Efrat Schneidman-Duhovny, Dina Peri, Aviyah Shavit, Yoli Nussinov, Ruth Wolfson, Haim J. TI An integrated suite of fast docking algorithms SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE CAPRI; protein-protein docking; docking refinement; side chain optimization; rigid body minimization; backbone flexibility ID PROTEIN-PROTEIN DOCKING; MOLECULAR DOCKING; ROUNDS 3-5; CAPRI; PROGRESS; COMPLEX; IDENTIFICATION; PREDICTIONS; REFINEMENT; INHIBITOR AB The CAPRI experiment (Critical Assessment of Predicted Interactions) simulates realistic and diverse docking challenges, each case having specific properties that may be exploited by docking algorithms. Motivated by the different CAPRI challenges, we developed and implemented a comprehensive suite of docking algorithms. These were incorporated into a dynamic docking protocol, consisting of four main stages: (1) Biological and bioinformatics research aiming to predict the binding site residues, to define distance constraints between interface atoms and to analyze the flexibility of molecules; (2) Rigid or flexible docking, performed by the Patch Dock or Flex Dock method, which utilizes the information gathered in the previous step. Symmetric complexes are predicted by the SymmDock method; (3) Flexible refinement and reranking of the rigid docking solution candidates, performed by Fiber Dock; and finally, (4) clustering and filtering the results based on energy funnels. We analyzed the performance of our docking protocol on a large benchmark and on recent CAPRI targets. The analysis has demonstrated the importance of biological information gathering prior to docking, which significantly increased the docking success rate, and of the refinement and rescoring stage that significantly improved the ranking of the rigid docking solutions. Our failures were mostly a result of mishandling backbone flexibility, inaccurate homology modeling, or incorrect biological assumptions. Most of the methods are available at http://bioinfo3d.cs.tau.ac.il/. Proteins 2010; 78:3197-3204. (C) 2010 Wiley-Liss, Inc. C1 [Mashiach, Efrat; Schneidman-Duhovny, Dina; Peri, Aviyah; Shavit, Yoli; Wolfson, Haim J.] Tel Aviv Univ, Blavatnik Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI Frederick, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM wolfson@tau.ac.il FU Israel Science Foundation [1403/09]; Hermann Minkowski Minerva Geometry Center; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Israel Academy of Sciences and Humanities; NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Israel Science Foundation; Grant number: 1403/09; Grant sponsor: The Hermann Minkowski Minerva Geometry Center; Grant sponsor: The National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E.; We thank Yuval Inbar, Alexandra Shulman-Peleg, Oranit Dror, and Itamar Banitt for their help in the CAPRI challenges. EM is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 32 TC 38 Z9 38 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD NOV 15 PY 2010 VL 78 IS 15 SI SI BP 3197 EP 3204 DI 10.1002/prot.22790 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 672EE UT WOS:000283565000018 PM 20607855 ER PT J AU Quinlan, SC Landgren, O Morton, LM Engels, EA AF Quinlan, Scott C. Landgren, Ola Morton, Lindsay M. Engels, Eric A. TI Hodgkin Lymphoma Among US Solid Organ Transplant Recipients SO TRANSPLANTATION LA English DT Article DE Hodgkin lymphoma; Transplantation; Epstein-Barr virus; United States ID POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER; KIDNEY-TRANSPLANTATION; RENAL-TRANSPLANTATION; CANCER INCIDENCE; UNITED-STATES; RISK-FACTORS; DISEASE; HIV/AIDS AB Background. To assess the risk and identify risk factors of Hodgkin lymphoma (HL) in solid organ transplant recipients. Prior research has been limited by the rarity of HL and the requirement for extended follow-up after transplantation. Methods. Using data from the Scientific Registry of Transplant Recipients (SRTR), we conducted a retrospective cohort study of US solid organ transplant recipients (1997-2007). We estimated hazard ratios (HRs) for HL risk factors using proportional hazards regression. Standardized incidence ratios (SIRs) compared HL risk in the transplant cohort with the general population. Results. The cohort included 283,190 transplant recipients (average follow-up: 3.7 years after transplantation). Based on 73 cases, HL risk factors included male gender (HR: 2.1, 95% CI: 1.2-3.7), young age (4.0, 2.3-6.8), and Epstein-Barr virus (EBV) seronegativity at the time of transplantation (3.1, 1.2-8.1). Among tumors with EBV status information, 79% were EBV positive, including all tumors in recipients who were initially seronegative. Overall, HL risk was higher than in the general population (SIR: 2.2) and increased monotonically over time after transplantation (SIR: 4.1 at 8-10 years posttransplant). Excess HL risk was especially high after heart and/or lung transplantation (SIR: 3.2). Conclusion. HL is a late complication of solid organ transplantation. The high HL risk in recipients who were young or EBV seronegative at the time of transplant and the fact that most HL tumors were EBV positive highlight the role of primary EBV infection and poor immune control of this virus. The occurrence of HL may rise with improved long-term survival in transplant recipients. C1 [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, DHHS, Rockville, MD 20892 USA. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, DHHS, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@exchange.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute, National Institutes of Health; US Department of Health Resources and Services Administration (HRSA), US Department of Health and Human Services [231-00-0116] FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Scientific Registry of Transplant Recipients (SRTR) is supported by contract 231-00-0116 from the US Department of Health Resources and Services Administration (HRSA), US Department of Health and Human Services. NR 23 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD NOV 15 PY 2010 VL 90 IS 9 BP 1011 EP 1015 DI 10.1097/TP.0b013e3181f5c3a6 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 673HN UT WOS:000283650200013 PM 20733533 ER PT J AU Bonville, CA Ptaschinski, C Percopo, CM Rosenberg, HF Domachowske, JB AF Bonville, Cynthia A. Ptaschinski, Catherine Percopo, Caroline M. Rosenberg, Helene F. Domachowske, Joseph B. TI Inflammatory responses to acute pneumovirus infection in neonatal mice SO VIROLOGY JOURNAL LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; INNATE IMMUNITY; INFANTS; AGE; BRONCHIOLITIS; ANTIBODIES; DISEASE; PATHOGENESIS; REINFECTION; MATURATION AB Background: The innate immune responses of neonates differ dramatically from those of adults. Here we examine the acute inflammatory responses of neonatal and weanling mice infected with pneumonia virus of mice (PVM), a rodent pathogen (family Paramyxoviridae, genus Pneumovirus) that replicates the sequelae of severe respiratory syncytial virus infection. Results: We demonstrate that virus replication proceeds indistinguishably in all age groups (inoculated at 1, 2, 3 and 4 weeks of age), although inflammatory responses vary in extent and character. Some of the biochemical mediators detected varied minimally with age at inoculation. Most of the mediators evaluated demonstrated elevated expression over baseline correlating directly with age at the time of virus inoculation. Among the latter group are CCL2, CCL3, and IFN-gamma, all cytokines previously associated with PVM-induced inflammatory pathology in mature mice. Likewise, we detect neutrophil recruitment to lung tissue in all age groups, but recruitment is most pronounced among the older (3 - 4 week old) mice. Interestingly, all mice exhibit failure to thrive, lagging in expected weight gain for given age, including the youngest mice that present little overt evidence of inflammation. Conclusions: Our findings among the youngest mice may explain in part the phenomenon of atypical or minimally symptomatic respiratory infections in human neonates, which may be explored further with this infection model. C1 [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY USA. [Bonville, Cynthia A.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY USA. [Ptaschinski, Catherine] Univ Newcastle, Sch Biomed Sci, Newcastle, NSW 2300, Australia. [Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Domachowske, JB (reprint author), SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY USA. EM domachoj@upstate.edu FU Children's Miracle Network of New York; NIAID Division of Intramural Research [Z01-AI00943] FX The authors thank Mr. Ricardo Dreyfuss for his assistance with preparation of the microscopic images. Funding for this work was provided by Children's Miracle Network of New York (to JBD) and NIAID Division of Intramural Research Z01-AI00943 (to HFR). NR 31 TC 6 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD NOV 15 PY 2010 VL 7 AR 320 DI 10.1186/1743-422X-7-320 PG 8 WC Virology SC Virology GA 686QH UT WOS:000284710300002 PM 21078159 ER PT J AU Gebo, KA Fleishman, JA Conviser, R Hellinger, J Hellinger, FJ Josephs, JS Keiser, P Gaist, P Moore, RD AF Gebo, Kelly A. Fleishman, John A. Conviser, Richard Hellinger, James Hellinger, Fred J. Josephs, Joshua S. Keiser, Philip Gaist, Paul Moore, Richard D. CA HIV Res Network TI Contemporary costs of HIV healthcare in the HAART era SO AIDS LA English DT Article DE CD4 cell count; cost; HAART; HIV; HIV Research Network; utilization ID ACTIVE ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; UNITED-STATES; MEDICAL-CARE; HOSPITALIZATION RATES; INPATIENT ADMISSIONS; SERVICES UTILIZATION; EXPENDITURES; MODELS; TRENDS AB Background: The delivery of HIV healthcare historically has been expensive. The most recent national data regarding HIV healthcare costs were from 1996-1998. We provide updated estimates of expenditures for HIV management. Methods: We performed a cross-sectional review of medical records at 10 sites in the HIV Research Network, a consortium of high-volume HIV care providers across the United States. We assessed inpatient days, outpatient visits, and prescribed antiretroviral and opportunistic illness prophylaxis medications for 14 691 adult HIV-infected patients in primary HIV care in 2006. We estimated total care expenditures, stratified by the median CD4 cell count obtained in 2006 (<= 50, 51-200, 201-350, 351-500, >500 cells/mu l). Per-unit costs of care were based on Healthcare Cost and Utilization Project (HCUP)data for inpatient care, discounted average wholesale prices for medications, and Medicare physician fees for outpatient care. Results: Averaging over all CD4 strata, the mean annual total expenditures per person for HIV care in 2006 in three sites was US $19 912, with an interquartile range from US $11 045 to 22 626. Average annual per-person expenditures for care were greatest for those with CD4 cell counts 50 cell/mu l or less (US $40 678) and lowest for those with CD4 cell counts more than 500 cells/ml (US $16 614). The majority of costs were attributable to medications, except for those with CD4 cell counts 50 cells/ml or less, for whom inpatient costs were highest. Conclusion: HIV healthcare in the United States continues to be expensive, with the majority of expenditures attributable to medications. With improved HIV survival, costs may increase and should be monitored in the future. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Gebo, Kelly A.; Josephs, Joshua S.; Moore, Richard D.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Fleishman, John A.; Hellinger, Fred J.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Conviser, Richard] Global Hlth Policy Partners, Missoula, MT USA. [Hellinger, James] Community Med Alliance, Boston, MA USA. [Keiser, Philip] Univ Texas Galveston, Galveston, TX 77555 USA. [Gaist, Paul] NIH, Bethesda, MD 20892 USA. RP Gebo, KA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1830 E Monument St,Room 435, Baltimore, MD 21287 USA. EM kgebo@jhmi.edu FU Agency for Healthcare Research and Quality [290-01-0012]; National Institutes of Aging [R01 AG026250]; Drug Abuse, NIH [K23-DA00523, K24-DA00432]; Johns Hopkins University; AHRQ FX This work was supported by the Agency for Healthcare Research and Quality (290-01-0012) and National Institutes of Aging (R01 AG026250) and Drug Abuse, NIH (K23-DA00523, and K24-DA00432). K. A. G. was also supported by the Johns Hopkins University Richard Ross Clinician Scientist Award. These agencies had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication.; The authors would like to acknowledge the state data organizations that participate in the HCUP: California Office of Statewide Health Planning and Development; Colorado Health and Hospital Association; Florida Agency for Healthcare Administration; Iowa Hospital Association; Illinois Healthcare Cost Containment Council; Kansas Hospital Association; Maryland Health Services Cost Review Commission; New Jersey Department of Health and Senior Services; New York State Department of Health; Washington State Department of Health. HCUP is sponsored by AHRQ. NR 43 TC 62 Z9 65 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD NOV 13 PY 2010 VL 24 IS 17 BP 2705 EP 2715 DI 10.1097/QAD.0b013e32833f3c14 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 672KV UT WOS:000283582800013 PM 20859193 ER PT J AU Geneau, R Stuckler, D Stachenko, S Mckee, M Ebrahim, S Basu, S Chockalingham, A Mwatsama, M Jamal, R Alwan, A Beaglehole, R AF Geneau, Robert Stuckler, David Stachenko, Sylie McKee, Martin Ebrahim, Shah Basu, Sanjay Chockalingham, Arun Mwatsama, Modi Jamal, Rozmin Alwan, Ala Beaglehole, Robert TI Chronic Diseases: Chronic Diseases and Development 1 Raising the priority of preventing chronic diseases: a political process SO LANCET LA English DT Article ID MIDDLE-INCOME COUNTRIES; GLOBAL HEALTH; NONCOMMUNICABLE DISEASES; SYSTEMATIC ANALYSIS; CLIMATE-CHANGE; RISK-FACTORS; MORTALITY; TOBACCO; POLICY; TUBERCULOSIS AB Chronic diseases especially cardiovascular diseases, diabetes cancer and chronic obstructive respiratory diseases, are neglected globally despite growing awareness of the serious burden that they cause Global and national policies have failed to stop, and in many cases have contributed to, the chronic disease pandemic Low cost and highly effective solutions for the prevention of chronic diseases are readily available the failure to respond is now a political rather than a technical issue We seek to understand this failure and to position chronic disease centrally on the global health and development agendas To identify strategies for generation of increased political priority for chronic diseases and to further the involvement of development agencies we use an adapted political process model This model has previously been used to assess the success and failure of social movements On the basis of this analysis we recommend three strategies reframe the debate to emphasise the societal determinants of disease and the inter relation between chronic disease, poverty, and development, mobilise resources through a cooperative and inclusive approach to development and by equitably distributing resources on the basis of avoidable mortality and build on emerging strategic and political opportunities such as the World Health Assembly 2008-13 Action Plan and the high level meeting of the UN General Assembly in 2011 on chronic disease Until the full set of threats which-include chronic disease-that trap poor households in cycles of debt and illness are addressed, progress towards equitable human development will remain inadequate C1 [Geneau, Robert] Univ Ottawa, Elizabeth Bruyere Res Inst, Ottawa, ON, Canada. [Stuckler, David] Univ Oxford, Dept Sociol, Oxford OX1 2JD, England. [Stachenko, Sylie] Univ Alberta, Sch Publ Hlth, Edmonton, AB T6G 2M7, Canada. [McKee, Martin] London Sch Hyg & Trop Med, European Ctr Hlth Soc Transit, London WC1, England. [Ebrahim, Shah] S Asia Network Chron Dis, New Delhi, India. [Ebrahim, Shah] Publ Hlth Fdn India, New Delhi, India. [Basu, Sanjay] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Basu, Sanjay] San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA USA. [Chockalingham, Arun] NHLBI, Off Global Hlth, Bethesda, MD 20892 USA. [Jamal, Rozmin] Aga Khan Univ, Clin Res Unit, Karachi, Pakistan. [Alwan, Ala] WHO, CH-1211 Geneva, Switzerland. [Beaglehole, Robert] Univ Auckland, Auckland 1, New Zealand. RP Geneau, R (reprint author), Univ Ottawa, Elizabeth Bruyere Res Inst, 43 Bruyere, Ottawa, ON, Canada. RI Stuckler, David/H-2261-2012 NR 87 TC 101 Z9 101 U1 4 U2 23 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 NOV 13 PY 2010 VL 376 IS 9753 BP 1689 EP 1698 DI 10.1016/S0140-6736(10)61414-6 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 683DD UT WOS:000284451000034 PM 21074260 ER PT J AU Birk, E Har-Zahav, A Manzini, CM Pasmanik-Chor, M Kornreich, L Walsh, CA Noben-Trauth, K Albin, A Simon, AJ Colleaux, L Morad, Y Rainshtein, L Tischfield, DJ Wang, P Magal, N Maya, I Shoshani, N Rechavi, G Gothelf, D Maydan, G Shohat, M Basel-Vanagaite, L AF Birk, Efrat Har-Zahav, Adi Manzini, Chiara M. Pasmanik-Chor, Metsada Kornreich, Liora Walsh, Christopher A. Noben-Trauth, Konrad Albin, Adi Simon, Amos J. Colleaux, Laurence Morad, Yair Rainshtein, Limor Tischfield, David J. Wang, Peter Magal, Nurit Maya, Idit Shoshani, Noa Rechavi, Gideon Gothelf, Doron Maydan, Gal Shohat, Mordechai Basel-Vanagaite, Lina TI SOBP Is Mutated in Syndromic and Nonsyndromic Intellectual Disability and Is Highly Expressed in the Brain Limbic System SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RECESSIVE MENTAL-RETARDATION; BINDING-PROTEIN; DEFECT; ENDOCYTOSIS; MUTATIONS; DYNAMIN-1; TRAPPC9; CORTEX; MOUSE; RAT AB Intellectual disability (ID) affects 1%-3% of the general population We recently reported on a family with autosomal recessive mental retardation with anterior maxillary protrusion and strabismus (MRAMS) syndrome One of the reported patients with ID did not have dysmorphic features but did have temporal lobe epilepsy and psychosis We report on the identification of a truncating mutation in the SOBP that is responsible for causing both syndromic and nonsyndromic ID in the same family The protein encoded by the SOBP sine oculis binding protein ortholog, is a nuclear zinc finger protein In mice Sobp (also known as Jxc1) is critical for patterning of the organ of Corti, one of our patients has a subclinical cochlear hearing loss but no gross cochlear abnormalities In situ RNA expression studies in postnatal mouse brain showed strong expression in the limbic system at the time interval of active synaptogenesis The limbic system regulates learning, memory, and affective behavior, but limbic circuitry expression of other genes mutated in ID is unusual By comparing the protein content of the +/Jc to Jc/Jc mice brains with the use of proteomics we detected 24 proteins with greater than 1 5 fold differences in expression including two interacting proteins, dynamin and pacsin1 This study shows mutated SOBP involvement in syndromic and nonsyndromic ID with psychosis in humans C1 [Birk, Efrat; Har-Zahav, Adi; Morad, Yair; Shoshani, Noa; Rechavi, Gideon; Gothelf, Doron; Shohat, Mordechai; Basel-Vanagaite, Lina] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Manzini, Chiara M.; Walsh, Christopher A.; Tischfield, David J.; Wang, Peter] Childrens Hosp, Div Genet, Manton Ctr Orphan Dis, Boston, MA 02115 USA. [Pasmanik-Chor, Metsada] Childrens Hosp, Howard Hughes Med Ctr, Boston, MA 02115 USA. [Pasmanik-Chor, Metsada] Tel Aviv Univ, Bioinformat Unit, CSW Fac Life Sci, IL-69978 Tel Aviv, Israel. [Kornreich, Liora] Schneider Childrens Med Ctr Israel, Dept Imaging, IL-49202 Petah Tiqwa, Israel. [Noben-Trauth, Konrad] Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. [Albin, Adi; Rainshtein, Limor; Magal, Nurit; Maya, Idit; Shohat, Mordechai; Basel-Vanagaite, Lina] Rabin Med Ctr, Raphael Recanati Genet Inst, IL-49100 Petah Tiqwa, Israel. [Simon, Amos J.; Rechavi, Gideon] Chaim Sheba Med Ctr, Sheba Canc Res Ctr, IL-52621 Tel Hashomer, Israel. [Colleaux, Laurence] Univ Paris 05, INSERM, U781, Hop Necker Enfants Malades, F-75015 Paris, France. [Morad, Yair] Assaf Harofeh Med Ctr, Pediat Ophthalmol Serv, IL-73000 Zerifin, Israel. [Gothelf, Doron] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Maydan, Gal] Beilinson Med Ctr, Dept Internal Med D, Rabin Med Ctr, IL-49100 Petah Tiqwa, Israel. [Shohat, Mordechai] Tel Aviv Univ, Felsenstein Med Res Ctr, Rabin Med Ctr, IL-49100 Petah Tiqwa, Israel. RP Basel-Vanagaite, L (reprint author), Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. OI Manzini, M. Chiara/0000-0001-7175-1096 FU Israeli Ministry of Health Chief Scientist Foundation [3 4963]; Israeli Science Foundation [558/09] FX This study was supported by the Israeli Ministry of Health Chief Scientist Foundation (grant no 3 4963) and the Israeli Science Foundation (grant no 558/09) The authors thank Gabrielle J Halpern for her help with editing of the manuscript and the members of the family for their cooperation NR 25 TC 10 Z9 12 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD NOV 12 PY 2010 VL 87 IS 5 BP 694 EP 700 DI 10.1016/j.ajhg.2010.10.005 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 686AE UT WOS:000284668400016 PM 21035105 ER PT J AU Wu, FB Mattson, MP Yao, PJ AF Wu, Fangbai Mattson, Mark P. Yao, Pamela J. TI Neuronal activity and the expression of clathrin-assembly protein AP180 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE AP180; Hippocampal neuron; CALM; Epsin1; HIP1 ID DOMAIN; CALM; BINDING; SYNAPSE; EPSIN; IDENTIFICATION; LOCALIZATION; ENDOCYTOSIS; COMPONENTS; HOMOLOG AB The clathrin-assembly protein AP180 is known to promote the assembly of clathrin-coated vesicles in the neuron. However, it is unknown whether the expression of AP180 is influenced by neuronal activity. In this study, we report that chronic depolarization results in a reduction of AP180 from hippocampal neurons, while acute depolarization causes a dispersed synaptic distribution of AP180. Activity-induced effects are observed only for AP180, but not for the structurally-related clathrin-assembly proteins CALM, epsin1, or HIP1. These findings suggest that AP180 levels and synaptic distribution are highly sensitive to neuronal activity. Published by Elsevier Inc. C1 [Yao, Pamela J.] NIA, Neurosci Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging of the NIH FX This work was supported by The Intramural Research Program of the National Institute on Aging of the NIH. We wish to thank Dr. Linton M. Traub for the epsin1 and HIP1 antibodies. NR 25 TC 5 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 12 PY 2010 VL 402 IS 2 BP 297 EP 300 DI 10.1016/j.bbrc.2010.10.018 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 688PA UT WOS:000284862300023 PM 20937255 ER PT J AU Xu, KY Zhu, WZ Xiao, RP AF Xu, Kai Y. Zhu, Weizhong Xiao, Rui-Ping TI Serine(496) of beta(2) subunit of L-type Ca2+ channel participates in molecular crosstalk between activation of (Na++K+)-ATPase and the channel SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE (Na++K+)-ATPase; L-type Ca2+ channel; Enzyme activator; Phosphorylation; Molecular crosstalk ID CALCIUM-CHANNELS; PHOSPHORYLATION; HEART; SITE AB Activation of (Na++K+)-ATPase (NKA) regulates cardiac L-type Ca2+ channel (LTCC) function through molecular crosstalk. The mechanism underlying NKA-LTCC crosstalk remains poorly understood. We have previously shown that activation of NKA leads to phosphorylation of LTCC alpha(1) Ser(1928). Here we investigated whether LTCC beta(2) subunit is modulated by NKA activation and found that LTCC beta(2) Ser(496) is phosphorylated in response to activation of NKA. Src inhibitor PP1 and Erk1/2 inhibitor PD98059 abolish LTCC beta(2) Ser(496) phosphorylation, suggesting that NKA-mediated beta(2) Ser(496) phosphorylation is dependent of Src/Erk1/2 signaling pathway. Protein kinase G (PKG) inhibitor KT5823 failed to inhibit the phosphorylation of beta(2) Ser496, indicating that the NKA-LTCC crosstalk is independent of PKG activity. The results of nifedipine sensitive Ca-45 influx experiments suggest that phosphorylation of beta(2) Ser(496) may play a key down-regulation role in attenuating the accelerated activity of alpha(1) subunit of the channel. Ouabain does not cause a phosphorylation on beta(2) Ser(496), indicating a fundamental difference between activation and inhibition of NKA-mediated biological processes. This study provides the first evidence to demonstrate that LTCC beta(2) subunit is coupled with the movement of signals in the mechanism of activation of NKA-mediated crosstalk with LTCC. (C) 2010 Elsevier Inc. All rights reserved. C1 [Xu, Kai Y.] Univ Maryland, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21201 USA. [Zhu, Weizhong; Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Xu, KY (reprint author), 10 S Pine St,MSTF 434E, Baltimore, MD 21201 USA. EM kxu002@umaryland.edu FU NIH [HL-52175] FX We are grateful to Dr. Steven O. Marx for his important advices and for providing critical materials for the study including cDNA clones of WT and Mut LTCC alpha1 and beta2 subunits, anti-pSer498, and anti-pSer1928 antibodies. We also thank Drs. Terry Rogers, Lin Yang, and Kim Collins for helpful discussions, Mr. B. Ziman and Dr. Su Wang for isolating rat myocytes. The work was supported by NIH grant HL-52175 (K.Y. Xu) and NIH Intramural Research grant (R.-P. Xiao). NR 22 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 12 PY 2010 VL 402 IS 2 BP 319 EP 323 DI 10.1016/j.bbrc.2010.10.024 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 688PA UT WOS:000284862300028 PM 20937253 ER PT J AU Kutty, RK Nagineni, CN Samuel, W Vijayasarathy, C Hooks, JJ Redmond, TM AF Kutty, R. Krishnan Nagineni, Chandrasekharam N. Samuel, William Vijayasarathy, Camasamudram Hooks, John J. Redmond, T. Michael TI Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Retinal pigment epithelium; MicroRNA-155; TNF-alpha; IL-1beta; IFN-gamma; JAK/STAT pathway ID MACULAR DEGENERATION; INTERFERON-GAMMA; MIR-155; PROTEINS; RECEPTOR; TARGET AB Inflammatory response of the retinal pigment epithelium plays a critical role in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration. Our previous studies have shown that human retinal pigment epithelial (HRPE) cells, established from adult donor eyes, respond to inflammatory cytokines by enhancing the expression of a number of cytokines and chemokines. To investigate the role of microRNA (miRNA) in regulating this response, we performed microarray analysis of miRNA expression in HRPE cells exposed to inflammatory cytokine mix (IFN-gamma + TNE-alpha + IL-1 beta). Microarray analysis revealed similar to 11-fold increase in miR-155 expression, which was validated by real-time PCR analysis. The miR-155 expression was enhanced when the cells were treated individually with IFN-gamma. TNE-alpha or IL-1 beta, but combinations of the cytokines exaggerated the effect. The increase in miR-155 expression by the inflammatory cytokines was associated with an increase in STAT1 activation as well as an increase in protein binding to putative STAT1 binding elements present in the MIR155 gene promoter region. All these activities were effectively blocked by JAK inhibitor 1. Our results show that the inflammatory cytokines increase miR-155 expression in human retinal pigment epithelial cells by activating the JAK/STAT signaling pathway. Published by Elsevier Inc. C1 [Kutty, R. Krishnan; Samuel, William; Redmond, T. Michael] NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Nagineni, Chandrasekharam N.; Hooks, John J.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bldg 6,Room 112,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM kuttyk@nei.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU National Eye Institute, NIH FX This study was supported by the Intramural Research Program of the National Eye Institute, NIH. NR 23 TC 57 Z9 67 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 12 PY 2010 VL 402 IS 2 BP 390 EP 395 DI 10.1016/j.bbrc.2010.10.042 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 688PA UT WOS:000284862300041 PM 20950585 ER PT J AU Gilchrist, DA Dos Santos, G Fargo, DC Xie, B Gao, YA Li, LP Adelman, K AF Gilchrist, Daniel A. Dos Santos, Gilberto Fargo, David C. Xie, Bin Gao, Yuan Li, Leping Adelman, Karen TI Pausing of RNA Polymerase II Disrupts DNA-Specified Nucleosome Organization to Enable Precise Gene Regulation SO CELL LA English DT Article ID P-TEFB; TRANSCRIPTIONAL REGULATION; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; PRODUCTIVE ELONGATION; PROMOTER ARCHITECTURE; HUMAN GENOME; GAGA FACTOR; IN-VIVO; POL-II AB Metazoan transcription is controlled through either coordinated recruitment of transcription machinery to the gene promoter or regulated pausing of RNA polymerase II (Pol II) in early elongation. We report that a striking difference between genes that use these distinct regulatory strategies lies in the "default" chromatin architecture specified by their DNA sequences. Pol II pausing is prominent at highly regulated genes whose sequences inherently disfavor nucleosome formation within the gene but favor occlusion of the promoter by nucleosomes. In contrast, housekeeping genes that lack pronounced Pol II pausing show higher nucleosome occupancy downstream, but their promoters are deprived of nucleosomes regardless of polymerase binding. Our results indicate that a key role of paused Pol II is to compete with nucleosomes for occupancy of highly regulated promoters, thereby preventing the formation of repressive chromatin architecture C1 [Gilchrist, Daniel A.; Dos Santos, Gilberto; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Lib Informat Serv, NIH, Res Triangle Pk, NC 27709 USA. [Li, Leping] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Gao, Yuan] Johns Hopkins Univ, Inst Cell Engn, Neurogenerat & Stem Cell Biol Program, Baltimore, MD 21205 USA. [Xie, Bin; Gao, Yuan] Johns Hopkins Univ, Lieber Inst Brain Dev, Div Genom Epigenom & Bioinformat, Baltimore, MD 21205 USA. RP Adelman, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov RI Gao, Yuan/E-1706-2011; OI Gilchrist, Daniel/0000-0003-1668-2790 FU NIH, National Institute of Environmental Health Sciences [Z01 ES101987, ES101765] FX We thank S. Nechaev, T. Kunkel, and G. Hu for critical reading of the manuscript. We acknowledge L. Pederson for production of the NELF-B protein, J. Tucker and the NIEHS microarray core for help with arrays, and S. Dai and J. Grovenstein for computational support. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (grant Z01 ES101987 to K.A. and grant ES101765 to L.L.). D.A.G. and K.A. designed experiments, D.A.G., G.D.S., B.X., and Y.G. performed experiments, D.A.G., D.C.F., L.L., and K.A. performed data analysis, and D.A.G. and K.A. prepared the manuscript. NR 42 TC 175 Z9 176 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD NOV 12 PY 2010 VL 143 IS 4 BP 540 EP 551 DI 10.1016/j.cell.2010.10.004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 679GF UT WOS:000284149100012 PM 21074046 ER PT J AU Khandelwal, S Roche, PA AF Khandelwal, Sanjay Roche, Paul A. TI Distinct MHC Class II Molecules Are Associated on the Dendritic Cell Surface in Cholesterol-dependent Membrane Microdomains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIPID RAFTS; PEPTIDE COMPLEXES; PLASMA-MEMBRANE; TETRASPANIN PROTEINS; ANTIGEN PRESENTATION; T-CELLS; ACTIVATION; CD81; PALMITOYLATION; TRANSPORT AB Very small amounts of MHC class II-peptide complexes expressed on the surface of antigen-presenting cells (APCs) are capable of stimulating antigen-specific CD4 T cells. There is intense interest to elucidate the molecular mechanisms by which these small amounts of MHC-II can cluster, cross-link T cell receptors, and promote T cell proliferation. We now demonstrate that a significant fraction of the total pool of MHC-II molecules on the surface of dendritic cells is physically associated in macromolecular aggregates. These MHC-II/MHC-II interactions have been probed by co-immunoprecipitation analysis of the MHC-II I-A molecule with the related I-E molecule. These molecular associations are maintained in gentle detergents but are disrupted in harsh detergents such as Triton X-100. MHC-II I-A/I-E interactions are disrupted when plasma membrane cholesterol is extracted using methyl beta-cyclodextrin, suggesting that lipid raft microdomains are important mediators of these MHC-II interactions. Although it has been proposed that tetraspanin proteins regulate molecular clustering, aggregation, and co-immunoprecipitation in APCs, genetic deletion of the tetraspanin family members CD9 or CD81 had no effect on MHC-II I-A/I-E binding. These data demonstrate that the presence of distinct forms of MHC-II with plasma membrane lipid rafts is required for MHC-II aggregation in APCs and provides a molecular mechanism allowing dendritic cells expressing small amounts of MHC-II-peptide complexes to cross-link and stimulate CD4 T cells. C1 [Khandelwal, Sanjay; Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Rm 4B36,Bldg 10, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program. NR 50 TC 13 Z9 14 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 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 12 PY 2010 VL 285 IS 46 BP 35303 EP 35310 DI 10.1074/jbc.M110.147793 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675QK UT WOS:000283845300008 PM 20833718 ER PT J AU Foley, JF Singh, SP Cantu, M Chen, LY Zhang, HWH Farber, JM AF Foley, John F. Singh, Satya P. Cantu, Michelle Chen, Lingye Zhang, Hongwei H. Farber, Joshua M. TI Differentiation of Human T Cells Alters Their Repertoire of G Protein alpha-Subunits SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GTP-BINDING-PROTEIN; STIMULATING-HORMONE INCREASES; OPIOID RECEPTOR EXPRESSION; MESSENGER-RNA; SIGNALING PATHWAYS; ADENYLYL-CYCLASE; CALCIUM-CHANNELS; MICE DEFICIENT; SERTOLI CELLS; CUTTING EDGE AB Because T cell differentiation leads to an expanded repertoire of chemokine receptors, a subgroup of G protein-coupled receptors, we hypothesized that the repertoire of G proteins might be altered in parallel. We analyzed the abundance of mRNA and/or protein of six G protein alpha-subunits in human CD4(+) and CD8(+) T cell subsets from blood. Although most G protein alpha-subunits were similarly expressed in all subsets, the abundance of G alpha(o), a protein not previously described in hematopoietic cells, was much higher in memory versus naive cells. Consistent with these data, activation of naive CD4(+) T cells in vitro significantly increased the abundance of G alpha(o) in cells stimulated under nonpolarizing or T(H)17 (but not T(H)1 or T(H)2)-polarizing conditions. In functional studies, the use of a chimeric G protein alpha-subunit, G alpha(qo5), demonstrated that chemokine receptors could couple to G alpha(o)-containing G proteins. We also found that G alpha(i1), another alpha-subunit not described previously in leukocytes, was expressed in naive T cells but virtually absent from memory subsets. Corresponding to their patterns of expression, siRNA-mediated knockdown of G alpha(o) in memory (but not naive) and G alpha(i1) in naive (but not memory) CD4(+) T cells inhibited chemokine-dependent migration. Moreover, although even in G alpha(o)- and G alpha(i1)-expressing cells mRNAs of these alpha-subunits were much less abundant than G alpha(i2) or G alpha(i3), knockdown of any of these subunits impaired chemokine receptor-mediated migration similarly. Together, our data reveal a change in the repertoire of G alpha(i/o) subunits during T cell differentiation and suggest functional equivalence among G alpha(i/o) subunits irrespective of their relative abundance. C1 [Foley, John F.; Singh, Satya P.; Cantu, Michelle; Chen, Lingye; Zhang, Hongwei H.; Farber, Joshua M.] NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Rm 11N112,Bldg 10,MSC 1886,10 Ctr Dr, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov FU National Institutes of Health NIAID FX This work was supported, in whole or in part, by the National Institutes of Health NIAID Intramural Research Program. NR 83 TC 8 Z9 9 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 12 PY 2010 VL 285 IS 46 BP 35537 EP 35550 DI 10.1074/jbc.M110.128033 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675QK UT WOS:000283845300032 PM 20829352 ER PT J AU Keppler, BR Archer, TK AF Keppler, Brian R. Archer, Trevor K. TI Ubiquitin-dependent and Ubiquitin-independent Control of Subunit Stoichiometry in the SWI/SNF Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; HUMAN BREAST-CANCER; PROTEASOMAL DEGRADATION; NUCLEAR RECEPTORS; RHABDOID TUMORS; CELL-LINES; MUTATIONS; INI1; P53; EXPRESSION AB The mammalian SWI/SNF chromatin remodeling complex is a key player in multiple chromatin transactions. Core subunits of this complex, including the ATPase, Brg-1, and various Brg-1-associated factors (BAFs), work in concert to maintain a functional remodeling complex. This intra-complex regulation is supervised by protein-protein interactions, as stoichiometric levels of BAF proteins are maintained by proteasomal degradation. We show that the mechanism of BAF155-mediated stabilization of BAF57 involves blocking its ubiquitination by preventing interaction with TRIP12, an E3 ubiquitin ligase. Consequently, as opposed to complexed BAF57, whose principal lysines are unavailable for ubiquitination, uncomplexed BAF57 can be freely ubiquitinated and degraded by the proteasome. Additionally, a BAF57 mutant, which contains no lysine residues, was found to retain its ability to be stabilized by interaction with BAF155, suggesting that in addition to the ubiquitin-dependent mechanism of BAF57 degradation, there exists a ubiquitin-independent mechanism that may involve the direct interaction of BAF57 with the proteasome. We propose that this regulatory mechanism exists to ensure functional fidelity of the complex and prevent the accumulation of uncomplexed proteins, which may disrupt the normal activity of the complex. C1 [Keppler, Brian R.; Archer, Trevor K.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, MD D4-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov OI Keppler, Bernhard/0000-0003-0877-1822 FU National Institutes of Health [Z01 ES071006-10] FX This work was supported, in whole or in part, by National Institutes of Health Grant Z01 ES071006-10 (Intramural Research Program of the NIEHS). NR 43 TC 12 Z9 15 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 12 PY 2010 VL 285 IS 46 BP 35665 EP 35674 DI 10.1074/jbc.M110.173997 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675QK UT WOS:000283845300045 PM 20829358 ER PT J AU Quintero, OA Moore, JE Unrath, WC Manor, U Salles, FT Grati, M Kachar, B Yengo, CM AF Quintero, Omar A. Moore, Judy E. Unrath, William C. Manor, Uri Salles, Felipe T. Grati, M'hamed Kachar, Bechara Yengo, Christopher M. TI Intermolecular Autophosphorylation Regulates Myosin IIIa Activity and Localization in Parallel Actin Bundles SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE; UNCONVENTIONAL MYOSIN; STRUCTURAL BASIS; ATPASE ACTIVITY; TAIL DOMAIN; CELL-CYCLE; MOTOR; STEREOCILIA; FILOPODIA; MUSCLE AB Myosin IIIa (Myo3A) transports cargo to the distal end of actin protrusions and contains a kinase domain that is thought to autoregulate its activity. Because Myo3A tends to cluster at the tips of actin protrusions, we investigated whether intermolecular phosphorylation could regulate Myo3A biochemical activity, cellular localization, and cellular function. Inactivation of Myo3A 2IQ kinase domain with the point mutation K50R did not alter maximal ATPase activity, whereas phosphorylation of Myo3A 2IQ resulted in reduced maximal ATPase activity and actin affinity. The rate and degree of Myo3A 2IQ autophosphorylation was unchanged by the presence of actin but was found to be dependent upon Myo3A 2IQ concentration within the range of 0.1 to 1.2 mu M, indicating intermolecular autophosphorylation. In cultured cells, we observed that the filopodial tip localization of Myo3A lacking the kinase domain decreased when co-expressed with kinase-active, full-length Myo3A. The cellular consequence of reduced Myo3A tip localization was decreased filopodial density along the cell periphery, identifying a novel cellular function for Myo3A in mediating the formation and stability of actin-based protrusions. Our results suggest that Myo3A motor activity is regulated through a mechanism involving concentration-dependent autophosphorylation. We suggest that this regulatory mechanism plays an essential role in mediating the transport and actin bundle formation/stability functions of Myo3A. C1 [Yengo, Christopher M.] Penn State Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Manor, Uri; Salles, Felipe T.; Grati, M'hamed; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20894 USA. [Moore, Judy E.; Yengo, Christopher M.] Univ N Carolina, Dept Biol, Charlotte, NC 28223 USA. RP Yengo, CM (reprint author), Penn State Coll Med, Dept Cellular & Mol Physiol, 500 Univ Dr, Hershey, PA 17033 USA. EM cmy11@psu.edu RI Grati, M'hamed/C-9563-2011; Salles, Felipe/H-7544-2013; OI Quintero, Omar/0000-0002-9314-1704 FU National Institutes of Health [EY018141, HL093531]; NIH DIR [DC000002-22] FX This work was supported, in whole or in part, by National Institutes of Health Grants EY018141 and HL093531 (to C.M.Y.) and NIH DIR Grant DC000002-22 (to B.K.). NR 46 TC 25 Z9 25 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 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 12 PY 2010 VL 285 IS 46 BP 35770 EP 35782 DI 10.1074/jbc.M110.144360 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675QK UT WOS:000283845300055 PM 20826793 ER PT J AU Wang, QY Shinkre, BA Lee, JG Weniger, MA Liu, YF Chen, WP Wiestner, A Trenkle, WC Ye, YH AF Wang, Qiuyan Shinkre, Bidhan A. Lee, Jin-gu Weniger, Marc A. Liu, Yanfen Chen, Weiping Wiestner, Adrian Trenkle, William C. Ye, Yihong TI The ERAD Inhibitor Eeyarestatin I Is a Bifunctional Compound with a Membrane-Binding Domain and a p97/VCP Inhibitory Group SO PLOS ONE LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; CELL CARCINOMA-CELLS; AAA-ATPASE; PROTEASOME INHIBITORS; RETRO-TRANSLOCATION; MISFOLDED PROTEINS; QUALITY-CONTROL; HEAVY-CHAINS; CANCER-CELLS AB Background: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anticancer activities resembling that of Bortezomib. Methodology and Principal Findings: Here we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI. Conclusions and Significance: Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics. C1 [Wang, Qiuyan; Lee, Jin-gu; Liu, Yanfen; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Weniger, Marc A.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Shinkre, Bidhan A.; Trenkle, William C.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD USA. [Chen, Weiping] NIDDK, Genom Core Lab, NIH, Bethesda, MD USA. RP Wang, QY (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIH; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health; Korean Government [KRF-2008-357-C00103] FX The research is supported by the NIH intramural AIDS Targeted Antiviral Program (IATAP), and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and of the National Heart, Lung, and Blood Institute, National Institutes of Health, and by the Korea Research Foundation Grant funded by the Korean Government [KRF-2008-357-C00103] to J.-G. Lee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 43 Z9 43 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 12 PY 2010 VL 5 IS 11 AR e15479 DI 10.1371/journal.pone.0015479 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679FT UT WOS:000284147700032 PM 21124757 ER PT J AU Rohani, P Zhong, X King, AA AF Rohani, Pejman Zhong, Xue King, Aaron A. TI Contact Network Structure Explains the Changing Epidemiology of Pertussis SO SCIENCE LA English DT Article ID BORDETELLA-PERTUSSIS; VACCINATION PROGRAMS; ADULTS; IMMUNIZATION; RESURGENCE; INFANTS; AGE; ADOLESCENTS; INFECTION; MEASLES AB The epidemiology of whooping cough (pertussis) remains enigmatic. A leading cause of infant mortality globally, its resurgence in several developed nations-despite the availability and use of vaccines for many decades-has caused alarm. We combined data from a singular natural experiment and a detailed contact network study to show that age-specific contact patterns alone can explain shifts in prevalence and age-stratified incidence in the vaccine era. The practical implications of our results are notable: Ignoring age-structured contacts is likely to result in misinterpretation of epidemiological data and potentially costly policy missteps. C1 [Rohani, Pejman; Zhong, Xue; King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman; Zhong, Xue] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Rohani, Pejman; King, Aaron A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rohani, P (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM rohani@umich.edu RI King, Aaron/B-8092-2012 OI King, Aaron/0000-0001-6159-3207 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation FX We thank three anonymous reviewers for comments. P.R. and A.A.K. are supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. P.R. was also supported by the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation. NR 32 TC 85 Z9 87 U1 0 U2 15 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 NOV 12 PY 2010 VL 330 IS 6006 BP 982 EP 985 DI 10.1126/science.1194134 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678XY UT WOS:000284118000048 PM 21071671 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI Eosinophils are in the swim! SO BLOOD LA English DT Editorial Material ID ZEBRAFISH; DISEASE C1 NIAID, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3692 EP + DI 10.1182/blood-2010-09-304345 PG 2 WC Hematology SC Hematology GA 678VM UT WOS:000284110400006 PM 21071614 ER PT J AU Wu, YL Sommers, JA Suhasini, AN Leonard, T Deakyne, JS Mazin, AV Shin-ya, K Kitao, H Brosh, RM AF Wu, Yuliang Sommers, Joshua A. Suhasini, Avvaru N. Leonard, Thomas Deakyne, Julianna S. Mazin, Alexander V. Shin-ya, Kazuo Kitao, Hiroyuki Brosh, Robert M., Jr. TI Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes SO BLOOD LA English DT Article ID SINGLE-STRANDED-DNA; ATP-DEPENDENT TRANSLOCATION; FAMILIAL BREAST-CANCER; HOMOLOGOUS RECOMBINATION; XPD HELICASE; BACH1; BRIP1; BRIP1/BACH1; BRCA1; RISK AB Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, bone marrow failure, and susceptibility to leukemia and other cancers. FANCJ, one of 13 genes linked to FA, encodes a DNA helicase proposed to operate in homologous recombination repair and replicational stress response. The pathogenic FANCJ-A349P amino acid substitution resides immediately adjacent to a highly conserved cysteine of the iron-sulfur domain. Given the genetic linkage of the FANCJ-A349P allele to FA, we investigated the effect of this particular mutation on the biochemical and cellular functions of the FANCJ protein. Purified recombinant FANCJ-A349P protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line as detected by cell survival or gamma-H2AX foci formation. Furthermore, expression of FANCJ-A349P in a wild-type background exerted a dominant-negative effect, indicating that the mutant protein interferes with normal DNA metabolism. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind DNA or destabilize protein bound to DNA is required for its role in DNA repair. (Blood. 2010;116(19):3780-3791) C1 [Wu, Yuliang; Sommers, Joshua A.; Suhasini, Avvaru N.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Leonard, Thomas] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Deakyne, Julianna S.; Mazin, Alexander V.] Drexel Univ, Dept Biochem & Mol Biol, Coll Med, Philadelphia, PA 19104 USA. [Shin-ya, Kazuo] Natl Inst Adv Ind Sci & Technol, Tokyo, Japan. [Kitao, Hiroyuki] Kyoto Univ, Ctr Radiat Biol, Dept Late Effect Studies, Lab DNA Damage Signaling, Kyoto 606, 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 RI Leonard, Thomas/A-5143-2013 OI Leonard, Thomas/0000-0001-6853-666X FU National Institutes of Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases; Fanconi Anemia Research Fund; National Institutes of Health [CA100839]; Leukemia & Lymphoma Society [1054-09] FX This study was supported by the Intramural Research program of the National Institutes of Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases, the Fanconi Anemia Research Fund (R.M.B.), National Institutes of Health grant CA100839 (A.V.M.), and the Leukemia & Lymphoma Society Scholar Award 1054-09 (A.V.M.). NR 40 TC 30 Z9 32 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3780 EP 3791 DI 10.1182/blood-2009-11-256016 PG 12 WC Hematology SC Hematology GA 678VM UT WOS:000284110400018 PM 20639400 ER PT J AU Valeri, VW Hryniewicz, A Andresen, V Jones, K Fenizia, C Bialuk, I Chung, HK Fukumoto, R Parks, RW Ferrari, MG Nicot, C Cecchinato, V Ruscetti, F Franchini, G AF Valeri, Valerio W. Hryniewicz, Anna Andresen, Vibeke Jones, Kathy Fenizia, Claudio Bialuk, Izabela Chung, Hye Kyung Fukumoto, Risaku Parks, Robyn Washington Ferrari, Maria Grazia Nicot, Christophe Cecchinato, Valentina Ruscetti, Frank Franchini, Genoveffa TI Requirement of the human T-cell leukemia virus p12 and p30 products for infectivity of human dendritic cells and macaques but not rabbits SO BLOOD LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; PERSISTENCE IN-VIVO; READING FRAME II; TYPE-1 P12(I); HTLV-I; LYMPHOCYTE-PROLIFERATION; VIRAL TRANSCRIPTION; NUCLEAR FACTOR; PROTEIN; ACTIVATION AB The identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wildtype genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species. (Blood. 2010;116(19):3809-3817) C1 [Valeri, Valerio W.; Hryniewicz, Anna; Andresen, Vibeke; Fenizia, Claudio; Bialuk, Izabela; Fukumoto, Risaku; Parks, Robyn Washington; Cecchinato, Valentina; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [Jones, Kathy] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Chung, Hye Kyung; Ferrari, Maria Grazia] Adv BioSci Labs Inc, Kensington, MD USA. [Nicot, Christophe] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Ruscetti, Frank] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, 9000 Rockville Pike,41-D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU National Cancer Institute, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Program at the National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 51 TC 38 Z9 39 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3809 EP 3817 DI 10.1182/blood-2010-05-284141 PG 9 WC Hematology SC Hematology GA 678VM UT WOS:000284110400021 PM 20647569 ER PT J AU Antonelli, LRV Mahnke, Y Hodge, JN Porter, BO Barber, DL DerSimonian, R Greenwald, JH Roby, G Mican, J Sher, A Roederer, M Sereti, I AF Antonelli, Lis R. V. Mahnke, Yolanda Hodge, Jessica N. Porter, Brian O. Barber, Daniel L. DerSimonian, Rebecca Greenwald, Jamieson H. Roby, Gregg Mican, JoAnn Sher, Alan Roederer, Mario Sereti, Irini TI Elevated frequencies of highly activated CD4(+) T cells in HIV+ patients developing immune reconstitution inflammatory syndrome SO BLOOD LA English DT Article ID CHRONIC VIRAL-INFECTION; VERSUS-HOST-DISEASE; ANTIRETROVIRAL THERAPY; RESTORATION SYNDROME; RISK-FACTORS; HOMEOSTASIS; TUBERCULOSIS; PROLIFERATION; EXHAUSTION; INTERLEUKIN-7 AB Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of anti-retroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1(+), HLA-DR+, and Ki67(+) CD4(+) T cells than patients without IRIS. Moreover, PD-1(+) CD4(+) T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-gamma, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767. (Blood. 2010;116(19):3818-3827) C1 [Hodge, Jessica N.; Porter, Brian O.; Greenwald, Jamieson H.; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Antonelli, Lis R. V.; Barber, Daniel L.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mahnke, Yolanda; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [DerSimonian, Rebecca; Roby, Gregg; Mican, JoAnn] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Magnuson Clin Ctr,Rm 11B07A,10 Ctr Dr, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Vacinas, Inct/J-9431-2013; Antonelli, Lis/G-2907-2012 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was funded through the intramural research program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD) and, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 44 TC 81 Z9 83 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3818 EP 3827 DI 10.1182/blood-2010-05-285080 PG 10 WC Hematology SC Hematology GA 678VM UT WOS:000284110400022 PM 20660788 ER PT J AU Sabado, RL O'Brien, M Subedi, A Qin, L Hu, N Taylor, E Dibben, O Stacey, A Fellay, J Shianna, KV Siegal, F Shodell, M Shah, K Larsson, M Lifson, J Nadas, A Marmor, M Hutt, R Margolis, D Garmon, D Markowitz, M Valentine, F Borrow, P Bhardwaj, N AF Sabado, Rachel Lubong O'Brien, Meagan Subedi, Abhignya Qin, Li Hu, Nan Taylor, Elizabeth Dibben, Oliver Stacey, Andrea Fellay, Jacques Shianna, Kevin V. Siegal, Frederick Shodell, Michael Shah, Kokila Larsson, Marie Lifson, Jeffrey Nadas, Arthur Marmor, Michael Hutt, Richard Margolis, David Garmon, Donald Markowitz, Martin Valentine, Fred Borrow, Persephone Bhardwaj, Nina TI Evidence of dysregulation of dendritic cells in primary HIV infection SO BLOOD LA English DT Article ID I INTERFERON-PRODUCTION; VIRUS TYPE-1 INFECTION; ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; HIV-1-INFECTED PATIENTS; LYMPHOID-TISSUE; BLOOD; EXPRESSION; INDIVIDUALS; MATURATION AB Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation. (Blood. 2010;116(19):3839-3852) C1 [Sabado, Rachel Lubong; O'Brien, Meagan; Subedi, Abhignya; Bhardwaj, Nina] NYU, Inst Canc, Sch Med, New York, NY 10003 USA. [Sabado, Rachel Lubong; O'Brien, Meagan; Subedi, Abhignya; Qin, Li; Hu, Nan; Taylor, Elizabeth; Dibben, Oliver; Stacey, Andrea; Fellay, Jacques; Shianna, Kevin V.; Margolis, David; Garmon, Donald; Markowitz, Martin; Borrow, Persephone; Bhardwaj, Nina] NIAID, CHAVI, Bethesda, MD 20892 USA. [Qin, Li; Hu, Nan; Borrow, Persephone] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98104 USA. [Taylor, Elizabeth; Dibben, Oliver; Stacey, Andrea] Univ Oxford, Jenner Inst, Newbury, Berks, England. [Fellay, Jacques; Shianna, Kevin V.] Duke Univ, Ctr Human Genome Variat, Durham, NC USA. [Siegal, Frederick; Shodell, Michael; Shah, Kokila] St Vincent Catholic Med Ctr, New York, NY USA. [Larsson, Marie] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Lifson, Jeffrey] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Nadas, Arthur; Marmor, Michael] NYU, Dept Environm Med, New York, NY 10016 USA. [Marmor, Michael; Hutt, Richard; Valentine, Fred] NYU, Ctr HIV AIDS Res, New York, NY USA. [Margolis, David] Univ N Carolina, Chapel Hill, NC USA. [Marmor, Michael; Hutt, Richard; Valentine, Fred] NYU, Dept Med, New York, NY 10016 USA. [Garmon, Donald; Markowitz, Martin] Aaron Diamond AIDS Res Ctr, New York, NY USA. RP Bhardwaj, N (reprint author), NYU, Inst Canc, Sch Med, 522 1st Ave SML 1307, New York, NY 10003 USA. EM Nina.bhardwaj@nyumc.org RI Fellay, Jacques/A-6681-2009; OI Fellay, Jacques/0000-0002-8240-939X; Valentine, Fred/0000-0002-6046-5913; Marmor, Michael/0000-0001-6605-2661; Margolis, David/0000-0001-5714-0002 FU NIAID Center for HIV/AIDS Vaccine Immunology [AI067854]; NYU CFAR [P30AI027742]; Elizabeth Glaser Pediatric AIDS Foundation; Bill and Melinda Gates Foundation; Doris Duke Charitable Foundation; Emerald Foundation; National Institutes of Health (NIH) [AI057127, AI044628, AI061684]; Senior Jenner Fellowship FX This work has been supported by grants through: NIAID Center for HIV/AIDS Vaccine Immunology grant AI067854, NYU CFAR grant P30AI027742, Elizabeth Glaser Pediatric AIDS Foundation, the Bill and Melinda Gates Foundation, the Doris Duke Charitable Foundation, the Emerald Foundation, and National Institutes of Health (NIH) grant nos. AI057127, AI044628, and AI061684. P. B. is a Jenner Institute Investigator and received salary support from a Senior Jenner Fellowship. NR 49 TC 95 Z9 95 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3839 EP 3852 DI 10.1182/blood-2010-03-273763 PG 14 WC Hematology SC Hematology GA 678VM UT WOS:000284110400024 PM 20693428 ER PT J AU Kochenderfer, JN Yu, ZY Frasheri, D Restifo, NP Rosenberg, SA AF Kochenderfer, James N. Yu, Zhiya Frasheri, Dorina Restifo, Nicholas P. Rosenberg, Steven A. TI Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells SO BLOOD LA English DT Article ID ANTITUMOR-ACTIVITY; IN-VIVO; ENHANCED SURVIVAL; REGULATORY-CELLS; IMMUNOTHERAPY; LYMPHOCYTES; ANTIBODY; EXPRESSION; GENE; EFFICACY AB Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)-expressing T cells is a new approach for treating advanced B-cell malignancies. To evaluate anti-CD19-CAR-transduced T cells in a murine model of adoptive T-cell therapy, we developed a CAR that specifically recognized murine CD19. We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19. One infusion of anti-CD19-CAR-transduced T cells completely eliminated normal B cells from mice for at least 143 days. Anti-CD19- CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses. The antilymphoma efficacy of anti-CD19-CAR-transduced T cells was critically dependent on irradiation of mice before anti-CD19-CAR-transduced T-cell infusion. Anti-CD19-CAR- transduced T cells had superior antilymphoma efficacy compared with the anti-CD19 monoclonal antibody from which the anti-CD19 CAR was derived. Our results demonstrated impressive antilymphoma activity and profound destruction of normal B cells caused by anti-CD19-CAR-transduced T cells in a clinically relevant murine model. (Blood. 2010; 116(19):3875-3886) C1 [Kochenderfer, James N.; Yu, Zhiya; Frasheri, Dorina; Restifo, Nicholas P.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Kochenderfer, JN (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,CRC Rm 3-3888, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Center for Cancer Research, National Cancer Institute, National Institutes of Health (intramural funding). NR 52 TC 82 Z9 85 U1 2 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 11 PY 2010 VL 116 IS 19 BP 3875 EP 3886 DI 10.1182/blood-2010-01-265041 PG 12 WC Hematology SC Hematology GA 678VM UT WOS:000284110400027 PM 20631379 ER PT J AU Hajjo, R Grulke, CM Golbraikh, A Setola, V Huang, XP Roth, BL Tropsha, A AF Hajjo, Rima Grulke, Christopher M. Golbraikh, Alexander Setola, Vincent Huang, Xi-Ping Roth, Bryan L. Tropsha, Alexander TI Development, Validation, and Use of Quantitative Structure-Activity Relationship Models of 5-Hydroxytryptamine (2B) Receptor Ligands to Identify Novel Receptor Binders and Putative Valvulopathic Compounds among Common Drugs SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID VALVULAR HEART-DISEASE; DOPAMINE AGONISTS; PARKINSONS-DISEASE; MOLECULAR GRAPHS; ELECTROTOPOLOGICAL STATE; CARDIAC VALVULOPATHY; COMBINATORIAL QSAR; 5-HT2B RECEPTORS; SEROTONIN; INDEX AB Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT(2B) receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT(2B) actives. The classification accuracies of the models built to discriminate 5-HT(2B) actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59 000 compounds included in the World Drug Index, and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active, suggesting a success rate of 90%. All validated actives were then tested in functional assays, and one compound was identified as a true 5-HT(2B) agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy. C1 [Hajjo, Rima; Grulke, Christopher M.; Golbraikh, Alexander; Roth, Bryan L.; Tropsha, Alexander] Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Tropsha, A (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. EM alex_tropsha@unc.edu RI Roth, Bryan/F-3928-2010; Tropsha, Alexander/G-6245-2014 FU NIH [GM066940, HG003898, U19MH82441]; University of Jordan scholarship; [ROIMH61887] FX We are grateful to Dr. Steve Marron for providing us with the DWD program and to Drs. Weifan Zheng and Raed Khashan for developing the SG descriptors and for helpful discussions. We thank Tripos, Chemical Computing Group, and eduSoft for software grants. We also thank Xin Chin from the Center for Integrative Chemical Biology and Drug Discovery at UNC-Chapel Hill, NC, for performing the purity control tests. Finally, we acknowledge the access to the computing facilities at the ITS Research Computing Division of the University of North Carolina at Chapel Hill. The studies reported in this paper were supported in part by the NIH Research Grant GM066940 and the Planning Grant HG003898 (awarded to A.T.); Grant ROIMH61887 and NIH Contract U19MH82441, supporting the NIMH Psychoactive Drug Screening Program (awarded to B.L.R.); and the University of Jordan scholarship (awarded to R.H.). NR 90 TC 20 Z9 20 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD NOV 11 PY 2010 VL 53 IS 21 BP 7573 EP 7586 DI 10.1021/jm100600y PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 673ZP UT WOS:000283703000007 PM 20958049 ER PT J AU Lee, CH AF Lee, Chi-Hon TI NEUROSCIENCE The split view of motion SO NATURE LA English DT Editorial Material ID DROSOPHILA-MELANOGASTER; VISUAL-SYSTEM C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov RI Lee, Chi-Hon/G-9190-2012 FU Intramural NIH HHS [ZIA HD008776-05] NR 12 TC 3 Z9 3 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD NOV 11 PY 2010 VL 468 IS 7321 BP 178 EP 179 DI 10.1038/468178a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678DG UT WOS:000284051000029 PM 21068820 ER PT J AU Insel, TR AF Insel, Thomas R. TI Rethinking schizophrenia SO NATURE LA English DT Article ID CHILDHOOD-ONSET SCHIZOPHRENIA; 22Q11 DELETION SYNDROME; 2-YEAR FOLLOW-UP; ULTRA-HIGH RISK; PSYCHOTIC DISORDERS; PREFRONTAL CORTEX; OBSTETRIC COMPLICATIONS; PSYCHIATRIC-DISORDERS; ADULT SCHIZOPHRENIA; PRENATAL EXPOSURE AB How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades. C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 99 TC 495 Z9 510 U1 20 U2 150 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD NOV 11 PY 2010 VL 468 IS 7321 BP 187 EP 193 DI 10.1038/nature09552 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678DG UT WOS:000284051000034 PM 21068826 ER PT J AU Balasubbu, S Sundaresan, P Rajendran, A Ramasamy, K Govindarajan, G Perumalsamy, N Hejtmancik, JF AF Balasubbu, Suganthalakshmi Sundaresan, Periasamy Rajendran, Anand Ramasamy, Kim Govindarajan, Gowthaman Perumalsamy, Namperumalsamy Hejtmancik, J. Fielding TI Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy SO BMC MEDICAL GENETICS LA English DT Article ID GLYCATION END-PRODUCTS; MACULAR DEGENERATION; RAGE GENE; ADVANCED GLYCOSYLATION; PROMOTER POLYMORPHISM; GLY82SER POLYMORPHISM; SUSCEPTIBILITY GENES; EXFOLIATION GLAUCOMA; JAPANESE POPULATION; ENOS GENE AB Background: Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM). It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM). Methods: Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. Results: Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied. Conclusions: This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM. C1 [Balasubbu, Suganthalakshmi; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Balasubbu, Suganthalakshmi; Sundaresan, Periasamy; Govindarajan, Gowthaman] Aravind Eye Hosp, Aravind Med Res Fdn, Dr G Venkataswamy Eye Res Inst, Madurai 625020, Tamil Nadu, India. [Rajendran, Anand; Ramasamy, Kim; Perumalsamy, Namperumalsamy] Aravind Eye Hosp, Retina Clin, Madurai 625020, Tamil Nadu, India. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Rockville, MD 20852 USA. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov FU National Eye Institute, NIH; TIFAC-CORE in Diabetic Retinopathy; Counsil of Scientific and Industrial Research FX The authors like to thank all the participants for their kind cooperation in this study. The authors also acknowledge the support extended by the National Eye Institute, NIH for providing pre-doctoral fellowship, TIFAC-CORE in Diabetic Retinopathy and Counsil of Scientific and Industrial Research for technical and financial support. We thank Dr. VR. Muthukkaruppan, director of research, Aravind Medical Research Foundation, for providing valuable suggestions; we also thank Dr. G. Kumaramanickavel, advisor of research in Narayana Nethralaya, Bangalore and Aditya Jyot Eye Hospital, Mumbai and Dr S Uthra for their help with the combined analysis, providing valuable suggestions and reviewing the manuscript. Finally we would like to thank Dr. S. Senthilkumari for a close reading of the manuscript and Drs. S. Daiger (UTHSC, Houston) and Lijia Chen ( Chinese University of Hong Kong) for helpful discussions regarding inverse association and VR. Muthulakshmi, T. P. Vasanthi, A. Gomathy, D. Muthuselvi for their help in samples collection. NR 41 TC 43 Z9 45 U1 1 U2 7 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 NOV 10 PY 2010 VL 11 AR 158 DI 10.1186/1471-2350-11-158 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 687DU UT WOS:000284757000001 PM 21067572 ER PT J AU Cooper, PS Lipshultz, D Matten, WT McGinnis, SD Pechous, S Romiti, ML Tao, T Valjavec-Gratian, M Sayers, EW AF Cooper, Peter S. Lipshultz, Dawn Matten, Wayne T. McGinnis, Scott D. Pechous, Steven Romiti, Monica L. Tao, Tao Valjavec-Gratian, Majda Sayers, Eric W. TI Education resources of the National Center for Biotechnology Information SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE Bioinformatics; education; tutorials; NCBI; databases; GenBank ID TUTORIAL AB The National Center for Biotechnology Information (NCBI) hosts 39 literature and molecular biology databases containing almost half a billion records. As the complexity of these data and associated resources and tools continues to expand, so does the need for educational resources to help investigators, clinicians, information specialists and the general public make use of the wealth of public data available at the NCBI. This review describes the educational resources available at NCBI via the NCBI Education page (www.ncbi.nlm.nih.gov/Education). These resources include materials designed for new users, such as About NCBI and the NCBI Guide, as well as documentation, Frequently Asked Questions (FAQs) and writings on the NCBI Bookshelf such as the NCBI Help Manual and the NCBI Handbook. NCBI also provides teaching materials such as tutorials, problem sets and educational tools such as the Amino Acid Explorer, PSSM Viewer and Ebot. NCBI also offers training programs including the Discovery Workshops, webinars and tutorials at conferences. To help users keep up-to-date, NCBI produces the online NCBI News and offers RSS feeds and mailing lists, along with a presence on Facebook, Twitter and YouTube. C1 [Cooper, Peter S.] NCBI NLM NIH, Bethesda, MD 20892 USA. RP Cooper, PS (reprint author), NCBI NLM NIH, 45 Ctr Dr, Bethesda, MD 20892 USA. EM cooper@ncbi.nlm.nih.gov FU National Institutes of Health; National Library of Medicine FX Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 4 TC 10 Z9 12 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD NOV 10 PY 2010 VL 11 IS 6 SI SI BP 563 EP 569 DI 10.1093/bib/bbq022 PG 7 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 682VC UT WOS:000284430100005 PM 20570844 ER PT J AU Frieden, TR Collins, FS AF Frieden, Thomas R. Collins, Francis S. TI Intentional Infection of Vulnerable Populations in 1946-1948 Another Tragic History Lesson SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Frieden, Thomas R.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Frieden, TR (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS D-14, Atlanta, GA 30333 USA. EM txf2@cdc.gov NR 8 TC 13 Z9 13 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 10 PY 2010 VL 304 IS 18 BP 2063 EP 2064 DI 10.1001/jama.2010.1554 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 677OB UT WOS:000284000600028 PM 20937719 ER PT J AU Quirk, GJ Pare, D Richardson, R Herry, C Monfils, MH Schiller, D Vicentic, A AF Quirk, Gregory J. Pare, Denis Richardson, Rick Herry, Cyril Monfils, Marie H. Schiller, Daniela Vicentic, Aleksandra TI Erasing Fear Memories with Extinction Training SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CYCLOSERINE FACILITATES EXTINCTION; CONDITIONED FEAR; PREFRONTAL CORTEX; PERINEURONAL NETS; AMYGDALA DEPOTENTIATION; IMMEDIATE EXTINCTION; POTENTIATED STARTLE; VISUAL-CORTEX; RECONSOLIDATION; MECHANISMS AB Decades of behavioral studies have confirmed that extinction does not erase classically conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. This symposium focuses on several of these new developments, which involve the timing of extinction training. Extinction-induced erasure of fear occurs in very young rats, but is lost with the development of perineuronal nets in the amygdala that render fear memories impervious to extinction. Moreover, extinction administered during the reconsolidation phase, when fear memory is destabilized, updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. The use of modified extinction protocols to eliminate fear memories complements existing pharmacological strategies for strengthening extinction. C1 [Quirk, Gregory J.] Univ Puerto Rico, Sch Med, Dept Psychiat, San Juan, PR 00936 USA. [Quirk, Gregory J.] Univ Puerto Rico, Sch Med, Dept Anat & Neurobiol, San Juan, PR 00936 USA. [Pare, Denis] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. [Richardson, Rick] Univ New S Wales, Sch Psychol, Sydney, NSW 2052, Australia. [Herry, Cyril] INSERM, U862, Neuroctr Magendie, F-33077 Bordeaux, France. [Monfils, Marie H.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Schiller, Daniela] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Vicentic, Aleksandra] NIMH, Rockville, MD 20852 USA. RP Quirk, GJ (reprint author), Univ Puerto Rico, Sch Med, Dept Psychiat, POB 365067, San Juan, PR 00936 USA. EM gjquirk@yahoo.com RI Monfils, Marie/F-1282-2013; OI Richardson, Rick/0000-0003-1833-9777; Monfils, Marie-H./0000-0001-8971-6651 FU NIMH NIH HHS [P50 MH086400, R01 MH058883, R01 MH081975, R01 MH091147] NR 69 TC 92 Z9 93 U1 9 U2 44 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 10 PY 2010 VL 30 IS 45 BP 14993 EP 14997 DI 10.1523/JNEUROSCI.4268-10.2010 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 678QY UT WOS:000284096300013 PM 21068303 ER PT J AU Baganz, N Horton, R Martin, K Holmes, A Daws, LC AF Baganz, Nicole Horton, Rebecca Martin, Kathryn Holmes, Andrew Daws, Lynette C. TI Repeated Swim Impairs Serotonin Clearance via a Corticosterone-Sensitive Mechanism: Organic Cation Transporter 3, the Smoking Gun SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HIGH-SPEED CHRONOAMPEROMETRY; DEPRESSION-LIKE BEHAVIOR; KNOCKOUT MICE; RAT-BRAIN; HIPPOCAMPAL SEROTONIN; MONOAMINE TRANSPORTER; IN-VIVO; QUANTITATIVE AUTORADIOGRAPHY; EXTRACELLULAR SEROTONIN; MEDIAL HYPOTHALAMUS AB Activation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with increased extracellular serotonin (5-HT) in limbic brain regions. The mechanism through which this occurs remains unclear. One way could be via HPA axis-dependent impairment of serotonin transporter (SERT) function, the high-affinity uptake mechanism for 5-HT. Consistent with this idea, we found that 5-HT clearance rate in hippocampus was dramatically reduced in mice exposed to repeated swim, a stimulus known to activate the HPA axis. However, this phenomenon also occurred in mice lacking SERT, ruling out SERT as a mechanism. The organic cation transporter 3 (OCT3) is emerging as an important regulator of brain 5-HT. Moreover, corticosterone, which is released upon HPA axis activation, blocks 5-HT uptake by OCT3. Repeated swim produced a persistent elevation in plasma corticosterone, and, consistent with prolonged blockade by corticosterone, we found that OCT3 expression and function were reduced in these mice. Importantly, this effect of repeated swim to reduce 5-HT clearance rate was corticosterone dependent, as evidenced by its absence in adrenalectomized mice, in which plasma corticosterone levels were essentially undetectable. Behaviorally, mice subjected to repeated swim spent less time immobile in the tail suspension test than control mice, but responded similarly to SERT- and norepinephrine transporter-selective antidepressants. Together, these results show that reduced 5-HT clearance following HPA axis activation is likely mediated, at least in part, by the corticosterone-sensitive OCT3, and that drugs developed to selectively target OCT3 (unlike corticosterone) may be candidates for the development of novel antidepressant medications. C1 [Baganz, Nicole; Horton, Rebecca; Daws, Lynette C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Daws, Lynette C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Martin, Kathryn; Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Daws, LC (reprint author), 7703 Floyd Curl Dr,MC7756, San Antonio, TX 78229 USA. EM daws@uthscsa.edu FU National Institutes of Health [R01-MH64489]; National Alliance for Research on Schizophrenia and Depression; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by National Institutes of Health Grant R01-MH64489 (L.C.D.), a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (L.C.D.), and National Institute on Alcohol Abuse and Alcoholism intramural research program (A.H.). We thank Drs. Randy Blakely, Ana Carneiro, Georgianna Gould, Julie Hensler, Wouter Koek, and Glenn Toney for helpful discussions. We also thank Teri Frosto-Burke, Jaclyn Munn, David Aguilar, and Steven Alvarado for excellent technical assistance. NR 78 TC 30 Z9 30 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 10 PY 2010 VL 30 IS 45 BP 15185 EP 15195 DI 10.1523/JNEUROSCI.2740-10.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 678QY UT WOS:000284096300034 PM 21068324 ER PT J AU Grishaev, A Guo, LA Irving, T Bax, A AF Grishaev, Alexander Guo, Liang Irving, Thomas Bax, Ad TI Improved Fitting of Solution X-ray Scattering Data to Macromolecular Structures and Structural Ensembles by Explicit Water Modeling SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEIN-STRUCTURE; BIOLOGICAL MACROMOLECULES; NMR; REFINEMENT; RESOLUTION; DYNAMICS; CRYSTALLOGRAPHY; LYSOZYME; ANGSTROM; COMPLEX AB A new procedure, AXES, is introduced for fitting small-angle X-ray scattering (SAXS) data to macromolecular structures and ensembles of structures. By using explicit water models to account for the effect of solvent, and by restricting the adjustable fitting parameters to those that dominate experimental uncertainties, including sample/buffer rescaling, detector dark current, and, within a narrow range, hydration layer density, superior fits between experimental high resolution structures and SAXS data are obtained. AXES results are found to be more discriminating than standard Crysol fitting of SAXS data when evaluating poorly or incorrectly modeled protein structures. AXES results for ensembles of structures previously generated for ubiquitin show improved fits over fitting of the individual members of these ensembles, indicating these ensembles capture the dynamic behavior of proteins in solution. C1 [Grishaev, Alexander; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Guo, Liang; Irving, Thomas] IIT, Biophys Collaborat Access Team, CSRRI, BCPS Dept, Chicago, IL 60616 USA. RP Grishaev, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM AlexanderG@intra.niddk.nih.gov; bax@nih.gov RI ID, BioCAT/D-2459-2012 FU NIDDK, NIH; Office of the Director, NIH; U.S. Department of Energy [W-31-109-ENG-38]; BioCAT Research Center; NIH [RR-08630]; NCI, NIH [PUP-77]; Argonne National Laboratory [PUP-77] FX We thank Gerhard Hummer for helpful discussions, Yang Shen for the Rosetta models of GB3, and Frank Delaglio for assistance with webserver implementation of AXES. This work was supported by the Intramural Research Program of the NIDDK, NIH, and by the Intramural Antiviral Target Program of the Office of the Director, NIH. We gratefully acknowledge use of the Advanced Photon Source, supported by the U.S. Department of Energy, Contract No. W-31-109-ENG-38, the BioCAT Research Center, supported by the NIH, RR-08630, and the shared scattering beamline resource allocated under the PUP-77 agreement between the NCI, NIH, and the Argonne National Laboratory. NR 25 TC 55 Z9 57 U1 3 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 10 PY 2010 VL 132 IS 44 BP 15484 EP 15486 DI 10.1021/ja106173n PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 676YL UT WOS:000283955600009 PM 20958032 ER PT J AU Nakashima, H Fujisawa, T Husain, SR Puri, RK AF Nakashima, Hideyuki Fujisawa, Toshio Husain, Syed R. Puri, Raj K. TI Interleukin-13 receptor alpha 2 DNA prime boost vaccine induces tumor immunity in murine tumor models SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID THERAPEUTIC CANCER VACCINES; REGULATORY T-CELLS; IL-13 RECEPTOR; FUNCTIONAL-CHARACTERIZATION; PSEUDOMONAS EXOTOXIN; MAMMARY-TUMOR; CLASS-II; IN-VIVO; PROTEIN; CHAIN AB Background: DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13 receptor alpha 2 chain (IL-13R alpha 2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13R alpha 2 are expressed on a variety of human tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-13R alpha 2 (ECD alpha 2) as a protein-boost against murine tumor models. Methods: We have developed murine models of tumors naturally expressing IL-13R alpha 2 (MCA304 sarcoma, 4T1 breast carcinoma) and D5 melanoma tumors transfected with human IL-13R alpha 2 in syngeneic mice and examined the antitumor activity of DNA vaccine expressing IL-13R alpha 2 gene with or without ECD alpha 2 protein mixed with CpG and IFA adjuvants as a boost vaccine. Results: Mice receiving IL-13R alpha 2 DNA vaccine boosted with ECD alpha 2 protein were superior in exhibiting inhibition of tumor growth, compared to mice receiving DNA vaccine alone, in both prophylactic and therapeutic vaccine settings. In addition, prime-boost vaccination significantly prolonged the survival of mice compared to DNA vaccine alone. Furthermore, ECD alpha 2 booster vaccination increased IFN-gamma production and CTL activity against tumor expressing IL-13R alpha 2. The immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and IFN-gamma-induced chemokines (CXCL9 and CXCL10) in regressing tumors of immunized mice. Finally, the prime boost strategy was able to reduce immunosuppressive CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) in the spleen and tumor of vaccinated mice. Conclusion: These results suggest that immunization with IL-13R alpha 2 DNA vaccine followed by ECD alpha 2 boost mixed with CpG and IFA adjuvants inhibits tumor growth in T cell dependent manner. Thus our results show an enhancement of efficacy of IL-13R alpha 2 DNA vaccine with ECD alpha 2 protein boost and offers an exciting approach in the development of new DNA vaccine targeting IL-13R alpha 2 for cancer immunotherapy. C1 [Nakashima, Hideyuki; Fujisawa, Toshio; Husain, Syed R.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN20,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov NR 44 TC 9 Z9 10 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 10 PY 2010 VL 8 AR 116 DI 10.1186/1479-5876-8-116 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 686NH UT WOS:000284702500001 PM 21067607 ER PT J AU Kofinger, J Dellago, C AF Koefinger, Juergen Dellago, Christoph TI Microscopic properties of nanopore water from its time-dependent dielectric response SO PHYSICAL REVIEW B LA English DT Article ID CARBON NANOTUBE MEMBRANES; BORON-NITRIDE NANOTUBE; PROTON CONDUCTION; MASS-TRANSPORT; ISING-MODEL; DYNAMICS; CHANNEL; PERMEATION; SIMULATION; AQUAPORIN-1 AB We present a simple kinetic model for the orientational dynamics of a chain of hydrogen-bonded molecules due to the diffusion of orientational defects. We derive an event-driven algorithm which allows us to do kinetic simulations for chains from nanoscopic to macroscopic lengths, spanning huge orders of magnitude in time. Our simulations and analytical calculations show that nanopore water exhibits Debye behavior arising from the diffusive dynamics of orientational defects. For the limits of short and long chains we derive analytical expressions for the relaxation times which allow to extract the diffusion constant, the effective interaction, and the excitation energy of these defects from dielectric spectroscopy experiments. We also discuss the possibility to use such experiments to detect if the two possible kinds of orientational defects differ in excitation energy and diffusion constant. C1 [Koefinger, Juergen] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. RP Kofinger, J (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Dellago, Christoph/E-1625-2011 FU Austrian Science Fund (FWF) [P20942-N16, W004]; University of Vienna through the Focus Research Area Materials Science; NIDDK; NIH FX We thank Gerhard Hummer and Attila Szabo for useful discussions. We acknowledge support from the Austrian Science Fund (FWF) under Grants No. P20942-N16 and No. W004, and from the University of Vienna through the Focus Research Area Materials Science. J.K. was also supported by the Intramural Research Program of the NIDDK, NIH. Part of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md, (http://biowulf.nih.gov) and of the Vienna Scientific Cluster (VSC). NR 53 TC 4 Z9 4 U1 2 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 J9 PHYS REV B JI Phys. Rev. B PD NOV 10 PY 2010 VL 82 IS 20 AR 205416 DI 10.1103/PhysRevB.82.205416 PG 14 WC Physics, Condensed Matter SC Physics GA 678CS UT WOS:000284047800013 ER PT J AU Im, YJ Kuo, L Ren, XF Burgos, PV Zhao, XZ Liu, F Burke, TR Bonifacino, JS Freed, EO Hurley, JH AF Im, Young Jun Kuo, Lillian Ren, Xuefeng Burgos, Patricia V. Zhao, Xue Zhi Liu, Fa Burke, Terrence R., Jr. Bonifacino, Juan S. Freed, Eric O. Hurley, James H. TI Crystallographic and Functional Analysis of the ESCRT-I/HIV-1 Gag PTAP Interaction SO STRUCTURE LA English DT Article ID TSG101 UEV DOMAIN; TRANSPORT ESCRT-I; ENDOSOMAL TRAFFICKING; PARTICLE-PRODUCTION; PEPTIDE MOTIFS; PROTEIN; COMPLEX; MUTATIONS; MACHINERY; UBIQUITIN AB Budding of HIV-1 requires the binding of the PTAP late domain of the Gag p6 protein to the UEV domain of the TSG101 subunit of ESCRT-I. The normal function of this motif in cells is in receptor downregulation. Here, we report the 1.4-1.6 angstrom structures of the human TSG101 UEV domain alone and with wild-type and mutant HIV-1 PTAP and Hrs PSAP nonapeptides. The hydroxyl of the Thr or Ser residue in the P(S/T)AP motif hydrogen bonds with the main chain of Asn69. Mutation of the Asn to Pro, blocking the main-chain amide, abrogates PTAP motif binding in vitro and blocks budding of HIV-1 from cells. N69P and other PTAP binding-deficient alleles of TSG101 did not rescue HIV-1 budding. However, the mutant alleles did rescue downregulation of endogenous EGF receptor. This demonstrates that the PSAP motif is not rate determining in EGF receptor downregulation under normal conditions. C1 [Im, Young Jun; Ren, Xuefeng; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kuo, Lillian; Freed, Eric O.] NCI, HIV Drug Resistance Program, CCR, Frederick, MD 21702 USA. [Burgos, Patricia V.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Zhao, Xue Zhi; Liu, Fa; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, CCR, Frederick, MD 21702 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014; OI Zhao, Xue Zhi/0000-0003-1006-6364; Bonifacino, Juan S./0000-0002-5673-6370 FU NCI [Y1-CO-1020]; NIGMS [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; NIDDK; NCI; NICHD; NIH FX We thank M. Stewart for technical assistance, W. Sundquist for the siRNA-resistant TSG101 expression vector, J. Schlessinger for an antibody, and G. Mardones for discussions. GM/CA CAT has been funded in whole or in part with federal funds from the NCI (Y1-CO-1020) and the NIGMS (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. This work was supported by the NIDDK, NCI, NICHD, and IATAP programs of the NIH intramural research program. Y.J.I. and X.R. were supported in part by NIH Intramural AIDS Research Fellowships. NR 47 TC 27 Z9 28 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD NOV 10 PY 2010 VL 18 IS 11 BP 1536 EP 1547 DI 10.1016/j.str.2010.08.010 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 682XA UT WOS:000284435100017 PM 21070952 ER PT J AU Tycko, R Savtchenko, R Ostapchenko, VG Makarava, N Baskakov, IV AF Tycko, Robert Savtchenko, Regina Ostapchenko, Valeriy G. Makarava, Natallia Baskakov, Ilia V. TI The alpha-Helical C-Terminal Domain of Full-Length Recombinant PrP Converts to an In-Register Parallel beta-Sheet Structure in PrP Fibrils: Evidence from Solid State Nuclear Magnetic Resonance SO BIOCHEMISTRY LA English DT Article ID HUMAN PRION PROTEIN; AMYLOID FIBRILS; PHYSICAL-PROPERTIES; MOLECULAR-STRUCTURE; VITRO CONVERSION; Y145STOP VARIANT; ROTATING SOLIDS; NMR; RESIDUES; PEPTIDE AB We report the results of solid state nuclear magnetic resonance (NMR) measurements on amyloid fibrils formed by the full-length prion protein PrP (residues 23-231, Syrian hamster sequence). Measurements of intermolecular C-13-C-13 dipole-dipole couplings in selectively carbonyl-labeled samples indicate that beta-sheets in these fibrils have an in-register parallel structure, as previously observed in amyloid fibrils associated with Alzheimer's disease and type 2 diabetes and in yeast prion fibrils. Two-dimensional C-13-C-13 and N-15-C-13 solid state NMR spectra of a uniformly N-15- and C-13-labeled sample indicate that a relatively small fraction of the full sequence, localized to the C-terminal end, forms the structurally ordered, immobilized core. Although unique site-specific assignments of the solid state NMR signals cannot be obtained from these spectra, analysis with a Monte Carlo/simulated annealing algorithm suggests that the core is comprised primarily of residues in the 173-224 range. These results are consistent with earlier electron paramagnetic resonance studies of fibrils formed by residues 90-231 of the human PrP sequence, formed under somewhat different conditions [Cobb, N. J., Sonnichsen, F. D., McHaourab, H., and Surewicz, W. K. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 18946-18951], suggesting that an in-register parallel beta-sheet structure formed by the C-terminal end may be a general feature of PrP fibrils prepared in vitro. C1 [Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Savtchenko, Regina; Ostapchenko, Valeriy G.; Makarava, Natallia; Baskakov, Ilia V.] Univ Maryland, Dept Anat & Neurobiol, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH); NIH [NS045585] FX Ibis work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) and by NIH Grant NS045585 in I.V.B. NR 77 TC 68 Z9 69 U1 2 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 9 PY 2010 VL 49 IS 44 BP 9488 EP 9497 DI 10.1021/bi1013134 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 672YR UT WOS:000283624500008 PM 20925423 ER PT J AU Fledderman, EL Fujii, K Ghanam, RH Waki, K Prevelige, PE Freed, EO Saad, JS AF Fledderman, Emily L. Fujii, Ken Ghanam, Ruba H. Waki, Kayoko Prevelige, Peter E. Freed, Eric O. Saad, Jamil S. TI Myristate Exposure in the Human Immunodeficiency Virus Type 1 Matrix Protein Is Modulated by pH SO BIOCHEMISTRY LA English DT Article ID GAG-MEMBRANE-BINDING; HISTIDINE SIDE-CHAINS; MURINE LEUKEMIA-VIRUS; ROUS-SARCOMA-VIRUS; ASSEMBLY IN-VITRO; PLASMA-MEMBRANE; HIV-1 GAG; ANALYTICAL ULTRACENTRIFUGATION; 3-DIMENSIONAL STRUCTURE; CAPSID PROTEIN AB Human immunodeficiency virus type 1 (HIV-1) encodes a polypeptide called Gag that is capable of forming virus-like particles (VLPs) in vitro in the absence of other cellular or viral constituents. During the late phase of HIV-1 infection, Gag polyproteins are transported to the plasma membrane (PM) for assembly. A combination of in vivo, in vitro, and structural studies have shown that Gag targeting and assembly on the PM are mediated by specific interactions between the myristoylated matrix [myr(+)MA] domain of Gag and phosphatidylinositol 4,5-bisphosphate[PI(4,5)P-2]. Exposure of the MA myristyl (myr) group is triggered by PI(4,5)P-2 binding and is enhanced by factors that promote protein self-association. In the studies reported here, we demonstrate that myr exposure in MA is modulated by pH. Our data show that deprotonation of the His89 imidazole ring in myr(+)MA destabilizes the salt bridge formed between His89(H delta 2) and Glu12 (COO-), leading to tight sequestration of the myr group and a shift in the equilibrium from trimer to monomer. Furthermore, we show that oligomerization of a Gag-like construct containing matrix-capsid is also pH-dependent. Disruption of the His-Glu salt bridge by single-amino acid substitutions greatly altered the myr-sequestered-myr-exposed equilibrium. In vivo intracellular localization data revealed that the H89G mutation retargets Gag to intracellular compartments and severely inhibits virus production. Our findings reveal that the MA domain acts as a "pH sensor" in vitro, suggesting that the effect of pH on HIV-1 Gag targeting and binding to the PM warrants investigation. C1 [Fledderman, Emily L.; Ghanam, Ruba H.; Prevelige, Peter E.; Saad, Jamil S.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Fujii, Ken; Waki, Kayoko; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Saad, JS (reprint author), 845 19th St S, Birmingham, AL 35294 USA. EM saad@uab.edu FU UAB Comprehensive Cancer Center (National Cancer Institute) [P30CA13148]; Center for Cancer Research (National Cancer Institute); Intramural AIDS Targeted Antiviral Program FX This work was supported by the UAB Comprehensive Cancer Center (National Cancer Institute Grant P30CA13148) to J.S.S., the Intramural Research Program of the Center for Cancer Research (National Cancer Institute), and the Intramural AIDS Targeted Antiviral Program (to E.O.F.). NR 91 TC 21 Z9 21 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 9 PY 2010 VL 49 IS 44 BP 9551 EP 9562 DI 10.1021/bi101245j PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 672YR UT WOS:000283624500014 PM 20886905 ER PT J AU Vaine, M Wang, SX Liu, Q Arthos, J Montefiori, D Goepfert, P McElrath, MJ Lu, S AF Vaine, Michael Wang, Shixia Liu, Qin Arthos, James Montefiori, David Goepfert, Paul McElrath, M. Juliana Lu, Shan TI Profiles of Human Serum Antibody Responses Elicited by Three Leading HIV Vaccines Focusing on the Induction of Env-Specific Antibodies SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY VIRUS CHALLENGE; NEUTRALIZING ANTIBODIES; CONFORMATIONAL EPITOPES; MONOCLONAL-ANTIBODIES; PASSIVE-IMMUNIZATION; NEONATAL MACAQUES; SUBTYPE-B; INFECTION; PROTECTION; TRIAL AB In the current report, we compared the specificities of antibody responses in sera from volunteers enrolled in three US NIH-supported HIV vaccine trials using different immunization regimens. HIV-1 Env-specific binding antibody, neutralizing antibody, antibody-dependent cell-mediated cytotoxicity (ADCC), and profiles of antibody specificity were analyzed for human immune sera collected from vaccinees enrolled in the NIH HIV Vaccine Trial Network (HVTN) Study #041 (recombinant protein alone), HVTN Study #203 (poxviral vector prime-protein boost), and the DP6-001 study (DNA prime-protein boost). Vaccinees from HVTN Study #041 had the highest neutralizing antibody activities against the sensitive virus along with the highest binding antibody responses, particularly those directed toward the V3 loop. DP6-001 sera showed a higher frequency of positive neutralizing antibody activities against more resistant viral isolate with a significantly higher CD4 binding site (CD4bs) antibody response compared to both HVTN studies #041 and #203. No differences were found in CD4-induced (CD4i) antibody responses, ADCC activity, or complement activation by Env-specific antibody among these sera. Given recent renewed interest in realizing the importance of antibody responses for next generation HIV vaccine development, different antibody profiles shown in the current report, based on the analysis of a wide range of antibody parameters, provide critical biomarker information for the selection of HIV vaccines for more advanced human studies and, in particular, those that can elicit antibodies targeting conformational-sensitive and functionally conserved epitopes. C1 [Vaine, Michael; Wang, Shixia; Lu, Shan] Univ Massachusetts, Sch Med, Dept Med, Lab Nucle Acid Vaccines, Worcester, MA 01605 USA. [Liu, Qin] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA USA. [Arthos, James] NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. [Montefiori, David] Duke Univ, Med Ctr, Durham, NC USA. [Goepfert, Paul] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Goepfert, Paul] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [McElrath, M. Juliana] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Sch Med, Lab Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98104 USA. RP Vaine, M (reprint author), Univ Massachusetts, Sch Med, Dept Med, Lab Nucle Acid Vaccines, Worcester, MA 01605 USA. EM shan.lu@umassmed.edu OI Lu, Shan/0000-0002-8417-7588 FU NIH [AI065250, AI082274, AI082676, AI 27742] FX This work was supported in part by NIH grants AI065250, AI082274, & AI082676. Dr. Susan Zolla-Pazner provided mAb 447-52D supported under NIH grant AI 27742. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 24 Z9 24 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 9 PY 2010 VL 5 IS 11 AR e13916 DI 10.1371/journal.pone.0013916 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677ZE UT WOS:000284035900021 PM 21085486 ER PT J AU Gherghe, C Lombo, T Leonard, CW Datta, SAK Bess, JW Gorelick, RJ Rein, A Weeks, KM AF Gherghe, Cristina Lombo, Tania Leonard, Christopher W. Datta, Siddhartha A. K. Bess, Julian W., Jr. Gorelick, Robert J. Rein, Alan Weeks, Kevin M. TI Definition of a high-affinity Gag recognition structure mediating packaging of a retroviral RNA genome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE retrovirus; RNA recognition code; RNA SHAPE chemistry ID MURINE-LEUKEMIA-VIRUS; NUCLEOCAPSID PROTEIN; IN-VITRO; SECONDARY STRUCTURE; ZINC-FINGER; VIRAL RNAS; HIV-1 GAG; BINDING; TYPE-1; DOMAIN AB All retroviral genomic RNAs contain a cis-acting packaging signal by which dimeric genomes are selectively packaged into nascent virions. However, it is not understood how Gag (the viral structural protein) interacts with these signals to package the genome with high selectivity. We probed the structure of murine leukemia virus RNA inside virus particles using SHAPE, a high-throughput RNA structure analysis technology. These experiments showed that NC (the nucleic acid binding domain derived from Gag) binds within the virus to the sequence UCUG-UR-UCUG. Recombinant Gag and NC proteins bound to this same RNA sequence in dimeric RNA in vitro; in all cases, interactions were strongest with the first U and final G in each UCUG element. The RNA structural context is critical: High-affinity binding requires base-paired regions flanking this motif, and two UCUG-UR-UCUG motifs are specifically exposed in the viral RNA dimer. Mutating the guanosine residues in these two motifs-only four nucleotides per genomic RNA-reduced packaging 100-fold, comparable to the level of nonspecific packaging. These results thus explain the selective packaging of dimeric RNA. This paradigm has implications for RNA recognition in general, illustrating how local context and RNA structure can create information-rich recognition signals from simple single-stranded sequence elements in large RNAs. C1 [Lombo, Tania; Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Gherghe, Cristina; Leonard, Christopher W.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Bess, Julian W., Jr.; Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM reina@mail.nih.gov; weeks@unc.edu OI Datta, Siddhartha/0000-0002-4098-7490 FU National Institutes of Health (NIH) [GM064803]; NIH, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program; National Cancer Institute [N01-CO-12400] FX We thank Jane Mirro and Demetria Harvin for superb technical assistance. This work was supported by National Institutes of Health (NIH) Grant GM064803 (to K.M.W.); the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and a grant from the Intramural AIDS Targeted Antiviral Program (to A.R.); and the National Cancer Institute under Contract N01-CO-12400 (to J.W.B and R.J.G.). NR 49 TC 37 Z9 37 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 9 PY 2010 VL 107 IS 45 BP 19248 EP 19253 DI 10.1073/pnas.1006897107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800025 PM 20974908 ER PT J AU Winuthayanon, W Hewitt, SC Orvis, GD Behringer, RR Korach, KS AF Winuthayanon, Wipawee Hewitt, Sylvia C. Orvis, Grant D. Behringer, Richard R. Korach, Kenneth S. TI Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE conditional knockout; paracrine regulation ID EPIDERMAL-GROWTH-FACTOR; FEMALE REPRODUCTIVE-TRACT; MOUSE UTERUS; CELL-PROLIFERATION; PROGESTERONE-RECEPTOR; C/EBP-BETA; PARACRINE REGULATION; CROSS-TALK; FACTOR-I; EXPRESSION AB Female fertility requires estrogen to specifically stimulate estrogen receptor alpha (ER alpha)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ER alpha in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ER alpha knockout (UtEpi alpha ERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ER alpha in uterine epithelium, and female UtEpi alpha ERKO are infertile. Herein, we demonstrate that 17 beta-estradiol (E(2))-induced uterine epithelial proliferation was independent of uterine epithelial ER alpha because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpi alpha ERKO uteri after E(2) treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wildtype (WT) and UtEpi alpha ERKO and mimicked the E(2) stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ER alpha was necessary to induce lactoferrin, an E(2)-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ER alpha did not alter the E(2)-dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpi alpha ERKO had robust evidence of apoptosis after 3 d of E(2) treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ER alpha in the proliferative response, but ER alpha is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ER alpha in uterine tissue and its contribution during pregnancy. C1 [Winuthayanon, Wipawee; Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Orvis, Grant D.] Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA. [Orvis, Grant D.; Behringer, Richard R.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. RP Korach, KS (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU National Institute of Environmental Health Sciences, Division of Intramural Research [Z01ES70065]; NIH [HD30284, CA098258]; National Cancer Institute [CA09299] FX We thank James Clark, Page Myers, David Goulding from the National Institute of Environmental Health Sciences (NIEHS) Animal Surgery Group of Comparative Medicine branch for performing the animal surgeries and embryo transfer analysis, David Monroy for animal care, Geoffrey Hurlburt and Dave Olsen (NIEHS Immunohistochemistry core) for cleaved caspase-3 and TUNEL staining, Casey Reed for mouse genotyping and Drs. April Binder and Diane Klotz for the critical reading of the manuscript and helpful suggestions. This research was supported by the National Institute of Environmental Health Sciences, Division of Intramural Research (funding to W. W., S. C. H., and K. S. K.) project Z01ES70065 as well as NIH HD30284 and CA098258 (SPORE in Uterine Cancer) to R. R. B. G.D.O. was supported by the National Cancer Institute CA09299 Training Program in the Molecular Genetics of Cancer. NR 44 TC 85 Z9 92 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 9 PY 2010 VL 107 IS 45 BP 19272 EP 19277 DI 10.1073/pnas.1013226107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800029 PM 20974921 ER PT J AU Shive, HR West, RR Embree, LJ Azuma, M Sood, R Liu, P Hickstein, DD AF Shive, Heather R. West, Robert R. Embree, Lisa J. Azuma, Mizuki Sood, Raman Liu, Paul Hickstein, Dennis D. TI brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gonad development; meiosis; sex determination; fancd1 ID DNA MISMATCH REPAIR; FANCONI-ANEMIA; PROTEIN BRCA2; CANCER RISKS; GERM-CELLS; GENE; BREAST; MOUSE; DEFICIENCY; MUTATIONS AB Humans with inherited mutations in BRCA2 are at increased risk for developing breast and ovarian cancer; however, the relationship between BRCA2 mutation and these cancers is not understood. Studies of Brca2 mutation by gene targeting in mice are limited, given that homozygous Brca2 mutation typically leads to early embryonic lethality. We established a zebrafish line with a nonsense mutation in brca2 exon 11 (brca2(Q658X)), a mutation similar in location and type to BRCA2 mutations found in humans with hereditary breast and ovarian cancer. brca2(Q658X) homozygous zebrafish are viable and survive to adulthood; however, juvenile homozygotes fail to develop ovaries during sexual differentiation. Instead, brca2(Q658X) homozygotes develop as infertile males with meiotic arrest in spermatocytes. Germ cell migration to the embryonic gonadal ridge is unimpaired in brca2(Q658X) homozygotes; thus, failure of ovarian development is not due to defects in early establishment of the embryonic gonad. Homozygous tp53 mutation rescues ovarian development in brca2(Q658X) homozygous zebrafish, reflecting the importance of germ cell apoptosis in gonad morphogenesis. Adult brca2(Q658X) homozygous zebrafish are predisposed to testicular neoplasias. In addition, tumorigenesis in multiple tissues is significantly accelerated in combination with homozygous tp53 mutation in both brca2(Q658X) homozygous and brca2(Q658X) heterozygous zebrafish. These studies reveal critical roles for brca2 in ovarian development and tumorigenesis in reproductive tissues. C1 [Shive, Heather R.; West, Robert R.; Embree, Lisa J.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Azuma, Mizuki] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. [Sood, Raman; Liu, Paul] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Shive, HR (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM shiveh@mail.nih.gov RI Liu, Paul/A-7976-2012; Perez , Claudio Alejandro/F-8310-2010 OI Liu, Paul/0000-0002-6779-025X; Perez , Claudio Alejandro/0000-0001-9688-184X FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; National Human Genome Research Institute FX We thank the sequencing team at Beijing Genomics Institute for help with PCR analyses and sequencing of the ENU-mutagenized library, Kevin Bishop for help with recovery of the mutant line, and Jennifer Edwards for assistance with immunohisto-chemistry. This research was supported by the National Institutes of Health's Intramural Research Program, the National Cancer Institute, the Center for Cancer Research, and the National Human Genome Research Institute. NR 38 TC 20 Z9 22 U1 2 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 NOV 9 PY 2010 VL 107 IS 45 BP 19350 EP 19355 DI 10.1073/pnas.1011630107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800042 PM 20974951 ER PT J AU Quigley, MF Greenaway, HY Venturi, V Lindsay, R Quinn, KM Seder, RA Douek, DC Davenport, MP Price, DA AF Quigley, Maire F. Greenaway, Hui Yee Venturi, Vanessa Lindsay, Ross Quinn, Kylie M. Seder, Robert A. Douek, Daniel C. Davenport, Miles P. Price, David A. TI Convergent recombination shapes the clonotypic landscape of the naive T-cell repertoire SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIV INFECTION; RESPONSES; ANTIGEN; MICE; CYTOMEGALOVIRUS; RECOGNITION; FREQUENCY; ESCAPE; ALPHA; USAGE AB Adaptive T-cell immunity relies on the recruitment of antigen-specific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naive T-cell precursors. Despite the enormous clonotypic diversity that resides within the naive T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide-major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or "public," TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naive CD8(+) TCR beta repertoire in mice. Within defined segments of the naive CD8(+) T-cell repertoire, TCR beta sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naive CD8(+) T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8(+) T-cell clonotypes, which can exert profound biological effects during acute infectious processes. C1 [Quigley, Maire F.; Douek, Daniel C.; Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Greenaway, Hui Yee; Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Unit, Kensington, NSW 2052, Australia. [Lindsay, Ross; Quinn, Kylie M.; Seder, Robert A.] NIAID, Cellular Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Kensington, NSW 2052, Australia. [Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff CF14 4XN, S Glam, Wales. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov; m.davenport@unsw.edu.au; dprice1@mail.nih.gov RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council (MRC) UK; Australian Research Council (ARC); Australian National Health and Medical Research Council (NHMRC); Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Medical Research Council (MRC) UK, the Australian Research Council (ARC), the Australian National Health and Medical Research Council (NHMRC), and the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. D. A. P. is an MRC Senior Clinical Fellow, M. F. Q. is a Marie Curie International Outgoing Fellow, M. P. D. is an NHMRC Senior Research Fellow, and V. V. is an ARC Future Fellow. NR 25 TC 51 Z9 52 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 NOV 9 PY 2010 VL 107 IS 45 BP 19414 EP 19419 DI 10.1073/pnas.1010586107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800053 PM 20974936 ER PT J AU Rochman, Y Kashyap, M Robinson, GW Sakamoto, K Gomez-Rodriguez, J Wagner, KU Leonard, WJ AF Rochman, Yrina Kashyap, Mohit Robinson, Gertraud W. Sakamoto, Kazuhito Gomez-Rodriguez, Julio Wagner, Kay-Uwe Leonard, Warren J. TI Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INTERLEUKIN-2-RECEPTOR GAMMA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; T-CELL DEVELOPMENT; IGM(+) B-CELLS; IL-2 RECEPTOR; MOLECULAR-CLONING; IN-VITRO; CYTOKINE; RESPONSES; TSLP AB Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays essential roles in allergic/inflammatory skin and airway disorders, in helminth infections, and in regulating intestinal immunity. TSLP signals via IL-7R alpha and a specific TSLPR subunit that is highly related to the common cytokine receptor gamma chain, gamma(c). Although TSLP has effects on a broad range of hematopoetic cells and can induce STAT5 phosphorylation, TSLP was reported to not signal via JAK kinases, and the mechanism by which TSLP regulates STAT5 phosphorylation has been unclear. We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7. We also show that just as JAK1 interacts with IL-7R alpha, JAK2 is associated with TSLPR protein. Moreover, we demonstrate the importance of STAT5 activation for TSLP-mediated survival and proliferation of CD4(+) T cells. These findings clarify the basis for TSLP-mediated signaling and provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5. C1 [Rochman, Yrina; Kashyap, Mohit; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Robinson, Gertraud W.] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Sakamoto, Kazuhito; Wagner, Kay-Uwe] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Gomez-Rodriguez, Julio] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Kashyap, Mohit/F-4534-2011; Wagner, Kay-Uwe/B-6044-2009; Robinson, Gertraud/I-2136-2012 FU Divisions of Intramural Research, National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Dr. Robert D. Schreiber (Washington University, St. Louis, MO) for Jak1 KO MEFs; Drs. Bingmei Zhu and Lothar Hennighausen (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health) for valuable discussions; Dr. Pamela L. Schwartzberg (National Human Genome Research Institute) for Tec, Itk, and Rlk knockout mice; Ms. Leigh Samsel (Flow Cytometry Core, National Heart, Lung, and Blood Institute) for helping with FACS sorting; and Drs. Rosanne Spolski and Jian-Xin Lin (National Heart, Lung, and Blood Institute) for critical comments. This work was supported by the Divisions of Intramural Research, National Heart, Lung, and Blood Institute, and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 45 TC 65 Z9 69 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 9 PY 2010 VL 107 IS 45 BP 19455 EP 19460 DI 10.1073/pnas.1008271107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800060 PM 20974963 ER PT J AU Kallupi, M Cannella, N Economidou, D Ubaldi, M Ruggeri, B Weiss, F Massi, M Marugan, J Heilig, M Bonnavion, P de Lecea, L Ciccocioppo, R AF Kallupi, Marsida Cannella, Nazzareno Economidou, Daina Ubaldi, Massimo Ruggeri, Barbara Weiss, Friedbert Massi, Maurizio Marugan, Juan Heilig, Markus Bonnavion, Patricia de Lecea, Luis Ciccocioppo, Roberto TI Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LOCUS-COERULEUS; REWARD-SEEKING; OREXIN NEURONS; FOOD-INTAKE; RAT-BRAIN; RECEPTOR; ADDICTION; OREXIN/HYPOCRETIN; BEHAVIOR; REINSTATEMENT AB Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Environmental conditioning factors are among the major determinants of relapse in abstinent cocaine users. Here we describe a role of the neuropeptide S (NPS) system in regulating relapse. In rats with a history of cocaine self-administration, presentation of stimuli predictive of drug availability reinstates drug seeking, triggering relapse. Intracerebroventricular (ICV) injection of NPS increased conditioned reinstatement of cocaine seeking, whereas peripheral administration of the NPS receptor antagonist SHA 68 reduced it. Manipulation of the NPS receptor system did not modify cocaine self-administration. We also found that ICV NPS administration activates c-Fos expression in hypocretin-1/orexin-A (Hcrt-1/Ox-A) immunoreactive neurons in the lateral hypothalamus (LH) and in the perifornical area (PeF). Of note, intra-LH and intra-PeF administration of NPS increased conditioned reinstatement of cocaine responding, an effect that was selectively blocked with the Hcrt-1/Ox-A receptor selective antagonist SB334867. Finally, results showed that intra-LH injection of the NPS antagonist [D-Cys(tBu) (5)] NPS blocked cue-induced cocaine seeking, indicating a role for this system in the pathophysiology of drug relapse. C1 [Kallupi, Marsida; Cannella, Nazzareno; Economidou, Daina; Ubaldi, Massimo; Ruggeri, Barbara; Massi, Maurizio; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. [Weiss, Friedbert] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Marugan, Juan] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Heilig, Markus] NIAAA, NIH, Bethesda, MD 20892 USA. [Bonnavion, Patricia; de Lecea, Luis] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. RP Ciccocioppo, R (reprint author), Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. EM roberto.ciccocioppo@unicam.it RI Ruggeri, Barbara/A-9787-2013; de Lecea, Luis/B-3171-2009; OI de Lecea, Luis/0000-0002-8921-5942; Ruggeri, Barbara/0000-0002-6231-8829; Ubaldi, Massimo/0000-0002-4089-2483; Kallupi, Marsida/0000-0002-8688-709X; Cannella, Nazzareno/0000-0002-2891-8679 FU Compagnia San Paolo Foundation; [AA014351] FX We thank Sheila Beatty for linguistic revision of the paper. This work was supported by Grant AA014351 (to F. W.), and by a Compagnia San Paolo Foundation grant (to R.C.). NR 28 TC 39 Z9 40 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 NOV 9 PY 2010 VL 107 IS 45 BP 19567 EP 19572 DI 10.1073/pnas.1004100107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 677MZ UT WOS:000283997800079 PM 20974945 ER PT J AU Fields, RD VanHook, AM AF Fields, R. Douglas VanHook, Annalisa M. TI Science Signaling Podcast: 9 November 2010 SO SCIENCE SIGNALING LA English DT Editorial Material DE Science Signaling; action potential; ATP; axon; glia; neuron; nonvesicular; membrane stretch; swelling; synapse; volume-activated anion channel AB This is a conversation with Doug Fields about a Research Article published in the 5 October 2010 issue of Science Signaling. Fields and Ni report that axonal swelling allows neurons to communicate with glia by releasing ATP through volume-activated anion channels. This nonvesicular, nonsynaptic form of communication may mediate activity-dependent communication between neurons and neighboring cells under normal conditions and may play a role in disease. C1 [Fields, R. Douglas] NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. [VanHook, Annalisa M.] Amer Assoc Advancement Sci, Sci Signaling, Washington, DC 20005 USA. RP Fields, RD (reprint author), NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bldg 35,Room 2A211,MSC 3713,35 Lincoln Dr, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD NOV 9 PY 2010 VL 3 IS 147 AR pc20 DI 10.1126/scisignal.3147pc20 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 677NJ UT WOS:000283998800002 ER PT J AU Fields, RD AF Fields, R. Douglas TI Visualizing Calcium Signaling in Astrocytes SO SCIENCE SIGNALING LA English DT Editorial Material DE neuron-glia interactions; calcium wave; glial cell; imaging; movie ID COMMUNICATION AB Astrocytes are nonneuronal cells in the brain ( glia) that do not generate electrical impulses but communicate by chemical signaling. This communication can be observed under a microscope with fluorescent calcium indicators that glow more brightly when the concentration of calcium increases inside the cell. Astrocytes release adenosine 5'-triphosphate and other cell signaling molecules that excite membrane receptors on other astrocytes to cause an increase in intracellular calcium in the recipient cell. Many of the substances released by astrocytes also excite neurons, and astrocytes have on their own cell membrane many of the same neurotransmitter receptors used by neurons to communicate across synapses. This allows astrocytes to respond to neural impulse activity, communicate among other astrocytes, and influence neuronal communication by taking up or releasing neurotransmitters from synapses. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHHD, NIH, Bldg 35,Room 2A211,MSC3713, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [Z01 HD000713-13] NR 2 TC 2 Z9 2 U1 1 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD NOV 9 PY 2010 VL 3 IS 147 AR tr5 DI 10.1126/scisignal.3147tr5 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 677NJ UT WOS:000283998800008 PM 21062994 ER PT J AU Han, LY Suzek, TO Wang, YL Bryant, SH AF Han, Lianyi Suzek, Tugba O. Wang, Yanli Bryant, Steve H. TI The Text-mining based PubChem Bioassay neighboring analysis SO BMC BIOINFORMATICS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; BIOMEDICAL TEXT; GENE-EXPRESSION; ENTITY RECOGNITION; INFORMATION; RETRIEVAL; NETWORK; SYSTEM; NAMES AB Background: In recent years, the number of High Throughput Screening (HTS) assays deposited in PubChem has grown quickly. As a result, the volume of both the structured information (i.e. molecular structure, bioactivities) and the unstructured information (such as descriptions of bioassay experiments), has been increasing exponentially. As a result, it has become even more demanding and challenging to efficiently assemble the bioactivity data by mining the huge amount of information to identify and interpret the relationships among the diversified bioassay experiments. In this work, we propose a text-mining based approach for bioassay neighboring analysis from the unstructured text descriptions contained in the PubChem BioAssay database. Results: The neighboring analysis is achieved by evaluating the cosine scores of each bioassay pair and fraction of overlaps among the human-curated neighbors. Our results from the cosine score distribution analysis and assay neighbor clustering analysis on all PubChem bioassays suggest that strong correlations among the bioassays can be identified from their conceptual relevance. A comparison with other existing assay neighboring methods suggests that the text-mining based bioassay neighboring approach provides meaningful linkages among the PubChem bioassays, and complements the existing methods by identifying additional relationships among the bioassay entries. Conclusions: The text-mining based bioassay neighboring analysis is efficient for correlating bioassays and studying different aspects of a biological process, which are otherwise difficult to achieve by existing neighboring procedures due to the lack of specific annotations and structured information. It is suggested that the text-mining based bioassay neighboring analysis can be used as a standalone or as a complementary tool for the PubChem bioassay neighboring process to enable efficient integration of assay results and generate hypotheses for the discovery of bioactivities of the tested reagents. C1 [Han, Lianyi; Suzek, Tugba O.; Wang, Yanli; Bryant, Steve H.] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), US Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Suzek, Tugba/B-6943-2015; OI Suzek, Tugba/0000-0002-3243-1759 FU NIH FX This research was supported by the Intramural Research Program of NIH. We acknowledge the editorial assistance of the NIH Fellows Editorial Board. NR 39 TC 16 Z9 16 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD NOV 8 PY 2010 VL 11 AR 549 DI 10.1186/1471-2105-11-549 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 684FB UT WOS:000284534400001 PM 21059237 ER PT J AU Ghosh, AK Xu, CX Rao, KV Baldridge, A Agniswamy, J Wang, YF Weber, IT Aoki, M Miguel, SGP Amano, M Mitsuya, H AF Ghosh, Arun K. Xu, Chun-Xiao Rao, Kalapala Venkateswara Baldridge, Abigail Agniswamy, Johnson Wang, Yuan-Fang Weber, Irene T. Aoki, Manabu Miguel, Salcedo Gomez Pedro Amano, Masayuki Mitsuya, Hiroaki TI Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors SO CHEMMEDCHEM LA English DT Article DE dimerization inhibitors; HIV-1 protease; multidrug resistance; oxatricyclic ligands; X-ray crystallography ID RESOLUTION CRYSTAL-STRUCTURES; HIGH-AFFINITY P-2-LIGANDS; COMBAT DRUG-RESISTANCE; HUMAN-IMMUNODEFICIENCY; BIOLOGICAL EVALUATION; X-RAY; POTENT; BACKBONE; ALCOHOLS; THERAPY C1 [Ghosh, Arun K.; Xu, Chun-Xiao; Rao, Kalapala Venkateswara; Baldridge, Abigail] Purdue Univ, Dept Chem & Med Chem, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Aoki, Manabu; Miguel, Salcedo Gomez Pedro; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan. [Aoki, Manabu; Miguel, Salcedo Gomez Pedro; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem & Med Chem, 560 Oval Dr, 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]; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Welfare, and Labor of Japan [H15-AIDS-001]; Kumamoto University FX This research was supported by grants from the National Institutes of Health (GM53386, A.K.G. and GM62920, I.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 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 (Kosei Rohdosho: H15-AIDS-001), and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Kumamoto University) of Monbu-Kagakusho. NR 32 TC 30 Z9 30 U1 4 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD NOV 8 PY 2010 VL 5 IS 11 SI SI BP 1850 EP 1854 DI 10.1002/cmdc.201000318 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 684WI UT WOS:000284585500008 PM 20827746 ER PT J AU Parapuram, SK Cojocaru, RI Chang, JR Khanna, R Brooks, M Othman, M Zareparsi, S Khan, NW Gotoh, N Cogliati, T Swaroop, A AF Parapuram, Sunil K. Cojocaru, Radu I. Chang, Jessica R. Khanna, Ritu Brooks, Matthew Othman, Mohammad Zareparsi, Sepideh Khan, Naheed W. Gotoh, Norimoto Cogliati, Tiziana Swaroop, Anand TI Distinct Signature of Altered Homeostasis in Aging Rod Photoreceptors: Implications for Retinal Diseases SO PLOS ONE LA English DT Article ID GENE-EXPRESSION PROFILE; MACULAR DEGENERATION; FATTY-ACIDS; RETINITIS-PIGMENTOSA; CALORIE RESTRICTION; RECEPTOR-ALPHA; LIFE-SPAN; IN-VITRO; CELLS; MICE AB Background: Advanced age contributes to clinical manifestations of many retinopathies and represents a major risk factor for age-related macular degeneration, a leading cause of visual impairment and blindness in the elderly. Rod photoreceptors are especially vulnerable to genetic defects and changes in microenvironment, and are among the first neurons to die in normal aging and in many retinal degenerative diseases. The molecular mechanisms underlying rod photoreceptor vulnerability and potential biomarkers of the aging process in this highly specialized cell type are unknown. Methodology/Principal Findings: To discover aging-associated adaptations that may influence rod function, we have generated gene expression profiles of purified rod photoreceptors from mouse retina at young adult to early stages of aging (1.5, 5, and 12 month old mice). We identified 375 genes that showed differential expression in rods from 5 and 12 month old mouse retina compared to that of 1.5 month old retina. Quantitative RT-PCR experiments validated expression change for a majority of the 25 genes that were examined. Macroanalysis of differentially expressed genes using gene class testing and protein interaction networks revealed overrepresentation of cellular pathways that are potentially photoreceptor-specific (angiogenesis and lipid/retinoid metabolism), in addition to age-related pathways previously described in several tissue types (oxidative phosphorylation, stress and immune response). Conclusions/Significance: Our study suggests a progressive shift in cellular homeostasis that may underlie aging-associated functional decline in rod photoreceptors and contribute to a more permissive state for pathological processes involved in retinal diseases. C1 [Parapuram, Sunil K.; Cojocaru, Radu I.; Khanna, Ritu; Brooks, Matthew; Othman, Mohammad; Zareparsi, Sepideh; Khan, Naheed W.; Swaroop, Anand] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Cojocaru, Radu I.; Chang, Jessica R.; Brooks, Matthew; Gotoh, Norimoto; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Chang, Jessica R.] Natl Inst Hlth Res Scholars Program, Howard Hughes Med Inst, Bethesda, MD USA. RP Parapuram, SK (reprint author), Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. EM swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute; National Institutes of Health [EY11115, EY07003, DK20572]; Foundation Fighting Blindness; Elmer and Sylvia Sramek Foundation; Research to Prevent Blindness FX This research was supported by intramural funds of the National Eye Institute and by grants (EY11115, EY07003, DK20572) from the National Institutes of Health, http://grants.nih.gov/grants/oer.htm, the Foundation Fighting Blindness, http://www.blindness.org/, the Elmer and Sylvia Sramek Foundation, and Research to Prevent Blindness, http://www.rpbusa.org/rpb/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 11 Z9 11 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 NOV 8 PY 2010 VL 5 IS 11 AR e13885 DI 10.1371/journal.pone.0013885 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 676NU UT WOS:000283920000016 PM 21079736 ER PT J AU Pugacheva, EM Suzuki, T Pack, SD Kosaka-Suzuki, N Yoon, J Vostrov, AA Barsov, E Strunnikov, AV Morse, HC Loukinov, D Lobanenkov, V AF Pugacheva, Elena M. Suzuki, Teruhiko Pack, Svetlana D. Kosaka-Suzuki, Natsuki Yoon, Jeongheon Vostrov, Alexander A. Barsov, Eugene Strunnikov, Alexander V. Morse, Herbert C., III Loukinov, Dmitri Lobanenkov, Victor TI The Structural Complexity of the Human BORIS Gene in Gametogenesis and Cancer SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR; ENHANCER-BLOCKING; IMPRINTED SITES; TESTIS ANTIGEN; CTCF-BINDING; H19 GENE; EXPRESSION; PROMOTER; METHYLATION; CELLS AB Background: BORIS/CTCFL is a paralogue of CTCF, the major epigenetic regulator of vertebrate genomes. BORIS is normally expressed only in germ cells but is aberrantly activated in numerous cancers. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions. Methodology/Principal Findings: Here we show that BORIS is expressed as 23 isoforms in germline and cancer cells. The isoforms are comprised of alternative N- and C-termini combined with varying numbers of zinc fingers (ZF) in the DNA binding domain. The patterns of BORIS isoform expression are distinct in germ and cancer cells. Isoform expression is activated by downregulation of CTCF, upregulated by reduction in CpG methylation caused by inactivation of DNMT1 or DNMT3b, and repressed by activation of p53. Studies of ectopically expressed isoforms showed that all are translated and localized to the nucleus. Using the testis-specific cerebroside sulfotransferase (CST) promoter and the IGF2/H19 imprinting control region (ICR), it was shown that binding of BORIS isoforms to DNA targets in vitro is methylation-sensitive and depends on the number and specific composition of ZF. The ability to bind target DNA and the presence of a specific long amino terminus (N258) in different isoforms are necessary and sufficient to activate CST transcription. Comparative sequence analyses revealed an evolutionary burst in mammals with strong conservation of BORIS isoproteins among primates. Conclusions: The extensive repertoire of spliced BORIS variants in humans that confer distinct DNA binding and transcriptional activation properties, and their differential patterns of expression among germ cells and neoplastic cells suggest that the gene is involved in a range of functionally important aspects of both normal gametogenesis and cancer development. In addition, a burst in isoform diversification may be evolutionarily tied to unique aspects of primate speciation. C1 [Pugacheva, Elena M.; Suzuki, Teruhiko; Kosaka-Suzuki, Natsuki; Yoon, Jeongheon; Strunnikov, Alexander V.; Morse, Herbert C., III; Loukinov, Dmitri; Lobanenkov, Victor] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. [Pack, Svetlana D.] NCI, Chromosome Pathol Unit, Pathol Lab, CCR,NIH, Bethesda, MD 20892 USA. [Vostrov, Alexander A.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. [Barsov, Eugene] SAIC Frederick NCI Frederick, AIDS & Canc Viruses Program, Frederick, MD USA. RP Pugacheva, EM (reprint author), NIAID, Immunopathol Lab, NIH, Rockville, MD USA. EM epugacheva@niaid.nih.gov RI Pack, Svetlana/C-2020-2014; OI Lobanenkov, Victor/0000-0001-6665-3635; Strunnikov, Alexander/0000-0002-9058-2256; Morse, Herbert/0000-0002-9331-3705 FU NIAID; NIH Office of AIDS Research FX This work was supported by the intramural research program of NIAID and by the intramural grant from NIH Office of AIDS Research to A. V. S. and D. L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 23 Z9 24 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 NOV 8 PY 2010 VL 5 IS 11 AR e13872 DI 10.1371/journal.pone.0013872 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 676NU UT WOS:000283920000006 PM 21079786 ER PT J AU Broutin, H Viboud, C Grenfell, BT Miller, MA Rohani, P AF Broutin, H. Viboud, C. Grenfell, B. T. Miller, M. A. Rohani, P. TI Impact of vaccination and birth rate on the epidemiology of pertussis: a comparative study in 64 countries SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE pertussis; vaccination; birth rate; periodicity; comparative approach ID TIME-SERIES ANALYSIS; BORDETELLA-PERTUSSIS; WHOOPING-COUGH; PERSISTENT COUGH; ADULTS; TRANSMISSION; ADOLESCENTS; DISEASE; IMMUNIZATION; FREQUENCY AB Bordetella pertussis infection remains an important public health problem worldwide despite decades of routine vaccination. A key indicator of the impact of vaccination programmes is the inter-epidemic period, which is expected to increase with vaccine uptake if there is significant herd immunity. Based on empirical data from 64 countries across the five continents over the past 30-70 years, we document the observed relationship between the average inter-epidemic period, birth rate and vaccine coverage. We then use a mathematical model to explore the range of scenarios for duration of immunity and transmission resulting from repeat infections that are consistent with empirical evidence. Estimates of pertussis periodicity ranged between 2 and 4.6 years, with a strong association with susceptible recruitment rate, defined as birth rate x (1 - vaccine coverage). Periodicity increased by 1.27 years on average after the introduction of national vaccination programmes (95% CI: 1.13, 1.41 years), indicative of increased herd immunity. Mathematical models suggest that the observed patterns of pertussis periodicity are equally consistent with loss of immunity that is not as rapid as currently thought, or with negligible transmission generated by repeat infections. We conclude that both vaccine coverage and birth rate drive pertussis periodicity globally and that vaccination induces strong herd immunity effects. A better understanding of the role of repeat infections in pertussis transmission is critical to refine existing control strategies. C1 [Broutin, H.; Viboud, C.; Grenfell, B. T.; Miller, M. A.; Rohani, P.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, B. T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Rohani, P.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, P.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. RP Broutin, H (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM broutinh@mail.nih.gov FU intramural research group of Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation; Science and Technology Directorate of the Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The authors thank the various colleagues who provided original data. This study was funded by the intramural research group of Fogarty International Center, National Institutes of Health. B. G. and P. R. were supported by the Bill and Melinda Gates Foundation and the RAPIDD programme of the Science and Technology Directorate of the Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 36 TC 45 Z9 45 U1 0 U2 12 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD NOV 7 PY 2010 VL 277 IS 1698 BP 3239 EP 3245 DI 10.1098/rspb.2010.0994 PG 7 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 660MC UT WOS:000282646300004 PM 20534609 ER PT J AU Goulielmos, GN Petraki, E Vassou, D Eliopoulos, E Iliopoulos, D Sidiropoulos, P Aksentijevich, I Kardassis, D Boumpas, DT AF Goulielmos, George N. Petraki, Eleni Vassou, Despoina Eliopoulos, Elias Iliopoulos, Dimitris Sidiropoulos, Prodromos Aksentijevich, Ivona Kardassis, Dimitrios Boumpas, Dimitrios T. TI The role of the pro-apoptotic protein Siva in the pathogenesis of Familial Mediterranean fever: A structural and functional analysis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Familial Mediterranean fever (FMF); Pyrin; MEFV; Three-dimensional model; Gene network ID PYRIN; MEFV; INTERACTS; DOMAIN; CELLS; GENE AB Familial Mediterranean fever (FMF) is an autosomal, recessive disease, attributed to mutations in MEFV gene encoding pyrin, which is characterized by recurrent, acute and self-limiting attacks of fever as well as an increased neutrophil and monocyte apoptosis. Most disease-associated mutations in MEW gene reside on the C-terminal PRYSPRY (B30.2) domain of pyrin, an area found to interact with the pro-apoptotic protein Siva. Because apoptotic events may be contributing to endogenous inflammation we hypothesized that mutations in pyrin may affect Siva-mediated apoptosis. The confirmation of this hypothesis would be of a great biological significance since it would be demonstrated a connection between apoptosis and inflammation. We used homology modeling to construct a 3-D model of Siva protein and the constructed model of Siva defined structural elements with potential of binding other proteins to induce apoptosis. Given that Siva protein binds pyrin as shown by transfection and immunoprecipitation experiments, apoptosis was assessed by FACS and Western blotting. No differences in rates of apoptosis in myeloid cells (THP-1) upon transfection with either wt pyrin or mutant forms of pyrin were found. Patients with FMF did not display any mutations in the Siva-1 (full length) gene. Siva-1 was not linked to pyrin in the major predicted FMF gene network constructed using a literature-curated gene signature for FMF. These results suggest that Siva-mediated unprovoked apoptosis is not likely to be involved in the pathogenesis of FMF. (C) 2010 Elsevier Inc. All rights reserved. C1 [Goulielmos, George N.; Petraki, Eleni; Vassou, Despoina; Boumpas, Dimitrios T.] Univ Crete, Dept Med, Lab Mol Med & Human Genet, Iraklion 71409, Greece. [Eliopoulos, Elias] Agr Univ Athens, Dept Agr Biotechnol, Genet Lab, Athens, Greece. [Iliopoulos, Dimitris] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Aksentijevich, Ivona] NIAMSD, Genet Sect, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. [Kardassis, Dimitrios] Univ Crete, Dept Med, Biochem Lab, Iraklion 71409, Greece. RP Goulielmos, GN (reprint author), Univ Crete, Dept Med, Lab Mol Med & Human Genet, Iraklion 71409, Greece. EM goulielmos@med.uoc.gr FU FP6 European AUTOCURE; Hellenic Society of Rheumatology FX The authors thank Prof. Deborah Gumucio (University of Michigan Medical School, Ann Arbor, MI) for making us available the various pyrin and Siva constructs used in this study as well as for her constructive criticism. The authors also thank Argyro Repa (Rheumatology Clinique of University Hospital of Heraklion) for her help in the collection of clinical data of the FMF patients enrolled in this study. This work was supported in part by grants from the FP6 European AUTOCURE program and the Hellenic Society of Rheumatology. NR 27 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 5 PY 2010 VL 402 IS 1 BP 141 EP 146 DI 10.1016/j.bbrc.2010.10.004 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 679TB UT WOS:000284182600025 PM 20934406 ER PT J AU Hair, JM Terzoudi, GI Hatzi, VI Lehockey, KA Srivastava, D Wang, WX Pantelias, GE Georgakilas, AG AF Hair, Jessica M. Terzoudi, Georgia I. Hatzi, Vasiliki I. Lehockey, Katie A. Srivastava, Devika Wang, Weixin Pantelias, Gabriel E. Georgakilas, Alexandros G. TI BRCA1 role in the mitigation of radiotoxicity and chromosomal instability through repair of clustered DNA lesions SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE BRCA1; Clustered DNA lesions; Human breast cancer; Oxidative stress; Radiotoxicity; Chromosomal instability ID DOUBLE-STRAND BREAKS; CANCER CELL-LINE; IONIZING-RADIATION; OXIDATIVE STRESS; MOLECULAR-MECHANISMS; GENE-EXPRESSION; DAMAGE RESPONSE; DSB REPAIR; COMPLEX; ABERRATIONS AB Oxidatively-induced clustered DNA lesions are considered the signature of any ionizing radiation like the ones human beings are exposed daily from various environmental sources (medical X-rays, radon, etc.). To evaluate the role of BRCA1 deficiencies in the mitigation of radiation-induced toxicity and chromosomal instability we have used two human breast cancer cell lines, the BRCA1 deficient HCC1937 cells and as a control the BRCA1 wild-type MCF-7 cells. As an additional control for the DNA damage repair measurements, the HCC1937 cells with partially reconstituted BRCA1 expression were used. Since clustered DNA damage is considered the signature of ionizing radiation, we have measured the repair of double strand breaks (DSBs), non-DSB bistranded oxidative clustered DNA lesions (OCDLs) as well as single strand breaks (SSBs) in cells exposed to radiotherapy-relevant gamma-ray doses. Parallel measurements were performed in the accumulation of chromatid and isochromatid breaks. For the measurement of OCDL repair, we have used a novel adaptation of the denaturing single cell gel electrophoresis (Comet assay) and pulsed field gel electrophoresis with Escherichia coli repair enzymes as DNA damage probes. Independent monitoring of the gamma-H2AX foci was also performed while metaphase chromatid lesions were measured as an indicator of chromosomal instability. HCC1937 cells showed a significant accumulation of all types of DNA damage and chromatid breaks compared to MCF-7 while BRCA1 partial expression contributed significantly in the overall repair of OCDLs. These results further support the biological significance of repair resistant clustered DNA damage leading to chromosomal instability. The current results combined with previous findings on the minimized ability of base clusters to induce cell death (mainly induced by DSBs), enhance the potential association of OCDLs with breast cancer development especially in the case of a BRCA1 deficiency leading to the survival of breast cells carrying a high load of unrepaired DNA damage clusters. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Hair, Jessica M.; Lehockey, Katie A.; Srivastava, Devika; Georgakilas, Alexandros G.] E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Greenville, NC 27858 USA. [Terzoudi, Georgia I.; Hatzi, Vasiliki I.; Pantelias, Gabriel E.] Natl Ctr Sci Res Demokritos, Athens 15310, Greece. [Wang, Weixin] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Georgakilas, AG (reprint author), E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Howell Sci Complex,1000 E 5th Str, Greenville, NC 27858 USA. EM georgakilasa@ecu.edu FU ECU Research/Creative Activity Award; UICC-ICRETT FX This work was supported by funds provided to Dr. Georgakilas by a 2009/2010 ECU Research/Creative Activity Award and by an UICC-ICRETT 2008 fellowship. NR 57 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD NOV 5 PY 2010 VL 188 IS 2 SI SI BP 350 EP 358 DI 10.1016/j.cbi.2010.03.046 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 665MQ UT WOS:000283040100010 PM 20371364 ER PT J AU Rao, VA Klein, SR Bonar, SJ Zielonka, J Mizuno, N Dickey, JS Keller, PW Joseph, J Kalyanaraman, B Shacter, E AF Rao, V. Ashutosh Klein, Sarah R. Bonar, Spencer J. Zielonka, Jacek Mizuno, Naoko Dickey, Jennifer S. Keller, Paul W. Joseph, Joy Kalyanaraman, Balaraman Shacter, Emily TI The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUBSTRATE ADAPTER PROTEIN; MALIGNANT GLIOMA-CELLS; CANCER-CELLS; TARGETED ANTIOXIDANTS; OXIDATIVE DAMAGE; ARSENIC TRIOXIDE; TOPOISOMERASE-I; DT-DIAPHORASE; MCF-7 CELLS; DNA-DAMAGE AB Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ treatment led to irreversible inhibition of clonogenic growth of breast cancer cells through a combination of autophagy and apoptotic cell death mechanisms. Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme Q(10). Inhibition of cancer cell growth by MitoQ was associated with G(1)/S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The possible role of oxidative stress in MitoQ activity was investigated by measuring the products of hydroethidine oxidation. Increases in ethidium and dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor protein that regulates the antioxidant transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 protein levels, nuclear localization, and transcriptional activity also increased following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in autophagy and an increase in G(1) cell cycle arrest in response to MitoQ but had no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox sensors for oxidative perturbations that lead to autophagy. MitoQ and similar compounds should be further evaluated for novel anticancer activity. C1 [Rao, V. Ashutosh; Klein, Sarah R.; Bonar, Spencer J.; Dickey, Jennifer S.; Shacter, Emily] US FDA, Biochem Lab, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Free Radical Res Ctr, Milwaukee, WI 53226 USA. [Mizuno, Naoko; Keller, Paul W.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Rao, VA (reprint author), 29 Lincoln Dr,Bldg 29A,Rm 2A-09,HFD-122, Bethesda, MD 20892 USA. EM ashutosh.rao@fda.hhs.gov; emily.shacter@fda.hhs.gov RI Zielonka, Jacek/N-9546-2014 OI Zielonka, Jacek/0000-0002-2524-0145 FU NIAMS; NCI; National Institutes of Health [RO1CA125112, RO1CA136799] FX This work was supported in part by National Institutes of Health Intramural Research Programs of NIAMS and NCI and by National Institutes of Health Grants RO1CA125112 and RO1CA136799. NR 58 TC 62 Z9 63 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 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 5 PY 2010 VL 285 IS 45 BP 34447 EP 34459 DI 10.1074/jbc.M110.133579 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673KL UT WOS:000283659100019 PM 20805228 ER PT J AU Zhang, LP Ten Hagen, KG AF Zhang, Liping Ten Hagen, Kelly G. TI Dissecting the Biological Role of Mucin-type O-Glycosylation Using RNA Interference in Drosophila Cell Culture SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; UDP-GALNAC; CAENORHABDITIS-ELEGANS; EXPRESSION; FAMILY; GOLGI; CYTOKINESIS; SECRETION; ADHESION; HT-29 AB Mucin type O-glycosylation is a highly conserved form of post-translational modification initiated by the family of enzymes known as the polypeptide alpha-N-acetylgalactosaminyltransferases (ppGalNAcTs in mammals and PGANTs in Drosophila). To address the cellular functions of the many PGANT family members, RNA interference (RNAi) to each pgant gene was performed in two independent Drosophila cell culture lines. We demonstrate that RNAi to individual pgant genes results in specific reduction in gene expression without affecting the expression of other family members. Cells with reduced expression of individual pgant genes were then examined for changes in viability, morphology, adhesion, and secretion to assess the contribution of each family member to these cellular functions. Here we find that RNAi to pgant3, pgant6, or pgant7 resulted in reduced secretion, further supporting a role for O-glycosylation in proper secretion. Additionally, RNAi to pgant3 or pgant6 resulted in altered Golgi organization, suggesting a role for each in establishing or maintaining proper secretory apparatus structure. Other subcellular effects observed included multinucleated cells seen after RNAi to either pgant2 or pgant35A, suggesting a role for these genes in the completion of cytokinesis. These studies demonstrate the efficient and specific knockdown of pgant gene expression in two Drosophila cell culture systems, resulting in specific morphological and functional effects. Our work provides new information regarding the biological roles of O-glycosylation and illustrates a new platform for interrogating the cellular and subcellular effects of this form of post-translational modification. C1 [Zhang, Liping; Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), Bldg 30,Rm 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health (Intramural Research Program of the NIDCR). NR 44 TC 14 Z9 14 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 5 PY 2010 VL 285 IS 45 BP 34477 EP 34484 DI 10.1074/jbc.M110.133561 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673KL UT WOS:000283659100022 PM 20807760 ER PT J AU Park, YD Panepinto, J Shin, S Larsen, P Giles, S Williamson, PR AF Park, Yoon-Dong Panepinto, John Shin, Soowan Larsen, Peter Giles, Steven Williamson, Peter R. TI Mating Pheromone in Cryptococcus neoformans Is Regulated by a Transcriptional/Degradative "Futile" Cycle SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FUNGAL PATHOGEN CRYPTOCOCCUS; MESSENGER-RNA; PROTEIN-KINASE; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; SEXUAL REPRODUCTION; STRESS-RESPONSE; VIRULENCE; DIFFERENTIATION; HELICASE AB Sexual reproduction in fungi requires induction of signaling pheromones within environments that are conducive to mating. The fungus Cryptococcus neoformans is currently the fourth greatest cause of infectious death in regions of Africa and undergoes mating in phytonutrient-rich environments to create spores with infectious potential. Here we show that under conditions where sexual development is inhibited, a similar to 17-fold excess of MF alpha pheromone transcript is synthesized and then degraded by a DEAD box protein, Vad1, resulting in low steady state transcript levels. Transfer to mating medium or deletion of the VAD1 gene resulted in high level accumulation of MF alpha transcripts and enhanced mating, acting in concert with the mating-related HOG1 pathway. We then investigated whether the high metabolic cost of this apparently futile transcriptional cycle could be justified by a more rapid induction of mating. Maintenance of Vad1 activity on inductive mating medium by constitutive expression resulted in repressed levels of MF alpha that did not prevent but rather prolonged the time to successful mating from 5-6 h to 15 h (p < 0.0001). In sum, these data suggest that VAD1 negatively regulates the sexual cell cycle via degradation of constitutive high levels of MF alpha transcripts in a synthetic/degradative cycle, providing a mechanism of mRNA induction for time-critical cellular events, such as mating induction. C1 NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Panepinto, John] SUNY Buffalo, Dept Microbiol & Immunol, Witebsky Ctr Microbial Pathogenesis & Immunol, Buffalo, NY 14214 USA. [Shin, Soowan; Williamson, Peter R.] Univ Illinois, Infect Dis Sect, Dept Med, Chicago, IL 60612 USA. [Larsen, Peter] Argonne Natl Lab, Biosci Div, Lemont, IL 60439 USA. [Giles, Steven] Univ Wisconsin, Dept Bacteriol, Madison, WI 53701 USA. RP Williamson, PR (reprint author), 9000 Rockville Pike,Bldg 10,Rm 11N234,MSC 1888, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU National Institutes of Health [AI45995, AI49371]; National Institutes of Health, NIAID; American Heart Association [0725736Z] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI45995 and AI49371 and by the Intramural Research Program of the National Institutes of Health, NIAID. This work was also supported by American Heart Association Grant 0725736Z. NR 59 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 5 PY 2010 VL 285 IS 45 BP 34746 EP 34756 DI 10.1074/jbc.M110.136812 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673KL UT WOS:000283659100050 PM 20801870 ER PT J AU Park, J Kang, SI Lee, SY Zhang, XF Kim, MS Beers, LF Lim, DS Avruch, J Kim, HS Lee, SB AF Park, Jikyoung Kang, Soo Im Lee, Sun-Young Zhang, Xian F. Kim, Myoung Shin Beers, Lisa F. Lim, Dae-Sik Avruch, Joseph Kim, Ho-Shik Lee, Sean Bong TI Tumor Suppressor Ras Association Domain Family 5 (RASSF5/NORE1) Mediates Death Receptor Ligand-induced Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMATIN CONDENSATION; NUCLEAR TRANSLOCATION; HIPPO PATHWAY; KINASE MST1; RASSF1A; ACTIVATION; PROTEIN; IDENTIFICATION; NORE1; PHOSPHORYLATION AB Epigenetic silencing of RASSF (Ras association domain family) genes RASSF1 and RASSF5 (also called NORE1) by CpG hypermethylation is found frequently in many cancers. Although the physiological roles of RASSF1 have been studied in some detail, the exact functions of RASSF5 are not well understood. Here, we show that RASSF5 plays an important role in mediating apoptosis in response to death receptor ligands, TNF-alpha and TNF-related apoptosis-inducing ligand. Depletion of RASSF5 by siRNA significantly reduced TNF-alpha-mediated apoptosis, likely through its interaction with proapoptotic kinase MST1, a mammalian homolog of Hippo. Consistent with this, siRNA knockdown of MST1 also resulted in resistance to TNF-alpha-induced apoptosis. To further study the role of Rassf5 in vivo, we generated Rassf5-deficient mouse. Inactivation of Rassf5 in mouse embryonic fibroblasts (MEFs) resulted in resistance to TNF-alpha- and TNF-related apoptosis-inducing ligand-mediated apoptosis. Importantly, Rassf5-null mice were significantly more resistant to TNF-alpha-induced apoptosis and failed to activate Mst1. Loss of Rassf5 also resulted in spontaneous immortalization of MEFs at earlier passages than the control MEFs, and Rassf5-null immortalized MEFs, but not the immortalized wild type MEFs, were fully transformed by K-RasG12V. Together, our results demonstrate a direct role for RASSF5 in death receptor ligand-mediated apoptosis and provide further evidence for RASSF5 as a tumor suppressor. C1 [Park, Jikyoung; Kang, Soo Im; Kim, Myoung Shin; Beers, Lisa F.; Lee, Sean Bong] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Lee, Sun-Young; Kim, Ho-Shik] Catholic Univ Korea, Coll Med, Dept Biochem, Seoul 137701, South Korea. [Zhang, Xian F.; Avruch, Joseph] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lim, Dae-Sik] Korea Adv Inst Sci & Technol, Biomed Res Ctr, Dept Biol Sci, Natl Res Lab Mol Genet, Taejon 305701, South Korea. RP Lee, SB (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,9D11, Bethesda, MD 20892 USA. EM seanL@intra.niddk.nih.gov RI Lim, Dae-Sik/C-1599-2011 OI Lim, Dae-Sik/0000-0003-2356-7555 FU National Institutes of Health NIDDK FX This work was supported, in whole or in part, by a grant the National Institutes of Health NIDDK Intramural Research Program (to S. B. L.). NR 43 TC 35 Z9 37 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 5 PY 2010 VL 285 IS 45 BP 35029 EP 35038 DI 10.1074/jbc.M110.165506 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673KL UT WOS:000283659100077 PM 20810663 ER PT J AU Jha, KN Wong, L Zerfas, PM De Silva, RS Fan, YX Spiridonov, NA Johnson, GR AF Jha, Kula N. Wong, Lily Zerfas, Patricia M. De Silva, Rukman S. Fan, Ying-Xin Spiridonov, Nikolay A. Johnson, Gibbes R. TI Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HSP90 CHAPERONE MACHINERY; MOLECULAR CHAPERONES; SIGNAL-TRANSDUCTION; MALE-INFERTILITY; PROTEIN-KINASES; CO-CHAPERONE; BINDING; CELL; SPERMATOGENESIS; RECEPTOR AB We previously reported the identification of small serine/threonine kinase (SSTK) that is expressed in postmeiotic germ cells, associates with HSP90, and is indispensable for male fertility. Sperm from SSTK-null mice cannot fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida. Here, using the yeast two-hybrid screen, we have discovered a novel SSTK-interacting protein (SIP) that is expressed exclusively in testis. The gene encoding SIP is restricted to mammals and encodes a 125-amino acid polypeptide with a predicted tetratricopeptide repeat domain. SIP is co-localized with SSTK in the cytoplasm of spermatids as they undergo restructuring and chromatin condensation, but unlike SSTK, is not retained in the mature sperm. SIP binds to SSTK with high affinity (K-d similar to 10 nM), and the proteins associate with each other when co-expressed in cells. In vitro, SIP inhibited SSTK kinase activity, whereas the presence of SIP in cells resulted in enzymatic activation of SSTK without affecting Akt or MAPK activity. SIP was found to be associated with cellular HSP70, and analyses with purified proteins revealed that SIP directly bound HSP70. Importantly, SSTK recruited SIP onto HSP90, and treatment of cells with the specific HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, completely abolished SSTK catalytic activity. Hence, these findings demonstrate that HSP90 is essential for functional maturation of the kinase and identify SIP as a cochaperone that is critical to the HSP90-mediated activation of SSTK. C1 [Jha, Kula N.; Wong, Lily; De Silva, Rukman S.; Fan, Ying-Xin; Spiridonov, Nikolay A.; Johnson, Gibbes R.] US FDA, Chem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Zerfas, Patricia M.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. RP Johnson, GR (reprint author), US FDA, Chem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, 29 Lincoln Dr,Bldg 29A,HFD 122, Bethesda, MD 20892 USA. EM gibbes.johnson@fda.hhs.gov RI Spiridonov, Nikolay/B-6287-2014 NR 39 TC 3 Z9 6 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 J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 5 PY 2010 VL 285 IS 45 BP 35180 EP 35187 DI 10.1074/jbc.M110.134767 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 673KL UT WOS:000283659100091 PM 20829357 ER PT J AU Fields, RD AF Fields, R. Douglas TI Change in the Brain's White Matter SO SCIENCE LA English DT Editorial Material ID MYELINATION; RELEASE; OLIGODENDROCYTES; ARCHITECTURE; MECHANISM; IMPULSES; NEURONS; CELLS C1 NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov RI Messier, Claude/A-2322-2008 OI Messier, Claude/0000-0002-4791-1763 NR 18 TC 62 Z9 65 U1 1 U2 17 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 NOV 5 PY 2010 VL 330 IS 6005 BP 768 EP 769 DI 10.1126/science.1199139 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 675SY UT WOS:000283855700028 PM 21051624 ER PT J AU Filipovich, AH Zhang, KJ Snow, AL Marsh, RA AF Filipovich, Alexandra H. Zhang, Kejian Snow, Andrew L. Marsh, Rebecca A. TI X-linked lymphoproliferative syndromes: brothers or distant cousins? SO BLOOD LA English DT Review ID STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELLS; COMMON VARIABLE IMMUNODEFICIENCY; SYNDROME GENE-PRODUCT; BARR-VIRUS INFECTION; CD8(+) T-CELLS; NF-KAPPA-B; HUMORAL IMMUNITY; XIAP DEFICIENCY; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AB X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies. (Blood. 2010;116(18):3398-3408) C1 [Filipovich, Alexandra H.; Marsh, Rebecca A.] Cincinnati Childrens Hosp, Med Ctr, Div Bone Marrow Transplantat & Immunodeficiency, Cincinnati, OH 45229 USA. [Filipovich, Alexandra H.; Zhang, Kejian] Cincinnati Childrens Hosp, Med Ctr, Diagnost Ctr Heritable Immunodeficiencies, Cincinnati, OH 45229 USA. [Zhang, Kejian] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Snow, Andrew L.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Filipovich, AH (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Bone Marrow Transplantat & Immunodeficiency, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM Lisa.Filipovich@cchmc.org OI Snow, Andrew/0000-0002-8728-6691 FU Histiocytosis Association of America; National Institutes of Health [R03 1R03AI079797-01]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Histiocytosis Association of America and the National Institutes of Health (grant R03 1R03AI079797-01). A. L. S. is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 79 TC 71 Z9 75 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 4 PY 2010 VL 116 IS 18 BP 3398 EP 3408 DI 10.1182/blood-2010-03-275909 PG 11 WC Hematology SC Hematology GA 675SM UT WOS:000283853200009 PM 20660790 ER PT J AU Tumanov, AV Grivennikov, SI Kruglov, AA Shebzukhov, YV Koroleva, EP Piao, YL Cui, CY Kuprash, DV Nedospasov, SA AF Tumanov, Alexei V. Grivennikov, Sergei I. Kruglov, Andrei A. Shebzukhov, Yuriy V. Koroleva, Ekaterina P. Piao, Yulan Cui, Chang-Yi Kuprash, Dmitry V. Nedospasov, Sergei A. TI Cellular source and molecular form of TNF specify its distinct functions in organization of secondary lymphoid organs SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; LYMPHOTOXIN-BETA-RECEPTOR; FOLLICULAR DENDRITIC CELLS; B-CELLS; GERMINAL-CENTERS; IN-VIVO; PEYERS-PATCHES; SPLENIC FOLLICLES; DEFICIENT MICE; KNOCKOUT MICE AB Secondary lymphoid organs provide a unique microenvironment for generation of immune responses. Using a cell type-specific conditional knockout approach, we have dissected contributions of tumor necrosis factor (TNF) produced by B cells (B-TNF) or T cells (T-TNF) to the genesis and homeostatic organization of secondary lymphoid organs. In spleen, lymph nodes and Peyer patches, the cellular source of TNF, and its molecular form (soluble versus membrane-bound) appeared distinct. In spleen, in addition to major B-TNF signal, a complementary T-TNF signal contributed to the microstructure. In contrast, B-TNF predominantly controlled the development of follicular dendritic cells and B-cell follicles in Peyer patches. In lymph nodes, cooperation between TNF expressed by B and T cells was necessary for the maintenance of microarchitecture and for generation of an efficient humoral immune response. Unexpectedly, soluble but not membrane TNF expressed by B cells was essential for the organization of the secondary lymphoid organs. Thus, the maintenance of each type of secondary lymphoid organ is orchestrated by distinct contributions of membrane-bound and soluble TNF produced by B and T lymphocytes. (Blood. 2010;116(18):3456-3464) C1 [Tumanov, Alexei V.; Grivennikov, Sergei I.; Kruglov, Andrei A.; Shebzukhov, Yuriy V.; Kuprash, Dmitry V.; Nedospasov, Sergei A.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. [Tumanov, Alexei V.; Grivennikov, Sergei I.; Kruglov, Andrei A.; Shebzukhov, Yuriy V.; Kuprash, Dmitry V.; Nedospasov, Sergei A.] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia. [Tumanov, Alexei V.; Grivennikov, Sergei I.; Kruglov, Andrei A.; Shebzukhov, Yuriy V.; Kuprash, Dmitry V.; Nedospasov, Sergei A.] Moscow MV Lomonosov State Univ, Fac Biol, Moscow, Russia. [Tumanov, Alexei V.; Koroleva, Ekaterina P.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Kruglov, Andrei A.; Shebzukhov, Yuriy V.; Nedospasov, Sergei A.] German Rheumatism Res Ctr DRFZ, Berlin, Germany. [Piao, Yulan; Cui, Chang-Yi] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Kuprash, DV (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Vavilov St 32, Moscow 119991, Russia. EM sergei.nedospasov@gmail.com RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016; OI Kuprash, Dmitry/0000-0002-1488-4148; kruglov, andrey/0000-0002-4597-2087 FU Russian Academy of Sciences; Russian Foundation for Basic Research [09-04-12185]; Russian Federation [02.120.11.8796]; Deutsche Forschungsgemeinschaft [SFB633]; National Institute on Aging, National Institutes of Health; Helmholtz-Humboldt award FX This project has been funded in part with Molecular and Cell Biology grants from the Russian Academy of Sciences, by grant 09-04-12185 from the Russian Foundation for Basic Research, by Grant of the President of the Russian Federation for support of leading scientific schools (grant 02.120.11.8796), and by Deutsche Forschungsgemeinschaft (SFB633). This work was also in part supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. S.A.N. is International Research Scholar of the Howard Hughes Medical Institute and the recipient of Helmholtz-Humboldt award. NR 51 TC 31 Z9 33 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 4 PY 2010 VL 116 IS 18 BP 3456 EP 3464 DI 10.1182/blood-2009-10-249177 PG 9 WC Hematology SC Hematology GA 675SM UT WOS:000283853200015 PM 20634375 ER PT J AU Tewary, P Yang, D de la Rosa, G Li, YN Finn, MW Krensky, AM Clayberger, C Oppenheim, JJ AF Tewary, Poonam Yang, De de la Rosa, Gonzalo Li, Yana Finn, Michael W. Krensky, Alan M. Clayberger, Carol Oppenheim, Joost J. TI Granulysin activates antigen-presenting cells through TLR4 and acts as an immune alarmin SO BLOOD LA English DT Article ID TOLL-LIKE RECEPTORS; T-CELLS; SERUM GRANULYSIN; DENDRITIC CELLS; HOST-DEFENSE; MYCOBACTERIUM-TUBERCULOSIS; CYTOLYTIC MOLECULE; INDUCED APOPTOSIS; EXPRESSION; RESPONSES AB Granulysin (GNLY), an antimicrobial protein present in the granules of human cytotoxic T lymphocytes and natural killer (NK) cells, is produced as an intact 15-kDa form that is cleaved to yield a 9-kDa form. Alarmins are endogenous mediators that can induce recruitment and activation of antigen-presenting cells (APCs) and consequently promote the generation of immune response. We hypothesized that GNLY might function as an alarmin. Here, we report that both 9- and 15-kDa forms of recombinant GNLY-induced in vitro chemotaxis and activation of both human and mouse dendritic cells (DCs), recruited inflammatory leucocytes, including APCs in mice, and promoted antigen-specific immune responses upon coadministration with an antigen. GNLY-induced APC recruitment and activation required the presence of Toll-like receptor 4. The observed activity of recombinant GNLY was not due to endotoxin contamination. The capability of the supernatant of GNLY-expressing HuT78 cells to activate DC was blocked by anti-GNLY antibodies. Finally we present evidence that supernatants of degranulated human NK92 or primary NK cells also activated DCs in a GNLY- and Toll-like receptor 4-dependent manner, indicating the physiologic relevance of our findings. Thus, GNLY is the first identified lymphocyte-derived alarmin capable of promoting APC recruitment, activation, and antigen-specific immune response. (Blood. 2010;116(18):3465-3474) C1 [Tewary, Poonam; Yang, De; de la Rosa, Gonzalo; Li, Yana; Oppenheim, Joost J.] NCI, LMI, CIP, CCR, Frederick, MD 21702 USA. [Yang, De] NCI, BRP, Sci Applicat Int Corp Frederick, NIH, Frederick, MD 21702 USA. [Finn, Michael W.; Krensky, Alan M.; Clayberger, Carol] NCI, Cellular & Mol Biol Lab, CCR, Bethesda, MD 21702 USA. RP Tewary, P (reprint author), NCI, LMI, CIP, CCR, 1050 Boyles St,POB B,Rm 31-19,Bldg 560, Frederick, MD 21702 USA. EM tewaryp@mail.nih.gov; oppenhej@mail.nih.gov FU NCI, National Institutes of Health [N01-CO-12400] FX The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. This project has been funded in whole or in part with federal funds from the NCI, National Institutes of Health, under contract N01-CO-12400. The publisher or recipient acknowledges right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. NR 41 TC 45 Z9 49 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 4 PY 2010 VL 116 IS 18 BP 3465 EP 3474 DI 10.1182/blood-2010-03-273953 PG 10 WC Hematology SC Hematology GA 675SM UT WOS:000283853200016 PM 20660289 ER PT J AU Barber, DL Mayer-Barber, KD Antonelli, LRV Wilson, MS White, S Caspar, P Hieny, S Sereti, I Sher, A AF Barber, Daniel L. Mayer-Barber, Katrin D. Antonelli, Lis R. V. Wilson, Mark S. White, Sandra Caspar, Patricia Hieny, Sara Sereti, Irini Sher, Alan TI Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice SO BLOOD LA English DT Article ID CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; INFLAMMATORY SYNDROME; HIV-1-INFECTED PATIENTS; RESTORATION SYNDROME; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; OMENN-SYNDROME; PROLIFERATION; TUBERCULOSIS AB Following antiretroviral therapy, a significant proportion of HIV+ patients with mycobacterial coinfections develop a paradoxical, poorly understood inflammatory disease termed immune reconstitution inflammatory syndrome (IRIS). Here, we show that Mycobacterium avium-infected T cell-deficient mice injected with CD4 T cells also develop an immune reconstitution disease (IRD) manifesting as weight loss, impaired lung function, and rapid mortality. This form of IRD requires Ag recognition and interferon gamma production by the donor CD4 T cells and correlates with marked alterations in blood and tissue CD11b(+) myeloid cells. Interestingly, disease is associated with impaired, rather than augmented, T-cell expansion and function and is not strictly dependent on lymphopenia-induced T-cell proliferation. Instead, our findings suggest that mycobacterial-associated IRIS results from a heightened sensitivity of infected lymphopenic hosts to the detrimental effects of Ag-driven CD4 T-cell responses. (Blood. 2010;116(18):3485-3493) C1 [Barber, Daniel L.; Mayer-Barber, Katrin D.; Antonelli, Lis R. V.; White, Sandra; Caspar, Patricia; Hieny, Sara; Sher, Alan] NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Mark S.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Barber, DL (reprint author), NIAID, Immunol Sect, Parasit Dis Lab, NIH, 50 South Dr,Rm 6146, Bethesda, MD 20892 USA. EM barberd@niaid.nih.gov RI Vacinas, Inct/J-9431-2013; Antonelli, Lis/G-2907-2012 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 36 TC 39 Z9 39 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 4 PY 2010 VL 116 IS 18 BP 3485 EP 3493 DI 10.1182/blood-2010-05-286336 PG 9 WC Hematology SC Hematology GA 675SM UT WOS:000283853200018 PM 20656932 ER PT J AU Contreras, JE Chen, J Lau, AY Jogini, V Roux, B Holmgren, M AF Contreras, Jorge E. Chen, Jin Lau, Albert Y. Jogini, Vishwanath Roux, Benoit Holmgren, Miguel TI Voltage Profile along the Permeation Pathway of an Open Channel SO BIOPHYSICAL JOURNAL LA English DT Article ID NUCLEOTIDE-GATED CHANNELS; RECTIFIER K+ CHANNELS; POTASSIUM CHANNEL; SELECTIVITY FILTER; ION CONDUCTION; CYCLIC-GMP; INTRACELLULAR POLYAMINES; MONOVALENT CATIONS; ACTIVATED CHANNEL; INNER PORE AB For ion channels, the transmembrane potential plays a critical role by acting as a driving force for permeant ions. At the microscopic level, the transmembrane potential is thought to decay nonlinearly across the ion permeation pathway because of the irregular three-dimensional shape of the channel's pore. By taking advantage of the current structural and functional understanding of cyclic nucleotide-gated channels, in this study we experimentally explore the transmembrane potential's distribution across the open pore. As a readout for the voltage drop, we engineered cysteine residues along the selectivity filter and scanned the sensitivity of their modification rates by Ag(+) to the transmembrane potential. The experimental data, which indicate that the majority of the electric field drops across the selectivity filter, are in good agreement with continuum electrostatic calculations using a homology model of an open CNG channel. By focusing the transmembrane potential across the selectivity filter, the electromotive driving force is coupled with the movement of permeant ions in the filter, maximizing the efficiency of this process. C1 [Contreras, Jorge E.; Chen, Jin; Holmgren, Miguel] NINDS, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Lau, Albert Y.; Jogini, Vishwanath; Roux, Benoit] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. RP Contreras, JE (reprint author), NINDS, Mol Neurophysiol Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM contrerjo@ninds.nih.gov; holmgren@ninds.nih.gov FU Ruth L. Kirschstein Postdoctoral Fellowship; National Institutes of Health, National Institute of Neurological Disorders and Stroke; National Institutes of Health [GM-62342] FX J.E.C. was supported by a Ruth L. Kirschstein Postdoctoral Fellowship. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. V.J., A.Y.L., and B.R. are supported by grant No. GM-62342 from the National Institutes of Health. NR 56 TC 8 Z9 8 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD NOV 3 PY 2010 VL 99 IS 9 BP 2863 EP 2869 DI 10.1016/j.bpj.2010.08.053 PG 7 WC Biophysics SC Biophysics GA 676LJ UT WOS:000283912600020 PM 21044583 ER PT J AU Knight, JD Lerner, MG Marcano-Velazquez, JG Pastor, RW Falke, JJ AF Knight, Jefferson D. Lerner, Michael G. Marcano-Velazquez, Joan G. Pastor, Richard W. Falke, Joseph J. TI Single Molecule Diffusion of Membrane-Bound Proteins: Window into Lipid Contacts and Bilayer Dynamics SO BIOPHYSICAL JOURNAL LA English DT Article ID SFP PHOSPHOPANTETHEINYL TRANSFERASE; PLECKSTRIN HOMOLOGY DOMAINS; KINASE-C-ALPHA; LATERAL DIFFUSION; BINDING; SYNAPTOTAGMIN; SIMULATIONS; MECHANISM; TRANSLOCATION; FLUORESCENCE AB Membrane targeting proteins are recruited to specific membranes during cell signaling events, including signals at the leading edge of chemotaxing cells. Recognition and binding to specific lipids play a central role in targeting reactions, but it remains difficult to analyze the molecular features of such protein-lipid interactions. We propose that the surface diffusion constant of peripheral membrane-bound proteins contains useful information about protein-lipid contacts and membrane dynamics. To test this hypothesis, we use single-molecule fluorescence microscopy to probe the effects of lipid binding stoichiometry on the diffusion constants of engineered proteins containing one to three pleckstrin homology domains coupled by flexible linkers. Within error, the lateral diffusion constants of these engineered constructs are inversely proportional to the number of tightly bound phosphatidylinositol-(3,4,5)-trisphosphate lipids. The same trend is observed in coarse-grained molecular dynamics simulations and hydrodynamic bead calculations of lipid multimers connected by model tethers. Overall, single molecule diffusion measurements are found to provide molecular information about protein-lipid interactions. Moreover, the experimental and computational results independently indicate that the frictional contributions of multiple, coupled but well-separated lipids are additive, analogous to the free-draining limit for isotropic fluids-an insight with significant implications for theoretical description of bilayer lipid dynamics. C1 [Knight, Jefferson D.; Marcano-Velazquez, Joan G.; Falke, Joseph J.] Univ Colorado, Mol Biophys Program, Boulder, CO 80309 USA. [Knight, Jefferson D.; Marcano-Velazquez, Joan G.; Falke, Joseph J.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Lerner, Michael G.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Falke, JJ (reprint author), Univ Colorado, Mol Biophys Program, Boulder, CO 80309 USA. EM falke@colorado.edu OI Knight, Jefferson/0000-0003-2208-4420 FU National Institutes of Health (NIH) [R01 GM-063235]; NIH, National Heart, Lung, and Blood Institute (NHLBI); W.M. Keck Foundation; NIH, Bethesda, MD FX Research support was provided by National Institutes of Health (NIH) grant No. R01 GM-063235 to J.J.F., and by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI) to R.W.P. and M.G.L. This study employed the shared single molecule TIRFM facility at the University of Colorado, Boulder (supported by the W.M. Keck Foundation, to Prof. Art Pardi, P.I.), and the high-performance computational facility at the NIH, Bethesda, MD (NHLBI LoBoS clusters). NR 46 TC 58 Z9 59 U1 3 U2 62 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD NOV 3 PY 2010 VL 99 IS 9 BP 2879 EP 2887 DI 10.1016/j.bpj.2010.08.046 PG 9 WC Biophysics SC Biophysics GA 676LJ UT WOS:000283912600022 PM 21044585 ER PT J AU Stasevich, TJ Mueller, F Michelman-Ribeiro, A Rosales, T Knutson, JR McNally, JG AF Stasevich, Timothy J. Mueller, Florian Michelman-Ribeiro, Ariel Rosales, Tilman Knutson, Jay R. McNally, James G. TI Cross-Validating FRAP and FCS to Quantify the Impact of Photobleaching on In Vivo Binding Estimates SO BIOPHYSICAL JOURNAL LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; DNA-BINDING; LIVE CELLS; GLUCOCORTICOID-RECEPTOR; DIFFUSION-COEFFICIENTS; NUCLEAR PROTEINS; LIVING CELLS; DYNAMICS; RECOVERY; HETEROCHROMATIN AB Binding can now be quantified in live cells, but the accuracy of such measurements remains uncertain. To address this uncertainty, we compare fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS) measurements of the binding kinetics of a transcription factor, the glucocorticoid receptor, in the nuclei of live cells. We find that the binding residence time measured by FRAP is 15 times longer than that obtained by FCS. We show that this discrepancy is not likely due to the significant differences in concentrations typically used for FRAP and FCS, nor is it likely due to spatial heterogeneity of the nucleus, improper calibration of the FCS focal volume, or the intentional FRAP photobleach. Instead, our data indicate that photobleaching of bound molecules in FCS is mainly responsible. When this effect is minimized, FRAP and FCS measurements nearly agree, although cross-validation by other approaches is now required to rule out mutual errors. Our results demonstrate the necessity of a photobleach correction for FCS measurements of GFP-tagged molecules that are bound for >0.25 s, and represent an important step forward in establishing a gold standard for in vivo binding measurements. C1 [Stasevich, Timothy J.; Mueller, Florian; Michelman-Ribeiro, Ariel; McNally, James G.] NCI, NIH, Bethesda, MD 20892 USA. [Rosales, Tilman; Knutson, Jay R.] NHLBI, Lab Mol Biophys, Bethesda, MD 20892 USA. RP McNally, JG (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov RI Mueller, Florian/C-9075-2012 OI Mueller, Florian/0000-0002-9622-4396 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Heart, Lung, and Blood Institute FX This research was supported in part by the intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Heart, Lung, and Blood Institute. NR 43 TC 40 Z9 41 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD NOV 3 PY 2010 VL 99 IS 9 BP 3093 EP 3101 DI 10.1016/j.bpj.2010.08.059 PG 9 WC Biophysics SC Biophysics GA 676LJ UT WOS:000283912600045 PM 21044608 ER PT J AU Stitzel, ML Sethupathy, P Pearson, DS Chines, PS Song, LY Erdos, MR Welch, R Parker, SCJ Boyle, AP Scott, LJ Margulies, EH Boehnke, M Furey, TS Crawford, GE Collins, FS AF Stitzel, Michael L. Sethupathy, Praveen Pearson, Daniel S. Chines, Peter S. Song, Lingyun Erdos, Michael R. Welch, Ryan Parker, Stephen C. J. Boyle, Alan P. Scott, Laura J. Margulies, Elliott H. Boehnke, Michael Furey, Terrence S. Crawford, Gregory E. Collins, Francis S. CA NISC Comparative Sequencing Progra TI Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci SO CELL METABOLISM LA English DT Article ID RANGE CHROMOSOMAL INTERACTIONS; GENOME-WIDE ASSOCIATION; INSULIN-SECRETION; BETA-CELLS; OPEN CHROMATIN; HISTONE MODIFICATIONS; REGULATORY ELEMENTS; GENE-EXPRESSION; BINDING-SITES; IN-VIVO AB Identifying cis-regulatory elements is important to understanding how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified 18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (nonpromoter) regulatory elements, 47% are islet unique and 22% are CTCF bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12 of 33 tested. Among six regulatory elements harboring T2D-associated variants, two exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of T2D and other islet disorders. C1 [Stitzel, Michael L.; Sethupathy, Praveen; Pearson, Daniel S.; Chines, Peter S.; Erdos, Michael R.; Parker, Stephen C. J.; Margulies, Elliott H.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. [Song, Lingyun; Boyle, Alan P.; Furey, Terrence S.; Crawford, Gregory E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27708 USA. [Crawford, Gregory E.] Duke Univ, Dept Pediat, Div Med Genet, Durham, NC 27708 USA. [Welch, Ryan; Scott, Laura J.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov RI Boyle, Alan/I-1848-2014; OI Boyle, Alan/0000-0002-2081-1105; Furey, Terry/0000-0001-5546-9672 FU NIH Division of Intramural Research/NHGRI [Z01-HG000024]; NIH [DK062370]; NIH/NHGRI ENCODE Consortium [U54HG004563] FX Human pancreatic islets used in this study were obtained through the ICR Basic Science Islet Distribution Program (University of Minnesota, University of Alabama-Birmingham, University of Illinois, University of Miami, Northwestern University) and the National Disease Research Interchange (NDRI). We thank Fangfei Ye and Lisa Bukovnik at the Duke IGSP Sequencing Core Facility for sequencing DNase libraries, the DIAGRAM Consortium for helpful discussion regarding variants in the KCNQ1 locus, and members of the Collins and Boehnke labs for insightful discussions during the study and critical comments on the manuscript. Special thanks to Cristen Willer and Greg Keele for help with statistical analyses of ChIP/GWAS data. This study was supported by the NIH Division of Intramural Research/NHGRI project number Z01-HG000024 (F.S.C.), by NIH grant DK062370 (M.B.), and by an NIH/NHGRI ENCODE Consortium grant (U54HG004563 to G.E.C. and T.S.F.). NR 64 TC 102 Z9 102 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD NOV 3 PY 2010 VL 12 IS 5 BP 443 EP 455 DI 10.1016/j.cmet.2010.09.012 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 676XP UT WOS:000283952300008 PM 21035756 ER PT J AU King, AC Guralnik, JM AF King, Abby C. Guralnik, Jack M. TI Maximizing the Potential of an Aging Population SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DISABILITY; TRIAL; CARE C1 [King, Abby C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP King, AC (reprint author), Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, 159 Campus Dr,HRP Redwood Bldg,T221, Stanford, CA 94305 USA. EM king@stanford.edu FU NIA NIH HHS [2U01 AG022376-05A1] NR 10 TC 19 Z9 20 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 3 PY 2010 VL 304 IS 17 BP 1944 EP 1945 DI 10.1001/jama.2010.1577 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 674GT UT WOS:000283725900025 PM 21045101 ER PT J AU Eisenberg, DP Kohn, PD Baller, EB Bronstein, JA Masdeu, JC Berman, KF AF Eisenberg, Daniel P. Kohn, Philip D. Baller, Erica B. Bronstein, Joel A. Masdeu, Joseph C. Berman, Karen F. TI Seasonal Effects on Human Striatal Presynaptic Dopamine Synthesis SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AFFECTIVE-DISORDER; HUMAN BRAIN; MELATONIN; EXPRESSION; DEPRESSION; RECEPTORS; RHYTHM; DECREASES; PATIENT; BINDING AB Past studies in rodents have demonstrated circannual variation in central dopaminergic activity as well as a host of compelling interactions between melatonin-a scotoperiod-responsive neurohormone closely tied to seasonal adaptation-and dopamine in the striatum and in midbrain neuronal populations with striatal projections. In humans, seasonal effects have been described for dopaminergic markers in CSF and postmortem brain, and there exists a range of affective, psychotic, and substance abuse disorders that have been associated with both seasonal symptomatic fluctuations and dopamine neurotransmission abnormalities. Together, these data indirectly suggest a potentially crucial link between circannual biorhythms and central dopamine systems. However, seasonal effects on dopamine function in the living, healthy human brain have never been tested. For this study, 86 healthy adults underwent (18)F-DOPA positron emission tomography scanning, each at a different time throughout the year. Striatal regions of interest (ROIs) were evaluated for differences in presynaptic dopamine synthesis, measured by the kinetic rate constant, K(i), between fall-winter and spring-summer scans. Analyses comparing ROI average K(i) values showed significantly greater putamen (18)F-DOPA K(i) in the fall-winter relative to the spring-summer group (p = 0.038). Analyses comparing voxelwise K(i) values confirmed this finding and evidenced intrastriatal localization of seasonal effects to the caudal putamen (p < 0.05, false-discovery rate corrected), a region that receives dopaminergic input predominantly from the substantia nigra. These data are the first to directly demonstrate a seasonal effect on striatal presynaptic dopamine synthesis and merit future research aimed at elucidating underlying mechanisms and implications for neuropsychiatric disease and new treatment approaches. C1 [Eisenberg, Daniel P.; Kohn, Philip D.; Baller, Erica B.; Bronstein, Joel A.; Masdeu, Joseph C.; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,NIH,Dept Hlth &, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,NIH,Dept Hlth &, 9000 Rockville Pike,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM Karen.Berman@nih.gov RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health. We thank the staff of the NIH PET Center for their assistance in data acquisition. NR 40 TC 19 Z9 20 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 3 PY 2010 VL 30 IS 44 BP 14691 EP 14694 DI 10.1523/JNEUROSCI.1953-10.2010 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 674ZT UT WOS:000283793400011 PM 21048126 ER PT J AU Porter, FD Scherrer, DE Lanier, MH Langmade, SJ Molugu, V Gale, SE Olzeski, D Sidhu, R Dietzen, DJ Fu, R Wassif, CA Yanjanin, NM Marso, SP House, J Vite, C Schaffer, JE Ory, DS AF Porter, Forbes D. Scherrer, David E. Lanier, Michael H. Langmade, S. Joshua Molugu, Vasumathi Gale, Sarah E. Olzeski, Dana Sidhu, Rohini Dietzen, Dennis J. Fu, Rao Wassif, Christopher A. Yanjanin, Nicole M. Marso, Steven P. House, John Vite, Charles Schaffer, Jean E. Ory, Daniel S. TI Cholesterol Oxidation Products Are Sensitive and Specific Blood-Based Biomarkers for Niemann-Pick C1 Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TANDEM MASS-SPECTROMETRY; DIABETES-MELLITUS; PLASMA-LEVELS; NPC1 MOUSE; MICE; HOMEOSTASIS; STRESS; OXYSTEROLS; BRAIN; LIVER AB Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by accumulation of cholesterol in the endolysosomes. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that nonenzymatic formation of cholesterol oxidation products could serve as disease biomarkers. We measured these metabolites in the plasma and tissues of the Npc1(-/-) mouse model and found several cholesterol oxidation products that were elevated in Npc1-/- mice, were detectable before the onset of symptoms, and were associated with disease progression. Nonenzymatically formed cholesterol oxidation products were similarly increased in the plasma of all human NPC1 subjects studied and delineated an oxysterol profile specific for NPC1 disease. This oxysterol profile also correlated with the age of disease onset and disease severity. We further show that the plasma oxysterol markers decreased in response to an established therapeutic intervention in the NPC1 feline model. These cholesterol oxidation products are robust blood-based biochemical markers for NPC1 disease that may prove transformative for diagnosis and treatment of this disorder, and as outcome measures to monitor response to therapy. C1 [Scherrer, David E.; Lanier, Michael H.; Langmade, S. Joshua; Molugu, Vasumathi; Gale, Sarah E.; Olzeski, Dana; Sidhu, Rohini; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Porter, Forbes D.; Fu, Rao; Wassif, Christopher A.; Yanjanin, Nicole M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Dietzen, Dennis J.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Marso, Steven P.; House, John] Univ Missouri, Kansas City Sch Med, St Lukes Mid Amer Heart & Vasc Inst, Kansas City, MO 64111 USA. [Vite, Charles] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA. RP Ory, DS (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. EM dory@wustl.edu RI Sidhu, Rohini/G-3547-2012; OI Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Rare Diseases; Washington University Specialized Centers of Clinically Oriented Research [P50 HL083762, RR02512]; Dana's Angels Research Trust; Ara Parseghian Medical Research Foundation; NIH [06-CH-0186]; Hadley Hope Fund; [P20 RR020643]; [P60 DK020579] FX We are grateful to the Hadley Hope Fund and Ed Cutler (Phlebotomy Services International) for their assistance in obtaining samples from control subjects. We also thank A. Mukherjee, C. Tifft, B. Shamburek, and E. Sidransky for non-NPC1 patient samples. We thank A. Bielska for assistance with figure preparation. This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside award from the Office of Rare Diseases (F.D.P.). The authors express their appreciation to the families and patients who participated in this study.; This work was performed in the Metabolomics Core at Washington University. The authors received support from the Washington University Specialized Centers of Clinically Oriented Research grants P50 HL083762 (D.S.O.) and RR02512 (C.V.), Dana's Angels Research Trust (D.S.O. and N.M.Y.), and Ara Parseghian Medical Research Foundation (D.S.O., N.M.Y., and C.V.). Support was also provided by P20 RR020643 and P60 DK020579. Human samples were obtained under NIH protocol 06-CH-0186. NR 61 TC 79 Z9 84 U1 1 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD NOV 3 PY 2010 VL 2 IS 56 AR 56ra81 DI 10.1126/scitranslmed.3001417 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735TL UT WOS:000288441100002 PM 21048217 ER PT J AU Stang, PE Ryan, PB Racoosin, JA Overhage, JM Hartzema, AG Reich, C Welebob, E Scarnecchia, T Woodcock, J AF Stang, Paul E. Ryan, Patrick B. Racoosin, Judith A. Overhage, J. Marc Hartzema, Abraham G. Reich, Christian Welebob, Emily Scarnecchia, Thomas Woodcock, Janet TI Advancing the Science for Active Surveillance: Rationale and Design for the Observational Medical Outcomes Partnership SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SAFETY SURVEILLANCE; CLAIMS DATA; EVENTS; CARE; ALGORITHMS; DATABASE; NETWORK; RECORDS AB The U.S. Food and Drug Administration (FDA) Amendments Act of 2007 mandated that the FDA develop a system for using automated health care data to identify risks of marketed drugs and other medical products. The Observational Medical Outcomes Partnership is a public-private partnership among the FDA, academia, data owners, and the pharmaceutical industry that is responding to the need to advance the science of active medical product safety surveillance by using existing observational databases. The Observational Medical Outcomes Partnership's transparent, open innovation approach is designed to systematically and empirically study critical governance, data resource, and methodological issues and their interrelationships in establishing a viable national program of active drug safety surveillance by using observational data. This article describes the governance structure, data-access model, methods-testing approach, and technology development of this effort, as well as the work that has been initiated. C1 [Stang, Paul E.] Johnson & Johnson, Pharmaceut Res & Dev, Titusville, NJ 08560 USA. Fdn Natl Inst Hlth, Bethesda, MD USA. GlaxoSmithKline, Res Triangle Pk, NC USA. Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC USA. US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Univ Florida, Coll Pharm, Gainesville, FL USA. Digital Aurora, Manchester, VT USA. RP Stang, PE (reprint author), Johnson & Johnson, Pharmaceut Res & Dev, 1125 Trenton Harbourton Rd,POB 200,MS K304, Titusville, NJ 08560 USA. EM PStang@its.jnj.com OI Overhage, Joseph/0000-0003-0223-0195 FU Foundation for the National Institutes of Health FX The OMOP is funded by the Foundation for the National Institutes of Health, with contributions from a consortium of 17 organizations (Appendix Table, available at www.annals.org). Three members of the research team (Dr. Stang, Mr. Ryan, and Dr. Racoosin) serve in-kind and are not compensated for their participation. NR 35 TC 133 Z9 134 U1 2 U2 16 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 2 PY 2010 VL 153 IS 9 BP 600 EP 606 DI 10.7326/0003-4819-153-9-201011020-00010 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 673MH UT WOS:000283667000007 PM 21041580 ER PT J AU Sanghvi, M Moaddel, R Frazier, C Wainer, IW AF Sanghvi, M. Moaddel, R. Frazier, C. Wainer, I. W. TI Synthesis and characterization of liquid chromatographic columns containing the immobilized ligand binding domain of the estrogen related receptor alpha and estrogen related receptor gamma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Glioblastoma; Astrocytomas; Estrogen related receptor; Screening; Biochromatography ID STATIONARY-PHASE; NONCOMPETITIVE INHIBITORS; AFFINITY-CHROMATOGRAPHY; GLIOMA AB The ligand binding domains of the estrogen related receptors, ERR alpha and ERR gamma were covalently immobilized onto the surface of an aminopropyl silica liquid chromatography stationary phase to create the ERR alpha-silica and ERR gamma-silica columns and onto the surface of open tubular capillaries to create the ERR alpha-OT and ERR gamma-OT columns The ERR-silica and ERR-OT columns were characterized using frontal chromatographic techniques with diethylstibesterol and the binding affinities, K(d) values, to the immobilized receptors were consistent with the values obtained by a radioligand binding assay The ERR gamma-silica column was also characterized using non-linear chromatographic techniques using a series of tamoxifen derivatives The relative K(d) values obtained for the derivatives were consistent with the relative ability of the compounds to inhibit the cellular proliferation of the human-derived T98G glioma cell line, expressed as IC(50) values The results indicate that the columns containing immobilized ERR alpha and ERR gamma can be created and used to characterize the binding of compounds to the immobilized receptors and that the relative retention of compounds on these columns reflects the magnitude of their inhibitory activity Published by Elsevier B V C1 [Moaddel, R.] NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Moaddel, R (reprint author), NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Sanghvi, Mitesh/C-6740-2013 FU NIH, National Institute on Aging FX The research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging NR 15 TC 8 Z9 8 U1 0 U2 12 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 NOV 2 PY 2010 VL 53 IS 3 BP 777 EP 780 DI 10.1016/j.jpba.2010.05.016 PG 4 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 632PD UT WOS:000280435800078 PM 20542653 ER PT J AU Assimes, TL Holm, H Kathiresan, S Reilly, MP Thorleifsson, G Voight, BF Erdmann, J Willenborg, C Vaidya, D Xie, CC Patterson, CC Morgan, TM Burnett, MS Li, MY Hlatky, MA Knowles, JW Thompson, JR Absher, D Iribarren, C Go, A Fortmann, SP Sidney, S Risch, N Tang, H Myers, RM Berger, K Stoll, M Shah, SH Thorgeirsson, G Andersen, K Havulinna, AS Herrera, JE Faraday, N Kim, Y Kral, BG Mathias, RA Ruczinski, I Suktitipat, B Wilson, AF Yanek, LR Becker, LC Linsel-Nitschke, P Lieb, W Konig, IR Hengstenberg, C Fischer, M Stark, K Reinhard, W Winogradow, J Grassl, M Grosshennig, A Preuss, M Schreiber, S Wichmann, HE Meisinger, C Yee, J Friedlander, Y Do, R Meigs, JB Williams, G Nathan, DM MacRae, CA Qu, LM Wilensky, RL Matthai, WH Qasim, AN Hakonarson, H Pichard, AD Kent, KM Satler, L Lindsay, JM Waksman, R Knouff, CW Waterworth, DM Walker, MC Mooser, VE Marrugat, J Lucas, G Subirana, I Sala, J Ramos, R Martinelli, N Olivieri, O Trabetti, E Malerba, G Pignatti, PF Guiducci, C Mirel, D Parkin, M Hirschhorn, JN Asselta, R Duga, S Musunuru, K Daly, MJ Purcell, S Eifert, S Braund, PS Wright, BJ Balmforth, AJ Ball, SG Ouwehand, WH Deloukas, P Scholz, M Cambien, F Huge, A Scheffold, T Salomaa, V Girelli, D Granger, CB Peltonen, L McKeown, PP Altshuler, D Melander, O Devaney, JM Epstein, SE Rader, DJ Elosua, R Engert, JC Anand, SS Hall, AS Ziegler, A O'Donnell, CJ Spertus, JA Siscovick, D Schwartz, SM Becker, D Thorsteinsdottir, U Stefansson, K Schunkert, H Samani, NJ Quertermous, T AF Assimes, Themistocles L. Holm, Hilma Kathiresan, Sekar Reilly, Muredach P. Thorleifsson, Gudmar Voight, Benjamin F. Erdmann, Jeanette Willenborg, Christina Vaidya, Dhananjay Xie, Changchun Patterson, Chris C. Morgan, Thomas M. Burnett, Mary Susan Li, Mingyao Hlatky, Mark A. Knowles, Joshua W. Thompson, John R. Absher, Devin Iribarren, Carlos Go, Alan Fortmann, Stephen P. Sidney, Stephen Risch, Neil Tang, Hua Myers, Richard M. Berger, Klaus Stoll, Monika Shah, Svati H. Thorgeirsson, Gudmundur Andersen, Karl Havulinna, Aki S. Herrera, J. Enrique Faraday, Nauder Kim, Yoonhee Kral, Brian G. Mathias, Rasika A. Ruczinski, Ingo Suktitipat, Bhoom Wilson, Alexander F. Yanek, Lisa R. Becker, Lewis C. Linsel-Nitschke, Patrick Lieb, Wolfgang Koenig, Inke R. Hengstenberg, Christian Fischer, Marcus Stark, Klaus Reinhard, Wibke Winogradow, Janina Grassl, Martina Grosshennig, Anika Preuss, Michael Schreiber, Stefan Wichmann, H-Erich Meisinger, Christa Yee, Jean Friedlander, Yechiel Do, Ron Meigs, James B. Williams, Gordon Nathan, David M. MacRae, Calum A. Qu, Liming Wilensky, Robert L. Matthai, William H., Jr. Qasim, Atif N. Hakonarson, Hakon Pichard, Augusto D. Kent, Kenneth M. Satler, Lowell Lindsay, Joseph M. Waksman, Ron Knouff, Christopher W. Waterworth, Dawn M. Walker, Max C. Mooser, Vincent E. Marrugat, Jaume Lucas, Gavin Subirana, Isaac Sala, Joan Ramos, Rafael Martinelli, Nicola Olivieri, Oliviero Trabetti, Elisabetta Malerba, Giovanni Pignatti, Pier Franco Guiducci, Candace Mirel, Daniel Parkin, Melissa Hirschhorn, Joel N. Asselta, Rosanna Duga, Stefano Musunuru, Kiran Daly, Mark J. Purcell, Shaun Eifert, Sandra Braund, Peter S. Wright, Benjamin J. Balmforth, Anthony J. Ball, Stephen G. Ouwehand, Willem H. Deloukas, Panos Scholz, Michael Cambien, Francois Huge, Andreas Scheffold, Thomas Salomaa, Veikko Girelli, Domenico Granger, Christopher B. Peltonen, Leena McKeown, Pascal P. Altshuler, David Melander, Olle Devaney, Joseph M. Epstein, Stephen E. Rader, Daniel J. Elosua, Roberto Engert, James C. Anand, Sonia S. Hall, Alistair S. Ziegler, Andreas O'Donnell, Christopher J. Spertus, John A. Siscovick, David Schwartz, Stephen M. Becker, Diane Thorsteinsdottir, Unnur Stefansson, Kari Schunkert, Heribert Samani, Nilesh J. Quertermous, Thomas CA Myocardial Infarction Genet Wellcome Trust Case Control Cardiogenics TI Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery disease; KIF6; kinesin-like protein 6; myocardial infarction; polymorphism ID NONFATAL MYOCARDIAL-INFARCTION; HEART-DISEASE; CARDIOVASCULAR-DISEASE; GENE VARIANTS; RISK-FACTORS; GENOMEWIDE ASSOCIATION; CHROMOSOME 9P21.3; GENOTYPE DATA; POPULATION; HEALTH AB Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation C1 [Assimes, Themistocles L.; Hlatky, Mark A.; Knowles, Joshua W.; Fortmann, Stephen P.; Waksman, Ron; Quertermous, Thomas] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94304 USA. [Holm, Hilma; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Kathiresan, Sekar; MacRae, Calum A.; Musunuru, Kiran; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar; MacRae, Calum A.; Musunuru, Kiran; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar; Voight, Benjamin F.; Musunuru, Kiran; Daly, Mark J.; Purcell, Shaun; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar; Voight, Benjamin F.; Guiducci, Candace; Mirel, Daniel; Parkin, Melissa; Hirschhorn, Joel N.; Musunuru, Kiran; Daly, Mark J.; Purcell, Shaun; Peltonen, Leena; Altshuler, David] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Kathiresan, Sekar; Meigs, James B.; Williams, Gordon; Nathan, David M.; MacRae, Calum A.; Waksman, Ron; Musunuru, Kiran; Daly, Mark J.; Altshuler, David; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Reilly, Muredach P.; Wilensky, Robert L.; Matthai, William H., Jr.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach P.; Wilensky, Robert L.; Qasim, Atif N.; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Voight, Benjamin F.; Altshuler, David; Rader, Daniel J.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Erdmann, Jeanette; Willenborg, Christina; Linsel-Nitschke, Patrick; Lieb, Wolfgang; Grosshennig, Anika; Preuss, Michael; Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Willenborg, Christina; Koenig, Inke R.; Grosshennig, Anika; Preuss, Michael; Ziegler, Andreas] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Vaidya, Dhananjay; Herrera, J. Enrique; Kral, Brian G.; Mathias, Rasika A.; Yanek, Lisa R.; Becker, Lewis C.; Becker, Diane] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Xie, Changchun; Anand, Sonia S.] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Xie, Changchun; Anand, Sonia S.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Xie, Changchun; Anand, Sonia S.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Patterson, Chris C.; McKeown, Pascal P.] Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci, Belfast, Antrim, North Ireland. [Morgan, Thomas M.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Burnett, Mary Susan; Pichard, Augusto D.; Kent, Kenneth M.; Satler, Lowell; Lindsay, Joseph M.; Devaney, Joseph M.; Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, MedStar Hlth Res Inst, Washington, DC 20010 USA. [Thompson, John R.; Wright, Benjamin J.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Absher, Devin; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Iribarren, Carlos; Go, Alan; Sidney, Stephen] Kaiser Permanente, Div Res, Oakland, CA USA. [Risch, Neil] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Tang, Hua] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany. [Stoll, Monika; Huge, Andreas] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Shah, Svati H.; Granger, Christopher B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Shah, Svati H.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Thorgeirsson, Gudmundur; Andersen, Karl; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Thorgeirsson, Gudmundur; Andersen, Karl] Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland. [Havulinna, Aki S.; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Kim, Yoonhee; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Suktitipat, Bhoom] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hengstenberg, Christian; Fischer, Marcus; Stark, Klaus; Reinhard, Wibke; Winogradow, Janina; Grassl, Martina] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Schreiber, Stefan] Univ Kiel, Inst Klin Mol Biol, Kiel, Germany. [Wichmann, H-Erich; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Meisinger, Christa] Klinikum Augsburg, KORA Myocardial Infarct Registry, Augsburg, Germany. [Yee, Jean; Siscovick, David; Schwartz, Stephen M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Yee, Jean; Siscovick, David; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Yee, Jean; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Friedlander, Yechiel] Hebrew Univ Jerusalem, Epidemiol Unit, Hadassah Sch Publ Hlth, Jerusalem, Israel. [Do, Ron; Engert, James C.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MD USA. [Williams, Gordon] Brigham & Womens Hosp, Cardiovasc Endocrinol Sect, Div Endocrinol Diabet & Hypertens, Boston, MD USA. [Nathan, David M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MD USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Knouff, Christopher W.; Waterworth, Dawn M.; Walker, Max C.; Mooser, Vincent E.] GlaxoSmithKline Inc, Genet Div & Drug Discovery, King Of Prussia, PA USA. [Marrugat, Jaume; Lucas, Gavin; Subirana, Isaac; Elosua, Roberto] IMIM, Barcelona, Spain. [Marrugat, Jaume; Lucas, Gavin; Subirana, Isaac; Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Sala, Joan] Hosp Girona Josep Trueta, Serv Cardiol, Girona, Spain. [Sala, Joan] Hosp Girona Josep Trueta, Unitat Coronaria, Girona, Spain. [Sala, Joan] Inst Invest Biomed Girona, Girona, Spain. [Ramos, Rafael] Family Med, Res Unit, Girona, Spain. [Ramos, Rafael] Jordi Gol Inst Primary Care Res IDIAP Jordi Gol &, Girona, Spain. [Ramos, Rafael] Catalan Inst Hlth ICS, Catalunya, Spain. [Ramos, Rafael] Univ Girona, Dept Med Sci, Sch Med, Girona, Spain. [Martinelli, Nicola; Olivieri, Oliviero; Girelli, Domenico] Univ Verona, Dept Med, I-37100 Verona, Italy. [Trabetti, Elisabetta; Malerba, Giovanni; Pignatti, Pier Franco] Univ Verona, Dept Life & Reprod Sci, Sect Biol & Genet, I-37100 Verona, Italy. [Hirschhorn, Joel N.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MD USA. [Asselta, Rosanna; Duga, Stefano] Univ Milan, Dipartimento Biol & Genet Sci Med, Milan, Italy. [Purcell, Shaun] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MD USA. [Eifert, Sandra] Univ Munich, Herzchirurg Klin & Poliklin, Munich, Germany. [Braund, Peter S.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester, Leics, England. [Balmforth, Anthony J.; Ball, Stephen G.; Hall, Alistair S.] Univ Leeds, MCRC, LIGHT, Leeds, W Yorkshire, England. [Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge, England. [Ouwehand, Willem H.; Deloukas, Panos; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Scholz, Michael] Trium Anal Online GmbH, Munich, Germany. [Cambien, Francois] Univ Paris 06, INSERM, UMRS 936, Paris, France. [Scheffold, Thomas] Univ Witten Herdecke, Inst Heart & Circulat Res, Dortmund, Germany. [Granger, Christopher B.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Peltonen, Leena] Univ Helsinki, Inst Mol Med, Helsinki, Finland. [Melander, Olle] Lund Univ, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo Univ Hosp, Malmo, Sweden. [Engert, James C.] McGill Univ, Dept Med, Montreal, PQ, Canada. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Spertus, John A.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. RP Assimes, TL (reprint author), Stanford Univ, Sch Med, Dept Med, Hlth Sci Bldg, Stanford, CA 94304 USA. EM tassimes@stanford.edu RI Ramos , Rafel/D-9627-2016; Martinelli, Nicola/J-5622-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Erdmann, Jeanette/P-7513-2014; Deloukas, Panos/B-2922-2013; Meisinger, Christine/B-5358-2014; Granger, Christopher/D-3458-2014; Altshuler, David/A-4476-2009; Schreiber, Stefan/B-6748-2008; Voight, Benjamin/F-1775-2011; Stark, Klaus/D-3813-2009; Wilson, Alexander/C-2320-2009; Duga, Stefano/F-8173-2014; Lieb, Wolfgang/C-1990-2012; Morgan, Tom/C-3478-2012; Willenborg, Christina/D-2668-2012; Lucas, Gavin/D-4346-2012; OI Ramos , Rafel/0000-0001-8146-5288; Martinelli, Nicola/0000-0001-6465-5119; Malerba, Giovanni/0000-0001-8705-8560; Ramos , Rafel/0000-0001-7970-5537; Asselta, Rosanna/0000-0001-5351-0619; Meisinger, Christa/0000-0002-9026-6544; ELOSUA, ROBERTO/0000-0001-8235-0095; Erdmann, Jeanette/0000-0002-4486-6231; Ziegler, Andreas/0000-0002-8386-5397; Deloukas, Panos/0000-0001-9251-070X; Granger, Christopher/0000-0002-0045-3291; Altshuler, David/0000-0002-7250-4107; Schreiber, Stefan/0000-0003-2254-7771; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Duga, Stefano/0000-0003-3457-1410; Suktitipat, Bhoom/0000-0001-8034-7757; Marrugat, Jaume/0000-0003-3320-554X; Vaidya, Dhananjay/0000-0002-7164-1601; Ouwehand, Willem/0000-0002-7744-1790 FU German Migraine & Headache Society (DMKG); AstraZeneca; Berlin Chemie; Boots Healthcare; GlaxoSmithKline; McNeil Pharma (former Woelm Pharma); MSD Sharp Dohme; Pfizer; Alnylam; Merck; Daiichi Sankyo; Novartis; Medtronic FX The collection of clinical and sociodemographic data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from AstraZeneca, Berlin Chemie, Boots Healthcare, GlaxoSmithKline, McNeil Pharma (former Woelm Pharma), MSD Sharp & Dohme and Pfizer to the University of Muenster. Recruitment of the Medstar sample was supported by a research grant from GlaxoSmithKline and genotyping of the PennCATH and Medstar samples was supported by GlaxoSmithKline. Drs. Holm, Thorleifsson, Thorsteinsdottir, and Stefansson are employees of deCODE genetics, a for-profit company that develops SNP based diagnostic tests for various diseases including coronary artery disease. Drs. Mooser, Walker, and Waterworth are employees of GlaxoSmithKline. Dr. Knouff was employed at GlaxoSmithKline at the time data were generated for this manuscript. Dr. Altshuler has received research funds from Pfizer. Dr. Kathiresan has received consulting fees from Pfizer, Alnylam, Merck, Daiichi Sankyo, and Novartis. Dr. Reilly has received research funds from Merck. Dr. Shah has received research funds from Medtronic. All other authors have reported that they have no relationships to disclose. NR 48 TC 51 Z9 53 U1 0 U2 10 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 NOV 2 PY 2010 VL 56 IS 19 BP 1552 EP 1563 DI 10.1016/j.jacc.2010.06.022 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 671UX UT WOS:000283538000005 PM 20933357 ER PT J AU Gupta, L Noh, JY Jo, YH Oh, SH Kumar, S Noh, MY Lee, YS Cha, SJ Seo, SJ Kim, I Han, YS Barillas-Mury, C AF Gupta, Lalita Noh, Ju Young Jo, Yong Hun Oh, Seung Han Kumar, Sanjeev Noh, Mi Young Lee, Yong Seok Cha, Sung-Jae Seo, Sook Jae Kim, Iksoo Han, Yeon Soo Barillas-Mury, Carolina TI Apolipophorin-III Mediates Antiplasmodial Epithelial Responses in Anopheles gambiae (G3) Mosquitoes SO PLOS ONE LA English DT Article ID BUNDLE EXCHANGEABLE APOLIPOPROTEIN; INSECT IMMUNE ACTIVATION; LIPID-BINDING PROPERTIES; GALLERIA-MELLONELLA; PLASMODIUM-BERGHEI; HELIX-BUNDLE; HYPHANTRIA-CUNEA; MIDGUT CELLS; HEMOLYMPH; LIPOPHORIN AB Background: Apolipophorin-III (ApoLp-III) is known to play an important role in lipid transport and innate immunity in lepidopteran insects. However, there is no evidence of involvement of ApoLp-IIIs in the immune responses of dipteran insects such as Drosophila and mosquitoes. Methodology/Principal Findings: We report the molecular and functional characterization of An. gambiae apolipophorin-III (AgApoLp-III). Mosquito ApoLp-IIIs have diverged extensively from those of lepidopteran insects; however, the predicted tertiary structure of AgApoLp-III is similar to that of Manduca sexta (tobacco hornworm). We found that AgApoLp-III mRNA expression is strongly induced in the midgut of An. gambiae (G3 strain) mosquitoes in response to Plasmodium berghei infection. Furthermore, immunofluorescence stainings revealed that high levels of AgApoLp-III protein accumulate in the cytoplasm of Plasmodium-invaded cells and AgApoLp-III silencing increases the intensity of P. berghei infection by five fold. Conclusion: There are broad differences in the midgut epithelial responses to Plasmodium invasion between An. gambiae strains. In the G3 strain of An. gambiae AgApoLp-III participates in midgut epithelial defense responses that limit Plasmodium infection. C1 [Gupta, Lalita; Kumar, Sanjeev; Barillas-Mury, Carolina] NIAID, Mosquito Immun & Vector Competence Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Noh, Ju Young; Jo, Yong Hun; Oh, Seung Han; Noh, Mi Young; Kim, Iksoo; Han, Yeon Soo] Chonnam Natl Univ, Coll Agr & Life Sci, Dept Agr Biol, Kwangju, South Korea. [Lee, Yong Seok] Inje Univ, Coll Med & Frontier Inje Res Sci & Technol, Dept Parasitol, Pusan, South Korea. [Cha, Sung-Jae] Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Cha, Sung-Jae] Johns Hopkins Sch Publ Hlth, Malaria Res Inst, Baltimore, MD USA. [Seo, Sook Jae] Gyeongsang Natl Univ, Div Appl Life Sci, Jinju, South Korea. RP Gupta, L (reprint author), Birla Inst Technol & Sci, Biol Sci Grp, Pilani, Rajasthan, India. EM hanys@chonnam.ac.kr; cbarillas@niaid.nih.gov OI Lee, Yongseok/0000-0002-8687-589X FU Korean Government [KRF 2008 531 C00064]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the National Research Foundation of Korea Grant funded by the Korean Government (KRF 2008 531 C00064). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 27 Z9 27 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 2 PY 2010 VL 5 IS 11 AR e15410 DI 10.1371/journal.pone.0015410 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 674VY UT WOS:000283779700018 PM 21072214 ER PT J AU Niesen, FH Schultz, L Jadhav, A Bhatia, C Guo, KD Maloney, DJ Pilka, ES Wang, MH Oppermann, U Heightman, TD Simeonov, A AF Niesen, Frank H. Schultz, Lena Jadhav, Ajit Bhatia, Chitra Guo, Kunde Maloney, David J. Pilka, Ewa S. Wang, Minghua Oppermann, Udo Heightman, Tom D. Simeonov, Anton TI High-Affinity Inhibitors of Human NAD(+)-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships SO PLOS ONE LA English DT Article ID SHORT-CHAIN DEHYDROGENASES/REDUCTASES; PROSTAGLANDIN-E SYNTHASE; ALCOHOL-DEHYDROGENASE; LUNG-CANCER; STATISTICAL PARAMETER; SEQUENCE-ANALYSIS; CRYSTAL-STRUCTURE; CRITICAL RESIDUES; SDR; LEUKOTRIENES AB Background: 15-hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. Principal Findings: To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing > 160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action. Conclusions: Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways. C1 [Niesen, Frank H.; Bhatia, Chitra; Guo, Kunde; Pilka, Ewa S.; Wang, Minghua; Heightman, Tom D.] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford, England. [Schultz, Lena; Jadhav, Ajit; Maloney, David J.; Oppermann, Udo; Simeonov, Anton] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Oppermann, Udo] Univ Oxford, Botnar Res Ctr, Nuffield Dept Orthoped Surg Rheumatol & Musculosk, Biomed Res Unit, Oxford, England. RP Niesen, FH (reprint author), Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford, England. EM asimeono@mail.nih.gov FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; NHGRI, NIH; Oxford Biomedical Research Unit; Canadian Institutes for Health Research [1097737]; Canadian Foundation for Innovation; Genome Canada through the Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co., Inc.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust FX This research was supported in part by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Intramural Research Program of the NHGRI, NIH, and the Oxford Biomedical Research Unit. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 8 Z9 10 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 2 PY 2010 VL 5 IS 11 AR e13719 DI 10.1371/journal.pone.0013719 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 674VY UT WOS:000283779700002 PM 21072165 ER PT J AU Hickman, HD Yewdell, JW AF Hickman, Heather D. Yewdell, Jonathan W. TI Mining the plasma immunopeptidome for cancer peptides as biomarkers and beyond SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MHC CLASS-I; MOLECULES; ANTIGENS; TRANSLATION; DEGRADATION; HYPOTHESIS; CELLS C1 [Hickman, Heather D.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 20 TC 7 Z9 7 U1 2 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 2 PY 2010 VL 107 IS 44 BP 18747 EP 18748 DI 10.1073/pnas.1013851107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 674MJ UT WOS:000283749000005 PM 20974971 ER PT J AU Shin, HS Roubertoux, PL Kang, C Kim, E Han, JH AF Shin, Hee-Sup Roubertoux, Pierre L. Kang, Changsoo Kim, Eunjun Han, Jin-hee TI "Mouse genetic approaches to understanding higher cognitive functions: genes, synapses, and circuits'' SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 40th Annual Meeting of Behavior-Genetics-Association CY MAY, 2009 CL State Coll, Pennsylvania, PA SP Behavior Genet Assoc HO State Coll C1 [Shin, Hee-Sup] KIST, Taejon, South Korea. [Roubertoux, Pierre L.] INSERM, F-75654 Paris 13, France. [Kang, Changsoo] NIDCD, NIH, Bethesda, MD USA. [Kim, Eunjun; Han, Jin-hee] Korea Adv Inst Sci & Technol, Taejon, South Korea. 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 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2010 VL 40 IS 6 SI SI BP 812 EP 812 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 686KW UT WOS:000284696200104 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wiestner, A Stevenson, MAS Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Dian C. Wiestner, Adrian Stevenson, M. A. Stetler Marti, Gerald E. TI ONE STEP METHOD TOWARD STANDARDIZATION OF ZAP-70 EXPRESSION ANALYSIS IN CLL. SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Degheidy, Heba A.; Abbasi, Fatima; Arthur, Dian C.; Stevenson, M. A. Stetler; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Rockville, MD USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 393 EP 393 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100016 ER PT J AU Degheidy, HA Venzon, D Farooqui, MZH Abbasi, F Arthur, DC Wiestner, A Stevenson, MAS Marti, GE AF Degheidy, Heba A. Venzon, David Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wiestner, Adrian Stevenson, M. A. Stetler Marti, Gerald E. TI COMBINED ANALYSIS OF ZAP-70,CD38,CD69,CD26,CD49D,CD27 AS A PREDICTOR FOR IGVH MUTATIONAL STATUS IN CLL SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Degheidy, Heba A.; Abbasi, Fatima; Arthur, Diane C.; Stevenson, M. A. Stetler; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Venzon, David] NCI, Biostat & Data Management Sect, Rockville, MD USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 393 EP 394 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100017 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wiestner, A Stevenson, MAS Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wiestner, Adrian Stevenson, M. A. Stetler Marti, Gerald E. TI ZAP-70 ANALYSIS IN CLL USING TWO DIFFERENT MONOCLONAL ANTIBODIES SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Degheidy, Heba A.; Abbasi, Fatima; Arthur, Diane C.; Stevenson, M. A. Stetler; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Rockville, MD USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 394 EP 394 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100018 ER PT J AU Degheidy, HA Gadalla, SM Farooqui, MZH Abbasi, F Arthur, DC Wiestner, A Stevenson, MAS Marti, GE AF Degheidy, Heba A. Gadalla, Shahinaz M. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wiestner, Adrian Stevenson, M. A. Stetler Marti, Gerald E. TI BCL-2: BIOMARKER FOR 13Q14 DELETION STATUS IN CLL SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Degheidy, Heba A.; Abbasi, Fatima; Arthur, Diane C.; Stevenson, M. A. Stetler; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Gadalla, Shahinaz M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 394 EP 395 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100019 ER PT J AU Liu, QY Raffeld, M Kreitman, R Stetler-Stevenson, M Yuan, CM AF Liu, Qingyan Raffeld, Mark Kreitman, Robert Stetler-Stevenson, Maryalice Yuan, Constance M. TI LARGE GRANULAR LYMPHOCYTOSIS AND T CELL CLONALITY IN HAIRY CELL LEUKEMIA: A STUDY OF 13 CASES WITH LONG TERM FOLLOW UP. SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Liu, Qingyan; Raffeld, Mark; Kreitman, Robert; Stetler-Stevenson, Maryalice; Yuan, Constance M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 396 EP 397 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100025 ER PT J AU Tembhare, PR Yuan, CM Janik, J Morris, J Stetler-Stevenson, M AF Tembhare, Prashant R. Yuan, Constance M. Janik, John Morris, John Stetler-Stevenson, Maryalice TI TCR-V BETA REPERTOIRE ANALYSIS: DETECTION OF T CELL CLONALITY AT DIAGNOSIS AND MONITORING OF MINIMAL RESIDUAL DISEASE (MRD) SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Tembhare, Prashant R.; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, LP, NIH, Bethesda, MD 20892 USA. [Janik, John; Morris, John] NCI, MB, DBS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 400 EP 400 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100034 ER PT J AU Fulton, JE Carlson, SA Craig, CL Cameron, C Troiano, RP Pratt, M AF Fulton, Janet E. Carlson, Susan A. Craig, Cora L. Cameron, Christine Troiano, Richard P. Pratt, Michael TI From Physical Activity Guidelines to Public Health Policies SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Meeting Abstract DE recommendations; exercise; surveillance; international C1 [Fulton, Janet E.; Carlson, Susan A.; Pratt, Michael] US Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA USA. [Craig, Cora L.; Cameron, Christine] Canadian Fitness & Lifestyle Inst, Ottawa, ON, Canada. [Troiano, Richard P.] NCI, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD NOV PY 2010 VL 7 SU 3 BP S347 EP S349 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 679RR UT WOS:000284179000025 ER PT J AU Riddoch, C Sherar, L Cooper, A Ekelund, U Troiano, R AF Riddoch, Chris Sherar, Lauren Cooper, Ashley Ekelund, Ulf Troiano, Richard TI The International Children's Accelerometry Database (ICAD): Methods and Major Findings SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Meeting Abstract DE pooling; physical activity ID PHYSICAL-ACTIVITY; YOUTH; RISK C1 [Riddoch, Chris] Univ Bath, Sch Hlth, Bath BA2 7AY, Avon, England. [Sherar, Lauren] Univ Saskatchewan, Coll Kinesiol, Saskatoon, SK, Canada. [Cooper, Ashley] Univ Bristol, Dept Exercise Nutr & Hlth Sci, Bristol BS8 1TH, Avon, England. [Ekelund, Ulf] MRC, Epidemiol Unit, Cambridge, England. [Troiano, Richard] NCI, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD NOV PY 2010 VL 7 SU 3 BP S324 EP S326 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 679RR UT WOS:000284179000014 ER PT J AU Freeman, EW Anderson, GL Caan, BJ Caldwell, SA Carpenter, JS Cohen, LS Ensrud, K Guthrie, KA Joffe, H LaCroix, AZ Newton, KM Parrott, E Reed, SD Sherman, S Sternfeld, B AF Freeman, Ellen W. Anderson, Garnet L. Caan, Bette J. Caldwell, Sheila A. Carpenter, Janet S. Cohen, Lee S. Ensrud, Kristine Guthrie, Katherine A. Joffe, Hadine LaCroix, Andrea Z. Newton, Katherine M. Parrott, Estella Reed, Susan D. Sherman, Sheryl Sternfeld, Barbara CA MsFLASH Investigator Grp TI Efficacy of Escitalopram for Menopausal Hot Flashes: A Randomized Controlled Trial in the MsFlash Network SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 21st Annual Meeting of the North-American-Menopause-Society CY OCT 06-09, 2010 CL Chicago, IL SP N Amer Menopause Soc C1 [Freeman, Ellen W.] Univ Penn, Philadelphia, PA 19104 USA. [Cohen, Lee S.; Joffe, Hadine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Anderson, Garnet L.; Guthrie, Katherine A.; LaCroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Sherman, Sheryl; MsFLASH Investigator Grp] NIA, Bethesda, MD 20892 USA. [Ensrud, Kristine] Univ Minnesota, Minneapolis, MN USA. [Caan, Bette J.; Sternfeld, Barbara] Kaiser Permanente No Calif, Oakland, CA USA. [Carpenter, Janet S.] Indiana Univ, Indianapolis, IN 46204 USA. [Newton, Katherine M.; Reed, Susan D.] Grp Hlth Res Inst, Seattle, WA USA. [Reed, Susan D.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Parrott, Estella] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Caldwell, Sheila A.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Ensrud, Kristine] Minneapolis VAMC, Minneapolis, MN 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 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV-DEC PY 2010 VL 17 IS 6 BP 1217 EP 1217 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 677LK UT WOS:000283993700056 ER PT J AU Kershanskaya, OI Nurmagambetova, AS Skvortsova, LA Nelidova, DS Rovenskaya, LI Mukhanov, TM AF Kershanskaya, O. I. Nurmagambetova, A. S. Skvortsova, L. A. Nelidova, D. S. Rovenskaya, L. I. Mukhanov, T. M. TI Plant genetic transformation for increased yield through C-3 to C-4 photosynthesis engineering strategy SO JOURNAL OF BIOTECHNOLOGY LA English DT Meeting Abstract CT 14th International Biotechnology Symposium and Exhibition (IBS) CY SEP 14-18, 2010 CL Rimini, ITALY DE transformation; C3-C4 engineering; yield; wheat C1 [Kershanskaya, O. I.; Nurmagambetova, A. S.; Skvortsova, L. A.; Nelidova, D. S.; Rovenskaya, L. I.; Mukhanov, T. M.] Natl Biotechnol Ctr, Inst Plant Biol & Biotechnol, Alma Ata, Kazakhstan. NR 0 TC 0 Z9 0 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD NOV PY 2010 VL 150 SU 1 BP S477 EP S477 DI 10.1016/j.jbiotec.2010.09.720 PG 1 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 741OQ UT WOS:000288873402038 ER PT J AU Griffiths, GL Basuli, F Wu, H Li, C Tatum, JL Doroshow, JH AF Griffiths, G. L. Basuli, F. Wu, H. Li, C. Tatum, J. L. Doroshow, J. H. TI A first synthesis of [18F]-lapatinib: a new agent for positron emission tomographic studies of kinase receptors SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Griffiths, G. L.; Basuli, F.; Wu, H.; Li, C.] NHLBI, IPDC, Rockville, MD USA. [Tatum, J. L.; Doroshow, J. H.] NIH, NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 4 EP 4 DI 10.1016/S1359-6349(10)71701-8 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100005 ER PT J AU Collins, JM AF Collins, J. M. TI NCI initiatives in developmental therapeutics SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Collins, J. M.] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 15 EP 15 DI 10.1016/S1359-6349(10)71720-1 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100022 ER PT J AU Smith, MA Maris, JM Keir, ST Lock, RB Carol, H Kolb, EA Kang, MH Reynolds, CP Hickson, I Houghton, PJ AF Smith, M. A. Maris, J. M. Keir, S. T. Lock, R. B. Carol, H. Kolb, E. A. Kang, M. H. Reynolds, C. P. Hickson, I. Houghton, P. J. TI Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of JNJ-26481585, a second generation histone deacetylase inhibitor SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Smith, M. A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Maris, J. M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Keir, S. T.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. [Lock, R. B.; Carol, H.] Childrens Canc Inst Australia, Leukemia Biol Program, Randwick, NSW, Australia. [Kolb, E. A.] Alfred I DuPont Hosp Children, Dept Oncol, Wilmington, NC USA. [Kang, M. H.; Reynolds, C. P.] Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, Lubbock, TX 79430 USA. [Hickson, I.] Johnson & Johnson, Oncol Res, Turnhoutseweg, Belgium. [Houghton, P. J.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. RI Carol, Hernan/F-5750-2013 OI Carol, Hernan/0000-0002-9443-8032 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 49 EP 49 DI 10.1016/S1359-6349(10)71840-1 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100135 ER PT J AU Gaedcke, J Grade, M Jung, K Camps, J Jo, P Becker, H Beissbarth, T Ried, T Ghadimi, M AF Gaedcke, J. Grade, M. Jung, K. Camps, J. Jo, P. Becker, H. Beissbarth, T. Ried, T. Ghadimi, M. TI The effect of KRAS mutations on the rectal cancer transcriptome: clinical implications SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Gaedcke, J.; Grade, M.; Jung, K.; Jo, P.; Becker, H.; Beissbarth, T.; Ghadimi, M.] Univ Gottingen, Gottingen, Germany. [Camps, J.; Ried, T.] NCI, Sect Canc Genom, Genet Branch, Bethesda, MD 20892 USA. RI Beissbarth, Tim/B-3129-2013 OI Beissbarth, Tim/0000-0001-6509-2143 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 63 EP 63 DI 10.1016/S1359-6349(10)71892-9 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100187 ER PT J AU Nechiporchik, N Lieb, K Marquette, L Polin, L Peters, GJ Chen, A Ethier, SP LoRusso, PM Burger, AM AF Nechiporchik, N. Lieb, K. Marquette, L. Polin, L. Peters, G. J. Chen, A. Ethier, S. P. LoRusso, P. M. Burger, A. M. TI Preclinical activity of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in combination with irinotecan in ovarian and triple negative breast cancers SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Nechiporchik, N.; Lieb, K.; Marquette, L.; Polin, L.; Ethier, S. P.; LoRusso, P. M.; Burger, A. M.] Karmanos Canc Inst, Detroit, MI USA. [Peters, G. J.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Chen, A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 64 EP 64 DI 10.1016/S1359-6349(10)71894-2 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100189 ER PT J AU Holbeck, S Hollingshead, M Newton, D Rubinstein, L Collins, J AF Holbeck, S. Hollingshead, M. Newton, D. Rubinstein, L. Collins, J. TI Combination drug screening at the NCI SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Holbeck, S.; Collins, J.] NCI, Dev Therapeut Program, Rockville, MD USA. [Hollingshead, M.] NCI, Dev Therapeut Program, Frederick, MD 21701 USA. [Newton, D.] SAIC Inc, SAIC Frederick, Frederick, MD USA. [Rubinstein, L.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 94 EP 94 DI 10.1016/S1359-6349(10)71998-4 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100285 ER PT J AU Grade, M Kendziorra, E Ahlborn, K Spitzner, M Gaedcke, J Rave-Frank, M Becker, H Ghadimi, BM Pukrop, T Ried, T AF Grade, M. Kendziorra, E. Ahlborn, K. Spitzner, M. Gaedcke, J. Rave-Fraenk, M. Becker, H. Ghadimi, B. M. Pukrop, T. Ried, T. TI Silencing of TCF7L2 sensitizes colorectal cancer cells to radiation therapy SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Grade, M.; Kendziorra, E.; Ahlborn, K.; Spitzner, M.; Gaedcke, J.; Rave-Fraenk, M.; Becker, H.; Ghadimi, B. M.; Pukrop, T.] Univ Med Gottingen, Gottingen, Germany. [Ried, T.] NCI, Genet Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 97 EP 97 DI 10.1016/S1359-6349(10)72008-5 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100295 ER PT J AU Gupta, S Alqwasmi, A Hunsberger, S Rubinstein, L Ivy, P Royds, R LoRusso, P AF Gupta, S. Alqwasmi, A. Hunsberger, S. Rubinstein, L. Ivy, P. Royds, R. LoRusso, P. TI Dose of the molecularly targeted agents (MTA) in Phase 1 trials correlates with clinical benefit SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Gupta, S.; LoRusso, P.] Karmanos Canc Inst, Detroit, MI USA. [Alqwasmi, A.] Wayne State Univ, Dept Med, Detroit, MI 48202 USA. [Hunsberger, S.; Rubinstein, L.] NCI, NIH, Biometr Res Branch, Rockville, MD USA. [Ivy, P.] NCI, NIH, Canc Therapy Evaluat Program, Rockville, MD USA. [Royds, R.] Theradex Syst, Clin Trials Monitoring Syst, Princeton, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 115 EP 115 DI 10.1016/S1359-6349(10)72070-X PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100357 ER PT J AU Shapiro, GI Molina, J Bendell, J Brana, I Spicer, J Kwak, E Pandya, S Millham, R Houk, B Bell-McGuinn, K AF Shapiro, G. I. Molina, J. Bendell, J. Brana, I. Spicer, J. Kwak, E. Pandya, S. Millham, R. Houk, B. Bell-McGuinn, K. TI First-in-human study of PF-05212384, a small molecule intravenous dual inhibitor of PI3K and mTOR in patients with advanced cancer: preliminary report on safety and pharmacokinetics SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Shapiro, G. I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Molina, J.] Mayo Clin, Rochester, MN USA. [Bendell, J.] Sarah Cannon Canc Res Inst, Nashville, TN USA. [Brana, I.] Val dHebron Hosp, Barcelona, Spain. [Spicer, J.] Guys Hosp, London SE1 9RT, England. [Kwak, E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pandya, S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Millham, R.] Pfizer Oncol, NIA, New London, CT USA. [Houk, B.] Pfizer Oncol, NIA, La Jolla, CA USA. [Bell-McGuinn, K.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 123 EP 123 DI 10.1016/S1359-6349(10)72094-2 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100381 ER PT J AU Mahalingam, D Beeram, M Rodon, J Sankhala, K Mita, A Benjamin, D Michalek, J Tolcher, A Wright, J Sarantopoulos, J AF Mahalingam, D. Beeram, M. Rodon, J. Sankhala, K. Mita, A. Benjamin, D. Michalek, J. Tolcher, A. Wright, J. Sarantopoulos, J. TI Phase II study evaluating the efficacy, safety and pharmacodynamic correlative study of dual anti-angiogenic inhibition using Bevacizumab (B) in combination with Sorafenib (S) in patients (pts) with advanced malignant melanoma SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Mahalingam, D.; Beeram, M.; Rodon, J.; Sankhala, K.; Mita, A.; Benjamin, D.; Tolcher, A.; Sarantopoulos, J.] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX USA. [Michalek, J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX USA. [Wright, J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 131 EP 131 DI 10.1016/S1359-6349(10)72120-0 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100407 ER PT J AU Asad, U Chen, C AF Asad, U. Chen, C. TI Hydroxamate-tethered short chain fatty acid designer cancer prevention molecule SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Asad, U.] NCI, DCP, Rockville, MD USA. [Chen, C.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 171 EP 172 DI 10.1016/S1359-6349(10)72246-1 PG 2 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100531 ER PT J AU Bates, SE Tamaki, A Ward, Y Ierano, C Robey, RW Hegde, R To, KKW AF Bates, S. E. Tamaki, A. Ward, Y. Ierano, C. Robey, R. W. Hegde, R. To, K. K. W. TI Histone deacetylase inhibitors mediate pharmacological rescue and increase membrane expression of ABCG2 harboring the Q141K single nucleotide polymorphism SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Bates, S. E.; Tamaki, A.; Ierano, C.; Robey, R. W.] NCI, CCR Med Oncol Branch, Bethesda, MD 20892 USA. [Ward, Y.] NCI, CCR Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Hegde, R.] NICHHD, Intracellular Prot Trafficking Sect, Bethesda, MD 20892 USA. [To, K. K. W.] Chinese Univ Hong Kong, Sch Pharm, Hong Kong, Hong Kong, Peoples R China. RI To, Kenneth /M-4500-2013 OI To, Kenneth /0000-0003-2755-0283 NR 0 TC 0 Z9 0 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 176 EP 176 DI 10.1016/S1359-6349(10)72261-8 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100546 ER PT J AU Chyla, B Smith, M Tahir, S Wilson, W O'Connor, O Czuczman, M Gerecitano, J Enschede, S Krivoshik, A McKeegan, E AF Chyla, B. Smith, M. Tahir, S. Wilson, W. O'Connor, O. Czuczman, M. Gerecitano, J. Enschede, S. Krivoshik, A. McKeegan, E. TI Bcl-2 family protein expression in navitoclax-treated patients (pts) with lymphoid malignancies SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Chyla, B.] Abbott Labs, R4CD, Abbott Pk, IL 60064 USA. [Wilson, W.] NCI, NIH, Bethesda, MD 20892 USA. [O'Connor, O.] NYU, Langone Med Ctr, New York, NY USA. [Czuczman, M.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Gerecitano, J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Smith, M.; Tahir, S.] Abbott Labs, R4N6, Abbott Pk, IL 60064 USA. RI Jones, Jeffrey/E-9827-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 192 EP 192 DI 10.1016/S1359-6349(10)72318-1 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100603 ER PT J AU Pressler, HM Sissung, TM Price, DK Figg, WD AF Pressler, H. M. Sissung, T. M. Price, D. K. Figg, W. D. TI Organic anion transporting polypeptides contribute to prostate cancer progression SO EJC SUPPLEMENTS LA English DT Meeting Abstract CT 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 16-19, 2010 CL Berlin, GERMANY C1 [Pressler, H. M.; Sissung, T. M.; Price, D. K.; Figg, W. D.] NIH, Mol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1359-6349 J9 EJC SUPPL JI EJC Suppl. PD NOV PY 2010 VL 8 IS 7 BP 201 EP 201 DI 10.1016/S1359-6349(10)72349-1 PG 1 WC Oncology SC Oncology GA 735ZU UT WOS:000288460100634 ER PT J AU Milaneschi, Y Shardell, M Corsi, AM Vazzana, R Bandinelli, S Guralnik, JM Ferrucci, L AF Milaneschi, Yuri Shardell, Michelle Corsi, Anna Maria Vazzana, Rosamaria Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi TI Serum 25-Hydroxyvitamin D and Depressive Symptoms in Older Women and Men SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Hypovitaminosis D is common in older adults. Vitamin D deficiency in this population has been linked to a large number of poor health outcomes. Several investigators have hypothesized that hypovitaminosis D may contribute to depression in older adults. The few small studies that examined the association between vitamin D and depression in the elderly had conflicting results. This prospective population-based study was designed to investigate the longitudinal relationship between vitamin D and depressive symptoms over a 6-year follow-up period in a representative group of older adults. The participants were enrolled in the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) Study. The study sample was comprised of 954 participants (531 women and 423 men) aged 65 years or older. The primary study outcome measure was 25-hydroxyvitamin D (serum 25[ OH] D). Vitamin D insufficiency was defined as a 25(OH) D level of less than 50 nmol/L. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to assess depressive symptoms at baseline and at 3- and 6-year follow-up. A CES-D score of 16 or higher was considered a clinically relevant depressed mood. The data were stratified by gender. Multivariable analysis was used to adjust for relevant biomarkers and covariates related to sociodemographics, somatic health, and functional status. Compared to women with 25(OH) D levels more than 50 nmol/L, those with levels below this threshold had average adjusted increases in CES-D scores at the 3- and 6-year follow-up of 2.1 (P = 0.02) and 2.2 (P = 0.04), respectively. Lower baseline serum levels of 25(OH) D in women were also associated with a significant higher risk of developing depressed mood during the follow-up; the hazard ratio was 2.0, with a 95% confidence interval of 1.2-3.2 (P = 0.005). Compared to men with 25(OH) D levels above the cutoff of 50 nmol/L, men with lower levels at 3- and 6-year follow-up had increases in CES-D scores of 1.9 (P = 0.01) and 1.1 (P = 0.20), respectively. Lower baseline serum 25(OH) D levels among men were associated with an insignificant increase in risk for depression compared with those with higher levels (hazard ratio, 1.6; 95% confidence interval, 0.9-2.8; P = 0.1). These findings provide evidence of a prospective independent association between hypovitaminosis D and new depression over time. The association is stronger in women than in men. The investigators believe that prevention of vitamin D deficiency may become a future strategy to substantially lower the risk of depression in the elderly patients. C1 [Milaneschi, Yuri] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Tuscany Hlth Reg Agcy, Florence, Italy. Univ G DAnnunzio, Dept Med & Sci Aging, Lab Clin Epidemiol, Chieti, Italy. Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Milaneschi, Y (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 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 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD NOV PY 2010 VL 65 IS 11 BP 706 EP 708 DI 10.1097/OGX.0b013e3182022107 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 730BE UT WOS:000288002900010 ER PT J AU Krasna, MJ AF Krasna, Mark J. TI Collaboration as a foundation for advancing research in personalized medicine in cancer care SO PERSONALIZED MEDICINE LA English DT Article DE community cancer centers; individualized care; personalized therapy; targeted therapy; translational research AB Transforming healthcare through collaborative relationships is the key to making successful advances in personalized medicine. The strategies for building a framework to bring together expertise and resources in order to realize all the possibilities of personalized medicine are discussed in this article. The key to this endeavor is the ability to identify potential collaboration with academic medical centers, research laboratories, biotechnology companies and community cancer centers. Translation of research from bench to bedside is only paradigm changing if it can then be translated to community care. The value of clinical prospective biospecimen collection with high quality clinical annotation will be explored. Recognizing the opportunities for performing clinical trials, beta-testing of new technology especially in community clinical practice will be emphasized. The goal is to expand the realm of personalized cancer care to allow for integration of molecular marker and individualized therapy to the majority of cancer patients worldwide. C1 Catholic Hlth Initiat, NCI Community Canc Ctr Program, Inst Canc, St Joseph Med Ctr, Baltimore, MD 21204 USA. RP Krasna, MJ (reprint author), Catholic Hlth Initiat, NCI Community Canc Ctr Program, Inst Canc, St Joseph Med Ctr, 7501 Oster Dr,Suite 104, Baltimore, MD 21204 USA. EM markkrasna@catholichealth.net NR 14 TC 0 Z9 0 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD NOV PY 2010 VL 7 IS 6 BP 669 EP 675 DI 10.2217/PME.10.60 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 699ZL UT WOS:000285701800011 ER PT J AU Van Schaick, JA Akagi, K Burkett, S DiFabio, C Tuskan, R Walrath, J Reilly, K AF Van Schaick, Jessica A. Akagi, Keiko Burkett, Sandra DiFabio, Christina Tuskan, Robert Walrath, Jessica Reilly, Karlyne TI IDENTIFYING MODIFIER GENES OF MPNSTS IN THE NF1;P53C1S MOUSE MODEL OF NEUROFIBROMATOSIS TYPE 1 SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT Advances in Inflammatory Bowel Diseases Crohns and Colitis Foundations National Clinical and Research Conference CY DEC 09-12, 2010 CL Hollywood, FL C1 [Van Schaick, Jessica A.; Burkett, Sandra; DiFabio, Christina; Tuskan, Robert; Walrath, Jessica; Reilly, Karlyne] NCI, Bethesda, MD 20892 USA. [Akagi, Keiko] Ohio State Univ, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2010 VL 12 SU 4 BP 14 EP 14 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 691LX UT WOS:000285082400062 ER PT J AU Iwamoto, F Lamborn, K Kuhn, J Wen, P Yung, WKA Gilbert, M Chang, S Lieberman, F Prados, M Fine, H AF Iwamoto, Fabio Lamborn, Kathleen Kuhn, John Wen, Patrick Yung, W. K. A. Gilbert, Mark Chang, Susan Lieberman, Frank Prados, Michael Fine, Howard TI PHASE II TRIAL OF HISTONE DEACETYLASE INHIBITOR ROMIDEPSIN FOR ADULTS WITH RECURRENT HIGH-GRADE GLIOMAS (NORTH AMERICAN BRAIN TUMOR CONSORTIUM STUDY 03-03) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT Advances in Inflammatory Bowel Diseases Crohns and Colitis Foundations National Clinical and Research Conference CY DEC 09-12, 2010 CL Hollywood, FL C1 [Iwamoto, Fabio; Fine, Howard] Natl Canc Inst, Bethesda, MD USA. [Lamborn, Kathleen; Chang, Susan; Prados, Michael] UCSF, San Francisco, CA USA. [Kuhn, John] Univ Texas San Antonio, San Antonio, TX USA. [Wen, Patrick] Dana Farber Canc Inst, Boston, MA USA. [Yung, W. K. A.; Gilbert, Mark] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Lieberman, Frank] Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2010 VL 12 SU 4 BP 37 EP 38 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 691LX UT WOS:000285082400164 ER PT J AU Shonka, N Gilbert, M Yung, WKA Piao, YJ Liu, J Bekele, N Wen, P Chen, A Heymach, J de Groor, J AF Shonka, Nicole Gilbert, Mark Yung, W. K. Alfred Piao, Yuji Liu, Jun Bekele, Nebiyou Wen, Patrick Chen, Alice Heymach, John de Groor, John TI CYTOKINES PREDICT ON-TARGET TOXICITY FROM AFLIBERCEPT IN PATIENTS WITH RECURRENT GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT Advances in Inflammatory Bowel Diseases Crohns and Colitis Foundations National Clinical and Research Conference CY DEC 09-12, 2010 CL Hollywood, FL C1 [Shonka, Nicole; Gilbert, Mark; Yung, W. K. Alfred; Piao, Yuji; Liu, Jun; Bekele, Nebiyou; Heymach, John; de Groor, John] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Wen, Patrick] Dana Farber Canc Inst, Boston, MA USA. [Chen, Alice] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2010 VL 12 SU 4 BP 39 EP 39 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 691LX UT WOS:000285082400170 ER PT J AU Cavaliere, R Abrey, LE Mason, WP Lassman, AB Perentesis, J Ivy, P Villalona, M AF Cavaliere, Robert Abrey, Lauren E. Mason, Warren P. Lassman, Andrew B. Perentesis, John Ivy, Percy Villalona, Miguel TI PHASE 2 STUDY OF SUNITINIB MALATE IN RECURRENT MALIGNANT GLIOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT Advances in Inflammatory Bowel Diseases Crohns and Colitis Foundations National Clinical and Research Conference CY DEC 09-12, 2010 CL Hollywood, FL C1 [Cavaliere, Robert; Villalona, Miguel] Ohio State Univ, Columbus, OH 43210 USA. [Abrey, Lauren E.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Mason, Warren P.] Princess Margaret Hosp, Toronto, ON, Canada. [Lassman, Andrew B.] Mem Sloan Kettering, New York, NY USA. [Perentesis, John] Nationwide Childrens Hosp, Columbus, OH USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2010 VL 12 SU 4 BP 56 EP 56 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 691LX UT WOS:000285082400244 ER PT J AU Hong, SY Borchert, GL Maciag, AE Nandurdikar, RS Saavedra, JE Keefer, LK Phang, JM Chakrapani, H AF Hong, Sam Y. Borchert, Gregory L. Maciag, Anna E. Nandurdikar, Rahul S. Saavedra, Joseph E. Keefer, Larry K. Phang, James M. Chakrapani, Harinath TI The Nitric Oxide Prodrug V-PROLI/NO Inhibits Cellular Uptake of Proline SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Nitric oxide; prodrug; proline; transporter; PROLI/NO-V-PROLI/NO ID INDUCED HEPATOTOXICITY; DONOR PRODRUG; PYRRO/NO; LIVER; PROTECTS; MICE; TOXICITY; APOPTOSIS; TRANSPORTERS; CELLS AB V-PYRRO/NO is a well-studied nitric oxide (NO) prodrug that has been shown to protect human liver cells from arsenic, acetaminophen, and other toxic assaults in vivo. Its proline based analogue, V-PROLI/NO, was designed to be a more biocompatible form that decomposes to the naturally occurring metabolites of proline, NO, and glycolaldehyde. Like V-PYRRO/NO, this cytochrome P450-activated prodrug was previously assumed to passively diffuse through the cellular membrane. Using (14)C-labeled proline in a competition assay, we show that V-PROLI/NO is transported through proline transporters into multiple cell lines. a fluorescent NO-sensitive dye (DAF-FM diacetate) and nitrite excretion indicated elevated intracellular NO release after metabolism over V-PYRRO/NO. These results also allowed us to predict and design a more permeable analogue, V-SARCO/NO. We report a proline transporter based strategy for the selective transport of NO prodrugs that may have enhanced and aid in the development of further NO prodrugs with increased permeability. C1 [Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA. [Hong, Sam Y.; Nandurdikar, Rahul S.; Keefer, Larry K.] SAIC Frederick, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. [Borchert, Gregory L.; Maciag, Anna E.; Saavedra, Joseph E.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Chakrapani, Harinath] Indian Inst Sci Educ & Res, Dept Chem, Pune 411008, Maharashtra, India. RP Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA. EM phangj@mail.nih.gov; harinath@iiserpune.ac.in RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center For Cancer Research FX This project has been funded with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center For Cancer Research. NR 41 TC 1 Z9 1 U1 2 U2 10 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 NOV PY 2010 VL 1 IS 8 BP 386 EP 389 DI 10.1021/ml1000905 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 680AS UT WOS:000284203100004 PM 21212855 ER PT J AU Kaczmarek, P Tocci, GM Keay, SK Adams, KM Zhang, CO Koch, KR Grkovic, D Guo, L Michejda, CJ Barchi, JJ AF Kaczmarek, Piotr Tocci, Gillian M. Keay, Susan K. Adams, Kristie M. Zhang, Chen-Ou Koch, Kristopher R. Grkovic, David Guo, Li Michejda, Christopher J. Barchi, Joseph J., Jr. TI Structure-Activity Studies on Antiproliferative Factor (APF) Glycooctapeptide Derivatives SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Interstitial cystitis/painful bladder syndrome; antiproliferative; glyco-peptide; hydrophobicity; peptide conformation ID INTERSTITIAL CYSTITIS PATIENTS; PARACELLULAR PERMEABILITY; CHEMICAL-SHIFTS; AMINO-ACIDS; PROTEIN; PEPTIDES; DIFFERENTIATION; DYSFUNCTION; UROTHELIUM; FEATURES AB Antiproliferative factor (APF) alsialylated glycopeptide secreted by explanted bladder epithelial cells from interstitial cystitis/painful bladder syndrome (IC/PBS) patients and its unsialylated analogue (as-APF) significantly decrease proliferation of bladder epithelial cells and/or certain carcinoma cell lines in vitro. We recently reported a structure-activity relationship profile for the peptide portion of as-APF and revealed that truncation of the C-terminal alanine did not significantly affect antiproliferative activity to better understand the structural basis for the maintenance of activity of this truncated eight amino acid as-APF. (as-APF8), we synthesized several amino acid-substituted derivatives and studied their ability to inhibit bladder epithelial cell proliferation in vitro as well as their solution conformations by CD and NMR spectroscopy. While single amino acid changes to as-APF8 often strongly reduced activity full potency was retained when the trivaline tail was replaced with three alanines. The Ala(6-8) derivative 9 is the simplest fully potent APF analogue synthesized to date. C1 [Kaczmarek, Piotr; Adams, Kristie M.; Barchi, Joseph J., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA. [Tocci, Gillian M.; Michejda, Christopher J.] NCI, Mol Aspects Drug Design Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Keay, Susan K.; Koch, Kristopher R.; Grkovic, David; Guo, Li] Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. [Keay, Susan K.] Vet Adm Maryland Hlth Care Syst, Res Serv, Baltimore, MD 21201 USA. [Zhang, Chen-Ou] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Barchi, JJ (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Frederick, MD 21702 USA. EM barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU National Institutes of Health (NIDDK) [R01 DK52596]; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by funding from the National Institutes of Health (NIDDK R01 DK52596), as well as funding from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, NR 29 TC 3 Z9 3 U1 1 U2 9 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 NOV PY 2010 VL 1 IS 8 BP 390 EP 394 DI 10.1021/ml100087a PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 680AS UT WOS:000284203100005 PM 24900223 ER PT J AU Brubaker, L Barber, MD Nygaard, I Nager, CW Varner, E Schaffer, J Visco, A Meikle, S Spino, C AF Brubaker, Linda Barber, Matthew D. Nygaard, Ingrid Nager, Charlie W. Varner, Edward Schaffer, Joseph Visco, Anthony Meikle, Susan Spino, Cathie CA Pelvic Floor Disorders Network TI Quantification of vaginal support: are continuous summary scores better than POPQ stage? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-of-Gynecologic-Surgeons CY APR 12-14, 2010 CL Tucson, AZ SP Soc Gynecol Surg DE outcome measures; pelvic organ prolapse; pelvic surgery; prolapse; quantification of prolapse ID PELVIC ORGAN PROLAPSE; STRESS URINARY-INCONTINENCE; QUALITY-OF-LIFE; FLOOR DISORDERS; US WOMEN; SYMPTOMS; STANDARDIZATION; SACROCOLPOPEXY; TERMINOLOGY; PREVALENCE AB OBJECTIVE: This analysis compared 3 continuous variables as summary support loss (SL) scores with pelvic organ prolapse (POP) quantification (POPQ) ordinal stages. STUDY DESIGN: We used pooled baseline data from 1141 subjects in 3 randomized trials (CARE, n = 322; OPUS, n = 380; ATLAS, n = 439) to test 3 SL measures. The relative responsiveness was assessed using the standardized response mean of 2-year outcome data from the CARE trial. RESULTS: Each SL measure was strongly correlated with POPQ ordinal staging; the single most distal POPQ point had the strongest correlation. Improvements in anatomic support were weakly correlated with improvements in POP Distress Inventory (r = 0.17-0.24; P < .01 for each) but not with changes in POP Impact Questionnaire for all measures of SL or POPQ stage. CONCLUSION: While continuous, single number summary measures compared favorably to ordinal POPQ staging system, the single most distal POPQ point may be preferable to POPQ ordinal stages to summarize or compare group data. C1 [Brubaker, Linda] Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Dept Urol, Chicago, IL 60611 USA. [Barber, Matthew D.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA. [Nygaard, Ingrid] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Nager, Charlie W.] Univ Calif San Diego, Dept Reprod Sci, San Diego, CA 92103 USA. [Varner, Edward] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Schaffer, Joseph] Univ Texas SW, Dept Obstet & Gynecol, Dallas, TX USA. [Visco, Anthony] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Spino, Cathie] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Brubaker, L (reprint author), Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. FU NICHD NIH HHS [U10 HD041261, U10 HD041250, U10 HD41267, U01 HD041249, U10 HD41250, U10 HD041267, U10 HD054215, U10 HD054214, U10 HD54215, U10 HD54214, U01 HD41249, U10 HD54136, U10 HD054241, U10 HD054136, U10 HD41261, U10 HD54241] NR 16 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2010 VL 203 IS 5 AR 512.e1 DI 10.1016/j.ajog.2010.06.071 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 675CF UT WOS:000283802000054 PM 20728072 ER PT J AU Gage, JC Duggan, MA Nation, JG Gao, S Castle, PE AF Gage, Julia C. Duggan, Maire A. Nation, Jill G. Gao, Song Castle, Philip E. TI Detection of cervical cancer and its precursors by endocervical curettage in 13,115 colposcopically guided biopsy examinations SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervical intraepithelial neoplasia; colposcopy; curettage; diagnosis; endocervical sampling ID ATYPICAL SQUAMOUS-CELLS; INTRAEPITHELIAL NEOPLASIA; WOMEN; MANAGEMENT; CYTOLOGY; HISTORY; LESION; DEBATE; TIME AB OBJECTIVE: Endocervical curettage (ECC) specimens obtained during colposcopy can detect cervical cancer and precursors otherwise missed by biopsy alone, but the procedure can be painful and reduce compliance with needed follow-up. ECC is routinely performed in the Calgary Health Region colposcopy clinics, permitting a look at its real-world utility. STUDY DESIGN: We analyzed pathology and colposcopy reports from 2003 to 2007. We calculated the added diagnostic utility of ECC compared with cervical biopsy alone. RESULTS: ECC increased the diagnostic yield of cervical intraepithelial neoplasia grade 2 or worse (cervical intraepithelial neoplasia [CIN]2+) in 1.01% of 13,115 colposcopically guided biopsy examinations. Therefore, 99 ECC specimens were taken to detect 1 additional CIN2+. ECC detected 5.4% of 2443 CIN2+ subjects otherwise missed by biopsy alone. Utility was greatest among women aged 46 years or older referred after a high-grade cytology. CONCLUSION: ECC is rarely informative when used routinely in colposcopic practice. Older women referred after high-risk cytology benefit most from ECC. C1 [Gage, Julia C.; Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Duggan, Maire A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada. [Nation, Jill G.] Univ Calgary, Dept Obstet & Gynecol, Calgary, AB, Canada. [Gao, Song] Alberta Canc Board, Alberta Cerv Canc Screening Program, Edmonton, AB, Canada. RP Gage, JC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7013,MSC 7234, Rockville, MD 20892 USA. EM gagej@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX J.C.G. and P.E.C. were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 23 TC 4 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2010 VL 203 IS 5 AR 481.e1 DI 10.1016/j.ajog.2010.06.048 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 675CF UT WOS:000283802000034 PM 20800216 ER PT J AU Vaisbuch, E Romero, R Mazaki-Tovi, S Erez, O Kusanovic, JP Mittal, P Gotsch, F Ward, C Romero, V Chaiworapongsa, T Pacora, P Yeo, L Hassan, SS AF Vaisbuch, Edi Romero, Roberto Mazaki-Tovi, Shali Erez, Offer Kusanovic, Juan Pedro Mittal, Pooja Gotsch, Francesca Ward, Clara Romero, Vivian Chaiworapongsa, Tinnakorn Pacora, Percy Yeo, Lami Hassan, Sonia S. TI The risk of impending preterm delivery in asymptomatic patients with a nonmeasurable cervical length in the second trimester SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest DE inflammation; interleukin-6 (IL-6); intraamniotic infection; pregnancy; preterm delivery; preterm labor; short cervix; sludge; sonography; transvaginal ultrasound ID AMNIOTIC-FLUID SLUDGE; LOW-BIRTH-WEIGHT; CLINICAL-SIGNIFICANCE; SONOGRAPHIC MEASUREMENT; OBSTETRIC HISTORY; WEEKS GESTATION; DEMOGRAPHIC CHARACTERISTICS; INTRAAMNIOTIC INFLAMMATION; TRANSVAGINAL ULTRASOUND; PLACENTAL HISTOLOGY AB OBJECTIVE: The purpose of this study was to determine the pregnancy outcome of asymptomatic patients in the second trimester with a nonmeasurable cervical length (0 mm). STUDY DESIGN: This retrospective cohort study included 78 patients with singleton pregnancies and a sonographic nonmeasurable cervix that was detected at 14-28 weeks of gestation. Patients with cervical cerclage were excluded. RESULTS: We found that (1) 75.3% of the patients delivered before 32 weeks of gestation; (2) the median diagnosis-to-delivery interval was 20.5 days, and the delivery rate within 7 and 14 days was 28.2% and 35.6%, respectively; and (3) patients with a nonmeasurable cervix that was diagnosed at <24 weeks of gestation had a shorter median diagnosis-to-delivery interval than patients who were diagnosed at 24-28 weeks of gestation (17.5 vs 41 days; P = .009). CONCLUSION: Asymptomatic women with a nonmeasurable cervix in the second trimester have a median diagnosis-to-delivery interval of approximately 3 weeks. Almost 65% of these patients will not deliver within 2 weeks, yet 75% of them will deliver before 32 weeks of gestation. The earlier a nonmeasurable cervix is identified, the shorter the diagnosis-to-delivery interval. C1 [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kusanovic, Juan Pedro; Mittal, Pooja; Gotsch, Francesca; Chaiworapongsa, Tinnakorn; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div NICHD NIH DHHS, Detroit, MI 48201 USA. [Vaisbuch, Edi; Mazaki-Tovi, Shali; Erez, Offer; Kusanovic, Juan Pedro; Mittal, Pooja; Ward, Clara; Romero, Vivian; Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kusanovic, Juan Pedro; Mittal, Pooja; Gotsch, Francesca; Chaiworapongsa, Tinnakorn; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD NIH DHHS, Bethesda, MD USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div NICHD NIH DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [ZIA HD002400-20] NR 63 TC 2 Z9 2 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2010 VL 203 IS 5 AR 446.e1 DI 10.1016/j.ajog.2010.05.040 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 675CF UT WOS:000283802000018 PM 20659728 ER PT J AU Dogan, RI Lu, ZY AF Dogan, Rezarta Islamaj Lu, Zhiyong TI Click-words: learning to predict document keywords from a user perspective SO BIOINFORMATICS LA English DT Article ID BIOMEDICAL TEXT; RETRIEVAL; SEARCH AB Motivation: Recognizing words that are key to a document is important for ranking relevant scientific documents. Traditionally, important words in a document are either nominated subjectively by authors and indexers or selected objectively by some statistical measures. As an alternative, we propose to use documents' words popularity in user queries to identify click-words, a set of prominent words from the users' perspective. Although they often overlap, click-words differ significantly from other document keywords. Results: We developed a machine learning approach to learn the unique characteristics of click-words. Each word was represented by a set of features that included different types of information, such as semantic type, part of speech tag, term frequency-inverse document frequency (TF-IDF) weight and location in the abstract. We identified the most important features and evaluated our model using 6 months of PubMed click-through logs. Our results suggest that, in addition to carrying high TF-IDF weight, click-words tend to be biomedical entities, to exist in article titles, and to occur repeatedly in article abstracts. Given the abstract and title of a document, we are able to accurately predict the words likely to appear in user queries that lead to document clicks. C1 [Dogan, Rezarta Islamaj; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM luzh@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX Funding: Intramural Research Program of the NIH, National Library of Medicine. NR 31 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD NOV PY 2010 VL 26 IS 21 BP 2767 EP 2775 DI 10.1093/bioinformatics/btq459 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 673LT UT WOS:000283665000017 ER PT J AU Shanbhag, MS Lathia, JD Mughal, MR Francis, NL Pashos, N Mattson, MP Wheatley, MA AF Shanbhag, Mihir S. Lathia, Justin D. Mughal, Mohamed R. Francis, Nicola L. Pashos, Nicholas Mattson, Mark P. Wheatley, Margaret A. TI Neural Progenitor Cells Grown on Hydrogel Surfaces Respond to the Product of the Transgene of Encapsulated Genetically Engineered Fibroblasts SO BIOMACROMOLECULES LA English DT Article ID SPINAL-CORD-INJURY; EMBRYONIC STEM-CELLS; PRECURSOR CELLS; ADULT-RAT; ENHANCES ELONGATION; ALGINATE HYDROGELS; IMMUNE SUPPRESSION; GENE DELIVERY; DIFFERENTIATION; BDNF AB Engineered tissue strategies for central nervous system (CNS) repair have the potential for localizing treatment using a wide variety of cells or growth factors. However, these strategies are often limited by their ability to address only one aspect of the injury. Here we report the development of a novel alginate construct that acts as a multifunctional tissue scaffold for CNS repair, and as a localized growth factor delivery vehicle. We show that the surface of this alginate construct acts as an optimal growth environment for neural progenitor cell (NPC) attachment; survival, migration, and differentiation. Importantly, we show that tailor-made alginate constructs containing brain-derived neurotrophic factor or neurotrophin-3 differentially direct lineage fates of NPCs and may therefore be useful in treating a wide variety of injuries. It is this potential for directed differentiation of a scaffold prior to implantation at the injury site that we explore here. C1 [Shanbhag, Mihir S.; Francis, Nicola L.; Pashos, Nicholas; Wheatley, Margaret A.] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA. [Lathia, Justin D.; Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Lathia, Justin D.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Lathia, Justin D.] Univ Cambridge, Ctr Brain Repair, Cambridge, England. RP Wheatley, MA (reprint author), Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, 3141 Chestnut St, Philadelphia, PA 19104 USA. EM wheatley@coe.drexel.edu RI Mattson, Mark/F-6038-2012 FU NIH; Bryon Reisch Paralysis Foundation; [HL 52901] FX The authors would like to thank Prof. Charles ffrench-Constant (University of Edinburgh) for guidance and helpful discussions on the manuscript. J.D.L. was supported by the NIH-Cambridge Graduate Partnership Program. M.A.W. is supported by HL 52901 and the Bryon Reisch Paralysis Foundation. NR 58 TC 12 Z9 12 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD NOV PY 2010 VL 11 IS 11 BP 2936 EP 2943 DI 10.1021/bm100699q PG 8 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 675FD UT WOS:000283810900015 PM 20942395 ER PT J AU Xu, TM Zhang, XY Oh, HS Boyd, RL Korn, EL Baumrind, S AF Xu, Tian-Min Zhang, Xiaoyun Oh, Hee Soo Boyd, Robert L. Korn, Edward L. Baumrind, Sheldon TI Randomized clinical trial comparing control of maxillary anchorage with 2 retraction techniques SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID ORTHODONTIC TREATMENT; ADULT AB Introduction: The objective of this pilot randomized clinical trial was to investigate the relative effectiveness of anchorage conservation of en-masse and 2-step retraction techniques during maximum anchorage treatment in patients with Angle Class I and Class II malocclusions. Methods: Sixty-four growing subjects (25 boys, 39 girls; 10.2-15.9 years old) who required maximum anchorage were randomized to 2 treatment techniques: en-masse retraction (n = 32) and 2-step retraction (n = 32); the groups were stratified by sex and starting age. Each patient was treated by a full-time clinic instructor experienced in the use of both retraction techniques at the orthodontic clinic of Peking University School of Stomatology in China. All patients used headgear, and most had transpalatal appliances. Lateral cephalograms taken before treatment and at the end of treatment were used to evaluate treatment-associated changes. Differences in maxillary molar mesial displacement and maxillary incisor retraction were measured with the before and after treatment tracings superimposed on the anatomic best fit of the palatal structures. Differences in mesial displacement of the maxillary first molar were compared between the 2 treatment techniques, between sexes, and between different starting-age groups. Results: Average mesial displacement of the maxillary first molar was slightly less in the en-masse group than in the 2-step group (mean, -0.36 mm; 95% CI, -1.42 to 0.71 mm). The average mesial displacement of the maxillary first molar for both treatment groups pooled (n 5 63, because 1 patient was lost to follow-up) was 4.3 +/- 2.1 mm (mean +/- standard deviation). Boys had significantly more mesial displacement than girls (mean difference, 1.3 mm; P < 0.03). Younger adolescents had significantly more mesial displacement than older adolescents (mean difference, 1.3 mm; P < 0.02). Conclusions: Average mesial displacement of the maxillary first molar with 2-step retraction was slightly greater than that for en-masse retraction, but the difference did not reach statistical significance. This finding appears to contradict the belief of many clinicians that 2-step canine retraction is more effective than en-masse retraction in preventing clinically meaningful anchorage loss. (Am J Orthod Dentofacial Orthop 2010; 138: 544.e1-544.e9) C1 [Oh, Hee Soo; Boyd, Robert L.; Baumrind, Sheldon] Univ Pacific, Sch Dent, Dept Orthodont, San Francisco, CA 94115 USA. [Baumrind, Sheldon] Univ Pacific, Sch Dent, Craniofacial Res Instrumentat Lab, San Francisco, CA 94115 USA. [Xu, Tian-Min; Zhang, Xiaoyun] Peking Univ, Sch & Hosp Stomatol, Dept Orthodont, Beijing 100871, Peoples R China. [Korn, Edward L.] NCI, Biometr Res Branch, NIH, Rockville, MD USA. RP Baumrind, S (reprint author), Univ Pacific, Sch Dent, Dept Orthodont, 2155 Webster St, San Francisco, CA 94115 USA. EM Sbaumrind@PACIFIC.EDU NR 21 TC 1 Z9 3 U1 1 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD NOV PY 2010 VL 138 IS 5 AR 544.e1 DI 10.1016/j.ajodo.2009.12.027 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 675CC UT WOS:000283801700015 PM 21055588 ER PT J AU Debette, S Beiser, A Wang, TJ DeCarli, C Wolf, PA Fox, CS Seshadri, S AF Debette, Stephanie Beiser, Alexa Wang, Thomas J. DeCarli, Charles Wolf, Philip A. Fox, Caroline S. Seshadri, Sudha TI Visceral Obesity and Brain Volume Reply SO ANNALS OF NEUROLOGY LA English DT Letter C1 [Debette, Stephanie; Beiser, Alexa; Wang, Thomas J.; DeCarli, Charles; Wolf, Philip A.; Fox, Caroline S.; Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [Debette, Stephanie; Beiser, Alexa; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. RP Debette, S (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD NOV PY 2010 VL 68 IS 5 BP 771 EP 772 DI 10.1002/ana.22233 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 675HR UT WOS:000283819000032 ER PT J AU Gottesman, MM Jaffe, HB AF Gottesman, Michael M. Jaffe, Holli Beckerman TI Commentary: A Delicate Balance: Weighing the Effects of Conflict-of-Interest Rules on Intramural Research at the National Institutes of Health SO ACADEMIC MEDICINE LA English DT Editorial Material AB In 2005, in response to increasing public concerns about potential conflicts of interest in biomedical research, the Department of Health and Human Services (DHHS) tightened its ethics rules to prohibit National Institutes of Health (NIH) employees from receiving consulting fees from "significantly affected organizations." In response, NIH took steps to implement these regulations and ensure that relationships between intramural NIH researchers and industry could proceed without threatening the integrity of federally funded research. Examples of these steps include creating an ethics advisory committee to review outside activities of NIH scientists and subjecting its researchers to special scrutiny to eliminate any perception of personal profit or conflict of interest. In the authors' experiences, interactions between NIH scientists and industry have continued relatively unaffected by these regulations. The continuing success of the technology transfer program at NIH and the number and types of cooperative research and development agreements with industry are good measures of the extent of productive interactions with industry since the implementation of the 2005 ethics rules. Although recruitment of outstanding scientists to the intramural program has continued, these regulations also have challenged NIH's ability to attract and retain some of the most qualified scientists, who fear they may miss certain opportunities because of the tighter regulations. As DHHS revises the regulations governing oversight of financial conflicts of interest in the extramural community, the authors recognize that the NIH intramural experience may provide valuable lessons about developing and implementing the next generation of financial conflict-of-interest rules. C1 [Gottesman, Michael M.; Jaffe, Holli Beckerman] NIH, NIH Eth Off, Rockville, MD 20852 USA. RP Gottesman, MM (reprint author), NIH, NIH Eth Off, 9000 Rockville Pike,Bldg 1,Room 160, Rockville, MD 20852 USA. EM mgottesman@nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD NOV PY 2010 VL 85 IS 11 BP 1660 EP 1662 DI 10.1097/ACM.0b013e3181fa3f91 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 672LC UT WOS:000283583500010 PM 20980848 ER PT J AU Goker-Alpan, O Stubblefield, BK Giasson, BI Sidransky, E AF Goker-Alpan, Ozlem Stubblefield, Barbara K. Giasson, Benoit I. Sidransky, Ellen TI Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders SO ACTA NEUROPATHOLOGICA LA English DT Article DE Glucocerebrosidase; alpha-Synuclein; Parkinsonism; Lewy body dementia ID SPORADIC PARKINSONS-DISEASE; GAUCHER-DISEASE; NEURODEGENERATIVE DISEASES; MUTATIONS; BODIES; DEMENTIA; GENE; SUSCEPTIBILITY; MANIFESTATIONS; ASSOCIATION AB Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42-77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32-90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, < 10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of alpha-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates. C1 [Goker-Alpan, Ozlem; Stubblefield, Barbara K.; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Giasson, Benoit I.] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; Udall Centre of Excellence in Parkinson's Disease Research [NS053488] FX We thank Stephen Wincovitch for technical assistance with confocal microscopy, and Julia Fekecs and Jae Choi for preparation of the figures. This work was supported by the Intramural Research Program of the National Human Genome Research Institute and Udall Centre of Excellence in Parkinson's Disease Research Grant (NS053488). NR 33 TC 84 Z9 85 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD NOV PY 2010 VL 120 IS 5 BP 641 EP 649 DI 10.1007/s00401-010-0741-7 PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 665XU UT WOS:000283071800009 PM 20838799 ER PT J AU Forooghian, F Cukras, C Meyerle, CB Nussenblatt, RB Gottlieb, CC Chew, EY Wong, WT AF Forooghian, Farzin Cukras, Catherine Meyerle, Catherine B. Nussenblatt, Robert B. Gottlieb, Chloe C. Chew, Emily Y. Wong, Wai T. TI Gallium scintigraphy in the investigation of retinal inflammatory vasculopathy SO ACTA OPHTHALMOLOGICA LA English DT Letter ID SARCOIDOSIS C1 [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin; Cukras, Catherine; Meyerle, Catherine B.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Nussenblatt, Robert B.; Gottlieb, Chloe C.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Off Sci Director, NIH, 7 Mem Dr,Bldg 7,Room 217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [Z99 EY999999, ZIE EY000487-01] NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-375X J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD NOV PY 2010 VL 88 IS 7 BP e291 EP e292 DI 10.1111/j.1755-3768.2009.01725.x PG 2 WC Ophthalmology SC Ophthalmology GA 672OQ UT WOS:000283596200018 PM 19878127 ER PT J AU Ko, SU Hausdorff, JM Ferrucci, L AF Ko, Seung-uk Hausdorff, Jeffrey M. Ferrucci, Luigi TI Age-associated differences in the gait pattern changes of older adults during fast-speed and fatigue conditions: results from the Baltimore longitudinal study of ageing SO AGE AND AGEING LA English DT Article DE gait analysis; ageing; medial-lateral control; exacerbated decline; mechanical work expenditure; elderly ID DYNAMIC STABILITY; WALKING; PERFORMANCE; KINETICS; POWERS; YOUNG AB Methods: investigated walking under three conditions: (i) usual speed, (ii) fast speed and (iii) post-activity in 183 Baltimore Longitudinal Study of Aging participants (mean 73 +/- 9 years) who could walk unassisted. Results: across all tasks, gait speed decreased with older age and this decline rate was exacerbated in the fast-speed walking task, compared with usual-speed walking (P < 0.001). Medial-lateral (ML) hip-generative mechanical work expenditure declined with age and the rate of decline was steeper for walking at fast speed and post-activity during hip extension (P = 0.032 and 0.027, respectively), compared with usual-speed walking. Conclusions: these findings indicate that older adults experience exacerbated declines in gait speed and ML control of the hip, which is explicitly evident during challenging walking. Exercise programmes aimed at improving gait speed and ML joint power from hip and ankle may help reverse age-associated changes in gait pattern among older adults. C1 [Ko, Seung-uk; Ferrucci, Luigi] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. [Hausdorff, Jeffrey M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Tel Aviv, Israel. [Hausdorff, Jeffrey M.] Harvard Univ, Sch Med, Boston, MA USA. RP Ko, SU (reprint author), NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. EM kos2@mail.nih.gov FU NIH, National Institute on Aging FX This research was entirely supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 23 TC 29 Z9 29 U1 3 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD NOV PY 2010 VL 39 IS 6 BP 688 EP 694 DI 10.1093/ageing/afq113 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 673KO UT WOS:000283659700007 PM 20833863 ER PT J AU Sack, MN AF Sack, Michael N. TI Mitochondrial Fe-S cluster biogenesis, frataxin and the modulation of susceptibility to drug-induced cardiomyopathy SO AGING-US LA English DT Article ID OVEREXPRESSION; PROTECTION; FAILURE; DISEASE C1 NIH, NHLBI Ctr Mol Med, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NIH, NHLBI Ctr Mol Med, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.go NR 13 TC 1 Z9 1 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2010 VL 2 IS 11 BP 754 EP 755 PG 2 WC Cell Biology SC Cell Biology GA 699WP UT WOS:000285693900004 PM 21113085 ER PT J AU Gadalla, SM Cawthon, R Giri, N Alter, BP Savage, SA AF Gadalla, Shahinaz M. Cawthon, Richard Giri, Neelam Alter, Blanche P. Savage, Sharon A. TI Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes SO AGING-US LA English DT Article DE telomere; correlation; dyskeratosis congenita; bone marrow failure ID DYSKERATOSIS-CONGENITA; CHROMOSOMAL INSTABILITY; DIFFERENT TISSUES; APLASTIC-ANEMIA; CANCER-RISK; POPULATION; AGE AB Telomeres, the nucleotide repeats and protein complex at chromosome ends, are required for chromosomal stability and are important markers of aging. Patients with dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), have mutations in telomere biology genes, and very short telomeres. There are limited data on intra-individual telomere length (TL) variability in DC and related disorders. We measured relative TL by quantitative-PCR in blood, buccal cells, and fibroblasts from 21 patients with an IBMFS (5 Diamond-Blackfan anemia, 6 DC, 6 Fanconi anemia, and 4 Shwachman-Diamond syndrome). As expected, TL in patients with DC was significantly (p<0.01) shorter in all tissues compared with other IBMFS. In all disorders combined, the median Q-PCR TL was longer in fibroblast and buccal cells than in blood (overall T/S ratio=1.42 and 1.16 vs. 1.05, p=0.001, 0.006, respectively). Although the absolute values varied, statistically significant intra-individual correlations in TL were present in IBMFS patients: blood and fibroblast (r=0.66, p=0.002), blood and buccal cells (r=0.74, p<0.0001), and fibroblast and buccal cells (r= 0.65,p=0.004). These data suggest that relative TL is tissue-independent in DC and possibly in the other IBMFS. C1 [Gadalla, Shahinaz M.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Gadalla, Shahinaz M.] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. [Cawthon, Richard] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, National Institutes of Health FX We thank the patients and their families for their generous participation in the study. We are grateful to Lisa Leathwood, RN, Westat Inc., for outstanding clinical support. This work was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, National Institutes of Health. NR 36 TC 56 Z9 58 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2010 VL 2 IS 11 BP 867 EP 874 PG 8 WC Cell Biology SC Cell Biology GA 699WP UT WOS:000285693900016 PM 21113082 ER PT J AU Araujo, AF Brites, C Monteiro-Cunha, J Santos, LA Galvao-Castro, B Alcantara, LCJ AF Araujo, Adriano Fernando Brites, Carlos Monteiro-Cunha, Joana Santos, Luciane Amorim Galvao-Castro, Bernardo Junior Alcantara, Luiz Carlos TI Lower Prevalence of Human Immunodeficiency Virus Type 1 Brazilian Subtype B Found in Northeastern Brazil with Slower Progression to AIDS SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID V3 REGION; HIV-1 AB Besides being extremely useful in measuring the level of HIV-1 diversity and prevalence in populations, the molecular analysis of genomic sequences provides crucial surveillance support and aids in the development of new therapies and effective vaccines. The present study focused on gag and env DNA and amino acid sequences that were generated from samples taken from 61 infected patients in the City of Salvador, Bahia, located in northeastern Brazil. In order to determine selective pressure and predict coreceptor usage, Bioinformatics tools were employed in phylogeny reconstruction. Fifty-six (91.8%) viruses were classified as belonging to subtype B, three (4.9%) from F1, and two (3.3%) from BF1 recombinants. Based on the characterization of the V3 region, the subtype B strains were represented by eight (18.2%) Brazilian variants (B'-GWGR), 20 (46.5%) European/EUA B variants (GPGR), and 15 (34.9%) GXGX variants. The mean time elapsed since diagnosis was 13 years among subtype B' and 9 years in subtype B. The mean dN/dS ratios from the GWGR, GPGR, and GXGX groups, when compared to an HXB2 reference, were 0.72, 0.77, and 0.67, respectively. Seventy-six percent of the viruses studied were predicted to use the CCR5 coreceptor for cell entry (R5 viruses), while 24% were predicted to use the CXCR4 or were classified as dual tropic viruses. The prevalence of subtypes B' and recombinant B/F1 was shown to be lower than findings from previous studies performed both in Brazil (B') and in Bahia (B/F1). The association between subtype B' and a lengthy period of time since diagnosis can be correlated with a slower disease progression in infected patients, when compared with those infected with subtype B. C1 [Junior Alcantara, Luiz Carlos] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Araujo, Adriano Fernando; Monteiro-Cunha, Joana; Santos, Luciane Amorim; Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] Fundacao Oswaldo Cruz, Adv Publ Hlth Lab, Goncalo Moniz Res Ctr, Salvador, BA, Brazil. [Brites, Carlos] Univ Fed Bahia, Salvador, BA, Brazil. [Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] Fdn Dev Sci, Bahia Sch Med & Publ Hlth, Salvador, BA, Brazil. RP Alcantara, LCJ (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bldg 41,Room C-303, Bethesda, MD 20892 USA. EM alcantaralc@mail.nih.gov RI Brites , Carlos /D-1353-2013; OI Brites , Carlos /0000-0002-4673-6991; Araujo, Fernando/0000-0001-6471-5564 NR 16 TC 6 Z9 6 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV PY 2010 VL 26 IS 11 BP 1249 EP 1254 DI 10.1089/aid.2010.0068 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 681KL UT WOS:000284311900014 PM 20854208 ER PT J AU Vuppalanchi, R Hayashi, PH Chalasani, N Fontana, RJ Bonkovsky, H Saxena, R Kleiner, D Hoofnagle, JH AF Vuppalanchi, R. Hayashi, P. H. Chalasani, N. Fontana, R. J. Bonkovsky, H. Saxena, R. Kleiner, D. Hoofnagle, J. H. CA Drug-Induced Liver Injury Network TI Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID UNITED-STATES; HEPATITIS; HYDROCHLORIDE AB P>Background Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well-described. Aim To describe the presenting features and outcomes of seven well-characterized patients with suspected duloxetine hepatotoxicity. Methods Patients enrolled in the Drug-Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity. Results Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre-existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury. Conclusions Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra-hepatic features were noted at presentation. C1 [Vuppalanchi, R.; Chalasani, N.; Saxena, R.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Hayashi, P. H.] Univ N Carolina, Dept Internal Med, Chapel Hill, NC USA. [Fontana, R. J.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Bonkovsky, H.] Carolinas Med Ctr, Canon Res Ctr, Charlotte, NC 28203 USA. [Bonkovsky, H.] Carolinas Med Ctr, Ctr Liver & Digest Dis, Charlotte, NC 28203 USA. [Kleiner, D.] Natl Canc Inst, Pathol Lab, Bethesda, MD USA. [Hoofnagle, J. H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, Natl Inst Hlth, Bethesda, MD USA. RP Chalasani, N (reprint author), Indiana Univ, Sch Med, Dept Med, RG 4100,1050 Wishard Blvd, Indianapolis, IN 46202 USA. EM nchalasa@iupui.edu OI Vuppalanchi, Raj/0000-0003-0637-1577; Kleiner, David/0000-0003-3442-4453 FU Teva pharmaceuticals; KaroBio; JJ; Abbott; Salix Pharmaceuticals; Gilead; Eli Lilly; National Institutes of Health; American Porphyria Foundation; Clinuvel; Novartis; Vertex; National Institute of Diabetes and Digestive and Kidney Diseases [1U01DK065021, 1U01DK065193, 1U01DK065201, 1U01DK065184, 1U01DK065211, 1U01DK065238, 1U01DK065176] FX Declaration of personal interests: We are grateful to Laura P. James, MD (University of Arkansas for Medical Sciences), for measuring acetaminophen adducts from the serum of patient 1. We thank research participants for their enrolment in the DILIN studies and research coordinators for their dedication and contributions to the DILIN. Dr Chalasani has received consulting fees regarding drug-induced liver injury in the past 12 months from the following companies: Teva pharmaceuticals, KaroBio, J&J, Abbott, Salix Pharmaceuticals and Gilead. He has received research support from Eli Lilly for research on drug-induced liver disease. In the preceding 12 months, Dr Bonkovsky served as a paid advisor to Clinuvel, Inc., Novartis Pharmaceuticals and Lundbeck SA. He is on the speakers' bureau of Lundbeck. He receives support for research studies from The National Institutes of Health, The American Porphyria Foundation, Clinuvel, Novartis and Vertex. During the past 12 months, Dr Bonkovsky has served as an expert witness for plaintiffs in litigation regarding suspected drug-induced liver injury. Dr Fontana served as a paid consultant to GlaxoSmithKline, Hoffman-La Roche, Bristol-Myer-Squibbs and Novartis. Dr Vuppalanchi has served on the Roche Speaker's bureau. Drs Hoofnagle, Kleiner, Hayashi and Saxena have no conflicts to declare. Declaration of funding interests: The DILIN network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065021, 1U01DK065193, 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238 and 1U01DK065176. NR 15 TC 23 Z9 24 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD NOV 1 PY 2010 VL 32 IS 9 BP 1174 EP 1183 DI 10.1111/j.1365-2036.2010.04449.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 659MO UT WOS:000282570800014 PM 20815829 ER PT J AU Matsui, EC Sampson, HA Bahnson, HT Gruchalla, RS Pongracic, JA Teach, SJ Gergen, PJ Bloomberg, GR Chmiel, JF Liu, AH Kattan, M Sorkness, CA Steinbach, SF Story, RE Visness, CM AF Matsui, E. C. Sampson, H. A. Bahnson, H. T. Gruchalla, R. S. Pongracic, J. A. Teach, S. J. Gergen, P. J. Bloomberg, G. R. Chmiel, J. F. Liu, A. H. Kattan, M. Sorkness, C. A. Steinbach, S. F. Story, R. E. Visness, C. M. CA Inner-City Asthma Consortium TI Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma SO ALLERGY LA English DT Article DE allergen exposure; allergen-specific IgE; biomarker; childhood asthma; Inner-city Asthma Consortium ID MOUSE ALLERGEN; PRESCHOOL-CHILDREN; MORBIDITY; SENSITIVITY; COCKROACH; WHEEZE; ADULTS; CAT AB P>Background: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. Methods: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. Results: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. Conclusions: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity. C1 [Matsui, E. C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Sampson, H. A.] Mt Sinai Sch Med, New York, NY USA. [Bahnson, H. T.; Visness, C. M.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gruchalla, R. S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Pongracic, J. A.; Story, R. E.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Teach, S. J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gergen, P. J.] NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Bloomberg, G. R.] Washington Univ, Sch Med, St Louis, MO USA. [Chmiel, J. F.] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Liu, A. H.] Natl Jewish Hlth, Denver, CO USA. [Liu, A. H.] Univ Colorado, Sch Med, Denver, CO USA. [Kattan, M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Sorkness, C. A.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Steinbach, S. F.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Matsui, EC (reprint author), Johns Hopkins Univ Hosp, CMSC 1102,600 N Wolfe St, Baltimore, MD 21287 USA. EM ematsui1@jhmi.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [NO1-AI-25496, NO1-AI-25482]; National Center for Research Resources, National Institutes of Health [RR00052, M01RR00533, M01 RR00071, 5UL1RR024992-02, 5M01RR020359-04] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Contracts number NO1-AI-25496 and NO1-AI-25482, and from the National Center for Research Resources, National Institutes of Health, under grants RR00052, M01RR00533, M01 RR00071, 5UL1RR024992-02, and 5M01RR020359-04. NR 22 TC 36 Z9 36 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-4538 J9 ALLERGY JI Allergy PD NOV PY 2010 VL 65 IS 11 BP 1414 EP 1422 DI 10.1111/j.1398-9995.2010.02412.x PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 661AJ UT WOS:000282693900009 PM 20560910 ER PT J AU Melloni, C Rao, SV Povsic, TJ Melton, L Kim, RJ Kilaru, R Patel, MR Talan, M Ferrucci, L Longo, DL Lakatta, EG Najjar, SS Harrington, RA AF Melloni, Chiara Rao, Sunil V. Povsic, Thomas J. Melton, Laura Kim, Raymond J. Kilaru, Rakhi Patel, Manesh R. Talan, Mark Ferrucci, Luigi Longo, Dan L. Lakatta, Edward G. Najjar, Samer S. Harrington, Robert A. TI Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; ISCHEMIA-REPERFUSION INJURY; IMPROVES CARDIAC-FUNCTION; PERCUTANEOUS CORONARY INTERVENTION; DELAYED CONTRAST-ENHANCEMENT; ENDOTHELIAL PROGENITOR CELLS; HEART-FAILURE; DARBEPOETIN-ALPHA; RANDOMIZED-TRIAL; DOUBLE-BLIND AB Background Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells. Study Design REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin a on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin a dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin a or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling. Conclusion The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin a in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. (Am Heart J 2010;160:795-803.e2.) C1 [Melloni, Chiara; Rao, Sunil V.; Povsic, Thomas J.; Kim, Raymond J.; Patel, Manesh R.; Harrington, Robert A.] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA. [Melloni, Chiara; Rao, Sunil V.; Povsic, Thomas J.; Melton, Laura; Kim, Raymond J.; Kilaru, Rakhi; Patel, Manesh R.; Harrington, Robert A.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Rao, Sunil V.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Talan, Mark; Ferrucci, Luigi; Longo, Dan L.; Lakatta, Edward G.; Najjar, Samer S.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Najjar, Samer S.] MedStar Hlth Res Inst, Washington, DC USA. RP Melloni, C (reprint author), Duke Univ SOM, Dept Med Cardiol, DUMC Box 3850, Durham, NC 27710 USA. EM chiara.melloni@duke.edu RI Kim, Raymond/B-1426-2008 FU National Institute on Aging, the National Institutes of Health, Bethesda, MD, USA FX This study was supported by the Intramural Research Program of the National Institute on Aging, the National Institutes of Health, Bethesda, MD, USA. NR 59 TC 12 Z9 13 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD NOV PY 2010 VL 160 IS 5 BP 795 EP U39 DI 10.1016/j.ahj.2010.09.007 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 683FX UT WOS:000284458700004 PM 21095264 ER PT J AU Maslova, E Bhattacharya, S Lin, SW Michels, KB AF Maslova, Ekaterina Bhattacharya, Sayanti Lin, Shih Wen Michels, Karin B. TI Caffeine consumption during pregnancy and risk of preterm birth a meta-analysis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID MEDITERRANEAN-TYPE DIET; COFFEE CONSUMPTION; FETAL-GROWTH; PROSPECTIVE COHORT; GESTATIONAL-AGE; HUMAN CYP1A2; WEIGHT; DELIVERY; SMOKING; ASSOCIATION AB Background The effect of caffeine intake during pregnancy on the risk of preterm delivery has been studied for the past 3 decades with inconsistent results Objective We performed a meta analysis ex miming the association between caffeine consumption during pregnancy and risk of preterm birth Design We searched MEDLINE and EMBASE articles published between 1966 and July 2010 cross referenced reference lists of the retrieved articles and identified 15 cohort and 7 case control studies that met inclusion criteria for this meta analysis Results The combined odds ratios (ORs) obtained by using fixed effects models for cohort studies were 1 11(95% CI 096 1 28) 110 (95% CI 1 01 1 19) and 1 08(95% CI 093 1 27) for risk of preterm birth comparing the highest with the lowest level of caffeine intake (or no intake) (mg/d) during the first second and third trimesters respectively Results for the case control studies yielded no associations for the first (OR 1 07, 95% CI 084 1 37) second (OR 117 95% CI 094 1 45) or third (OR 094 95% CI 079 1 12) trimesters No overall heterogeneity was found by region publication decade exposure and outcome assessment caffeine sources or adjustment for confounding, which was largely driven by individual studies Conclusion In this meta analysis we observed no important association between caffeine intake during pregnancy and the risk of preterm birth for cohort and case-control studies Am J Clin Mar 2010 92 1120-32 C1 [Maslova, Ekaterina] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Bhattacharya, Sayanti] Univ Texas Hlth Sci Ctr San Antonio, Inst Mol Med, Houston, TX USA. [Lin, Shih Wen] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Michels, Karin B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Obstet & Gynecol Epidemiol Ctr,Dept Obstet & Gyne, Boston, MA 02115 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Maslova, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2, Boston, MA 02115 USA. FU National Institutes of Health Bethesda MD; Institute of Molecular Medicine at the University of Texas Health Science Center Houston TX FX There were no funding sources for this work S WL was funded by the Cancer Prevention Fellowship Program National Institutes of Health Bethesda MD SB was funded by a postdoctoral fellowship at the Institute of Molecular Medicine at the University of Texas Health Science Center Houston TX NR 59 TC 15 Z9 15 U1 0 U2 12 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2010 VL 92 IS 5 BP 1120 EP 1132 DI 10.3945/ajcn.2010.29789 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 677DJ UT WOS:000283969000016 PM 20844077 ER PT J AU McKeown, NM Troy, LM Jacques, PF Hoffmann, U O'Donnell, CJ Fox, CS AF McKeown, Nicola M. Troy, Lisa M. Jacques, Paul F. Hoffmann, Udo O'Donnell, Christopher J. Fox, Caroline S. TI Whole- and refined-grain intakes are differentially associated with abdominal visceral and subcutaneous adiposity in healthy adults the Framingham Heart Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID OVERWEIGHT LATINO ADOLESCENTS; FOOD FREQUENCY QUESTIONNAIRE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; METABOLIC SYNDROME; HYPOCALORIC DIET; OBESITY; FIBER; CONSUMPTION AB Background Observational studies have linked higher intakes of whole grains to lower abdominal adiposity however the association between whole and refined-grain intake and body fat compartments has yet to be reported Objective Different aspects of diet may be differentially related to body fat distribution The purpose of this study was to assess associations between whole- and refined grain intake and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) Design Cross sectional associations between whole and refined-grain intakes waist circumference measures and abdominal SAT and VAT volumes were examined in 2834 Framingham Heart Study participants (49 4% women age range 32-83 y) Dietary information was assessed with the use of a semiquantitative food frequency questionnaire Results Whole grain intake was inversely associated with SAT (2895 compared with 2552 cm(3) in the lowest compared with the highest quintile category P for trend < 0 001) and VAT (1883 compared with 1563 cm(3) P for trend < 0 001) after adjustment for age sex current smoking status total energy and alcohol intake In contrast, refined-grain intake was positively associated with SAT (2748 compared with 2934 cm(3) P for trend = 0 01) and VAT (1727 compared with 19'8 cm(3), P for trend < 0 001) in multivanable models When SAT and VAT were evaluated jointly the P value for SAT was attenuated (P = 0 28 for whole grains P = 0 60 for refined grams) whereas VAT remained associated with both whole grains (P < 0 001) and refined grains (P < 0 001) Conclusions Increasing whole grain Intake is associated with lower VAT in adults whereas higher intakes of refined grains are associated with higher VAT Further research is required to elicit the potential mechanisms whereby whole- and refined grain foods may influence body fat distribution Am J Clin Altar 2010 92 1165-71 C1 [McKeown, Nicola M.; Troy, Lisa M.; Jacques, Paul F.] Tufts Univ, Nutr Epidemiol Program, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Cardiac Unit, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Hoffmann, Udo; O'Donnell, Christopher J.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP McKeown, NM (reprint author), Tufts Univ, Nutr Epidemiol Program, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. FU USDA [58 1950 7 707]; Framingham Heart Study of the National Heart Lung and Blood Institute of the NIH [NO1 HC 25195]; General Mills Bell Institute of Health and Nutrition Minneapolis MN FX Supported by the USDA (agreement 58 1950 7 707) the Framingham Heart Study of the National Heart Lung and Blood Institute of the NIH (contract NO1 HC 25195) and by a research grant from General Mills Bell Institute of Health and Nutrition Minneapolis MN NR 28 TC 58 Z9 58 U1 2 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2010 VL 92 IS 5 BP 1165 EP 1171 DI 10.3945/ajcn.2009.29106 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 677DJ UT WOS:000283969000021 PM 20881074 ER PT J AU Szymanski, KM Wheeler, DC Mucci, LA AF Szymanski, Konrad M. Wheeler, David C. Mucci, Lorelet A. TI Fish consumption and prostate cancer risk a review and meta-analysis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FATTY FISH; DIET; COHORT; MEN; POPULATION; MORTALITY; CANADA; FOODS; MEAT; ASSOCIATION AB Background Prostate cancer incidence varies 60 fold globally which suggests the roles of lifestyle and dietary factors in its cause To our knowledge a comprehensive assessment of the association between fish consumption and prostate cancer incidence and mortality has not been reported Objective We conducted a meta analysis of fish intake and prostate cancer by focusing on the incidence of prostate cancer and prostate cancer specific mortality and included subgroup analyses based on race, fish type method of fish preparation and high grade and high stage cancer Design We searched MEDLINE and EMBASE databases (May 2009) for case control and cohort studies that assessed fish intake and prostate cancer risk Two authors independently assessed eligibility and extracted data Results There was no association between fish consumption and a significant reduction in prostate cancer incidence [12 case-control studies (n = 5777 cases and 9805 control subjects) odds ratio (OR) 085 95% CI 072 1 00 and 12 cohort studies (n = 445 820) relative risk (RR) 1 01 95% CI 090 1 14] It was not possible to perform a meta-analyst, for high-grade disease (one case-control study OR 1 44 95% CI 0 58 3 03) locally advanced disease (one cohort study RR 080 95% CI 061 1 13) or metastatic disease (one cohort study RR 0 56 95% CI 0 37 0 86) There was an association between fish consumption and a significant 63% reduction in prostate cancer specific mortality [4 cohort studies (n = 49 661) RR 037 95% (I 018 0 74] Conclusion Our analyses provide no strong evidence of a protective association of fish consumption with prostate cancer incidence but showed a significant 63% reduction in prostate cancer specific mortality Am J Clin Nutr 2010 92 1223-33 C1 [Szymanski, Konrad M.] McGill Univ Hlth Ctr, Div Urol, Montreal, PQ H3A 1A1, Canada. [Wheeler, David C.] NCI, Bethesda, MD 20892 USA. [Mucci, Lorelet A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelet A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Szymanski, KM (reprint author), McGill Univ Hlth Ctr, Royal Victoria Hosp, Div Urol, 687 Pine Ave W S6 52D, Montreal, PQ H3A 1A1, Canada. NR 51 TC 69 Z9 72 U1 1 U2 10 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2010 VL 92 IS 5 BP 1223 EP 1233 DI 10.3945/ajcn.2010.29530 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 677DJ UT WOS:000283969000028 PM 20844069 ER PT J AU Copersino, ML Boyd, SJ Tashkin, DP Huestis, MA Heishman, SJ Dermand, JC Simmons, MS Gorelick, DA AF Copersino, Marc L. Boyd, Susan J. Tashkin, Donald P. Huestis, Marilyn A. Heishman, Stephen J. Dermand, John C. Simmons, Michael S. Gorelick, David A. TI Sociodemographic Characteristics of Cannabis Smokers and the Experience of Cannabis Withdrawal SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Age; cannabis; marijuana; quitting; race; relapse; sex; withdrawal ID NATIONAL EPIDEMIOLOGIC SURVEY; MARIJUANA USE; SPONTANEOUS-RECOVERY; UNITED-STATES; SUBSTANCE USE; USE DISORDERS; DEPENDENCE; ADOLESCENTS; POPULATION; SYMPTOMS AB Background: Cannabis withdrawal can be a negative reinforcer for relapse, but little is known about its association with demographic characteristics. Objectives: Evaluate the association of demographic characteristics with the experience of cannabis withdrawal. Methods: Retrospective self-report of a "serious" cannabis quit attempt without formal treatment in a convenience sample of 104 non-treatment-seeking, adult cannabis smokers (mean age 35 years, 52% white, 78% male) with no other current substance use disorder (except tobacco) or chronic health problems. Reasons for quitting, coping strategies to help quit, and 18 specific withdrawal symptoms were assessed by questionaire. Results: Among withdrawal symptoms, only anxiety, increased sex drive, and craving showed significant associations with age, race, or sex. Women were more likely than men to report a physical withdrawal symptom (OR = 3.2, 95% CI = .99-10.4, p = .05), especially upset stomach. There were few significant demographic associations with coping strategies or reasons for quitting. Conclusions and Scientific Significance: This small study suggests that there are few robust associations between demographic characteristics and cannabis withdrawal. Future studies with larger samples are needed. Attention to physical withdrawal symptoms in women may help promote abstinence. C1 [Copersino, Marc L.; Boyd, Susan J.; Huestis, Marilyn A.; Heishman, Stephen J.; Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Copersino, Marc L.] Harvard Univ, Sch Med, Belmont, MA USA. [Copersino, Marc L.] McLean Hosp, Belmont, MA 02178 USA. [Tashkin, Donald P.; Dermand, John C.; Simmons, Michael S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Gorelick, DA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU NIDA NIH HHS [K23 DA027045, R0-1 DA03018, K23DA027045-01A1, R01 DA003018] NR 31 TC 14 Z9 14 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD NOV PY 2010 VL 36 IS 6 BP 311 EP 319 DI 10.3109/00952990.2010.503825 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 677PD UT WOS:000284003400002 PM 20678028 ER PT J AU Hasler, WL Parkman, HP Wilson, LA Pasricha, PJ Koch, KL Abell, TL Snape, WJ Farrugia, G Lee, L Tonascia, J Unalp-Arida, A Hamilton, F AF Hasler, William L. Parkman, Henry P. Wilson, Laura A. Pasricha, Pankaj J. Koch, Kenneth L. Abell, Thomas L. Snape, William J. Farrugia, Gianrico Lee, Linda Tonascia, James Unalp-Arida, Aynur Hamilton, Frank CA Niddk Gastroparesis Clinical Res TI Psychological Dysfunction Is Associated With Symptom Severity but Not Disease Etiology or Degree of Gastric Retention in Patients With Gastroparesis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; FUNCTIONAL DYSPEPSIA; EMPTYING SCINTIGRAPHY; SENSORIMOTOR FUNCTION; PSYCHOSOCIAL FACTORS; DIABETIC-PATIENTS; ANXIETY; DEPRESSION; ADULTS; PREVALENCE AB OBJECTIVES: Gastroparesis patients may have associated psychological distress. This study aimed to measure depression and anxiety in gastroparesis in relation to disease severity, etiology, and gastric retention. METHODS: Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) scores for state (Y1) and trait (Y2) anxiety were obtained from 299 gastroparesis patients from 6 centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium. Severity was investigator graded as grades 1, 2, or 3 and patient reported by Gastroparesis Cardinal Symptom Index (GCSI) scores. Antiemetic/prokinetic medication use, anxiolytic and antidepressant medication use, supplemental feedings, and hospitalizations were recorded. BDI, Y1, and Y2 scores were compared in diabetic vs. idiopathic etiologies and mild (<= 20%) vs. moderate (>20-35%) vs. severe (>35-50%) vs. very severe (>50%) gastric retention at 4 h. RESULTS: BDI, Y1, and Y2 scores were greater with increasing degrees of investigator-rated gastroparesis severity (P<0.05). BDI, Y1, and Y2 scores were higher for GCSI>3.1 vs. pi 3.1 (P<0.05). Antiemetic and prokinetic use and >= 6 hospitalizations/year were more common with BDI >= 20 vs. <20 (P<0.05). Anxiolytic use was more common with Y1 >= 46; antidepressant use and >= 6 hospitalizations/year were more common with Y2 >= 44 (P<0.05). BDI, Y1, and Y2 scores were not different in diabetic and idiopathic gastroparesis and did not relate to degree of gastric retention. On logistic regression, GCSI>3.1 was associated with BDI >= 20 and Y1 >= 46; antiemetic/prokinetic use was associated with BDI >= 20; anxiolytic use was associated with Y1 >= 46; and antidepressant use was associated with Y2 >= 44. CONCLUSIONS: Higher depression and anxiety scores are associated with gastroparesis severity on investigator-and patient-reported assessments. Psychological dysfunction does not vary by etiology or degree of gastric retention. Psychological features should be considered in managing gastroparesis. C1 [Hasler, William L.] Univ Michigan, Dept Gastroenterol, Ann Arbor, MI 48109 USA. [Parkman, Henry P.] Temple Univ, Philadelphia, PA 19122 USA. [Wilson, Laura A.; Lee, Linda; Tonascia, James; Unalp-Arida, Aynur] Johns Hopkins Univ, Baltimore, MD USA. [Pasricha, Pankaj J.] Stanford Univ, Palo Alto, CA 94304 USA. [Koch, Kenneth L.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Hamilton, Frank] NIDDK, Bethesda, MD USA. RP Hasler, WL (reprint author), Univ Michigan, Dept Gastroenterol, 3912 Taubman Ctr,Box 0362, Ann Arbor, MI 48109 USA. EM whasler@umich.edu RI Vaughn, Ivana/B-6138-2016 OI Vaughn, Ivana/0000-0002-7201-0289 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008]; Gastroparesis Clinical Research Consortium FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, and U01DK074008) as part of its funding of the Gastroparesis Clinical Research Consortium. NR 41 TC 34 Z9 34 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD NOV PY 2010 VL 105 IS 11 BP 2357 EP 2367 DI 10.1038/ajg.2010.253 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 674UM UT WOS:000283775600005 PM 20588262 ER PT J AU O'Seaghdha, CM Hwang, SJ Upadhyay, A Meigs, JB Fox, CS AF O'Seaghdha, Conall M. Hwang, Shih-Jen Upadhyay, Ashish Meigs, James B. Fox, Caroline S. TI Predictors of Incident Albuminuria in the Framingham Offspring Cohort SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Microalbuminuria; albuminuria; proteinuria ID CARDIOVASCULAR RISK-FACTORS; GLYCOSYLATION END-PRODUCTS; TYPE-2 DIABETIC-PATIENTS; CHRONIC KIDNEY-DISEASE; URINARY ALBUMIN; GENERAL-POPULATION; NONDIABETIC POPULATION; INSULIN-RESISTANCE; METABOLIC SYNDROME; CIGARETTE-SMOKING AB Background: Predictors for incident albuminuria are not well known in population-based cohorts. The purpose of this study is to identify predictors of incident albuminuria in an unselected middle-aged population. Study Design: Observational cohort study. Setting & Participants: Framingham Offspring Study participants who attended both the sixth (baseline; 1995-1998) and eighth (2005-2008) examination cycles. Predictors: Standard clinical predictors were used. Predictors of incident albuminuria were identified using stepwise logistic regression analysis with age and sex forced into the model. Outcomes & Measurements: Albuminuria was defined as urine albumin-creatinine ratio (UACR) >= 17 mg/g (men) or >= 25 mg/g (women). Individuals with albuminuria at baseline were excluded. Results: 1,916 participants were available for analysis (mean age, 56 years; 54% women). Albuminuria developed in 10.0% of participants (n = 192) during 9.5 years. Age (OR, 2.09; P < 0.001), baseline diabetes (OR, 1.93; P = 0.01), smoking (OR, 2.09; P < 0.001), and baseline log UACR (OR per 1-SD increase in log UACR, 1.56; P < 0.001) were associated with incident albuminuria in a stepwise model. An inverse relationship with female sex (OR, 0.53; P < 0.001) and high-density lipoprotein (HDL) cholesterol level (OR, 0.80; P = 0.007) also was observed. Results were similar when participants with baseline chronic kidney disease (n = 102), defined as estimated glomerular filtration rate < 60 mL/min/1.73m(2), were excluded from the model. Age, male sex, low HDL cholesterol level, smoking, and log UACR continued to be associated with incident albuminuria when baseline diabetes (n = 107) was excluded. Age, male sex, and log UACR correlated with incident albuminuria after participants with baseline hypertension were excluded (n = 651). Limitations: Causality may not be inferred because of the observational nature of the study. One-third of participants did not return for follow-up, potentially attenuating the observed risks of albuminuria. Conclusions: The known cardiovascular risk factors of increasing age, male sex, diabetes, smoking, low HDL cholesterol level, and albuminuria within the reference range are correlates of incident albuminuria in the general population. Am J Kidney Dis 56: 852-860. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Upadhyay, Ashish] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Upadhyay, Ashish] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Upadhyay, Ashish/0000-0002-0536-5776 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; American Diabetes Association FX Support: The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). Dr Meigs is supported by Career Development Awards from the American Diabetes Association Research Grant and the American Diabetes Association. Urinary albumin excretion assay reagents were donated by Roche Diagnostics Inc. NR 56 TC 30 Z9 31 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2010 VL 56 IS 5 BP 852 EP 860 DI 10.1053/j.ajkd.2010.04.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 668IL UT WOS:000283261700012 PM 20599306 ER PT J AU Menon, V Tighiouart, H Vaughn, NS Beck, GJ Kusek, JW Collins, AJ Greene, T Sarnak, MJ AF Menon, Vandana Tighiouart, Hocine Vaughn, Nubia Smith Beck, Gerald J. Kusek, John W. Collins, Allan J. Greene, Tom Sarnak, Mark J. TI Serum Bicarbonate and Long-term Outcomes in CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; bicarbonate; progression ID CHRONIC KIDNEY-DISEASE; METABOLIC-ACIDOSIS; HEMODIALYSIS-PATIENTS; RENAL-DISEASE; PROGRESSION; ASSOCIATION; PREDICTORS; MORTALITY; AMMONIA; ALBUMIN AB Background: A low serum bicarbonate level is prevalent in chronic kidney disease (CKD); however, its relationship to long-term outcomes is unclear. Study Design: Cohort study. Setting & Participants: The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 942 screened but non-randomized individuals and 839 randomized participants with baseline serum bicarbonate measurements with stage 2-4 CKD. Factor: Serum bicarbonate level categorized into quartiles. Outcomes: Kidney failure, all-cause mortality, and a composite outcome of mortality and kidney failure. Measurements: Local laboratories at each participating site measured bicarbonate in fasting serum samples. Kidney failure outcomes were obtained from the US Renal Data System, and mortality data, from the National Death Index. Results: Mean glomerular filtration rate (GFR) was 39 +/- 21 (SD) mL/min/1.73 m(2) and serum bicarbonate level was 23.3 +/- 3.8 mEq/L. Kidney failure rates were 72%, 64%, 50%, and 41%; mortality rates were 31%, 25%, 21%, and 25%, and rates of the composite outcome were 78%, 71%, 58%, and 54% in bicarbonate quartiles 1, 2, 3, and 4, respectively. In analyses adjusted for demographic and cardiovascular disease factors, serum albumin level, proteinuria, and cause of kidney disease, compared with quartile 4, quartile 1 was associated with a 2.22 HR (95% CI, 1.83-2.68) of kidney failure; 1.39 HR (95% CI, 1.07-1.18) of all-cause mortality; and 1.36 HR (95% CI, 1.15-1.62) of the composite outcome. These associations were rendered nonsignificant with adjustment for GFR (kidney failure HR, 1.05 [95% CI, 0.87-1.28]; all-cause mortality HR, 0.99 [95% CI, 0.75-1.13]; composite HR, 1.04 [95% CI, 0.87-1.24]). Limitations: Single baseline measurement of serum bicarbonate. Conclusions: Low serum bicarbonate level was associated with increased risk of long-term outcomes in nondiabetic patients with CKD. However, this risk is not independent of baseline GFR. Clinical trials are necessary to evaluate whether bicarbonate supplementation slows the progression of CKD. Am J Kidney Dis 56: 907-914. (C) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Menon, Vandana; Vaughn, Nubia Smith; Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA. [Tighiouart, Hocine] Tufts Med Ctr, Biostat Res Ctr, Boston, MA 02111 USA. [Tighiouart, Hocine] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Beck, Gerald J.] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Collins, Allan J.] Hennepin Cty Med Ctr, Div Nephrol, Minneapolis, MN 55415 USA. [Greene, Tom] Univ Utah, Div Clin Epidemiol, Salt Lake City, UT USA. RP Menon, V (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM vandana.menon@gmail.com FU National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK067303, K23 DK02904, K24 DK078204] FX Support: The authors have received support through grants K23 DK067303, K23 DK02904, and K24 DK078204 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 16 TC 42 Z9 46 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2010 VL 56 IS 5 BP 907 EP 914 DI 10.1053/j.ajkd.2010.03.023 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 668IL UT WOS:000283261700017 PM 20605301 ER PT J AU Peled, JU Sellers, RS Iglesias-Ussel, MD Shin, DM Montagna, C Zhao, CF Li, ZQ Edelmann, W Morse, HC Scharff, MD AF Peled, Jonathan U. Sellers, Rani S. Iglesias-Ussel, Maria D. Shin, Dong-Mi Montagna, Cristina Zhao, Chunfang Li, Ziqiang Edelmann, Winfried Morse, Herbert C., III Scharff, Matthew D. TI Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID INDUCED CYTIDINE DEAMINASE; DNA MISMATCH REPAIR; CLASS-SWITCH RECOMBINATION; NONPOLYPOSIS COLORECTAL-CANCER; SOMATIC HYPERMUTATION; MICROSATELLITE INSTABILITY; TRANSGENIC MICE; ANTIBODY DIVERSIFICATION; REPEAT MARKERS; BETA RECEPTOR AB Most human B-cell non-Hodgkin's lymphomas arise from germinal centers. Within these sites, the mismatch repair factor MSH6 participates in antibody diversification. Reminiscent of the neoplasms arising in patients with Lynch syndrome HI, mice deficient in MSH6 die prematurely of lymphoma. In this study, we characterized the B-cell tumors in MSH6-deficient mice and describe their histological, immunohistochemical, and molecular features, which include moderate microsatellite instability. Based on histological markers and gene expression, the tumor cells seem to be at or beyond the germinal center stage. The simultaneous loss of MSH6 and of activation-induced cytidine deaminase did not appreciably affect the survival of these animals, suggesting that these germinal center-like tumors arose by an activation-induced cytidine deaminase-independent pathway. We conclude that MSH6 protects B cells from neoplastic transformation by preserving genomic stability. (Am J Pathol 2010, 177:2597-2608; DOI: 10.2353/ajpath.2010.100234) C1 [Peled, Jonathan U.; Iglesias-Ussel, Maria D.; Zhao, Chunfang; Li, Ziqiang; Edelmann, Winfried; Scharff, Matthew D.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Sellers, Rani S.; Montagna, Cristina] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. RP Scharff, MD (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Chanin 403,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM hmorse@niaid.nih.gov; matthew.scharff@einstein.yu.edu OI Peled, Jonathan/0000-0002-4029-7625; Morse, Herbert/0000-0002-9331-3705 FU NIH, National Institute of Allergy and Infectious Diseases; National Cancer Institute [P30CA013330]; Albert Einstein College of Medicine [T32-GM007288]; Harry Eagle Chair by the National Women's Division of the Albert Einstein College of Medicine; [R01-CA72649]; [R01-CA102705]; [R01-CA76329]; [R01-CA93484] FX Supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (D.-M.S. and H.C.M.) and in part by the National Cancer Institute (award P30CA013330 to R.S.S. and C.M.). J.U.P. is supported by the Medical Scientist Training Program at Albert Einstein College of Medicine (grant T32-GM007288). M.D.S. is supported by grants R01-CA72649 and R01-CA102705 and by the Harry Eagle Chair provided by the National Women's Division of the Albert Einstein College of Medicine. W.E. is supported by grants R01-CA76329 and R01-CA93484. NR 110 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2010 VL 177 IS 5 BP 2597 EP 2608 DI 10.2353/ajpath.2010.100234 PG 12 WC Pathology SC Pathology GA 679TE UT WOS:000284182900044 PM 20934970 ER PT J AU Bakhshi, T Landon, MB Lai, YL Spong, CY Rouse, DJ Leveno, KJ Varner, MW Caritis, SN Meis, PJ Wapner, RJ Sorokin, Y Miodovnik, M Carpenter, M Peaceman, AM O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Mercer, BM AF Bakhshi, Tiki Landon, Mark B. Lai, Yinglei Spong, Catherine Y. Rouse, Dwight J. Leveno, Kenneth J. Varner, Michael W. Caritis, Steve N. Meis, Paul J. Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem Carpenter, Marshall Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Mercer, Brian M. TI Maternal and Neonatal Outcomes of Repeat Cesarean Delivery in Women with a Prior Classical versus Low Transverse Uterine Incision SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE Cesarean delivery; classical cesarean delivery; prior cesarean; maternal outcomes; neonatal outcomes ID SECTION AB We compared maternal and neonatal outcomes following repeat cesarean delivery (CD) of women with a prior classical CD with those with a prior low transverse CD. The Maternal Fetal Medicine Units Network Cesarean Delivery Registry was used to identify women with one previous CD who underwent an elective repeat CD prior to the onset of labor at >= 36 weeks. Outcomes were compared between women with a previous classical CD and those with a prior low transverse CD. Of the 7936 women who met study criteria, 122 had a prior classical CD. Women with a prior classical CD had a higher rate of classical uterine incision at repeat CD (12.73% versus 0.59%; p<0.001), had longer total operative time and hospital stay, and had higher intensive care unit admission. Uterine dehiscence was more frequent in women with a prior classical CD (2.46% versus 0.27%, odds ratio 9.35, 95% confidence interval 1.76 to 31.93). After adjusting for confounding factors, there were no statistical differences in major maternal or neonatal morbidities between groups. Uterine dehiscence was present at repeat CD in 2.46% of women with a prior classical CD. However, major maternal morbidities were similar to those with a prior low transverse CD. C1 [Bakhshi, Tiki] Univ Texas Hlth Sci Ctr Houston, Dept Obstet, Houston, TX USA. [Bakhshi, Tiki] Univ Texas Hlth Sci Ctr Houston, Dept Gynecol, Houston, TX USA. [Landon, Mark B.] Ohio State Univ, Columbus, OH 43210 USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Varner, Michael W.] Univ Utah, Salt Lake City, UT USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Meis, Paul J.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [Miodovnik, Menachem] Columbia Univ, New York, NY USA. [Carpenter, Marshall] Brown Univ, Providence, RI 02912 USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Sibai, Baha M.] Univ Tennessee, Memphis, TN USA. [Langer, Oded] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. RP Bakhshi, T (reprint author), Tripler Army Med Ctr, Dept OB GYN, 1 Jarrett White Rd, Honolulu, HI 96859 USA. EM tiki.bakh-shi@amedd.army.mil RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U10 HD027917-18, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD34210, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, R24 HD050924, U01 HD036801, U01 HD036801-10, U10 HD021410, U10 HD021410-22, U10 HD021414-15S2, U10 HD027860, U10 HD027860-15, U10 HD027861-10S2, U10 HD027869, U10 HD027869-10, U10 HD027905, U10 HD027905-10, U10 HD027915, U10 HD027915-19, U10 HD027917, U10 HD034116, U10 HD034116-13, U10 HD034122, U10 HD034122-05, U10 HD034136, U10 HD034136-10S2, U10 HD034208, U10 HD034208-12, U10 HD034210-05, U10 HD036801, U10 HD040485, U10 HD040485-10, U10 HD040500, U10 HD040500-08, U10 HD040512, U10 HD040512-10, U10 HD040544, U10 HD040544-10, U10 HD040545, U10 HD040545-10, U10 HD040560, U10 HD040560-10, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 7 TC 13 Z9 13 U1 0 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2010 VL 27 IS 10 BP 791 EP 795 DI 10.1055/s-0030-1254238 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 664GJ UT WOS:000282948100006 PM 20458666 ER PT J AU Ramirez, MM Gilbert, S Landon, MB Rouse, DJ Spong, CY Varner, MW Caritis, SN Wapner, RJ Sorokin, Y Miodovnik, M Carpenter, M Peaceman, AM O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Mercer, BM AF Ramirez, Mildred M. Gilbert, Sharon Landon, Mark B. Rouse, Dwight J. Spong, Catherine Y. Varner, Michael W. Caritis, Steve N. Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem Carpenter, Marshall Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Mercer, Brian M. CA Eunice Kennedy Shriver Natl Inst TI Mode of Delivery in Women with Antepartum Fetal Death and Prior Cesarean Delivery SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 23-26, 2005 CL Los Angeles, CA SP Soc Gynecol Invest DE Vaginal birth after cesarean; fetal demise; induction of labor ID UTERINE RUPTURE; MISOPROSTOL; LABOR AB We describe obstetric outcomes in a group of patients with prior cesarean delivery (CD) presenting with an intrauterine fetal demise (IUFD). A secondary analysis of an observational study of women with prior CD was performed. All antepartum singleton pregnancies with a prior CD and IUFD >= 20 weeks' gestation or 500 g were evaluated. Two hundred nine patients met inclusion criteria for analysis. The mean gestational age +/- standard deviation at delivery was 31.3 +/- 6.5 weeks. The trial of labor rate was 75.6% (158/209), and the vaginal birth after cesarean (VBAC) success rate was 86.7%. Labor induction or augmentation occurred in 83.3% of attempted VBAC. Uterine rupture occurred in five women (2.4%), and in 3.4% of those being induced but none of these required hysterectomy. Women with a history of previous CD and an IUFD often undergo trial of labor with a high VBAC success rate. Uterine rupture complicates 2.4% of such cases. C1 [Ramirez, Mildred M.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet, Houston, TX USA. [Ramirez, Mildred M.] Univ Texas Hlth Sci Ctr Houston, Dept Gynecol, Houston, TX USA. [Gilbert, Sharon] George Washington Univ, Ctr Biostat, Washington, DC USA. [Landon, Mark B.] Ohio State Univ, Columbus, OH 43210 USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Spong, Catherine Y.; Varner, Michael W.; Caritis, Steve N.; Wapner, Ronald J.; Sorokin, Yoram; Miodovnik, Menachem; Carpenter, Marshall; Peaceman, Alan M.; O'Sullivan, Mary J.; Sibai, Baha M.; Langer, Oded; Thorp, John M.; Mercer, Brian M.] Univ Utah, Salt Lake City, UT USA. [Varner, Michael W.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [Miodovnik, Menachem] Columbia Univ, New York, NY USA. [Carpenter, Marshall] Brown Univ, Providence, RI 02912 USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Sibai, Baha M.] Univ Tennessee, Memphis, TN USA. [Langer, Oded] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Ramirez, MM (reprint author), Univ Texas Med Sch Houston, Dept Obstet Gynecol & Reprod Sci, 6431 Fannin,Suite 3-276, Houston, TX 77030 USA. EM Mildred.M.Ramirez@uth.tmc.edu RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [HD36801, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD34210, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD021410-21, U10 HD021414-15, U10 HD027860, U10 HD027860-15, U10 HD027861-10, U10 HD027869, U10 HD027869-18, U10 HD027905, U10 HD027905-10, U10 HD027915, U10 HD027915-19, U10 HD027917, U10 HD027917-18, U10 HD034116, U10 HD034116-13, U10 HD034122, U10 HD034122-05, U10 HD034136, U10 HD034136-10, U10 HD034208, U10 HD034208-12, U10 HD034210-05, U10 HD036801, U10 HD036801-11, U10 HD040485, U10 HD040485-11, U10 HD040500, U10 HD040500-08, U10 HD040512, U10 HD040512-11, U10 HD040544, U10 HD040544-11, U10 HD040545, U10 HD040545-11, U10 HD040560, U10 HD040560-11, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 11 TC 9 Z9 10 U1 0 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2010 VL 27 IS 10 BP 825 EP 829 DI 10.1055/s-0030-1254548 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 664GJ UT WOS:000282948100010 PM 20486068 ER PT J AU Ramalingam, A Wang, XX Gabello, M Valenzano, MC Soler, AP Ko, A Morin, PJ Mullin, JM AF Ramalingam, Arivudainambi Wang, Xuexuan Gabello, Melissa Valenzano, M. Carmen Soler, Alejandro P. Ko, Akihiro Morin, Patrice J. Mullin, James M. TI Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE claudin-3; occludin; mannitol flux; paracellular ID PROTEIN-KINASE-C; EPITHELIAL-CELL SHEETS; ACTIVE CROHNS-DISEASE; PROSTATE-CANCER CELLS; LIFE-SPAN; CALORIC RESTRICTION; PHORBOL ESTER; DNA METHYLATION; DEFICIENT DIET; IN-VITRO AB Ramalingam A, Wang X, Gabello M, Valenzano MC, Soler AP, Ko A, Morin PJ, Mullin JM. Dietary methionine restriction improves colon tight junction barrier function and alters claudin expression pattern. Am J Physiol Cell Physiol 299: C1028-C1035, 2010. First published August 18, 2010; doi: 10.1152/ajpcell.00482.2009.-The beneficial effects of caloric restriction in increasing longevity and forestalling age-related diseases are well known. Dietary restriction of methionine also renders similar benefits. We recently showed in a renal epithelial cell culture system that reduction of culture medium methionine by 80% resulted in altered tight junctional (TJ) claudin composition and also improved epithelial barrier function (51). In the current study, we examined the effect of dietary restriction of methionine on TJ barrier function in rat gastrointestinal tissue to see whether this phenomenon also holds true in a tissue model and for a different epithelial cell type. After 28 days on methionine-restricted (MR) diet, rats showed small but significant reductions in the plasma and (intracellular) colonocyte levels of methionine. Colon mucosal sheets from rats on the MR diet showed increased transepithelial electrical resistance with concomitant decrease in paracellular diffusion of (14)C-D-mannitol, suggesting improved barrier function relative to rats on control diet. This improved barrier function could not be explained by changes in colon crypt length or frequency. Neither was the colonocyte mitotic index nor the apoptotic frequency altered significantly. However, TJ composition/structure was being altered by the MR diet. RT-PCR and Western blot analysis showed an increase in the abundance of claudin-3 and an apparent change in the post-translational modification of occludin, data reinforcing a paracellular barrier alteration. Overall, our data suggest that reduction in dietary intake of methionine results in improved epithelial barrier function by inducing altered TJ protein composition. C1 [Ramalingam, Arivudainambi; Wang, Xuexuan; Gabello, Melissa; Valenzano, M. Carmen; Soler, Alejandro P.; Mullin, James M.] Lankenau Inst Med Res, Wynnewood, PA 19096 USA. [Gabello, Melissa; Mullin, James M.] St Josephs Univ, Dept Biol, Philadelphia, PA 19131 USA. [Ko, Akihiro; Morin, Patrice J.] NIA, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Mullin, James M.] Lankenau Hosp, Div Gastroenterol, Wynnewood, PA USA. RP Mullin, JM (reprint author), Lankenau Inst Med Res, 100 Lancaster Ave,Rm 229, Wynnewood, PA 19096 USA. EM mullinj@mlhs.org OI Mullin, James/0000-0001-5285-7530 FU Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital (Bryn Mawr, PA); Broad Foundation FX The current study was supported in part by a generous grant from the Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital (Bryn Mawr, PA) and by the Broad Medical Research Program of The Broad Foundation. NR 64 TC 11 Z9 12 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD NOV PY 2010 VL 299 IS 5 BP C1028 EP C1035 DI 10.1152/ajpcell.00482.2009 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 672RK UT WOS:000283604400020 PM 20739626 ER PT J AU Sun, JH Murphy, E AF Sun, Junhui Murphy, Elizabeth TI Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardioprotection; caveolae; caveolin-1 ID GLYCOGEN-SYNTHASE KINASE-3-BETA; HORMONE-RELATED PEPTIDE; PERMEABILITY TRANSITION PORE; PARATHYROID-HORMONE; ISCHEMIA/REPERFUSION INJURY; VENTRICULAR CARDIOMYOCYTES; CARDIAC PROTECTION; PLASMA-MEMBRANE; RAT HEARTS; MYOCARDIUM AB Sun J, Murphy E. Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol 299: H1309-H1317, 2010. First published September 10, 2010; doi:10.1152/ajpheart.00373.2010.-As a G protein-coupled receptor, the extracellular Ca2+-sensing receptor (CaSR) responds to changes not only in extracellular Ca2+, but also to many other ligands. CaSR has been found to be expressed in the hearts and cardiovascular system. In this study, we confirmed that CaSR is expressed in mouse cardiomyocytes and showed that it is predominantly localized in caveolae. The goal of this study was to investigate whether CaSR plays a cardioprotective role in ischemic preconditioning (IPC). Hearts from C57BL/6J mice (male, 12-16 wk) were perfused in the Langendorff mode and subjected to the following treatments: 1) control perfusion; 2) perfusion with a specific CaSR antagonist, NPS2143; 3) IPC (four cycles of 5 min of global ischemia and 5 min of reperfusion); or 4) perfusion with NPS2143 before and during IPC. Following these treatments, hearts were subjected to 20 min of no-flow global ischemia and 120 min of reperfusion. Compared with control, IPC significantly improved postischemic left ventricular functional recovery and reduced infarct size. Although NPS2143 perfusion alone did not change the hemodynamic function and did not change the extent of postischemic injury, NPS2143 treatment abolished cardioprotection of IPC. Through immunoblot analysis, it was demonstrated that IPC significantly increased the levels of phosphorylated ERK1/2, AKT, and GSK-3 beta, which were also prevented by NPS2143 treatment. Taken together, the distribution of CaSR in caveolae along with NPS2143-blockade of IPC-induced cardioprotective signaling suggest that the activation of CaSR during IPC is cardioprotective by a process involving caveolae. C1 [Sun, Junhui; Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Sun, JH (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Rm 8N206, Bethesda, MD 20892 USA. EM sun1@mail.nih.gov RI Sun, Junhui/C-3499-2011 FU National Institutes of Health FX J. Sun and E. Murphy were supported by the National Institutes of Health Intramural Program. We thank Dr. Jianxin Hu from National Institute of Diabetes and Digestive and Kidney Diseases for providing us with NPS2143 for the initial trial experiments to test the dose-response of NPS2143. NR 57 TC 26 Z9 26 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD NOV PY 2010 VL 299 IS 5 BP H1309 EP H1317 DI 10.1152/ajpheart.00373.2010 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 673HB UT WOS:000283649000006 PM 20833954 ER PT J AU Klabunde, CN Marcus, PM Silvestri, GA Han, PKJ Richards, TB Yuan, GG Marcus, SE Vernon, SW AF Klabunde, Carrie N. Marcus, Pamela M. Silvestri, Gerard A. Han, Paul K. J. Richards, Thomas B. Yuan, Gigi Marcus, Stephen E. Vernon, Sally W. TI U.S. Primary Care Physicians' Lung Cancer Screening Beliefs and Recommendations SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COMPUTED-TOMOGRAPHY; SOCIETY GUIDELINES; FAMILY PHYSICIANS; UNITED-STATES; VIGNETTES; QUALITY; PROSTATE; PROGRAM; TESTS AB Background: No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients. Purpose: This study describes U.S. PCPs' beliefs about and recommendations for lung cancer screening and examines characteristics of PCPs who recommend screening. Methods: A nationally representative survey of practicing PCPs was conducted in 2006-2007. Mailed questionnaires were used to assess PCPs' beliefs about lung cancer screening guidelines and the effectiveness of screening tests and to determine whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009. Results: Nine hundred sixty-two PCPs completed the survey (absolute response rate = 70.6%; cooperation rate = 76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low-radiation dose spiral computed tomography (LDCT) screening is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest x-ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest x-ray; up to 26% would use LDCT. In adjusted analyses, PCPs' beliefs and practice style were strongly associated with their lung cancer screening recommendations. Conclusions: Many PCPs' lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding the evidence base and guideline content of lung cancer screening is indicated. (Am J Prev Med 2010;39(5):411-420) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Klabunde, Carrie N.; Han, Paul K. J.; Marcus, Stephen E.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Marcus, Pamela M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Richards, Thomas B.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Yuan, Gigi] Informat Management Serv Inc, Silver Spring, MD USA. [Silvestri, Gerard A.] Med Univ S Carolina, Div Pulm & Crit Care Med, Charleston, SC 29425 USA. [Vernon, Sally W.] Univ Texas Houston, Sch Publ Hlth, Div Hlth Promot & Behav Sci, Houston, TX USA. RP Klabunde, CN (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM KlabundC@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute [N02-PC-51308]; Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02]; CDC [Y3-PC-6017-01] FX Funding support for this study was provided by the National Cancer Institute (contract number N02-PC-51308), the Agency for Healthcare Research and Quality (inter-agency agreement numbers Y3-PC-5019-01 and Y3-PC-5019-02), and the CDC (inter-agency agreement number Y3-PC-6017-01). NR 43 TC 19 Z9 20 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2010 VL 39 IS 5 BP 411 EP 420 DI 10.1016/j.amepre.2010.07.004 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 665TQ UT WOS:000283058800004 PM 20965378 ER PT J AU Pate, RR Sallis, JF Ward, DS Stevens, J Dowda, M Welk, GJ Young, DR Jobe, JB Strikmiller, PK AF Pate, Russell R. Sallis, James F. Ward, Dianne S. Stevens, June Dowda, Marsha Welk, Gregory J. Young, Deborah R. Jobe, Jared B. Strikmiller, Patricia K. TI Age-Related Changes in Types and Contexts of Physical Activity in Middle School Girls SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ADOLESCENT GIRLS; CHILDREN; TIME AB Background: Because girls are less physically active than boys, it is important to understand the types of activities preferred by girls, and changes in those preferences over time, in order to design effective physical activity interventions. Purpose: To describe developmental trends in participation in specific forms of physical activity in 6th- and 8th-grade girls. Methods: Data for this study are from the Trial of Activity for Adolescent Girls. Self-reported physical activity, anthropometric, and demographic data were collected from random cross sections of 6th-grade girls in 36 middle schools in six U.S. communities. The same data were collected 2 years later from random cross sections of 8th-grade girls, as well as in previously measured 6th-grade girls who remained in the schools. Analyses were conducted with SAS using mixed-model ANOVAs to determine differences between 6th- and 8th-grade girls. Data were collected in 2002-2003 and 2004-2005 and analyzed in 2008-2009. Results: The top physical activities reported by 6th- and 8th-grade girls were similar. Of the top 13 activities reported by 6th- or 8th-grade girls, 8th-grade girls reported participating in more 30-minute blocks for ten of the activities and were more likely to report participating as part of an organized program. Conclusions: The activities reported by 6th- and 8th-grade girls were similar, but the way they participated in them changed from 6th to 8th grade. Eighth-grade girls were more likely to participate in activities that are often part of school-based team sports, and the time of participation in these activities was greater. Interventions to increase physical activity in adolescent girls should be informed by the factors that influence their participation in organized school sports programs and community-based activities that promote physical activity. (Am J Prev Med 2010;39(5):433-439) (C) 2010 American Journal of Preventive Medicine C1 [Pate, Russell R.; Dowda, Marsha] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. [Sallis, James F.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Ward, Dianne S.; Stevens, June] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Welk, Gregory J.] Iowa State Univ, Dept Hlth & Human Performance, Ames, IA USA. [Young, Deborah R.] Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. [Jobe, Jared B.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Strikmiller, Patricia K.] Tulane Univ, Dept Biostat, New Orleans, LA 70118 USA. RP Pate, RR (reprint author), Univ S Carolina, Dept Exercise Sci, 921 Assembly St, Columbia, SC 29208 USA. EM rpate@mailbox.sc.edu FU National Heart, Lung, and Blood Institute [U01 HL066855, U01HL066845, U01HL066852, U01HL066853, U01HL066856, U01HL066857, U01HL066858] FX This study was funded by the following cooperative agreements from the National Heart, Lung, and Blood Institute: U01 HL066855 (Tulane University); U01HL066845 (University of Minnesota); U01HL066852 (University of South Carolina); U01HL066853 (University of North Carolina at Chapel Hill); U01HL066856 (San Diego State University); U01HL066857 (University of Maryland); and U01HL066858 (University of Arizona). The authors thank Gaye Groover Christmus, MPH, University of South Carolina, for editing the manuscript. NR 18 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2010 VL 39 IS 5 BP 433 EP 439 DI 10.1016/j.amepre.2010.07.013 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 665TQ UT WOS:000283058800006 PM 20965380 ER PT J AU Leibenluft, E Yonkers, KA AF Leibenluft, Ellen Yonkers, Kimberly A. TI The Ties That Bind: Maternal-Infant Interactions and the Neural Circuitry of Postpartum Depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; INTERPERSONAL PSYCHOTHERAPY; WOMEN C1 [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bldg 15K,Rm 201,MSC 2670, Bethesda, MD 20892 USA. EM leibs@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999]; NIMH NIH HHS [K08 MH001908] NR 14 TC 5 Z9 5 U1 0 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2010 VL 167 IS 11 BP 1294 EP 1296 DI 10.1176/appi.ajp.2010.10081159 PG 3 WC Psychiatry SC Psychiatry GA 673NF UT WOS:000283669500003 PM 21041250 ER PT J AU Benjamin, GC Fee, E Brown, TM AF Benjamin, Georges C. Fee, Elizabeth Brown, Theodore M. TI William Augustus Evans (1865-1948): Public Health Leader at a Critical Time SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Benjamin, Georges C.] Amer Publ Hlth Assoc, Washington, DC USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Brown, Theodore M.] Univ Rochester, Dept Hist, Rochester, NY USA. [Brown, Theodore M.] Univ Rochester, Dept Prevent & Community Med, Rochester, NY USA. RP Benjamin, GC (reprint author), Care of Chang BB, NIH, Natl Lib Med, Bldg 38 1E21,8600 Rockville Pike,MSC 3819, Bethesda, MD 20974 USA. EM changb@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2010 VL 100 IS 11 BP 2073 EP 2073 DI 10.2105/AJPH.2010.191825 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 675DY UT WOS:000283807600021 PM 20864704 ER PT J AU Blum, N Katz, E Fee, E AF Blum, Nava Katz, Ehud Fee, Elizabeth TI Professor Natan Goldblum: The Pioneer Producer of the Inactivated Poliomyelitis Vaccine in Israel SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Blum, Nava] Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Sci Studies, IL-31905 Haifa, Israel. [Katz, Ehud] Hebrew Univ Jerusalem, Dept Biochem, Jerusalem, Israel. [Katz, Ehud] Hebrew Univ Jerusalem, Dept Mol Biol, Jerusalem, Israel. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Blum, N (reprint author), Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Sci Studies, IL-31905 Haifa, Israel. EM navablum@yahoo.com NR 6 TC 1 Z9 1 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2010 VL 100 IS 11 BP 2074 EP 2075 DI 10.2105/AJPH.2010.192922 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 675DY UT WOS:000283807600022 PM 20864699 ER PT J AU MacDorman, MF Declercq, E Zhang, J AF MacDorman, Marian F. Declercq, Eugene Zhang, Jun TI Obstetrical Intervention and the Singleton Preterm Birth Rate in the United States From 1991-2006 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID GESTATIONAL-AGE; CESAREAN DELIVERY; PREMATURE RUPTURE; NEONATAL OUTCOMES; MORTALITY; TRENDS; INFANTS; TERM; MORBIDITY; MEMBRANES AB Objectives. We examined the relationship between obstetrical intervention and preterm birth in the United States between 1991 and 2006. Methods. We assessed changes in preterm birth, cesarean delivery, labor induction, and associated risks. Logistic regression modeled the odds of preterm obstetrical intervention after risk adjustment. Results. From 1991 to 2006, the percentage of singleton preterm births increased 13%. The cesarean delivery rate for singleton preterm births increased 47%, and the rate of induced labor doubled. In 2006, 51% of singleton preterm births were spontaneous vaginal deliveries, compared with 69% in 1991. After adjustment for demographic and medical risks, the mother of a preterm infant was 88% (95% confidence interval [CI] = 1.87, 1.90) more likely to have an obstetrical intervention in 2006 than in 1991. Using new birth certificate data from 19 states, we estimated that 42% of singleton preterm infants were delivered via induction or cesarean birth without spontaneous onset of labor. Conclusions. Obstetrical interventions were related to the increase in the US preterm birth rate between 1991 and 2006. The public health community can play a central role in reducing medically unnecessary interventions. (Am J Public Health. 2010;100:2241-2247. doi:10.2105/AJPH.2009.180570) C1 [MacDorman, Marian F.] Natl Ctr Hlth Stat, Div Vital Stat, Reprod Stat Branch, Hyattsville, MD 20782 USA. [Declercq, Eugene] Boston Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Boston, MA USA. [Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. RP MacDorman, MF (reprint author), Natl Ctr Hlth Stat, Div Vital Stat, Reprod Stat Branch, 3311 Toledo Rd,Room 7318, Hyattsville, MD 20782 USA. EM mfm1@cdc.gov OI Declercq, Eugene/0000-0001-5411-3033 NR 51 TC 47 Z9 50 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2010 VL 100 IS 11 BP 2241 EP 2247 DI 10.2105/AJPH.2009.180570 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 675DY UT WOS:000283807600047 PM 20864720 ER PT J AU George, SM Irwin, ML Matthews, CE Mayne, ST Gail, MH Moore, SC Albanes, D Ballard-Barbash, R Hollenbeck, AR Schatzkin, A Leitzmann, MF AF George, Stephanie M. Irwin, Melinda L. Matthews, Charles E. Mayne, Susan T. Gail, Mitchell H. Moore, Steven C. Albanes, Demetrius Ballard-Barbash, Rachel Hollenbeck, Albert R. Schatzkin, Arthur Leitzmann, Michael F. TI Beyond Recreational Physical Activity: Examining Occupational and Household Activity, Transportation Activity, and Sedentary Behavior in Relation to Postmenopausal Breast Cancer Risk SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID TELEVISION VIEWING TIME; ACTIVITY SCALE; ELDERLY PASE; CARDIOVASCULAR-DISEASE; ENERGY-EXPENDITURE; SITTING TIME; LIFE-STYLE; WOMEN; MORTALITY; VALIDITY AB Objectives. We prospectively examined nonrecreational physical activity and sedentary behavior in relation to breast cancer risk among 97039 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. Methods. We identified 2866 invasive and 570 in situ breast cancer cases recorded between 1996 and 2003 and used Cox proportional hazards regression to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs). Results. Routine activity during the day at work or at home that included heavy lifting or carrying versus mostly sitting was associated with reduced risk of invasive breast cancer (RR=0.62; 95% CI = 0.42, 0.91; P(trend) = .024). Conclusions. Routine activity during the day at work or home may be related to reduced invasive breast cancer risk. Domains outside of recreation time may be attractive targets for increasing physical activity and reducing sedentary behavior among postmenopausal women. (Am J Public Health. 2010;100: 2288-2295. doi: 10.2105/AJPH.2009.180828) C1 [George, Stephanie M.; Matthews, Charles E.; Moore, Steven C.; Albanes, Demetrius; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [George, Stephanie M.; Irwin, Melinda L.; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Leitzmann, Michael F.] Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. RP George, SM (reprint author), 6120 Execut Blvd,Suite 320,MSC 7232, Rockville, MD 20852 USA. EM materess@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016 OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661 FU National Cancer Institute [T32 CA105666]; National Cancer Institute, National Institutes of Health (NIH) FX This research was supported by the National Cancer Institute (grant T32 CA105666) and, in part, by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH). NR 57 TC 29 Z9 29 U1 2 U2 15 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD NOV PY 2010 VL 100 IS 11 BP 2288 EP 2295 DI 10.2105/AJPH.2009.180828 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 675DY UT WOS:000283807600053 PM 20864719 ER PT J AU Elfline, M Clark, A Petty, HR Romero, R AF Elfline, Megan Clark, Andrea Petty, Howard R. Romero, Roberto TI Bi-Directional Calcium Signaling Between Adjacent Leukocytes and Trophoblast-Like Cells SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Monocytes; neutrophils; signal transduction ID PLACENTAL SYNCYTIOTROPHOBLASTS; JAR CELLS; HLA-G; PREGNANCY; TOLERANCE; INTERFACE; MONOCYTES; ALLOGRAFT; ADHESION; NETWORK AB Problem Trophoblasts are believed to play an important role in mitigating immunological responses against the fetus. To better understand the nature of trophoblast-leukocyte interactions, we have studied signal transduction during intercellular interactions. Method of study Using a highly sensitive microfluorometric ratioing method and Ca2+-sensitive dyes, we measured Ca2+ signals in trophoblast-like cell lines (JEG-3 and JAR) or in leukocytes (neutrophils and monocytes) during intercellular contact. Results Trophoblast cell lines exhibit Ca2+ signals during leukocyte contact. In contrast, leukocytes cannot elicit Ca2+ signals in non-opsonized tumour cells, suggesting that Ca2+ signaling is not a general feature of cell-cell encounters. Similarly, leukocytes demonstrate Ca2+ signals during contact with trophoblast cell lines. Ca2+ signals were confirmed using three dyes and with the Ca2+ buffer BAPTA. Conclusion We suggest that leukocyte-to-trophoblast interactions lead to mutual Ca2+ signaling events in both cell types, which may contribute to immunoregulation at the materno-fetal interface. C1 [Petty, Howard R.] Univ Michigan, Dept Ophthalmol & Visual Sci, Sch Med, Ann Arbor, MI 48105 USA. [Petty, Howard R.] Univ Michigan, Dept Microbiol & Immunol, Sch Med, Ann Arbor, MI 48105 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, Bethesda, MD 20892 USA. [Romero, Roberto] Hutzel Hosp, Detroit, MI 48201 USA. RP Petty, HR (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, Sch Med, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU National Institute of Child Health and Human Development, NIH, DHHS FX This work was supported, in part, by Intramural Program of the National Institute of Child Health and Human Development, NIH, DHHS. NR 27 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD NOV PY 2010 VL 64 IS 5 BP 339 EP 346 DI 10.1111/j.1600-0897.2010.00839.x PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 661AE UT WOS:000282693400007 PM 20367627 ER PT J AU Valera, A Balague, O Colomo, L Martinez, A Delabie, J Taddesse-Heath, L Jaffe, ES Campo, E AF Valera, Alexandra Balague, Olga Colomo, Luis Martinez, Antonio Delabie, Jan Taddesse-Heath, Lekidelu Jaffe, Elaine S. Campo, Elias TI IG/MYC Rearrangements are the Main Cytogenetic Alteration in Plasmablastic Lymphomas SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE plasmablastic lymphoma; MYC; FISH ID PRIMARY EFFUSION LYMPHOMA; B-CELL LYMPHOMA; COMPARATIVE GENOMIC HYBRIDIZATION; OF-THE-LITERATURE; MULTIPLE-MYELOMA; C-MYC; CLINICOPATHOLOGICAL FEATURES; BURKITTS-LYMPHOMA; KAPOSIS-SARCOMA; ORAL-CAVITY AB Plasmablastic lymphoma (PBL) is an aggressive lymphoma characterized by a terminally differentiated B-cell phenotype that usually occurs in the immunocompromised or elderly patients. Although the clinical and pathologic characteristics of these tumors have been defined, the genetic alterations involved in their pathogenesis are not well known. In this study, we have investigated the chromosomal alterations of MYC, BCL2, BCL6, MALT1, PAX5, and IGH loci using fluorescence in situ hybridization in 42 PBL and 3 extracavitary primary effusion lymphomas. MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumors. MYC rearrangements were more common in Epstein-Barr virus (EBV)-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumors (P < 0.05). No rearrangements of BCL2, BCL6, MALT1, or PAX5 were detected in any PBL but gains of these loci were observed in 31% to 41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the 4 patients with the longest survival (> 50mo) had no or low number of gains (< 3). No rearrangements of any of these loci were seen in the primary effusion lymphomas. In conclusion, PBL are genetically characterized by frequent IG/MYC translocations and gains in multiple chromosomal loci. The oncogenic activation of MYC in these lymphomas may be an important pathogenetic element associated with EBV infection. C1 [Valera, Alexandra; Balague, Olga; Colomo, Luis; Martinez, Antonio; Campo, Elias] Univ Barcelona, Hosp Clin, Hematopathol Sect, Pathol Lab,Inst Invest Biomed August Pi & Sunyer, E-08036 Barcelona, Spain. [Delabie, Jan] Univ Oslo, Rikshosp Radiumhosp HF, Dept Pathol, Oslo, Norway. [Taddesse-Heath, Lekidelu] Howard Univ Hosp, Dept Pathol, Washington, DC USA. [Jaffe, Elaine S.] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Colomo, L (reprint author), Univ Barcelona, Hosp Clin, Hematopathol Sect, Pathol Lab,Inst Invest Biomed August Pi & Sunyer, Villarroel 170, E-08036 Barcelona, Spain. EM lcolomo@clinic.ub.es RI Martinez, Antonio/D-8188-2012; Colomo, Luis/A-2259-2016; OI Martinez, Antonio/0000-0003-0790-9017; Colomo, Luis/0000-0001-5236-5085; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU Spanish Ministry of Science and Innovation [SAF2008/3630]; Instituto de Salud Carlos III "Red Tematica de Investigacion Cooperativa de Cancer" [RD07/0020/2004]; Asociacion Espanola Contra el Cancer [AECC_07_011]; Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias [PI080095] FX This study was supported by the Spanish Ministry of Science and Innovation SAF2008/3630, the Instituto de Salud Carlos III "Red Tematica de Investigacion Cooperativa de Cancer" RD07/0020/2004, Asociacion Espanola Contra el Cancer AECC_07_011 and Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias PI080095. NR 42 TC 105 Z9 111 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2010 VL 34 IS 11 BP 1686 EP 1694 DI 10.1097/PAS.0b013e3181f3e29f PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 671IG UT WOS:000283493800015 PM 20962620 ER PT J AU Morris, C Onyamboko, MA Tshefu, AK Atibu, J Lokomba, V Meshnick, SR Douoguih, M Hemingway-Foday, J Koch, MA Capparelli, E Ryder, R Bose, C Wright, L Wesche, D Fleckenstein, L AF Morris, Carrie Onyamboko, Marie A. Tshefu, Antoinette K. Atibu, Jef Lokomba, Vicky Meshnick, Steven R. Douoguih, Macaya Hemingway-Foday, Jennifer Koch, Matthew A. Capparelli, Edmund Ryder, Robert Bose, Carl Wright, Linda Wesche, David Fleckenstein, Lawrence TI POPULATION PHARMACOKINETICS OF ARTESUNATE AND DIHYDROARTEMISININ FOLLOWING A SINGLE ORAL DOSE OF ARTESUNATE DURING THE 2(ND) AND 3(RD) TRIMESTER OF PREGNANCY SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Morris, Carrie; Fleckenstein, Lawrence] Univ Iowa, Iowa City, IA USA. [Onyamboko, Marie A.; Tshefu, Antoinette K.; Atibu, Jef; Lokomba, Vicky] Kinshasa Sch Publ Hlth, Kinshasa, Congo. [Meshnick, Steven R.; Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Douoguih, Macaya] Aeras Global TB Vaccine Fdn, Rockville, MD USA. [Hemingway-Foday, Jennifer; Koch, Matthew A.] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. [Capparelli, Edmund; Ryder, Robert] Univ Calif San Diego, San Diego, CA 92103 USA. [Wright, Linda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Wesche, David] David Wesche Consulting LLC, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 7 BP 3 EP 3 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700008 ER PT J AU Ranford-Cartwright, LC Mwangi, JM Ricklefs, SM Porcella, SF Su, XZ AF Ranford-Cartwright, Lisa C. Mwangi, Jonathan M. Ricklefs, Stacy M. Porcella, Stephen F. Su, Xin-Zhuan TI INHERITANCE PATTERNS AND RECOMBINATION FREQUENCY IN THE 3D7 X HB3 PLASMODIUM FALCIPARUM EXPERIMENTAL CROSS: A NEW GENETIC MAP SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Ranford-Cartwright, Lisa C.; Mwangi, Jonathan M.] Univ Glasgow, Glasgow, Lanark, Scotland. [Ricklefs, Stacy M.; Porcella, Stephen F.] NIH, Rocky Mt Labs, Res Technol Sect, Hamilton, MT USA. [Su, Xin-Zhuan] NIAID, Malaria Funct Genom Sect, NIH, Bethesda, MD 20892 USA. RI Ranford-Cartwright, Lisa/H-4701-2013 OI Ranford-Cartwright, Lisa/0000-0003-1992-3940 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 36 BP 12 EP 12 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700037 ER PT J AU Oleinikov, AV Amos, E Voronkova, V Getz, T Duffy, PE AF Oleinikov, Andrew V. Amos, Emily Voronkova, Valentina Getz, Tony Duffy, Patrick E. TI STRUCTURE-FUNCTION-IMMUNOGENICITY STUDIES OF PFEMP1 DOMAIN DBL2BC2 PF11-0521, A LIGAND FOR ICAM1 AND MALARIA VACCINE CANDIDATE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Oleinikov, Andrew V.; Amos, Emily; Voronkova, Valentina; Getz, Tony] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Duffy, Patrick E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 40 BP 13 EP 13 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700041 ER PT J AU Uchime, O Plassmeyer, ML Herrera, R Reiter, K Kotova, S Shimp, RL Lebowitz, J Hurt, DE Jin, AJ Miller, LH Narum, DL AF Uchime, Onyinyechukwu Plassmeyer, Matthew L. Herrera, Raul Reiter, Karine Kotova, Svetlana Shimp, Richard L., Jr. Lebowitz, Jacob Hurt, Darrell E. Jin, Albert J. Miller, Louis H. Narum, David L. TI A RECOMBINANT PLASMODIUM FALCIPARUM MEROZOITE-SPECIFIC THROMBOSPONDIN RELATED ANONYMOUS PROTEIN (MTRAP) IS A HIGHLY EXTENDED FLEXIBLE ROD LIKE PROTEIN THAT BINDS HUMAN ERYTHROCYTES SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Uchime, Onyinyechukwu; Plassmeyer, Matthew L.; Herrera, Raul; Reiter, Karine; Shimp, Richard L., Jr.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Kotova, Svetlana; Lebowitz, Jacob; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. OI Jin, Albert/0000-0003-3826-1081 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 41 BP 13 EP 13 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700042 ER PT J AU Mejia, R Booth, G Klein, HG Nutman, TB Hsieh, MM Flegel, WA Klion, A AF Mejia, Rojelio Booth, Garrett Klein, Harvey G. Nutman, Thomas B. Hsieh, Matthew M. Flegel, Willy A. Klion, Amy TI PERIPHERAL BLOOD STEM CELL TRANSPLANT RELATED PLASMODIUM FALCIPARUM INFECTION IN A SICKLE CELL ANEMIA PATIENT SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Mejia, Rojelio; Nutman, Thomas B.; Klion, Amy] NIAID, NIH, Bethesda, MD 20892 USA. [Booth, Garrett; Klein, Harvey G.; Flegel, Willy A.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Hsieh, Matthew M.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 53 BP 17 EP 17 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700054 ER PT J AU Doumbia, S Lopera-Mesa, TM Diakite, SAS Konate, D Traore, K Doumbia, M Krause, MA Tullo, G Anderson, JM Fay, MP Diakite, M Long, CA Fairhurst, RM AF Doumbia, Saibou Lopera-Mesa, Tatiana M. Diakite, Seidina A. S. Konate, Drissa Traore, Karim Doumbia, Mory Krause, Michael A. Tullo, Greg Anderson, Jennifer M. Fay, Michael P. Diakite, Mahamadou Long, Carole A. Fairhurst, Rick M. TI THE IMPORTANCE OF HEMOGLOBIN LEVEL AT ENROLLMENT ON SUBSEQUENT MALARIA RISK: RESULTS FROM A PEDIATRIC COHORT IN MALI, WEST AFRICA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Doumbia, Saibou; Diakite, Seidina A. S.; Konate, Drissa; Traore, Karim; Doumbia, Mory; Krause, Michael A.; Diakite, Mahamadou] Univ Bamako, Bamako, Mali. [Lopera-Mesa, Tatiana M.; Tullo, Greg; Anderson, Jennifer M.; Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 121 BP 37 EP 37 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700122 ER PT J AU Muehlenbachs, A Lachowitzer, J Harrington, WE Fried, M Duffy, PE AF Muehlenbachs, Atis Lachowitzer, Jeff Harrington, Whitney E. Fried, Michal Duffy, Patrick E. TI ELEVATED SFLT-1 AND DECREASED VEGF LEVELS ARE ASSOCIATED WITH MALARIA-RELATED RESPIRATORY DISTRESS IN TANZANIAN CHILDREN SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Muehlenbachs, Atis; Harrington, Whitney E.] Univ Washington, Seattle, WA 98195 USA. [Lachowitzer, Jeff; Fried, Michal] Seattle Biomed, Seattle, WA USA. [Duffy, Patrick E.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 127 BP 38 EP 39 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700128 ER PT J AU Muehlenbachs, A Speake, C Duffy, PE Fligner, CL AF Muehlenbachs, Atis Speake, Cate Duffy, Patrick E. Fligner, Corinne L. TI MINIMALLY INVASIVE POST MORTEM TISSUE SAMPLING: A PROTOCOL TO ELUCIDATE HOST-PARASITE INTERACTIONS IN TROPICAL AREAS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Muehlenbachs, Atis; Fligner, Corinne L.] Univ Washington, Seattle, WA 98195 USA. [Speake, Cate] Seattle Biomed, Seattle, WA USA. [Duffy, Patrick E.] NIAID, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 126 BP 38 EP 38 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700127 ER PT J AU Awandare, GA Jiang, LB Moch, JK Ockenhouse, CF Haynes, JD Miller, LH Stoute, JA AF Awandare, Gordon A. Jiang, Lubin Moch, J. Kathleen Ockenhouse, Christian F. Haynes, J. David Miller, Louis H. Stoute, Jose A. TI MALARIA PARASITE PLASMODIUM FALCIPARUM DD2 SPONTANEOUSLY SWITCHES FROM SIALIC ACID-DEPENDENT TO SIALIC-ACID INDEPENDENT ERYTHROCYTE INVASION IN SUSPENSION CULTURE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Awandare, Gordon A.; Moch, J. Kathleen; Ockenhouse, Christian F.; Haynes, J. David] Walter Reed Army Inst Res, Div Malaria Vaccine Dev, Silver Spring, MD USA. [Jiang, Lubin; Miller, Louis H.] NIAID, Malaria Cell Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Stoute, Jose A.] Penn State Univ, Coll Med, Div Infect Dis, Dept Med, Hershey, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 128 BP 39 EP 39 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700129 ER PT J AU Sheehy, SH Duncan, CJ Elias, S Collins, K Ewer, K Edwards, N Blagborough, A Sinden, R Murphy, J Correa, S Hunt-Cooke, A Meyer, J Lillie, P Colloca, S Cortese, R Nicosia, A Poulton, I Long, CA Gilbert, SC Lawrie, A Hill, AV Draper, SJ AF Sheehy, Susanne H. Duncan, Christopher J. Elias, Sean Collins, Katharine Ewer, Katie Edwards, Nick Blagborough, Andrew Sinden, Robert Murphy, Jitta Correa, Simon Hunt-Cooke, Angela Meyer, Joel Lillie, Patrick Colloca, Stefano Cortese, Riccardo Nicosia, Alfredo Poulton, Ian Long, Carole A. Gilbert, Sarah C. Lawrie, Alison Hill, Adrian V. Draper, Simon J. TI HETEROLOGOUS PRIME-BOOST VACCINATION WITH ADCH63 AND MVA EXPRESSING MSP1 CAN INDUCE PROTECTIVE EFFICACY AGAINST SPOROZOITE CHALLENGE IN VOLUNTEERS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Sheehy, Susanne H.; Duncan, Christopher J.; Hunt-Cooke, Angela; Meyer, Joel; Lillie, Patrick; Poulton, Ian; Lawrie, Alison] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford, England. [Elias, Sean; Collins, Katharine; Ewer, Katie; Edwards, Nick; Gilbert, Sarah C.; Hill, Adrian V.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford, England. [Blagborough, Andrew; Sinden, Robert] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London, England. [Murphy, Jitta] Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, MD 20307 USA. [Correa, Simon] MRC Labs, Banjul, Gambia. [Colloca, Stefano; Cortese, Riccardo; Nicosia, Alfredo] Okairos SRL, Rome, Italy. [Long, Carole A.] NIAID, NIH, Rockville, MD USA. RI Duncan, Christopher/A-2018-2012 OI Duncan, Christopher/0000-0003-4181-2315 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 160 BP 48 EP 49 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700161 ER PT J AU Zhu, DM McClellan, H MacDonald, N Duffy, P Wu, YM AF Zhu, Daming McClellan, Holly MacDonald, Nicholas Duffy, Patrick Wu, Yimin TI CHARACTERIZATION OF PFS25-EPA CONJUGATES BY AGAROSE GEL ELECTROPHORESIS AND WESTERN BLOTTING SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Zhu, Daming; McClellan, Holly; MacDonald, Nicholas; Duffy, Patrick; Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 163 BP 49 EP 50 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700164 ER PT J AU Wu, YM Rausch, K Lambert, L Gonzalez, SO Dutill, TS Fox, CB Miura, K Fay, M Narum, D Jones, D Anders, R Coppel, R Aebig, J Ellis, R Martin, L Howard, RF Davis, H Reed, S Miller, L AF Wu, Yimin Rausch, Kelly Lambert, Lynn Gonzalez, Sachy-Orr Dutill, Timothy S. Fox, Christopher B. Miura, Kazutoyo Fay, Michael Narum, David Jones, David Anders, Robbin Coppel, Ross Aebig, Joan Ellis, Ruth Martin, Laura Howard, Randall F. Davis, Heather Reed, Steve Miller, Louis TI PROTECTION AGAINST MALARIA CHALLENGE BY VACCINATION OF AOTUS MONKEYS WITH ADJUVANTED BLOOD STAGE MALARIA VACCINES SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Wu, Yimin; Rausch, Kelly; Lambert, Lynn; Gonzalez, Sachy-Orr; Miura, Kazutoyo; Narum, David; Jones, David; Aebig, Joan; Ellis, Ruth; Martin, Laura; Miller, Louis] NIAID, LMIV, NIH, Rockville, MD USA. [Dutill, Timothy S.; Fox, Christopher B.; Howard, Randall F.; Reed, Steve] Infect Dis Res Inst, Seattle, WA USA. [Fay, Michael] NIAID, BRB, NIH, Rockville, MD USA. [Anders, Robbin] La Trobe Univ, Melbourne, Vic, Australia. [Coppel, Ross] Monash Univ, Melbourne, Vic 3004, Australia. [Davis, Heather] Pfizer, Ottawa, ON, Canada. RI Coppel, Ross/A-6626-2008 OI Coppel, Ross/0000-0002-4476-9124 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 164 BP 50 EP 50 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700165 ER PT J AU Abdoulaye, A Dao, A Yaro, AS Kassogue, Y Diallo, M Traore, S Huestis, DL Lehmann, T AF Abdoulaye, Adamou Dao, Adama Yaro, Alpha Seydou Kassogue, Yaya Diallo, Moussa Traore, Sekou Huestis, Diana L. Lehmann, Tovi TI THE CONTRIBUTION OF AESTIVATING MOSQUITOES TO THE SUBSEQUENT WET SEASON POPULATIONS IN THE SAHEL SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Abdoulaye, Adamou; Dao, Adama; Yaro, Alpha Seydou; Kassogue, Yaya; Diallo, Moussa; Traore, Sekou] Fac Med Pharm & Odontostomatol, MRTC, Bamako, Mali. [Huestis, Diana L.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 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 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 182 BP 55 EP 55 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700183 ER PT J AU Bahuadze, G Sidamonidze, K Kalandadze, I Iosava, M Giorgobiani, E Chanturia, G Tsertsvadze, N Imnadze, P AF Bahuadze, George Sidamonidze, Ketevan Kalandadze, Irine Iosava, Merab Giorgobiani, Ekaterine Chanturia, Gvantsa Tsertsvadze, Nikoloz Imnadze, Paata TI NEW LEISHMANIASIS FOCI IN WESTERN GEORGIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Bahuadze, George; Sidamonidze, Ketevan; Kalandadze, Irine; Iosava, Merab; Chanturia, Gvantsa; Tsertsvadze, Nikoloz; Imnadze, Paata] Natl Ctr Dis Control, Tbilisi, Rep of Georgia. [Giorgobiani, Ekaterine] NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 199 BP 60 EP 60 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700200 ER PT J AU Aravindhan, V Mohan, V Surender, J Rao, MM Kumar, NP Kumaraswami, V Nutman, TB Babu, S AF Aravindhan, V. Mohan, V. Surender, J. Rao, M. M. Kumar, N. P. Kumaraswami, V. Nutman, Thomas B. Babu, Subash TI DECREASED PREVALENCE OF FILARIAL INFECTION AMONG DIABETIC SUBJECTS ASSOCIATED WITH A DIMINISHED PRO-INFLAMMATORY CYTOKINE RESPONSE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Aravindhan, V.; Mohan, V.; Surender, J.; Rao, M. M.] MDRF, Chennai, Tamil Nadu, India. [Kumar, N. P.] NIH TRC ICER, Chennai, Tamil Nadu, India. [Kumaraswami, V.] TB Res Ctr, Madras, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, LPD, NIH, Bethesda, MD 20892 USA. [Babu, Subash] NIH TRC ICER & SAIC Frederick Inc, NCI Frederick, Chennai, Tamil Nadu, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 213 BP 64 EP 64 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700214 ER PT J AU Blaney, J Johnson, R Dyall, J Huzzelle, L Ragland, D Chen, DY Mollura, D St Claire, M Byrum, R Jett, C Paragas, J Jahrling, P AF Blaney, Joseph Johnson, Reed Dyall, Julie Huzzelle, Louis Ragland, Dan Chen, Dar-Yeong Mollura, Daniel St Claire, Marisa Byrum, Russ Jett, Catherine Paragas, Jason Jahrling, Peter TI PATHOGENESIS OF MONKEYPOX VIRUS IN CYNOMOLGUS MACAQUES INFECTED BY THE INTRAVENOUS OR INTRABRONCHIAL ROUTE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Blaney, Joseph; Johnson, Reed] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD USA. [Dyall, Julie; Huzzelle, Louis; Ragland, Dan; Chen, Dar-Yeong; Mollura, Daniel; St Claire, Marisa; Byrum, Russ; Jett, Catherine; Paragas, Jason; Jahrling, Peter] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 380 BP 113 EP 114 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700381 ER PT J AU Gray, KK Freiberg, AN Holbrook, MR AF Gray, Kimberly K. Freiberg, Alexander N. Holbrook, Michael R. TI INNATE IMMUNE RESPONSE TO RIFT VALLEY FEVER VIRUS INFECTION SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Gray, Kimberly K.; Freiberg, Alexander N.] Univ Texas Med Branch, Galveston, TX USA. [Holbrook, Michael R.] NIH, Integrated Res Facil, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 378 BP 113 EP 113 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700379 ER PT J AU Kortepeter, MG Honko, A Johnson, JC Olinger, GG Purcell, BK Rivard, R Hepburn, MJ Hensley, LE Lawler, JV AF Kortepeter, Mark G. Honko, Anna Johnson, Joshua C. Olinger, Gene G. Purcell, Bret K. Rivard, Robert Hepburn, Matthew J. Hensley, Lisa E. Lawler, James V. TI PATHOPHYSIOLOGIC ASSESSMENT OF EBOLA VIRUS INFECTION WITH AND WITHOUT INTRAVENOUS FLUID TREATMENT IN A NONHUMAN PRIMATE MODEL USING A MULTI-SENSOR TELEMETRY SYSTEM SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Kortepeter, Mark G.; Honko, Anna; Johnson, Joshua C.; Olinger, Gene G.; Purcell, Bret K.; Rivard, Robert; Hepburn, Matthew J.; Hensley, Lisa E.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Lawler, James V.] NIAID, Ft Detrick, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 381 BP 114 EP 114 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700382 ER PT J AU Steel, C Nutman, TB AF Steel, Cathy Nutman, Thomas B. TI CHRONIC HUMAN FILARIAL INFECTION LEADS TO ALTERED T CELL MEMORY AND A DEFECT IN EFFECTOR CELL TRANSITION SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Steel, Cathy; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 385 BP 115 EP 115 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700386 ER PT J AU Hubner, MP Shi, YH Torrero, MN Mueller, E Larson, D Soloviova, K Stocker, JT Tarbell, KV Mitre, E AF Huebner, Marc P. Shi, Yinghui Torrero, Marina N. Mueller, Ellen Larson, David Soloviova, Kateryna Stocker, J. Thomas Tarbell, Kristin V. Mitre, Edward TI HELMINTH-MEDIATED PROTECTION AGAINST AUTOIMMUNE DIABETES IN NOD MICE IS NOT DEPENDENT ON FOXP3(+) REGULATORY T-CELLS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Huebner, Marc P.; Shi, Yinghui; Torrero, Marina N.; Mueller, Ellen; Larson, David; Soloviova, Kateryna; Stocker, J. Thomas; Mitre, Edward] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Tarbell, Kristin V.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 388 BP 116 EP 116 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700389 ER PT J AU Semnani, RT Mahapatra, L Sanprasert, V Nutman, TB AF Semnani, Roshanak T. Mahapatra, Lily Sanprasert, Vivornpun Nutman, Thomas B. TI SECRETED FILARIAL PRODUCTS INDUCE HUMAN MONOCYTES TO HAVE THE FUNCTIONAL AND PHENOTYPIC CHARACTERISTICS OF ALTERNATIVE ACTIVATION SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Semnani, Roshanak T.; Mahapatra, Lily; Sanprasert, Vivornpun; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 387 BP 116 EP 116 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700388 ER PT J AU Oakley, MS Majam, V Majajan, B McCutchan, T Aravind, L Kumar, S AF Oakley, Miranda S. Majam, Victoria Majajan, Babita McCutchan, Thomas Aravind, L. Kumar, Sanjai TI MOLECULAR DETERMINANTS OF EXPERIMENTAL CEREBRAL MALARIA IN THE BRAIN AND CIRCULATION SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Oakley, Miranda S.; Majam, Victoria; Majajan, Babita; Kumar, Sanjai] US FDA, Rockville, MD 20857 USA. [McCutchan, Thomas; Aravind, L.] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 425 BP 127 EP 127 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700426 ER PT J AU Metenou, S Dembele, B Kovacs, M Konate, S Dolo, H Coulibaly, SY Coulibaly, YI Diallo, AA Soumaoro, L Coulibaly, ME Sanogo, D Doumbia, SS Traore, SF Mahanty, S Klion, A Nutman, TB AF Metenou, Simon Dembele, Benoit Kovacs, Michael Konate, Siaka Dolo, Housseini Coulibaly, Siaka Y. Coulibaly, Yaya I. Diallo, Abdallah A. Soumaoro, Lamine Coulibaly, Michel E. Sanogo, Dramane Doumbia, Salif S. Traore, Sekou F. Mahanty, Siddhartha Klion, Amy Nutman, Thomas B. TI MODULATION OF INTERFERON REGULATORY FACTORS (IRFS) UNDERLIES THE SUPPRESSION OF MALARIA-SPECIFIC IMMUNE RESPONSES IN HUMAN PATENT FILARIAL INFECTION SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Metenou, Simon; Kovacs, Michael; Mahanty, Siddhartha; Klion, Amy; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. [Dembele, Benoit; Konate, Siaka; Dolo, Housseini; Coulibaly, Siaka Y.; Coulibaly, Yaya I.; Diallo, Abdallah A.; Soumaoro, Lamine; Coulibaly, Michel E.; Sanogo, Dramane; Doumbia, Salif S.; Traore, Sekou F.] Univ Bamako, Fac Med Pharm & Dent, Filariasis Unit, Bamako, Mali. RI Metenou, Simon/C-1101-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 432 BP 129 EP 129 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700433 ER PT J AU Zuspann, JA Sedegah, MY Mita-Mendoza, NK Amaratunga, C Tse, JG Langsley, G Pollack, Y Fairhurst, RM AF Zuspann, Jordan A. Sedegah, Mary Y. Mita-Mendoza, Neida K. Amaratunga, Chanaki Tse, Jeanette G. Langsley, Gordon Pollack, Yaakov Fairhurst, Rick M. TI RESVERATROL, A COMPONENT OF RED WINE, IMPAIRS THE CYTOADHERENCE OF PLASMODIUM FALCIPARUM-INFECTED RED BLOOD CELLS BY REDUCING THE EXPRESSION OF PFEMP-1 SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Zuspann, Jordan A.; Sedegah, Mary Y.; Mita-Mendoza, Neida K.; Amaratunga, Chanaki; Tse, Jeanette G.; Fairhurst, Rick M.] NIH, Bethesda, MD 20892 USA. [Langsley, Gordon] Univ Paris 05, Inst Cochin, Paris, France. [Pollack, Yaakov] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 434 BP 130 EP 130 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700435 ER PT J AU Obiakor, HT Avril, M Zhang, YL MacDonald, N Reiter, K Shimp, R Srinivasan, P Cartwright, M Lambert, L Fried, M Duffy, P Smith, J Narum, DL Miller, LH AF Obiakor, Harold T. Avril, Marion Zhang, Yanling MacDonald, Nicholas Reiter, Karine Shimp, Richard, Jr. Srinivasan, Prakash Cartwright, Megan Lambert, Lynn Fried, Michal Duffy, Patrick Smith, Joseph Narum, David L. Miller, Louis H. TI ANTIBODIES AGAINST VAR2CSA OF PFEMP1 DBL2X AND DBL3X DOMAINS INHIBITED ADHESION OF IE TO CHONDROITIN SULFATE A SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Obiakor, Harold T.; Zhang, Yanling; MacDonald, Nicholas; Reiter, Karine; Shimp, Richard, Jr.; Lambert, Lynn; Duffy, Patrick; Narum, David L.] NIAID, LMIV, NIH, Rockville, MD USA. [Avril, Marion; Cartwright, Megan; Fried, Michal; Smith, Joseph] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Srinivasan, Prakash; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 437 BP 131 EP 131 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700438 ER PT J AU Lopera-Mesa, TM AF Lopera-Mesa, Tatiana M. TI PLASMA URIC ACID LEVELS CORRELATE WITH PARASITE DENSITY, INFLAMMATORY CYTOKINE LEVELS, AND DISEASE SEVERITY IN MALIAN CHILDREN WITH MALARIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Lopera-Mesa, Tatiana M.] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 543 BP 163 EP 163 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700544 ER PT J AU Ellis, RD Shafer, D Wu, YM Miura, K Aebig, J Rausch, K Zhu, DM Martin, L Fay, M Long, C Miller, L Durbin, A AF Ellis, Ruth D. Shafer, Donna Wu, Yimin Miura, Kazutoyo Aebig, Joan Rausch, Kelly Zhu, Daming Martin, Laura Fay, Michael Long, Carole Miller, Louis Durbin, Anna TI PHASE 1 STUDY OF BSAM2/ALHYDROGEL+CPG 7909 IN MALARIA NAIVE UNITED STATES ADULTS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Shafer, Donna; Durbin, Anna] Johns Hopkins Ctr Immunizat Res, Washington, DC USA. [Wu, Yimin; Aebig, Joan; Rausch, Kelly; Zhu, Daming; Martin, Laura; Miller, Louis] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Miura, Kazutoyo; Long, Carole] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. [Fay, Michael] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 584 BP 175 EP 175 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700585 ER PT J AU Bergmann-Leitner, ES Leitner, WW Angov, E AF Bergmann-Leitner, Elke S. Leitner, Wolfgang W. Angov, Evelina TI COMPARISON OF PLASMODIUM BERGHEI CHALLENGE MODEL FOR THE EVALUATION OF PRE-ERYTHROCYTIC MALARIA VACCINES AND THEIR EFFECT ON PERCEIVED VACCINE EFFICACY SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Bergmann-Leitner, Elke S.; Angov, Evelina] Walter Reed Army Inst Res, Silver Spring, MD USA. [Leitner, Wolfgang W.] NIAID, NIH, Bethesda, MD 20892 USA. RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 585 BP 176 EP 176 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700586 ER PT J AU Saveria, T Oleinikov, A Keitany, G Chaturvedi, R Lograsso, J Fried, M Duffy, P AF Saveria, Tracy Oleinikov, Andrew Keitany, Gladys Chaturvedi, Richa Lograsso, Joe Fried, Michal Duffy, Patrick TI VAR2CSA DBL4 AND DBL5 DOMAINS AS VACCINE CANDIDATES FOR PLACENTAL MALARIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Saveria, Tracy; Oleinikov, Andrew; Keitany, Gladys; Chaturvedi, Richa; Lograsso, Joe; Fried, Michal] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Duffy, Patrick] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 587 BP 176 EP 176 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700588 ER PT J AU Sogoba, N Keita, M Diallo, M Baber, I Kone, M Manoukis, NC Dotson, E Traore, SF Doumbia, S AF Sogoba, Nafomon Keita, Moussa Diallo, M'Bouye Baber, Ibrahima Kone, Massiriba Manoukis, Nicholas C. Dotson, Ellen Traore, Sekou F. Doumbia, Seydou TI DRY SEASON PILOT INDOOR RESIDUAL SPRAY (IRS) TARGETING RIVERBANK HAMLETS IN SUDAN SAVANNA AREAS OF MALI SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Sogoba, Nafomon; Keita, Moussa; Diallo, M'Bouye; Baber, Ibrahima; Kone, Massiriba; Traore, Sekou F.; Doumbia, Seydou] Univ Bamako, MRTC FMPOS, Bamako, Mali. [Manoukis, Nicholas C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Dotson, Ellen] Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 599 BP 180 EP 180 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700600 ER PT J AU Assumpcao, TC Alvarenga, PH Ribeiro, JM Andersen, JF Francischetti, IM AF Assumpcao, Teresa C. Alvarenga, Patricia H. Ribeiro, Jose M. Andersen, John F. Francischetti, Ivo M. TI DIPETALODIPIN, A NOVEL SALIVARY PLATELET AGGREGATION INHIBITOR THAT DISPLAYS HIGH-AFFINITY BINDING TO TXA(2) SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Assumpcao, Teresa C.; Alvarenga, Patricia H.; Ribeiro, Jose M.; Andersen, John F.; Francischetti, Ivo M.] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 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 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 629 BP 188 EP 188 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819700630 ER PT J AU Schmid, M Meneses, C Elnaiem, DE Lanzaro, G AF Schmid, Melody Meneses, Claudio Elnaiem, Dia-Eldin Lanzaro, Gregory TI DEVELOPING A MOUSE MODEL TO DETERMINE THE EFFECT OF SAND FLY SALIVA ON THE VISCERALIZATION OF LEISHMANIA CHAGASI SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Schmid, Melody; Lanzaro, Gregory] Univ Calif Davis, Davis, CA 95616 USA. [Meneses, Claudio; Elnaiem, Dia-Eldin] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 697 BP 208 EP 208 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701066 ER PT J AU Fowkes, FJ McGready, R Hommel, M Cross, NJ Simpson, JA Lackovic, K Richards, JS Viladpai-Nguen, SJ Avril, M Smith, JD Narum, DL Anders, RF Nosten, F Beeson, JG AF Fowkes, Freya J. McGready, Rose Hommel, Mirja Cross, Nadia J. Simpson, Julie A. Lackovic, Kurt Richards, Jack S. Viladpai-nguen, Samuel J. Avril, Marion Smith, Joseph D. Narum, David L. Anders, Robin F. Nosten, Francois Beeson, James G. TI LONGITUDINAL PATTERNS OF ANTIBODY RESPONSES AND PLASMODIUM SPP. INFECTION DURING PREGNANCY SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Fowkes, Freya J.; Hommel, Mirja; Cross, Nadia J.; Lackovic, Kurt; Richards, Jack S.; Beeson, James G.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [McGready, Rose; Viladpai-nguen, Samuel J.; Nosten, Francois] Shoklo Malaria Res Unit, Mae Sot, Thailand. [Simpson, Julie A.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Avril, Marion; Smith, Joseph D.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Narum, David L.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD USA. [Anders, Robin F.] La Trobe Univ, Melbourne, Vic, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 727 BP 216 EP 216 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701095 ER PT J AU Madrid, E Dorny, P Nash, TE Mahanty, S AF Madrid, Elise Dorny, Pierre Nash, Theodore E. Mahanty, Siddhartha TI IN VITRO EFFECTS OF ANTHELMINTICS ON TAENIA CRASSICEPS REVEAL LIMITATIONS OF ITS USE AS A MODEL FOR T. SOLIUM CYSTICERCOSIS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Madrid, Elise; Nash, Theodore E.; Mahanty, Siddhartha] NIH, Bethesda, MD 20892 USA. [Dorny, Pierre] Inst Trop Med, B-2000 Antwerp, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 792 BP 234 EP 234 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701160 ER PT J AU Mahanty, S Schwendeman, A Madrid, E Torres-Velez, F Berns, A Scott, E Lizak, M Nash, T AF Mahanty, Siddhartha Schwendeman, Andrew Madrid, Elise Torres-Velez, Fernando Berns, Abby Scott, Erick Lizak, Martin Nash, Theodore TI INVESTIGATION OF POST-TREATMENT INFLAMMATORY RESPONSES IN A RAT MODEL OF NEUROCYSTICERCOSIS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Mahanty, Siddhartha; Schwendeman, Andrew; Madrid, Elise; Torres-Velez, Fernando; Berns, Abby; Scott, Erick; Lizak, Martin; Nash, Theodore] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 791 BP 234 EP 234 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701159 ER PT J AU Duncan, CJ Sheehy, SH Ewer, K Douglas, AD Halstead, F Edwards, N Collins, K Lillie, PJ Poulton, I Hunt-Cooke, A Lawrie, AM Draper, SJ Gilbert, SC Fay, MP Miura, K Long, CA Wu, YM Hill, AV Ellis, RD AF Duncan, Christopher J. Sheehy, Susanne H. Ewer, Katie Douglas, Alexander D. Halstead, Fenella Edwards, Nick Collins, Katharine Lillie, Patrick J. Poulton, Ian Hunt-Cooke, Angela Lawrie, Alison M. Draper, Simon J. Gilbert, Sarah C. Fay, Michael P. Miura, Kazutoyo Long, Carol A. Wu, Yimin Hill, Adrian V. Ellis, Ruth D. TI SAFETY, IMMUNOGENICITY AND IMPACT ON PARASITE MULTIPLICATION RATES OF THE CANDIDATE BLOOD-STAGE VACCINE AMA1-C1/ALHYDROGEL WITH THE NOVEL ADJUVANT CPG 7909 AGAINST BLOOD-STAGE MALARIA CHALLENGE IN HEALTHY MALARIA-NAIVE VOLUNTEERS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Duncan, Christopher J.; Sheehy, Susanne H.; Lillie, Patrick J.; Poulton, Ian; Hunt-Cooke, Angela; Lawrie, Alison M.; Hill, Adrian V.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford OX1 2JD, England. [Ewer, Katie; Douglas, Alexander D.; Halstead, Fenella; Edwards, Nick; Collins, Katharine; Draper, Simon J.; Gilbert, Sarah C.] Univ Oxford, Jenner Inst, Oxford OX1 2JD, England. [Fay, Michael P.; Miura, Kazutoyo; Long, Carol A.; Wu, Yimin; Ellis, Ruth D.] NIAID, Bethesda, MD 20892 USA. RI Duncan, Christopher/A-2018-2012 OI Duncan, Christopher/0000-0003-4181-2315 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 804 BP 238 EP 238 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701172 ER PT J AU Sagara, I Ellis, RD Assadou, MH Kone, M Guindo, MA Saye, R Guindo, O Kamate, B Niambele, MB Sissoko, MS Fay, MP Miura, K Aebig, J Wu, YM Long, C Rausch, K Dicko, A Dolo, A Diallo, DA Miller, L Doumbo, OK AF Sagara, Issaka Ellis, Ruth D. Assadou, Mahamadoun Hamady Kone, Mamady Guindo, Merepen A. Saye, Renion Guindo, Ousmane Kamate, Beh Niambele, Mohamed B. Sissoko, Mahamadou S. Fay, Michael P. Miura, Kazutoyo Aebig, Joan Wu, Yimin Long, Carole Rausch, Kelly Dicko, Alassane Dolo, Amagana Diallo, Dapa A. Miller, Louis Doumbo, Ogobara K. TI PHASE 1 STUDY OF THE SAFETY AND IMMUNOGENICITY OF BSAM-2/ALHYDROGEL (R)+CPG 7909, AN ASEXUAL BLOOD STAGE VACCINE FOR PLASMODIUM FALCIPARUM MALARIA IN ADULTS IN MALI SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Sagara, Issaka; Assadou, Mahamadoun Hamady; Kone, Mamady; Guindo, Merepen A.; Saye, Renion; Guindo, Ousmane; Kamate, Beh; Niambele, Mohamed B.; Sissoko, Mahamadou S.; Dicko, Alassane; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Dent, Bamako, Mali. [Ellis, Ruth D.; Miura, Kazutoyo; Aebig, Joan; Wu, Yimin; Rausch, Kelly; Miller, Louis] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 805 BP 239 EP 239 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701173 ER PT J AU Sedegah, M Chuang, IL McGrath, S House, B Ganeshan, H Lejano, J Abot, E Banania, G Sayo, R Farooq, F Belmonte, M Richie, NO Wood, C Long, CA Regis, D Tamminga, C Spring, M Limbach, K Patterson, NB Bruder, J Doolan, DL Soisson, L Diggs, C Ockenhouse, CF Richie, TL AF Sedegah, Martha Chuang, Ilin McGrath, Shannon House, Brent Ganeshan, Harini Lejano, Jennylynn Abot, Esteban Banania, Glenna Sayo, Renato Farooq, Fouzia Belmonte, Maria Richie, Nancy O. Wood, Chloe Long, Carole A. Regis, David Tamminga, Cindy Spring, Michele Limbach, Keith Patterson, Noelle B. Bruder, Joe Doolan, Denise L. Soisson, Lorraine Diggs, Carter Ockenhouse, Christian F. Richie, Thomas L. TI ANALYSIS OF CELL-MEDIATED IMMUNE RESPONSES IN VOLUNTEERS STERILELY PROTECTED AGAINST PLASMODIUM FALCIPARUM SPOROZOITE CHALLENGE FOLLOWING IMMUNIZATION WITH A GENE-BASED VACCINE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Sedegah, Martha; Chuang, Ilin; House, Brent; Ganeshan, Harini; Lejano, Jennylynn; Abot, Esteban; Banania, Glenna; Sayo, Renato; Farooq, Fouzia; Belmonte, Maria; Regis, David; Tamminga, Cindy; Limbach, Keith; Patterson, Noelle B.; Richie, Thomas L.] USN, Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [McGrath, Shannon; Richie, Nancy O.; Wood, Chloe; Spring, Michele; Ockenhouse, Christian F.] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Bruder, Joe] GenVec Inc, Gaithersburg, MD USA. [Doolan, Denise L.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Soisson, Lorraine; Diggs, Carter] US Agcy Int Dev, Washington, DC 20523 USA. RI Doolan, Denise/F-1969-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 806 BP 239 EP 239 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701174 ER PT J AU Bennuru, S Meng, ZJ Semnani, RT Ghedin, E Chan, K Lucas, D Ribeiro, JM Veenstra, TD Nutman, TB AF Bennuru, Sasisekhar Meng, Zhaojing Semnani, Roshanak T. Ghedin, Elodie Chan, King Lucas, David Ribeiro, Jose M. Veenstra, Timothy D. Nutman, Thomas B. TI BEYOND FILARIAL GENOMICS: PROTEOMIC ANALYSES PROVIDE INSIGHTS INTO BOTH THE FILARIAL HOST AND ITS WOLBACHIA ENDOSYMBIONT SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Bennuru, Sasisekhar; Semnani, Roshanak T.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Meng, Zhaojing; Chan, King; Lucas, David; Veenstra, Timothy D.] NCI Frederick, Lab Prote & Analyt Technol, SAIC Frederick Inc, NIH, Frederick, MD USA. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA USA. [Ribeiro, Jose M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 829 BP 246 EP 246 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701197 ER PT J AU Durbin, AP Kirkpatrick, B Pierce, K Elwood, D Tibery, C Lewis, R Wanionek, K Thumar, B Luke, C Murphy, B Subbarao, K Whitehead, S AF Durbin, Anna P. Kirkpatrick, Beth Pierce, Kristen Elwood, Daniel Tibery, Cecilia Lewis, Robbyn Wanionek, Kimberli Thumar, Bhavin Luke, Catherine Murphy, Brian Subbarao, Kanta Whitehead, Stephen TI EVALUATION OF THE SAFETY AND IMMUNOGENICITY OF TETRAVAX-DV, A LIVE ATTENUATED TETRAVALENT DENGUE VACCINE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Durbin, Anna P.; Elwood, Daniel; Tibery, Cecilia; Lewis, Robbyn; Wanionek, Kimberli; Thumar, Bhavin] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kirkpatrick, Beth; Pierce, Kristen] Univ Vermont, Burlington, VT USA. [Luke, Catherine; Murphy, Brian; Subbarao, Kanta; Whitehead, Stephen] NIAID, NIH, Bethesda, MD 20892 USA. RI Mavoa, Suzanne/B-5372-2010 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 834 BP 248 EP 248 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701202 ER PT J AU Konate, D Lopera-Mesa, TM Traore, K Diakite, SAS Doumbia, S Doumbia, M Krause, MA Tullo, G Miura, K Anderson, JM Fay, MP Long, CA Diakite, M Fairhurst, RM AF Konate, Drissa Lopera-Mesa, Tatiana M. Traore, Karim Diakite, Seidina A. S. Doumbia, Saibou Doumbia, Mory Krause, Michael A. Tullo, Greg Miura, Kazutoyo Anderson, Jennifer M. Fay, Michael P. Long, Carole A. Diakite, Mahamadou Fairhurst, Rick M. TI COMMON RED BLOOD CELL POLYMORPHISMS CONFER DIFFERENT LEVELS OF PROTECTION AGAINST PLASMODIUM FALCIPARUM MALARIA: RESULTS FROM A PEDIATRIC COHORT IN MALI, WEST AFRICA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Konate, Drissa; Traore, Karim; Diakite, Seidina A. S.; Doumbia, Saibou; Doumbia, Mory; Diakite, Mahamadou] Univ Bamako, Bamako, Mali. [Lopera-Mesa, Tatiana M.; Krause, Michael A.; Tullo, Greg; Miura, Kazutoyo; Anderson, Jennifer M.; Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 845 BP 251 EP 252 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701213 ER PT J AU Murphy, SC Prentice, JL Williamson, KS Fried, M Talley, AK Wang, RB Duffy, PE Cookson, BT AF Murphy, Sean C. Prentice, Jennifer L. Williamson, Kathryn S. Fried, Michal Talley, Angela K. Wang, Ruobing Duffy, Patrick E. Cookson, Brad T. TI REAL-TIME QUANTITATIVE RT-PCR FOR MONITORING PARASITEMIA IN MALARIA HUMAN CHALLENGE TRIALS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Murphy, Sean C.; Prentice, Jennifer L.; Cookson, Brad T.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Williamson, Kathryn S.; Fried, Michal; Talley, Angela K.; Wang, Ruobing] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Duffy, Patrick E.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 844 BP 251 EP 251 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701212 ER PT J AU Gwamaka, MM Kurtis, JD Sorensen, BE Mutabingwa, TK Fried, M Duffy, PE AF Gwamaka, Moses M. Kurtis, Jonathan D. Sorensen, Bess E. Mutabingwa, Theonest K. Fried, Michal Duffy, Patrick E. TI IRON DEFICIENCY DECREASES THE RISK OF PLASMODIUM FALCIPARUM MALARIA AND DEATH IN CHILDREN SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Gwamaka, Moses M.] Muheza Designated Dist Hosp, Mother Offspring Malaria Studies Project, Muheza, Tanzania. [Kurtis, Jonathan D.] Brown Univ, Sch Med, Providence, RI 02912 USA. [Gwamaka, Moses M.] Ifakara Hlth Inst, Morogoro, Tanzania. [Sorensen, Bess E.; Fried, Michal] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Mutabingwa, Theonest K.] Natl Inst Med Res, Dar Es Salaam, Tanzania. [Duffy, Patrick E.] NIAID, NIH, Lab Malaria Immunol & Vaccinol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 846 BP 252 EP 252 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701214 ER PT J AU Molina-Cruz, A Kumar, S Gupta, L Rodrigues, J Barillas-Mury, C AF Molina-Cruz, Alvaro Kumar, Sanjeev Gupta, Lalita Rodrigues, Janneth Barillas-Mury, Carolina TI A PEROXIDASE/DUAL OXIDASE SYSTEM MODULATES MIDGUT EPITHELIAL IMMUNITY IN ANOPHELES GAMBIAE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Molina-Cruz, Alvaro; Kumar, Sanjeev; Gupta, Lalita; Rodrigues, Janneth; Barillas-Mury, Carolina] NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 861 BP 257 EP 257 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701229 ER PT J AU Santiago, HC Wilson, M Bennuru, S Ribeiro-Gomes, F Grainger, J Wynn, T Urban, J Nutman, T AF Santiago, Helton C. Wilson, Mark Bennuru, Sasisehkhar Ribeiro-Gomes, Flavia Grainger, John Wynn, Thomas Urban, Joe Nutman, Thomas TI MOLECULAR MIMICRY BETWEEN ALLERGENS AND HELMINTH PROTEINS UNDERLIES RESPONSES AT THE HELMINTH-ALLERGY INTERFACE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Santiago, Helton C.; Wilson, Mark; Bennuru, Sasisehkhar; Ribeiro-Gomes, Flavia; Grainger, John; Wynn, Thomas; Nutman, Thomas] NIH, Bethesda, MD 20892 USA. [Urban, Joe] USDA, Beltsville, MD 20705 USA. RI Ribeiro-Gomes, Flavia/F-7609-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 867 BP 258 EP 259 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701235 ER PT J AU Shott, JP Guindo, MA Saye, R Lamine, DM Sanogo, S Dembele, MB Sekouba, K Sagara, I Sakai, R Mays, G Nagel, M Rizzo-Price, PA Miller, LH Ellis, RD Doumbo, O Diallo, D AF Shott, Joseph P. Guindo, Merepen A. Saye, Renion Lamine, Diakite M. Sanogo, Sintry Dembele, Moussa B. Sekouba, Keita Sagara, Issaka Sakai, Richard Mays, Gary Nagel, Mary Rizzo-Price, Patricia A. Miller, Louis H. Ellis, Ruth D. Doumbo, Ogobara Diallo, Dapa TI QUALITY SYSTEMS IMPROVEMENT FOR COLLEGE OF AMERICAN PATHOLOGISTS ACCREDITATION OF A CLINICAL LABORATORY TO SUPPORT BIOMEDICAL RESEARCH IN BAMAKO, MALI SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Shott, Joseph P.] SAIC Frederick Inc, Clin Monitoring Res Program, Bethesda, MD USA. [Guindo, Merepen A.; Saye, Renion; Lamine, Diakite M.; Sanogo, Sintry; Dembele, Moussa B.; Sekouba, Keita; Sagara, Issaka; Sakai, Richard; Doumbo, Ogobara; Diallo, Dapa] Univ Bamako, Fac Med Pharm & Odonto Stomatol, Bamako, Mali. [Mays, Gary] NIAID, Off Director, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Nagel, Mary; Rizzo-Price, Patricia A.] Clin & Lab Stand Inst, Wayne, PA USA. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA. [Ellis, Ruth D.] NIAID, Lab Malaria Immunol & Vaccinol, Div Intramural Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 893 BP 267 EP 267 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701261 ER PT J AU Ostera, G Tokumasu, F AF Ostera, Graciela Tokumasu, Fuyuki TI COPPER FLUORESCEIN COMPOUND CONFIRMS THE PRESENCE OF NITRIC OXIDE IN PLASMODIUM FALCIPARUM TROPHOZOITES SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Ostera, Graciela] Georgetown Univ, Washington, DC USA. [Tokumasu, Fuyuki] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 938 BP 280 EP 280 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701306 ER PT J AU Yusibov, V Farrance, CE Chichester, JA Jones, RM Mett, V Musiychuk, K Shamloul, M Sharma, S Streatfield, S Sauerwein, RW Roeffen, W Wu, YM Muratova, O Duffy, P Culpepper, J AF Yusibov, Vidadi Farrance, Christine E. Chichester, Jessica A. Jones, R. Mark Mett, Vadim Musiychuk, Konstantin Shamloul, Moneim Sharma, Satish Streatfield, Stephen Sauerwein, Robert W. Roeffen, Will Wu, Yimin Muratova, Olga Duffy, Patrick Culpepper, Janice TI FORMULATION AND PRE-CLINICAL EVALUATION OF TRANSMISSION BLOCKING POTENTIAL OF PLANT-PRODUCED PLASMODIUM FALCIPARUM SEXUAL STAGE PFS25 AND PFS230 VACCINE CANDIDATES SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Yusibov, Vidadi; Farrance, Christine E.; Chichester, Jessica A.; Jones, R. Mark; Mett, Vadim; Musiychuk, Konstantin; Shamloul, Moneim; Sharma, Satish; Streatfield, Stephen] Fraunhofer CMB, Newark, DE USA. [Sauerwein, Robert W.; Roeffen, Will] Radboud Univ Nijmegen, NL-6525 ED Nijmegen, Netherlands. [Wu, Yimin; Muratova, Olga; Duffy, Patrick] NIH, Rockville, MD USA. [Culpepper, Janice] Bill & Melinda Gates Fdn, Seattle, WA USA. RI Sauerwein, Robert/C-8519-2013; Roeffen, W.F.G./L-4607-2015 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 982 BP 293 EP 294 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701349 ER PT J AU Oliveira, GA Barillas-Mury, C AF Oliveira, Giselle A. Barillas-Mury, Carolina TI ROLE OF AN INVASION-INDUCED HEME PEROXIDASE FROM ANOPHELES GAMBIAE DURING PLASMODIUM DEVELOPMENT SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Oliveira, Giselle A.; Barillas-Mury, Carolina] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 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 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1015 BP 303 EP 304 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701382 ER PT J AU Mahanty, S Paredes, A Marzal, M Dorny, P Rodriguez, S Gonzalez, E Guerra, C Garcia, H Nash, T AF Mahanty, Siddhartha Paredes, Adriana Marzal, Miguel Dorny, Pierre Rodriguez, Silvia Gonzalez, Emico Guerra, Cristina Garcia, Hugo Nash, Theodore CA Cysticercosis Working Grp Peru TI IN VITRO MORPHOLOGICAL AND BIOCHEMICAL EFFECTS OF PRAZIQUANTEL AND ALBENDAZOLE ON TAENIA SOLIUM CYSTS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Mahanty, Siddhartha] NIH, Rockville, MD USA. [Paredes, Adriana; Marzal, Miguel; Rodriguez, Silvia; Guerra, Cristina; Garcia, Hugo] Univ Paruana Cayetano Heredia, Lab Expt Immunopathol, Lima, Peru. [Dorny, Pierre] Inst Trop Med, B-2000 Antwerp, Belgium. [Gonzalez, Emico] Univ Nacl Mayor San Marcos, Sch Vet Med, Lima 14, Peru. [Nash, Theodore] NIH, Bethesda, MD 20892 USA. [Cysticercosis Working Grp Peru] Cysticercosis Working Grp Peru, Lima, Peru. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1046 BP 312 EP 313 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701413 ER PT J AU Chancey, C Lee-Stroka, A Rios, M AF Chancey, Caren Lee-Stroka, Agnes Rios, Maria TI WEST NILE VIRUS BINDS TO RED BLOOD CELLS OF SEVERAL VERTEBRATE SPECIES SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Chancey, Caren; Rios, Maria] Food & Drug Adm CBER, Bethesda, MD USA. [Lee-Stroka, Agnes] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1060 BP 316 EP 316 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701427 ER PT J AU Hernandez, Y Kelada, AY Joshi, MB Dwyer, DM AF Hernandez, Yunuen Kelada, Andrew Y. Joshi, Manju B. Dwyer, Dennis M. TI TWO HIGHLY CONSERVED SECRETORY NUCLEASES FACILITATE PURINE SALVAGE IN LEISHMANIA MEXICANA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Hernandez, Yunuen; Kelada, Andrew Y.; Joshi, Manju B.; Dwyer, Dennis M.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1084 BP 323 EP 324 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701451 ER PT J AU McCoy, A Husain, T Angov, E Narum, D Bruder, J Stoyanov, C Trager, L Flynn, B Tewari, K Leitner, E Komisar, J Ockenhouse, C Richie, T Weiss, W Seder, R AF McCoy, Andrea Husain, Tupur Angov, Evelina Narum, David Bruder, Joseph Stoyanov, Cristina Trager, Lauren Flynn, Barbara Tewari, Kavita Leitner, Elke Komisar, Jack Ockenhouse, Christian Richie, Thomas Weiss, Walter Seder, Robert TI PRIME-BOOST MALARIA VACCINES IN RHESUS MONKEYS USING PROTEIN IN POLY I:C ADJUVANT AND ADENOVIRUS VECTORS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [McCoy, Andrea; Husain, Tupur; Richie, Thomas; Weiss, Walter] USN, Med Res Ctr, Silver Spring, MD USA. [Angov, Evelina; Leitner, Elke; Komisar, Jack; Ockenhouse, Christian] Walter Reed Army Inst Res, Silver Spring, MD USA. [Narum, David; Stoyanov, Cristina; Trager, Lauren; Flynn, Barbara; Tewari, Kavita; Seder, Robert] NIH, Bethesda, MD 20892 USA. [Bruder, Joseph] GenVec Inc, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1173 BP 349 EP 349 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701540 ER PT J AU Miura, K Diakite, M Moretz, SE Zhou, H Diouf, A Tullo, G Lopera-Mesa, TM Anderson, JM Fairhurst, RM Long, CA AF Miura, Kazutoyo Diakite, Mahamadou Moretz, Samuel E. Zhou, Hong Diouf, Ababacar Tullo, Gregory Lopera-Mesa, Tatiana M. Anderson, Jennifer M. Fairhurst, Rick M. Long, Carole A. TI DIFFERENCES IN HUMORAL IMMUNITY AGAINST PLASMODIUM FALCIPARUM MALARIA IN MALIAN CHILDREN CARRYING NORMAL HEMOGLOBIN A OR SICKLE HEMOGLOBIN S SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Miura, Kazutoyo; Moretz, Samuel E.; Zhou, Hong; Diouf, Ababacar; Tullo, Gregory; Lopera-Mesa, Tatiana M.; Anderson, Jennifer M.; Fairhurst, Rick M.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1178 BP 350 EP 350 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701545 ER PT J AU Ramanathan, R Abraham, D Nolan, TJ Lok, JB Varma, S Nutman, TB AF Ramanathan, Roshan Abraham, David Nolan, Thomas J. Lok, James B. Varma, Sudhir Nutman, Thomas B. TI UNRAVELING THE BIOLOGY OF AUTOINFECTION BY STRONGYLOIDES STERCORALIS: A MICROARRAY BASED ANALYSIS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Ramanathan, Roshan; Varma, Sudhir; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. [Abraham, David] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Nolan, Thomas J.; Lok, James B.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1189 BP 353 EP 353 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701556 ER PT J AU Vermeire, JJ Pool, CD Wong, CC Harrison, LM Rai, G Maloney, DJ Simeonov, A Jadhav, A Thomas, CJ Williams, DL Cappello, M AF Vermeire, Jon J. Pool, Christopher D. Wong, Christina C. Harrison, Lisa M. Rai, Ganesha Maloney, David J. Simeonov, Anton Jadhav, Ajit Thomas, Craig J. Williams, David L. Cappello, Michael TI DEFINING TARGET SPECIFICITY OF OXADIAZOLE COMPOUNDS ON REDOX PATHWAY MEMBERS OF THE HOOKWORM ANCYLOSTOMA CEYLANICUM SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Vermeire, Jon J.; Pool, Christopher D.; Wong, Christina C.; Harrison, Lisa M.; Cappello, Michael] Yale Univ, Sch Med, New Haven, CT USA. [Rai, Ganesha; Maloney, David J.; Simeonov, Anton; Jadhav, Ajit; Thomas, Craig J.] NIH, Chem Genom Ctr, Rockville, MD USA. [Williams, David L.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1282 BP 381 EP 381 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701649 ER PT J AU Manoukis, NC Butail, S Paley, D Yaro, AS Diallo, M Traore, SF Dao, A Ribeiro, JM Lehmann, T AF Manoukis, Nicholas C. Butail, Sachit Paley, Derek Yaro, Alpha S. Diallo, Moussa Traore, Sekou F. Dao, Adama Ribeiro, Jose M. Lehmann, Tovi TI QUANTIFYING AND ANALYZING DANCE OF ANOPHELES GAMBIAE IN MATING SWARMS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Manoukis, Nicholas C.; Ribeiro, Jose M.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Biol, Natl Inst Hlth, Bethesda, MD USA. [Butail, Sachit; Paley, Derek] Univ Maryland, Dept Aerosp Engn, College Pk, MD 20742 USA. [Yaro, Alpha S.; Diallo, Moussa; Traore, Sekou F.; Dao, Adama] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. RI Paley, Derek/B-4437-2013 OI Paley, Derek/0000-0002-3086-2395 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1299 BP 386 EP 387 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701666 ER PT J AU Kubofcik, J Fink, DL Nutman, TB AF Kubofcik, Joseph Fink, Doran L. Nutman, Thomas B. TI IDENTIFICATION OF A WUCHERERIA BANCROFTI LARVAL STAGE SPECIFIC STAGE PROTEIN THAT IS BOTH SENSITIVE AND SPECIFIC IN DETECTING ANTIBODIES IN W. BANCROFTI INFECTED PATIENTS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Kubofcik, Joseph; Fink, Doran L.; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1329 BP 396 EP 396 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701696 ER PT J AU Tenaguem, J Wawo-Yonta, E Fotsing, RN Tatuene, JK Djeunga, HN Bopda, J Hopkins, A Nutman, TB Kuaban, C Boussinesq, M Klion, A Kamgno, J AF Tenaguem, Jean Wawo-Yonta, Edwine Fotsing, Raceline Ngounou Tatuene, Joseph Kamtchum Djeunga, Hugues Nana Bopda, Jean Hopkins, Adrian Nutman, Thomas B. Kuaban, Christopher Boussinesq, Michel Klion, Amy Kamgno, Joseph TI CARDIAC LESIONS IN AN AREA HYPERENDEMIC FOR LOIASIS IN CAMEROON SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Tenaguem, Jean; Djeunga, Hugues Nana] Univ Yaounde 1, Filariasis Res Ctr, Yaounde, Cameroon. [Tenaguem, Jean; Wawo-Yonta, Edwine; Tatuene, Joseph Kamtchum; Kuaban, Christopher; Kamgno, Joseph] Univ Yaounde 1, Fac Med & Biomed Sci, Yaounde, Cameroon. [Fotsing, Raceline Ngounou; Djeunga, Hugues Nana] Univ Yaounde 1, Fac Sci, Yaounde, Cameroon. [Bopda, Jean] Filariasis Res Ctr, Yaounde, Cameroon. [Hopkins, Adrian] Mectizan Donat Program, Decatur, GA USA. [Nutman, Thomas B.] NIH, Helminth Immunol Sect, Bethesda, MD 20892 USA. [Boussinesq, Michel] Inst Rech Dev, Unite Mixte Rech 145, Montpellier, France. [Boussinesq, Michel] Univ Montpellier 1, Montpellier, France. [Klion, Amy] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RI Boussinesq, Michel/J-7256-2016 OI Boussinesq, Michel/0000-0001-6312-0681 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1330 BP 396 EP 397 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701697 ER PT J AU Dembele, B Coulibaly, YI Konate, S Dolo, H Coulibaly, SY Sanogo, D Soumaoro, L Coulibaly, ME Doumbia, SS Diallo, AA Traore, SF Keita, AD Nutman, TB Klion, AD AF Dembele, Benoit Coulibaly, Yaya I. Konate, Siaka Dolo, Housseini Coulibaly, Siaka Y. Sanogo, Dramane Soumaoro, Lamine Coulibaly, Michel E. Doumbia, Salif S. Diallo, Abdallah A. Traore, Sekou F. Keita, Adama D. Nutman, Thomas B. Klion, Amy D. TI HIGH DOSE BIANNUAL ALBENDAZOLE AND IVERMECTIN SUPPRESS WUCHERERIA BANCROFTI MICROFILARIAL LEVELS MORE EFFECTIVELY THAN STANDARD DOSE ANNUAL TREATMENT SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Dembele, Benoit; Coulibaly, Yaya I.; Konate, Siaka; Dolo, Housseini; Coulibaly, Siaka Y.; Sanogo, Dramane; Soumaoro, Lamine; Coulibaly, Michel E.; Doumbia, Salif S.; Diallo, Abdallah A.; Traore, Sekou F.] Univ Bamako, Bamako, Mali. [Keita, Adama D.] Hosp Point G, Bamako, Mali. [Nutman, Thomas B.; Klion, Amy D.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1332 BP 397 EP 397 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701699 ER PT J AU Grainger, J Hall, J Wohlfert, E Naik, S Belkaid, Y AF Grainger, John Hall, Jason Wohlfert, Elizabeth Naik, Shruti Belkaid, Yamine TI SYSTEMIC AND LOCAL CONTROL OF DENDRITIC CELL (DC) POPULATIONS DURING GUT-DWELLING HELMINTH INFECTION: INSIGHTS INTO LOCAL VERSUS BYSTANDER EFFECTS OF CHRONIC INFECTIONS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 59th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH) CY NOV 03-07, 2010 CL Atlanta, GA SP Amer Soc Trop Med & Hyg (ASTMH) C1 [Grainger, John; Hall, Jason; Wohlfert, Elizabeth; Naik, Shruti; Belkaid, Yamine] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2010 VL 83 IS 5 SU S MA 1339 BP 399 EP 399 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 832QF UT WOS:000295819701705 ER PT J AU Koroshetz, WJ AF Koroshetz, Walter J. CA NIH Task Force Res Emergency Setti TI NIH and Research in the Emergency Setting: Progress, Promise, and Process SO ANNALS OF EMERGENCY MEDICINE LA English DT Editorial Material C1 [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), NINDS, BG 31 RM 8A52 MSC 2540,31 Ctr Dr, Bethesda, MD 20892 USA. EM koroshetzw@ninds.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X NR 0 TC 3 Z9 3 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD NOV PY 2010 VL 56 IS 5 BP 565 EP 567 DI 10.1016/j.annemergmed.2010.04.021 PG 3 WC Emergency Medicine SC Emergency Medicine GA 681DY UT WOS:000284292800021 PM 21036296 ER PT J AU Costa, RB Kurra, G Greenberg, L Geyer, CE AF Costa, R. B. Kurra, G. Greenberg, L. Geyer, C. E. TI Efficacy and cardiac safety of adjuvant trastuzumab-based chemotherapy regimens for HER2-positive early breast cancer SO ANNALS OF ONCOLOGY LA English DT Review DE adjuvant; anthracyclines; breast cancer; cardiac dysfunction; HER2; trastuzumab ID METASTATIC BREAST; MONOCLONAL-ANTIBODY; DOXORUBICIN-CYCLOPHOSPHAMIDE; RANDOMIZED-TRIALS; PACLITAXEL; THERAPY; HER2; PLUS; DOCETAXEL; TAMOXIFEN AB Background: Trastuzumab-based adjuvant therapy has become the standard of care for human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (EBC). Both anthracycline- and non-anthracycline-containing trastuzumab regimens are approved in the United States, but cardiotoxicity is increased with anthracycline- containing regimens. Design: This paper reviews published and reported efficacy and cardiac safety data from the adjuvant trastuzumab trials [National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31/North Central Cancer Treatment Group (NCCTG) N9831, Breast Cancer International Research Group (BCIRG) 006, Herceptin Adjuvant (HERA), FinHer, and Programme Adjuvant Cancer Sein (PACS) 04]. Results: The addition of trastuzumab to adjuvant chemotherapy significantly improved disease-free survival (from 24% to 58%) in five of the six trials. Overall survival was significantly improved (23%-35%) in the large trials. In NSABP B-31/NCCTG N9831, 5.0%-6.6% of patients who received doxorubicin and cyclophosphamide (AC) were unable to receive trastuzumab. Cardiac event rate was highest in the anthracycline- containing trastuzumab arms (1.9%-3.8%) and lowest with the regimen of docetaxel, carboplatin, and trastuzumab (TCH) (0.4%). Conclusions: Incorporation of trastuzumab into anthracycline and non-anthracycline adjuvant chemotherapy regimens has substantially improved outcomes in HER2-postive EBC. The TCH regimen has the lowest rates of cardiac dysfunction, but uncertainty exists regarding the relative efficacy of TCH compared with anthracycline-containing trastuzumab regimens. Cardiac risk factor assessment can aid in selection of trastuzumab-based adjuvant therapy regimens. C1 [Costa, R. B.; Kurra, G.] Western Penn Hosp, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15224 USA. [Greenberg, L.; Geyer, C. E.] Allegheny Gen Hosp, Dept Oncol, Pittsburgh, PA 15212 USA. [Geyer, C. E.] Natl Surg Adjuvant Breast & Bowel Project Operat, Div Hematol Oncol, Pittsburgh, PA USA. RP Geyer, CE (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Allegheny Ctr 4, 5th Floor, Pittsburgh, PA 15212 USA. EM charles.geyer@nsabp.org NR 31 TC 38 Z9 44 U1 4 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2010 VL 21 IS 11 BP 2153 EP 2160 DI 10.1093/annonc/mdq096 PG 8 WC Oncology SC Oncology GA 673LF UT WOS:000283662800004 PM 20351072 ER PT J AU Smith, NF Mani, S Schuetz, EG Yasuda, K Sissung, TM Bates, SE Figg, WD Sparreboom, A AF Smith, Nicola F. Mani, Sridhar Schuetz, Erin G. Yasuda, Kazuto Sissung, Tristan M. Bates, Susan E. Figg, William D. Sparreboom, Alex TI Induction of CYP3A4 by Vinblastine: Role of the Nuclear Receptor NR1I2 SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE CYP3A4; induction; NR1I2 (PXR); vinblastine ID PREGNANE-X-RECEPTOR; VITAMIN-D-RECEPTOR; DRUG-INTERACTIONS; P-GLYCOPROTEIN; CYTOCHROME-P450 3A; HUMAN HEPATOCYTES; GENE-EXPRESSION; VINCA ALKALOIDS; CANCER-PATIENTS; CELL CARCINOMA AB BACKGROUND: Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2). OBJECTIVE: To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3). METHODS: Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than 1 occasion. Genotyping was conducted in CYP3A4, CYP3A5, and ABCB1 to rule out potential pharmacogenetic influences. Clinical data were followed-up by Western blotting and reporter assays in HepG2 and NIH3T3 cells treated with vinblastine over a dose range of 150-4800 ng/mL for 48 hours. RESULTS: In 6 patients with cancer, vinblastine increased the median (95% Cl) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 L/h (12.6 to 28.1) to 32.3 L/h (17.3 to 53.9) (p = 0.0156, Wilcoxon signed-rank test). No obvious effect of polymorphisms in CYP3A4, CYP3A5, and ABCB1 on midazolam clearance was observed. In vitro, vinblastine induced CYP3A4 protein. Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150-4800 ng/mL) weakly activated human and mouse full-length NR1I2, but had no influence on NR1I3. CONCLUSIONS: Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates. C1 [Smith, Nicola F.; Sissung, Tristan M.; Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, Bethesda, MD 20892 USA. [Mani, Sridhar] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Mani, Sridhar] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Yasuda, Kazuto] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Bates, Susan E.] NCI, Expt Therapeut Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Med Oncol Branch, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Damon Runyon Cancer Research Foundation [CI: 15-02] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by a grant from the Damon Runyon Cancer Research Foundation (CI: 15-02 to SM). NR 37 TC 11 Z9 15 U1 0 U2 2 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD NOV PY 2010 VL 44 IS 11 BP 1709 EP 1717 DI 10.1345/aph.1P354 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 679XX UT WOS:000284195200002 PM 20959500 ER PT J AU Bonmassar, L Fossile, E Scoppola, A Graziani, G Prete, SP Formica, V Cappelletti, D De Vecchis, L Cardillo, A Concolino, F D'Atri, S Balduzzi, A Torino, F Caporaso, P Greiner, JW Bonmassar, E Roselli, M Aquino, A AF Bonmassar, Laura Fossile, Emanuela Scoppola, Alessandro Graziani, Grazia Prete, Salvatore P. Formica, Vincenzo Cappelletti, Daniela De Vecchis, Liana Cardillo, Anna Concolino, Francesco D'Atri, Stefania Balduzzi, Alessandra Torino, Francesco Caporaso, Patrizia Greiner, Jack W. Bonmassar, Enzo Roselli, Mario Aquino, Angelo TI Detection of Circulating Tumor Cells Is Improved by Drug-induced Antigen Up-regulation: Preclinical and Clinical Studies SO ANTICANCER RESEARCH LA English DT Article DE Carcinoembryonic antigen; staurosporine; circulating tumor cells; immunomagnetic isolation; RT-PCR analysis ID METASTATIC COLORECTAL-CANCER; BONE-MARROW MICROMETASTASIS; RNA-POSITIVE CELLS; PERIPHERAL-BLOOD; CARCINOEMBRYONIC ANTIGEN; BREAST-CANCER; MESSENGER-RNA; RT-PCR; PROGNOSTIC-SIGNIFICANCE; MOLECULAR-DETECTION AB Cr-51-prelabelled colon cancer cells (simulating 'circulating tumor cells', CTCs) were added to human peripheral blood and exposed to staurosporine (ST) to increase carcinoembryonic antigen (CEA) expression. CTCs were captured with immunomagnetic beads coated with Ber-EP4 monoclonal antibody, recognizing the common epithelial antigen present in the majority of cancer cells of epithelial origin, with capture efficiency of more than 80%. Moreover, ST treatment increased CEA expression without compromising Ber-EP4 capture efficiency. In a pilot clinical study on 37 patients, CTCs were captured using Ber-EP4 beads, and recognized by RT-PCR set for CEA or cytokeratin-19 (CK) mRNA detection. The results showed that: (a) the percentage of CEA-positive CTCs (CTCCEA, 54.1%) was lower than that of CK-positive CTCs (CTCCK, 70.3%); (b) in vitro ST treatment converted a significant number of CTCCEA-negative into CTCCEA-positive cases. Therefore, immunomagnetic capture combined with exposure to ST provides a feasible and sensitive technique for the detection of functionally-active CTCs responsive to ST-mediated CEA up-regulation. C1 [Graziani, Grazia; Prete, Salvatore P.; Cappelletti, Daniela; De Vecchis, Liana; Bonmassar, Enzo; Aquino, Angelo] Univ Roma Tor Vergata, Dept Neurosci, I-00133 Rome, Italy. [Bonmassar, Laura; D'Atri, Stefania; Caporaso, Patrizia] Ist Dermopat Immacolata IRCCS, Mol Oncol Lab, I-00167 Rome, Italy. [Scoppola, Alessandro; Concolino, Francesco] Ist Dermopat Immacolata IRCCS, Div Oncol, I-00167 Rome, Italy. [Fossile, Emanuela; Formica, Vincenzo; Roselli, Mario] Univ Rome, Med Oncol Unit, Tor Vergata Clin Ctr, I-00133 Rome, Italy. [Cardillo, Anna; Balduzzi, Alessandra] European Inst Oncol, Res Unit Med Senol, I-20141 Milan, Italy. [Torino, Francesco] San Filippo Neri Hosp, Div Med Oncol, I-00135 Rome, Italy. [Bonmassar, Enzo] State Univ Milan, Dept Pharmacol, Sch Med, I-20129 Milan, Italy. [Greiner, Jack W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aquino, A (reprint author), Univ Roma Tor Vergata, Dept Neurosci, Via Montpellier 1, I-00133 Rome, Italy. EM angelo.aquino@uniroma2.it RI Graziani, Grazia/G-5747-2012; OI D'Atri, Stefania/0000-0001-9852-7377; GRAZIANI, GRAZIA/0000-0002-0221-768X FU 'Lega Italiana per la lotta contro i tumori' (Research Unit, Enzo Bonmassar); Italian Ministry of University; Italian Ministry of Labour, Health and Social Policies; MIUR (Research Unit: Angelo Aquino) FX This work was supported in part by a grant from the 'Lega Italiana per la lotta contro i tumori' (Research Unit, Enzo Bonmassar), in part by 'Programma Nazionale di Ricerca', Oncology project (task 12), Italian Ministry of University and Scientific and Technological Research, in part by the Italian Ministry of Labour, Health and Social Policies and in part by 'Programma di Ricerca Scientifica di rilevante interesse Nazionale' MIUR-2008 (Research Unit: Angelo Aquino). NR 42 TC 2 Z9 2 U1 0 U2 1 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 J9 ANTICANCER RES JI Anticancer Res. PD NOV PY 2010 VL 30 IS 11 BP 4721 EP 4730 PG 10 WC Oncology SC Oncology GA 693PX UT WOS:000285237100048 PM 21115931 ER PT J AU Jiang, ZG Cohen, J Marshall, LJ Major, EO AF Jiang, Zhi-Gang Cohen, Jeffrey Marshall, Leslie J. Major, Eugene O. TI Hexadecyloxypropyl-Cidofovir (CMX001) Suppresses JC Virus Replication in Human Fetal Brain SVG Cell Cultures SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; ACYCLIC NUCLEOSIDE PHOSPHONATES; PROGENITOR CELLS; GLIAL-CELLS; IN-VITRO; INFECTION; AIDS; PATIENT; DNA; MULTIPLICATION AB JC virus (JCV) is a polyomavirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegalovirus infection in hematopoietic stem cell transplant recipients and of BK virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 mu M and 0.1 mu M. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients. C1 [Jiang, Zhi-Gang; Marshall, Leslie J.; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Cohen, Jeffrey] NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, 10 Ctr Dr,Bldg 10,Room 3B14,MSC 1296, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke FX This research was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Neurological Disorders and Stroke. NR 45 TC 20 Z9 20 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2010 VL 54 IS 11 BP 4723 EP 4732 DI 10.1128/AAC.00837-10 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 679IL UT WOS:000284155000029 PM 20823288 ER PT J AU Hope, WW Petraitis, V Petraitiene, R Aghamolla, T Bacher, J Walsh, TJ AF Hope, William W. Petraitis, Vidmantas Petraitiene, Ruta Aghamolla, Tamarra Bacher, John Walsh, Thomas J. TI The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology, Comparative Kinetics of Galactomannan and (1 -> 3)-beta-D-Glucan, and Consequences of Delayed Antifungal Therapy SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID AMPHOTERICIN-B; INTRAPULMONARY PHARMACOKINETICS; CANDIDA-ALBICANS; INFECTION; SERUM; FORMULATIONS; NEUTROPENIA; FLUCONAZOLE; COMBINATION; MORTALITY AB Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1 -> 3)-beta-D-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1 -> 3)-beta-D-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1 -> 3)-beta-D-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1 -> 3)-beta-D-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at >= 48 h postinoculation is associated with suboptimal therapeutic outcomes. C1 [Hope, William W.] Univ Manchester, Univ Hosp S Manchester NHS Fdn Trust, NIHR Translat Res Facil Resp Med, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Hope, William W.; Petraitis, Vidmantas; Petraitiene, Ruta; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Petraitis, Vidmantas; Petraitiene, Ruta; Aghamolla, Tamarra] SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD USA. [Petraitis, Vidmantas; Petraitiene, Ruta; Walsh, Thomas J.] Cornell Univ, Transplantat Oncol Infect Dis Program, Div Infect Dis, Weill Cornell Med Coll, New York, NY 10021 USA. [Bacher, John] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Hope, WW (reprint author), 1-800 Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM william.hope@manchester.ac.uk OI Hope, William/0000-0001-6187-878X FU National Institutes of Health; National Cancer Institute, National Institutes of Health FX W.H. is supported by a National Institutes of Health Clinician Scientist Fellowship. This study was supported by the intramural program of the National Cancer Institute, National Institutes of Health. NR 23 TC 34 Z9 37 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2010 VL 54 IS 11 BP 4879 EP 4886 DI 10.1128/AAC.00673-10 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 679IL UT WOS:000284155000048 PM 20713673 ER PT J AU Joo, HS Chan, JL Cheung, GYC Otto, M AF Joo, Hwang-Soo Chan, June L. Cheung, Gordon Y. C. Otto, Michael TI Subinhibitory Concentrations of Protein Synthesis-Inhibiting Antibiotics Promote Increased Expression of the agr Virulence Regulator and Production of Phenol-Soluble Modulin Cytolysins in Community-Associated Methicillin-Resistant Staphylococcus aureus SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID GENE; IDENTIFICATION; EVOLUTION; SEQUENCE; USA300; CLONE AB Tetracycline, clindamycin, and other protein synthesis inhibitors at subinhibitory concentrations significantly increased the expression of the pivotal virulence regulator agr and production of the agr-regulated cytolytic phenol-soluble modulins in the community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300. Our results suggest that such protein synthesis inhibitors may exacerbate the progression of CA-MRSA disease when applied at concentrations that are too low or when treating infections caused by strains resistant to those antibiotics. C1 [Joo, Hwang-Soo; Chan, June L.; Cheung, Gordon Y. C.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012; OI JOO, HWANG-SOO/0000-0003-4668-3225 FU National Institute of Allergy and Infectious Diseases (NIAID); U.S. National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). NR 14 TC 23 Z9 24 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2010 VL 54 IS 11 BP 4942 EP 4944 DI 10.1128/AAC.00064-10 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 679IL UT WOS:000284155000064 PM 20713669 ER PT J AU Bray, M Di Mascio, M de Kok-Mercado, F Mollura, DJ Jagoda, E AF Bray, Mike Di Mascio, Michele de Kok-Mercado, Fabian Mollura, Daniel J. Jagoda, Elaine TI Radio labeled antiviral drugs and antibodies as virus-specific imaging probes SO ANTIVIRAL RESEARCH LA English DT Review DE Antiviral therapy; Infectious disease imaging; Single-photon emission computed tomography; Positron emission tomography; Radiopharmaceuticals ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; REPORTER GENE-EXPRESSION; SODIUM-IODIDE SYMPORTER; IN-VIVO; RECEPTOR-BINDING; RADIOLABELED ANTIBODIES; HEALTHY-VOLUNTEERS; THYMIDINE KINASES AB A number of small-molecule drugs inhibit viral replication by binding directly to virion structural proteins or to the active site of a viral enzyme, or are chemically modified by a viral enzyme before inhibiting a downstream process. Similarly, antibodies used to prevent or treat viral infections attach to epitopes on virions or on viral proteins expressed on the surface of infected cells. Such drugs and antibodies can therefore be thought of as probes for the detection of viral infections, suggesting that they might be used as radiolabeled tracers to visualize sites of viral replication by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. A current example of this approach is the PET imaging of herpes simplex virus infections, in which the viral thymidine kinase phosphorylates radiolabeled thymidine analogues, trapping them within infected cells. One of many possible future applications might be the use of a radiolabeled hepatitis C protease inhibitor to image infection in animals or humans and provide a quantitative measure of viral burden. This article reviews the basic features of radionuclide imaging and the characteristics of ideal tracer molecules, and discusses how antiviral drugs and antibodies could be evaluated for their suitability as virus-specific imaging probes. The use of labeled drugs as low-dose tracers would provide an alternative application for compounds that have failed to advance to clinical use because of insufficient in vivo potency, an unsuitable pharmacokinetic profile or hepato- or nephrotoxicity. Published by Elsevier B.V. C1 [Bray, Mike; de Kok-Mercado, Fabian] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. [Di Mascio, Michele] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Jagoda, Elaine] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Integrated Res Facil, NIH, 8200 Res Plaza, Ft Detrick, MD 21702 USA. EM mbray@niaid.nih.gov NR 104 TC 8 Z9 8 U1 1 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD NOV PY 2010 VL 88 IS 2 BP 129 EP 142 DI 10.1016/j.antiviral.2010.08.005 PG 14 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 686ER UT WOS:000284680100001 PM 20709111 ER PT J AU Hayes, BM Jewett, MW Rosa, PA AF Hayes, Beth M. Jewett, Mollie W. Rosa, Patricia A. TI lacZ Reporter System for Use in Borrelia burgdorferi SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; CIRCULAR PLASMID; GENE-EXPRESSION; OSPC OPERATOR; OUTER SURFACE; TRANSFORMATION; PROMOTERS; PROTEINS; RPOS; IDENTIFICATION AB Regulation of gene expression is critical for the ability of Borrelia burgdorferi to adapt to different environments during its natural infectious cycle. Reporter genes have been used successfully to study gene regulation in multiple organisms. We have introduced a lacZ gene into B. burgdorferi, and we show that B. burgdorferi produces a protein with detectable beta-galactosidase activity in both liquid and solid media when lacZ is expressed from a constitutive promoter. Furthermore, when lacZ is expressed from the ospC promoter, beta-galactosidase activity is detected only in B. burgdorferi clones that express ospC, and it accurately monitors endogenous gene expression. The addition of lacZ to the repertoire of genetic tools available for use in B. burgdorferi should contribute to a better understanding of how B. burgdorferi gene expression is regulated during the infectious cycle. C1 [Hayes, Beth M.; Jewett, Mollie W.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hayes, BM (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM hayesb@niaid.nih.gov FU NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 40 TC 4 Z9 4 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD NOV PY 2010 VL 76 IS 22 BP 7407 EP 7412 DI 10.1128/AEM.01389-10 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 675PX UT WOS:000283843900005 PM 20851957 ER PT J AU Son, YJ Bae, JY Chong, SH Lee, HS Mo, SH Kim, TY Choe, H AF Son, Young-Jin Bae, Ji-Young Chong, Seon-Ha Lee, Hui Sun Mo, Sang Hyun Kim, Tae Yoon Choe, Han TI Expression, High Cell Density Culture and Purification of Recombinant EC-SOD in Escherichia coli SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE rEC-SOD; Fermentation; Refolding; Purification; MALDI-TOF ID EXTRACELLULAR-SUPEROXIDE-DISMUTASE; HEPARIN-BINDING DOMAIN; N-TERMINAL DOMAIN; YIELD; GENE; LUNG; INFLAMMATION; HYPEROXIA; COLLAGEN; YEAST AB Superoxide dismutase (SOD) catalyzes the dismutation of the biologically toxic superoxide anion into oxygen and hydrogen peroxide and is deployed by the immune system to kill invading microorganisms. Extracellular SOD (EC-SOD) is a copper- and zinc-containing glycoprotein found predominantly in the soluble extracellular compartment that consists of similar to 30-kDa subunits. Here, we purified recombinant EC-SOD3 (rEC-SOD) from Escherichia coli BL21(DE3) expressing a pET-SOD3-1 construct. Cells were cultured by high-density fed-batch fermentation to a final OD(600) of 51.8, yielding a final dry cell weight of 17.6 g/L. rEC-SOD, which was expressed as an inclusion body, comprised 48.7% of total protein. rEC-SOD was refolded by a simple dilution refolding method and purified by cation-exchange and reverse-phase chromatography. The highly purified rEC-SOD thus obtained was a mixture of monomers and dimers, both of which were active. The molecular weights of monomeric and dimeric rEC-SOD were 25,255 and 50,514 Da, respectively. The purified rEC-SOD had 4.3 EU/mg of endotoxin and the solubility of rEC-SOD was more than 80% between pH 7 and 10. In 2 L of fed-batch fermentation, 60 mg of EC-SOD (99.9% purity) could be produced and total activity was 330.24 U. The process established in this report, involving high-cell-density fermentation, simple dilution refolding, and purification with ion-exchange and reverse-phase chromatography, represents a commercially viable process for producing rEC-SOD. C1 [Son, Young-Jin; Bae, Ji-Young; Chong, Seon-Ha; Lee, Hui Sun; Choe, Han] Univ Ulsan, Coll Med, Dept Physiol, Seoul 138736, South Korea. [Son, Young-Jin; Bae, Ji-Young; Chong, Seon-Ha; Lee, Hui Sun; Choe, Han] Univ Ulsan, Coll Med, Res Inst Biomacromol, Seoul 138736, South Korea. [Mo, Sang Hyun] Nanomol Co Ltd, Seoul 137130, South Korea. [Kim, Tae Yoon] Catholic Univ Korea, Lab Dermatoimmunol, Coll Med, Seoul 130701, South Korea. [Son, Young-Jin] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. RP Choe, H (reprint author), Univ Ulsan, Coll Med, Dept Physiol, 388-1,PoongNap Dong, Seoul 138736, South Korea. EM hchoe@amc.seoul.kr RI choe, han/A-5679-2010 OI choe, han/0000-0003-4604-647X FU Priority Research Center [2009-009454]; Ministry of Education, Science and Technology [2009-0075362] FX This work was supported by Priority Research Center Program (2009-009454) and a grant (2009-0075362) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology. NR 40 TC 8 Z9 9 U1 11 U2 19 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD NOV PY 2010 VL 162 IS 6 BP 1585 EP 1598 DI 10.1007/s12010-010-8940-1 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 644PL UT WOS:000281391800008 PM 20467833 ER PT J AU Victor, TA Furey, ML Fromm, SJ Ohman, A Drevets, WC AF Victor, Teresa A. Furey, Maura L. Fromm, Stephen J. Ohman, Arne Drevets, Wayne C. TI Relationship Between Amygdala Responses to Masked Faces and Mood State and Treatment in Major Depressive Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID EMOTIONAL FACIAL EXPRESSIONS; ANTIDEPRESSANT TREATMENT; NEURAL RESPONSE; INFORMATION; BIAS; FEAR; SAD; PERFORMANCE; INVENTORY; ATTENTION AB Context: Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence of mood-congruent processing biases toward explicitly presented, emotionally valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli. Objective: To investigate differential amygdala responses to sad, happy, and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated participants with MDD and healthy controls (HCs). Design: Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging. Setting: Psychiatric outpatient clinic at the National Institute of Mental Health. Participants: We studied 22 unmedicated, currently depressed people with MDD (dMDD), 16 unmedicated individuals with MDD in full remission (rMDD), and 25 HCs. Intervention: Ten dMDD participants underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor sertraline hydrochloride. Main Outcome Measures: Amygdala region-of-interest and whole-brain analyses evaluated the hemodynamic response during exposure to masked sad vs masked happy faces, to masked sad vs neutral faces, and to masked happy vs neutral faces. Results: The dMDD participants showed greater amygdala responses than HCs to masked sad faces, whereas HCs showed greater amygdala responses to masked happy faces. The bias toward sad faces also was evident in rMDD participants relative to HCs and did not differ between dMDD and rMDD participants. This processing bias reversed toward the normative pattern in dMDD participants after sertraline treatment. Conclusions: Emotional-processing biases occur in amygdala responses to sad faces presented below the level of conscious awareness in dMDD or rMDD individuals and to happy faces in HCs. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in patients with MDD during selective serotonin reuptake inhibitor treatment. C1 [Drevets, Wayne C.] Univ Oklahoma, Sch Community Med, Laureate Inst Brain Res, Dept Psychiat, Tulsa, OK 74136 USA. [Victor, Teresa A.; Furey, Maura L.; Fromm, Stephen J.; Drevets, Wayne C.] NIMH, NIH, Bethesda, MD 20892 USA. [Victor, Teresa A.; Ohman, Arne] Karolinska Inst, Stockholm, Sweden. RP Drevets, WC (reprint author), Univ Oklahoma, Sch Community Med, Laureate Inst Brain Res, Dept Psychiat, 6655 S Yale Ave, Tulsa, OK 74136 USA. EM wdrevets@laureateinstitute.org RI Furey, Maura/H-5273-2013 FU National Institutes of Health (NIH), National Institute of Mental Health (NIMH) [Z01-MH002792] FX This research was supported by grant Z01-MH002792 from the Intra-mural Program of the National Institutes of Health (NIH), National Institute of Mental Health (NIMH). NR 54 TC 166 Z9 171 U1 5 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD NOV PY 2010 VL 67 IS 11 BP 1128 EP 1138 PG 11 WC Psychiatry SC Psychiatry GA 674JP UT WOS:000283737500009 PM 21041614 ER PT J AU Robinson, TN Matheson, DM Kraemer, HC Wilson, DM Obarzanek, E Thompson, NS Alhassan, S Spencer, TR Haydel, KF Fujimoto, M Varady, A Killen, JD AF Robinson, Thomas N. Matheson, Donna M. Kraemer, Helena C. Wilson, Darrell M. Obarzanek, Eva Thompson, Nikko S. Alhassan, Sofiya Spencer, Tirzah R. Haydel, K. Farish Fujimoto, Michelle Varady, Ann Killen, Joel D. TI A Randomized Controlled Trial of Culturally Tailored Dance and Reducing Screen Time to Prevent Weight Gain in Low- Income African American Girls SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID BODY-MASS INDEX; HEALTH ENRICHMENT MULTISITE; ADOLESCENT GIRLS; RISK-FACTORS; US CHILDREN; OBESITY; TELEVISION; OVERWEIGHT; MODERATORS; GEMS AB Objective: To test a 2-year community-and family-based obesity prevention program for low-income African American girls: Stanford GEMS (Girls' health Enrichment Multi-site Studies). Design: Randomized controlled trial with follow-up measures scheduled at 6, 12, 18, and 24 months. Setting: Low-income areas of Oakland, California. Participants: African American girls aged 8 to 10 years (N=261) and their parents or guardians. Interventions: Families were randomized to one of two 2-year, culturally tailored interventions: (1) after-school hip-hop, African, and step dance classes and a home/family-based intervention to reduce screen media use or (2) information-based health education. Main Outcome Measure: Changes in body mass index (BMI). Results: Changes in BMI did not differ between groups (adjusted mean difference [95% confidence interval] = 0.04 [-0.18 to 0.27] per year). Among secondary outcomes, fasting total cholesterol level (adjusted mean difference, -3.49 [95% confidence interval, -5.28 to -1.70] mg/dL per year), low-density lipoprotein cholesterol level (-3.02 [-4.74 to -1.31] mg/dL per year), incidence of hyperinsulinemia (relative risk, 0.35 [0.13 to 0.93]), and depressive symptoms (-0.21 [-0.42 to -0.001] per year) decreased more among girls in the dance and screen time reduction intervention. In exploratory moderator analysis, the dance and screen time reduction intervention slowed BMI gain more than health education among girls who watched more television at baseline (P=.02) and/or those whose parents or guardians were unmarried (P=.01). Conclusions: A culturally tailored after-school dance and screen time reduction intervention for low-income, pre-adolescent African American girls did not significantly reduce BMI gain compared with health education but did produce potentially clinically important reductions in lipid levels, hyperinsulinemia, and depressive symptoms. There was also evidence for greater effectiveness in high-risk subgroups of girls. C1 [Robinson, Thomas N.] Stanford Univ, Sch Med, Div Gen Pediat, Stanford, CA 94305 USA. [Wilson, Darrell M.] Stanford Univ, Sch Med, Div Pediat Endocrinol, Stanford, CA 94305 USA. [Kraemer, Helena C.] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Kraemer, Helena C.] Stanford Univ, Sch Med, Div Biostat, Dept Psychiat & Behav Med, Stanford, CA 94305 USA. [Robinson, Thomas N.; Matheson, Donna M.; Thompson, Nikko S.; Alhassan, Sofiya; Spencer, Tirzah R.; Haydel, K. Farish; Fujimoto, Michelle; Varady, Ann; Killen, Joel D.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Obarzanek, Eva] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Robinson, TN (reprint author), Stanford Univ, Sch Med, Div Gen Pediat, 1070 Arastradero Rd,Ste 300, Palo Alto, CA 94304 USA. EM tom.robinson@stanford.edu FU NHLBI, National Institutes of Health [UO1 HL62663] FX This research was funded by cooperative agreement UO1 HL62663 from the NHLBI, National Institutes of Health. NR 62 TC 66 Z9 66 U1 3 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD NOV PY 2010 VL 164 IS 11 BP 995 EP 1004 PG 10 WC Pediatrics SC Pediatrics GA 674JB UT WOS:000283735700006 PM 21041592 ER PT J AU Klesges, RC Obarzanek, E Kumanyika, S Murray, DM Klesges, LM Relyea, GE Stockton, MB Lanctot, JQ Beech, BM McClanahan, BS Sherrill-Mittleman, D Slawson, DL AF Klesges, Robert C. Obarzanek, Eva Kumanyika, Shiriki Murray, David M. Klesges, Lisa M. Relyea, George E. Stockton, Michelle B. Lanctot, Jennifer Q. Beech, Bettina M. McClanahan, Barbara S. Sherrill-Mittleman, Deborah Slawson, Deborah L. TI The Memphis Girls' health Enrichment Multi-site Studies (GEMS) SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; CHILDHOOD OBESITY; ADOLESCENT GIRLS; BASE-LINE; PREVENTION; CHILDREN; OVERWEIGHT; INTERVENTIONS; PREVALENCE AB Objective: To determine the efficacy of a 2-year obesity prevention program in African American girls. Design: Memphis GEMS(Girls' health Enrichment Multi-site Studies) was a controlled trial in which girls were randomly assigned to an obesity prevention program or alternative intervention. Setting: Local community centers and YWCAs (Young Women's Christian Associations) in Memphis, Tennessee. Participants: Girls aged 8 to 10 years(N=303) who were identified by a parent or guardian as African American and who had a body mass index (BMI) at or higher than the 25th percentile for age or 1 parent with a BMI of 25 or higher. Interventions: Group behavioral counseling to promote healthy eating and increased physical activity (obesity prevention program) or self-esteem and social efficacy (alternative intervention). Main Outcome Measure: The BMI at 2 years. Results: The BMI increased in all girls with no treatment effect (obesity prevention minus alternative intervention) at 2 years (mean, 0.09; 95% confidence interval [CI], -0.40 to 0.58). Two-year treatment effects in the expected direction were observed for servings per day of sweetened beverages (mean, -0.19; 95% CI, -0.39 to 0.09), water (mean, 0.21; 95% CI, 0.03 to 0.40), and vegetables (mean, 0.15; 95% CI,-0.02 to 0.30), but there were no effects on physical activity. Post hoc analyses suggested a treatment effect in younger girls (P for interaction=.08). The mean BMI difference at 2 years was -2.41 (95% CI, -4.83 to 0.02) in girls initially aged 8 years and -1.02 (95% CI, -2.31 to 0.27) in those initially aged 10 years. Conclusions: The lack of significant BMI change at 2 years indicates that this intervention alone is insufficient for obesity prevention. Effectiveness may require more explicit behavior change goals and a stronger physical activity component as well as supportive changes in environmental contexts. C1 [Klesges, Robert C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38105 USA. [Klesges, Robert C.; Lanctot, Jennifer Q.; Sherrill-Mittleman, Deborah] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Klesges, Robert C.; Relyea, George E.] Univ Memphis, Sch Publ Hlth, Memphis, TN 38152 USA. [Stockton, Michelle B.; McClanahan, Barbara S.] Dept Hlth & Sport Sci, Memphis, TN USA. [Obarzanek, Eva] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Kumanyika, Shiriki] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Murray, David M.] Ohio State Univ, Dept Epidemiol, Columbus, OH 43210 USA. [Beech, Bettina M.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Slawson, Deborah L.] E Tennessee State Univ, Dept Family & Consumer Sci, Johnson City, TN 37614 USA. RP Klesges, RC (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, 66 N Pauline St,Ste 633, Memphis, TN 38105 USA. EM Bob.Klesges@STJUDE.ORG FU National Heart, Lung, and Blood Institute, National Institutes of Health [HL62662, HL62663] FX This study was supported by cooperative agreements HL62662 and HL62663 from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 43 TC 40 Z9 40 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD NOV PY 2010 VL 164 IS 11 BP 1007 EP 1014 PG 8 WC Pediatrics SC Pediatrics GA 674JB UT WOS:000283735700007 PM 21041593 ER PT J AU Buckley, AW Rodriguez, AJ Jennison, K Buckley, J Thurm, A Sato, S Swedo, S AF Buckley, Ashura Williams Rodriguez, Alcibiades J. Jennison, Kaitlin Buckley, Jack Thurm, Audrey Sato, Susumu Swedo, Susan TI Rapid Eye Movement Sleep Percentage in Children With Autism Compared With Children With Developmental Delay and Typical Development SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID LONG-TERM POTENTIATION; REM-SLEEP; SPECTRUM DISORDERS; BASAL FOREBRAIN; ABNORMALITIES; DEPRIVATION; RATS; EXPRESSION; PLASTICITY; PATTERNS AB Objective: To compare objective polysomnographic parameters between 3 cohorts: children with autism, typical development, and developmental delay without autism. Design: Overnight polysomnographic recordings were scored for sleep architecture according to American Academy of Sleep Medicine criteria by a board-certified sleep medicine specialist blind to diagnosis for studies collected between July 2006 and September 2009. Setting: Subjects were evaluated in the pediatric ward in the Clinical Research Center of the National Institutes of Health. Participants: First 60 consecutive children with autism, 15 with typical development, and 13 with developmental delay matched for nonverbal IQ to the autism group, ranging in age from 2 to 13 years, selected without regard to the presence or absence of sleep problem behavior. Main Outcome Measures: Total sleep time, latencies to non-rapid eye movement (REM) and REM sleep, and percentages of total sleep time for stages 1 and 2 sleep, slow-wave sleep, and REM sleep. Results: There were no differences between the typical vs developmental delay groups. Comparison of children with autism vs typical children revealed shorter total sleep time (P=.004), greater slow-wave sleep percentage (P=.001), and much smaller REM sleep percentage (14.5% vs 22.6%; P<.001). Comparison of children with autism vs children with developmental delay revealed shorter total sleep time (P=.001), greater stage 1 sleep percentage (P<.001), greater slow-wave sleep percentage (P<.001), and much less REM sleep percentage (14.5% v 25%; P<.001). Conclusion: A relative deficiency of REM sleep may indicate an abnormality in neural organization in young children with autism that is not directly associated with or related to inherent intellectual disability but may serve as a window into understanding core neurotransmitter abnormalities unique to this disorder. C1 [Buckley, Ashura Williams; Jennison, Kaitlin; Thurm, Audrey; Swedo, Susan] NIMH, Bethesda, MD 20892 USA. [Sato, Susumu] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Buckley, Ashura Williams; Rodriguez, Alcibiades J.; Buckley, Jack] NYU, New York, NY USA. RP Buckley, AW (reprint author), NIMH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM ashura.buckley@gmail.com FU National Institutes of Health FX All research was funded by the National Institutes of Health intramural research program. NR 49 TC 25 Z9 25 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD NOV PY 2010 VL 164 IS 11 BP 1032 EP 1037 PG 6 WC Pediatrics SC Pediatrics GA 674JB UT WOS:000283735700010 PM 21041596 ER PT J AU Meert, KL Donaldson, AE Newth, CJL Harrison, R Berger, J Zimmerman, J Anand, KJS Carcillo, J Dean, JM Willson, DF Nicholson, C Shear, K AF Meert, Kathleen L. Donaldson, Amy E. Newth, Christopher J. L. Harrison, Rick Berger, John Zimmerman, Jerry Anand, K. J. S. Carcillo, Joseph Dean, J. Michael Willson, Douglas F. Nicholson, Carol Shear, Katherine CA Eunice Kennedy Shriver Natl Inst TI Complicated Grief and Associated Risk Factors Among Parents Following a Child's Death in the Pediatric Intensive Care Unit SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID SOCIAL SUPPORT; PSYCHOLOGICAL ADJUSTMENT; PSYCHIATRIC-DISORDERS; BEREAVED SPOUSES; MARITAL QUALITY; TRAUMATIC GRIEF; OLDER-ADULTS; ATTACHMENT; PREDICTORS; SYMPTOMS AB Objective: To investigate the extent of complicated grief symptoms and associated risk factors among parents whose child died in a pediatric intensive care unit. Design: Cross-sectional survey conducted by mail and telephone. Setting: Seven children's hospitals affiliated with the Collaborative Pediatric Critical Care Research Network from January 1, 2006, to June 30, 2008. Participants: Two hundred sixty-one parents from 872 families whose child died in a pediatric intensive care unit 6 months earlier. Main Exposure: Assessment of potential risk factors, including demographic and clinical variables, and parent psychosocial characteristics, such as attachment style, caregiving style, grief avoidance, and social support. Main Outcome Measure: Parent report of complicated grief symptoms using the Inventory of Complicated Grief. Total scale range is from 0 to 76; scores of 30 or higher suggest complicated grief. Results: Mean (SD) Inventory of Complicated Grief scores among parents were 33.7 (14.1). Fifty-nine percent of parents (95% confidence interval, 53%-65%) had scores of 30 or higher. Variables independently associated with higher symptom scores in multivariable analysis included being the biological mother or female guardian, trauma as the cause of death, greater attachment-related anxiety and attachment related avoidance, and greater grief avoidance. Conclusions: Parents who responded to our survey experienced a high level of complicated grief symptoms 6 months after their child's death in the pediatric intensive care unit. However, our estimate of the extent of complicated grief symptoms may be biased because of a high number of nonresponders. Better understanding of complicated grief and its risk factors among parents will allow those most vulnerable to receive professional bereavement support. C1 [Meert, Kathleen L.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Donaldson, Amy E.; Dean, J. Michael] Univ Utah, Salt Lake City, UT USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, Rick] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Berger, John] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Anand, K. J. S.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Willson, Douglas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] NICHHD, Rockville, MD USA. [Shear, Katherine] Columbia Univ, New York, NY USA. RP Meert, KL (reprint author), Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM kmeert@med.wayne.edu OI Anand, Kanwaljeet/0000-0001-6498-1483 FU National Institute of Child Health and Human Development [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, U01HD049934]; Department of Health and Human Services FX The study was funded by cooperative agreements U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, and U01HD049934 from the National Institute of Child Health and Human Development and the Department of Health and Human Services. NR 44 TC 27 Z9 28 U1 3 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1072-4710 EI 1538-3628 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD NOV PY 2010 VL 164 IS 11 BP 1045 EP 1051 PG 7 WC Pediatrics SC Pediatrics GA 674JB UT WOS:000283735700012 PM 21041597 ER PT J AU Thurmond, VA Hicks, R Gleason, T Miller, AC Szuflita, N Orman, J Schwab, K AF Thurmond, Veronica A. Hicks, Ramona Gleason, Theresa Miller, A. Cate Szuflita, Nicholas Orman, Jean Schwab, Karen TI Advancing Integrated Research in Psychological Health and Traumatic Brain Injury: Common Data Elements SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Analysis, demographics; Biomarkers; Brain injuries, traumatic; Outcome measures; Rehabilitation; Stress disorders, posttraumatic ID IRAQ AB In civilian, military, and veteran populations, there is increased recognition of the interrelationship between traumatic brain injury (TBI) and some psychological health (PH) disorders and the need to better understand the relationships by integrating research for these topics. The use of different measures to assess similar study variables and/or assess outcomes may limit important advances in PH and TBI research. Without a set of common data elements (CDEs; to include variable definitions and recommended measures for the purpose of this discussion), comparison of findings across studies is challenging. The federal agencies involved in PH and TBI research, the National Institute of Neurological Disorders and Stroke, Department of Veterans Affairs, National Institute on Disability and Rehabilitation Research, Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, and Defense and Veterans Brain Injury Center, therefore cosponsored a scientific initiative to develop CDEs for PH and TBI research. Scientific experts were invited to participate in 1 of 8 working groups to develop recommendations for specific topic-driven CDEs. Draft recommendations were presented and discussed in the workshop "Advancing Integrated Research in Psychological Health and Traumatic Brain Injury: Common Data Elements (CDE)" held on March 23-24, 2009, in Silver Spring, MD. The overall process leading to the workshop and subsequent recommendations by the working groups are presented in this article. Topic-driven recommendations for CDEs are presented in individual reports in this edition. C1 [Hicks, Ramona] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Gleason, Theresa; Orman, Jean] Dept Vet Affairs, Washington, DC USA. [Miller, A. Cate] Natl Inst Disabil & Rehabil Res, US Dept Educ, Washington, DC USA. [Schwab, Karen] Walter Reed Army Med Ctr, Def & Vet Brain Injury Ctr, Washington, DC 20307 USA. [Thurmond, Veronica A.; Szuflita, Nicholas] Def Ctr Excellence PH TBI, Silver Spring, MD 20910 USA. RP Thurmond, VA (reprint author), Def Ctr Excellence PH TBI, 1335 East West Highway, Silver Spring, MD 20910 USA. EM veronica.thurmond@us.anny.mil NR 7 TC 32 Z9 32 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2010 VL 91 IS 11 BP 1633 EP 1636 DI 10.1016/j.apmr.2010.06.034 PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681UQ UT WOS:000284346400001 PM 21044705 ER PT J AU Duhaime, AC Gean, AD Haacke, EM Hicks, R Wintermark, M Mukherjee, P Brody, D Latour, L Riedy, G AF Duhaime, Ann-Christine Gean, Alisa D. Haacke, E. Mark Hicks, Ramona Wintermark, Max Mukherjee, Pratik Brody, David Latour, Lawrence Riedy, Gerard CA Common Data Elements Neuroimaging Pediat Working Grp Members TI Common Data Elements in Radiologic Imaging of Traumatic Brain Injury SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Clinical research; Clinical trials; Database; Head injury; Magnetic resonance imaging; Radiology; Rehabilitation; Traumatic brain injury ID DIFFUSE AXONAL INJURY; HEAD-INJURY; CLASSIFICATION; MICROBLEEDS; CHILDREN; VOLUME; MILD AB Radio logic brain imaging is the most useful means of visualizing and categorizing the location, nature, and degree of damage to the central nervous system sustained by patients with traumatic brain injury (TBI). In addition to determining acute patient management and prognosis, imaging is crucial for the characterization and classification of injuries for natural history studies and clinical trials. This article is the initial result of a workshop convened by multiple national health care agencies in March 2009 to begin to make recommendations for potential data elements dealing with specific radiologic features and definitions needed to characterize injuries, as well as specific techniques and parameters needed to optimize radiologic data acquisition. The neuroimaging work group included professionals with expertise in basic imaging research and physics, clinical neuroradiology, neurosurgery, neurology, physiatry, psychiatry, TBI research, and research database formation. This article outlines the rationale and overview of their specific recommendations. In addition, we review the contributions of various imaging modalities to the understanding of TBI and the general principles needed for database flexibility and evolution over time to accommodate technical advances. C1 [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gean, Alisa D.] San Francisco Gen Hosp, Dept Radiol, Brain & Spinal Cord Injury Ctr, San Francisco, CA 94110 USA. [Haacke, E. Mark] Wayne State Univ, Dept Biomed Engn, Detroit, MI USA. [Hicks, Ramona] NIH, Repair & Plast Program, Bethesda, MD 20892 USA. [Wintermark, Max; Mukherjee, Pratik] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Mukherjee, Pratik] Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94143 USA. [Brody, David] Washington Univ, Dept Neurol, St Louis, MO USA. [Latour, Lawrence] Natl Inst Neurol Disorders & Stroke, Stroke Diagnost & Therapeut Sect, Stroke Branch, Bethesda, MD USA. [Riedy, Gerard] Walter Reed Army Med Ctr, Dept Radiol, Washington, DC 20307 USA. RP Duhaime, AC (reprint author), Massachusetts Gen Hosp, Wang 331,115 Parkman St, Boston, MA 02114 USA. EM aduhaime@partners.org RI Mukherjee, Pratik/A-5446-2008; OI Mukherjee, Pratik/0000-0001-7473-7409; Wintermark, Max/0000-0002-6726-3951 NR 18 TC 43 Z9 43 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2010 VL 91 IS 11 BP 1661 EP 1666 DI 10.1016/j.apmr.2010.07.238 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681UQ UT WOS:000284346400005 PM 21044709 ER PT J AU Manley, GT Diaz-Arrastia, R Brophy, M Engel, D Goodman, C Gwinn, K Veenstra, TD Ling, G Ottens, AK Tortella, F Hayes, RL AF Manley, Geoffrey T. Diaz-Arrastia, Ramon Brophy, Mary Engel, Doortje Goodman, Clay Gwinn, Katrina Veenstra, Timothy D. Ling, Geoffrey Ottens, Andrew K. Tortella, Frank Hayes, Ronald L. TI Common Data Elements for Traumatic Brain Injury: Recommendations From the Biospecimens and Biomarkers Working Group SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Biological Markers; Brain Injuries; Rehabilitation ID HUMAN CEREBROSPINAL-FLUID; PROTEOMIC ANALYSIS; GENOTYPE; STANDARDIZATION; POLYMORPHISM; ASSOCIATION; PROTEINS; EVENTS; APOE; CSF AB Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers Working Group was to provide recommendations for core data elements for TBI research and develop best practice guidelines to standardize the quality and accessibility of these specimens. Consensus recommendations were developed through interactions with focus groups and input from stakeholders participating in the interagency workshop on Standardization of Data Collection in TBI and Psychological Health held in Washington, DC, in March 2009. With the adoption of these standards and best practices, future investigators will be able to obtain data across multiple studies with reduced costs and effort and accelerate the progress of genomic, proteomic, and metabolomic research in TBI. C1 [Manley, Geoffrey T.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94110 USA. [Diaz-Arrastia, Ramon] Univ Texas SW Med Sch, Dallas, TX USA. [Brophy, Mary] Dept Vet Affairs Cooperat Studies Program, Boston, MA USA. [Engel, Doortje] Univ Heidelberg Hosp, Heidelberg, Germany. [Goodman, Clay; Gwinn, Katrina] Baylor Coll Med, Houston, TX 77030 USA. [Veenstra, Timothy D.] NCI, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Ling, Geoffrey] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Tortella, Frank] Walter Reed Army Inst Res, Silver Spring, MD USA. [Ottens, Andrew K.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA. [Ottens, Andrew K.] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA USA. [Hayes, Ronald L.] Banyan Biomarkers Inc, Alachua, FL USA. RP Manley, GT (reprint author), Univ Calif San Francisco, Dept Neurosurg, 1001 Potrero Ave,Bldg 1,Room 101, San Francisco, CA 94110 USA. EM manleyg@neurosurg.ucsf.edu RI Ottens, Andrew/K-3352-2012; OI Gwinn, Katrina/0000-0002-8277-651X NR 31 TC 36 Z9 36 U1 2 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2010 VL 91 IS 11 BP 1667 EP 1672 DI 10.1016/j.apmr.2010.05.018 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681UQ UT WOS:000284346400006 PM 21044710 ER PT J AU Nash, WP Vasterling, J Ewing-Cobbs, L Horn, S Gaskin, T Golden, J Riley, WT Bowles, SV Favret, J Lester, P Koffman, R Farnsworth, LC Baker, DG AF Nash, William P. Vasterling, Jennifer Ewing-Cobbs, Linda Horn, Sarah Gaskin, Thomas Golden, John Riley, William T. Bowles, Stephen V. Favret, James Lester, Patricia Koffman, Robert Farnsworth, Laura C. Baker, Dewleen G. TI Consensus Recommendations for Common Data Elements for Operational Stress Research and Surveillance: Report of a Federal Interagency Working Group SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Combat disorders; Military personnel; Preventive psychiatry; Rehabilitation; Research design; Stress; psychological ID MENTAL-HEALTH; POSTTRAUMATIC GROWTH; MILITARY PERSONNEL; COMBAT DEPLOYMENT; IRAQ-WAR; AFGHANISTAN; DISORDERS; INVENTORY; RESILIENCE; PREVENTION AB Empirical studies and surveillance projects increasingly assess and address potentially adverse psychological health outcomes from the stress of military operations, but no standards yet exist for common concept definitions, variable categories, and measures. This article reports the consensus recommendations of the federal interagency Operational Stress Working Group for common data elements to be used in future operational stress research and surveillance with the goal of improving comparability across studies. Operational stress encompasses more than just combat; it occurs everywhere service members and their families live and work. Posttraumatic stress is not the only adverse mental or behavioral health outcome of importance. The Operational Stress Working Group contends that a primary goal of operational stress research and surveillance is to promote prevention of adverse mental and behavioral outcomes, especially by recognizing the preclinical and subclinical states of distress and dysfunction that portend a risk for failure of role performance or future mental disorders. Recommendations for data elements are divided into 3 tiers: core, supplemental, and emerging, including variable domains and specific measures for assessing operational stressor exposures, stress outcomes, moderating factors, and mediating processes. Attention is drawn to the emerging construct of stress injury as a generic term for subclinical operational stress, and to emerging data elements addressing biological, psychological, and spiritual mediators of risk. Methodologies are needed for identifying preclinical and subclinical states of distress or dysfunction that are markers of risk for failure of role performance and future clinical mental disorders, so that targeted prevention interventions can be developed and evaluated. C1 [Nash, William P.; Horn, Sarah; Golden, John] Def Ctr Excellence Psychol Hlth & Traumat Brain I, Vet Adm, Arlington, VA USA. [Nash, William P.; Baker, Dewleen G.] Vet Adm San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Vasterling, Jennifer] VA Boston Healthcare Syst, Boston, MA USA. [Vasterling, Jennifer] Natl Ctr PTSD, Boston, MA USA. [Ewing-Cobbs, Linda] Univ Texas Houston, Houston, TX USA. [Ewing-Cobbs, Linda] Childrens Learning Inst, Dan L Duncan Neurodev Clin, Houston, TX USA. [Nash, William P.; Baker, Dewleen G.] Univ Calif San Diego, San Diego, CA 92103 USA. [Gaskin, Thomas] Marine Corps, Headquarters, Combat & Operat Stress Control, Quantico, VA USA. [Riley, William T.] NIMH, Bethesda, MD 20892 USA. [Bowles, Stephen V.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Favret, James] USAF, Washington, DC 20330 USA. [Lester, Patricia] Univ Calif Los Angeles, Semel Inst Neurosc & Human Behav, Los Angeles, CA USA. [Koffman, Robert] USN, Bur Med & Surg, Washington, DC USA. [Farnsworth, Laura C.] San Jose State Univ, San Jose, CA 95192 USA. RP Nash, WP (reprint author), POB 10920, Burke, VA 22015 USA. EM william.nash@opstress.net NR 69 TC 20 Z9 20 U1 3 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2010 VL 91 IS 11 BP 1673 EP 1683 DI 10.1016/j.apmr.2010.06.035 PG 11 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681UQ UT WOS:000284346400007 PM 21044711 ER PT J AU Kaloupek, DG Chard, KM Freed, MC Peterson, AL Riggs, DS Stein, MB Tuma, F AF Kaloupek, Danny G. Chard, Kathleen M. Freed, Michael C. Peterson, Alan L. Riggs, David S. Stein, Murray B. Tuma, Farris TI Common Data Elements for Posttraumatic Stress Disorder Research SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Diagnostic techniques and procedures; Outcome assessment; Rehabilitation; Stress disorders, post-traumatic ID TRAUMATIC BRAIN-INJURY; LIFE EVENTS QUESTIONNAIRE; INTERAGENCY WORKING GROUP; PREFERENCE-BASED MEASURE; ADMINISTERED PTSD SCALE; MENTAL-HEALTH PROBLEMS; PSYCHOMETRIC PROPERTIES; MILITARY SERVICE; RISK-FACTORS; DSM-IV AB An expert work group with 7 members was formed under the cosponsorship of 5 U.S. federal agencies to identify common data elements for research related to posttraumatic stress disorder (PTSD). The work group reviewed both previous and contemporary measurement standardization efforts for PTSD research and engaged in a series of electronic and live discussions to address a set of predefined aims. Eight construct domains relevant to PTSD were identified: (1) traditional demographics, (2) exposure to stressors and trauma, (3) potential stress moderators, (4) trauma assessment, (5) PTSD screening, (6) PTSD symptoms and diagnosis, (7) PTSD-related functioning and disability, and (8) mental health history. Measures assigned to the core data elements category have relatively low time-and-effort costs in order to make them potentially applicable across a wide range of studies for which PTSD is a relevant condition. Measures assigned to the supplemental data elements category have greater costs but generally demonstrate stronger psychometric performance and provide more extensive information. Accordingly, measures designated as supplemental are recommended instead of or in addition to corresponding core measures whenever resources and study design allow. The work group offered 4 caveats that highlight potential limitations and emphasize the voluntary nature of standardization for PTSD-related measurement. C1 [Kaloupek, Danny G.] Boston Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Vet Affairs Natl Ctr Posttraumat Stress Disorder, Boston, MA 02118 USA. [Kaloupek, Danny G.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. [Chard, Kathleen M.] Univ Cincinnati, Dept Psychiat, Cincinnati, OH USA. [Chard, Kathleen M.] Univ Cincinnati, Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Freed, Michael C.] Walter Reed Army Med Ctr, Deployment Hlth Clin Ctr, Washington, DC 20307 USA. [Freed, Michael C.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. [Freed, Michael C.] Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Riggs, David S.] Uniformed Serv Univ Hlth Sci, Ctr Deployment Psychol, Bethesda, MD 20814 USA. [Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Tuma, Farris] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Kaloupek, DG (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, 150 S Huntington Ave, Boston, MA 02130 USA. EM danny.kaloupek@va.gov OI Kaloupek, Danny/0000-0002-0795-593X NR 69 TC 18 Z9 18 U1 4 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2010 VL 91 IS 11 BP 1684 EP 1691 DI 10.1016/j.apmr.2010.06.032 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681UQ UT WOS:000284346400008 PM 21044712 ER PT J AU Van Regenmortel, MHV Burke, DS Calisher, CH Dietzgen, RG Fauquet, CM Ghabrial, SA Jahrling, PB Johnson, KM Holbrook, MR Horzinek, MC Keil, GM Kuhn, JH Mahy, BWJ Martelli, GP Pringle, C Rybicki, EP Skern, T Tesh, RB Wahl-Jensen, V Walker, PJ Weaver, SC AF Van Regenmortel, Marc H. V. Burke, Donald S. Calisher, Charles H. Dietzgen, Ralf G. Fauquet, Claude M. Ghabrial, Said A. Jahrling, Peter B. Johnson, Karl M. Holbrook, Michael R. Horzinek, Marian C. Keil, Guenther M. Kuhn, Jens H. Mahy, Brian W. J. Martelli, Giovanni P. Pringle, Craig Rybicki, Edward P. Skern, Tim Tesh, Robert B. Wahl-Jensen, Victoria Walker, Peter J. Weaver, Scott C. TI A proposal to change existing virus species names to non-Latinized binomials SO ARCHIVES OF VIROLOGY LA English DT Article ID TAXONOMY; NOMENCLATURE; ABBREVIATIONS; VIROIDS; LIST AB A proposal has been posted on the ICTV website (2011.001aG.N.v1.binomial_sp_names) to replace virus species names by non-Latinized binomial names consisting of the current italicized species name with the terminal word "virus" replaced by the italicized and non-capitalized genus name to which the species belongs. If implemented, the current italicized species name Measles virus, for instance, would become Measles morbillivirus while the current virus name measles virus and its abbreviation MeV would remain unchanged. The rationale for the proposed change is presented. C1 [Van Regenmortel, Marc H. V.] Ecole Biotechnol Strasbourg, Inst Rech, F-67412 Illkirch Graffenstaden, France. [Burke, Donald S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Calisher, Charles H.] Colorado State Univ, Coll Vet Med & Biomed Sci, Ft Collins, CO 80523 USA. [Dietzgen, Ralf G.] Univ Queensland, Queensland Agr Biotechnol Ctr, DEEDI, St Lucia, Qld 4067, Australia. [Fauquet, Claude M.] Danforth Plant Sci Ctr, ILTAB, St Louis, MO 63132 USA. [Ghabrial, Said A.] Univ Kentucky, Dept Plant Pathol, Lexington, KY 40546 USA. [Jahrling, Peter B.; Holbrook, Michael R.; Kuhn, Jens H.; Wahl-Jensen, Victoria] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, NIH, Ft Detrick, MD 21702 USA. [Johnson, Karl M.] Ctr Dis Control, Placitas, NM 87043 USA. [Horzinek, Marian C.] Spes Nostra, NL-3723 KE Bilthoven, Netherlands. [Keil, Guenther M.] Fed Res Inst Anim Hlth, Friedrich Loeffler Inst, Greifswald, Germany. [Kuhn, Jens H.; Wahl-Jensen, Victoria] Tunnell Consulting Inc, King Of Prussia, PA 19406 USA. [Mahy, Brian W. J.] CDC, NCEZID, Atlanta, GA 30333 USA. [Martelli, Giovanni P.] Dipartimento Protez Piante & Microbiol Applicata, I-70126 Bari, Italy. [Pringle, Craig] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Rybicki, Edward P.] Univ Cape Town, Dept Mol & Cell Biol, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa. [Skern, Tim] Med Univ Vienna, Max F Perutz Labs, A-1030 Vienna, Austria. [Tesh, Robert B.; Weaver, Scott C.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Walker, Peter J.] AAHL, CSIRO Livestock Ind, Geelong, Vic 3220, Australia. RP Van Regenmortel, MHV (reprint author), Ecole Biotechnol Strasbourg, Inst Rech, Blvd Sebastien Brant, F-67412 Illkirch Graffenstaden, France. EM vanregen@unistra.fr RI Dietzgen, Ralf/A-5565-2010; Rybicki, Edward/B-8918-2008; Kuhn, Jens H./B-7615-2011; Weaver, Scott/D-6490-2011; Walker, Peter/H-6059-2013; Rybicki, Edward/D-6138-2014 OI /0000-0002-5704-8094; Rybicki, Edward/0000-0001-8024-9911; Kuhn, Jens H./0000-0002-7800-6045; Walker, Peter/0000-0003-1851-642X; Rybicki, Edward/0000-0001-8024-9911 NR 31 TC 16 Z9 16 U1 0 U2 2 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD NOV PY 2010 VL 155 IS 11 BP 1909 EP 1919 DI 10.1007/s00705-010-0831-9 PG 11 WC Virology SC Virology GA 680MY UT WOS:000284238700024 PM 20953644 ER PT J AU Ma, X Cao, JC Luo, JH Nilius, B Huang, Y Ambudkar, IS Yao, XQ AF Ma, Xin Cao, Jingyuan Luo, Jianhong Nilius, Bernd Huang, Yu Ambudkar, Indu S. Yao, Xiaoqiang TI Depletion of Intracellular Ca(2+) Stores Stimulates the Translocation of Vanilloid Transient Receptor Potential 4-C1 Heteromeric Channels to the Plasma Membrane SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE TRPV4-C1 heteromeric channel; depletion intracellular Ca(2+) stores; endothelial cell; flow; translocation ID CATION CHANNEL; MOLECULAR DETERMINANTS; ENDOTHELIAL-CELLS; OPERATED CHANNEL; SMOOTH-MUSCLE; TRPC1; COMPLEX; TRPV4; FORM; ACTIVATION AB Objective-To examine the effect of Ca(2+) store depletion on the translocation of vanilloid transient receptor potential (TRPV) 4-C1 heteromeric channels to the plasma membrane. Methods and Results-Vesicular trafficking is a key mechanism for controlling the surface expression of TRP channels in the plasma membrane, where they perform their function. TRP channels in vivo are often composed of heteromeric subunits. Experiments using total internal fluorescence reflection microscopy and biotin surface labeling show that Ca(2+) store depletion enhanced TRPV4-C1 translocation into the plasma membrane in human embryonic kidney 293 cells that were coexpressed with TRPV4 and canonical transient receptor potential 1 (TRPC1). Fluorescent Ca(2+) measurement and patch clamp studies demonstrated that Ca(2+) store depletion enhanced 4 alpha-PDD-stimulated Ca(2+) influx and cation current. The translocation required stromal interacting molecule 1 (STIM1). TRPV4-C1 heteromeric channels were more favorably translocated to the plasma membrane than TRPC1 or TRPV4 homomeric channels. Similar results were obtained in native vascular endothelial cells. Conclusion-Ca(2+) store depletion stimulates the insertion of TRPV4-C1 heteromeric channels into the plasma membrane, resulting in an augmented Ca(2+) influx in response to flow in the human embryonic kidney cell overexpression system and native endothelial cells. (Arterioscler Thromb Vasc Biol. 2010;30:2249-2255.) C1 [Ma, Xin; Huang, Yu; Yao, Xiaoqiang] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China. [Ma, Xin; Huang, Yu; Yao, Xiaoqiang] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China. [Ma, Xin] Jiangnan Univ, Sch Med & Pharmacol, Dept Cellular & Mol Pharmacol, Wuxi, Peoples R China. [Nilius, Bernd] Katholieke Univ Leuven, Lab Ion Channel Res, Leuven, Belgium. [Cao, Jingyuan; Luo, Jianhong] Zhejiang Univ, Sch Med, Dept Neurobiol, Hangzhou 310027, Peoples R China. [Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Yao, XQ (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China. EM yao2068@cuhk.edu.hk RI Ma, Xin/G-1297-2013; Yao, Xiaoqiang /I-5413-2016 OI Yao, Xiaoqiang /0000-0002-0687-8186 FU Chinese University of Hong Kong, Hong Kong Research Grants Council [(CUHK)477307, CUHK477408, CUHK479109] FX This study was supported by grants Chinese University of Hong Kong (CUHK)477307, CUHK477408, and CUHK479109 from Hong Kong Research Grants Council; the Focused Investment Scheme of CUHK; and the Li Ka Shing Institute of Health Sciences. NR 30 TC 34 Z9 34 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP 2249 EP U520 DI 10.1161/ATVBAHA.110.212084 PG 18 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800652 PM 20705915 ER PT J AU Waterworth, DM Ricketts, SL Song, KJ Chen, L Zhao, JH Ripatti, S Aulchenko, YS Zhang, WH Yuan, X Lim, N Luan, JA Ashford, S Wheeler, E Young, EH Hadley, D Thompson, JR Braund, PS Johnson, T Struchalin, M Surakka, I Luben, R Khaw, KT Rodwell, SA Loos, RJF Boekholdt, SM Inouye, M Deloukas, P Elliott, P Schlessinger, D Sanna, S Scuteri, A Jackson, A Mohlke, KL Tuomilehto, J Roberts, R Stewart, A Kesaniemi, YA Mahley, RW Grundy, SM McArdle, W Cardon, L Waeber, G Vollenweider, P Chambers, JC Boehnke, M Abecasis, GR Salomaa, V Jarvelin, MR Ruokonen, A Barroso, I Epstein, SE Hakonarson, HH Rader, DJ Reilly, MP Witteman, JCM Hall, AS Samani, NJ Strachan, DP Barter, P van Duijn, CM Kooner, JS Peltonen, L Wareham, NJ McPherson, R Mooser, V Sandhu, MS AF Waterworth, Dawn M. Ricketts, Sally L. Song, Kijoung Chen, Li Zhao, Jing Hua Ripatti, Samuli Aulchenko, Yurii S. Zhang, Weihua Yuan, Xin Lim, Noha Luan, Jian'an Ashford, Sofie Wheeler, Eleanor Young, Elizabeth H. Hadley, David Thompson, John R. Braund, Peter S. Johnson, Toby Struchalin, Maksim Surakka, Ida Luben, Robert Khaw, Kay-Tee Rodwell, Sheila A. Loos, Ruth J. F. Boekholdt, S. Matthijs Inouye, Michael Deloukas, Panagiotis Elliott, Paul Schlessinger, David Sanna, Serena Scuteri, Angelo Jackson, Anne Mohlke, Karen L. Tuomilehto, Jaako Roberts, Robert Stewart, Alexandre Kesaeniemi, Y. Antero Mahley, Robert W. Grundy, Scott M. McArdle, Wendy Cardon, Lon Waeber, Gerard Vollenweider, Peter Chambers, John C. Boehnke, Michael Abecasis, Goncalo R. Salomaa, Veikko Jaervelin, Marjo-Riitta Ruokonen, Aimo Barroso, Ines Epstein, Stephen E. Hakonarson, Hakon H. Rader, Daniel J. Reilly, Muredach P. Witteman, Jacqueline C. M. Hall, Alistair S. Samani, Nilesh J. Strachan, David P. Barter, Philip van Duijn, Cornelia M. Kooner, Jaspal S. Peltonen, Leena Wareham, Nicholas J. McPherson, Ruth Mooser, Vincent Sandhu, Manjinder S. CA Wellcome Trust Case Control Consor TI Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary artery disease; epidemiology; lipids; genetics ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; EPIC-NORFOLK; WHOLE-GENOME; BIRTH COHORT; TRIGLYCERIDES AB Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Methods and Results-We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6X10(-8) to 3.1X10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1X10(-3) to 1.2X10(-9)). Conclusion-We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.) C1 [Ricketts, Sally L.; Ashford, Sofie; Young, Elizabeth H.; Luben, Robert; Khaw, Kay-Tee; Sandhu, Manjinder S.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Waterworth, Dawn M.; Song, Kijoung; Yuan, Xin; Lim, Noha; Cardon, Lon; Mooser, Vincent] GlaxoSmithKline R&D, Div Genet, King Of Prussia, PA USA. [Zhao, Jing Hua; Luan, Jian'an; Loos, Ruth J. F.; Wareham, Nicholas J.; Sandhu, Manjinder S.] Addenbrookes Hosp, Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. [Ripatti, Samuli; Surakka, Ida; Peltonen, Leena] Univ Helsinki, Inst Mol Med FIMM, FIN-00014 Helsinki, Finland. [Aulchenko, Yurii S.; Hall, Alistair S.; van Duijn, Cornelia M.] Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands. [Struchalin, Maksim] Erasmus Univ, Dept Forens Mol Biol, Rotterdam, Netherlands. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Elliott, Paul; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Jaervelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Biostat & Epidemiol, Sch Publ Hlth, London, England. [Wheeler, Eleanor; Young, Elizabeth H.; Inouye, Michael; Deloukas, Panagiotis; Barroso, Ines; Peltonen, Leena; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Cambridge, England. [Hadley, David] Univ London, Div Community Hlth Sci, London, England. [Thompson, John R.; Braund, Peter S.] Univ Leicester, Dept Hlth Sci & Genet, Leicester, Leics, England. [Johnson, Toby] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Surakka, Ida] Natl Publ Hlth Inst, Biomedicum, Helsinki, Finland. [Boekholdt, S. Matthijs] Univ Amsterdam, Acad Med Ctr, Med Res Council Ctr Nutr Epidemiol Canc Prevent &, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Boekholdt, S. Matthijs] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Scuteri, Angelo] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Sanna, Serena; Stewart, Alexandre] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Tuomilehto, Jaako] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. [Kesaeniemi, Y. Antero] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland. [Jaervelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, SF-90220 Oulu, Finland. [Kesaeniemi, Y. Antero; Jaervelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland. [Ruokonen, Aimo] Univ Oulu, Inst Diagnost, Oulu, Finland. [Mahley, Robert W.] Gladstone Inst Neurol Dis, San Francisco, CA USA. [Mahley, Robert W.] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA. [Grundy, Scott M.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dept Clin Nutr, Dallas, TX 75390 USA. [McArdle, Wendy] Univ Bristol, Avon Longitudinal Study Parents & Children, Bristol, Avon, England. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, Lausanne, Switzerland. [Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, MedStar Res Inst, Washington, DC 20010 USA. [Salomaa, Veikko; Jaervelin, Marjo-Riitta] Natl Inst Hlth & Welf, Helsinki, Finland. [Hakonarson, Hakon H.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Sch Med, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Hall, Alistair S.] Univ Leeds, LIGHT, Leeds, W Yorkshire, England. [Barter, Philip] Heart Res Inst, Sydney, NSW, Australia. [Peltonen, Leena] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA USA. RP Sandhu, MS (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. EM manj.sandhu@srl.cam.ac.uk RI Abecasis, Goncalo/B-7840-2010; Stewart, Alexandre/A-5677-2011; Hadley, David/I-6902-2012; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Boekholdt, Matthijs/G-7562-2014; Ripatti, Samuli/H-9446-2014; OI Abecasis, Goncalo/0000-0003-1509-1825; Stewart, Alexandre/0000-0003-2673-9164; Deloukas, Panos/0000-0001-9251-070X; Aulchenko, Yurii/0000-0002-7899-1575; Ripatti, Samuli/0000-0002-0504-1202; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Luben, Robert/0000-0002-5088-6343; Jarvelin, Marjo-Riitta/0000-0002-2149-0630 FU United Kingdom Medical Research Council; Wellcome Trust (WT) [068545/Z/02, 077016/Z/05/Z, 079895]; British Heart Foundation; European Commission; GlaxoSmithKline; Medical Research Council [G0000934, G0801566, G0500539]; European Union [LSHM-CT-2003-503041]; British Heart Foundation [PG/08/094]; HSFO [NA6001]; CIHR; Swiss National Science Foundation [33CSCO-122661]; Faculty of Biology and Medicine of Lausanne; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International (JDRF) [U01 DK062418]; National Institute of Diabetes and Digestive and Kidney Diseases [T1DGC]; JDRF; JDRF International; National Institute for Health Research Cambridge Biomedical Research Center; Cardiovascular Institute of the University of Pennsylvania; Netherlands Organisation for Scientific Research (NWO) [175.010.2005.011, 911.03.012]; Research Institute for Diseases in the Elderly [RIDE2, 01493015]; Netherlands Genomic Initiative (NGI/NWO) [050-060-810]; Academy of Finland, Center of Excellence in Complex Disease Genetics [104781, 120315, 1114194]; University Hospital Oulu, Biocenter; University of Oulu, Oulu, Finland; National Heart, Lung, and Blood Institute [5R01HL087679-02, 1RL1MH083268-01]; ENGAGE project [HEALTH-F4-2007-201413]; Wellcome Trust, United Kingdom [GR069224]; Academy of Finland and Biocentrum Helsinki FX This work was supported by the United Kingdom Medical Research Council, Wellcome Trust (WT), British Heart Foundation, European Commission, and GlaxoSmithKline. Specifically, we acknowledge use of genotype data from the 1958 British birth cohort DNA collection, funded by Medical Research Council Grant G0000934 and Wellcome Trust Grant 068545/Z/02. Dr Barroso and Dr Wheeler acknowledge support from European Union FP6 funding (contract no LSHM-CT-2003-503041). Dr Sandhu and Dr Ricketts are funded by the British Heart Foundation (PG/08/094) and Medical Research Council (G0801566). Dr Barroso (077016/Z/05/Z), Dr Peltonen, Dr Inouye, and Dr Deloukas are funded by the Wellcome Trust. Some computation was done on the Vital-IT system at the Swiss Institute of Bioinformatics. The Ottawa Heart Study is funded by HSFO NA6001 and CIHR. The GEMS study was sponsored in part by GlaxoSmithKline. The CoLaus study was supported by grants from GlaxoSmithKline, the Swiss National Science Foundation (Grant 33CSCO-122661) and the Faculty of Biology and Medicine of Lausanne. This research used resources provided by the Type 1 Diabetes Genetics Consortium (T1DGC), a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International (JDRF) and was supported by U01 DK062418. The T1DGC GWAS project was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and JDRF and was coordinated by the JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (Cambridge, United Kingdom), which is funded by the JDRF International, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Center. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). Recruitment of the PennCATH cohort was supported by the Cardiovascular Institute of the University of Pennsylvania. Genotyping for the PennCATH cohort 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 (to M.P.R. and D.J.R.) with the University of Pennsylvania School of Medicine. The Rotterdam Study was supported by the Netherlands Organisation for Scientific Research (NWO Groot, 175.010.2005.011, 911.03.012), the Research Institute for Diseases in the Elderly (RIDE2, 01493015), and the Netherlands Genomic Initiative (NGI/NWO) (050-060-810). NFBC 1966 received financial report from the Academy of Finland (project Grants 104781, 120315, 1114194, Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Oulu, Finland, National Heart, Lung, and Blood Institute Grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), ENGAGE project and grant agreement HEALTH-F4-2007-201413, the Medical Research Council (G0500539, PrevMetSyn/Medical Research Council), and the Wellcome Trust (GR069224), United Kingdom. The DNA extractions, sample quality controls, biobank upkeep, and aliquotting were performed in the National Public Health Institute, Biomedicum, Helsinki, Finland, supported financially by the Academy of Finland and Biocentrum Helsinki. NR 67 TC 198 Z9 203 U1 1 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP 2264 EP U566 DI 10.1161/ATVBAHA.109.201020 PG 35 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800654 PM 20864672 ER PT J AU Olive, M Harten, I Mitchell, R Beers, JK Djabali, K Cao, K Erdos, MR Blair, C Funke, B Smoot, L Gerhard-Herman, M Machan, JT Kutys, R Virmani, R Collins, FS Wight, TN Nabel, EG Gordon, LB AF Olive, Michelle Harten, Ingrid Mitchell, Richard Beers, Jeanette K. Djabali, Karima Cao, Kan Erdos, Michael R. Blair, Cecilia Funke, Birgit Smoot, Leslie Gerhard-Herman, Marie Machan, Jason T. Kutys, Robert Virmani, Renu Collins, Francis S. Wight, Thomas N. Nabel, Elizabeth G. Gordon, Leslie B. TI Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of Aging SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE aging; atherosclerosis; pathology; peripheral arterial disease; progeria ID SUDDEN CORONARY DEATH; ATHEROSCLEROSIS; CELLS; INHIBITORS; MUTATIONS; PHENOTYPE; FIBROSIS; ARTERIES; ANTIBODY; DEFECTS AB Objective-Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results-We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (P<0.0001) in coronary arteries. Conclusion-We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. (Arterioscler Thromb Vasc Biol. 2010;30:2301-2309.) C1 [Gordon, Leslie B.] Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Warren Alpert Med Sch, Providence, RI 02903 USA. [Olive, Michelle; Beers, Jeanette K.; Nabel, Elizabeth G.] NHLBI, NIH, Bethesda, MD 20892 USA. [Harten, Ingrid; Wight, Thomas N.] Benaroya Res Inst Virginia Mason, Hope Heart Program, Seattle, WA USA. [Harten, Ingrid; Wight, Thomas N.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Mitchell, Richard] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Gerhard-Herman, Marie] Brigham & Womens Hosp, Dept Cardiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Djabali, Karima] Univ Technol Munich, Dept Dermatol, Munich, Germany. [Funke, Birgit] Mol Med Lab, Cambridge, MA USA. [Cao, Kan; Erdos, Michael R.; Blair, Cecilia; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Funke, Birgit] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Smoot, Leslie] Childrens Hosp Boston, Dept Cardiol, Boston, MA USA. [Gordon, Leslie B.] Childrens Hosp Boston, Dept Anesthesia, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. [Machan, Jason T.] Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Dept Orthopaed, Providence, RI 02912 USA. [Machan, Jason T.] Brown Univ, Warren Alpert Med Sch, Dept Surg, Providence, RI 02912 USA. [Kutys, Robert; Virmani, Renu] CVPath Inst Inc, Gaithersburg, MD USA. RP Gordon, LB (reprint author), Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Warren Alpert Med Sch, 593 Eddy St, Providence, RI 02903 USA. EM Leslie_Gordon@brown.edu RI Machan, Jason/D-3897-2013 OI Machan, Jason/0000-0003-2048-4914 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; Progeria Research Foundation FX This study was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and by the Progeria Research Foundation. NR 35 TC 110 Z9 116 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP 2301 EP U636 DI 10.1161/ATVBAHA.110.209460 PG 26 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800659 PM 20798379 ER PT J AU Briest, W Cooper, TK Tae, HJ Schubert, R Krawczyk, M McDonnell, NB Talan, MI AF Briest, Wilfried Cooper, Timothy K. Tae, Hyun-Jin Schubert, Rudolf Krawczyk, Melissa McDonnell, Nazli B. Talan, Mark I. TI Doxycycline Treatment Attenuates the Development of Stress-Induced Aortic Lesions in a Mouse Experimental Model of Vascular Type Ehlers-Danlos Syndrome (vEDS) SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 08-10, 2010 CL San Francisco, CA C1 [Briest, Wilfried] Herzzentrum Univ Leipzig, Leipzig, Germany. [Cooper, Timothy K.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Tae, Hyun-Jin; Krawczyk, Melissa; McDonnell, Nazli B.; Talan, Mark I.] NIA, Baltimore, MD 21224 USA. [Schubert, Rudolf] Univ Heidelberg, Med Fak Mannheim, D-6800 Mannheim, Germany. 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP E318 EP E319 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800614 ER PT J AU McDermott, MM Ferrucci, L Liu, KA Guralnik, JM Tian, L Liao, YH Criqui, MH AF McDermott, Mary M. Ferrucci, Luigi Liu, Kiang Guralnik, Jack M. Tian, Lu Liao, Yihua Criqui, Michael H. TI Men with Peripheral Arterial Disease Have Greater Deterioration in Calf Muscle Characteristics and Function than Women with Peripheral Arterial Disease: A Longitudinal Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 08-10, 2010 CL San Francisco, CA C1 [McDermott, Mary M.; Liu, Kiang; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi; Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, Palo Alto, CA 94304 USA. [Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP E235 EP E235 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800240 ER PT J AU Sen, S Yadava, N Gershengorn, M AF Sen, Sabyasachi Yadava, Nagendra Gershengorn, Marvin TI Manganese Superoxide Dismutase (MnSOD) and Catalase (CAT) Enhance Survival and Influence Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells (MSCs) SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 08-10, 2010 CL San Francisco, CA C1 [Sen, Sabyasachi] Baystate Med Cntr, Springfield, MA USA. [Yadava, Nagendra] Univ Massachusetts, PVLSI, Springfield, MA USA. [Gershengorn, Marvin] NIDDK, NIH, Bethesda, MD 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP E278 EP E278 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800430 ER PT J AU Yokota, T Akita, N Yamamoto, J Remaley, AT Tsujita, M Yokoyama, S AF Yokota, Tomo Akita, Nobukatsu Yamamoto, Junki Remaley, Alan T. Tsujita, Maki Yokoyama, Shinji TI Determination of Plasma Pre beta-HDL in Normal- and Hypoalphalipoproteinemia Model Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology CY APR 08-10, 2010 CL San Francisco, CA C1 [Yokota, Tomo; Akita, Nobukatsu; Yamamoto, Junki; Tsujita, Maki; Yokoyama, Shinji] Nagoya City Univ, Nagoya, Aichi, Japan. [Remaley, Alan T.] 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2010 VL 30 IS 11 BP E249 EP E249 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 667YS UT WOS:000283234800304 ER PT J AU Pisitkun, P Claudio, E Ren, NN Wang, HS Siebenlist, U AF Pisitkun, Prapaporn Claudio, Estefania Ren, Nina Wang, Hongshan Siebenlist, Ulrich TI The Adaptor Protein CIKS/ACT1 Is Necessary for Collagen-Induced Arthritis, and It Contributes to the Production of Collagen-Specific Antibody SO ARTHRITIS AND RHEUMATISM LA English DT Article ID T-CELLS; NEUTROPHIL RECRUITMENT; RHEUMATOID-ARTHRITIS; GAMMA RECEPTOR; DEFICIENT MICE; BONE EROSION; INTERLEUKIN-17; IL-17; INFLAMMATION; ACT1 AB Objective. CIKS/ACT1 is an adaptor molecule that is necessary for signaling by members of the interleukin-17 cytokine family. The aim of this study was to determine whether this adaptor is required for the initiation of collagen-induced arthritis (CIA). If it is required, then CIKS-mediated signaling could be a potential target for therapeutic intervention in patients with rheumatoid arthritis (RA). Methods. CIA model studies were performed with CIKS-deficient and CIKS-sufficient mice on an otherwise wild-type (WT) C57BL/6 background or on a C57BL/6 background lacking Fc gamma receptor IIb (Fc gamma RIIb). In addition, collagen antibody-induced arthritis (CAIA) studies were performed in WT and CIKS-deficient mice. Pathologic changes of arthritis were evaluated by visual inspection of the paws, by histochemical analysis of tissue sections, and by measurements of collagen-specific antibodies. Results. Pathologic changes of CIA were readily induced in WT mice, with exacerbation of the changes in Fc gamma RIIb-deficient mice. In contrast, CIKS-deficient mice were protected from all aspects of CIA pathology, even on an Fc gamma RIIb-deficient background. The absence of CIKS completely prevented neutrophil infiltration into joints, bone erosion, and cartilage damage; furthermore, the production of type II collagen (CII)-specific antibodies was reduced. In contrast to the CIA model, CIKS-deficient mice in the CAIA model remained susceptible to arthritis. Conclusion. CIKS-mediated signaling is necessary for the pathogenesis of CIA, but not CAIA. These findings suggest critical functions of CIKS during the development of arthritis in the CIA model, including in the formation of CII antibodies, and they mark the CIKS adaptor as a potential therapeutic target in RA. C1 [Siebenlist, Ulrich] NIAID, Immune Activat Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIAID, Immune Activat Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11B15A, Bethesda, MD 20892 USA. EM Ulrich.Siebenlist@nih.gov FU National Institute of Allergy and Infectious Diseases, NIH FX Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 50 TC 16 Z9 21 U1 2 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2010 VL 62 IS 11 BP 3334 EP 3344 DI 10.1002/art.27653 PG 11 WC Rheumatology SC Rheumatology GA 674UU UT WOS:000283776400024 PM 20662069 ER PT J AU Ruperto, N Pistorio, A Ravelli, A Rider, LG Pilkington, C Oliveira, S Wulffraat, N Espada, G Garay, S Cuttica, R Hofer, M Quartier, P Melo-Gomes, J Reed, AM Wierzbowska, M Feldman, BM Harjacek, M Huppertz, HI Nielsen, S Flato, B Lahdenne, P Michels, H Murray, KJ Punaro, L Rennebohm, R Russo, R Balogh, Z Rooney, M Pachman, LM Wallace, C Hashkes, P Lovell, DJ Giannini, EH Gare, BA Martini, A AF Ruperto, Nicolino Pistorio, Angela Ravelli, Angelo Rider, Lisa G. Pilkington, Clarissa Oliveira, Sheila Wulffraat, Nico Espada, Graciela Garay, Stella Cuttica, Ruben Hofer, Michael Quartier, Pierre Melo-Gomes, Jose Reed, Ann M. Wierzbowska, Malgorzata Feldman, Brian M. Harjacek, Miroslav Huppertz, Hans-Iko Nielsen, Susan Flato, Berit Lahdenne, Pekka Michels, Harmut Murray, Kevin J. Punaro, Lynn Rennebohm, Robert Russo, Ricardo Balogh, Zsolt Rooney, Madeleine Pachman, Lauren M. Wallace, Carol Hashkes, Philip Lovell, Daniel J. Giannini, Edward H. Gare, Boel Andersson Martini, Alberto CA PRINTO PRCSG TI The Paediatric Rheumatology International Trials Organisation Provisional Criteria for the Evaluation of Response to Therapy in Juvenile Dermatomyositis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MYOSITIS ASSESSMENT SCALE; VALIDATED DISEASE-ACTIVITY; PRELIMINARY CORE SET; PRELIMINARY DEFINITION; DAMAGE INDEXES; OUTCOME ASSESSMENT; CLINICAL-TRIALS; MUSCLE FUNCTION AB Objective. To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (DM) based on the Paediatric Rheumatology International Trials Organisation juvenile DM core set of variables. Methods. Thirty-seven experienced pediatric rheumatologists from 27 countries achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patient's rating, statistical analysis, definition selection). Using the physicians' consensus ratings as the "gold standard measure," chi-square, sensitivity, specificity, false-positive and-negative rates, area under the receiver operating characteristic curve, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa values >0.8 were multiplied by the face validity score to select the top definitions. Results. The top definition of improvement was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second-highest scoring definition was at least 20% improvement from baseline in 3 of 6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength (definition P1 selected by the International Myositis Assessment and Clinical Studies group). The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process. Conclusion. We propose a provisional data-driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite end point for the evaluation of global response to therapy in juvenile DM. C1 [Ruperto, Nicolino] Pediat II Reumatol & Paediat Rheumatol Int Trials, IRCCS G Gaslini, Genoa, Italy. [Pistorio, Angela] IRCCS G Gaslini, Serv Epidemiol & Biostat, Genoa, Italy. [Rider, Lisa G.] NIEHS, NIH, Bethesda, MD USA. [Pilkington, Clarissa] Great Ormond St Hosp Sick Children, London, England. [Oliveira, Sheila] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Wulffraat, Nico] Wilhelmina Childrens Hosp, Utrecht, Netherlands. [Espada, Graciela] Hosp Ninos Dr Ricardo Gutierrez, Buenos Aires, DF, Argentina. [Garay, Stella] Hosp Sor Maria Ludovica, La Plata, Buenos Aires, Argentina. [Cuttica, Ruben] Hosp Gen Ninos Pedro de Elizalde, Buenos Aires, DF, Argentina. [Hofer, Michael] Ctr Multisite Romand Rhumatol Pediat, Lausanne, Switzerland. [Quartier, Pierre] Univ Paris 05, Hop Necker Enfants Malad, Paris, France. [Melo-Gomes, Jose] Inst Portugues Reumatol, Lisbon, Portugal. [Reed, Ann M.] Mayo Clin, Sch Med, Rochester, MN USA. [Reed, Ann M.] Mayo Fdn, Rochester, MN USA. [Wierzbowska, Malgorzata] Inst Rheumatol, Warsaw, Poland. [Feldman, Brian M.] Univ Toronto, Toronto, ON, Canada. [Feldman, Brian M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Harjacek, Miroslav] Childrens Hosp, Zagreb, Croatia. [Huppertz, Hans-Iko] Klinikum Bremen Mitte, Bremen, Germany. [Nielsen, Susan] Rigshosp, DK-2100 Copenhagen, Denmark. [Flato, Berit] Univ Hosp, Rikshosp, Oslo, Norway. [Lahdenne, Pekka] Hosp Children & Adolescents, Helsinki, Finland. [Michels, Harmut] Rheumakinderklin, Garmisch Partenkirchen, Germany. [Murray, Kevin J.] Princess Margaret Hosp Children, Perth, WA, Australia. [Punaro, Lynn] Texas Scottish Rite Hosp Children, Dallas, TX 75219 USA. [Rennebohm, Robert] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5C7, Canada. [Russo, Ricardo] Hosp Pediat Juan P Garrahan, Buenos Aires, DF, Argentina. [Balogh, Zsolt] Natl Inst Rheumatism & Physiotherapy, Budapest, Hungary. [Rooney, Madeleine] Musgrave Pk Hosp, Belfast, Antrim, North Ireland. [Pachman, Lauren M.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Wallace, Carol] Univ Washington, Childrens Hosp, Seattle, WA 98195 USA. [Hashkes, Philip] Shaare Zedek Med Ctr, Jerusalem, Israel. [Lovell, Daniel J.; Giannini, Edward H.] Childrens Hosp Med Ctr, Cincinnati, OH USA. [Gare, Boel Andersson] Ryhovs Cty Hosp, Jonkoping, Sweden. RP Ruperto, N (reprint author), Univ Genoa, IRCCS G Gaslini, Paediat Rheumatol Int Trials Org PRINTO, EULAR Ctr Excellence Rheumatol 2008 2013, Largo Gaslini 5, I-16147 Genoa, Italy. EM nicolaruperto@ospedale-gaslini.ge.it RI Feldman, Brian/A-8586-2011; Oliveira, Sheila/F-5213-2016; RAVELLI, ANGELO/J-8161-2016; OI Oliveira, Sheila/0000-0002-2426-716X; RAVELLI, ANGELO/0000-0001-9658-0385; , International Journal of Business and Applied Social Science/0000-0001-7850-0193; Rider, Lisa/0000-0002-6912-2458 FU European Union [QLG1-CT-2000-00514]; IRCCS G. Gaslini, Genoa, Italy; NIH [R03-AI-44046]; NIH, National Institute of Environmental Health Sciences FX Supported by a grant from the European Union (contract QLG1-CT-2000-00514), by IRCCS G. Gaslini, Genoa, Italy, and by the NIH (grant R03-AI-44046). Dr. Rider's work was supported by the intramural research program of the NIH, National Institute of Environmental Health Sciences. NR 33 TC 28 Z9 29 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD NOV PY 2010 VL 62 IS 11 BP 1533 EP 1541 DI 10.1002/acr.20280 PG 9 WC Rheumatology SC Rheumatology GA 678BA UT WOS:000284041200003 PM 20583105 ER PT J AU Zuliani, G Galvani, M Maggio, M Volpato, S Bandinelli, S Corsi, AM Lauretani, F Cherubini, A Guralnik, JM Fellin, R Ferrucci, L AF Zuliani, Giovanni Galvani, Matteo Maggio, Marcello Volpato, Stefano Bandinelli, Stefania Corsi, Anna Maria Lauretani, Fulvio Cherubini, Antonio Guralnik, Jack M. Fellin, Renato Ferrucci, Luigi TI Plasma soluble gp130 levels are increased in older subjects with metabolic syndrome. The role of insulin resistance SO ATHEROSCLEROSIS LA English DT Article DE Metabolic syndrome; Interleukin-6; sgp130; Pathway; Trans-Signalling ID POLYCYSTIC-OVARY-SYNDROME; NECROSIS-FACTOR-ALPHA; C-REACTIVE PROTEIN; ADIPOSE-TISSUE; INTERLEUKIN-6 RECEPTOR; HUMAN NEUTROPHILS; IN-VIVO; DISEASE; OBESITY; INFLAMMATION AB Objective: Increased interleukin-6 plasma levels have been reported in metabolic syndrome (MS); nevertheless, it is unclear whether interleukin-6 activity is exerted through direct signalling only or also through the "trans-signalling". This issue is important to clarify since signalling and "trans-signalling" affect different tissues. We investigated the relationship between MS and the interleukin-6 system in an older population. Methods: Data from 997 older community dwelling individuals (age >= 65 years; females: 56.2%) enrolled the InChianti study were analysed. Interleukin-6, soluble interleukin-6 receptor (sIL-6r), and soluble glycoprotein 130 (sgp130) were measured on plasma by ELISA. MS was defined by the NCEP ATP III criteria; 309 individuals (31%) resulted affected by MS. Results: Subjects with MS had higher interleukin-6 and sgp130 levels compared to controls; a trend toward higher levels of sIL-6R was also observed. The risk of having MS was increased in individuals with high sIL-6r or/and sgp130 levels, independent of age, gender, and interleukin-6 levels. Elevated sgp130 levels were associated with higher plasma glucose, HOMA, triglycerides, and with diabetes both in subjects with and without MS. Although the risk of high sgp130 levels was generally associated with MS (O.R.: 1.77, 95%C.I.: 1.39-2.25), this excess of risk was not present in MS phenotypes excluding the criteria "elevated glucose" or "elevated triglycerides". Furthermore, the association between sgp130 and MS disappeared after adjustment for HOMA. Conclusions: We found that older individuals with MS have increased sgp130 plasma levels compared with controls; nevertheless, our data suggest that this association might be mediated by insulin resistance. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Zuliani, Giovanni; Galvani, Matteo; Volpato, Stefano; Fellin, Renato] Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med Gerontol & Geriatr, I-44100 Ferrara, Italy. [Maggio, Marcello] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Geriatr Unit, Parma, Italy. [Cherubini, Antonio] Univ Perugia, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Guralnik, Jack M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Zuliani, G (reprint author), Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med Gerontol & Geriatr, Via Savonarola 9, I-44100 Ferrara, Italy. EM gzuliani@hotmail.com RI VOLPATO, STEFANO/H-2977-2014; Lauretani, Fulvio/K-5115-2016; OI VOLPATO, STEFANO/0000-0003-4335-6034; Zuliani, Giovanni/0000-0003-0969-3184; Lauretani, Fulvio/0000-0002-5287-9972; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111] FX Grants: The InChianti study baseline (1998-2000) was supported as a "targeted project" [ICS110.1/RF97.71] by the Italian Ministry of Health and in part by the U.S. National Institute on Aging [Contracts: 263 MD 9164 and 263 MD 821336]. The InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging [Contracts: N.1-AG-1-1 and N.1-AG-1-2111]. NR 29 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2010 VL 213 IS 1 BP 319 EP 324 DI 10.1016/j.atherosclerosis.2010.08.074 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 669NB UT WOS:000283356400099 PM 20869059 ER PT J AU Li, QQ Wang, GD Reed, E Huang, L Cuff, CF AF Li, Qingdi Quentin Wang, Gangduo Reed, Eddie Huang, Lan Cuff, Christopher F. TI Evaluation of Cisplatin in Combination with beta-Elemene as a Regimen for Prostate Cancer Chemotherapy SO BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY LA English DT Article ID CARCINOMA-CELL-LINES; APOPTOSIS-INDUCING LIGAND; ANDROGEN-INDEPENDENCE; DEATH PATHWAYS; MOLECULAR ALTERATIONS; MEDIATED APOPTOSIS; FUTURE-PROSPECTS; UP-REGULATION; PHASE-II; BCL-2 AB Cisplatin is one of the most potent chemotherapeutic agents for the treatment of many types of solid tumours. Nevertheless, it is not the first-line drug for prostate cancer chemotherapy, because prostate tumour cells exhibit intrinsic and acquired resistance to cisplatin. We have previously demonstrated that beta-elemene, a novel plant-derived anti-neoplastic with low toxicity, inhibits lung and ovarian carcinoma cell growth in vitro. In the present study, we explored the therapeutically chemosensitizing effect of beta-elemene on cisplatin anti-tumour efficacy in androgen-independent prostate cancer cells as well as the underlying mechanism. beta-Elemene significantly increased cisplatin cytotoxicity in the androgen-independent prostate carcinoma cell lines DU145 and PC-3. In addition, beta-elemene markedly promoted cisplatin-induced apoptotic cell death in both cell lines, as determined by three different apoptosis assays. beta-Elemene augmented the cisplatin-induced activation of caspase-3/7/10 and caspase-9, cleavage of caspase-3 and -9, suppression of Bcl-2 and Bcl-X(L) expression, and release of cytochrome c from mitochondria in these cells. Thus, beta-elemene enhancement of cisplatin-induced apoptosis via mitochondrial activation of the caspase-mediated apoptotic pathway may account for the augmented anti-cancer potency of cisplatin in prostate cancer. Cisplatin combined with beta-elemene as a chemosensitizer or adjuvant warrants further study and may be potentially useful as a first-line treatment of androgen-independent prostate carcinomas. C1 [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. [Li, Qingdi Quentin; Wang, Gangduo; Reed, Eddie; Cuff, Christopher F.] W Virginia Univ, Hlth Sci Ctr, Sch Med, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. [Huang, Lan] HYWE Pharmaceut Corp, Berkeley Hts, NJ USA. RP Li, QQ (reprint author), NIAID, NIH, Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM liquenti@niaid.nih.gov FU National Institutes of Health [P20RR16440-010003]; West Virginia University School of Medicine FX This work was supported by grants from the National Institutes of Health (No. P20RR16440-010003 to Q.Q. Li) and West Virginia University School of Medicine (to Q.Q. Li). NR 57 TC 31 Z9 34 U1 3 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-7835 J9 BASIC CLIN PHARMACOL JI Basic Clin. Pharmacol. Toxicol. PD NOV PY 2010 VL 107 IS 5 BP 868 EP 876 DI 10.1111/j.1742-7843.2010.00592.x PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 666DW UT WOS:000283093100004 PM 22545969 ER PT J AU Lacerda, L McCarthy, J Mungly, SFK Lynn, EG Sack, MN Opie, LH Lecour, S AF Lacerda, Lydia McCarthy, Joy Mungly, Shazia F. K. Lynn, Edward G. Sack, Michael N. Opie, Lionel H. Lecour, Sandrine TI TNF alpha protects cardiac mitochondria independently of its cell surface receptors SO BASIC RESEARCH IN CARDIOLOGY LA English DT Article DE Cytokines; Mitochondria; Oxygen consumption; Oxygen radicals; Sphingolipids ID TUMOR-NECROSIS-FACTOR; CORONARY MICROEMBOLIZATION; ELECTRON-TRANSFER; CONTRACTILE DYSFUNCTION; C2C12 MYOTUBES; CARDIOPROTECTION; SPHINGOSINE; INHIBITION; ISCHEMIA; KINASE AB Our novel proposal is that TNF alpha exerts a direct effect on mitochondrial respiratory function in the heart, independently of its cell surface receptors. TNF alpha-induced cardioprotection is known to involve reactive oxygen species (ROS) and sphingolipids. We therefore further propose that this direct mitochondrial effect is mediated via ROS and sphingolipids. The protective concentration of TNF alpha (0.5 ng/ml) was added to isolated heart mitochondria from black 6 x 129 mice (WT) and double TNF receptor knockout mice (TNFR1&2(-/-)). Respiratory parameters and inner mitochondrial membrane potential were analyzed in the presence/absence of two antioxidants, N-acetyl-l-cysteine or N-tert-butyl-alpha-(2-sulfophenyl)nitrone or two antagonists of the sphingolipid pathway, N-oleoylethanolamine (NOE) or imipramine. In WT, TNF alpha reduced State 3 respiration from 279.3 +/- A 3 to 119.3 +/- A 2 (nmol O(2)/mg protein/min), increased proton leak from 15.7 +/- A 0.6% (control) to 36.6 +/- A 4.4%, and decreased membrane potential by 20.5 +/- A 3.1% compared to control groups. In TNFR1&2(-/-) mice, TNF alpha reduced State 3 respiration from 205.2 +/- A 4 to 75.7 +/- A 1 (p < 0.05 vs. respective control). In WT mice, both antioxidants added with TNF alpha restored State 3 respiration to 269.2 +/- A 2 and 257.6 +/- A 2, respectively. Imipramine and NOE also restored State 3 respiration to 248.4 +/- A 2 and 249.0 +/- A 2, respectively (p < 0.01 vs. TNF alpha alone). Similarly, both antioxidant and inhibitors of the sphingolipid pathway restored the proton leak to pre-TNF values. TNF alpha-treated mitochondria or isolated cardiac muscle fibers showed an increase in respiration after anoxia-reoxygenation, but this effect was lost in the presence of an antioxidant or NOE. Similar data were obtained in TNFR1&2(-/-) mice. TNF alpha exerts a protective effect on respiratory function in isolated mitochondria subjected to an anoxia-reoxygenation insult. This effect appears to be independent of its cell surface receptors, but is likely to be mediated by ROS and sphingolipids. C1 [Lacerda, Lydia; McCarthy, Joy; Mungly, Shazia F. K.; Opie, Lionel H.; Lecour, Sandrine] Univ Cape Town, Cardioprotect Grp, Hatter Cardiovasc Res Inst, Dept Med,Fac Hlth Sci, ZA-7925 Cape Town, South Africa. [Lynn, Edward G.; Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Lacerda, L (reprint author), Univ Cape Town, Cardioprotect Grp, Hatter Cardiovasc Res Inst, Dept Med,Fac Hlth Sci, Anzio Rd, ZA-7925 Cape Town, South Africa. EM lydia.lacerda@uct.ac.za FU Wellcome; Interuniversity Cape Heart Group of the South African Medical Research Council; National Research Foundation; Servier Senior Fellowship for Research in Heart Failure; Medical Research Council; Wellcome Trust; Medical Research Council of South Africa FX This work was supported in part by a CRIG grant from the Wellcome, the Interuniversity Cape Heart Group of the South African Medical Research Council and the National Research Foundation. S.L. was supported by a Servier Senior Fellowship for Research in Heart Failure and a Medical Research Council career award. L.L. by the Wellcome Trust and the Medical Research Council of South Africa. NR 52 TC 27 Z9 27 U1 1 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8428 J9 BASIC RES CARDIOL JI Basic Res. Cardiol. PD NOV PY 2010 VL 105 IS 6 BP 751 EP 762 DI 10.1007/s00395-010-0113-4 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 672MO UT WOS:000283589000007 PM 20680307 ER PT J AU Kang, CS Riazuddin, S Mundorff, J Krasnewich, D Friedman, P Mullikin, JC Drayna, D AF Kang, Changsoo Riazuddin, Sheikh Mundorff, Jennifer Krasnewich, Donna Friedman, Penelope Mullikin, James C. Drayna, Dennis TI Genetic studies of stuttering SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 40th Annual Meeting of Behavior-Genetics-Association CY MAY, 2009 CL State Coll, Pennsylvania, PA SP Behavior Genet Assoc HO State Coll C1 [Kang, Changsoo; Drayna, Dennis] NIDCD, NIH, Bethesda, MD USA. [Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Mundorff, Jennifer] Hollins Communicat Res Inst, Roanoke, VA USA. [Krasnewich, Donna] NHGRI, NIH, Bethesda, MD 20892 USA. [Friedman, Penelope] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, Genome Technol Branch, 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 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2010 VL 40 IS 6 SI SI BP 798 EP 798 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 686KW UT WOS:000284696200054 ER PT J AU Jo, JO Kim, SR Bae, MK Kang, YJ Ock, MS Kleinman, HK Cha, HJ AF Jo, Jin-Ok Kim, Su-Ryun Bae, Moon-Kyung Kang, Yun-Jeong Ock, Mee Sun Kleinman, Hynda K. Cha, Hee-Jae TI Thymosin beta 4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1 alpha-dependent manner SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Thymosin beta 4; VEGF; HIF-1 alpha; Hypoxia; Angiogenesis; Protein stability ID UBIQUITIN-PROTEASOME PATHWAY; ACTIN-SEQUESTERING PROTEIN; PROMOTES ANGIOGENESIS; COLORECTAL-CARCINOMA; FACTOR 1-ALPHA; CELLS; BETA(4); GENE; METASTASIS; STABILIZATION AB Thymosin beta 4 has multi-functional roles in cell physiology, but little is known about its mechanism(s) of action. We previously reported that thymosin beta 4 stimulated angiogenesis through the induction of vascular endothelial growth factor (VEGF). To identify the mechanism of VEGF induction by thymosin beta 4, we have used a luciferase assay system with VEGF in the 5' promoter region. We also analyzed the effect of thymosin beta 4 on VEGF mRNA stability and on the expression and stability of hypoxia-inducible factor (HIF)-1 alpha. We found that thymosin beta 4 induces VEGF expression by an increase in the stability of HIF-1 alpha protein. Analysis of the expression patterns of thymosin beta 4 and HIF-1 alpha in colon cancer tissue microarray showed that thymosin beta 4 and HIF-1 alpha co-localized in these biopsies. These data show that thymosin beta 4 induces the expression of VEGF indirectly by increasing the protein stability of HIF-1 alpha. (C) 2010 Elsevier B.V. All rights reserved. C1 [Jo, Jin-Ok; Kang, Yun-Jeong; Ock, Mee Sun; Cha, Hee-Jae] Kosin Univ, Dept Parasitol & Genet, Coll Med, Pusan 602703, South Korea. [Cha, Hee-Jae] Kosin Univ, Inst Med Sci, Coll Med, Pusan 602703, South Korea. [Kim, Su-Ryun; Bae, Moon-Kyung] Pusan Natl Univ, Dept Physiol, Sch Dent, Pusan, South Korea. [Kleinman, Hynda K.] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD USA. RP Cha, HJ (reprint author), Kosin Univ, Dept Parasitol & Genet, Coll Med, 34 Annam Dong, Pusan 602703, South Korea. EM hcha@kosin.ac.kr FU Korea government (MEST) [KRF-20090066740] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (KRF-20090066740). NR 34 TC 24 Z9 24 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD NOV PY 2010 VL 1803 IS 11 BP 1244 EP 1251 DI 10.1016/j.bbamcr.2010.07.005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 657DC UT WOS:000282391600002 PM 20691219 ER PT J AU Sun, IC Lee, S Koo, H Kwon, IC Choi, K Ahn, CH Kim, K AF Sun, In-Cheol Lee, Seulki Koo, Heebeom Kwon, Ick Chan Choi, Kuiwon Ahn, Cheol-Hee Kim, Kwangmeyung TI Caspase Sensitive Gold Nanoparticle for Apoptosis Imaging in Live Cells SO BIOCONJUGATE CHEMISTRY LA English DT Article ID SOLE CRITERION; PHOSPHATIDYLSERINE; CLEAVAGE; DNA AB We developed a new apoptosis imaging probe with gold nanoparticles (AuNPs). A near-infrared fluorescence dye was attached to AuNP surface through the bridge of peptide substrate (DEVD). The fluorescence was quenched in physiological conditions due to the quenching effect of AuNP, and the quenched fluorescence was recovered after the DEVD had been cleaved by caspase-3, the enzyme involved in apoptotic process. The adhesion of DEVD substrates on AuNP surface was accomplished by conjugation of the 3,4-dihydroxy phenylalanine (DOPA) groups which are adhesive to inorganic surface and rich in mussels. This surface modification with DEVD substrates by DOPA groups resulted in increased stability of AuNP in cytosol condition for hours. Moreover, the cleavage of substrate and the dequenching process are very fast, and the cells did not need to be fixed for imaging. Therefore, the real-time monitoring of caspase activity could be achieved in live cells, which enabled early detection of apoptosis compared to a conventional apoptosis kit such as Annexin V-FITC. Therefore, our apoptosis imaging has great potential as a simple, inexpensive, and efficient apoptosis imaging probe for biomedical applications. C1 [Ahn, Cheol-Hee] Seoul Natl Univ, Dept Mat Sci & Engn, Res Inst Adv Mat, Seoul 151744, South Korea. [Sun, In-Cheol; Koo, Heebeom; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung] Korea Inst Sci & Technol, Biomed Res Ctr, Seoul 136791, South Korea. [Lee, Seulki] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Ahn, CH (reprint author), Seoul Natl Univ, Dept Mat Sci & Engn, Res Inst Adv Mat, San 56-1, Seoul 151744, South Korea. EM chahn@snu.ac.kr; kim@kist.re.kr FU MEST [2010-0019863, 2010-0019864]; Korea Health 21 RD Project [A062254] FX This research was financially supported by the Real-Time Molecular Imaging Project, GRL Program, M.D.-Ph.D. Program (2010-0019863, 2010-0019864) of MEST, and by a grant (A062254) of the Korea Health 21 R&D Project. NR 13 TC 32 Z9 35 U1 6 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD NOV PY 2010 VL 21 IS 11 BP 1939 EP 1942 DI 10.1021/bc1003026 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 680AT UT WOS:000284203200001 PM 20936793 ER PT J AU Miller, FG Truog, RD Brock, DW AF Miller, Franklin G. Truog, Robert D. Brock, Dan W. TI MORAL FICTIONS AND MEDICAL ETHICS SO BIOETHICS LA English DT Article DE fictions; end-of-life decisions; withdrawing life-sustaining treatment; euthanasia ID ASSISTED SUICIDE; DEATH; REFUSAL; DOCTORS; KILL AB Conventional medical ethics and the law draw a bright line distinguishing the permitted practice of withdrawing life-sustaining treatment from the forbidden practice of active euthanasia by means of a lethal injection. When clinicians justifiably withdraw life-sustaining treatment, they allow patients to die but do not cause, intend, or have moral responsibility for, the patient's death. In contrast, physicians unjustifiably kill patients whenever they intentionally administer a lethal dose of medication. We argue that the differential moral assessment of these two practices is based on a series of moral fictions - motivated false beliefs that erroneously characterize withdrawing life-sustaining treatment in order to bring accepted end-of-life practices in line with the prevailing moral norm that doctors must never kill patients. When these moral fictions are exposed, it becomes apparent that conventional medical ethics relating to end-of-life decisions is radically mistaken. C1 [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Brock, Dan W.] Harvard Univ, Sch Med, Div Med Eth, Cambridge, MA 02138 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 19 TC 26 Z9 26 U1 3 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD NOV PY 2010 VL 24 IS 9 BP 453 EP 460 DI 10.1111/j.1467-8519.2009.01738.x PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 658RH UT WOS:000282506600003 PM 19594726 ER PT J AU Saenz, C AF Saenz, Carla TI VIRTUE ETHICS AND THE SELECTION OF CHILDREN WITH IMPAIRMENTS: A REPLY TO ROSALIND MCDOUGALL SO BIOETHICS LA English DT Article DE virtue ethics; child selection; disability; Rosalind McDougall; Parenthood AB In 'Parental Virtues: A New Way of Thinking about the Morality of Reproductive Actions' Rosalind McDougall proposes a virtue-based framework to assess the morality of child selection. Applying the virtue-based account to the selection of children with impairments does not lead, according to McDougall, to an unequivocal answer to the morality of selecting impaired children. In 'Impairment, Flourishing, and the Moral Nature of Parenthood,' she also applies the virtue-based account to the discussion of child selection, and claims that couples with an impairment are morally justified in selecting a child with the same impairment. This claim, she maintains, reveals that the flourishing of a child should be understood as requiring environment-specific characteristics. I argue that McDougall's argument begs the question. More importantly, it does not do justice to virtue ethics. I also question to what extent a virtue ethics framework can be successfully applied to discussions about the moral permissibility of reproductive actions. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Saenz, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10-1C118, Bethesda, MD 20892 USA. EM saenzca@cc.nih.gov NR 3 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-9702 J9 BIOETHICS JI Bioethics PD NOV PY 2010 VL 24 IS 9 BP 499 EP 506 DI 10.1111/j.1467-8519.2009.01732.x PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 658RH UT WOS:000282506600008 PM 19508307 ER PT J AU Stojmirovic, A Yu, YK AF Stojmirovic, Aleksandar Yu, Yi-Kuo TI Robust and accurate data enrichment statistics via distribution function of sum of weights SO BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION DATA; SET ENRICHMENT; INFORMATION-FLOW; ONTOLOGY TERMS; TRANSCRIPTOME; KNOWLEDGE; NETWORKS; TOOL AB Motivation: Term-enrichment analysis facilitates biological interpretation by assigning to experimentally/computationally obtained data annotation associated with terms from controlled vocabularies. This process usually involves obtaining statistical significance for each vocabulary term and using the most significant terms to describe a given set of biological entities, often associated with weights. Many existing enrichment methods require selections of (arbitrary number of) the most significant entities and/or do not account for weights of entities. Others either mandate extensive simulations to obtain statistics or assume normal weight distribution. In addition, most methods have difficulty assigning correct statistical significance to terms with few entities. Results: Implementing the well-known Lugananni-Rice formula, we have developed a novel approach, called SaddleSum, that is free from all the aforementioned constraints and evaluated it against several existing methods. With entity weights properly taken into account, SaddleSum is internally consistent and stable with respect to the choice of number of most significant entities selected. Making few assumptions on the input data, the proposed method is universal and can thus be applied to areas beyond analysis of microarrays. Employing asymptotic approximation, SaddleSum provides a term-size-dependent score distribution function that gives rise to accurate statistical significance even for terms with few entities. As a consequence, SaddleSum enables researchers to place confidence in its significance assignments to small terms that are often biologically most specific. C1 [Stojmirovic, Aleksandar; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov OI Stojmirovic, Aleksandar/0000-0003-0957-6893 FU National Library of Medicine at the National Institutes of Health FX Funding: Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 32 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD NOV PY 2010 VL 26 IS 21 BP 2752 EP 2759 DI 10.1093/bioinformatics/btq511 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 673LT UT WOS:000283665000015 PM 20826881 ER PT J AU Cheng, TJ Wang, YL Bryant, SH AF Cheng, Tiejun Wang, Yanli Bryant, Stephen H. TI Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules SO BIOINFORMATICS LA English DT Article ID DRUG DISCOVERY DATABASES; HEAT-SHOCK RESPONSE; CAMPTOTHECIN ANALOG; ELLIPTICINE ANALOGS; GROWTH-INHIBITION; PUBCHEM; CANCER; IDENTIFICATION; RESOURCE; MECHANISMS AB Motivation: Most of the previous data mining studies based on the NCI-60 dataset, due to its intrinsic cell-based nature, can hardly provide insights into the molecular targets for screened compounds. On the other hand, the abundant information of the compound-target associations in PubChem can offer extensive experimental evidence of molecular targets for tested compounds. Therefore, by taking advantages of the data from both public repositories, one may investigate the correlations between the bioactivity profiles of small molecules from the NCI-60 dataset ( cellular level) and their patterns of interactions with relevant protein targets from PubChem ( molecular level) simultaneously. Results: We investigated a set of 37 small molecules by providing links among their bioactivity profiles, protein targets and chemical structures. Hierarchical clustering of compounds was carried out based on their bioactivity profiles. We found that compounds were clustered into groups with similar mode of actions, which strongly correlated with chemical structures. Furthermore, we observed that compounds similar in bioactivity profiles also shared similar patterns of interactions with relevant protein targets, especially when chemical structures were related. The current work presents a new strategy for combining and data mining the NCI-60 dataset and PubChem. This analysis shows that bioactivity profile comparison can provide insights into the mode of actions at the molecular level, thus will facilitate the knowledge-based discovery of novel compounds with desired pharmacological properties. C1 [Cheng, Tiejun; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010 OI Cheng, Tiejun/0000-0002-4486-3356 FU National Institutes of Health, National Library of Medicine FX Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 40 TC 16 Z9 16 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD NOV PY 2010 VL 26 IS 22 BP 2881 EP 2888 DI 10.1093/bioinformatics/btq550 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 676NS UT WOS:000283919800012 PM 20947527 ER PT J AU Hostetler, JA Onorato, DP Nichols, JD Johnson, WE Roelke, ME O'Brien, SJ Jansen, D Oli, MK AF Hostetler, Jeffrey A. Onorato, David P. Nichols, James D. Johnson, Warren E. Roelke, Melody E. O'Brien, Stephen J. Jansen, Deborah Oli, Madan K. TI Genetic introgression and the survival of Florida panther kittens SO BIOLOGICAL CONSERVATION LA English DT Article DE Burnham model; Carnivore; Florida panther; Juvenile; Model averaging; Survival ID LIFE-HISTORY VARIABLES; POPULATION-GROWTH RATE; ET-AL. 2006; INBREEDING DEPRESSION; RELATIVE IMPORTANCE; MULE DEER; CONSERVATION; CATS; MICROSATELLITES; CONSEQUENCES AB Estimates of survival for the young of a species are critical for population models. These models can often be improved by determining the effects of management actions and population abundance on this demographic parameter. We used multiple sources of data collected during 1982-2008 and a live-recapture dead-recovery modeling framework to estimate and model survival of Florida panther (Puma concolor coryi) kittens (age 0-1 year). Overall, annual survival of Florida panther kittens was 0.323 +/- 0.071 (SE), which was lower than estimates used in previous population models. In 1995, female pumas from Texas (P. c. stanleyana) were released into occupied panther range as part of an intentional introgression program to restore genetic variability. We found that kitten survival generally increased with degree of admixture: F-1 admixed and backcrossed to Texas kittens survived better than canonical Florida panther and backcrossed to canonical kittens. Average heterozygosity positively influenced kitten and older panther survival, whereas index of panther abundance negatively influenced kitten survival. Our results provide strong evidence for the positive population-level impact of genetic introgression on Florida panthers. Our approach to integrate data from multiple sources was effective at improving robustness as well as precision of estimates of Florida panther kitten survival, and can be useful in estimating vital rates for other elusive species with sparse data. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Hostetler, Jeffrey A.; Oli, Madan K.] Univ Florida, Dept Wildlife Ecol & Conservat, Gainesville, FL 32611 USA. [Onorato, David P.] Florida Fish & Wildlife Conservat Commiss, Fish & Wildlife Res Inst, Naples, FL 34114 USA. [Nichols, James D.] US Geol Survey, Patuxent Wildlife Res Ctr, Laurel, MD 20708 USA. [Johnson, Warren E.; Roelke, Melody E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Roelke, Melody E.] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Jansen, Deborah] Big Cypress Natl Preserve, Ochopee, FL 34141 USA. RP Hostetler, JA (reprint author), Univ Florida, Dept Wildlife Ecol & Conservat, 110 Newins Ziegler Hall, Gainesville, FL 32611 USA. EM hostetle@ufl.edu RI Hostetler, Jeffrey/A-3345-2011; Johnson, Warren/D-4149-2016 OI Hostetler, Jeffrey/0000-0003-3669-1758; Johnson, Warren/0000-0002-5954-186X FU Florida Panther Research and Management Trust Fund; National Park Service; University of Florida; United States Fish and Wildlife Service [401816G091] FX We thank D. Land, M. Cunningham, Roy McBride, M. Lotz, D. Shindle, M. Criffield, S. Schulze, D. Giardina, A. Johnson, L. Oberhofer, M. Alvarado, H. Fitting and Rocky, Rowdy, and C. McBride and others for assistance with fieldwork. We also thank B. Bolker, J. Hines, G. White, J. Laake, and E. Cooch for technical and statistical advice, and D. Land, T. O'Meara, J. Gore, P. Beier, and two anonymous reviewers for reviewing earlier versions of this manuscript. This work was funded through the Florida Panther Research and Management Trust Fund, National Park Service, University of Florida, and Grant Agreement No: 401816G091 from the United States Fish and Wildlife Service. The views and conclusions presented herein are those of the authors and do not necessarily reflect the views and conclusions of the federal government. NR 69 TC 14 Z9 15 U1 4 U2 80 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0006-3207 EI 1873-2917 J9 BIOL CONSERV JI Biol. Conserv. PD NOV PY 2010 VL 143 IS 11 BP 2789 EP 2796 DI 10.1016/j.biocon.2010.07.028 PG 8 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 670HR UT WOS:000283412300043 PM 21113436 ER PT J AU Salvadore, G Zarate, CA AF Salvadore, Giacomo Zarate, Carlos A., Jr. TI Magnetic Resonance Spectroscopy Studies of the Glutamatergic System in Mood Disorders: A Pathway to Diagnosis, Novel Therapeutics, and Personalized Medicine? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID MAJOR DEPRESSION C1 [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv,CRC, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv,CRC, 10 Ctr Dr,7 Southeast Unit,Room 7-3465, Bethesda, MD 20892 USA. EM zaratec@intra.nimh.nih.gov FU Intramural NIH HHS [ZIA MH002857-06] NR 8 TC 10 Z9 10 U1 0 U2 2 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 NOV 1 PY 2010 VL 68 IS 9 BP 780 EP 782 DI 10.1016/j.biopsych.2010.09.011 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 672TA UT WOS:000283608600001 PM 20946973 ER PT J AU Terracciano, A Tanaka, T Sutin, AR Sanna, S Deiana, B Lai, S Uda, M Schlessinger, D Abecasis, GR Ferrucci, L Costa, PT AF Terracciano, Antonio Tanaka, Toshiko Sutin, Angelina R. Sanna, Serena Deiana, Barbara Lai, Sandra Uda, Manuela Schlessinger, David Abecasis, Goncalo R. Ferrucci, Luigi Costa, Paul T., Jr. TI Genome-Wide Association Scan of Trait Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Depression; GRM8; GWA; mGlu8; neuroticism; RORA ID METABOTROPIC GLUTAMATE RECEPTORS; MAMMALIAN CIRCADIAN CLOCK; POPULATION-BASED TWIN; NEO-PI-R; MAJOR DEPRESSION; PERSONALITY-TRAITS; BIPOLAR DISORDER; ANXIOLYTIC-LIKE; MOOD DISORDERS; CANDIDATE GENE AB Background: Independent of temporal circumstances, some individuals have greater susceptibility to depressive affects, such as feelings of guilt, sadness, hopelessness, and loneliness. Identifying the genetic variants that contribute to these individual differences can point to biological pathways etiologically involved in psychiatric disorders. Methods: Genome-wide association scans for the depression scale of the Revised NEO Personality Inventory in community-based samples from a genetically homogeneous area of Sardinia, Italy (n = 3972) and from the Baltimore Longitudinal Study of Aging in the United States (n = 839). Results: Meta-analytic results for genotyped or imputed single nucleotide polymorphisms indicate that the strongest association signals for trait depression were found in RORA (rs12912233; p = 6 x 10(-7)), a gene involved in circadian rhythm. A plausible biological association was also found with single nucleotide polymorphisms within GRM8 (rs17864092; p = 5 x 10(-6)), a metabotropic receptor for glutamate, a major excitatory neurotransmitter in the central nervous system. Conclusions: These findings suggest shared genetic basis underlying the continuum from personality traits to psychopathology. C1 [Terracciano, Antonio] NIA, NIH, Dept Hlth & Human Serv, Lab Personal & Cognit, Baltimore, MD 21224 USA. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Sanna, Serena; Deiana, Barbara; Lai, Sandra; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Terracciano, A (reprint author), NIA, NIH, Dept Hlth & Human Serv, Lab Personal & Cognit, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Terraccianoa@mail.nih.gov RI Abecasis, Goncalo/B-7840-2010; terracciano, antonio/B-1884-2008; OI sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Costa, Paul/0000-0003-4375-1712 FU National Institutes of Health, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 76 TC 66 Z9 67 U1 1 U2 18 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 NOV 1 PY 2010 VL 68 IS 9 BP 811 EP 817 DI 10.1016/j.biopsych.2010.06.030 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 672TA UT WOS:000283608600006 PM 20800221 ER PT J AU Porter, DL Alyea, EP Antin, JH DeLima, M Estey, E Falkenburg, JHF Hardy, N Kroeger, N Leis, J Levine, J Maloney, DG Peggs, K Rowe, JM Wayne, AS Giralt, S Bishop, MR van Besien, K AF Porter, David L. Alyea, Edwin P. Antin, Joseph H. DeLima, Marcos Estey, Eli Falkenburg, J. H. Frederik Hardy, Nancy Kroeger, Nicolaus Leis, Jose Levine, John Maloney, David G. Peggs, Karl Rowe, Jacob M. Wayne, Alan S. Giralt, Sergio Bishop, Michael R. van Besien, Koen TI NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic hematopoietic stem cell transplantation; Treatment; Donor lymphocyte infusion ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; GRAFT-VERSUS-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; DONOR LEUKOCYTE INFUSIONS; CHRONIC MYELOGENOUS LEUKEMIA; NON-HODGKIN-LYMPHOMA; MINIMAL RESIDUAL DISEASE; MINOR HISTOCOMPATIBILITY ANTIGENS AB Relapse is a major cause of treatment failure after allogeneic hematopoietic stern cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT. C1 [Porter, David L.] Univ Penn, Div Hematol Oncol, Med Ctr, Philadelphia, PA 19104 USA. [Alyea, Edwin P.; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [DeLima, Marcos; Giralt, Sergio] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Estey, Eli; Maloney, David G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Falkenburg, J. H. Frederik] Leiden Univ, Med Ctr, Leiden, Netherlands. [Kroeger, Nicolaus] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Leis, Jose] Mayo Clin, Scottsdale, AZ USA. [Levine, John] Univ Michigan, Ann Arbor, MI 48109 USA. [Peggs, Karl] UCL, London, England. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [van Besien, Koen] Univ Chicago, Chicago, IL 60637 USA. RP Porter, DL (reprint author), Univ Penn, Div Hematol Oncol, Med Ctr, PCAM 2 W Pavil,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM david.porter@uphs.upenn.edu RI PEGGS, Karl/B-3869-2009; van Besien, Koen/G-4221-2012 OI van Besien, Koen/0000-0002-8164-6211 FU NCI NIH HHS [K24 CA117879] NR 321 TC 62 Z9 63 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2010 VL 16 IS 11 BP 1467 EP 1503 DI 10.1016/j.bbmt.2010.08.001 PG 37 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 675KY UT WOS:000283830800001 PM 20699125 ER PT J AU McIver, Z Stephens, N Grim, A Barrett, AJ AF McIver, Zachariah Stephens, Nicole Grim, Andrew Barrett, A. John TI Rituximab Administration within 6 Months of T Cell-Depleted Allogeneic SCT is Associated with Prolonged Life-Threatening Cytopenias SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic; T cell deplete; Stem cell transplant; Cytopenia; Neutrophenia; Transplant-related mortality ID LATE-ONSET NEUTROPENIA; VERSUS-HOST-DISEASE; LYMPHOMA PATIENTS; TRANSPLANTATION; PROLIFERATION; LEUKEMIA; THERAPY; RISK AB The monoclonal anti-CD20 antibody Rituximab (RTX) is increasingly used in allogeneic stem cell transplantation (SCT) to treat lymphoproliferative disorders and chronic graft-versus-host disease (GVHD). RTX administration can be complicated by delayed and prolonged neutropenia, but the mechanism is unclear. We report the occurrence of profound cytopenias following RTX given in the conditioning regimen or early after T cell-deplete SCT to treat B cell lymphoproliferative disorders or chronic GVHD (cGVHD). Between 2006 and 2009, 102 patients (median age: 43 years, range: 13-68 years), received a myeloablative matched-sibling T cell-deplete SCT for lymphoid or myeloid hematologic disorders. Neutropenia occurring within 4 weeks of treatment developed in 16 of 17 patients given RTX within the first 190 days after SCT. Fourteen patients developed severe neutropenia (count <0.5 K/mu L) lasting up to 10 months and 12 required hospitalization to treat severe neutropenic infections. Six of the 14 patients died of infection complicating GVHD treatment. Recovery of lymphocytes and immunoglobulins was also delayed, with a significantly lower absolute lymphocyte counts (ALC) at 9 months and 12 months post-SCT compared to patients with cGVHD not treated with early RTX (P <.02). In contrast, patients receiving RTX 1 year after SCT experienced only moderate neutropenia 3 to 5 months after treatment lasting 10 to 20 days while maintaining absolute neutrophil count (ANC) >1.0 x 10(9)/L. Although RTX rapidly controlled cGVHD, we conclude that its administration early after T cell-deplete SCT is associated with prolonged profound and life-threatening cytopenias, and should be avoided. C1 [McIver, Zachariah; Stephens, Nicole; Grim, Andrew; Barrett, A. John] NIH, Stem Cell Allotransplantat Sect, Hematol Branch, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. RP McIver, Z (reprint author), NIH, Stem Cell Allotransplantat Sect, Hematol Branch, Heart Lung & Blood Inst, Room 3-5288,10 Ctr Dr, Bethesda, MD 20892 USA. EM mciverza@nhibi.nih.gov NR 22 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2010 VL 16 IS 11 BP 1549 EP 1556 DI 10.1016/j.bbmt.2010.05.004 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 675KY UT WOS:000283830800006 PM 20580848 ER PT J AU Yin, WY Majumder, S Clayton, T Petrou, S VanLinn, ML Namjoshi, OA Ma, C Cromer, BA Roth, BL Platt, DM Cook, JM AF Yin, Wenyuan Majumder, Samarpan Clayton, Terry Petrou, Steven VanLinn, Michael L. Namjoshi, Ojas A. Ma, Chunrong Cromer, Brett A. Roth, Bryan L. Platt, Donna M. Cook, James M. TI Design, synthesis, and subtype selectivity of 3,6-disubstituted beta-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Beta-carboline; Benzodiazepine; Alcohol antagonist; GABA receptor ID AMINOBUTYRIC ACID(A) RECEPTORS; BENZODIAZEPINE BINDING-SITE; ETHANOL-MAINTAINED BEHAVIORS; CONDITIONED PLACE PREFERENCE; PREFERRING P RAT; GABA(A) RECEPTOR; VENTRAL PALLIDUM; INVERSE AGONIST; BIVALENT LIGANDS; PHARMACOLOGICAL-PROPERTIES AB A series of 3,6-disubstituted beta-carbolines was synthesized and evaluated for their in vitro affinities at alpha(x)beta(3)gamma(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of alpha(1) subtype selective ligands to treat alcohol abuse. Analogues of beta-carboline-3-carboxylate-t-butyl ester (beta CCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted beta-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-beta CCt (5). The bivalent ligands of bCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the b-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the beta-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel b-carboline ligands (bCCt, 3PBC and WYS8), which preferentially bound to alpha 1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these b-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) a1 selective ligand was the 6-substituted acetylenyl bCCt (WYS8, 7). Earlier both bCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration. 1-3 Moreover, these two b-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the bcarbolines presented here. Published by Elsevier Ltd. C1 [Yin, Wenyuan; Clayton, Terry; VanLinn, Michael L.; Namjoshi, Ojas A.; Ma, Chunrong; Cook, James M.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53201 USA. [Majumder, Samarpan; Roth, Bryan L.] Univ N Carolina Chapel Hill Med Sch, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Majumder, Samarpan; Roth, Bryan L.] Univ N Carolina Chapel Hill Med Sch, Div Med Chem, Chapel Hill, NC 27599 USA. [Majumder, Samarpan; Roth, Bryan L.] NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Majumder, Samarpan; Roth, Bryan L.] Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. [Petrou, Steven; Cromer, Brett A.] Univ Melbourne, Howard Florey Inst, Parkville, Vic 3010, Australia. [Cromer, Brett A.] Univ Melbourne, Dept Pharmacol, Parkville, Vic 3010, Australia. [Platt, Donna M.] Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. RP Cook, JM (reprint author), Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53201 USA. EM capncook@uwm.edu RI Roth, Bryan/F-3928-2010; Petrou, Steven/M-8332-2013; Yin, Wenyuan/I-6517-2016; OI Yin, Wenyuan/0000-0002-6108-6421; zaraat, javad/0000-0001-5341-7481; Namjoshi, Ojas/0000-0002-2142-3702; Cromer, Brett/0000-0003-0743-1535 FU NIMH [046851]; NIAAA [AA016179]; NCRR [RR00168]; Research Growth Initiative of the University of Wisconsin-Milwaukee; Lynde and Harry Bradley Foundation FX This work was supported in part by NIMH 046851 (J.M.C.) as well as NIAAA AA016179 (DMP) and NCRR RR00168 (DMP). We acknowledge support of this work by the Research Growth Initiative of the University of Wisconsin-Milwaukee and the Lynde and Harry Bradley Foundation. NR 141 TC 11 Z9 11 U1 1 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 1 PY 2010 VL 18 IS 21 BP 7548 EP 7564 DI 10.1016/j.bmc.2010.08.049 PG 17 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 663RA UT WOS:000282904200022 PM 20888240 ER PT J AU Dickstein, DP Finger, EC Skup, M Pine, DS Blair, JR Leibenluft, E AF Dickstein, Daniel P. Finger, Elizabeth C. Skup, Martha Pine, Daniel S. Blair, James R. Leibenluft, Ellen TI Altered neural function in pediatric bipolar disorder during reversal learning SO BIPOLAR DISORDERS LA English DT Article DE adolescent; bipolar disorder; child; magnetic resonance imaging; reversal learning ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; VOXEL-BASED MORPHOMETRY; EVENT-RELATED FMRI; PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; RESPONSE-REVERSAL; DECISION-MAKING; I DISORDER; COGNITIVE FLEXIBILITY AB Objective: Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial-and-error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event-related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. Method: We compared euthymic pediatric BD participants (n = 16) versus age-, sex-, and IQ-matched controls (n = 16). Our main outcome measure was blood oxygen level-dependent (BOLD) signal measured with fMRI during an event-related probabilistic reversal task. Results: Pediatric BD participants had significantly greater neural activity than controls in fronto-parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). Conclusions: Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations. C1 [Dickstein, Daniel P.] Brown Univ, Bradley Hasbro Childrens Res Ctr, EP Bradley Hosp, Providence, RI 02903 USA. [Dickstein, Daniel P.; Finger, Elizabeth C.; Skup, Martha; Pine, Daniel S.; Blair, James R.; Leibenluft, Ellen] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Dickstein, Daniel P.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Finger, Elizabeth C.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. [Skup, Martha] Yale Univ, Biostat Program, New Haven, CT USA. RP Dickstein, DP (reprint author), Brown Univ, Bradley Hasbro Childrens Res Ctr, EP Bradley Hosp, 1 Hoppin St,Coro W 2nd Floor, Providence, RI 02903 USA. EM daniel_dickstein@brown.edu RI Finger, Elizabeth/B-6453-2015; Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU NIMH [K22 MH74945]; NARSAD FX This research was supported by the NIMH Division of Intramural Research Programs, K22 MH74945 (PI: DPD, sponsor: EL), and a NARSAD Young Investigator Award (PI: DPD, sponsor: EL). We gratefully thank all of the participants and their families, without whom this study would not be possible. We also truly appreciate the work of the NIMH DIRP's Section on Bipolar Spectrum Disorders and NIH's fMRI facility. NR 88 TC 33 Z9 33 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD NOV PY 2010 VL 12 IS 7 BP 707 EP 719 DI 10.1111/j.1399-5618.2010.00863.x PG 13 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 673VA UT WOS:000283690700009 PM 21040288 ER PT J AU Kettermann, AE Ferrucci, L Trock, BJ Metter, EJ Loeb, S Carter, HB AF Kettermann, Anna E. Ferrucci, Luigi Trock, Bruce J. Metter, E. Jeffrey Loeb, Stacy Carter, H. Ballentine TI Interpretation of the prostate-specific antigen history in assessing life-threatening prostate cancer SO BJU INTERNATIONAL LA English DT Article DE PSA; prostate cancer; kinetics; velocity ID RADICAL PROSTATECTOMY; PSA VELOCITY; DOUBLING TIME; RISK; PREDICTORS; CURABILITY; MORTALITY; KINETICS; PROGRAM; WINDOW AB OBJECTIVE To present an effective approach to the early detection of lethal prostate cancer using longitudinal data on prostate-specific antigen (PSA) and its rate of change, i.e. PSA velocity (PSAV). This longitudinal approach might also be extendible to other biomarkers. SUBJECTS AND METHODS PSAV was calculated using five techniques for 634 subjects with at least three PSA measurements in a longitudinal ageing study, censoring PSA levels of > 10 ng/mL. The efficacy for predicting death from prostate cancer was assessed with concordance indices and by using net reclassification improvement (NRI), which indicated the net increase in sensitivity and specificity when adding a biomarker to a base Cox proportional hazards model. The PSAV techniques were compared for the 5-10 years before the clinical diagnosis of prostate cancer. The most effective technique was then applied at the transition point when each man's PSA history curve transformed from linear to exponentially increasing, and its predictive value was compared to that of concurrent PSA level. RESULTS A PSA transition point was found in 522 (82%) of the 634 men, including all 11 who died from prostate cancer. At the transition point, the mean PSA level was 1.4 ng/mL, and PSAV but not PSA level was significantly higher among men who died from prostate cancer than among men who did not (P = 0.021 vs P = 0.112; Wilcoxon two-sample test). At the transition point, adding PSAV to a base model consisting of age and date of diagnosis improved the concordance index by 0.05, and significantly improved the overall sensitivity and specificity (NRI, P = 0.028), while adding PSA level to the same base model resulted in little improvement (concordance index increase < 0.01 and NRI P = 0.275). CONCLUSION When the shape of a man's PSA history curve changes from linear to exponential, PSAV might help in the early identification of life-threatening prostate cancer at a time when PSA values are still low in most men. C1 [Kettermann, Anna E.; Trock, Bruce J.; Loeb, Stacy; Carter, H. Ballentine] Johns Hopkins Univ Sch Med, Dept Urol, James Buchanan Brady Urol Inst, Johns Hopkins Hosp, Baltimore, MD USA. [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. RP Kettermann, AE (reprint author), 5121 Kenesaw St, College Pk, MD 20740 USA. EM akettermann@yahoo.com OI Loeb, Stacy/0000-0003-3933-9207 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 28 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD NOV PY 2010 VL 106 IS 9 BP 1284 EP 1290 DI 10.1111/j.1464-410X.2010.09363.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 665XL UT WOS:000283070700007 PM 20477823 ER PT J AU Wilt, TJ MacDonald, R Hagerty, K Schellhammer, P Tacklind, J Somerfield, MR Kramer, BS AF Wilt, Timothy J. MacDonald, Roderick Hagerty, Karen Schellhammer, Paul Tacklind, James Somerfield, Mark R. Kramer, Barnett S. TI 5-alpha-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review SO BJU INTERNATIONAL LA English DT Review DE 5-alpha-reductase inhibitor; prostate cancer; prevention; systematic review ID RANDOMIZED CONTROLLED-TRIAL; FINASTERIDE; HYPERPLASIA; MEN; DUTASTERIDE; ANTIGEN; PREVENTION; EFFICACY; SAFETY AB OBJECTIVE To estimate the benefits and harms of 5-alpha-reductase inhibitors (5-alpha-RIs) in preventing prostate cancer. MATERIALS AND METHODS We searched MEDLINE and the Cochrane Collaboration Library through June 2010 to identify randomized trials. We included articles if they examined 5-alpha-RI vs control, were >= 1 year in duration and provided clinical outcomes. Our primary outcome was prostate cancer period-prevalence 'for-cause'. RESULTS Eight studies met inclusion criteria but only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events were designed to assess the impact of 5-alpha-RIs on prostate cancer period-prevalence. The mean age of enrolees was 64 years, 92% were White, and mean PSA level was 3.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected in placebo-controlled studies. Compared with placebo, 5-alpha-RI resulted in a 25% relative risk (RR) reduction in prostate cancers detected for-cause [RR 0.75, 95% confidence interval (CI) 0.67-0.83; 1.4% absolute risk reduction (3.5% vs 4.9%)]. One BPH trial reported that the risk of prostate cancers detected for-cause was significantly reduced with dutasteride and combined dutasteride plus tamsulosin compared with tamsulosin monotherapy. Six trials vs placebo assessed prostate cancers detected overall. There was a 26% RR reduction favouring 5-alpha-RI [RR 0.74, 95% CI 0.55-1.00; 2.9% absolute risk reduction (6.3% vs 9.2%)]. There were reductions across categories of age, race and family history of prostate cancer. One placebo-controlled trial of men that investigators considered at greater risk for prostate cancer (based on age, elevated PSA level and having a previous suspicion of prostate cancer leading to a prostate biopsy) reported that dutasteride did not reduce prostate cancers detected for-cause based on needle-biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23% [RR 0.77, 95% CI 0.70-0.85; absolute reduction 16.1% vs 20.8%]. There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. Incidences of erectile dysfunction, ejaculate volume, decreased libido, and gynaecomastia were greater with 5-alpha-RI vs placebo. CONCLUSIONS 5-alpha-RIs reduce the risk of being diagnosed with prostate cancer among men who are screened regularly for prostate cancer. Information is inadequate to assess the effect of 5-alpha-RIs on prostate cancer or all-cause mortality. 5-alpha-RIs increase sexual and erectile dysfunction. C1 [Wilt, Timothy J.; MacDonald, Roderick; Tacklind, James] Minneapolis VA Ctr Chron Dis Outcomes Res, Minneapolis, MN 55417 USA. [Wilt, Timothy J.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Wilt, Timothy J.] Sect Gen Med Minneapolis VAMC, Minneapolis, MN USA. [Kramer, Barnett S.] NIH, Bethesda, MD 20892 USA. [Hagerty, Karen; Somerfield, Mark R.] Amer Soc Clin Oncol, Alexandria, VA USA. [Somerfield, Mark R.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. RP Wilt, TJ (reprint author), Minneapolis VA Ctr Chron Dis Outcomes Res, 1 Vet Dr 111-0, Minneapolis, MN 55417 USA. EM tim.wilt@va.gov FU American Urological Association; American Society for Clinical Oncology FX Supported in part by a contract through the American Urological Association and the American Society for Clinical Oncology. NR 20 TC 20 Z9 20 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD NOV PY 2010 VL 106 IS 10 BP 1444 EP 1451 DI 10.1111/j.1464-410X.2010.09714.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 672PI UT WOS:000283598200005 PM 20977593 ER PT J AU Thayer, JF Sternberg, EM AF Thayer, Julian F. Sternberg, Esther M. TI Neural aspects of immunomodulation: Focus on the vagus nerve SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Review DE Neural-immune; Vagus; Heart rate variability; Immune; Innervation; Brain ID HEART-RATE-VARIABILITY; TO-BRAIN COMMUNICATION; CHOLINERGIC ANTIINFLAMMATORY PATHWAY; SYMPATHETIC-NERVE; IMMUNE-SYSTEM; RAT SPLEEN; NOREPINEPHRINE; INNERVATION; CORTEX; PAIN AB Inflammation and immunity have been implicated in a wide variety of diseases and disorders ranging from Alzheimer's disease to cardiovascular disease to hemorrhagic shock In this review, we will briefly consider the evidence for the neural concomitants of immunomodulation First, we will briefly review the anatomy and physiology of neural-immune communication. Evidence for the somatotopic organization of the vagus nerve and for pain processes suggests that such an organization may be relevant for the investigation of the neural concomitants of immunity. Then we will provide an overview of what is known from both animal and human studies including neuroimaging and clinical studies Finally, we will discuss some of the challenges and opportunities in this exciting area of investigation (C) 2010 Elsevier Inc All rights reserved C1 [Thayer, Julian F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Sternberg, Esther M.] NIMH, NIH, Bethesda, MD 20892 USA. RP Thayer, JF (reprint author), Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA. FU Intramural NIH HHS [ZIA MH002585-19] NR 58 TC 47 Z9 47 U1 3 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD NOV PY 2010 VL 24 IS 8 BP 1223 EP 1228 DI 10.1016/j.bbi.2010.07.247 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 665MD UT WOS:000283038600001 PM 20674737 ER PT J AU Shen, M Menashe, I Morton, LM Zhang, YW Armstrong, B Wang, SS Lan, Q Hartge, P Purdue, MP Cerhan, JR Grulich, A Cozen, W Yeager, M Holford, TR Vajdic, CM Davis, S Leaderer, B Kricker, A Severson, RK Zahm, SH Chatterjee, N Rothman, N Chanock, SJ Zheng, TZ AF Shen, Min Menashe, Idan Morton, Lindsay M. Zhang, Yawei Armstrong, Bruce Wang, Sophia S. Lan, Qing Hartge, Patricia Purdue, Mark P. Cerhan, James R. Grulich, Andrew Cozen, Wendy Yeager, Meredith Holford, Theodore R. Vajdic, Claire M. Davis, Scott Leaderer, Brian Kricker, Anne Severson, Richard K. Zahm, Shelia H. Chatterjee, Nilanjan Rothman, Nathaniel Chanock, Stephen J. Zheng, Tongzhang TI Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma in a pooled analysis of three studies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE non-Hodgkin lymphoma; DNA repair; single nucleotide polymorphism; pooled analysis ID LIGASE-IV; PROTEIN; CELLS; BLM AB P>Genetic variations in DNA repair genes are thought to play an important role in the pathogenesis and development of non-Hodgkin lymphoma (NHL). To further explore this hypothesis, we genotyped 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions in 1946 cases and 1808 controls pooled from three population-based case-control studies of NHL in the US and Australia. Relative risks of NHL and NHL subtypes in relation to SNP genotypes were assessed using logistic regression. Associations of gene regions and pathways with NHL or NHL subtypes were explored using the minP and tail-strength statistics, respectively. Overall, genetic polymorphisms within the DNA repair pathway were associated with NHL (P = 0 center dot 005). Similar associations were seen with the double-strand break repair (P = 0 center dot 02) and nucleotide excision repair (P = 0 center dot 04) pathways. Five SNPs (BLM rs441399, RAD50 rs2237060, FAM82A2 rs2304583, ERCC3 rs4150506, and XRCC4 rs13178127) were particularly noteworthy because their gene regions were significantly associated with NHL or NHL subtypes (minP < 0 center dot 05), or because of high level of statistical significance (P < 0 center dot 005) and consistent findings across the three studies. These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL. C1 [Menashe, Idan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Rockville, MD 20852 USA. [Zhang, Yawei; Holford, Theodore R.; Leaderer, Brian; Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Armstrong, Bruce; Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Cerhan, James R.] Mayo Clin, Div Epidemiol, Coll Med, Rochester, MN USA. [Grulich, Andrew] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. [Cozen, Wendy] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Yeager, Meredith; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, DHHS,NIH, Gaithersburg, MD USA. [Vajdic, Claire M.] Univ New S Wales, Canc Res Ctr, Prince Wales Clin Sch, Sydney, NSW, Australia. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Davis, Scott] Univ Washington, Seattle, WA 98195 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. RP Menashe, I (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, DHHS,NIH, 6120 Execut Blvd,Room 5066, Rockville, MD 20852 USA. EM menashei@mail.nih.gov RI Purdue, Mark/C-9228-2016; Morton, Lindsay/B-5234-2015; Armstrong, Bruce/K-9464-2015 OI Purdue, Mark/0000-0003-1177-3108; Vajdic, Claire/0000-0002-3612-8298; Cerhan, James/0000-0002-7482-178X; Morton, Lindsay/0000-0001-9767-2310; Armstrong, Bruce/0000-0001-8940-7525 FU Intramural NIH HHS [Z01 CP010123-12] NR 14 TC 11 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2010 VL 151 IS 3 BP 239 EP 244 DI 10.1111/j.1365-2141.2010.08364.x PG 6 WC Hematology SC Hematology GA 665XB UT WOS:000283069100004 PM 20813000 ER PT J AU Ustun, TB Chatterji, S Kostanjsek, N Rehm, J Kennedy, C Epping-Jordan, J Saxena, S von Korff, M Pull, C AF Uestuen, T. Bedirhan Chatterji, Somnath Kostanjsek, Nenad Rehm, Juergen Kennedy, Cille Epping-Jordan, Joanne Saxena, Shekhar von Korff, Michael Pull, Charles CA WHO NIH Joint Project TI Developing the World Health Organization Disability Assessment Schedule 2.0 SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article ID WHODAS-II; PSYCHOMETRIC PROPERTIES; DISORDERS; RELIABILITY; DAS AB Objective To describe the development of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for measuring functioning and disability in accordance with the International Classification of Functioning, Disability and Health. WHODAS 2.0 is a standard metric for ensuring scientific comparability across different populations. Methods A series of studies was carried out globally. Over 65 000 respondents drawn from the general population and from specific patient populations were interviewed by trained interviewers who applied the WHODAS 2.0 (with 36 items in its full version and 12 items in a shortened version). Findings The WHODAS 2.0 was found to have high internal consistency (Cronbach's alpha, alpha: 0.86), a stable factor structure; high test-retest reliability (intraclass correlation coefficient: 0.98); good concurrent validity in patient classification when compared with other recognized disability measurement instruments; conformity to Rasch scaling properties across populations, and good responsiveness (i.e. sensitivity to change). Effect sizes ranged from 0.44 to 1.38 for different health interventions targeting various health conditions. Conclusion The WHODAS 2.0 meets the need for a robust instrument that can be easily administered to measure the impact of health conditions, monitor the effectiveness of interventions and estimate the burden of both mental and physical disorders across different populations. C1 [Uestuen, T. Bedirhan; Chatterji, Somnath; Kostanjsek, Nenad; Epping-Jordan, Joanne; Saxena, Shekhar] WHO, CH-1211 Geneva 27, Switzerland. [Rehm, Juergen] Univ Toronto, Toronto, ON, Canada. [von Korff, Michael] Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. [Pull, Charles] Ctr Hosp Luxembourg, Luxembourg, Luxembourg. [Kennedy, Cille] NIH, US Dept HHS, Washington, DC USA. RP Ustun, TB (reprint author), WHO, Ave Appia 20, CH-1211 Geneva 27, Switzerland. EM ustunb@who.int RI Rem, Jurgen/H-1309-2011 FU WHO/National Institutes of Health (NIH) [MH 35883-17] FX The WHODAS 2.0 development was funded through the WHO/National Institutes of Health (NIH) Joint Project on Assessment and Classification of Disability (MH 35883-17). NR 42 TC 192 Z9 201 U1 4 U2 24 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD NOV PY 2010 VL 88 IS 11 BP 815 EP 823 DI 10.2471/BLT.09.067231 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 681EJ UT WOS:000284293900009 PM 21076562 ER PT J AU Andreotti, G Hou, LF Freeman, LEB Mahajan, R Koutros, S Coble, J Lubin, J Blair, A Hoppin, JA Alavanja, M AF Andreotti, Gabriella Hou, Lifang Freeman, Laura E. Beane Mahajan, Rajeev Koutros, Stella Coble, Joseph Lubin, Jay Blair, Aaron Hoppin, Jane A. Alavanja, Michael TI Body mass index, agricultural pesticide use, and cancer incidence in the Agricultural Health Study cohort SO CANCER CAUSES & CONTROL LA English DT Article DE Obesity; Body mass index; Pesticides; Cancer; Agriculture ID BREAST-CANCER; LUNG-CANCER; FAT DISTRIBUTION; ALCOHOL INTAKE; COLON-CANCER; HETEROCYCLIC AMINES; COLORECTAL-CANCER; OBESITY EPIDEMIC; HISTOLOGIC TYPES; UNITED-STATES AB Obesity is associated with increased risks of several cancers including colon and female breast. Pesticide use in agricultural populations has also been linked with higher risks of various cancers. However, the interaction between obesity and pesticide use on cancer risk has not been well studied. Using data from the Agricultural Health Study, we examined the association between body mass index (BMI) and the risk of cancer at 17 sites and the interaction between BMI and pesticide use. Pesticide applicators residing in Iowa and North Carolina and their spouses were enrolled between 1993 and 1997 and given a self-administered questionnaire to obtain pesticide use and other information. This analysis included 39,628 men and 28,319 women with height and weight data who were cancer-free at enrollment. Among these participants, 4,432 were diagnosed with cancer between enrollment and 2005 and 64% were overweight or obese. BMI (per 1 kg/m(2)) was positively associated with colon cancer in men (hazard ratio (HR) 1.05, 95% confidence interval (CI) 1.02-1.09) and breast cancer in postmenopausal women (HR 1.03, 95% CI 1.01-1.06). In contrast, BMI was inversely associated with lung cancer in men, with a significant association in ever smokers (HR 0.92, 95% CI 0.88-0.97) and a null association in never smokers. The positive association between BMI and colon cancer in men was significant in those who ever used carbofuran (HR = 1.10, 95% CI 1.04-1.17; p-interaction = 0.04) or metolachlor (HR = 1.09, 95% CI 1.04-1.15; p-interaction = 0.02) but was null in non-users of these pesticides. Among male ever smokers, the inverse association between BMI and lung cancer was significant in non-users of carbofuran (HR = 0.87, 95% CI = 0.82-0.92) but was null in users of carbofuran (p-interaction = 0.02). These findings suggest that certain pesticides may modify the effects of BMI on the risks of colon and lung cancers. C1 [Andreotti, Gabriella; Hou, Lifang; Freeman, Laura E. Beane; Mahajan, Rajeev; Koutros, Stella; Coble, Joseph; Lubin, Jay; Blair, Aaron; Alavanja, Michael] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC USA. RP Andreotti, G (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 8011,MSC 7240, Bethesda, MD 20892 USA. EM andreotg@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU NIH, National Cancer Institute [Z01 CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030-11] FX This paper has been supported by the Intramural Research Program of the NIH, National Cancer Institute (Z01 CP010119), and National Institute of Environmental Health Sciences (Z01-ES049030-11). We thank the Agricultural Health Study participants for their participation, and the field station and coordinating center staff for their efforts. NR 62 TC 24 Z9 26 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2010 VL 21 IS 11 BP 1759 EP 1775 DI 10.1007/s10552-010-9603-9 PG 17 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 669OF UT WOS:000283359400002 PM 20730623 ER PT J AU Schonfeld, SJ Bhatti, P Brown, EE Linet, MS Simon, SL Weinstock, RM Hutchinson, AA Stovall, M Preston, DL Alexander, BH Doody, MM Sigurdson, AJ AF Schonfeld, Sara J. Bhatti, Parveen Brown, Elizabeth E. Linet, Martha S. Simon, Steven L. Weinstock, Robert M. Hutchinson, Amy A. Stovall, Marilyn Preston, Dale L. Alexander, Bruce H. Doody, Michele M. Sigurdson, Alice J. TI Polymorphisms in oxidative stress and inflammation pathway genes, low-dose ionizing radiation, and the risk of breast cancer among US radiologic technologists SO CANCER CAUSES & CONTROL LA English DT Article DE PTGS2; COX-2; Inflammation; Breast cancer; Radiation ID A-BOMB SURVIVORS; EXPOSURE; CYCLOOXYGENASE-2; MARKERS; PROTEIN; HEALTH; CELLS AB Ionizing radiation, an established breast cancer risk factor, has been shown to induce oxidative damage and chronic inflammation. Polymorphic variation in oxidative stress and inflammatory-mediated pathway genes may modify radiation-related breast cancer risk. We estimated breast cancer risk for 28 common variants in 16 candidate genes involved in these pathways among 859 breast cancer cases and 1,083 controls nested within the US Radiologic Technologists cohort. We estimated associations between occupational and personal diagnostic radiation exposures with breast cancer by modeling the odds ratio (OR) as a linear function in logistic regression models and assessed heterogeneity of the dose-response across genotypes. There was suggestive evidence of an interaction between the rs5277 variant in PTGS2 and radiation-related breast cancer risk. The excess OR (EOR)/Gy from occupational radiation exposure = 5.5 (95%CI 1.2-12.5) for the GG genotype versus EOR/Gy < 0 (95%CI < 0-3.8) and EOR/Gy < 0 (95%CI < 0-14.8) for the GC and CC genotypes, respectively, (p (interaction) = 0.04). The association between radiation and breast cancer was not modified by other SNPs examined. This study suggests that variation in PTGS2 may modify the breast cancer risk from occupational radiation exposure, but replication in other populations is needed to confirm this result. C1 [Schonfeld, Sara J.; Linet, Martha S.; Simon, Steven L.; Doody, Michele M.; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Brown, Elizabeth E.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Brown, Elizabeth E.] Univ Alabama, Dept Med, Birmingham, AL USA. [Brown, Elizabeth E.] Univ Alabama, Dept Microbiol, Birmingham, AL USA. [Weinstock, Robert M.] RTI Int, Bethesda, MD USA. [Hutchinson, Amy A.] SAIC Frederick Inc, NCI, Core Genotyping Facil, Frederick, MD USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Preston, Dale L.] HiroSoft Int Corp, Seattle, WA USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Schonfeld, SJ (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,MSC 7238, Bethesda, MD 20892 USA. EM schonfes@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We are grateful to the radiologic technologists who participated in the USRT Study; Jerry Reid of the American Registry of Radiologic Technologists for continued support of this study; Diane Kampa and Allison Iwan of the University of Minnesota for data collection and study coordination; Laura Bowen of Information Management Systems for biomedical computing statistical support; and Chu-Ling Yu of the National Cancer Institute for editorial and scientific review. This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 29 TC 16 Z9 16 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2010 VL 21 IS 11 BP 1857 EP 1866 DI 10.1007/s10552-010-9613-7 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 669OF UT WOS:000283359400011 PM 20711808 ER PT J AU Kim, DH Smith-Warner, SA Spiegelman, D Yaun, SS Colditz, GA Freudenheim, JL Giovannucci, E Goldbohm, RA Graham, S Harnack, L Jacobs, EJ Leitzmann, M Mannisto, S Miller, AB Potter, JD Rohan, TE Schatzkin, A Speizer, FE Stevens, VL Stolzenberg-Solomon, R Terry, P Toniolo, P Weijenberg, MP Willett, WC Wolk, A Zeleniuch-Jacquotte, A Hunter, DJ AF Kim, Dong-Hyun Smith-Warner, Stephanie A. Spiegelman, Donna Yaun, Shiaw-Shyuan Colditz, Graham A. Freudenheim, Jo L. Giovannucci, Edward Goldbohm, R. Alexandra Graham, Saxon Harnack, Lisa Jacobs, Eric J. Leitzmann, Michael Mannisto, Satu Miller, Anthony B. Potter, John D. Rohan, Thomas E. Schatzkin, Arthur Speizer, Frank E. Stevens, Victoria L. Stolzenberg-Solomon, Rachael Terry, Paul Toniolo, Paolo Weijenberg, Matty P. Willett, Walter C. Wolk, Alicja Zeleniuch-Jacquotte, Anne Hunter, David J. TI Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Colon cancer; Folate; Cohort studies; Meta-analysis; Pooled analysis ID FOOD FREQUENCY QUESTIONNAIRE; NESTED CASE-CONTROL; COLORECTAL-CANCER; DNA METHYLATION; DIETARY-FOLATE; UNITED-STATES; FOLIC-ACID; SUPPLEMENT USE; RISK-FACTORS; POSTMENOPAUSAL WOMEN AB Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies. Study- and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model. Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84-1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77-0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78-0.98, comparing a parts per thousand yen560 mcg/days vs. < 240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0-3%) was estimated for every 100 mu g/day increase in total folate intake. These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer. C1 [Smith-Warner, Stephanie A.; Spiegelman, Donna; Giovannucci, Edward; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Smith-Warner, Stephanie A.; Yaun, Shiaw-Shyuan; Giovannucci, Edward; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kim, Dong-Hyun] Hallym Univ, Dept Social & Prevent Med, Coll Med, Chunchon, South Korea. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Speizer, Frank E.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Inst Publ Hlth, St Louis, MO USA. [Giovannucci, Edward; Speizer, Frank E.; Willett, Walter C.; Hunter, David J.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward; Speizer, Frank E.; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Freudenheim, Jo L.; Graham, Saxon] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Goldbohm, R. Alexandra] TNO Qual Life, Dept Prevent & Hlth, Leiden, Netherlands. [Harnack, Lisa] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, Eric J.; Stevens, Victoria L.] Amer Canc Soc, Atlanta, GA 30329 USA. [Leitzmann, Michael] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Mannisto, Satu] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Potter, John D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Serv, Seattle, WA 98104 USA. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Terry, Paul] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Weijenberg, Matty P.] Maastricht Univ, Dept Epidemiol, Sch Oncol & Dev Biol GROW, Maastricht, Netherlands. [Wolk, Alicja] Karolinska Inst, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. [Toniolo, Paolo; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, New York, NY 10016 USA. RP Smith-Warner, SA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM pooling@hsphsun2.harvard.edu RI Kattelmann, Kendra/E-8225-2013; Colditz, Graham/A-3963-2009; OI Colditz, Graham/0000-0002-7307-0291; Potter, John/0000-0001-5439-1500; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Institutes of Health [CA55075]; National Colorectal Cancer Research Alliance FX Supported by research grant CA55075 from the National Institutes of Health and by the National Colorectal Cancer Research Alliance. NR 84 TC 58 Z9 59 U1 2 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2010 VL 21 IS 11 BP 1919 EP 1930 DI 10.1007/s10552-010-9620-8 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 669OF UT WOS:000283359400018 PM 20820900 ER PT J AU Lam, ET Au, JLS Otterson, GA Wientjes, MG Chen, L Shen, T Wei, Y Li, XB Bekaii-Saab, T Murgo, AJ Jensen, RR Grever, M Villalona-Calero, MA AF Lam, Elaine T. Au, Jessie L. -S. Otterson, Gregory A. Wientjes, M. Guillaume Chen, Ling Shen, Tong Wei, Yong Li, Xiaobai Bekaii-Saab, Tanios Murgo, Anthony J. Jensen, Rhonda R. Grever, Michael Villalona-Calero, Miguel A. TI Phase I trial of non-cytotoxic suramin as a modulator of docetaxel and gemcitabine therapy in previously treated patients with non-small cell lung cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Suramin; Docetaxel; Gemcitabine; Chemosensitizer; Modulator; Non-small cell lung cancer ID PLATINUM-BASED CHEMOTHERAPY; FIBROBLAST-GROWTH-FACTOR; III TRIAL; PROSTATE-CANCER; 2ND-LINE TREATMENT; RANDOMIZED-TRIAL; NONTOXIC SURAMIN; FACTOR RECEPTORS; ENHANCE ACTIVITY; SUPPORTIVE CARE AB In preclinical models, non-cytotoxic suramin (concentrations < 50 mu M) potentiates the activity of multiple chemotherapeutic agents. The present study evaluated the safety and tolerability of suramin in combination with docetaxel or gemcitabine in previously chemotherapy-treated patients with advanced non-small cell lung cancer. Patients received suramin intravenously in combination with either docetaxel on day 1 or gemcitabine on days 1 and 8, of each 21-day treatment cycle. After 3 cycles, patients with partial response (PR) or better continued on the same combination, whereas patients with stable disease (SD) or worse crossed-over to the other combination. Pharmacokinetic analyses were performed before and after each treatment. Eighteen patients received a total of 79 courses (37 suramin plus docetaxel, 42 suramin plus gemcitabine). The dose-limiting toxicity (DLT) was febrile neutropenia, observed in three of six patients treated with suramin and docetaxel 75 mg/m(2). No DLTs were observed with suramin plus docetaxel 56 mg/m(2) or suramin plus gemcitabine 1,250 mg/m(2). Common adverse events included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, skin rash, hyperglycemia, and electrolyte abnormalities. The target plasma suramin concentration range of 10-50 mu M was achieved in 90% of treatments. Discernable antitumor activity was noted in 11 patients (2 PR, 9 SD). Non-cytotoxic suramin, in combination with docetaxel 56 mg/m(2) or gemcitabine 1,250 mg/m(2), was reasonably well-tolerated with a manageable toxicity profile. Target plasma concentrations were correctly predicted by our previously described dosing nomogram. The observed preliminary evidence of antitumor activity encourages evaluation of this strategy in efficacy trials. C1 [Villalona-Calero, Miguel A.] Ohio State Univ, Arthur G James Canc Hosp, Columbus, OH 43210 USA. [Murgo, Anthony J.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Lam, Elaine T.; Otterson, Gregory A.; Bekaii-Saab, Tanios; Jensen, Rhonda R.; Grever, Michael; Villalona-Calero, Miguel A.] Ohio State Univ, Dept Internal Med, Div Hematol & Oncol, Columbus, OH 43210 USA. [Au, Jessie L. -S.; Wientjes, M. Guillaume; Chen, Ling; Shen, Tong; Wei, Yong] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Villalona-Calero, Miguel A.] Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA. [Li, Xiaobai] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. RP Villalona-Calero, MA (reprint author), Ohio State Univ, Arthur G James Canc Hosp, B406 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM Miguel.Villalona@osumc.edu RI Bekaii-Saab, Tanios/E-2733-2011 FU National Institutes of Health [U01 CA 76576, R01 CA 93871] FX This study was supported by the National Institutes of Health Research Project Cooperative Agreement U01 CA 76576 (PI, Grever) and Research Project Grant R01 CA 93871 (PI, Au). Au and Wientjes have been awarded patents on the use of suramin as a chemosensitizer. NR 44 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2010 VL 66 IS 6 BP 1019 EP 1029 DI 10.1007/s00280-010-1252-x PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 666DF UT WOS:000283091100003 PM 20107799 ER PT J AU Paik, PK Rudin, CM Brown, A Rizvi, NA Takebe, N Travis, W James, L Ginsberg, MS Juergens, R Markus, S Tyson, L Subzwari, S Kris, MG Krug, LM AF Paik, Paul K. Rudin, Charles M. Brown, Andrew Rizvi, Naiyer A. Takebe, Naoko Travis, William James, Leonard Ginsberg, Michelle S. Juergens, Rosalyn Markus, Susan Tyson, Leslie Subzwari, Sara Kris, Mark G. Krug, Lee M. TI A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Small-cell lung cancer; Obatoclax mesylate; Topotecan; Apoptosis ID CELL LUNG-CANCER; FAMILY INHIBITOR; APOPTOSIS; EXPRESSION; CISPLATIN; GX15-070; THERAPY; RESISTANCE; ETOPOSIDE; LINES AB To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle. Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients. C1 [Paik, Paul K.; Brown, Andrew; Rizvi, Naiyer A.; Travis, William; James, Leonard; Ginsberg, Michelle S.; Tyson, Leslie; Subzwari, Sara; Kris, Mark G.; Krug, Lee M.] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Dept Med, New York, NY 10065 USA. [Rudin, Charles M.; Juergens, Rosalyn; Markus, Susan] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD USA. RP Krug, LM (reprint author), Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Dept Med, New York, NY 10065 USA. EM krugl@mskcc.org OI Kris, Mark/0000-0002-7317-5341 FU CTEP; National Institutes of Health (NIH) [5U01CA069856-15, U01CA070095]; NCI [7937] FX Supported by CTEP, NIH 5U01CA069856-15 and NIH U01CA070095; NCI-sponsored trial #`7937.; This study was funded by the National Institutes of Health (NIH) grants 5U01CA069856-15 and U01CA070095. NR 26 TC 48 Z9 49 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2010 VL 66 IS 6 BP 1079 EP 1085 DI 10.1007/s00280-010-1265-5 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 666DF UT WOS:000283091100010 PM 20165849 ER PT J AU Engel, C Versmold, B Wappenschmidt, B Simard, J Easton, DF Peock, S Cook, M Oliver, C Frost, D Mayes, R Evans, DG Eeles, R Paterson, J Brewer, C McGuffog, L Antoniou, AC Stoppa-Lyonnet, D Sinilnikova, OM Barjhoux, L Frenay, M Michel, C Leroux, D Dreyfus, H Toulas, C Gladieff, L Uhrhammer, N Bignon, YJ Meindl, A Arnold, N Varon-Mateeva, R Niederacher, D Preisler-Adams, S Kast, K Deissler, H Sutter, C Gadzicki, D Chenevix-Trench, G Spurdle, AB Chen, XQ Beesley, J Olsson, H Kristoffersson, U Ehrencrona, H Liljegren, A van der Luijt, RB van Os, TA van Leeuwen, FE Domchek, SM Rebbeck, TR Nathanson, KL Osorio, A Cajal, TRY Konstantopoulou, I Benitez, J Friedman, E Kaufman, B Laitman, Y Mai, PL Greene, MH Nevanlinna, H Aittomaki, K Szabo, CI Caldes, T Couch, FJ Andrulis, IL Godwin, AK Hamann, U Schmutzler, RK AF Engel, Christoph Versmold, Beatrix Wappenschmidt, Barbara Simard, Jacques Easton, Douglas F. Peock, Susan Cook, Margaret Oliver, Clare Frost, Debra Mayes, Rebecca Evans, D. Gareth Eeles, Rosalind Paterson, Joan Brewer, Carole McGuffog, Lesley Antoniou, Antonis C. Stoppa-Lyonnet, Dominique Sinilnikova, Olga M. Barjhoux, Laure Frenay, Marc Michel, Cecile Leroux, Dominique Dreyfus, Helene Toulas, Christine Gladieff, Laurence Uhrhammer, Nancy Bignon, Yves-Jean Meindl, Alfons Arnold, Norbert Varon-Mateeva, Raymonda Niederacher, Dieter Preisler-Adams, Sabine Kast, Karin Deissler, Helmut Sutter, Christian Gadzicki, Dorothea Chenevix-Trench, Georgia Spurdle, Amanda B. Chen, Xiaoqing Beesley, Jonathan Olsson, Hakan Kristoffersson, Ulf Ehrencrona, Hans Liljegren, Annelie van der Luijt, Rob B. van Os, Theo A. van Leeuwen, Flora E. Domchek, Susan M. Rebbeck, Timothy R. Nathanson, Katherine L. Osorio, Ana Ramon y Cajal, Teresa Konstantopoulou, Irene Benitez, Javier Friedman, Eitan Kaufman, Bella Laitman, Yael Mai, Phuong L. Greene, Mark H. Nevanlinna, Heli Aittomaki, Kristiina Szabo, Csilla I. Caldes, Trinidad Couch, Fergus J. Andrulis, Irene L. Godwin, Andrew K. Hamann, Ute Schmutzler, Rita K. CA Epidemiological Study Familial Bre Kathleen Cuningham Fdn Consortium Sweden SWE-BRCA Hereditary Breast Ovarian Canc Grp Consortium Investigators Modifiers TI Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CASPASE-8 GENE; INACTIVATING MUTATIONS; COMMON VARIANTS; REDUCED RISK; CELL-CYCLE; APOPTOSIS; SUSCEPTIBILITY; POLYMORPHISMS; PREDISPOSITION; CARCINOMAS AB Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P-trend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P-trend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev; 19(11); 2859-68. (C)2010 AACR. C1 [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Versmold, Beatrix; Wappenschmidt, Barbara; Schmutzler, Rita K.] Univ Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada. [Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Easton, Douglas F.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra] Univ Cambridge, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. [Mayes, Rebecca] Univ Cambridge, Dept Oncol, Cambridge, England. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Rosalind] Inst Canc Res, Oncogenet Team, Surrey, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, Surrey, England. [Paterson, Joan] Addenbrookes Hosp, Dept Clin Genet, E Anglian Reg Genet Serv, Cambridge, England. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [McGuffog, Lesley; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM U509, Serv Genet Oncol, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Paris, France. [Sinilnikova, Olga M.] Hosp Civils Lyon Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Barjhoux, Laure] Univ Lyon, Ctr Leon Berard, CNRS UMR5201, Equipe Iabellisee LIGUE 2008, Lyon, France. [Frenay, Marc; Michel, Cecile] Ctr Antoine Lacassagne, F-06054 Nice, France. [Leroux, Dominique; Dreyfus, Helene] CHU Grenoble, F-38043 Grenoble, France. [Toulas, Christine; Gladieff, Laurence] Inst Claudius Regaud, Toulouse, France. [Uhrhammer, Nancy; Bignon, Yves-Jean] Ctr Jean Perrin, Clermont Ferrand, France. [Meindl, Alfons] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Arnold, Norbert] Univ Schleswig Holstein, Dept Obstet & Gynaecol, Kiel, Germany. [Varon-Mateeva, Raymonda] Charite Univ Med Ctr, Inst Human Genet, Berlin, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dept Obstet & Gynaecol, Mol Genet Lab, Dusseldorf, Germany. [Preisler-Adams, Sabine] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Kast, Karin] Tech Univ Dresden, Dept Obstet & Gynaecol, Dresden, Germany. [Deissler, Helmut] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Sutter, Christian] Univ Heidelberg, Inst Human Genet, Dept Human Genet & Mol Diagnost, Heidelberg, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. [Chenevix-Trench, Georgia; Spurdle, Amanda B.; Chen, Xiaoqing; Beesley, Jonathan] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Peter MacCallum Canc Inst, Melbourne, Vic 3000, Australia. [Olsson, Hakan] Lund Univ, Dept Oncol, Lund, Sweden. [Kristoffersson, Ulf] Lund Univ, Dept Clin Genet, Lund, Sweden. [Ehrencrona, Hans] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden. [Liljegren, Annelie] Karolinska Inst, Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Sweden SWE-BRCA] Swedish Breast Canc Study, Gothenburg, Sweden. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Os, Theo A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [van Leeuwen, Flora E.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Domchek, Susan M.; Rebbeck, Timothy R.; Nathanson, Katherine L.] Univ Penn, Philadelphia, PA 19104 USA. [Osorio, Ana] Spanish Natl Canc Ctr, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Biomed Network Res Ctr Rare Dis, Barcelona, Spain. [Ramon y Cajal, Teresa] Hosp Santa Creu & Sant Pau, Med Oncol Serv, Barcelona, Spain. [Konstantopoulou, Irene] NCSR Demokritos, IRRP, Mol Diagnost Lab, Aghia Paraskevi, Greece. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Kaufman, Bella] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Israel. [Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Bethesda, MD 20892 USA. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Szabo, Csilla I.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Andrulis, Irene L.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Mol Genet, Toronto, ON M5G 1X5, Canada. [Godwin, Andrew K.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Hamann, Ute] German Canc Res Ctr, D-6900 Heidelberg, Germany. RP Schmutzler, RK (reprint author), Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Kerpener Str 34, D-50931 Cologne, Germany. EM rita.schmutzler@uk-koeln.de RI Spurdle, Amanda/A-4978-2011; Arnold, Norbert/E-3012-2010; Andrulis, Irene/E-7267-2013; Ligtenberg, Marjolijn/N-9666-2013; Hoogerbrugge, Nicoline/O-1016-2013; Leroux, Dominique/G-7309-2014; Osorio, Ana/I-4324-2014; Ehrencrona, Hans/M-5619-2014; Toulas, Christine/P-3838-2014; GLADIEFF, Laurence/O-5129-2014 OI Eeles, Rosalind/0000-0002-3698-6241; Spurdle, Amanda/0000-0003-1337-7897; Nevanlinna, Heli/0000-0002-0916-2976; Evans, Gareth/0000-0002-8482-5784; Arnold, Norbert/0000-0003-4523-8808; Ligtenberg, Marjolijn/0000-0003-1290-1474; Konstantopoulou, Irene/0000-0002-0470-0309; Nordling, Margareta/0000-0002-4047-4994; Nathanson, Katherine/0000-0002-6740-0901; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; Toulas, Christine/0000-0003-1261-1725; GLADIEFF, Laurence/0000-0002-6980-9719 FU Cancer Research UK [C1287/A10118, C1287/A8874, C8197/A10123, C5047/A8385]; NIHR; Ligue National Contre le Cancer, Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-enl"; Association for International Cancer Research [AICR-07-0454]; German Cancer Aid [107054]; Center for Molecular Medicine Cologne [TV93]; NHMRC [145684, 288704, 454508]; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI 2007-3756]; Breast Cancer Research Foundation (BCRF); QVC Network; Fashion Footwear Association of New York; Marjorie B. Cohen Foundation; Genome Spain Foundation; Mutual Madrilena; Asociacion Espanola Contra el Cancer; Ministry of Health [FIS061090, RD06/0020/1060, CR-MZ0 MOU 2005]; Ministry of Science and Innovation [PI081120]; Israel Cancer Association (ICA); National Cancer Institute, Division of Cancer Epidemiology and Genetics; NIH [NO2-CP-11019-50, N02-CP-65504, CA122340, CA128978]; Westat, Inc. (Rockville, MD); Helsinki University Central Hospital; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Grant Agency of the Czech Republic [GP301/08/P103]; Fund for Scientific Research Flanders (FWO) [1.5.150.07]; Ghent University [12051203]; Foundation Emmanuel van der Schueren; Spanish Ministry of Science and Innovation [FMMA/06, FIS 05/0864, RD06/0020/0021]; Mayo Clinic Breast Cancer SPORE [P50-CA116201]; Canadian Institutes of Health Research; Canadian Breast Cancer Research Alliance [019511]; SPORE [P50 CA83638, U01 CA69631, 5U01 CA113916]; Eileen Stein Jacoby Fund; DKFZ; Mayo Rochester Early Career Development Award; Fund for Scientific Research of Flanders (FWO-Vlaanderen); Vlaamse Liga tegen Kanker through Foundation Emmanuel van der Schueren L.F.; Vlaamse Liga tegen Kanker through Machackova Eva; Vlaamse Liga tegen Kanker through Lukesova Miroslava FX The CIMBA data management and genotyping is supported by Cancer Research UK.; Douglas F. Easton is the principal investigator of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare Oliver, Debra Frost. North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Laura Boyes. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark Rogers, Emma McCann. St James's Hospital, Dublin and National Centre for Medical Genetics, Dublin: John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Felicity Holt. North East Thames Regional Genetics Service, NE Thames: Alison Male, Lucy Side, Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins. Elena Castro, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. D. F. E., S. P., M. C., D. F., and C.O. are funded by Cancer Research UK grants C1287/A10118 and C1287/A8874. R. M. is supported by Cancer Research UK grant C8197/A10123. D. G. E. and F. L. are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R. E., E. B., and L.D'M. are also supported by Cancer Research UK grant C5047/A8385.; The GEMO study (Cancer Genetics Network "Groupe Genetique et Cancer," Federation Nationale des Centres de Lutte Contre le Cancer, France) is supported by the Ligue National Contre le Cancer, Association for International Cancer Research Grant AICR-07-0454 and the Association "Le cancer du sein, parlons-enl" Award. L. B. is supported by Association for International Cancer Research grant AICR-07-0454. We wish to thank all the GEMO collaborating groups for their contribution to this study.; GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054) and the Center for Molecular Medicine Cologne (grant TV93) to R. K. S. We thank Juliane Kohler for her excellent technical assistance, and D. Schafer, Farnoosh Fathali-Zadeh, Claus R. Bartram, and the 12 clinical centers for providing samples and clinical data. GC-HBOC center for data management and biostatistics: Michael Brosig, Ute Enders, Marlies Herold, Markus Loeffler, Jan Schaefer, Marcus Wetzler, Kerstin Wieland, Silke Zachariae.; We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704, and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia.; HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Senno Verhoef, Anouk Pijpe, Laura van't Veer, Flora van Leeuwen, Matti Rookus; Erasmus Medical Center, Rotterdam: Margriet Collee, Ans van den Ouweland, Mieke Kriege, Mieke Schutte, Maartje Hooning, Caroline Seynaeve; Leiden University Medical Center, Leiden: Christi van Asperen, Juul Wijnen, Maaike Vreeswijk, Peter Devilee, Rob Tollenaar; Radboud University Nijmegen Medical Center, Nijmegen: Nicoline Hoogerbrugge, Marjolijn Ligtenberg; University Medical Center Utrecht, Utrecht: Margreet Ausems, Rob B. van der Luijt; Amsterdam Medical Center: Cora Aalfs, Theo van Os; VU University Medical Center, Amsterdam: Hanne Meijers-Heijboer, Hans Gille; University Hospital Maastricht, Maastricht: Encarna Gomez-Garcia, Rien Blok. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI 2007-3756.; K.L.N. is supported by the Breast Cancer Research Foundation (BCRF). S. M. D. is supported by QVC Network, the Fashion Footwear Association of New York, and the Marjorie B. Cohen Foundation.; Thanks to Rosario Alonso, Alicia Barroso, and Guillermo Pita for their technical support. The samples studied at the CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2 [Spanish National Cancer Centre (Madrid), Sant Pau Hospital (Barcelona), Instituto Catalad Oncologia (Barcelona), Valladolid University (Valladolid), Cancer Research Centre (Salamanca), and Instituto Dexeus (Barcelona)] and the Instituto Demokritos (Greece). The work carried out at the CNIO was partly funded by grants from the Genome Spain Foundation, Mutual Madrilena/06, Asociacion Espanola Contra el Cancer/08, Ministry of Health FIS061090 and RD06/0020/1060, and Ministry of Science and Innovation PI081120.; The SMC study was supported in part by the Israel Cancer Association (ICA); We acknowledge the contributions of Dr. Jeffery A. Struewing and Marbin A Pineda from the NCI Laboratory of Population Genetics. Drs. Mai and Greene were supported by funding from the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics. Their data collection efforts were supported by NIH Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc. (Rockville, MD).; HEBCS wishes to thank Drs. Kirsimari Aaltonen and Carl Blomqvist and R.N. Hanna Jantti for their help with the patient data and Tuomas Heikkinen and Kati Kampjarvi for their help with the genetic analysis. HEBCS gratefully acknowledges the Finnish Cancer Registry for the cancer data. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.; C.I.S. is supported by the Mayo Rochester Early Career Development Award for Non-Clinician Scientists. We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and the support of the Grant Agency of the Czech Republic, project no. GP301/08/P103 (to M.Z.). We acknowledge the contribution of Kim De Leeneer and Anne De Paepe. This research was supported by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by grant 12051203 from the Ghent University to Anne De Paepe. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO-Vlaanderen). Kim De Leeneer is supported by the Vlaamse Liga tegen Kanker through a grant of the Foundation Emmanuel van der Schueren. L.F., Machackova Eva, and Lukesova Miroslava are supported through the Ministry of Health grant CR-MZ0 MOU 2005.; Trinidad Caldes and Miguel de la Hoya were supported by a FMMA/06; FIS 05/0864 and RD06/0020/0021 (RTICC; ISCIII) Spanish Ministry of Science and Innovation.; The Mayo Clinic study was supported in part by the Breast Cancer Research Foundation (BCRF), a grant from Susan G. Komen for the Cure, the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH grants CA122340 and CA128978 to F.J.C.; Jacques Simard, Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Quebec and Laval University, Quebec, Canada; Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children's Hospital, Calgary, Canada; Jocelyne Chiquette, Hopital du Saint-Sacrement, Quebec, Canada; Bernard Lesperance, H pital du Sacre-Coeur de Montreal, Montreal, Canada. J.S. is Chairholder of the Canada Research Chair in Oncogenomics. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program. This work was supported by the Canadian Breast Cancer Research Alliance grant 019511.; We thank JoEllen Weaver and John Malick for expert technical assistance. A. K. G. was funded by SPORE P50 CA83638, U01 CA69631, and 5U01 CA113916, and the Eileen Stein Jacoby Fund.; We thank Antje Seidel-Renkert for expert technical assistance. The study was supported by the DKFZ. NR 32 TC 25 Z9 27 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2010 VL 19 IS 11 BP 2859 EP 2868 DI 10.1158/1055-9965.EPI-10-0517 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 677KP UT WOS:000283991600020 PM 20978178 ER PT J AU Gu, FY Schumacher, FR Canzian, F Allen, NE Albanes, D Berg, CD Berndt, SI Boeing, H Bueno-de-Mesquita, HB Buring, JE Chabbert-Buffet, N Chanock, SJ Clavel-Chapelon, F Dumeaux, V Gaziano, JM Giovannucci, EL Haiman, CA Hankinson, SE Hayes, RB Henderson, BE Hunter, DJ Hoover, RN Johansson, M Key, TJ Khaw, KT Kolonel, LN Lagiou, P Lee, IM LeMarchand, L Lund, E Ma, J Onland-Moret, NC Overvad, K Rodriguez, L Sacerdote, C Sanchez, MJ Stampfer, MJ Stattin, P Stram, DO Thomas, G Thun, MJ Tjonneland, A Trichopoulos, D Tumino, R Virtamo, J Weinstein, SJ Willett, WC Yeager, M Zhang, SMM Kaaks, R Riboli, E Ziegler, RG Kraft, P AF Gu, Fangyi Schumacher, Fredrick R. Canzian, Federico Allen, Naomi E. Albanes, Demetrius Berg, Christine D. Berndt, Sonja I. Boeing, Heiner Bueno-de-Mesquita, H. Bas Buring, Julie E. Chabbert-Buffet, Nathalie Chanock, Stephen J. Clavel-Chapelon, Francoise Dumeaux, Vanessa Gaziano, J. Michael Giovannucci, Edward L. Haiman, Christopher A. Hankinson, Susan E. Hayes, Richard B. Henderson, Brian E. Hunter, David J. Hoover, Robert N. Johansson, Mattias Key, Timothy J. Khaw, Kay-Tee Kolonel, Laurence N. Lagiou, Pagona Lee, I-Min LeMarchand, Loic Lund, Eiliv Ma, Jing Onland-Moret, N. Charlotte Overvad, Kim Rodriguez, Laudina Sacerdote, Carlotta Sanchez, Maria-Jose Stampfer, Meir J. Stattin, Par Stram, Daniel O. Thomas, Gilles Thun, Michael J. Tjonneland, Anne Trichopoulos, Dimitrios Tumino, Rosario Virtamo, Jarmo Weinstein, Stephanie J. Willett, Walter C. Yeager, Meredith Zhang, Shumin M. Kaaks, Rudolf Riboli, Elio Ziegler, Regina G. Kraft, Peter TI Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ACID-LABILE SUBUNIT; MULTIETHNIC COHORT; COMPREHENSIVE ANALYSIS; SCREENING TRIAL; IGFBP-3 LEVELS; FACTOR (IGF)-I; SERUM-LEVELS; POLYMORPHISMS; ASSOCIATION; METAANALYSIS AB Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins. Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium. Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 x 10(-4)); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R-2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers. Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women. Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes. Cancer Epidemiol Biomarkers Prev; 19(11); 2877-87. (C)2010 AACR. C1 [Gu, Fangyi; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Gu, Fangyi; Buring, Julie E.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Lee, I-Min; Stampfer, Meir J.; Trichopoulos, Dimitrios; Willett, Walter C.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, D-6900 Heidelberg, Germany. [Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. [Allen, Naomi E.; Key, Timothy J.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Albanes, Demetrius; Berg, Christine D.; Berndt, Sonja I.; Chanock, Stephen J.; Hayes, Richard B.; Hoover, Robert N.; Thomas, Gilles; Weinstein, Stephanie J.; Yeager, Meredith; Ziegler, Regina G.] NCI, Bethesda, MD 20892 USA. [Boeing, Heiner] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Buring, Julie E.; Lee, I-Min; Zhang, Shumin M.] Brigham & Womens Hosp, Div Prevent Med, Dept 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.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Buring, Julie E.] Harvard Univ, Sch Med, Div Res & Educ Complementary & Integrat Med Thera, Boston, MA USA. [Chabbert-Buffet, Nathalie] Hop Tenon, APHP, Dept Gynecol, F-75970 Paris, France. [Chabbert-Buffet, Nathalie] Univ Paris 06, Paris, France. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, F-94805 Villejuif, France. [Clavel-Chapelon, Francoise] Paris S Univ, UMRS 1018, Villejuif, France. [Dumeaux, Vanessa; Lund, Eiliv] Univ Tromso, Inst Community Med, Tromso, Norway. [Gaziano, J. Michael] VA Boston Healthcare Syst, VA Cooperat Studies Programs, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hankinson, Susan E.; Ma, Jing; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hayes, Richard B.] NYU, Langone Med Ctr, NYU Canc Inst, Dept Environm Med,Div Epidemiol, New York, NY USA. [Johansson, Mattias] IARC, Lyon, France. [Johansson, Mattias; Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Honolulu, HI 96822 USA. [Kolonel, Laurence N.; LeMarchand, Loic] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Lagiou, Pagona] Univ Athens, Sch Med, WHO Collaborating Ctr Food & Nutr Policies, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Overvad, Kim] Aarhus Univ, Sch Publ Hlth, Dept Epidemiol, Aarhus, Denmark. [Rodriguez, Laudina] Hlth & Hlth Care Serv Council, Publ Hlth & Participat Directorate, Oviedo, Asturias, Spain. [Sacerdote, Carlotta] CPO Piemonte Torino, Turin, Italy. [Sacerdote, Carlotta] Human Genet Fdn, Turin, Italy. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada, Spain. [Thun, Michael J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Tumino, Rosario] Civile MP Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. RP Kraft, P (reprint author), 655 Huntington Ave,Bldg 2,Room 207, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Clavel-Chapelon, Francoise/G-6733-2014; Gu, Fangyi/I-5957-2014; SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Albanes, Demetrius/B-9749-2015; Onland-Moret, N. Charlotte/G-9185-2011; OI SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Sacerdote, Carlotta/0000-0002-8008-5096; Hayes, Richard/0000-0002-0918-661X FU U.S. NIH; National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics FX U.S. NIH and the National Cancer Institute (cooperative agreements: U01-CA98233, David J. Hunter; U01-CA98710, Michael J. Thun; U01-CA98216, Elio Riboli and Rudolf Kaaks; and U01-CA98758, Brian E. Henderson; and the Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). NR 57 TC 33 Z9 37 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2010 VL 19 IS 11 BP 2877 EP 2887 DI 10.1158/1055-9965.EPI-10-0507 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 677KP UT WOS:000283991600022 PM 20810604 ER PT J AU Shiels, MS Goedert, JJ Moore, RD Platz, EA Engels, EA AF Shiels, Meredith S. Goedert, James J. Moore, Richard D. Platz, Elizabeth A. Engels, Eric A. TI Reduced Risk of Prostate Cancer in U.S. Men with AIDS SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH INTERVIEW SURVEY; UNITED-STATES; SCREENING TRIAL; ANTIGEN; PEOPLE; COHORT; METAANALYSIS; MORTALITY; HIV/AIDS AB Background: Previous studies describe decreased prostate cancer risk in HIV-infected men. In the United States, prostate-specific antigen (PSA) screening is common and increases the detection of prostate cancer. We evaluated whether the prostate cancer deficit among men with AIDS reflects differential PSA screening. Methods: Data from the U. S. HIV/AIDS Cancer Match Study were used to calculate standardized incidence ratios (SIR) for prostate cancer, comparing men with AIDS (N = 287,247) to the general population. Furthermore, we estimated PSA testing rates in the Johns Hopkins HIV Clinical Cohort. Results: Prostate cancer rates increased over time in the general population and, beginning in the 1990s, were consistently higher than among men with AIDS. Men with AIDS had the same prostate cancer risk as the general population in the pre-PSA era (<1992, SIR = 1.00), but significantly reduced risk during the PSA era overall (1992-2007, SIR = 0.50) and across age, race, HIV risk group, antiretroviral therapy era, and CD4 counts. Local and regional stage prostate cancer risk was lower among men with AIDS (SIRs, 0.49 and 0.14, respectively), but distant stage cancer risk did not differ (SIR = 0.85). Among HIV-infected men >= 40 years old, PSA testing was uncommon (18.7% per year), but increased 2.4-fold from 2000 to 2008, after age adjustment. Conclusion: Prostate cancer risk was decreased by 50% among men with AIDS compared with the general population. This deficit was limited to the PSA era and early stage cancers. Impact: Our findings suggest that the prostate cancer deficit in HIV-infected men is largely due to differential PSA screening. Cancer Epidemiol Biomarkers Prev; 19(11); 2910-5. (C)2010 AACR. C1 [Shiels, Meredith S.] NCI, Infect & Immunoepidemiol Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Moore, Richard D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7059, Rockville, MD 20852 USA. EM shielsms@mail.nih.gov FU National Cancer Institute; NIH [R01 DA11601, K24 DA00432, R01 AA16893] FX Intramural Research Program of the National Cancer Institute. The Johns Hopkins HIV Clinical Cohort is supported by the following NIH grants: R01 DA11601, K24 DA00432, R01 AA16893. NR 27 TC 28 Z9 28 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2010 VL 19 IS 11 BP 2910 EP 2915 DI 10.1158/1055-9965.EPI-10-0741 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 677KP UT WOS:000283991600025 PM 20837717 ER PT J AU Almeida, MQ Stratakis, CA AF Almeida, Madson Q. Stratakis, Constantine A. TI Solid tumors associated with multiple endocrine neoplasias SO CANCER GENETICS AND CYTOGENETICS LA English DT Review ID GERM-LINE MUTATIONS; VON-HIPPEL-LINDAU; MEDULLARY-THYROID CARCINOMA; GASTROINTESTINAL STROMAL TUMORS; SCHWANNOMAS CARNEY COMPLEX; SPOTTY SKIN PIGMENTATION; RET PROTOONCOGENE; NEUROFIBROMATOSIS TYPE-1; ADRENOCORTICAL HYPERPLASIA; CLINICAL PREDICTORS AB We present an update on molecular and clinical genetics of solid tumors associated with the various multiple endocrine neoplasias (MEN) syndromes. MEN type 1 (MEN 1) describes the association of pituitary, parathyroid, and pancreatic islet cell tumors with a variety of many other lesions. MEN type 2 (MEN2) conditions represent at least four different syndromes that associate pheochromocytoma with medullary thyroid carcinoma, hyperparathyroidism, and a number of other manifestations. Other pheochromocytoma-associated syndromes include von Hippel-Lindau disease; neurofibromatosis 1; the recently defined paraganglioma syndromes type 1, 3, and 4; Carney-Stratakis syndrome; and the Carney triad. Carney-Stratakis syndrome is characterized by the association of paragangliomas and familial gastrointestinal stromal tumors. In the Carney triad, patients can manifest gastrointestinal stromal tumors, lung chondroma, paraganglioma. adrenal adenoma and pheochromocytoma, esophageal leiomyoma, and other conditions. The Carney complex is yet another form of MEN that is characterized by skin tumors and pigmented lesions, myxomas, schwannomas, and various endocrine neoplasias.(C) 2010 Elsevier Inc. All rights reserved. C1 [Almeida, Madson Q.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 63 TC 24 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD NOV PY 2010 VL 203 IS 1 BP 30 EP 36 DI 10.1016/j.cancergencyto.2010.09.006 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 675HC UT WOS:000283817200005 PM 20951316 ER PT J AU Cronin, KA Harlan, LC Dodd, KW Abrams, JS Ballard-Barbash, R AF Cronin, Kathleen A. Harlan, Linda C. Dodd, Kevin W. Abrams, Jeffrey S. Ballard-Barbash, Rachel TI Population-based Estimate of the Prevalence of HER-2 Positive Breast Cancer Tumors for Early Stage Patients in the US SO CANCER INVESTIGATION LA English DT Article DE Breast carcinoma; HER-2/neu; Population-based study; SEER program ID ADJUVANT CHEMOTHERAPY; HORMONE-RECEPTORS; ASSOCIATION; SURVIVAL; AMPLIFICATION; TRASTUZUMAB; EXPRESSION; ONCOGENE; WOMEN; RACE AB The goal of this study was to estimate prevalence of HER-2 positive tumors in a population-based sample of 1026 women diagnosed in 2005 with early stage breast cancer. We modeled the relationship between patient and tumor characteristics and HER-2. HER-2 positive estimates were 19% for women aged < 49 years and 15% aged >= 50 years. HER-2 varied by tumor grade and size in women aged < 49 years but was not significant in multivariate analysis. Tumor grade and race were associated with HER-2 for women aged >= 50 years after controlling for other variables. HER-2 varies by age and by race and tumor in older women. C1 [Cronin, Kathleen A.] NCI, Stat Res & Applicat Branch, Surveillance Res Program, Bethesda, MD 20892 USA. [Harlan, Linda C.; Ballard-Barbash, Rachel] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Cronin, KA (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, 6116 Execut Blvd,Suite 503, Bethesda, MD 20892 USA. EM cronink@mail.nih.gov FU National Cancer Institute [N01-PC-35133, N01-PC-35135, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35141, N01-PC-35142, N01-PC-35143, N01-PC-35145] FX National Cancer Institute Contract Numbers: N01-PC-35133, N01-PC-35135, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35141, N01-PC-35142, N01-PC-35143, N01-PC-35145. NR 17 TC 13 Z9 13 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0735-7907 J9 CANCER INVEST JI Cancer Invest. PD NOV PY 2010 VL 28 IS 9 BP 963 EP 968 DI 10.3109/07357907.2010.496759 PG 6 WC Oncology SC Oncology GA 661UO UT WOS:000282753800010 PM 20690807 ER PT J AU Kelly, RJ Darnell, C Rixe, O AF Kelly, Ronan J. Darnell, Colleen Rixe, Olivier TI Target Inhibition in Antiangiogenic Therapy A Wide Spectrum of Selectivity and Specificity SO CANCER JOURNAL LA English DT Review DE Vascular endothelial growth factor; selective; specific; on/off target ID ENDOTHELIAL-GROWTH-FACTOR; METASTATIC COLORECTAL-CANCER; VASCULAR-PERMEABILITY FACTOR; RECEPTOR TYROSINE KINASE; CELL LUNG-CANCER; TUMOR ANGIOGENESIS; ANTI-VEGF; THROMBOTIC MICROANGIOPATHY; SIGNALING PATHWAY; SPLICE VARIANT AB Recent studies have revealed a previously unsuspected degree of vascular specialization within the host tissue and a tumor's microenvironment. The "vascular zip code" has been used to describe the unique expression of cell-surface molecules found in each vascular bed. Characterization of tumor blood vessels includes selective overexpression of a heterogenous group of proteins such as proteases, integrins, growth factor receptors, and proteoglycans. The process of angiogenesis consists of a "true cytokine storm," requiring many molecular events and biological steps. Antiangiogenic drugs may target a single critical kinase pathway or may interact with several nonspecific molecular targets via a process termed extended spectrum kinase inhibition. The latter strategy may lead to an absence of selectivity and specificity and may result in enhanced toxicities. In this review, we discuss recent developments in the pathogenesis of commonly observed adverse events and summarize new strategies that may ultimately improve efficacy and limit toxicity. C1 [Rixe, Olivier] Univ Cincinnati, Expt Therapeut Program, Div Hematol Oncol, Coll Med, Cincinnati, OH 45267 USA. [Kelly, Ronan J.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Rixe, O (reprint author), Univ Cincinnati, Expt Therapeut Program, Div Hematol Oncol, Coll Med, 231 Albert Sabin Way,ML 0562, Cincinnati, OH 45267 USA. EM olivier.rixe@uc.edu NR 71 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD NOV-DEC PY 2010 VL 16 IS 6 BP 635 EP 642 DI 10.1097/PPO.0b013e3181ff37cf PG 8 WC Oncology SC Oncology GA 689PX UT WOS:000284941800014 PM 21131797 ER PT J AU Mohammed, A Janakiram, NB Li, QA Madka, V Ely, M Lightfoot, S Crawford, H Steele, VE Rao, CV AF Mohammed, Altaf Janakiram, Naveena B. Li, Qian Madka, Venkateshwar Ely, Misty Lightfoot, Stan Crawford, Howard Steele, Vernon E. Rao, Chinthalapally V. TI The Epidermal Growth Factor Receptor Inhibitor Gefitinib Prevents the Progression of Pancreatic Lesions to Carcinoma in a Conditional LSL-Kras(G12D/+) Transgenic Mouse Model SO CANCER PREVENTION RESEARCH LA English DT Article ID PHASE-I TRIAL; DUCTAL ADENOCARCINOMA; KINASE INHIBITOR; BREAST-CANCER; K-RAS; CYCLOOXYGENASE-2 INHIBITOR; INTRAEPITHELIAL NEOPLASIA; HEPATOCELLULAR-CARCINOMA; CELLS; ZD1839 AB Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal prognosis. Developing novel strategies to prevent or delay pancreatic cancer is currently of intense interest. The chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was evaluated against the progression of pancreatic intraepithelial neoplasms (PanIN) to PDAC in conditional LSL-Kras(G12D/+) transgenic mice. LSL-Kras(G12D/+) and p48(Cre/+) mice were bred, and offspring of activated Kras(G12D/+) were generated. Six-week-old male Kras(G12D/+) (20 per group) and C57BL/6 wild-type (12 per group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm of gefitinib for 35 weeks. At termination, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers were measured by immunohistochemistry, immunofluorescence, immunoblotting, and/or reverse transcription-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77% and 100%, respectively (P < 0.0001) when compared with control diet. Importantly, a significant inhibition of carcinoma and a dose-dependent suppression of PanINs [PanIN-1, 37-62% (P < 0.002); PanIN-2, 38-41 (P < 0.001); and PanIN-3, 7-34% (P < 0.0141)] were observed in mice treated with gefitinib. Furthermore, mice treated with 100 and 200 ppm of gefitinib exhibited 67.6% to 77.3% of the pancreas to be free from ductal lesions. Also, gefitinib reduced EGFR, proliferating cell nuclear antigen, cyclin D1, C(2)GNT, RhoA, beta-catenin, p38, phospho-extracellular signal-regulated kinase, caveolin-1, and mucin and increased cyclin B1 in the pancreatic lesions/PDAC. In summary, these results show that gefitinib can prevent the progression of pancreatic cancer precursor lesions to PDAC in a preclinical model. The present study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in individuals at high risk for pancreatic cancer. Cancer Prev Res; 3(11); 1417-26. (C) 2010 AACR. C1 [Mohammed, Altaf; Janakiram, Naveena B.; Li, Qian; Madka, Venkateshwar; Ely, Misty; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, OU Canc Inst, Dept Med,Hematol Oncol Sect,Ctr Chemoprevent & Dr, Oklahoma City, OK 73104 USA. [Lightfoot, Stan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Crawford, Howard] SUNY Stony Brook, Hlth Sci Ctr, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, OU Canc Inst, Dept Med,Hematol Oncol Sect,Ctr Chemoprevent & Dr, 975 NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu RI Crawford, Howard/A-2874-2008 FU National Cancer Institute [CN-N01-53300] FX National Cancer Institute grant CN-N01-53300. NR 52 TC 30 Z9 30 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2010 VL 3 IS 11 BP 1417 EP 1426 DI 10.1158/1940-6207.CAPR-10-0038 PG 10 WC Oncology SC Oncology GA 677KN UT WOS:000283991400010 PM 21084261 ER PT J AU Lee, YH Andersen, JB Song, HT Judge, AD Seo, D Ishikawa, T Marquardt, JU Kitade, M Durkin, ME Raggi, C Woo, HG Conner, EA Avital, I MacLachlan, I Factor, VM Thorgeirsson, SS AF Lee, Yun-Han Andersen, Jesper B. Song, Ho-Taek Judge, Adam D. Seo, Daekwan Ishikawa, Tsuyoshi Marquardt, Jens U. Kitade, Mitsuteru Durkin, Marian E. Raggi, Chiara Woo, Hyun Goo Conner, Elizabeth A. Avital, Itzhak MacLachlan, Ian Factor, Valentina M. Thorgeirsson, Snorri S. TI Definition of Ubiquitination Modulator COP1 as a Novel Therapeutic Target in Human Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID IN-VIVO; PATHOGENESIS; P53; POTENT AB The development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study, we tested the hypothesis that COP1 blockade by short interfering RNA (siRNA)-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53-null Hep3B cells were resistant. Microarray expression analysis revealed that the anti-proliferative effects of COP1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic acid-lipid particles suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC. Cancer Res; 70(21); 8264-9. (C) 2010 AACR. C1 [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] NCI, Surg Branch, Bethesda, MD 20892 USA. [Song, Ho-Taek] NIH, Frank Lab, Radiol & Imaging Sci Clin Ctr, Bethesda, MD 20892 USA. [Judge, Adam D.; MacLachlan, Ian] Tekmira Pharmaceut Corp, Burnaby, BC, Canada. [Song, Ho-Taek] Yonsei Univ, Coll Med, Dept Radiol, Seoul, South Korea. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244; RAGGI, Chiara/0000-0003-2473-3535 FU NIH, National Cancer Institute, Center for Cancer Research FX Grant Support; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 18 TC 29 Z9 32 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 NOV 1 PY 2010 VL 70 IS 21 BP 8264 EP 8269 DI 10.1158/0008-5472.CAN-10-0749 PG 6 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300003 PM 20959491 ER PT J AU Voortman, J Goto, A Mendiboure, J Sohn, JJ Schetter, AJ Saito, M Dunant, A Pham, TC Petrini, I Lee, A Khan, MA Hainaut, P Pignon, JP Brambilla, E Popper, HH Filipits, M Harris, CC Giaccone, G AF Voortman, Johannes Goto, Akiteru Mendiboure, Jean Sohn, Jane J. Schetter, Aaron J. Saito, Motonobu Dunant, Ariane Pham, Trung C. Petrini, Iacopo Lee, Alan Khan, Mohammed A. Hainaut, Pierre Pignon, Jean-Pierre Brambilla, Elisabeth Popper, Helmut H. Filipits, Martin Harris, Curtis C. Giaccone, Giuseppe TI MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non-Small Cell Lung Carcinoma SO CANCER RESEARCH LA English DT Article ID CISPLATIN-BASED CHEMOTHERAPY; VINORELBINE PLUS CISPLATIN; TRIAL BIOLOGIC PROGRAM; PREDICTS SURVIVAL; POOR-PROGNOSIS; CANCER; MIR-34A; P53; APOPTOSIS; PROFILES AB This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only. Cancer Res; 70(21); 8288-98. (C) 2010 AACR. C1 [Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Goto, Akiteru; Sohn, Jane J.; Schetter, Aaron J.; Saito, Motonobu; Khan, Mohammed A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Mendiboure, Jean; Dunant, Ariane; Pignon, Jean-Pierre] Inst Gustave Roussy, Biostat & Epidemiol Unit, Villejuif, France. [Hainaut, Pierre] Int Agcy Res Canc, F-69372 Lyon, France. [Brambilla, Elisabeth] Univ Grenoble 1, INSERM, Dept Pathol, Grenoble Hosp, Grenoble, France. [Popper, Helmut H.] Med Univ Graz, Inst Pathol, Graz, Austria. [Filipits, Martin] Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Brambilla, Elisabeth/L-8796-2013; Hainaut, Pierre /B-6018-2012; Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017 OI Hainaut, Pierre /0000-0002-1303-1610; Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562 FU Eli Lilly; Programme Hospitalier de Recherche Clinique; Canceropole Rhone-Alpes FX Grant Support; Unrestricted research grant from Eli Lilly and grants from the Programme Hospitalier de Recherche Clinique 2005, as well as Canceropole Rhone-Alpes. NR 46 TC 71 Z9 78 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 NOV 1 PY 2010 VL 70 IS 21 BP 8288 EP 8298 DI 10.1158/0008-5472.CAN-10-1348 PG 11 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300007 PM 20978195 ER PT J AU Kim, TH Chiera, SL Linder, KE Trempus, CS Smart, RC Horowitz, JM AF Kim, Tae-Hyung Chiera, Shannon L. Linder, Keith E. Trempus, Carol S. Smart, Robert C. Horowitz, Jonathan M. TI Overexpression of Transcription Factor Sp2 Inhibits Epidermal Differentiation and Increases Susceptibility to Wound- and Carcinogen-Induced Tumorigenesis SO CANCER RESEARCH LA English DT Article ID HAIR FOLLICLE BULGE; ROUS-SARCOMA-VIRUS; TRANSGENIC MICE; EMBRYONIC-DEVELOPMENT; STEM-CELLS; FACTOR FAMILY; EXPRESSION; MOUSE; GROWTH; PROLIFERATION AB Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound-and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within 2 weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional effect. Cancer Res; 70(21); 8507-16. (C)2010 AACR. C1 [Kim, Tae-Hyung; Chiera, Shannon L.; Horowitz, Jonathan M.] N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27606 USA. [Kim, Tae-Hyung; Chiera, Shannon L.; Linder, Keith E.; Smart, Robert C.; Horowitz, Jonathan M.] N Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC 27606 USA. [Linder, Keith E.] N Carolina State Univ, Dept Populat Hlth & Pathobiol, Coll Vet Med, Raleigh, NC 27606 USA. [Smart, Robert C.] N Carolina State Univ, Cell Signaling & Canc Grp, Dept Environm & Mol Toxicol, Raleigh, NC 27606 USA. [Trempus, Carol S.] Natl Inst Environm Hlth Sci, Metab & Mol Mech Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC USA. RP Horowitz, JM (reprint author), N Carolina State Univ, Dept Mol Biomed Sci, CVM Res Bldg,Room 354,4700 Hillsborough St, Raleigh, NC 27606 USA. EM jon_horowitz@ncsu.edu FU National Cancer Institute [CA105313]; National Institute of General Medical Sciences [GM065405]; Jimmy V-NCSU Cancer Therapeutics Training Program FX National Cancer Institute grant CA105313, National Institute of General Medical Sciences grant GM065405, and funds supplied by the Jimmy V-NCSU Cancer Therapeutics Training Program. NR 45 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2010 VL 70 IS 21 BP 8507 EP 8516 DI 10.1158/0008-5472.CAN-10-1213 PG 10 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300029 PM 20959487 ER PT J AU Wentzensen, N Wilson, LE Wheeler, CM Carreon, JD Gravitt, PE Schiffman, M Castle, PE AF Wentzensen, Nicolas Wilson, Lauren E. Wheeler, Cosette M. Carreon, Joseph D. Gravitt, Patti E. Schiffman, Mark Castle, Philip E. TI Hierarchical Clustering of Human Papilloma Virus Genotype Patterns in the ASCUS-LSIL Triage Study SO CANCER RESEARCH LA English DT Article ID CERVICAL-CANCER; DIAGNOSIS; COLPOSCOPY; WOMEN; HPV AB Anogenital cancers are associated with similar to 13 carcinogenic human papilloma virus (HPV) types in a broader group that cause cervical intraepithelial neoplasia (CIN). Multiple concurrent cervical HPV infections are common, which complicates the attribution of HPV types to different grades of CIN. Here we report the analysis of HPV genotype patterns in the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study with the use of unsupervised hierarchical clustering. Women who underwent colposcopy at baseline (n = 2,780) were grouped into 20 disease categories based on histology and cytology. Disease groups and HPV genotypes were clustered with the use of complete linkage. Risk of 2-year cumulative CIN3+, viral load, colposcopic impression, and age were compared between disease groups and major clusters. Hierarchical clustering yielded four major disease clusters: cluster 1 included all CIN3 histology with abnormal cytology; cluster 2 included CIN3 histology with normal cytology and combinations with either CIN2 or high-grade squamous intraepithelial lesion cytology; cluster 3 included older women with normal or low-grade histology/cytology and low viral load; and cluster 4 included younger women with low-grade histology/cytology, multiple infections, and the highest viral load. Three major groups of HPV genotypes were identified: group 1 included only HPV16; group 2 included nine carcinogenic types, plus noncarcinogenic HPV53 and HPV66; and group 3 included noncarcinogenic types, plus carcinogenic HPV33 and HPV45. Clustering results suggested that colposcopy missed a prevalent precancer in many women with no biopsy/normal histology and high-grade squamous intraepithelial lesion. This result was confirmed by an elevated 2-year risk of CIN3+ in these groups. Our novel approach to study multiple genotype infections in cervical disease with the use of unsupervised hierarchical clustering can address complex genotype distributions on a population level. Cancer Res; 70(21); 8578-86. (C)2010 AACR. C1 [Wentzensen, Nicolas; Wilson, Lauren E.; Carreon, Joseph D.; Schiffman, Mark; Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, Room 5024,6120 Execut Blvd, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov OI Wilson, Lauren/0000-0002-5953-2293 FU NIH; National Cancer Institute; Roche Molecular Systems FX Intramural Research Program of the NIH and the National Cancer Institute. Roche Molecular Systems provided reagents and research support to the laboratory of P. E. Gravitt. C. M. Wheeler received support through her institution from Roche Molecular Systems for HPV genotyping studies. NR 19 TC 11 Z9 13 U1 0 U2 0 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 NOV 1 PY 2010 VL 70 IS 21 BP 8578 EP 8586 DI 10.1158/0008-5472.CAN-10-1188 PG 9 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300036 PM 20959485 ER PT J AU Freedman, DM Looker, AC Abnet, CC Linet, MS Graubard, BI AF Freedman, D. Michal Looker, Anne C. Abnet, Christian C. Linet, Martha S. Graubard, Barry I. TI Serum 25-Hydroxyvitamin D and Cancer Mortality in the NHANES III Study (1988-2006) SO CANCER RESEARCH LA English DT Article ID VITAMIN-D STATUS; NON-HODGKINS-LYMPHOMA; UNITED-STATES; BREAST-CANCER; ULTRAVIOLET-RADIATION; COLORECTAL-CANCER; PANCREATIC-CANCER; SCREENING TRIAL; PLASMA 25-HYDROXYVITAMIN-D; GENERAL-POPULATION AB Vitamin D has been hypothesized to protect against cancer. We followed 16,819 participants in NHANES III (Third National Health and Nutritional Examination Survey) from 1988 to 2006, expanding on an earlier NHANES III study (1988-2000). Using Cox proportional hazards regression models, we examined risk related to baseline serum 25-hydroxyvitamin D [25(OH)D] for total cancer mortality, in both sexes, and by racial/ethnic groups, as well as for site-specific cancers. Because serum was collected in the south in cooler months and in the north in warmer months, we examined associations by collection season ("summer/higher latitude" and "winter/lower latitude"). We identified 884 cancer deaths during 225,212 person-years. Overall cancer mortality risks were unrelated to baseline 25(OH) D status in both season/latitude groups, and in non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. In men, risks were elevated at higher levels {e. g., for = 100 nmol/L, relative risk (RR) = 1.85 [95% confidence interval (CI), 1.02-3.35] compared with < 37.5 nmol/L}. Although risks were unrelated to 25(OH) D in all women combined, risks significantly decreased with increasing 25(OH) D in the summer/higher latitude group [for >= 100 nmol/L, RR = 0.52 (95% CI, 0.25-1.15) compared with < 37.5 nmol/L; P-trend = 0.03, based on continuous values]. We also observed a suggestion of an inverse association with colorectal cancer mortality (P-trend = 0.09) and a positive association with lung cancer mortality among males (P-trend = 0.03). Our results do not support the hypothesis that 25(OH) D is associated with reduced cancer mortality. Although cancer mortality in females was inversely associated with 25(OH) D in the summer/higher latitude group, cancer mortality at some sites was increased among men with higher 25(OH) D. These findings argue for caution before increasing 25(OH) D levels to prevent cancer. Cancer Res; 70(21); 8587-97. (C)2010 AACR. C1 [Freedman, D. Michal; Abnet, Christian C.; Linet, Martha S.; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Looker, Anne C.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, EPS Room 7036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM mf101e@nih.gov RI Abnet, Christian/C-4111-2015; Osborne, Nicholas/N-4915-2015 OI Abnet, Christian/0000-0002-3008-7843; Osborne, Nicholas/0000-0002-6700-2284 FU NIH; National Cancer Institute; USPHS of the Department of Health and Human Services FX Intramural Research Program of the NIH, National Cancer Institute, and the USPHS of the Department of Health and Human Services. NR 51 TC 64 Z9 67 U1 0 U2 4 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 NOV 1 PY 2010 VL 70 IS 21 BP 8587 EP 8597 DI 10.1158/0008-5472.CAN-10-1420 PG 11 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300037 PM 20847342 ER PT J AU Yin, JJ Zhang, LH Munasinghe, J Linnoila, RI Kelly, K AF Yin, Juan Juan Zhang, Luhua Munasinghe, Jeeva Linnoila, R. Ilona Kelly, Kathleen TI Cediranib/AZD2171 Inhibits Bone and Brain Metastasis in a Preclinical Model of Advanced Prostate Cancer SO CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; VEGF INHIBITORS; CELLS; GROWTH; ANGIOGENESIS; PROGRESSION; MECHANISMS; PROMOTES AB Late stage or aggressive cancers exhibit metastatic growth at multiple sites, and the characterization of treatment response in various organs to drugs with potentially wide-ranging efficacy is needed. Tumor cells that induce angiogenesis are a common characteristic of metastatic disease, and clinically, antiangiogenic therapies have shown value in the setting of advanced cancer. However, recent preclinical studies have suggested that exposure to antiangiogenic drugs can increase tumor invasiveness and metastasis, making it important to determine which contexts antiangiogenic therapy is most appropriate. We describe here the effects of cediranib, a receptor tyrosine kinase inhibitor, in a model of advanced prostate cancer metastatic to skeleton and brain. Treatment with cediranib decreased metastatic tumor burden in the brain and bone, decreased cerebral vasogenic edema, and improved survival, despite increasing the invasive histology of brain metastases. Short-duration cediranib treatment given at the time of tumor cell dissemination was sufficient to inhibit the establishment and subsequent growth of bone metastases, although brain metastases were subject to rebound growth after the discontinuation of cediranib. Distinct growth patterns at different organ sites in the same animal showed that certain tumor microenvironments such as bone may be most amenable to interventions by anti-vascular endothelial growth factor (VEGF) therapies. In addition, anti-VEGF treatment may be of utility in decreasing the rapid growth of solid brain metastases and vasogenic edema in patients with advanced cancer, leading to reduced morbidity and associated clinical benefit. Cancer Res; 70(21); 8662-73. (C)2010 AACR. C1 [Kelly, Kathleen] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging & Mouse Imaging Facil, NIH, Bethesda, MD USA. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, 37 Convent Dr,Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Institute of Neurological Disorders and Stroke FX Intramural Research Programs of NIH, National Cancer Institute, Center for Cancer Research and the National Institute of Neurological Disorders and Stroke. NR 27 TC 28 Z9 30 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2010 VL 70 IS 21 BP 8662 EP 8673 DI 10.1158/0008-5472.CAN-10-1435 PG 12 WC Oncology SC Oncology GA 673MJ UT WOS:000283667300044 PM 20959486 ER PT J AU Kohler, ME Johnson, BD Palen, K Chen, QR Khan, J Orentas, RJ AF Kohler, M. Eric Johnson, Bryon D. Palen, Katie Chen, Qing-Rong Khan, Javed Orentas, Rimas J. TI Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data SO CANCER SCIENCE LA English DT Article ID ARTIFICIAL NEURAL-NETWORKS; T-CELL RECOGNITION; GENOMIC ALTERATIONS; IMMUNE-RESPONSES; BREAST-CANCER; EXPRESSION; ANTIBODY; KINASE; IDENTIFICATION; CLASSIFICATION AB The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor-expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell-based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell-based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)-related kinase NEK2 was identified as a tumor-associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients. (Cancer Sci 2010; 101: 2316-2324). C1 [Chen, Qing-Rong; Khan, Javed; Orentas, Rimas J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kohler, M. Eric; Johnson, Bryon D.; Palen, Katie] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Chen, Qing-Rong] NCI Frederick, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD USA. RP Orentas, RJ (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM rimas.orentas@nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU Midwest Athletes Against Childhood Cancer (MACC Inc., Milwaukee, WI, USA); American Cancer Society [ACS IRG-170]; US Public Health Service [CA100030] FX These studies were supported by the Midwest Athletes Against Childhood Cancer (MACC Fund, Inc., Milwaukee, WI, USA), an American Cancer Society Internal Research Grant (ACS IRG-170) to R. Orentas, and a US Public Health Service Grant (CA100030) to B. Johnson. We thank James Weber for expert technical assistance. NR 55 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD NOV PY 2010 VL 101 IS 11 BP 2316 EP 2324 DI 10.1111/j.1349-7006.2010.01694.x PG 9 WC Oncology SC Oncology GA 666YG UT WOS:000283158300004 PM 20718755 ER PT J AU Yotsumoto, F Fukami, T Yagi, H Funakoshi, A Yoshizato, T Kuroki, M Miyamoto, S AF Yotsumoto, Fusanori Fukami, Tatsuya Yagi, Hiroshi Funakoshi, Akihiro Yoshizato, Toshiyuki Kuroki, Masahide Miyamoto, Shingo TI Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer SO CANCER SCIENCE LA English DT Article ID RANDOMIZED-TRIAL; OVARIAN-CANCER; HB-EGF; THERAPY; CELLS; PACLITAXEL; ADENOCARCINOMA; GEMCITABINE; INHIBITION; EXPRESSION AB Pancreatic cancer is one of the most lethal malignancies. Epidermal growth factor receptor (EGFR), HER3, Akt, and amphiregulin have been recognized as targets for pancreatic cancer therapy. Although gemcitabine + erlotinib has been the recommended chemotherapy for pancreatic cancer, the prognosis is extremely poor. The development of molecularly targeted therapies has been required for patients with pancreatic cancer. To assess the validation of amphiregulin as a target for pancreatic cancer therapy, we examined its expression in pancreatic cancer using real-time PCR analyses and ELISA. We also measured the apoptotic cell rate using TUNEL assays. In addition, alterations in signaling pathways were detected by immunoblotting analyses. Treatment with gemcitabine, which reduced the cell viability and augmented the cell apoptotic rate, activated and subsequently attenuated ERK and EGFR signals. However, gemcitabine, paclitaxel, or cisplatin treatment enhanced the Akt activation, heterodimer formation of EGFR with HER3, and secretion of amphiregulin, indicating that the presence of gemcitabine promoted the activity of targeted molecules including amphiregulin, Akt, and HER3 for pancreatic cancer therapy. Combined treatment with an inhibitor for amphiregulin and gemcitabine, paclitaxel, or cisplatin induced synergistic antitumor effects, accompanied by the suppression of Akt and ERK activation. Blockade of amphiregulin suppressed the activities of EGFR, HER3, and Akt and the expression of amphiregulin itself. According to this evidence, combination chemotherapy of conventional anticancer drugs plus an inhibitor for amphiregulin would allow us to provide more favorable clinical outcomes for patients with pancreatic cancer. (Cancer Sci 2010; 101: 2351-2360). C1 [Yotsumoto, Fusanori; Fukami, Tatsuya; Kuroki, Masahide; Miyamoto, Shingo] Fukuoka Univ, Ctr Adv Mol Med, Fukuoka 81401, Japan. [Yotsumoto, Fusanori; Kuroki, Masahide] Fukuoka Univ, Sch Med, Dept Biochem, Fukuoka 81401, Japan. [Fukami, Tatsuya; Yoshizato, Toshiyuki; Miyamoto, Shingo] Fukuoka Univ, Sch Med, Dept Obstet & Gynecol, Fukuoka 81401, Japan. [Yagi, Hiroshi] Natl Inst Dent & Craniofacial Res, Cell Growth Regulat Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Funakoshi, Akihiro] Kyushu Natl Canc Ctr, Dept Gastroenterol, Fukuoka, Japan. RP Miyamoto, S (reprint author), Fukuoka Univ, Ctr Adv Mol Med, Fukuoka 81401, Japan. EM smiya@cis.fukuoka-u.ac.jp FU Central Research Institute of Fukuoka University (Fukuoka, Japan); Kakihara Science and Technology Foundation (Fukuoka, Japan); Kyowa Hakko Kirin (Tokyo, Japan); Fukuoka University School of Medicine Eboshi Association (Fukuoka, Japan); International Research Fund for Subsidy of Kyushu University School of Medicine Alumni (Fukuoka, Japan) FX This work was supported in part by funds from the Central Research Institute of Fukuoka University (Fukuoka, Japan), a grant-in-aid from the Kakihara Science and Technology Foundation (Fukuoka, Japan), Kyowa Hakko Kirin (Tokyo, Japan), a Young Investigator Research Award from the Fukuoka University School of Medicine Eboshi Association (Fukuoka, Japan) and the International Research Fund for Subsidy of Kyushu University School of Medicine Alumni (Fukuoka, Japan). NR 30 TC 23 Z9 23 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD NOV PY 2010 VL 101 IS 11 BP 2351 EP 2360 DI 10.1111/j.1349-7006.2010.01671.x PG 10 WC Oncology SC Oncology GA 666YG UT WOS:000283158300008 PM 20726858 ER PT J AU Gucek, M Murphy, E AF Gucek, Marjan Murphy, Elizabeth TI What can we learn about cardioprotection from the cardiac mitochondrial proteome? SO CARDIOVASCULAR RESEARCH LA English DT Review DE Mitochondria; Cardioprotection; Phosphorylation; S-nitrosylation; Proteome ID PERMEABILITY TRANSITION PORE; ISCHEMIA-REPERFUSION INJURY; NITRIC-OXIDE SYNTHASE; KINASE-C-EPSILON; S-NITROSYLATION; PKC-EPSILON; MASS-SPECTROMETRY; ISCHEMIA/REPERFUSION INJURY; HEART-MITOCHONDRIA; PHOSPHORYLATION AB This review will summarize proteomic methods that are useful in studying the role of mitochondria in cardioprotection. The strengths and weaknesses of some of the different approaches are discussed. We focus on the cardiac mitochondrial proteome with emphasis on changes associated with cell death and protection, and we summarize how proteomic data have contributed to addressing the role of mitochondria in cardioprotection. C1 [Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Gucek, Marjan] NHLBI, NHLBI Prote Core, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU National Institutes of Health FX This work was supported by the National Heart, Lung, and Blood intramural program of the National Institutes of Health. NR 83 TC 20 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD NOV PY 2010 VL 88 IS 2 BP 211 EP 218 DI 10.1093/cvr/cvq277 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 666NQ UT WOS:000283122500004 PM 20805096 ER PT J AU Aprelikova, O Yu, XA Palla, J Wei, BR John, S Yi, M Stephens, R Simpson, RM Risinger, JI Jazaeri, A Niederhuber, J AF Aprelikova, Olga Yu, Xiang Palla, John Wei, Bih-Rong John, Simone Yi, Ming Stephens, Robert Simpson, R. Mark Risinger, John I. Jazaeri, Amir Niederhuber, John TI The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts SO CELL CYCLE LA English DT Article DE cancer-associated fibroblasts; microRNA; SATB2; endometrial cancer ID HUMAN BREAST-CANCER; STROMAL FIBROBLASTS; TUMOR MICROENVIRONMENT; COLORECTAL-CANCER; MALIGNANT BREAST; EPITHELIAL-CELLS; BINDING PROTEIN; EXPRESSION; METASTASIS; MICRORNA AB It is well established that there is a dynamic relationship between the expanding tumor and the host surrounding tissue. Cancer-associated fibroblasts (CAFs), the most common cellular population found in the tumor microenvironment, supporting tumor growth and dissemination. Here, we set out to determine the factors that may be involved in dramatic alteration of gene expression pattern in CAFs, focusing on microRNA and transcriptional regulators. We established matched pairs of human CAFs isolated from endometrial cancer and normal endometrial fibroblasts. MicroRNA and mRNA analyses identified differential expression of 11 microRNAs, with miR-31 being the most downregulated microRNA in CAFs (p=0.007). We examined several putative miR-31 target genes identified by microarray analysis and demonstrated that miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knockdown of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. These findings provide new insights into tumor-stroma interaction and document that miR-31 and its target gene SATB2, are involved in regulation of tumor cell motility. C1 [Aprelikova, Olga; Yu, Xiang; Palla, John; John, Simone; Niederhuber, John] NCI, Lab Tumor & Stem Cell Biol, Bethesda, MD 20892 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert] SAIC Inc, Frederick, MD USA. [Risinger, John I.] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, Coll Human Med, Grand Rapids, MI USA. [Jazaeri, Amir] Univ Virginia, Div Gynecol Oncol, Charlottesville, VA USA. RP Aprelikova, O (reprint author), NCI, Lab Tumor & Stem Cell Biol, Bethesda, MD 20892 USA. EM apreliko@mail.nih.gov RI Jazaeri, Amir/I-3458-2015 OI Jazaeri, Amir/0000-0003-4335-4151 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Girma Woldemichael for the kind gift of cells producing retrovirus with luciferase gene and Dr. Bradley Love (Invitrogen) for the help with microRNA array analysis. We are also grateful to Mrs. Hui Han (National Cancer Institute) for help with the cloning constructs and Ms. Susan Dalton (University of Virginia) for help with the sample collection. We thank Dr. Melinda Hollingshead, Ms. Jalpa Shah and Ms. Angelena Millione for help with fibroblast cultures in NOD. SCID mice. We thank Mr. Brian P. Hibler for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 54 TC 83 Z9 88 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD NOV PY 2010 VL 9 IS 21 BP 4387 EP 4398 DI 10.4161/cc.9.21.13674 PG 12 WC Cell Biology SC Cell Biology GA 673HQ UT WOS:000283650500029 PM 20980827 ER PT J AU Shukla, V Coumoul, X Lahusen, T Wang, RH Xu, XL Vassilopoulos, A Xiao, CY Lee, MH Man, YG Ouchi, M Ouchi, T Deng, CX AF Shukla, Vivek Coumoul, Xavier Lahusen, Tyler Wang, Rui-Hong Xu, Xiaoling Vassilopoulos, Athanassios Xiao, Cuiying Lee, Mi-Hye Man, Yan-Gao Ouchi, Mutsuko Ouchi, Toru Deng, Chu-Xia TI BRCA1 affects global DNA methylation through regulation of DNMT1 SO CELL RESEARCH LA English DT Article DE BRCA1; histone modification; DNA methylation; DNMT1; genomic imprinting; tumor formation ID EMBRYONIC STEM-CELLS; FULL-LENGTH ISOFORM; MAMMALIAN-CELLS; BREAST-CANCER; CHROMOSOME TERRITORIES; NUCLEAR ARCHITECTURE; GENETIC INTERACTIONS; TUMOR-FORMATION; DAMAGE REPAIR; MICE AB Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCA1-associated breast cancer formation. C1 [Shukla, Vivek; Coumoul, Xavier; Lahusen, Tyler; Wang, Rui-Hong; Xu, Xiaoling; Vassilopoulos, Athanassios; Xiao, Cuiying; Lee, Mi-Hye; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Man, Yan-Gao] Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. [Man, Yan-Gao] Armed Forces Inst Pathol, Dept Infect & Parasit Dis Pathol, Amer Registry Pathol, Washington, DC 20306 USA. [Ouchi, Mutsuko; Ouchi, Toru] Univ Chicago, Dept Med, NUHS, Pritzker Sch Med, Evanston, IL 60201 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA [CA79892, CA90631]; Susan G Komen Foundation FX I thank Dr E Li for providing the probe for Southern blots and members of Deng lab for their critical reading and discussion. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA(C-X D), and CA79892, CA90631, and Susan G Komen Foundation Grant (TO). NR 62 TC 31 Z9 31 U1 0 U2 10 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD NOV PY 2010 VL 20 IS 11 BP 1201 EP 1215 DI 10.1038/cr.2010.128 PG 15 WC Cell Biology SC Cell Biology GA 674DD UT WOS:000283713000006 PM 20820192 ER PT J AU Tell, G Wilson, DM AF Tell, Gianluca Wilson, David M., III TI Targeting DNA repair proteins for cancer treatment SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Base excision repair; Nucleotide excision repair; Translesion synthesis bypass; Homologous recombination; Nonhomologous end joining; DNA damage ID BASE EXCISION-REPAIR; MAMMALIAN-CELLS; REDOX FUNCTION; INHIBITORS; APE1/REF-1; MOLECULE; THERAPY; MGMT; APE1 C1 [Tell, Gianluca] Univ Udine, Dept Biomed Sci & Technol, Sch Med, Mol Biol Sect, I-33100 Udine, Italy. [Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH,IRP, Baltimore, MD 21224 USA. RP Tell, G (reprint author), Univ Udine, Dept Biomed Sci & Technol, Sch Med, Mol Biol Sect, Piazzale Kolbe 4, I-33100 Udine, Italy. EM gianluca.tell@uniud.it OI Tell, Gianluca/0000-0001-8845-6448 FU MIUR [FIRB RBRN07BMCT_008, PRIN 2008CCPKRP_003]; National Institutes of Health, National Institute on Aging FX This article was supported financially by grants from MIUR (FIRB RBRN07BMCT_008 and PRIN 2008CCPKRP_003) to G.T and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (D.M.W. III). NR 21 TC 14 Z9 15 U1 0 U2 7 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2010 VL 67 IS 21 BP 3569 EP 3572 DI 10.1007/s00018-010-0484-6 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666DP UT WOS:000283092400001 PM 20706767 ER PT J AU Wilson, DM Simeonov, A AF Wilson, David M., III Simeonov, Anton TI Small molecule inhibitors of DNA repair nuclease activities of APE1 SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE APE1/APEX1/REF-1; Abasic endonuclease; DNA damage; Base excision DNA repair; Inhibitor; Cancer treatment ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; BASE EXCISION-REPAIR; APURINIC-APYRIMIDINIC ENDONUCLEASE; HUMAN ABASIC ENDONUCLEASE; ENHANCES CELLULAR-SENSITIVITY; COLI EXONUCLEASE-III; STRAND BREAK ENDS; HELA-CELLS; CANCER CELLS; ARYLSTIBONIC ACIDS AB APE1 is a multifunctional protein that possesses several nuclease activities, including the ability to incise at apurinic/apyrimidinic (AP) sites in DNA or RNA, to excise 3'-blocking termini from DNA ends, and to cleave at certain oxidized base lesions in DNA. Pre-clinical and clinical data indicate a role for APE1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs, particularly monofunctional alkylators and antimetabolites. In an effort to improve the efficacy of therapeutic compounds, such as temozolomide, groups have begun to develop high-throughput screening assays and to identify small molecule inhibitors against APE1 repair nuclease activities. It is envisioned that such inhibitors will be used in combinatorial treatment paradigms to enhance the efficacy of DNA-interactive drugs that introduce relevant cytotoxic DNA lesions. In this review, we summarize the current state of the efforts to design potent and selective inhibitors against APE1 AP site incision activity. C1 [Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH,IRP, Baltimore, MD 21224 USA. [Simeonov, Anton] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH,IRP, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institute on Aging, NIH; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute, NIH; [1 R03 MH086444-01] FX We thank Drs. Mamta Naidu (Brookhaven National Laboratory, USA) and Srinivasan Madhusudan (University of Nottingham, UK) for sharing unpublished observations and for constructive input to the manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH; the Molecular Libraries Initiative of the NIH Roadmap for Medical Research; the Intramural Research Program of National Human Genome Research Institute, NIH; and grant 1 R03 MH086444-01 to D.M.W. III. NR 91 TC 41 Z9 44 U1 3 U2 21 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2010 VL 67 IS 21 BP 3621 EP 3631 DI 10.1007/s00018-010-0488-2 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666DP UT WOS:000283092400005 PM 20809131 ER PT J AU Wilson, SH Beard, WA Shock, DD Batra, VK Cavanaugh, NA Prasad, R Hou, EW Liu, YA Asagoshi, K Horton, JK Stefanick, DF Kedar, PS Carrozza, MJ Masaoka, A Heacock, ML AF Wilson, Samuel H. Beard, William A. Shock, David D. Batra, Vinod K. Cavanaugh, Nisha A. Prasad, Rajendra Hou, Esther W. Liu, Yuan Asagoshi, Kenjiro Horton, Julie K. Stefanick, Donna F. Kedar, Padmini S. Carrozza, Michael J. Masaoka, Aya Heacock, Michelle L. TI Base excision repair and design of small molecule inhibitors of human DNA polymerase beta SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Base excision repair; DNA polymerase beta; PARP-1; Small molecule inhibitors; PARP inhibitors; Structural biology; Mouse models; DNA repair deficiency ID N-TERMINAL DOMAIN; INDUCED-FIT MECHANISM; STRUCTURAL INSIGHTS; ESCHERICHIA-COLI; POLY(ADP-RIBOSE) POLYMERASE; MAMMALIAN-CELLS; SACCHAROMYCES-CEREVISIAE; INTERACTION INTERFACE; CATALYTIC MECHANISM; CRYSTAL-STRUCTURES AB Base excision repair (BER) can protect a cell after endogenous or exogenous genotoxic stress, and a deficiency in BER can render a cell hypersensitive to stress-induced apoptotic and necrotic cell death, mutagenesis, and chromosomal rearrangements. However, understanding of the mammalian BER system is not yet complete as it is extraordinarily complex and has many back-up processes that complement a deficiency in any one step. Due of this lack of information, we are unable to make accurate predictions on therapeutic approaches targeting BER. A deeper understanding of BER will eventually allow us to conduct more meaningful clinical interventions. In this review, we will cover historical and recent information on mammalian BER and DNA polymerase beta and discuss approaches toward development and use of small molecule inhibitors to manipulate BER. With apologies to others, we will emphasize results obtained in our laboratory and those of our collaborators. C1 [Wilson, Samuel H.; Beard, William A.; Shock, David D.; Batra, Vinod K.; Cavanaugh, Nisha A.; Prasad, Rajendra; Hou, Esther W.; Liu, Yuan; Asagoshi, Kenjiro; Horton, Julie K.; Stefanick, Donna F.; Kedar, Padmini S.; Carrozza, Michael J.; Masaoka, Aya; Heacock, Michelle L.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01-ES050158 Z01-ES050159] FX The authors thank Bonnie E. Mesmer for editorial assistance. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES050158 & Z01-ES050159). NR 98 TC 20 Z9 21 U1 0 U2 4 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2010 VL 67 IS 21 BP 3633 EP 3647 DI 10.1007/s00018-010-0489-1 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666DP UT WOS:000283092400006 PM 20844920 ER PT J AU Mun, SH Ko, NY Kim, HS Kim, JW Kim, DK Kim, AR Lee, SH Kim, YG Lee, CK Lee, SH Kim, BK Beaven, MA Kim, YM Choi, WS AF Mun, Se Hwan Ko, Na Young Kim, Hyuk Soon Kim, Jie Wan Kim, Do Kyun Kim, A-Ram Lee, Seung Hyun Kim, Yong-Gil Lee, Chang Keun Lee, Seoung Hoon Kim, Bo Kyung Beaven, Michael A. Kim, Young Mi Choi, Wahn Soo TI Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Interleukin-33; Osteoclasts; Differentiation; Human CD14(+) monocytes; Bone resorption ID KAPPA-B LIGAND; RHEUMATOID-ARTHRITIS; BONE-RESORPTION; THERAPEUTIC TARGET; RECEPTOR ACTIVATOR; IMMUNE-SYSTEM; MAST-CELLS; T-CELLS; IN-VIVO; IL-33 AB Interleukin (IL)-33 is a recently described pro-inflammatory cytokine. Here we demonstrate IL-33 as a regulator of functional osteoclasts (OCs) from human CD14(+) monocytes. IL-33 stimulates formation of tartrate-resistant acid phosphatase (TRAP)(+) multinuclear OCs from monocytes. This action was suppressed by anti-ST2 antibody, suggesting that IL-33 acts through its receptor ST2, but not by the receptor activator of NF-kappa B ligand (RANKL) decoy, osteoprotegerin, or anti-RANKL antibody. IL-33 stimulated activating phosphorylations of signaling molecules in monocytes that are critical for OC development. These included Syk, phospholipase C gamma 2, Gab2, MAP kinases, TAK-1, and NF-kappa B. IL-33 also enhanced expression of OC differentiation factors including TNF-alpha receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. IL-33 eventually induced bone resorption. This study suggests that the osteoclastogenic property of IL-33 is mediated through TRAF6 as well as the immunoreceptor tyrosine-based activation motif-dependent Syk/PLC gamma pathway in human CD14(+) monocytes. C1 [Choi, Wahn Soo] Konkuk Univ, Dept Immunol, Coll Med, Chungju 380701, South Korea. [Mun, Se Hwan; Ko, Na Young; Kim, Hyuk Soon; Kim, Jie Wan; Kim, Do Kyun; Kim, A-Ram; Lee, Seung Hyun; Kim, Bo Kyung; Choi, Wahn Soo] Konkuk Univ, Inst Biomed Sci & Technol, Coll Med, Chungju 380701, South Korea. [Kim, Yong-Gil; Lee, Chang Keun] Univ Ulsan, Div Rheumatol, Coll Med, Seoul 138736, South Korea. [Lee, Seung Hyun] Wonkwang Univ, Sch Dent, Dept Oral Microbiol & Immunol, Iksan 570749, 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, Dept Immunol, Coll Med, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU Konkuk University; Korea government (MEST) [20090077125]; Korean Ministry of Education, Science and Technology; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Konkuk University and partly by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 20090077125) and the grant of the Korean Ministry of Education, Science and Technology (The Regional Core Research Program/Chungbuk BIT Research-Oriented University Consortium). Dr. Michael A. Beaven was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 38 TC 28 Z9 29 U1 0 U2 5 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2010 VL 67 IS 22 BP 3883 EP 3892 DI 10.1007/s00018-010-0410-y PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 666DV UT WOS:000283093000010 PM 20532808 ER PT J AU Hernandez-Cruz, A Eiden, LE AF Hernandez-Cruz, Arturo Eiden, Lee E. TI Proceedings of the 15th International Symposium on Chromaffin Cell Biology: The Chromaffin Cell as a Stress Transducer FOREWORD SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Editorial Material C1 [Hernandez-Cruz, Arturo] Univ Nacl Autonoma Mexico, Div Neurociencias, Dept Neurociencia Cognit, Inst Fisiol Celular, Mexico City 04510, DF, Mexico. [Eiden, Lee E.] NIH, Mol Neurosci Sect, Bethesda, MD 20892 USA. RP Hernandez-Cruz, A (reprint author), Univ Nacl Autonoma Mexico, Div Neurociencias, Dept Neurociencia Cognit, Inst Fisiol Celular, Ciudad Univ, Mexico City 04510, DF, Mexico. EM ahernan@ifc.unam.mx FU Intramural NIH HHS [ZIA MH002386-23, Z01 MH002386-21, Z01 MH002386-22] NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1143 EP 1144 DI 10.1007/s10571-010-9623-8 PG 2 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200001 PM 21086157 ER PT J AU Stojilkovic, SS Yan, ZH Obsil, T Zemkova, H AF Stojilkovic, Stanko S. Yan, Zonghe Obsil, Tomas Zemkova, Hana TI Structural Insights into the Function of P2X4: An ATP-Gated Cation Channel of Neuroendocrine Cells SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article; Proceedings Paper CT 15th International Symposium on Chromaffin Cell Biology CY NOV 12-16, 2009 CL Merida, MEXICO DE P2X receptors; ATP; Gating; Orthosteric and allosteric regulation; Ivermectin; Trace metals; Scanning mutagenesis ID P2X(4) RECEPTOR CHANNELS; FIRST TRANSMEMBRANE DOMAIN; ALVEOLAR MACROPHAGES; IONOTROPIC RECEPTOR; CYSTEINE RESIDUES; SPINAL MICROGLIA; AGONIST BINDING; POLAR RESIDUES; NERVE INJURY; ION-CHANNEL AB The P2X4 receptor (P2X4R) is a member of a family of ATP-gated cation channels that are composed of three subunits. Each subunit has two transmembrane (TM) domains linked by a large extracellular loop and intracellularly located N- and C-termini. The receptors are expressed in excitable and non-excitable cells and have been implicated in the modulation of membrane excitability, calcium signaling, neurotransmitter and hormone release, and pain physiology. P2X4Rs activate rapidly and desensitize within the seconds of agonist application, both with the rates dependent on ATP concentrations, and deactivate rapidly and independently of ATP concentration. Disruption of conserved cysteine ectodomain residues affects ATP binding and gating. Several ectodomain residues of P2X4R were identified as critical for ATP binding, including K67, K313, and R295. Ectodomain residues also account for the allosteric regulation of P2X4R; HI 40 is responsible for copper binding and H286 regulates receptor functions with protons. Ivermectin sensitized receptors, amplified the current amplitude, and slowed receptor deactivation by binding in the TM region. Scanning mutagenesis of TMs revealed the helical topology of both domains, and suggested that receptor function is critically dependent on the conserved Y42 residue. In this brief article, we summarize this study and re-interpret it using a model based on crystallization of the zebrafish P2X4.1 receptor. C1 [Stojilkovic, Stanko S.; Yan, Zonghe] NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Obsil, Tomas] Charles Univ Prague, Dept Phys & Macromol Chem, Fac Sci, Prague, Czech Republic. [Obsil, Tomas; Zemkova, Hana] Acad Sci Czech Republic, Dept Cellular & Mol Neuroendocrinol, Inst Physiol, Prague 4, Czech Republic. RP Stojilkovic, SS (reprint author), NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Zemkova, Hana/C-1844-2012; Obsil, Tomas/B-7142-2012 OI Obsil, Tomas/0000-0003-4602-1272 FU Intramural NIH HHS [ZIA HD000195-17] NR 77 TC 11 Z9 11 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1251 EP 1258 DI 10.1007/s10571-010-9568-y PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200016 PM 21107680 ER PT J AU Eiden, LE AF Eiden, Lee E. TI Commentary on Chapters 'Clinical and Developmental Aspects' and 'Stress Responses of the Adrenal Medulla' SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Editorial Material C1 NIMH IRP, Bethesda, MD USA. RP Eiden, LE (reprint author), NIMH IRP, Bethesda, MD USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1371 EP 1375 DI 10.1007/s10571-010-9607-8 PG 5 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200033 PM 21088882 ER PT J AU Murthy, SRK Pacak, K Loh, YP AF Murthy, Saravana R. K. Pacak, Karel Loh, Y. Peng TI Carboxypeptidase E: Elevated Expression Correlated with Tumor Growth and Metastasis in Pheochromocytomas and Other Cancers SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article; Proceedings Paper CT 15th International Symposium on Chromaffin Cell Biology CY NOV 12-16, 2009 CL Merida, MEXICO DE Carboxypeptidase E; Pheochromocytomas; Neuroendocrine tumors; Non-endocrine cancers; Biomarker; Metastasis ID PEPTIDE PROCESSING ENZYMES; PATHWAY SORTING RECEPTOR; CPE(FAT) MICE; E MUTATION; PROINSULIN; SECRETION; MECHANISM; HORMONE; MOUSE; CELLS AB Expression of carboxypeptidase E (CPE), a prohormone processing enzyme in different cancer types, was analyzed from data in the GEO profile database (http://www.ncbi.nlm.nih.gov/geo/) and experimentally in pheochromocytomas. Analysis of microarray data demonstrated that significantly elevated levels of CPE mRNA was found in many metastatic non-endocrine cancers: cervical, colon rectal, renal cancers, Ewing sarcomas (bone cancer), and various types of astrocytomas and oligodendrogliomas, whereas expression of CPE mRNA was virtually absent in their respective counterpart normal tissues. Moreover, there was higher CPE mRNA expression in cells from the metastatic tumor compared to those from the primary tumor in colorectal cancer. Elevated CPE mRNA expression was found in neuroendocrine tumors in lung and pituitary adenomas, although the significance is unclear since endocrine and neuroendocrine cells normally express CPE. However, studies of neuroendocrine tumors, pheochromocytomas, revealed expression of not only wild-type CPE, but a variant which was correlated with tumor behavior. Extremely high CPE mRNA copy numbers of the variant were found in very large or invasive tumors, both of which usually indicate poor prognosis. Thus, collectively the data suggest that CPE may play a role in promoting tumor growth and invasion. CPE could potentially serve as a diagnostic and prognostic biomarker for metastasis in different cancer types. C1 [Murthy, Saravana R. K.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bldg 49,Rm 5A22,49 Convent Dr,MSC 4480, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural NIH HHS [ZIA HD008804-03] NR 24 TC 24 Z9 26 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1377 EP 1381 DI 10.1007/s10571-010-9592-y PG 5 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200034 PM 21061162 ER PT J AU Goldstein, DS AF Goldstein, David S. TI Adrenal Responses to Stress SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article; Proceedings Paper CT 15th International Symposium on Chromaffin Cell Biology CY NOV 12-16, 2009 CL Merida, MEXICO DE Stress; Adrenal; Epinephrine; Norepinephrine; Sympathetic nervous system ID SYMPATHETIC-NERVOUS-SYSTEM; ALLOSTATIC LOAD; ADRENOMEDULLARY ACTIVATION; SYMPATHOADRENAL SYSTEM; PANIC DISORDER; HUMANS; RATS; NOREPINEPHRINE; GLUCOCORTICOIDS; DISSOCIATION AB Based on concepts proposed by Langley, Cannon, and Se lye, adrenal responses to stress occur in a syndrome that reflects activation of the sympathoadrenal system and hypothalamic pituitary adrenocortical (HPA) axis; and a "stress syndrome" maintains homeostasis in emergencies such as "fight or flight" situations, but if the stress response is excessive or prolonged then any of a variety of clinical disorders can arise. The idea of a unitary sympathoadrenal system does not account for evidence that different stressors elicit different patterns of autonomic responses, with exposure to some stressors differentially affecting sympathetic noradrenergic and adrenomedullary hormonal activities. Instead, adrenomedullary responses to stressors are more closely tied to adrenocortical than to sympathetic noradrenergic responses. Distress involves concurrent activation of the HPA and adrenomedullary neuroendocrine systems. C1 Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bldg 10,Room 5N220,9000 Rockville Pike,10 Ctr Dr,, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural NIH HHS [Z01 NS003033-02, ZIA NS003033-03, ZIA NS003033-04, Z01 NS003033-01] NR 47 TC 35 Z9 35 U1 1 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1433 EP 1440 DI 10.1007/s10571-010-9606-9 PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200042 PM 21061156 ER PT J AU Ait-Ali, D Samal, B Mustafa, T Eiden, LE AF Ait-Ali, Djida Samal, Babru Mustafa, Tomris Eiden, Lee E. TI Neuropeptides, Growth Factors, and Cytokines: A Cohort of Informational Molecules Whose Expression Is Up-Regulated by the Stress-Associated Slow Transmitter PACAP in Chromaffin Cells SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article; Proceedings Paper CT 15th International Symposium on Chromaffin Cell Biology CY NOV 12-16, 2009 CL Merida, MEXICO DE Adrenal medulla; Chromaffin cell; Cytokine; Growth factor; Hormone; Microarray; Neuropeptide; PACAP; PC12; Stress ID CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; INDEPENDENT SIGNALING PATHWAY; RAT ADRENAL-GLAND; GENE-TRANSCRIPTION; SECRETOGRANIN-II; PC12 CELLS; CATECHOLAMINE SECRETION; MICROARRAY ANALYSES; INNATE IMMUNITY AB Pituitary adenylate cyclase-activating polypeptide (PACAP) is a co-transmitter with acetylcholine at the adrenomedullary synapse, mediating sustained hormone secretion and regulation of cellular plasticity in response to stress at the level of gene transcription. Here we have extended our investigation of PACAP-regulated neuroendocrine cell-specific genes from PC12 cells to PC12 cells expressing physiological levels of the PAC1hop receptor found on chromaffin cells in vivo. PACAP induces in these PC12_bPAC1hop cells an additional cohort of genes, compared to PC12 cells, enriched in informational molecules including cytokines, neuropeptides, and growth factors. Using two newly developed microarray platforms for expressed bovine transcripts, we further examined PACAP-induced genes in bovine chromaffin cells during a period of exposure (6 h) corresponding to a period of prolonged metabolic or psychogenic stress in vivo during which PACAP is released from the splanchnic nerve onto chromaffin cells. As in PC12_bPAC1hop cells, PACAP induced in bovine chromaffin cells a cohort of genes encoding secretory proteins, identified by tiling for cellular localization using Ingenuity Pathway Analysis, which were highly enriched in informational molecules (secreted proteins acting at extracellular receptors). These included cytokines, growth factors and hormones, as well as converting enzymes, or protease inhibitors modulating converting enzyme function. Several neuropeptide prohormone transcripts not previously shown to be PACAP-regulated in chromaffin cells, such as thyrotropin-releasing hormone, and tachykinin precursor 1, were identified. Identification of this cohort of informational molecule-encoding transcripts suggests a wider, more integrative role for PACAP as a co-transmitter specific to stress transduction in the adrenal medulla. C1 [Ait-Ali, Djida; Samal, Babru; Mustafa, Tomris; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Ait-Ali, D (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bldg 49,Room 5A-38, Bethesda, MD 20892 USA. EM aitalid@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-22, Z01 MH002386-21, ZIA MH002386-23, ZIA MH002386-24]; NIMH NIH HHS [Z01 MH002386] NR 57 TC 10 Z9 10 U1 1 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2010 VL 30 IS 8 SI SI BP 1441 EP 1449 DI 10.1007/s10571-010-9620-y PG 9 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 703AX UT WOS:000285947200043 PM 21107678 ER PT J AU Shirakawa, AK Liao, F Zhang, HH Hedrick, MN Singh, SP Wu, DQ Farber, JM AF Shirakawa, Aiko-Konno Liao, Fang Zhang, Hongwei H. Hedrick, Michael N. Singh, Satya P. Wu, Dianqing Farber, Joshua M. TI Pathway-selective suppression of chemokine receptor signaling in B cells by LPS through downregulation of PLC-beta 2 SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE B cells; calcium; chemokine; chemotaxis; GPCR ID PHOSPHOLIPASE-C-BETA; LYMPHOCYTE MIGRATION; SECRETING CELLS; T-LYMPHOCYTES; MICE LACKING; IFN-GAMMA; IN-VIVO; EXPRESSION; ACTIVATION; CHEMOTAXIS AB Lymphocyte activation leads to changes in chemokine receptor expression. There are limited data, however, on how lymphocyte activators can alter chemokine signaling by affecting downstream pathways. We hypothesized that B cell-activating agents might alter chemokine responses by affecting downstream signal transducers, and that such effects might differ depending on the activator. We found that activating mouse B cells using either anti-IgM or lipopolysaccharide (LPS) increased the surface expression of CCR6 and CCR7 with large increases in chemotaxis to their cognate ligands. By contrast, while anti-IgM also led to enhanced calcium responses, LPS-treated cells showed only small changes in calcium signaling as compared with cells that were freshly isolated. Of particular interest, we found that LPS caused a reduction in the level of B-cell phospholipase C (PLC)-beta 2 mRNA and protein. Data obtained using PLC-beta 2(-/-) mice showed that the beta 2 isoform mediates close to one-half the chemokine-induced calcium signal in resting and anti-IgM-activated B cells, and we found that calcium signals in the LPS-treated cells were boosted by increasing the level of PLC-beta 2 using transfection, consistent with a functional effect of downregulating PLC-beta 2. Together, our results show activator-specific effects on responses through B-cell chemokine receptors that are mediated by quantitative changes in a downstream signal-transducing protein, revealing an activity for LPS as a downregulator of PLC-beta 2, and a novel mechanism for controlling chemokine-induced signals in lymphocytes. Cellular & Molecular Immunology (2010) 7, 428-439; doi: 10.1038/cmi.2010.46; published online 27 September 2010 C1 [Shirakawa, Aiko-Konno; Liao, Fang; Zhang, Hongwei H.; Hedrick, Michael N.; Singh, Satya P.; Farber, Joshua M.] NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wu, Dianqing] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. RP Farber, JM (reprint author), NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bldg 10,Room 11N-112,10 Ctr Dr, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov FU NIAID, NIH FX We would like to thank Martin Dorf, Harvard Medical School, for providing the cDNA for mouse CXCR4; Kaimei Song, for sharing reagents; Paul Goldsmith, for help in making antibodies; and Sue Goo Rhee for advice and for supplying pMT2-PLC-beta 2. The Intramural Research Program of NIAID, NIH, supported this research. NR 53 TC 5 Z9 6 U1 0 U2 0 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD NOV PY 2010 VL 7 IS 6 BP 428 EP 439 DI 10.1038/cmi.2010.46 PG 12 WC Immunology SC Immunology GA 674DK UT WOS:000283713800004 PM 20871625 ER PT J AU Wang, H Yang, Y Sharma, N Tarasova, NI Timofeeva, OA Winkler-Pickett, RT Tanigawa, S Perantoni, AO AF Wang, Honghe Yang, Yili Sharma, Nirmala Tarasova, Nadya I. Timofeeva, Olga A. Winkler-Pickett, Robin T. Tanigawa, Shunsuke Perantoni, Alan O. TI STAT1 activation regulates proliferation and differentiation of renal progenitors SO CELLULAR SIGNALLING LA English DT Article DE STAT1; STAT3; Kidney; Wilms tumor; Mesenchymal-epithelial transition; Development ID MAMMARY-GLAND DEVELOPMENT; SIGNAL-TRANSDUCTION PATHWAYS; INTERFERON-GAMMA; WILMS-TUMOR; GROWTH-FACTOR; CELL-LINE; TRANSCRIPTIONAL CONTROL; METANEPHRIC MESENCHYME; TARGETED DISRUPTION; N-DOMAIN AB We have shown previously that activation of STAT1 contributes to the pathogenesis of Wilms tumor. This neoplasm caricatures metanephric development and is believed to originate from embryonic renal mesenchymal progenitors that lose their ability to undergo mesenchymal-epithelial transition (MET). Therefore, we hypothesized that STAT1 is also activated and functional during metanephric development. Here we have demonstrated that both STAT1 and STAT3 are activated during normal development of the embryonic kidney. Furthermore, activation of STAT1 stimulated the proliferation of metanephric mesenchymal cells, but it prevented MET and tubulogenesis induced by leukemia inhibitory factor, which preferentially activates STAT3. Consistent with its negative regulation of metanephric mesenchymal differentiation, inhibition of STAT1 activation with protein kinase CK2 inhibitor TBB or RNAi-mediated knockdown of STAT1 promoted differentiation of metanephric progenitors and abolished the effect of cytokine-induced STAT1 activation in these cells. Additionally, a cell-permeable peptide that inhibits STAT1-mediated transactivation by targeting the STAT1 N-domain also blocked cytokine-induced STAT1-dependent proliferation in metanephric progenitors and promoted LIF-induced MET and tubulogenesis. Finally, the STAT1 peptide inhibitor caused the down regulation of survival/anti-apoptotic factors, Mcl-1 and Hsp-27, and induced apoptosis in renal tumor cells with constitutively active STAT1, indicating that STAT1 is required for these cells to survive. These findings show that both metanephric progenitors and renal tumor cells utilize a STAT1-dependent mechanism for growth or survival. Published by Elsevier Inc. C1 [Wang, Honghe; Yang, Yili; Sharma, Nirmala; Tanigawa, Shunsuke; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Tarasova, Nadya I.; Winkler-Pickett, Robin T.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Timofeeva, Olga A.] Univ Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Perantoni, AO (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, Bldg 538,Room 205D, Frederick, MD 21702 USA. EM perantoa@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 56 TC 16 Z9 16 U1 0 U2 2 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 NOV PY 2010 VL 22 IS 11 BP 1717 EP 1726 DI 10.1016/j.cellsig.2010.06.012 PG 10 WC Cell Biology SC Cell Biology GA 645MK UT WOS:000281463500014 PM 20624457 ER PT J AU Simonyan, K Ludlow, CL AF Simonyan, Kristina Ludlow, Christy L. TI Abnormal Activation of the Primary Somatosensory Cortex in Spasmodic Dysphonia: An fMRI Study SO CEREBRAL CORTEX LA English DT Article DE laryngeal dystonia; neuroimaging; voice production ID EVENT-RELATED FMRI; WRITERS CRAMP; BASAL GANGLIA; FOCAL DYSTONIA; MOTOR CORTEX; INTERINDIVIDUAL VARIABILITY; STEREOTAXIC THALAMOTOMY; CERVICAL DYSTONIA; BOTULINUM TOXIN; MATTER CHANGES AB Spasmodic dysphonia (SD) is a task-specific focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speaking. Our aim was to identify symptom-specific functional brain activation abnormalities in adductor spasmodic dysphonia (ADSD) and abductor spasmodic dysphonia (ABSD). Both SD groups showed increased activation extent in the primary sensorimotor cortex, insula, and superior temporal gyrus during symptomatic and asymptomatic tasks and decreased activation extent in the basal ganglia, thalamus, and cerebellum during asymptomatic tasks. Increased activation intensity in SD patients was found only in the primary somatosensory cortex during symptomatic voice production, which showed a tendency for correlation with ADSD symptoms. Both SD groups had lower correlation of activation intensities between the primary motor and sensory cortices and additional correlations between the basal ganglia, thalamus, and cerebellum during symptomatic and asymptomatic tasks. Compared with ADSD patients, ABSD patients had larger activation extent in the primary sensorimotor cortex and ventral thalamus during symptomatic task and in the inferior temporal cortex and cerebellum during symptomatic and asymptomatic voice production. The primary somatosensory cortex shows consistent abnormalities in activation extent, intensity, correlation with other brain regions, and symptom severity in SD patients and, therefore, may be involved in the pathophysiology of SD. C1 [Simonyan, Kristina; Ludlow, Christy L.] Natl Inst Neurol Disorders & Stroke, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Simonyan, K (reprint author), Mt Sinai Sch Med, 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; Ludlow, Christy/0000-0002-2015-6171 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke [Z01NS00298]; National Institute on Deafness and Other Communication Disorders [R00DC009620] FX Intramural Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (Z01NS00298 to C. L. L); National Institute on Deafness and Other Communication Disorders (R00DC009620 to K.S.). NR 66 TC 41 Z9 42 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2010 VL 20 IS 11 BP 2749 EP 2759 DI 10.1093/cercor/bhq023 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 661TI UT WOS:000282750600023 PM 20194686 ER PT J AU Schelbert, EB Hsu, LY Anderson, SA Mohanty, BD Karim, SM Kellman, P Aletras, AH Arai, AE AF Schelbert, Erik B. Hsu, Li-Yueh Anderson, Stasia A. Mohanty, Bibhu D. Karim, Syed M. Kellman, Peter Aletras, Anthony H. Arai, Andrew E. TI Late Gadolinium-Enhancement Cardiac Magnetic Resonance Identifies Postinfarction Myocardial Fibrosis and the Border Zone at the Near Cellular Level in Ex Vivo Rat Heart SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE MRI; collagen; myocardial infarction; late gadolinium enhancement; fibrosis ID INFARCT TISSUE HETEROGENEITY; LEFT-VENTRICULAR DYSFUNCTION; DILATED CARDIOMYOPATHY; MRI; VIABILITY; HYPERTROPHY; PROPAGATION; IMPROVEMENT; ARRHYTHMIA; PREDICTOR AB Background-Using a resolution 1000-fold higher than prior studies, we studied (1) the degree to which late gadolinium-enhancement (LGE) cardiac magnetic resonance tracks fibrosis from chronic myocardial infarction and (2) the relationship between intermediate signal intensity and partial volume averaging at distinct "smooth" infarct borders versus disorganized mixtures of fibrosis and viable cardiomyocytes. Methods and Results-Sprague-Dawley rats underwent myocardial infarction by coronary ligation. Two months later, rats were euthanized 10 minutes after administration of 0.3 mmol/kg intravenous gadolinium. LGE images ex vivo at 7 T with a 3D gradient echo sequence with 50X50X50 mu m voxels were compared with histological sections (Masson trichrome). Planimetered histological and LGE regions of fibrosis correlated well (y=1.01x-0.01; R(2)=0.96; P<0.001). In addition, LGE images routinely detected clefts of viable cardiomyocytes 2 to 4 cells thick that separated bands of fibrous tissue. Although LGE clearly detected disorganized mixtures of fibrosis and viable cardiomyocytes characterized by intermediate signal intensity voxels, the percentage of apparent intermediate signal intensity myocardium increased significantly (P<0.01) when image resolution was degraded to resemble clinical resolution consistent with significant partial volume averaging. Conclusions-These data provide important validation of LGE at nearly the cellular level for detection of fibrosis after myocardial infarction. Although LGE can detect heterogeneous patches of fibrosis and viable cardiomyocytes as patches of intermediate signal intensity, the percentage of intermediate signal intensity voxels is resolution dependent. Thus, at clinical resolutions, distinguishing the peri-infarct border zone from partial volume averaging with LGE is challenging. (Circ Cardiovasc Imaging. 2010; 3: 743-752.) C1 [Schelbert, Erik B.; Hsu, Li-Yueh; Anderson, Stasia A.; Mohanty, Bibhu D.; Karim, Syed M.; Kellman, Peter; Aletras, Anthony H.; Arai, Andrew E.] NHLBI, Cardiac Energet Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Cardiac Energet Lab, NIH, US Dept HHS, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 FU National Heart, Lung, and Blood Institute [1 Z01 HL004607-12 TMB] FX This study was funded by the Intramural Research Program of National Heart, Lung, and Blood Institute (1 Z01 HL004607-12 TMB). NR 33 TC 69 Z9 71 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD NOV PY 2010 VL 3 IS 6 BP 743 EP 752 DI 10.1161/CIRCIMAGING.108.835793 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 680VN UT WOS:000284264400016 PM 20847191 ER PT J AU Carson, AP Fox, CS McGuire, DK Levitan, EB Laclaustra, M Mann, DM Muntner, P AF Carson, April P. Fox, Caroline S. McGuire, Darren K. Levitan, Emily B. Laclaustra, Martin Mann, Devin M. Muntner, Paul TI Low Hemoglobin A1c and Risk of All-Cause Mortality Among US Adults Without Diabetes SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE hemoglobin A1c; epidemiology; mortality ID CELL DISTRIBUTION WIDTH; CARDIOVASCULAR-DISEASE; GLYCATED HEMOGLOBIN; FASTING GLUCOSE; WOMEN; MELLITUS; ATHEROSCLEROSIS; HYPERGLYCEMIA; NORFOLK; PEOPLE AB Background-Among individuals without diabetes, elevated hemoglobin A1c (HbA1c) has been associated with increased morbidity and mortality, but the literature is sparse regarding the prognostic importance of low HbA1c. Methods and Results-National Health and Nutrition Examination Survey III (NHANES III) participants, 20 years and older, were followed up to 12 years (median follow-up, 8.8 years) for all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between HbA1c levels and all-cause mortality for 14 099 participants without diabetes. There were 1825 deaths during the follow-up period. Participants with a low HbA1c (<4.0%) had the highest levels of mean red blood cell volume, ferritin, and liver enzymes and the lowest levels of mean total cholesterol and diastolic blood pressure compared with their counterparts with HbA1c levels between 4.0% and 6.4%. An HbA1c <4.0% versus 5.0% to 5.4% was associated with an increased risk of all-cause mortality (HR, 3.73; 95% CI, 1.45 to 9.63) after adjustment for age, race-ethnicity, and sex. This association was attenuated but remained statistically significant after further multivariable adjustment for lifestyle, cardiovascular factors, metabolic factors, red blood cell indices, iron storage indices, and liver function indices (HR, 2.90; 95% CI, 1.25 to 6.76). Conclusions-In this nationally representative cohort, low HbA1c was associated with increased all-cause mortality among US adults without diabetes. Additional research is needed to confirm these results and identify potential mechanisms that may be underlying this association. (Circ Cardiovasc Qual Outcomes. 2010;3:661-667.) C1 [Carson, April P.; Levitan, Emily B.; Muntner, Paul] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol & Metab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [McGuire, Darren K.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Laclaustra, Martin] Natl Ctr Cardiovasc Res CNIC, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Mann, Devin M.] Mt Sinai Sch Med, Div Gen Internal Med, New York, NY USA. [Muntner, Paul] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Carson, AP (reprint author), Univ Alabama, Dept Epidemiol, 1530 3rd Ave S,RPHB 230N, Birmingham, AL 35294 USA. EM apcarson@uab.edu RI Levitan, Emily/E-2418-2011; Laclaustra, Martin/C-6709-2015; OI Laclaustra, Martin/0000-0003-3963-0846; Mann, Devin/0000-0002-2099-0852 FU Instituto de Salud Carlos III, Spain [CP08/00112]; Tethys Bioscience; Biosite, Inc; F. Hoffmann La Roche; Daiichi Sankyo FX Dr Laclaustra is supported by CP08/00112 "Miguel Servet" Grant (Instituto de Salud Carlos III, Spain).; Dr McGuire received consultancy fees <$10 000 from Tethys Bioscience, Biosite, Inc, F. Hoffmann La Roche, and Daiichi Sankyo. NR 30 TC 44 Z9 45 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD NOV PY 2010 VL 3 IS 6 BP 661 EP 667 DI 10.1161/CIRCOUTCOMES.110.957936 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 680VB UT WOS:000284262900014 PM 20923991 ER PT J AU Li, W Puertollano, R Bonifacino, JS Overbeek, PA Everett, ET AF Li, Wei Puertollano, Rosa Bonifacino, Juan S. Overbeek, Paul A. Everett, Eric T. TI EDITOR'S CHOICE Disruption of the Murine Ap2 beta 1 Gene Causes Nonsyndromic Cleft Palate SO CLEFT PALATE-CRANIOFACIAL JOURNAL LA English DT Article DE beta 2-adaptin; clathrin-coated pits; cleft palate; mouse; transgene insertional mutagenesis ID TGF-BETA RECEPTOR; CLATHRIN ADAPTERS; TRANSGENIC MICE; CONSTITUTIVE ENDOCYTOSIS; INSERTIONAL MUTATION; GABA(A) RECEPTORS; SORTING SIGNALS; ACTIVATION SARA; EARLY ENDOSOMES; III RECEPTOR AB Development of the secondary palate in mammals is a complex process that can be easily perturbed, leading to the common and distressing birth defect cleft palate Animal models are particularly useful tools for dissecting underlying genetic components of cleft palate We describe a new cleft palate model resulting from a transgene insertion mutation Transgene insertional mutagenesis disrupts the genomic organization and expression of the Ap2 beta 1 gene located on chromosome 11 This gene encodes the beta 2-adaptin subunit of the heterotetrameric adaptor protein 2 complex involved in clathrin-dependent endocytosis Homozygous cleft palate mutant mice express no Ap2 beta 1 messenger RNA or beta 2-adaptin protein and die during the perinatal period Heterozygous mice are phenotypically normal despite expressing diminished beta 2-adaptin messenger RNA and protein compared with wildtype Remarkably, the paralogous beta 1-adaptin subunit of the adaptor protein 1 complex partially substitutes for the missing beta 2-adaptin in embryonic fibroblasts from homozygous mutant mice, resulting in assembly of reduced levels of an adaptor protein 2 complex bearing beta 1-adaptin This variant adaptor protein 2 complex is, therefore, apparently capable of maintaining viability of the homozygous mutant embryos until birth but insufficient to support palatogenesis Nonsyndromic cleft palate in an animal model is associated with disruption of the Ap2 beta 1 gene C1 [Li, Wei; Everett, Eric T.] Indiana Univ, Sch Dent, Dept Oral Facial Dev, Indianapolis, IN USA. [Puertollano, Rosa; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Overbeek, Paul A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Everett, ET (reprint author), Univ N Carolina, Dept Pediat Dent, 228 Brauer Hall,CB 7450, Chapel Hill, NC 27599 USA. FU National Institute of Dental and Craniofacial Research [DE 015180]; National Institute of Child Health and Human Development National Institutes of Health FX This work was supported by Public Health Service grant DE 015180 from the National Institute of Dental and Craniofacial Research (E T E) and by the Intramural Program of National Institute of Child Health and Human Development National Institutes of Health (J S B) The authors state that they have no conflicts of interest NR 56 TC 8 Z9 8 U1 0 U2 0 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1055-6656 J9 CLEFT PALATE-CRAN J JI Cleft Palate-Craniofac. J. PD NOV PY 2010 VL 47 IS 6 BP 566 EP 573 DI 10.1597/09.145 PG 8 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 682EJ UT WOS:000284383000002 PM 20500056 ER PT J AU Yau, J Xie, J Lamoureux, E Klein, R Klein, B Cotch, MF Bertoni, A Shea, S Wong, TY AF Yau, Joanne Xie, Jing Lamoureux, Ecosse Klein, Ronald Klein, Barbara Cotch, Mary Frances Bertoni, Alain Shea, Steven Wong, Tien Yin TI RETINAL MICROVASCULAR SIGNS AND RISK OF INCIDENT DIABETES: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Meeting Abstract C1 [Yau, Joanne; Xie, Jing; Lamoureux, Ecosse; Wong, Tien Yin] Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Klein, Ronald; Klein, Barbara] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Bertoni, Alain] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. EM joanneyau82@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 1442-6404 EI 1442-9071 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD NOV PY 2010 VL 38 SU 2 SI SI MA 9 BP 12 EP 12 PG 1 WC Ophthalmology SC Ophthalmology GA V45OQ UT WOS:000209826300010 ER PT J AU Jayasundera, T Branham, K Rhoades, W Heckenlively, J Swaroop, A AF Jayasundera, Thiran Branham, Kari Rhoades, William Heckenlively, John Swaroop, Anand TI THE RP2 PHENOTYPE AND PATHOGENETIC CORRELATIONS SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Meeting Abstract C1 [Jayasundera, Thiran] McGill Univ, Montreal, PQ, Canada. [Branham, Kari; Rhoades, William; Heckenlively, John] Univ Michigan, Ann Arbor, MI 48109 USA. [Swaroop, Anand] NEI, Bethesda, MD 20892 USA. EM thiran.jayasundera@mail.mcgill.ca 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 1442-6404 EI 1442-9071 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD NOV PY 2010 VL 38 SU 2 SI SI MA 12 BP 21 EP 22 PG 2 WC Ophthalmology SC Ophthalmology GA V45OQ UT WOS:000209826300029 ER PT J AU Nakayama, E Yokoyama, A Miyamoto, H Igarashi, M Kishida, N Matsuno, K Marzi, A Feldmann, H Ito, K Saijo, M Takada, A AF Nakayama, Eri Yokoyama, Ayaka Miyamoto, Hiroko Igarashi, Manabu Kishida, Noriko Matsuno, Keita Marzi, Andrea Feldmann, Heinz Ito, Kimihito Saijo, Masayuki Takada, Ayato TI Enzyme-Linked Immunosorbent Assay for Detection of Filovirus Species-Specific Antibodies SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID EBOLA-VIRUS GLYCOPROTEIN; HEMORRHAGIC-FEVER; DEPENDENT ENHANCEMENT; NUCLEOPROTEIN; PARTICLES; EPITOPES; IDENTIFICATION; INFECTION; VP40; PATHOGENESIS AB Several enzyme-linked immunosorbent assays (ELISAs) for the detection of filovirus-specific antibodies have been developed. However, diagnostic methods to distinguish antibodies specific to the respective species of filoviruses, which provide the basis for serological classification, are not readily available. We established an ELISA using His-tagged secreted forms of the transmembrane glycoproteins (GPs) of five different Ebola virus (EBOV) species and one Marburg virus (MARV) strain as antigens for the detection of filovirus species-specific antibodies. The GP-based ELISA was evaluated by testing antisera collected from mice immunized with virus-like particles as well as from humans and nonhuman primates infected with EBOV or MARV. In our ELISA, little cross-reactivity of IgG antibodies was observed in most of the mouse antisera. Although sera and plasma from some patients and monkeys showed notable cross-reactivity with the GPs from multiple filovirus species, the highest reactions of IgG were uniformly detected against the GP antigen homologous to the virus species that infected individuals. We further confirmed that MARV-specific IgM antibodies were specifically detected in specimens collected from patients during the acute phase of infection. These results demonstrate the usefulness of our ELISA for diagnostics as well as ecological and serosurvey studies. C1 [Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Dept Global Epidemiol, Kita Ku, Sapporo, Hokkaido 0010020, Japan. [Saijo, Masayuki] Natl Inst Infect Dis, Dept Virol 1, Tokyo, Japan. [Kishida, Noriko] Natl Inst Infect Dis, Ctr Influenza Virus Res, Lab Influenza Virus Surveillance, Tokyo, Japan. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Dept Global Epidemiol, Kita Ku, Kita 20,Nishi 10, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp RI Inada, Mami/G-4783-2011; Takada, Ayato/A-6679-2012; Ito, Kimihito/E-9975-2012; Igarashi, Manabu/F-6871-2012 OI Ito, Kimihito/0000-0003-4986-1795; FU Ministry of Health, Labor, and Welfare of Japan; Takeda Science Foundation; Ministry of Education, Culture, Sports, Science, and Technology, Japan; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by a grant-in-aid from the Ministry of Health, Labor, and Welfare of Japan and in part by the Takeda Science Foundation and the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases and Global COE Program Establishment of International Collaboration Centers for Zoonosis Control from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The work was further supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 37 TC 43 Z9 47 U1 2 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD NOV PY 2010 VL 17 IS 11 BP 1723 EP 1728 DI 10.1128/CVI.00170-10 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 673HX UT WOS:000283651200010 PM 20861331 ER PT J AU Kimball, KJ Preuss, MA Barnes, MN Wang, MH Siegal, GP Wan, W Kuo, HC Saddekni, S Stockard, CR Grizzle, WE Harris, RD Aurigemma, R Curiel, DT Alvarez, RD AF Kimball, Kristopher J. Preuss, Meredith A. Barnes, Mack N. Wang, Minghui Siegal, Gene P. Wan, Wen Kuo, Huichien Saddekni, Souheil Stockard, Cecil R. Grizzle, William E. Harris, Raymond D. Aurigemma, Rosemarie Curiel, David T. Alvarez, Ronald D. TI A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER GENE-THERAPY; OVARIAN-CANCER; ONCOLYTIC ADENOVIRUS; TRIAL; EXPRESSION; CHEMOTHERAPY; VIROTHERAPY; ONYX-015; VECTORS; CELLS AB Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-.24-Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases. Experimental Design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 x 10(9) to 1 x 10(12) viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response. Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Delta 24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent. Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted. Clin Cancer Res; 16(21); 5277-87. (C)2010 AACR. C1 [Kimball, Kristopher J.; Preuss, Meredith A.; Barnes, Mack N.; Wang, Minghui; Siegal, Gene P.; Wan, Wen; Kuo, Huichien; Saddekni, Souheil; Stockard, Cecil R.; Grizzle, William E.; Curiel, David T.; Alvarez, Ronald D.] Univ Alabama, Birmingham, AL USA. [Harris, Raymond D.; Aurigemma, Rosemarie] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Alvarez, RD (reprint author), Room 538,Old Hillman Bldg,619 S 20th St, Birmingham, AL 35249 USA. EM ronald.alvarez@ccc.uab.edu FU NCI, NIH [N01-CO-12400]; Division of Cancer Treatment and Diagnosis of the NCI; NIH [5R01CA121187, NCI R21 CA128222, NCI P50-CA83591] FX Federal funds from the NCI, NIH, under contract no. N01-CO-12400 and the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the NCI (R.D. Harris); NIH grants 5R01CA121187, NCI R21 CA128222, and NCI P50-CA83591 (D.T. Curiel); and NIH grants NCI R21 CA128222 and NCI P50-CA83591 (R.D. Alvarez). NR 29 TC 42 Z9 42 U1 0 U2 4 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 NOV 1 PY 2010 VL 16 IS 21 BP 5277 EP 5287 DI 10.1158/1078-0432.CCR-10-0791 PG 11 WC Oncology SC Oncology GA 673MV UT WOS:000283668500020 PM 20978148 ER PT J AU Stratakis, CA Tichomirowa, MA Boikos, S Azevedo, MF Lodish, M Martari, M Verma, S Daly, AF Raygada, M Keil, MF Papademetriou, J Drori-Herishanu, L Horvath, A Tsang, KM Nesterova, M Franklin, S Vanbellinghen, JF Bours, V Salvatori, R Beckers, A AF Stratakis, C. A. Tichomirowa, M. A. Boikos, S. Azevedo, M. F. Lodish, M. Martari, M. Verma, S. Daly, A. F. Raygada, M. Keil, M. F. Papademetriou, J. Drori-Herishanu, L. Horvath, A. Tsang, K. M. Nesterova, M. Franklin, S. Vanbellinghen, J-F Bours, V. Salvatori, R. Beckers, A. TI The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes SO CLINICAL GENETICS LA English DT Article DE acromegaly; AIP; FIPA; multiple endocrine neoplasia; prolactinoma; tumor suppressor genes ID MULTIPLE-ENDOCRINE-NEOPLASIA; INTERACTING-PROTEIN GENE; CUSHINGS-DISEASE; TYPE-1 MEN1; EXPRESSION; VARIANT; TUMORS; 1A; MANIFESTATION; PROLACTINOMA AB The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex. C1 [Stratakis, C. A.; Boikos, S.; Azevedo, M. F.; Lodish, M.; Verma, S.; Raygada, M.; Keil, M. F.; Papademetriou, J.; Drori-Herishanu, L.; Horvath, A.; Tsang, K. M.; Nesterova, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [Stratakis, C. A.; Lodish, M.; Verma, S.; Keil, M. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PEITP, NIH, Bethesda, MD 20892 USA. [Tichomirowa, M. A.; Daly, A. F.; Beckers, A.] Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, B-4000 Liege, Belgium. [Martari, M.; Salvatori, R.] Johns Hopkins Univ, Div Endocrinol, Baltimore, MD 21287 USA. [Vanbellinghen, J-F; Bours, V.] Univ Liege, Dept Med Genet, Ctr Hosp Univ Liege, B-4000 Liege, Belgium. RP Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN & Pediat Endocrinol Program, NIH, Bldg 10,CRC E Labs,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Daly, Adrian /E-2178-2011 OI Daly, Adrian /0000-0001-6130-2975 FU NIH Clinical Center outpatient clinics; United States National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [Z01-HD-000642-04]; Fonds d'Investissement pour la Recherche Scientifiqu FX We would like to thank Drs. Stephen J. Marx and Sunita Agarwal (NIDDK, NIH, Bethesda, MD) for extensive discussions, guidance and advice on several aspects of the study and a critical review of the manuscript. We thank our patients and the support and nursing staff of the NIH Clinical Center outpatient clinics, and the 1NW and 5NW wards. This work was supported by United States National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) intramural project Z01-HD-000642-04 (Dr. C. A. Stratakis), Fonds d'Investissement pour la Recherche Scientifique 2007 (FIRS) du CHU de Liege, Belgium (Dr. A. Beckers). Finally, many thanks to Dr. Alex Vortmeyer (NCI, NIH) and Dr. Edward Oldfield (NINDS, NIH) for their pathology and surgical work, respectively, in our patients. NR 40 TC 68 Z9 69 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD NOV PY 2010 VL 78 IS 5 BP 457 EP 463 DI 10.1111/j.1399-0004.2010.01406.x PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 661AS UT WOS:000282695300010 PM 20507346 ER PT J AU Lantos, PM Charini, WA Medoff, G Moro, MH Mushatt, DM Parsonnet, J Sanders, JW Baker, CJ AF Lantos, Paul M. Charini, William A. Medoff, Gerald Moro, Manuel H. Mushatt, David M. Parsonnet, Jeffrey Sanders, John W. Baker, Carol J. TI Response of the Infectious Diseases Society of America Lyme Disease Review Panel to Johnson and Stricker SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID ANTIBIOTIC-THERAPY; TRIAL C1 [Lantos, Paul M.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Charini, William A.] Lawrence Gen Hosp, Lawrence, MA USA. [Medoff, Gerald] Washington Univ, Sch Med, St Louis, MO USA. [Moro, Manuel H.] Natl Inst Hlth, Bethesda, MD USA. [Mushatt, David M.] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Parsonnet, Jeffrey] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Baker, Carol J.] Baylor Coll Med, Houston, TX 77030 USA. [Sanders, John W.] USN, Med Res Ctr Detachment, Lima, Peru. RP Lantos, PM (reprint author), Duke Univ, Med Ctr, DUMC100800, Durham, NC 27710 USA. EM paul.lantos@duke.edu NR 14 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD NOV 1 PY 2010 VL 51 IS 9 BP 1110 EP 1111 DI 10.1086/656692 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 669FC UT WOS:000283331300026 ER PT J AU Eggers, PW AF Eggers, Paul W. TI CMS 2728: What Good Is It? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material C1 NIDDKD, Bethesda, MD 20892 USA. RP Eggers, PW (reprint author), NIDDKD, Room 615,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM eggersp@extra.niddk.nih.gov NR 2 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD NOV PY 2010 VL 5 IS 11 BP 1908 EP 1909 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 677UX UT WOS:000284018500002 PM 20930088 ER PT J AU Murray, PR AF Murray, P. R. TI Matrix-assisted laser desorption ionization time-of-flight mass spectrometry: usefulness for taxonomy and epidemiology SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Review DE Epidemiology; MALDI-TOF; mass spectrometry; review; taxonomy ID RESISTANT STAPHYLOCOCCUS-AUREUS; RAPID IDENTIFICATION; SPECIES IDENTIFICATION; CAMPYLOBACTER-JEJUNI; SUBSPECIES LEVELS; BACTERIA; DISCRIMINATION; CELLS; DIFFERENTIATION; STREPTOCOCCI AB P>Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a powerful tool for the species and subspecies classification of a broad spectrum of bacteria, including Gram-positive bacteria such as Staphylococcus, Streptococcus and Listeria, and Gram-negative bacteria such as Neisseria, Salmonella, Aeromonas, Campylobacter and Helicobacter. MALDI-TOF MS has also been used for the rapid identification and typing of potential bioterrorism agents, including Coxiella burnetii, Francisella tularensis and Bacillus anthracis. C1 NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,US Dept Hlth & Hum, Bethesda, MD 20892 USA. RP Murray, PR (reprint author), NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr,US Dept Hlth & Hum, 10 Ctr Dr,MSC 1508,Bldg 10,Room 2C-385, Bethesda, MD 20892 USA. EM Pmurray@cc.nih.gov FU Division of Intramural Research, Clinical Center, National Institutes of Health FX Financial support is provided by the Division of Intramural Research, Clinical Center, National Institutes of Health. No potential conflicts of interest. NR 32 TC 78 Z9 81 U1 0 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1198-743X J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD NOV PY 2010 VL 16 IS 11 BP 1626 EP 1630 DI 10.1111/j.1469-0691.2010.03364.x PG 5 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 662OQ UT WOS:000282819000005 PM 20825435 ER PT J AU Weil, EJ Curtis, JM Hanson, RL Knowler, WC Nelson, RG AF Weil, E. J. Curtis, J. M. Hanson, R. L. Knowler, W. C. Nelson, R. G. TI The impact of disadvantage on the development and progression of diabetic kidney disease SO CLINICAL NEPHROLOGY LA English DT Article DE diabetic nephropathy; minorities; obesity; Type 2 diabetes in youth ID IMPAIRED GLUCOSE-TOLERANCE; STAGE RENAL-DISEASE; CIGARETTE-SMOKING; PIMA-INDIANS; SOCIOECONOMIC-STATUS; DEVELOPING-COUNTRIES; MEXICAN-AMERICANS; HEALTH LITERACY; FETAL GROWTH; TYPE-2 AB Background Disadvantaged people include those experiencing economic, social or educational deprivation and, in some cases, those undergoing rapid transition from subsistence to industrial economies Disadvantaged people worldwide are affected disproportionately by the global epidemic of diabetes They are also at increased risk of kidney disease attributable to diabetes, and for many, the cost of managing their kidney disease far exceeds their available resources Methods We review factors associated with disadvantage that may increase the risk of diabetic kidney disease, and the barriers to care that hinder attempts to provide an adequate therapeutic response Results and conclusions A rapidly rising prevalence and magnitude of obesity among children and adults, increasing frequency of intrauterine exposure to diabetes, and inadequate access to healthcare are responsible, in part, for a surge in the frequency of diabetes and, in turn, diabetic kidney disease among disadvantaged people These factors may also predispose to an earlier onset of diabetes and kidney disease, thereby perpetuating the disadvantage by reducing the earning potential of those affected through illness and disability C1 [Weil, E. J.; Curtis, J. M.; Hanson, R. L.; Knowler, W. C.; Nelson, R. G.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases NR 47 TC 5 Z9 6 U1 1 U2 11 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD NOV PY 2010 VL 74 SU 1 BP S32 EP S38 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 690WL UT WOS:000285040200009 PM 20979961 ER PT J AU Dropulic, LK Cohen, JI AF Dropulic, L. K. Cohen, J. I. TI Update on New Antivirals Under Development for the Treatment of Double-Stranded DNA Virus Infections SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID REPLICATION IN-VITRO; HEPATITIS-B-VIRUS; HELICASE-PRIMASE INHIBITOR; HUMAN CYTOMEGALOVIRUS REPLICATION; BENZIMIDAZOLE D-RIBONUCLEOSIDES; ANTIPOXVIRUS COMPOUND ST-246; LIPID-ESTER PRODRUGS; ALKOXYALKYL ESTERS; CYCLIC CIDOFOVIR; ANIMAL-MODELS AB All the currently available antiviral agents used in the treatment of double-stranded (ds) DNA viruses, with the exception of interferon-alpha, inhibit the same target, the viral DNA polymerase. With increasing reports of the development of resistance of herpes simplex virus (HSV), cytomegalovirus (CMV), and hepatitis B virus (HBV) to some of these drugs, new antiviral agents are needed to treat these infections. Additionally, no drugs have been approved to treat several DNA virus infections, including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report the status of 10 new antiviral drugs for the treatment of dsDNA viruses. CMX-001 has broad activity against dsDNA viruses; 3 helicase-primase inhibitors, maribavir, and FV-100 have activity against certain herpesviruses; ST-246 inhibits poxviruses; GS-9191 inhibits papillomaviruses; and clevudine and emtricitabine are active against HBV. Most of these drugs have completed at least phase I trials in humans, and many are in additional clinical trials. C1 [Dropulic, L. K.; Cohen, J. I.] NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000058-37, Z99 AI999999] NR 55 TC 37 Z9 40 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2010 VL 88 IS 5 BP 610 EP 619 DI 10.1038/clpt.2010.178 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 668UJ UT WOS:000283296500016 PM 20881959 ER PT J AU Pau, AK Boyd, SD AF Pau, A. K. Boyd, S. D. TI Recognition and Management of Significant Drug Interactions in HIV Patients: Challenges in Using Available Data to Guide Therapy SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ANTIRETROVIRAL THERAPY; HOSPITALIZED-PATIENTS; INFECTED PATIENTS; DIDANOSINE; TENOFOVIR; RISK; PHARMACOKINETICS; RESISTANCE; INHIBITORS; RITONAVIR AB Combination antiretroviral therapy (cART) has improved survival rates in HIV-infected patients; however, patients now experience comorbidities that require pharmacological intervention, thereby increasing the risk of drug-drug interactions (DDIs). HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the CCR5 antagonist maraviroc are primarily metabolized via the cytochrome P450 (CYP) system and are prone to pharmacokinetic interactions.(1,2) This article addresses some key challenges that prescribers face when using available drug interaction-data resources in making day-to-day clinical decisions. C1 [Pau, A. K.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Boyd, S. D.] SAIC Frederick Inc, Natl Canc Inst Frederick, Frederick, MD USA. RP Pau, AK (reprint author), NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM apau@niaid.nih.gov FU Division of Clinical Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Scott Penzak for his critical review of the manuscript. This project is supported by the Division of Clinical Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. It is also funded in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 30 TC 8 Z9 8 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2010 VL 88 IS 5 BP 712 EP 719 DI 10.1038/clpt.2010.130 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 668UJ UT WOS:000283296500030 PM 20668439 ER PT J AU Bar-Haim, S Harries, N Nammourah, I Oraibi, S Malhees, W Loeppky, J Perkins, NJ Belokopytov, M Kaplanski, J Lahat, E AF Bar-Haim, Simona Harries, Netta Nammourah, Ibtisam Oraibi, Saleh Malhees, Waddah Loeppky, Jack Perkins, Neil J. Belokopytov, Mark Kaplanski, Jacob Lahat, Eli CA MERC Project TI Effectiveness of motor learning coaching in children with cerebral palsy: a randomized controlled trial SO CLINICAL REHABILITATION LA English DT Article ID MECHANICAL EFFICIENCY; PERFORMANCE; CLASSIFICATION; CAPABILITY; MOBILITY; STROKE; SYSTEM; COST AB Objective: To evaluate effectiveness of motor learning coaching on retention and transfer of gross motor function in children with cerebral palsy. Design: Block randomized trial, matched for age and gross motor function. Setting: Coordinated, multinational study (Israel, Jordan and Palestinian Authority) in schools and rehabilitation centers. Subjects: 78 children with spastic cerebral palsy, gross motor functional levels II and III, aged 66 to 146 months. Interventions: 1 hr/day, 3 days/week for 3 months treatment with motor learning coaching or neurodevelopmental treatment: two groups. Main measures: Gross motor function Measure (GMFM-66), stair-climbing mechanical efficiency (ME) and parent questionnaire rating their child's mobility. Immediate treatment effects were assessed after 3 months and retention determined from follow-up measurements 6 months after treatment. Results: GMFM-66, ME and parent questionnaires were obtained from 65, 31 and 64 subjects, respectively. Although both groups increased GMFM-66 score over 3 months, measurements 6 months later indicated retention was significantly superior by 2.7 in the motor learning coaching children of level-II. Similar retention trend was evident for ME, increasing 6 months after motor learning coaching by 1.1% and declining 0.3% after neurodevelopmental treatment. Mobility performance in the outdoors and community environment increased 13% from 3 to 9 months after motor learning coaching and decreased 12% after neurodevelopmental treatment. Minor group differences occurred in children of level-III. Conclusions: In higher functioning children with cerebral palsy, the motor learning coaching treatment resulted in significantly greater retention of gross motor function and transfer of mobility performance to unstructured environments than neurodevelopmental treatment. C1 [Bar-Haim, Simona; Harries, Netta; Belokopytov, Mark; Lahat, Eli] Assaf Harofeh Med Ctr, Human Mot Anal Lab, IL-70300 Zerifin, Israel. [Bar-Haim, Simona; Kaplanski, Jacob] Ben Gurion Univ Negev, Fac Hlth Sci, Beer Sheva, Israel. [Nammourah, Ibtisam; Malhees, Waddah] Jerusalem Princess Basma Ctr Disabled Children, Jerusalem, Israel. [Oraibi, Saleh] Bournemouth Univ, Sch Hlth & Social Care, Bournemouth, Dorset, England. [Loeppky, Jack] VA Med Ctr, Res Sect, Albuquerque, NM USA. [Perkins, Neil J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol, Bethesda, MD USA. RP Bar-Haim, S (reprint author), Assaf Harofeh Med Ctr, Human Mot Anal Lab, IL-70300 Zerifin, Israel. EM adi-star@013.net RI Belokopytov, Mark/A-5120-2012; Bar-Haim , Simona/J-7331-2013; OI Perkins, Neil/0000-0002-6802-4733 FU USAID [TA-MOU-05-M25-026] FX This study was funded by the Middle East Regional Cooperation Program/USAID grant TA-MOU-05-M25-026. NR 34 TC 14 Z9 15 U1 0 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2155 J9 CLIN REHABIL JI Clin. Rehabil. PD NOV PY 2010 VL 24 IS 11 BP 1009 EP 1020 DI 10.1177/0269215510371428 PG 12 WC Rehabilitation SC Rehabilitation GA 671UU UT WOS:000283537700005 PM 20576667 ER PT J AU Maudsley, S AF Maudsley, Stuart TI Hot topic: New Frontiers in G Protein-Coupled Receptor Regulation of Neurological Disorders SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Editorial Material C1 NIA, Receptor Pharmacol Unit, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 525 EP 525 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800002 PM 20632974 ER PT J AU Cadet, JL Jayanthi, S McCoy, MT Beauvais, G Cai, NS AF Cadet, Jean Lud Jayanthi, Subramaniam McCoy, Michael T. Beauvais, Genevieve Cai, Ning Sheng TI Dopamine D1 Receptors, Regulation of Gene Expression in the Brain, and Neurodegeneration SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Amphetamines; AP-1; apoptosis; basal ganglia; cocaine; DA receptors; Egr; signal transduction ID SENSITIVE ADENYLATE CYCLASE; MESSENGER-RNA EXPRESSION; TRANSCRIPTION FACTOR GENES; INDUCED NEURONAL APOPTOSIS; CULTURED STRIATAL NEURONS; INDUCED UP-REGULATION; CAMP EARLY REPRESSOR; RAT CAUDATE-PUTAMEN; INDUCED CELL-DEATH; BASAL GANGLIA AB Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA. C1 [Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T.; Beauvais, Genevieve; Cai, Ning Sheng] NIDA, Mol Neuropsychiat Res Branch, DHHS, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, DHHS, NIH,Intramural Res Program, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000551-04] NR 163 TC 33 Z9 33 U1 4 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 526 EP 538 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800003 PM 20632973 ER PT J AU Cong, WN Golden, E Pantaleo, N White, CM Maudsley, S Martin, B AF Cong, Wei-na Golden, Erin Pantaleo, Nick White, Caitlin M. Maudsley, Stuart Martin, Bronwen TI Ghrelin Receptor Signaling: A Promising Therapeutic Target for Metabolic Syndrome and Cognitive Dysfunction SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Cognitive function; energy balance; ghrelin; growth hormone secretagagogue receptor; memory; metabolic disorders; neuroprotection; obesity ID HORMONE SECRETAGOGUE RECEPTOR; PARKINSONS-DISEASE; CELL-DEATH; BULIMIA-NERVOSA; FOOD-INTAKE; DOPAMINERGIC-NEURONS; CIRCULATING GHRELIN; PANCREATIC-ISLETS; ANOREXIA-NERVOSA; SUBSTANTIA-NIGRA AB The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders. C1 [Cong, Wei-na; White, Caitlin M.; Martin, Bronwen] NIA, Metab Unit, Clin Invest Lab, Baltimore, MD 21224 USA. [Golden, Erin] Johns Hopkins Sch Med, Baltimore, MD 21287 USA. [Pantaleo, Nick; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, Clin Invest Lab, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The authors have no conflicts of scientific interest with respect to the manuscript. NR 80 TC 19 Z9 19 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 557 EP 563 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800005 PM 20632971 ER PT J AU Ferre, S Lluis, C Lanciego, JL Franco, R AF Ferre, Sergi Lluis, Carmen Luis Lanciego, Jose Franco, Rafael TI Prime Time for G-Protein-Coupled Receptor Heteromers as Therapeutic Targets for CNS disorders: The Dopamine D-1-D-3 Receptor Heteromer SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE G-protein-coupled receptors; CNS; homo and hetero-oligomers; heteromer-tailored drugs; dopamine D-1-D-3 receptor heteromer; Parkinson's disease ID LEVODOPA-INDUCED DYSKINESIA; ADENOSINE A(2A) RECEPTORS; DELTA-OPIOID RECEPTORS; IN-VIVO; HISTAMINE H-3; D2 RECEPTORS; LIVING CELLS; CROSS-TALK; D-1; HETERODIMERIZATION AB A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that heteromer-tailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the heteromer. It can therefore be predicted that customized drugs targeting a specific receptor heteromer in the CNS might imporove safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D-1-D-3 receptor heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinson's disease. C1 [Ferre, Sergi] Natl Inst Drug Abuse, IRP, NIH, DHHS, Baltimore, MD 21224 USA. [Lluis, Carmen; Franco, Rafael] Univ Barcelona, Inst Invest Biomed Agusti Pi I Sunyer, CIBERNED, Dept Biochem & Mol Biol,Fac Biol, E-08028 Barcelona, Spain. [Luis Lanciego, Jose; Franco, Rafael] CIMA Neurociencias, Pamplona 31008, Spain. RP Ferre, S (reprint author), Natl Inst Drug Abuse, IRP, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015 OI Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919 FU Spanish Ministerio de Ciencia y Tecnologia [SAF2006-05481]; Fundacio La Marato de TV3 [060110]; National Institute on Drug Abuse FX This work was supported by Grants from Spanish Ministerio de Ciencia y Tecnologia (SAF2006-05481), Grant 060110 from Fundacio La Marato de TV3 and by the intramural funds of the National Institute on Drug Abuse. NR 50 TC 12 Z9 12 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 596 EP 600 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800008 PM 20632968 ER PT J AU Pantaleo, N Chadwick, W Park, SS Wang, LY Zhou, Y Martin, B Maudsley, S AF Pantaleo, Nick Chadwick, Wayne Park, Sung-Soo Wang, Liyun Zhou, Yu Martin, Bronwen Maudsley, Stuart TI The Mammalian Tachykinin Ligand-Receptor System: An Emerging Target for Central Neurological Disorders SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Central neurological disorders; substance P; neurokinin A; neurokinin B; neurotherapeutics; receptor-ligand systems; tachykinin ID SUBSTANCE-P-LIKE; TRAUMATIC BRAIN-INJURY; CEREBROSPINAL-FLUID LEVELS; MESENCEPHALIC DOPAMINERGIC-NEURONS; AMYOTROPHIC-LATERAL-SCLEROSIS; FREE MAGNESIUM CONCENTRATION; DISEASE CEREBRAL-CORTEX; PRIMARY SENSORY NEURONS; CENTRAL-NERVOUS-SYSTEM; IN-SITU HYBRIDIZATION AB Our understanding of the complex signaling neurophysiology of the central nervous system has facilitated the exploration of potential novel receptor-ligand system targets for disorders of this most complex organ. In recent years, many relatively neglected receptor-ligand systems have been re-evaluated with respect to their ability to potently modulate discrete tracts in the central nervous system. One such system is the tachykinin (previously neurokinin) system. The multiple heptahelical G protein-coupled receptors and neuropeptide ligands that comprise this system may be significantly involved in more central nervous systems actions than previously thought, including sleep disorders, amyotrophic lateral sclerosis, Alzheimer's disease and Machado-Joseph disease. The development of our understanding of the role of the tachykinin receptor-ligand system in higher order central functions is likely to allow the creation of more specific and selective tachykinin-related neurotherapeutics. C1 [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Biomed Res Ctr, Neurosci Lab,NIH, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Metab Unit, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, Biomed Res Ctr, Neurosci Lab,NIH, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov RI Zhou, Yu/M-7975-2014 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The authors have no conflicts of scientific interest with respect to the manuscript. NR 135 TC 13 Z9 13 U1 2 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 EI 1996-3181 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 627 EP 635 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800011 PM 20632965 ER PT J AU Wang, LY Chadwick, W Park, SS Zhou, Y Silver, N Martin, B Maudsley, S AF Wang, Liyun Chadwick, Wayne Park, Sung-Soo Zhou, Yu Silver, Nathan Martin, Bronwen Maudsley, Stuart TI Gonadotropin-Releasing Hormone Receptor System: Modulatory Role in Aging and Neurodegeneration SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Gonadotropin releasing hormone; hypothalamic-pituitary-gonadal axis; brain; GnRH receptors; Alzheimer's disease; amyloid precursor protein; neuron ID PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR RECEPTOR; CHICKEN GNRH-II; RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; ALZHEIMERS-DISEASE; AMYLOID-BETA; TRANSGENIC MICE; ANDROGEN RECEPTOR; LH-RH AB Receptors for hormones of the hypothalamic-pituitary-gonadal axis are expressed throughout the brain. Age-related decline in gonadal reproductive hormones cause imbalances of this axis and many hormones in this axis have been functionally linked to neurodegenerative pathophysiology. Gonadotropin-releasing hormone (GnRH) plays a vital role in both central and peripheral reproductive regulation. GnRH has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in GnRH actions at non-pituitary peripheral targets. GnRH ligands and receptors are found throughout the brain where they may act to control multiple higher functions such as learning and memory function and feeding behavior. The actions of GnRH in mammals are mediated by the activation of a unique rhodopsin-like G protein-coupled receptor that does not possess a cytoplasmic carboxyl terminal sequence. Activation of this receptor appears to mediate a wide variety of signaling mechanisms that show diversity in different tissues. Epidemiological support for a role of GnRH in central functions is evidenced by a reduction in neurodegenerative disease after GnRH agonist therapy. It has previously been considered that these effects were not via direct GnRH action in the brain, however recent data has pointed to a direct central action of these ligands outside the pituitary. We have therefore summarized the evidence supporting a central direct role of GnRH ligands and receptors in controlling central nervous physiology and pathophysiology. C1 [Wang, Liyun; Chadwick, Wayne; Park, Sung-Soo; Zhou, Yu; Silver, Nathan; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Metab Unit, Clin Invest Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov RI Zhou, Yu/M-7975-2014 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The authors have no conflicts of scientific interest with respect to the manuscript. NR 152 TC 20 Z9 21 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 651 EP 660 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800013 PM 20632963 ER PT J AU White, CM Ji, SG Cai, HA Maudsley, S Martin, B AF White, Caitlin M. Ji, Sunggoan Cai, Huan Maudsley, Stuart Martin, Bronwen TI Therapeutic Potential of Vasoactive Intestinal Peptide and its Receptors in Neurological Disorders SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Alzheimer's disease; Autism Spectrum Disorders; neurological disorders; Parkinson's disease; pharmacotherapeutics; pituitary adenylate cyclase-activating peptide; vasoactive intestinal peptide ID CYCLASE-ACTIVATING POLYPEPTIDE; PROTEIN-COUPLED RECEPTORS; INDUCED PHASE-SHIFT; MICE LACKING PACAP; PARKINSONS-DISEASE; VPAC(2) RECEPTOR; INDUCED NEURODEGENERATION; SUPRACHIASMATIC NUCLEI; ALZHEIMERS-DISEASE; CIRCADIAN-RHYTHM AB Vasoactive intestinal peptide (VIP) is a basic 28 amino acid peptide that binds to a member of the class II family of G protein-coupled receptors (GPCRs). It is widely expressed throughout the body and plays an important role in numerous biological functions. VIP acts via three different GPCRs: VPAC1, VPAC2, and PAC1, which have been identified in various tissues, including brain, lung, kidney, gastrointestinal tract, tongue, and also on immunocompetent cells such as macrophages and lymphocytes. There is mounting evidence that VIP expression and signaling is altered in numerous neurological disorders, and it is becoming apparent that VIP and its receptors could be therapeutic loci for the treatment of several pathological conditions of the central nervous system. In this review, we describe the pathology of several major neurological disorders and discuss the potential pharmacotherapeutic role of VIP and its receptors for the treatment of disorders such as Alzheimer's disease, Parkinson's disease, and Autism Spectrum Disorders. C1 [White, Caitlin M.; Ji, Sunggoan; Cai, Huan; Martin, Bronwen] NIA, Metab Unit, Clin Invest Lab, Baltimore, MD 21224 USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, Clin Invest Lab, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov RI Cai, Huan/B-6578-2016 OI Cai, Huan/0000-0001-7731-8891 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The authors have no conflicts of scientific interest with respect to the manuscript. NR 62 TC 10 Z9 13 U1 1 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD NOV PY 2010 VL 9 IS 5 BP 661 EP 666 PG 6 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 685HW UT WOS:000284620800014 PM 20632962 ER PT J AU Hesse, BW Hansen, D Finholt, T Munson, S Kellogg, W Thomas, JC AF Hesse, Bradford W. Hansen, Derek Finholt, Thomas Munson, Sean Kellogg, Wendy Thomas, John C. TI SOCIAL PARTICIPATION IN HEALTH 2.0 SO COMPUTER LA English DT Article AB Computer scientists are working with biomedical researchers, policy specialists, and medical practitioners to usher in a new era in healthcare. A recently convened panel of experts considered various research opportunities for technology-mediated social participation in Health 2.0. C1 [Hesse, Bradford W.] NCI, Hlth Commun & Informat Res Branch, NIH, Bethesda, MD 20892 USA. [Hansen, Derek] Univ Maryland, Coll Informat Studies, College Pk, MD 20742 USA. [Hansen, Derek] Univ Maryland, CASCI, College Pk, MD 20742 USA. [Finholt, Thomas; Munson, Sean] Univ Michigan, Sch Informat, Ann Arbor, MI 48109 USA. [Finholt, Thomas] Univ Michigan, CITI, Ann Arbor, MI 48109 USA. RP Hesse, BW (reprint author), NCI, Hlth Commun & Informat Res Branch, NIH, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov; dlhansen@umd.edu; finholt@umich.edu; samunson@umich.edu; wkellogg@us.ibm.com; jcthomas@us.ibm.com OI Finholt, Thomas/0000-0001-9529-4467; Hansen, Derek/0000-0002-9645-3279; Munson, Sean/0000-0002-0472-6138; Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 16 TC 24 Z9 26 U1 0 U2 9 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0018-9162 J9 COMPUTER JI Computer PD NOV PY 2010 VL 43 IS 11 BP 45 EP 52 DI 10.1109/MC.2010.326 PG 8 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering SC Computer Science GA 678YD UT WOS:000284118500010 PM 21379365 ER PT J AU Lazzeroni, M Guerrieri-Gonzaga, A Serrano, D Varricchio, MC Veronesi, G Radice, D Feroce, I Nardi-Pantoli, A Lippman, SM Szabo, E Bonanni, B AF Lazzeroni, Matteo Guerrieri-Gonzaga, Aliana Serrano, Davide Varricchio, Maria Clara Veronesi, Giulia Radice, Davide Feroce, Irene Nardi-Pantoli, Angela Lippman, Scott M. Szabo, Eva Bonanni, Bernardo TI Budesonide versus placebo in high-risk population with screen-detected lung nodules: Rationale, design and methodology SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Budesonide; Lung cancer; Chemoprevention; Low-dose CT scan; Screening ID OBSTRUCTIVE PULMONARY-DISEASE; DOSE COMPUTED-TOMOGRAPHY; GROUND-GLASS OPACITY; BASE-LINE; CANCER; CT; TUMORS; TRIAL; CHEMOPREVENTION; MODULATION AB Background: Screening-CT is able to discover small peripheral lung nodules. The nature of these nodules is uncertain but it is reasonable that some of them, in particular the non-solid ones, could represent precancerous lesions. A previous trial showed a reduction in size of peripheral nodules by inhaled budesonide in subjects with bronchial dysplasia. Objective: The primary objective of the study was the evaluation of the effect of budesonide as a chemopreventive agent for lung lesions. The primary endpoint was the modification of lung lesions at Id-CT scan (according to RECIST criteria) after one year of treatment in a person-specific analysis. Methods: We performed a randomized, double-blind, placebo controlled trial to evaluate whether inhaled budesonide was able to reduce size and number of persistent, undetermined CT-detected lung nodules in high-risk asymptomatic subjects currently undergoing a five-year CT scan screening program at the European Institute of Oncology. Results: Trial enrollment started in April 2006 and ended in July 2007 with the randomization of 202 current or former smokers with stable CT-detected lung nodules set to receive budesonide 800 mu g or placebo twice daily for 12 months. Conclusion: Our trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. The research was nested into a screening project with clear advantages in participant accrual and reduction of costs. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial. (Clinicaltrials.gov number. NCT00321893) (C) 2010 Elsevier Inc. All rights reserved. C1 [Lazzeroni, Matteo; Guerrieri-Gonzaga, Aliana; Serrano, Davide; Varricchio, Maria Clara; Feroce, Irene; Nardi-Pantoli, Angela; Bonanni, Bernardo] European Inst Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy. [Lazzeroni, Matteo] Univ Roma Tor Vergata, Sch Oncol, Rome, Italy. [Veronesi, Giulia] European Inst Oncol, Div Thorac Surg, I-20141 Milan, Italy. [Radice, Davide] European Inst Oncol, Dept Epidemiol & Biostat, I-20141 Milan, Italy. [Lippman, Scott M.] Univ Texas MD Anderson Canc Ctr, Clin Canc Prevent Ctr, Houston, TX USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Lazzeroni, M (reprint author), European Inst Oncol, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. EM matteo.lazzeroni@ieo.it RI Lazzeroni, Matteo/I-8001-2012; OI Lazzeroni, Matteo/0000-0002-2162-4002 FU National Cancer Institute [N01-CN-35159] FX The trial was supported by the National Cancer Institute (grant number: N01-CN-35159). Drug and placebo were provided at no cost by AstraZeneca, Sweden. NR 23 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2010 VL 31 IS 6 BP 612 EP 619 DI 10.1016/j.cct.2010.08.006 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 681GC UT WOS:000284298400017 PM 20719253 ER PT J AU Bonnefoi, MS Belanger, SE Devlin, DJ Doerrer, NG Embry, MR Fukushima, S Harpur, ES Hines, RN Holsapple, MP Kim, JH MacDonald, JS O'Lone, R Pettit, SD Stevens, JL Takei, AS Tinkle, SS van der Laan, JW AF Bonnefoi, Marc S. Belanger, Scott E. Devlin, Dennis J. Doerrer, Nancy G. Embry, Michelle R. Fukushima, Shoji Harpur, Ernest S. Hines, Ronald N. Holsapple, Michael P. Kim, James H. MacDonald, James S. O'Lone, Raegan Pettit, Syril D. Stevens, James L. Takei, Ayako S. Tinkle, Sally S. van der Laan, Jan Willem TI Human and environmental health challenges for the next decade (2010-2020) SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE Environmental health challenges; HESI; human health challenges; priority setting; risk assessment; scientific mapping; strategic planning; toxicology ID 21ST-CENTURY; TOXICITY AB The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future. C1 [Doerrer, Nancy G.; Embry, Michelle R.; Holsapple, Michael P.; Kim, James H.; O'Lone, Raegan; Pettit, Syril D.] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Bonnefoi, Marc S.] Sanofi Aventis, Bridgewater, NJ USA. [Belanger, Scott E.] Procter & Gamble Co, Cincinnati, OH USA. [Devlin, Dennis J.] Exxon Mobil Corp, Irving, TX USA. [Fukushima, Shoji] Japan Bioassay Res Ctr, Hadano, Japan. [Hines, Ronald N.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [MacDonald, James S.] Chrysalis Pharma Partners LLC, Chester, NJ USA. [Stevens, James L.] Eli Lilly & Co, Greenfield, IN USA. [Takei, Ayako S.] ICaRuS Japan Ltd, Tokyo, Japan. [Tinkle, Sally S.] NIEHS, Res Triangle Pk, NC 27709 USA. [van der Laan, Jan Willem] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. RP Doerrer, NG (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Suite 200, Washington, DC 20005 USA. EM ndoerrer@hesiglobal.org OI Hines, Ronald/0000-0002-3094-4200; Belanger, Scott/0000-0003-0369-9673 FU HESI; US and international government agencies FX The authors have sole responsibility for the writing and content of the paper. Affiliations are shown on the first page. HESI provided funding and resources for the July 2009 scientific mapping meeting, as well as for the preparation of this paper. Although industry members provide primary financial support for HESI programs, HESI also receives financial and in-kind support from a variety of US and international government agencies. NR 18 TC 5 Z9 5 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD NOV PY 2010 VL 40 IS 10 BP 893 EP 911 DI 10.3109/10408444.2010.506640 PG 19 WC Toxicology SC Toxicology GA 664NF UT WOS:000282967700002 PM 20854192 ER PT J AU Tokar, EJ Benbrahim-Tallaa, L Ward, JM Lunn, R Sams, RL Waalkes, MP AF Tokar, Erik J. Benbrahim-Tallaa, Lamia Ward, Jerrold M. Lunn, Ruth Sams, Reeder L., II Waalkes, Michael P. TI Cancer in experimental animals exposed to arsenic and arsenic compounds SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE Arsenicals; carcinogenesis; inhalation; mouse; oral exposure; rat; rodents; transplacental exposure ID MALE F344 RATS; DIMETHYLARSINIC ACID; MAIN METABOLITE; URINARY-BLADDER; DRINKING-WATER; MOUSE SKIN; INORGANIC ARSENICS; LUNG-CANCER; IN-UTERO; POSTNATAL DIETHYLSTILBESTROL AB Inorganic arsenic is a ubiquitous environmental contaminant that has long been considered a human carcinogen. Recent studies raise further concern about the metalloid as a major, naturally occurring carcinogen in the environment. However, during this same period it has proven difficult to provide experimental evidence of the carcinogenicity of inorganic arsenic in laboratory animals and, until recently, there was considered to be a lack of clear evidence for carcinogenicity of any arsenical in animals. More recent work with arsenical methylation metabolites and early life exposures to inorganic arsenic has now provided evidence of carcinogenicity in rodents. Given that tens of millions of people worldwide are exposed to potentially unhealthy levels of environmental arsenic, in vivo rodent models of arsenic carcinogenesis are a clear necessity for resolving critical issues, such as mechanisms of action, target tissue specificity, and sensitive subpopulations, and in developing strategies to reduce cancers in exposed human populations. This work reviews the available rodent studies considered relevant to carcinogenic assessment of arsenicals, taking advantage of the most recent review by the International Agency for Research on Cancer (IARC) that has not yet appeared as a full monograph but has been summarized (IARC, 2009, IARC Special Report: Policy, Vol. 10. Lyon: IARC Press, 453-454). Many valid studies show that arsenic can interact with other carcinogens/agents to enhance oncogenesis, and help elucidate mechanisms, and these too are summarized in this review. Finally, this body of rodent work is discussed in light of its impact on mechanisms and in the context of the persistent argument that arsenic is not carcinogenic in animals. C1 [Lunn, Ruth; Waalkes, Michael P.] NIEHS, Natl Toxicol Program, Report Carcinogens Off, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Benbrahim-Tallaa, Lamia] Int Agcy Res Canc, IARC Monographs Sect, F-69372 Lyon, France. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD USA. [Sams, Reeder L., II] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Waalkes, MP (reprint author), NIEHS, Natl Toxicol Program, Report Carcinogens Off, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIEHS FX The authors' employment affiliations are as shown on the first page. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the National Toxicology Program, NIEHS. This article is the work product of an employee or group of employees of the NIEHS, NIH; however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH, or the United States Government. The authors alone are responsible for the content and writing of the paper. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services. NR 71 TC 53 Z9 57 U1 1 U2 24 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD NOV PY 2010 VL 40 IS 10 BP 912 EP 927 DI 10.3109/10408444.2010.506641 PG 16 WC Toxicology SC Toxicology GA 664NF UT WOS:000282967700003 PM 20812815 ER PT J AU Oliveira, JB Fleisher, TA AF Oliveira, Joao B. Fleisher, Thomas A. TI Molecular- and Flow Cytometry-based Diagnosis of Primary Immunodeficiency Disorders SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Flow cytometry; Genetics; Primary immunodeficiency; Diagnosis; Molecular ID LINKED LYMPHOPROLIFERATIVE DISEASE; COMMON VARIABLE IMMUNODEFICIENCY; ANTIBODY-DEFICIENCY SYNDROME; WISKOTT-ALDRICH-SYNDROME; BRUTONS TYROSINE KINASE; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; CYTOTOXIC LYMPHOCYTES; FAMILY-MEMBERS; CELL FUNCTION; HYPER IGM AB Primary immunodeficiencies are an expanding group of genetic disorders resulting in recurrent and/or severe infections, autoimmunity, or autoinflammation. The laboratory plays a critical role in the diagnosis of these conditions given their frequently overlapping signs and symptoms. We discuss here advances in flow cytometry and molecular techniques applied to the study of primary immunodeficiencies. C1 [Oliveira, Joao B.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Fleisher, TA (reprint author), NIH, Dept Lab Med, Ctr Clin, NIH Bldg 10,Room 2C306,10 Ctr Dr,MSC 1508, Bethesda, MD 20892 USA. EM oliveirajb@cc.nih.gov; tfleishe@mail.nih.gov OI Oliveira, Joao/0000-0001-9388-8173 FU National Institutes of Health Clinical Center FX Preparation of this manuscript was supported by the National Institutes of Health Intramural Research Program of the National Institutes of Health Clinical Center. NR 51 TC 5 Z9 5 U1 0 U2 7 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD NOV PY 2010 VL 10 IS 6 BP 460 EP 467 DI 10.1007/s11882-010-0137-8 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 655AB UT WOS:000282211900012 PM 20683683 ER PT J AU Becker, RE Greig, NH AF Becker, R. E. Greig, N. H. TI Why So Few Drugs for Alzheimer's Disease? Are Methods Failing Drugs? SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; Alzheimer clinical trial; error management; checklist; tarenflurabil; metrifonate; phenserine ID CLINICAL-TRIALS; COGNITIVE DECLINE; DOUBLE-BLIND; METRIFONATE; TARENFLURBIL; PHARMACOLOGY; EFFICACY AB Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In three case studies of recent AD drug development failures with phenserine, metrifonate, and tarenflurbil we identified methodological lapses able to account for the failures. Errors in complex systems such as drug developments are both almost inescapable due to human mistakes and most frequently hidden at the time of occurrence and thereafter. We propose preemptive error management as a preventive strategy to exclude or control error intrusions into neuropsychiatric drug developments. We illustrate the functions we anticipate for a preemptive error management preventive strategy with a checklist and identify the limitations of this aspect of the proposal with three drug examples. This strategy applies core scientific practices to insure the quality of data within the current context of AD drug development practices. C1 [Becker, R. E.] Aristea Translat Med Corp, Freeport, ME 04078 USA. [Becker, R. E.; Greig, N. H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Becker, RE (reprint author), Aristea Translat Med Corp, Freeport, ME 04078 USA. EM rebecker2008@comcast.net FU National Institute on Aging, NIH FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH. The authors are grateful to Jason Eaton (Senior Visual Media Specialist, Intramural Research Program of the National Institute on Drug Abuse) for creating Figs. (1 and 3). NR 42 TC 23 Z9 25 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD NOV PY 2010 VL 7 IS 7 BP 642 EP 651 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 685IG UT WOS:000284621800009 PM 20704560 ER PT J AU Smith, EJ Allantaz, F Bennett, L Zhang, DP Gao, XC Wood, G Kastner, DL Punaro, M Aksentijevich, I Pascual, V Wise, CA AF Smith, Elisabeth J. Allantaz, Florence Bennett, Lynda Zhang, Dongping Gao, Xiaochong Wood, Geryl Kastner, Daniel L. Punaro, Marilynn Aksentijevich, Ivona Pascual, Virginia Wise, Carol A. TI Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review SO CURRENT GENOMICS LA English DT Article DE Auto-inflammatory disease; PAPA syndrome; PSTPIP1; CD2BP1; PTP-PEST; pyrin; neutrophils; microarray transcript profiling; anakinra; IL-1 beta ID PROTEIN-TYROSINE-PHOSPHATASE; FAMILIAL MEDITERRANEAN FEVER; SYSTEMIC AUTOINFLAMMATORY DISEASES; RECURRENT MULTIFOCAL OSTEOMYELITIS; JUVENILE IDIOPATHIC ARTHRITIS; ENCODING MEVALONATE KINASE; PYODERMA-GANGRENOSUM; PYOGENIC ARTHRITIS; ACNE SYNDROME; PTP-PEST AB PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in activation of the "inflammasome" involved in interleukin-1 (IL-1) production. Overproduction of IL-1 is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders. C1 [Smith, Elisabeth J.; Zhang, Dongping; Gao, Xiaochong; Punaro, Marilynn; Wise, Carol A.] Scottish Rite Hosp Children, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Dallas, TX 75219 USA. [Smith, Elisabeth J.] Garvan Inst Med Res, Sydney, NSW 2027, Australia. [Allantaz, Florence; Bennett, Lynda; Pascual, Virginia] Baylor Inst Immunol Res, Dallas, TX 75204 USA. [Wood, Geryl; Kastner, Daniel L.; Aksentijevich, Ivona] NIAMSD, Clin Invest Lab, Bethesda, MD 20892 USA. RP Wise, CA (reprint author), Texas Scottish Rite Hosp Children, Seay Ctr Musculoskeletal Res, 2222 Welborn St, Dallas, TX 75219 USA. EM Carol.Wise@tsrh.org OI Wise, Carol/0000-0002-6790-2194 FU TSRHC [05-02-592] FX We thank J. Brandon and M. Walford for help with figures. We particularly thank the patients and families for their inspiration and participation in these studies. This work was funded by the TSRHC Research Grant #05-02-592. NR 66 TC 56 Z9 57 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2029 J9 CURR GENOMICS JI Curr. Genomics PD NOV PY 2010 VL 11 IS 7 BP 519 EP 527 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 685IM UT WOS:000284622400004 PM 21532836 ER PT J AU Cabarcas, SM Hurt, EM Farrar, WL AF Cabarcas, S. M. Hurt, E. M. Farrar, W. L. TI Defining the Molecular Nexus of Cancer, Type 2 Diabetes and Cardiovascular Disease SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Cancer; cancer stem cells; cardiovascular; diabetes; metabolic syndrome ID ACTIVATED PROTEIN-KINASE; FATTY-ACID SYNTHASE; CELL-CYCLE PROGRESSION; LEUCINE-ZIPPER KINASE; WNT SIGNALING PATHWAY; PROSTATE-CANCER; METABOLIC SYNDROME; BREAST-CANCER; PPAR-GAMMA; STEM-CELLS AB The metabolic syndrome is characterized by a state of metabolic dysfunction resulting in the development of several chronic diseases that are potentially deadly. These metabolic deregulations are complex and intertwined and it has been observed that many of the mechanisms and pathways responsible for diseases characterizing the metabolic syndrome such as type 2 diabetes and cardiovascular disease are linked with cancer development as well. Identification of molecular pathways common to these diverse diseases may prove to be a critical factor in disease prevention and development of potential targets for therapeutic treatments. This review focuses on several molecular pathways, including AMPK, PPARs and FASN that interconnect cancer development, type 2 diabetes and cardiovascular disease. AMPK, PPARs and FASN are crucial regulators involved in the maintenance of key metabolic processes necessary for proper homeostasis. It is critical to recognize and identify common pathways deregulated in interrelated diseases as it may provide further information and a much more global picture in regards to disease development and prevention. Thus, this review focuses on three key metabolic regulators, AMPK, PPARs and FASN, that may potentially serve as therapeutic targets. C1 [Cabarcas, S. M.; Farrar, W. L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Hurt, E. M.] MedImmune LLC, Gaithersburg, MD USA. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, 1050 Boyles St,Bldg 560,Room 21-78, Frederick, MD 21702 USA. EM farrarw@mail.nih.gov FU National Cancer Institute, National Institute of Health [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institute of Health, under contract No. N01-CO-12400. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views 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 133 TC 2 Z9 2 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD NOV PY 2010 VL 10 IS 8 BP 741 EP 755 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 685IS UT WOS:000284623000005 ER PT J AU Milaneschi, Y Tanaka, T Ferrucci, L AF Milaneschi, Yuri Tanaka, Toshiko Ferrucci, Luigi TI Nutritional determinants of mobility SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Article DE advanced glycation end products; aging; antioxidants; mobility; nutrition; vitamins ID POOR GRIP STRENGTH; SERUM MICRONUTRIENT CONCENTRATIONS; COMMUNITY-DWELLING ADULTS; SEVERE WALKING DISABILITY; GLYCATION END-PRODUCTS; HUMAN SKELETAL-MUSCLE; OLDER WOMEN; VITAMIN-D; PHYSICAL PERFORMANCE; OXIDATIVE STRESS AB Purpose of review In many countries, persons over 65 are one of the fastest growing segments of the population. Mobility disability is one of the major risk factors for morbidity and mortality in this age group. There is increasing evidence that improved nutrition can reduce the risk of developing disability in older age. This review summarizes the recent literature showing the associations between different nutrients and mobility-related outcomes in older adults. Recent findings Recent studies suggested an association between low intake and low serum concentrations of micronutrients, such as antioxidants and vitamins, with measures of physical performance, muscle strength, and disability in older adults. Summary The role of low micronutrients as cross-sectional and longitudinal correlates of mobility disability is consistent with a growing number of studies showing that a diet rich in fruits and vegetables, such as the Mediterranean diet, has a beneficial role in healthy aging. C1 [Tanaka, Toshiko] Medstar Hlth Res Inst, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Harbor Hosp Ctr, Baltimore, MD 21225 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Harbor Hosp Ctr, Room NM540,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health FX The InCHIANTI study baseline' (1998-2000) was supported as a 'targeted project' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health. NR 52 TC 23 Z9 23 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD NOV PY 2010 VL 13 IS 6 BP 625 EP 629 DI 10.1097/MCO.0b013e32833e337d PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 671HV UT WOS:000283492600004 PM 20736822 ER PT J AU Lundgren, JD Baxter, J Deeks, SG Lane, HC AF Lundgren, Jens D. Baxter, John Deeks, Steven G. Lane, H. Clifford TI Biomarkers in HIV disease SO CURRENT OPINION IN HIV AND AIDS LA English DT Editorial Material ID COMBINATION ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL DEPLETION; COLLAGEN DEPOSITION; INFECTED PATIENTS; MARKERS; RECONSTITUTION; RESTORATION; COAGULATION; SUPPRESSION C1 [Lane, H. Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Lundgren, Jens D.] Univ Copenhagen, Natl Univ Hosp, Copenhagen, Denmark. [Baxter, John] Cooper Univ Hosp, UMDNJ Robert Wood Johnson Med Sch, Camden, NJ USA. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Lane, HC (reprint author), NIAID, NIH, CRC Room 4-1479, Bethesda, MD 20892 USA. EM clane@nih.gov OI Lundgren, Jens/0000-0001-8901-7850 NR 22 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2010 VL 5 IS 6 BP 459 EP 462 DI 10.1097/COH.0b013e32833f2ed6 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NX UT WOS:000295509900001 PM 20978387 ER PT J AU Strimbu, K Tavel, JA AF Strimbu, Kyle Tavel, Jorge A. TI What are biomarkers? SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE biomarkers; clinical endpoints; surrogate endpoints ID SURROGATE END-POINTS; CLINICAL-TRIALS; ENDPOINTS AB Purpose of review This article provides working definitions and a conceptual framework to understand the roles of biomarkers in clinical research. Recent findings The definitions of the terms discussed in this article - medical signs, symptoms, biomarkers, surrogate endpoints, clinical endpoints, validation - are still under discussion, as are their relationships to each other, but broad consensus has developed in the past decade and a half about the necessity of distinguishing between, in particular, surrogate and clinical endpoints. Summary This article outlines the major definitions of the key terms in this field and considers select cases in which misunderstandings about the terms led to flawed research conclusions. C1 [Strimbu, Kyle; Tavel, Jorge A.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Tavel, JA (reprint author), NIAID, Div Clin Res, NIH, 6700B Rockledge Dr,Room 1127,MSC 7609, Bethesda, MD 20892 USA. EM Jtavel@niaid.nih.gov NR 11 TC 167 Z9 173 U1 16 U2 49 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2010 VL 5 IS 6 BP 463 EP 466 DI 10.1097/COH.0b013e32833ed177 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NX UT WOS:000295509900002 PM 20978388 ER PT J AU Sereti, I Rodger, AJ French, MA AF Sereti, Irini Rodger, Alison J. French, Martyn A. TI Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE C-reactive protein; IRIS; Th1 responses; tuberculosis ID ACTIVE ANTIRETROVIRAL THERAPY; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; MEMORY T-CELLS; RESTORATION SYNDROME; HIV-INFECTION; CRYPTOCOCCAL MENINGITIS; HIV-1-INFECTED PATIENTS; DISEASE PROGRESSION; MULTIPLE-SCLEROSIS; IFN-GAMMA AB Purpose of review Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening or unmasking of an infection or neoplasm in HIV-1-infected patients shortly after antiretroviral therapy (ART) initiation. New insights into the pathogenesis of IRIS may help identify biomarkers that could be useful in predicting or diagnosing IRIS. Recent findings Studies of immunopathogenesis have shown a signification activation of both innate and adaptive immune responses with elevation of plasma or serum chemokines and cytokines. Markers of inflammation such as C-reactive protein, interferon-inducible protein 10 or interferon g may be helpful as predictors of IRIS events. In addition, tuberculosis (TB)-associated IRIS is associated with a prominent Th1 response that can be heightened even prior to ART initiation in cases of unmasking TB, and may assist in early diagnosis. Large prospective studies are needed to elucidate the predictive and diagnostic value of IRIS biomarkers and advance them to the clinic. Summary Reversal of immunosuppression by ART leads to exaggerated pathogen-specific immune responses (known as IRIS) that appear to be primed prior to therapy. Inflammatory markers, chemokines and cytokines that signify innate and adaptive immune activation are biomarkers that could prove of clinical value after appropriate validation. C1 [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Rodger, Alison J.] UCL, UCL Med Sch, HIV Epidemiol & Biostat Grp, Res Dept Infect & Populat Hlth, London, England. [French, Martyn A.] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. RP Sereti, I (reprint author), 10 Ctr Dr,Bldg 10,Room 11B-07A, Bethesda, MD 20892 USA. EM isereti@mail.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH FX The work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. The authors would like to thank Anita Mora from Visual Medical Arts, Rocky Mountain Laboratories, Division of Intramural Research, NIAID, for her assistance with the figure design. NR 45 TC 36 Z9 36 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2010 VL 5 IS 6 BP 504 EP 510 DI 10.1097/COH.0b013e32833ed774 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NX UT WOS:000295509900008 PM 20966640 ER PT J AU Ambinder, RF Bhatia, K Martinez-Maza, O Mitsuyasu, R AF Ambinder, Richard F. Bhatia, Kishor Martinez-Maza, Otoniel Mitsuyasu, Ronald TI Cancer biomarkers in HIV patients SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE cervical cancer; HIV; Hodgkin's; Kaposi's sarcoma; lymphoma ID NON-HODGKIN-LYMPHOMA; ACTIVE ANTIRETROVIRAL THERAPY; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; NERVOUS-SYSTEM LYMPHOMA; AIDS-RELATED LYMPHOMA; NECROSIS-FACTOR TNF; B-CELL LYMPHOMA; BARR-VIRUS LOAD; PREDICTIVE-VALUE; KAPOSI-SARCOMA AB Purpose of review In this review, we update investigations related to cancer biomarkers in HIV-infected populations. Recent findings CD4 lymphocyte count is associated with primary central nervous system lymphoma (PCNSL), systemic non-Hodgkin's lymphoma (NHL) (except perhaps for Burkitt lymphoma), Kaposi's sarcoma, cervical cancer, and anal cancer. HIV load is associated with Burkitt lymphoma and systemic NHL (but not PCNSL), with Kaposi's sarcoma and with anal cancer. CD40 ligand incorporated into the HIV envelope and expression of activation-induced cytidine deaminase may help explain the relationship between HIV load and Burkitt lymphoma. Genetic polymorphisms have been identified that are linked to lymphoma in HIV patients. B-cell activation as manifest in immunoglobulin light chain production may be an important marker for NHL risk. Cytokines and related molecules (IL10, sCD30) may identify patients at high risk for NHL. Epstein-Barr virus (EBV) in cerebrospinal fluid (CSF) is useful as a marker for PCNSL, although with the falling incidence of PCNSL, the specificity of the test has been called into question. EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) have not yet emerged as especially promising markers of risk for either lymphoma or Kaposi's sarcoma. Summary CD4 lymphocyte count, HIV load, germline genetic polymorphisms, cytokine and related molecules, and immunoglobulin light chains all show increasing promise as biomarkers of malignancy in HIV patients. C1 [Ambinder, Richard F.] Sidney Kimmel Canc Ctr Johns Hopkins, Baltimore, MD USA. [Bhatia, Kishor] NCI, Bethesda, MD 20892 USA. [Martinez-Maza, Otoniel; Mitsuyasu, Ronald] Univ Calif Los Angeles, Los Angeles, CA USA. [Mitsuyasu, Ronald] UCLA Med Ctr, Los Angeles, CA USA. RP Ambinder, RF (reprint author), CRB1,Room 389,1650 Orleans St, Baltimore, MD 21287 USA. EM rambind1@jhmi.edu RI Martinez-Maza, Otoniel/B-2667-2009 OI Martinez-Maza, Otoniel/0000-0003-1364-0675 FU National Cancer Institute [UO1 CA 121947]; National Cancer Institute, Bethesda, Maryland, USA FX R.F.A., K.B., O.M.-M., and R.M. are supported in part by National Cancer Institute grant UO1 CA 121947 to the AIDS Malignancy Consortium which has facilitated interactions related to this review. K.B. is supported by the National Cancer Institute, Bethesda, Maryland, USA. The authors report no conflicts of interest as relates to this review. NR 46 TC 13 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2010 VL 5 IS 6 BP 531 EP 537 DI 10.1097/COH.0b013e32833f327e PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NX UT WOS:000295509900012 PM 20978397 ER PT J AU Hullsiek, KH George, M Brown, SK AF Hullsiek, Katherine H. George, Michelle Brown, Shawn K. TI Designing and managing a flexible and dynamic biorepository system: a 15-year perspective from the CPCRA, ESPRIT, and INSIGHT clinical trial networks SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE biomarkers; biorepository; HIV; repository data management systems ID HIV-INFECTION; HUMAN-PLATELETS; COLLECTION; STORAGE; MARKERS; COAGULATION; ANONYMITY; PROTEIN; CD40 AB Purpose of review We provide a long-term perspective of our experience with designing and managing a successful biorepository system. We include a brief history, a description of our current process, and lessons learned. Recent findings Biologic specimens, collected and stored as part of HIV-related research for years, are now being used for biomarker analyses that have important implications for both AIDS and non-AIDS events. If appropriately collected, documented, and stored, biospecimens are a valuable resource that can help answer current and future scientific questions. International networks must be able to monitor and adhere to country-specific specimen use regulations. Specimens for human DNA research need increased levels of privacy protection. Issues to consider when designing a biorepository system include expertise, communication, data management, technology, standardized methods and procedures, shipping, and specimen use policies. Summary As biorepositories are an integral part of research their design should not be an afterthought. Good designs consider all stages of research, and the most critical components are expertise and planning. Successful biorepository systems must have a balance of flexibility and standardization. The need for adaptable data management systems, whether commercial products or systems developed specifically for the network, should not be underestimated. Investment in appropriate technology, including a barcoding system with high-quality labels and printers, will pay off in the long term. To meet the needs of emerging technologies, it is becoming increasingly important to document the conditions at the time of specimen collection and processing. Regular communication between all components of the biorepository system is critical. C1 [Hullsiek, Katherine H.; George, Michelle] Univ Minnesota, Div Biostat, Minneapolis, MN 55414 USA. [Brown, Shawn K.] NCI, AIDS Monitoring Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Hullsiek, KH (reprint author), Univ Minnesota, Div Biostat, 2221 Univ Ave SE,Suite 200, Minneapolis, MN 55414 USA. EM hulls003@umn.edu FU National Institute of Allergy and Infectious Diseases [U01 AI068641]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the National Institute of Allergy and Infectious Diseases, including grant number U01 AI068641. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 28 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2010 VL 5 IS 6 BP 538 EP 544 DI 10.1097/COH.0b013e32833f2058 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NX UT WOS:000295509900013 PM 20978398 ER PT J AU Capala, J Bouchelouche, K AF Capala, Jacek Bouchelouche, Kirsten TI Molecular imaging of HER2-positive breast cancer: a step toward an individualized 'image and treat' strategy SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE breast cancer; HER2; magnetic resonance imaging; molecular imaging; optical imaging; positron emission tomography; single photon emission tomography ID HER2 DOWN-REGULATION; IN-VIVO; AFFIBODY MOLECULES; ANTI-HER2 STRATEGIES; TUMOR XENOGRAFT; THERAPY; EXPRESSION; RECEPTOR; FLUORESCENCE; PET AB Purpose of review HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate individual approaches to targeted therapy of HER2-positive breast cancers. Recent findings Because of the heterogeneity of breast cancer and possible discordance in HER2 status between primary tumors and distant metastases, assessment of HER2 expression by noninvasive imaging may become an important complement to immunohistochemistry or fluorescence in-situ hybridization analyses of biopsied tissue. Monoclonal antibodies such as trastuzumab and pertuzumab, or small scaffold proteins such as affibody molecules are used as HER2-targeting agents. For imaging purposes, these agents are labeled with positron or gamma-emitting radionuclides, optical dyes, or paramagnetic contrast molecules for positron emission tomography single photon emission tomography optical, and magnetic resonance imaging, respectively. HER2-specific molecular probes, combined with modern imaging techniques to provide information on HER2 expression not only in primary tumors but also in distant metastases not amenable to biopsy, may reduce problems with false negative results and, thereby, influence patient management by selecting patients that would benefit from HER2-targeted therapies. Summary The new 'image and treat' strategy, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, may potentially improve efficacy of cancer treatment while reducing side effects. C1 [Capala, Jacek] NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Bouchelouche, Kirsten] Univ Copenhagen, Rigshosp, PET & Cyclotron Unit, PET 3982, DK-2100 Copenhagen, Denmark. RP Capala, J (reprint author), NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM CapalaJ@mail.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NIH; Center for Cancer Research 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 HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 47 TC 48 Z9 51 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD NOV PY 2010 VL 22 IS 6 BP 559 EP 566 DI 10.1097/CCO.0b013e32833f8c3a PG 8 WC Oncology SC Oncology GA 659WG UT WOS:000282597200004 PM 20842031 ER PT J AU Song, JY Filie, AC Stetler-Stevenson, M Yuan, CM AF Song, Joo Y. Filie, Armando C. Stetler-Stevenson, Maryalice Yuan, Constance M. TI CORRELATION OF FLOW CYTOMETRIC ANALYSIS AND CYTOLOGY IN BRONCHOALVEOLAR LAVAGE SPECIMENS IN PATIENTS WITH A HEMATOLYMPHOID NEOPLASM SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Song, Joo Y.; Filie, Armando C.; Stetler-Stevenson, Maryalice; Yuan, Constance M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 395 EP 396 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100022 ER PT J AU Aguhar, C Venkataraman, G Yuan, CM Stetler-Stevenson, M AF Aguhar, Christine Venkataraman, Girish Yuan, Constance M. Stetler-Stevenson, Maryalice TI CD103 AND CD123 EXPRESSION IN HAIRY CELL LEUKEMIA AND OTHER B-CELL LYMPHOPROLIFERATIVE DISORDERS SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 25th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 01-05, 2010 CL Houston, TX SP Int Clin Cytometry Soc C1 [Aguhar, Christine; Venkataraman, Girish; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, LP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 399 EP 399 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100032 ER PT J AU McCoy, P Samsel, L Woodhouse, K Dagur, PK Raghavachari, N AF McCoy, Philip Samsel, Leigh Woodhouse, Kimberly Dagur, Pradeep K. Raghavachari, Nalini TI MULTI-COLOR IMAGING FLOW CYTOMETRY FOR CHARACTERIZATION OF CIRCULATING ENDOTHELIAL CELLS SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 10th Euroconference on Clinical Cell Analysis of the European-Society-for-Clinical-Cell-Analysis (ESCCA)/ Iberian Society-for-Cytometry (SIC) CY SEP 21-25, 2010 CL Valencia, SPAIN SP European Soc Clinical Cell Anal(ESCCA), Iberian Soc Cytometry(SIC) C1 [McCoy, Philip; Samsel, Leigh; Woodhouse, Kimberly; Dagur, Pradeep K.; Raghavachari, Nalini] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 409 EP 409 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100052 ER PT J AU Mccoy, JP Biancotto, A Fuchs, JC Williams, A Dagur, PK AF McCoy, J. Philip Biancotto, Angelique Fuchs, John C. Williams, Ann Dagur, Pradeep K. TI COMPREHENSIVE LEUKOCYTE IMMUNOPHENOTYPING (CLIP) USING HIGH DIMENSIONAL FLOW CYTOMETRY FOR TRANSLATIONAL RESEARCH SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 10th Euroconference on Clinical Cell Analysis of the European-Society-for-Clinical-Cell-Analysis (ESCCA)/ Iberian Society-for-Cytometry (SIC) CY SEP 21-25, 2010 CL Valencia, SPAIN SP European Soc Clinical Cell Anal(ESCCA), Iberian Soc Cytometry(SIC) C1 [McCoy, J. Philip; Biancotto, Angelique; Fuchs, John C.; Williams, Ann; Dagur, Pradeep K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2010 VL 78B IS 6 BP 434 EP 435 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 677BW UT WOS:000283965100124 ER PT J AU Song, JK Kannan, R Merdes, G Singh, J Mlodzik, M Giniger, E AF Song, Jeong K. Kannan, Ramakrishnan Merdes, Gunter Singh, Jaskirat Mlodzik, Marek Giniger, Edward TI Disabled is a bona fide component of the Abl signaling network SO DEVELOPMENT LA English DT Article DE Disabled; Abl tyrosine kinase; Axon guidance; Drosophila; Epithelial morphogenesis ID TRANSMEMBRANE RECEPTOR NEUROTACTIN; ABELSON TYROSINE KINASE; DROSOPHILA-ABL; FAMILY KINASES; EPITHELIAL MORPHOGENESIS; ACTIN POLYMERIZATION; GENETIC INTERACTIONS; ENA/VASP PROTEINS; AXON OUTGROWTH; ROLES AB Abl is an essential regulator of cell migration and morphogenesis in both vertebrates and invertebrates. It has long been speculated that the adaptor protein Disabled (Dab), which is a key regulator of neuronal migration in the vertebrate brain, might be a component of this signaling pathway, but this idea has been controversial. We now demonstrate that null mutations of Drosophila Dab result in phenotypes that mimic Abl mutant phenotypes, both in axon guidance and epithelial morphogenesis. The Dab mutant interacts genetically with mutations in Abl, and with mutations in the Abl accessory factors trio and enabled (ena). Genetic epistasis tests show that Dab functions upstream of Abl and ena, and, consistent with this, we show that Dab is required for the subcellular localization of these two proteins. We therefore infer that Dab is a bona fide component of the core Abl signaling pathway in Drosophila. C1 [Song, Jeong K.; Kannan, Ramakrishnan; Giniger, Edward] NINDS, Axon Guidance & Neural Connect Unit, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. [Merdes, Gunter] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, D BSSE, CH-4058 Basel, Switzerland. [Singh, Jaskirat; Mlodzik, Marek] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. RP Giniger, E (reprint author), NINDS, Axon Guidance & Neural Connect Unit, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU NIH (NINDS) [Z01NS003013]; Alzheimer Forschung Initiative; DFG; NIH [EY014597] FX We thank Drs. M. Peifer, F. Gertler and C.-H. Lee for critical comments and members of our laboratories for helpful discussions; the Bloomington Drosophila Stock Center and Exelixis Collection at Harvard for Dab P-element insertion lines, and the Developmental Studies Hybridoma Bank for antibody reagents. This work was supported in part by the Intramural Research Program of NIH (NINDS: Z01NS003013 to E.G.). G.M. was supported by the Alzheimer Forschung Initiative eV and DFG., J.K.S. and M.M. were supported by NIH grant (EY014597). Deposited in PMC for release after 12 months. NR 42 TC 14 Z9 14 U1 0 U2 3 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 NOV 1 PY 2010 VL 137 IS 21 BP 3719 EP 3727 DI 10.1242/dev.050948 PG 9 WC Developmental Biology SC Developmental Biology GA 673ND UT WOS:000283669300019 PM 20940230 ER PT J AU Bornstein, MH Hahn, CS Haynes, OM AF Bornstein, Marc H. Hahn, Chun-Shin Haynes, O. Maurice TI Social competence, externalizing, and internalizing behavioral adjustment from early childhood through early adolescence: Developmental cascades SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID AMERICAN PRESCHOOL-CHILDREN; LIMITED ANTISOCIAL PATHWAYS; SELF-PERCEPTION PROFILE; LIFE-COURSE-PERSISTENT; 14-YEAR FOLLOW-UP; DEPRESSIVE SYMPTOMS; CONDUCT PROBLEMS; PSYCHIATRIC-DISORDERS; PEER RELATIONSHIPS; EPIDEMIOLOGIC SAMPLE AB This study used a three-wave longitudinal design to investigate developmental cascades among social competence and externalizing and internalizing behavioral adjustment in a normative sample of 117 children seen at 4, 10, and 14 years. Children, mothers, and teachers provided data. A series of nested path analysis models was used to determine the most parsimonious and plausible cascades across the three constructs over and above their covariation at each age and stability across age. Children with lower social competence at age 4 years exhibited more externalizing and internalizing behaviors at age 10 years and more externalizing behaviors at age 14 years. Children with lower social competence at age 4 years also exhibited more internalizing behaviors at age 10 years and more internalizing behaviors at age 14 years. Children who exhibited more internalizing behaviors at age 4 years exhibited more internalizing behaviors at age 10 years and more externalizing behaviors at age 14 years. These cascades among social competence and behavioral adjustment obtained independent of child intelligence and maternal education and social desirability of responding. C1 [Bornstein, Marc H.; Hahn, Chun-Shin; Haynes, O. Maurice] Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM marc_h_bornstein@nih.gov FU Intramural NIH HHS [Z01 HD001119-20] NR 176 TC 93 Z9 102 U1 6 U2 33 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2010 VL 22 IS 4 SI SI BP 717 EP 735 DI 10.1017/S0954579410000416 PG 19 WC Psychology, Developmental SC Psychology GA 667JZ UT WOS:000283190600001 PM 20883577 ER PT J AU Klimes-Dougan, B Long, JD Lee, CYS Ronsaville, DS Gold, PW Martinez, PE AF Klimes-Dougan, Bonnie Long, Jeffrey D. Lee, Chih-Yuan Steven Ronsaville, Donna S. Gold, Philip W. Martinez, Pedro E. TI Continuity and cascade in offspring of bipolar parents: A longitudinal study of externalizing, internalizing, and thought problems SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID AFFECTIVE-DISORDER; DEVELOPMENTAL PSYCHOPATHOLOGY; HIGH-RISK; DEPRESSIVE-DISORDERS; SUICIDAL IDEATION; MENTAL-DISORDERS; MODEL SELECTION; AFFECTIVELY ILL; CHILDREN; SCHIZOPHRENIA AB There is growing evidence that many offspring of bipolar parents will develop moderate to severe forms of psychopathology during childhood and adolescence. The purpose of this study was to apply growth curve models to evaluate developmental progression with regard to continuity and cascades representative within the context of a family risk study of bipolar disorder (BD). Repeated assessments of externalizing, internalizing, and thought problems, spanning more than a decade, were examined in a total of 94 offspring of parents with BD (O-BD), major depressive disorder (O-UNI), or no significant psychiatric or medical problems (O-WELL). Continuity was defined by the growth curve of the O-WELL group who exhibited low levels of problems from early childhood through late adolescence. Discontinuity, as evidenced by greater complexity of growth curves relative to the O-WELL group, was exhibited in the at-risk offspring groups for internalizing problems. Different patterns of developmental cascades were supported for the at-risk group with O-UNI showing a robust cascade from self-regulatory deficits (externalizing problems) to internalizing problems. There was also support for a cascade from self-regulatory deficits to thought problems across the entire group (with some support that this pattern was accounted for primarily by O-BD). This study not only serves to advance our understanding of the risks associated with a family history of BD, but also provides a novel approach to examining developmental cascades. C1 [Klimes-Dougan, Bonnie] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Ronsaville, Donna S.; Gold, Philip W.; Martinez, Pedro E.] NIMH, Bethesda, MD 20892 USA. RP Klimes-Dougan, B (reprint author), Univ Minnesota, Dept Psychol, N-414 Elliot Hall,75 W River Rd, Minneapolis, MN 55455 USA. EM klimes@umn.edu NR 87 TC 8 Z9 8 U1 3 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2010 VL 22 IS 4 SI SI BP 849 EP 866 DI 10.1017/S0954579410000507 PG 18 WC Psychology, Developmental SC Psychology GA 667JZ UT WOS:000283190600010 PM 20883586 ER PT J AU Ryo, S Wijdeven, RHM Tyagi, A Hermsen, T Kono, T Karunasagar, I Rombout, JHWM Sakai, M Verburg-van Kemenade, BML Savan, R AF Ryo, Sogabe Wijdeven, Ruud H. M. Tyagi, Anuj Hermsen, Trudi Kono, Tomoya Karunasagar, Indrani Rombout, Jan H. W. M. Sakai, Masahiro Kemenade, B. M. Lidy Verburg-van Savan, Ram TI Common carp have two subclasses of bonyfish specific antibody IgZ showing differential expression in response to infection SO DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY LA English DT Article DE Teleosts; Immunoglobulin heavy chain; Expression; Larval development; Ig isotypes ID IMMUNOGLOBULIN HEAVY-CHAIN; PHYLOGENETICALLY PRIMITIVE VERTEBRATE; PARALICHTHYS-OLIVACEUS IGD; CONSTANT-REGION GENES; CYPRINUS-CARPIO; ATLANTIC SALMON; JAPANESE FLOUNDER; CHANNEL CATFISH; TRYPANOPLASMA-BORRELI; SEQUENCE-ANALYSIS AB Immunoglobulin heavy chains identified in bony fish are broadly classified into three classes namely IgM, IgD and IgZ. The most recently described isotype is IgZ, a teleosts-fish specific isotype that shows variations in gene structure across teleosts. In this study we have identified two IgZ subclasses in common carp. IgZ1 is a four constant heavy chain domains containing antibody isolated across teleosts and IgZ2 is a two constant domains containing heavy chain chimera with a ill and 4 domain. Sequence analyses suggest that these subtypes' are expressed from two separate genomic loci. Expression analyses show that IgZ1 is more abundant in systemic organs and IgZ2 chimera is preferentially expressed at mucosal sites. The basal expression level of IgM in fish is much higher than of the other isotypes. We show that IgZ1 expression in systemic and mucosal organs is responsive to blood parasites, while mucosal parasite infection induces IgM and IgZ2 gene expression. This report is the first to show differential expression of the IgZ variants in response to pathogens and suggests that the IgZ subtypes in carps may have mutually exclusive humoral functions. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ryo, Sogabe; Kono, Tomoya; Sakai, Masahiro; Savan, Ram] Miyazaki Univ, Fac Agr, Miyazaki 8892192, Japan. [Wijdeven, Ruud H. M.; Hermsen, Trudi; Rombout, Jan H. W. M.; Kemenade, B. M. Lidy Verburg-van] Wageningen Univ, Wageningen Inst Anim Sci, Cell Biol & Immunol Grp, Wageningen, Netherlands. [Tyagi, Anuj; Karunasagar, Indrani] Karnataka Vet Anim & Fisheries Sci Univ, Coll Fisheries, Dept Fishery Microbiol, Mangalore, India. RP Savan, R (reprint author), NCI, Frederick, MD 21701 USA. EM lidy.vankemenade@wur.nl; savanr@mail.nih.gov OI Tyagi, Anuj/0000-0002-4818-0827 NR 37 TC 36 Z9 41 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0145-305X J9 DEV COMP IMMUNOL JI Dev. Comp. Immunol. PD NOV PY 2010 VL 34 IS 11 BP 1183 EP 1190 DI 10.1016/j.dci.2010.06.012 PG 8 WC Immunology; Zoology SC Immunology; Zoology GA 659HY UT WOS:000282558800006 PM 20600275 ER PT J AU Yaguchi, S Yaguchi, J Angerer, RC Angerer, LM Burke, RD AF Yaguchi, Shunsuke Yaguchi, Junko Angerer, Robert C. Angerer, Lynne M. Burke, Robert D. TI TGF beta signaling positions the ciliary band and patterns neurons in the sea urchin embryo SO DEVELOPMENTAL BIOLOGY LA English DT Article DE TGFbeta signaling; Neurogenesis; Ciliary band; Oral signaling; Nodal; BMP; Lefty; Smad; Alk; Urchin ID ORAL-ABORAL AXIS; ELECTRICAL-ACTIVITY; NERVOUS-SYSTEM; ANIMAL-VEGETAL; GENE NETWORK; CELL FATE; SPECIFICATION; EXPRESSION; ECTODERM; PATHWAY AB The ciliary band is a distinct region of embryonic ectoderm that is specified between oral and aboral ectoderm. Flask-shaped ciliary cells and neurons differentiate in this region and they are patterned to form an integrated tissue that functions as the principal swimming and feeding organ of the larva. TGF beta signaling, which is known to mediate oral and aboral patterning of the ectoderm, has been implicated in ciliary band formation. We have used morpholino knockdown and ectopic expression of RNA to alter TGF beta, signaling at the level of ligands, receptors, and signal transduction components and assessed the differentiation and patterning of the ciliary band cells and associated neurons. We propose that the primary effects of these signals are to position the ciliary cells, which in turn support neural differentiation. We show that Nodal signaling, which is known to be localized by Lefty, positions the oral margin of the ciliary band. Signaling from BMP through Alk3/6, affects the position of the oral and aboral margins of the ciliary band. Since both Nodal and BMP signaling produce ectoderm that does not support neurogenesis, we propose that formation of a ciliary band requires protection from these signals. Expression of BMP2/4 and Nodal suppress neural differentiation. However, the response to receptor knockdown or dominant-negative forms of signal transduction components indicate signaling is not acting directly on unspecified ectoderm cells to prevent their differentiation as neurons. Instead, it produces a restricted field of ciliary band cells that supports neurogenesis. We propose a model that incorporates spatially regulated control of Nodal and BMP signaling to determine the position and differentiation of the ciliary band, and subsequent neural patterning. (c) 2010 Elsevier Inc. All rights reserved. C1 [Burke, Robert D.] Univ Victoria, Dept Biochem & Microbiol, STN CSC, Victoria, BC V8W 3N5, Canada. [Yaguchi, Shunsuke; Yaguchi, Junko] Univ Tsukuba, Shimoda Marine Res Ctr, Tsukuba, Ibaraki 305, Japan. [Yaguchi, Shunsuke; Yaguchi, Junko; Angerer, Robert C.; Angerer, Lynne M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Burke, RD (reprint author), Univ Victoria, Dept Biochem & Microbiol, STN CSC, POB 3020,3800 Finnerty Rd, Victoria, BC V8W 3N5, Canada. EM rburke@uvic.ca OI Yaguchi, Shunsuke/0000-0002-8326-5762 FU Natural Sciences and Engineering Research Council (Canada); National Institutes of Health, NIDCR; Japanese Government FX This work was supported in part by a Discovery grant from the Natural Sciences and Engineering Research Council (Canada) to RDB, in part by the Intramural Program of the National Institutes of Health, NIDCR, and in part by Special Coordination Funds for Promoting Science and Technology of the Japanese Government to SY. We thank Thierry Lepage and Francois Lapraz for sharing reagents and unpublished data with us. NR 30 TC 38 Z9 39 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD NOV 1 PY 2010 VL 347 IS 1 BP 71 EP 81 DI 10.1016/j.ydbio.2010.08.009 PG 11 WC Developmental Biology SC Developmental Biology GA 666EF UT WOS:000283094600007 PM 20709054 ER PT J AU Aamar, E Dawid, IB AF Aamar, Emil Dawid, Igor B. TI Sox17 and Chordin are Required for Formation of Kupffer's Vesicle and Left-Right Asymmetry Determination in Zebrafish SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Sox17; Chordin; Kupffer's vesicle (KV); left-right asymmetry; dorsal forerunner cells (DFC) ID XENOPUS ENDODERM DEVELOPMENT; DORSAL FORERUNNER CELLS; LEFT-RIGHT AXIS; BETA-CATENIN; NODAL CILIA; STEM-CELLS; ROLES; EXPRESSION; EMBRYOS; GENES AB Kupffer's vesicle (KV), a ciliated fluid-filled sphere in the zebrafish embryo with a critical role in laterality determination, is derived from a group of superficial cells in the organizer region of the gastrula named the dorsal forerunner cells (DFC). We have examined the role of the expression of sox17 and chordin (chd) in the DFC in KV formation and laterality determination. Whereas sox17 was known to be expressed in DFC, its function in these cells was not studied before. Further, expression of chd in these cells has not been reported previously. Targeted knockdown of Sox17 and Chd in DFC led to aberrant Left-Right (L-R) asymmetry establishment, as visualized by the expression of southpaw and lefty, and heart and pancreas placement in the embryo. These defects correlated with the formation of small KVs with apparently diminished cilia, consistent with the known requirement for ciliary function in the laterality organ for the establishment of L-R asymmetry. Developmental Dynamics 239:2980-2988, 2010. Published 2010 Wiley-Liss, Inc.(double dagger) C1 [Aamar, Emil; Dawid, Igor B.] NICHHD, Program Genom Dev, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Program Genom Dev, NIH, Bldg 6B,Room 420, Bethesda, MD 20892 USA. EM idawid@nih.gov FU Children's Hospital (Boston, MA); National Institute of Child Health and Human Development, National Institutes of Health FX We thank Dr. Wayne Lencer, Children's Hospital (Boston, MA), for support of this project. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 60 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD NOV PY 2010 VL 239 IS 11 BP 2980 EP 2988 DI 10.1002/dvdy.22431 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 678CQ UT WOS:000284047500017 PM 20925124 ER PT J AU Swanwick, CC Shapiro, ME Vicini, S Wenthold, RJ AF Swanwick, Catherine Croft Shapiro, Marietta E. Vicini, Stefano Wenthold, Robert J. TI Flotillin-1 Promotes Formation of Glutamatergic Synapses in Hippocampal Neurons SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE rat; lipid raft; development; GABA; synaptogenesis ID ADHESION-LIKE MOLECULES; LIPID RAFTS; MEMBRANE MICRODOMAINS; CNS SYNAPTOGENESIS; AXON REGENERATION; NMDA RECEPTORS; PROTEINS; CHOLESTEROL; DIFFERENTIATION; FAMILY AB Synapse malformation underlies numerous neurodevelopmental illnesses, including autism spectrum disorders. Here we identify the lipid raft protein flotillin-1 as a promoter of glutamatergic synapse formation. We cultured neurons from the hippocampus, a brain region important for learning and memory, and examined them at two weeks in vitro, a time period rich with synapse formation. Double-label immunocytochemistry of native flot-1 with glutamatergic and GABAergic synapse markers showed that flot-1 was preferentially colocalized with the glutamatergic presynaptic marker vesicular glutamate transporter 1 (VGLUT1), compared to the GABAergic presynaptic marker glutamic acid decarboxylase-65 (GAD-65). Triple-label immunocytochemistry of native flot-1, VGLUT1, and NR1, the obligatory subunit of NMDA receptors, indicates that Flot-1 was preferentially localized to synaptic rather than extrasynaptic NR1. Furthermore, electrophysiological results using whole-cell patch clamp showed that Flot-1 increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) but not miniature inhibitory postsynaptic currents (mIPSCs), whereas amplitude and decay kinetics of either type of synaptic current was not affected. Corresponding immunocytochemical data confirmed that the number of glutamatergic synapses increased with flot-1 overexpression. Overall, our anatomical and physiological results show that flot-1 enhances the formation of glutamatergic synapses but not GABAergic synapses, suggesting that the role of flot-1 in neurodevelopmental disorders should be explored. (C) 2010 Wiley Periodicals, Inc.* Develop Neurobiol 70: 875-883, 2010 C1 [Swanwick, Catherine Croft; Shapiro, Marietta E.; Wenthold, Robert J.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Vicini, Stefano] Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. RP Swanwick, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM catherine.c.swanwick@gmail.com FU National Institute on Deafness and Other Communication Disorders; National Institute of General Medical Sciences FX Contract grant sponsors: National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences. NR 36 TC 12 Z9 12 U1 2 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD NOV PY 2010 VL 70 IS 13 BP 875 EP 883 DI 10.1002/dneu.20828 PG 9 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 672UT UT WOS:000283613100003 PM 20669324 ER PT J AU Bornstein, MH Cote, LR Haynes, OM Hahn, CS Park, Y AF Bornstein, Marc H. Cote, Linda R. Haynes, O. Maurice Hahn, Chun-Shin Park, Yoonjung TI Parenting Knowledge: Experiential and Sociodemographic Factors in European American Mothers of Young Children SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE parenting; knowledge; toddlers ID ADOLESCENT MOTHERS; SOCIOECONOMIC-STATUS; COGNITIVE READINESS; PEDIATRIC PRACTICE; HEALTHY STEPS; UNITED-STATES; PRIMARY-CARE; BIRTH-ORDER; UNREALISTIC EXPECTATIONS; ANTICIPATORY GUIDANCE AB Knowledge of child rearing and child development is relevant to parenting and the well-being of children. Using a sociodemographically heterogeneous sample of 268 European American mothers of 2-year-olds, we assessed the state of mothers' parenting knowledge; compared parenting knowledge in groups of mothers who varied in terms of parenthood and social status; and identified principal sources of mothers' parenting knowledge in terms of social factors, parenting supports, and formal classes. On the whole, European American mothers demonstrated fair but less than complete basic parenting knowledge; age, education, and rated helpfulness of written materials each uniquely contributed to mothers' knowledge. Adult mothers scored higher than adolescent mothers, and mothers improved in their knowledge of parenting from their first to their second child (and were stable across time). No differences were found between mothers of girls and boys, mothers who varied in employment status, or birth and adoptive mothers. The implications of variation in parenting knowledge and its sources for parenting education and clinical interactions with parents are discussed. C1 [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [Z01 HD001119-20] NR 207 TC 26 Z9 26 U1 4 U2 22 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD NOV PY 2010 VL 46 IS 6 BP 1677 EP 1693 DI 10.1037/a0020677 PG 17 WC Psychology, Developmental SC Psychology GA 676KX UT WOS:000283911100022 PM 20836597 ER PT J AU Perez-Edgar, K McDermott, JNM Korelitz, K Degnan, KA Curby, TW Pine, DS Fox, NA AF Perez-Edgar, Koraly McDermott, Jennifer N. Martin Korelitz, Katherine Degnan, Kathryn A. Curby, Timothy W. Pine, Daniel S. Fox, Nathan A. TI Patterns of Sustained Attention in Infancy Shape the Developmental Trajectory of Social Behavior From Toddlerhood Through Adolescence SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE sustained attention; temperament; social behavior; infancy; childhood and adolescence ID EXTENDED VISUAL FIXATION; SELECTIVE ATTENTION; ANXIETY DISORDERS; ANGRY FACES; INHIBITION; CHILDREN; THREAT; BIAS; AGE; TEMPERAMENT AB The current study examined the relations between individual differences in sustained attention in infancy, the temperamental trait behavioral inhibition in childhood, and social behavior in adolescence. The authors assessed 9-month-old infants using an interrupted-stimulus attention paradigm. Behavioral inhibition was subsequently assessed in the laboratory at 14 months, 24 months, 4 years, and 7 years. At age 14 years, adolescents acted out social scenarios in the presence of an unfamiliar peer as observers rated levels of social discomfort. Relative to infants with high levels of sustained attention, infants with low levels of sustained attention showed increasing behavioral inhibition throughout early childhood. Sustained attention also moderated the, relation between childhood behavioral inhibition and adolescent social discomfort, such that initial levels of inhibition at 14 months predicted later adolescent social difficulties only for participants with low levels of sustained attention in infancy. These findings suggest that early individual differences in attention shape how children respond to their social environments, potentially via attention's gate-keeping role in framing a child's environment for processing. C1 [Perez-Edgar, Koraly; Curby, Timothy W.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [McDermott, Jennifer N. Martin; Korelitz, Katherine; Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD USA. RP Perez-Edgar, K (reprint author), George Mason Univ, Dept Psychol, 4400 Univ Dr,MS3F5, Fairfax, VA 22030 USA. EM kperezed@gmu.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU NICHD NIH HHS [R37 HD017899, R01 HD017899, HD17899]; NIMH NIH HHS [MH073569, MH074454, R01 MH074454, U01 MH074454, K01 MH073569] NR 49 TC 22 Z9 22 U1 2 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD NOV PY 2010 VL 46 IS 6 BP 1723 EP 1730 DI 10.1037/a0021064 PG 8 WC Psychology, Developmental SC Psychology GA 676KX UT WOS:000283911100025 PM 20873921 ER PT J AU Ma, LJ Hanson, RL Traurig, MT Muller, YL Kaur, BP Perez, JM Meyre, D Fu, M Korner, A Franks, PW Kiess, W Kobes, S Knowler, WC Kovacs, P Froguel, P Shuldiner, AR Bogardus, C Baler, LJ AF Ma, Lijun Hanson, Robert L. Traurig, Michael T. Muller, Yunhua L. Kaur, Bakhshish P. Perez, Jessica M. Meyre, David Fu, Mao Koerner, Antje Franks, Paul W. Kiess, Wieland Kobes, Sayuko Knowler, William C. Kovacs, Peter Froguel, Philippe Shuldiner, Alan R. Bogardus, Clifton Baler, Leslie J. TI Evaluation of A2BP1 as an Obesity Gene SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; WILLI-LIKE PHENOTYPE; PIMA-INDIANS; SIM1 GENE; DIABETIC-NEPHROPATHY; QUANTITATIVE TRAITS; INSULIN-RECEPTOR; ADULT OBESITY; DELETION; ATAXIN-2 AB OBJECTIVE-A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. RESEARCH DESIGN AND METHODS-Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. RESULTS-No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 x 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 x 10(-10)) and children (rs8054147, P = 9.2 x 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. CONCLUSIONS-Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway. Diabetes 59:2837-2845, 2010 C1 [Ma, Lijun; Hanson, Robert L.; Traurig, Michael T.; Muller, Yunhua L.; Kaur, Bakhshish P.; Perez, Jessica M.; Kobes, Sayuko; Knowler, William C.; Bogardus, Clifton; Baler, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Meyre, David; Froguel, Philippe] Inst Pasteur, CNRS 8090, Inst Biol, F-59019 Lille, France. [Fu, Mao; Shuldiner, Alan R.] Univ Maryland Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD USA. [Koerner, Antje; Kiess, Wieland] Univ Leipzig, Univ Hosp Children & Adolescents, Leipzig, Germany. [Franks, Paul W.] Lund Univ, Malmo Gen Hosp, Clin Res Ctr, S-21401 Malmo, Sweden. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, Leipzig, Germany. RP Baler, LJ (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM lbaier@phx.niddk.nih.gov RI Meyre, David/D-7315-2011; Baier, Leslie/F-9008-2013; Korner, Antje/B-3988-2015; Hanson, Robert/O-3238-2015; OI Korner, Antje/0000-0001-6001-0356; Hanson, Robert/0000-0002-4252-7068; Franks, Paul/0000-0002-0520-7604 FU NIDDK, National Institutes of Health; NTH [R01-DK-54261, P30-DK-072488, P60-DK-079637]; American Diabetes Association; Deutsche Forschungsgemeinschaft (DFG) [KFO 152, KO 3512/1-1, 1264/10-1]; European Community FX This work was supported by the intramural research program of NIDDK, National Institutes of Health, and NTH Grants R01-DK-54261 (to A.S.), P30-DK-072488 (Clinical Nutrition Research Unit of Maryland), and P60-DK-079637 (Baltimore Diabetes Research and Training Center). Grant support was also provided by the American Diabetes Association (individually to C.B. and A.S.). Additional support was provided by grants from the Deutsche Forschungsgemeinschaft (DFG) KFO 152: project KO 3512/1-1, 1264/10-1, and the European Community integrated project grant "PIONEER." No potential conflicts of interest relevant to this article were reported. NR 48 TC 17 Z9 17 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD NOV PY 2010 VL 59 IS 11 BP 2837 EP 2845 DI 10.2337/db09-1604 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 679BC UT WOS:000284133400020 PM 20724578 ER PT J AU Miyazaki, S Taniguchi, H Moritoh, Y Tashiro, F Yamamoto, T Yamato, E Ikegami, H Ozato, K Miyazaki, J AF Miyazaki, Satsuki Taniguchi, Hidenori Moritoh, Yusuke Tashiro, Funti Yamamoto, Tsunehiko Yamato, Eiji Ikegami, Hiroshi Ozato, Keiko Miyazaki, Jun-ichi TI Nuclear Hormone Retinoid X Receptor (RXR) Negatively Regulates the Glucose-Stimulated Insulin Secretion of Pancreatic beta-Cells SO DIABETES LA English DT Article ID PEROXISOME-PROLIFERATOR; GENE-EXPRESSION; MUTANT MICE; VITAMIN-A; LIVER; TRANSCRIPTION; ACTIVATION; ACID; OVEREXPRESSION; GLUCOKINASE AB OBJECTIVE-Retinoid X receptors (RXRs) are members of the nuclear hormone receptor superfamily and are thought to be key regulators in differentiation, cellular growth, and gene expression. Although several experiments using pancreatic beta-cell lines have shown that the ligands of nuclear hormone receptors modulate insulin secretion, it is not clear whether RXRs have any role in insulin secretion. RESEARCH DESIGN AND METHODS-To elucidate the function of RXRs in pancreatic beta-cells, we generated a double-transgenic mouse in which a dominant-negative form of RXR beta was inducibly expressed in pancreatic beta-cells using the Tet-On system. We also established a pancreatic beta-cell line from an insulinoma caused by the beta-cell-specific expression of simian virus 40 T antigen in the above transgenic mouse. RESULTS-In the transgenic mouse, expression of the dominant-negative RXR enhanced the insulin secretion with high glucose stimulation. In the pancreatic beta-cell line, the suppression of RXRs also enhanced glucose-stimulated insulin secretion at a high glucose concentration, while 9-cis-retinoic acid, an RXR agonist, repressed it. High-density oligonucleotide microarray analysis showed that expression of the dominant-negative RXR affected the expression levels of a number of genes, some of which have been implicated in the function and/or differentiation of beta-cells. CONCLUSIONS-These results suggest that endogenous RXR negatively regulates the glucose-stimulated insulin secretion. Given these findings, we propose that the modulation of endogenous RXR in beta-cells may be a new therapeutic approach for improving impaired insulin secretion in type 2 diabetes. Diabetes 59:2854-2861, 2010 C1 [Miyazaki, Satsuki; Taniguchi, Hidenori; Moritoh, Yusuke; Tashiro, Funti; Yamamoto, Tsunehiko; Yamato, Eiji; Miyazaki, Jun-ichi] Osaka Univ, Grad Sch Med, Div Stem Cell Regulat Res, Osaka, Japan. [Ikegami, Hiroshi] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan. [Ozato, Keiko] NICHHD, Sect Mol Genet Immun, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Miyazaki, J (reprint author), Osaka Univ, Grad Sch Med, Div Stem Cell Regulat Res, Osaka, Japan. EM jimiyaza@nutri.med.osaka-u.ac.jp RI Miyazaki, Jun-ichi/N-1976-2015 OI Miyazaki, Jun-ichi/0000-0003-2475-589X FU Ministry of Education, Science, Sports, and Culture of Japan FX The authors are grateful to Mayu Yamamoto and Masafumi Ashida of Osaka University for technical assistance. We acknowledge the editorial assistance of Leslie A. Miglietta and Grace E. Gray, Clarity Editing. This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan. NR 36 TC 17 Z9 18 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD NOV PY 2010 VL 59 IS 11 BP 2854 EP 2861 DI 10.2337/db09-1897 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 679BC UT WOS:000284133400022 PM 20798333 ER PT J AU Wang, XXX Jiang, T Shen, Y Caldas, Y Miyazaki-Anzai, S Santamaria, H Urbanek, C Solis, N Scherzer, P Lewis, L Gonzalez, FJ Adorini, L Pruzanski, M Kopp, JB Verlander, JW Levi, M AF Wang, Xiaoxin X. Jiang, Tao Shen, Yan Caldas, Yupanqui Miyazaki-Anzai, Shinobu Santamaria, Hannah Urbanek, Cydney Solis, Nathaniel Scherzer, Pnina Lewis, Linda Gonzalez, Frank J. Adorini, Luciano Pruzanski, Mark Kopp, Jeffrey B. Verlander, Jill W. Levi, Moshe TI Diabetic Nephropathy Is Accelerated by Farnesoid X Receptor Deficiency and Inhibited by Farnesoid X Receptor Activation in a Type 1 Diabetes Model SO DIABETES LA English DT Article ID RENAL LIPID-METABOLISM; BILE-ACIDS; KIDNEY-DISEASE; TGF-BETA; MICE; FXR; FIBROSIS; INJURY; GLOMERULOSCLEROSIS; INFLAMMATION AB OBJECTIVE The pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determine if FXR deficiency accelerates type 1 diabetic nephropathy in part by further stimulation of SREBPs and related pathways, and conversely, if a selective FXR agonist can prevent the development of type 1 diabetic nephropathy. RESEARCH DESIGN AND METHODS Insulin deficiency and hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice. Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ. DBA/2J mice with STZ-induced hyperglycemia were treated with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development. RESULTS The present study demonstrates accelerated renal injury in diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis, and modulating renal lipid metabolism, macrophage infiltration, and renal expression of SREBPs, profibrotic growth factors, and oxidative stress enzymes in the diabetic DBA/2J strain. CONCLUSIONS Our findings indicate a critical role for FXR in the development of diabetic nephropathy and show that FXR activation prevents nephropathy in type 1 diabetes. Diabetes 59:2916-2927, 2010 C1 [Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Caldas, Yupanqui; Miyazaki-Anzai, Shinobu; Santamaria, Hannah; Urbanek, Cydney; Solis, Nathaniel; Lewis, Linda; Levi, Moshe] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Caldas, Yupanqui; Miyazaki-Anzai, Shinobu; Santamaria, Hannah; Urbanek, Cydney; Solis, Nathaniel; Lewis, Linda; Levi, Moshe] VA Med Ctr, Aurora, CO USA. [Scherzer, Pnina] Hadassah Univ Hosp, Serv Nephrol, IL-91120 Jerusalem, Israel. [Scherzer, Pnina] Hadassah Univ Hosp, Hypertens Serv, IL-91120 Jerusalem, Israel. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Adorini, Luciano] Intercept Pharmaceut, Perugia, Italy. [Pruzanski, Mark] Intercept Pharmaceut, New York, NY USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Verlander, Jill W.] Univ Florida, Dept Med, Div Nephrol Hypertens & Transplantat, Gainesville, FL USA. RP Levi, M (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO USA. EM moshe.levi@ucdenver.edu RI Verlander, Jill/I-5991-2015; OI Levi, Moshe/0000-0002-6225-946X; Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health (NIH) [U01 DK-076134, R01AG-026529]; Juvenile Diabetes Research Foundation; Veterans Affairs Merit Review; University of Colorado Denver FX This work was supported by grants from the National Institutes of Health (NIH) (U01 DK-076134 and R01AG-026529), Juvenile Diabetes Research Foundation, and the Veterans Affairs Merit Review. Y.C. was supported by a minority graduate student supplement from NIH and H.S. was supported by the LAB COATS Program at the University of Colorado Denver. NR 51 TC 62 Z9 70 U1 3 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD NOV PY 2010 VL 59 IS 11 BP 2916 EP 2927 DI 10.2337/db10-0019 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 679BC UT WOS:000284133400029 PM 20699418 ER PT J AU Looker, HC Krakoff, J Andre, V Kobus, K Nelson, RG Knowler, WC Hanson, RL AF Looker, Helen C. Krakoff, Jonathan Andre, Vickie Kobus, Kathy Nelson, Robert G. Knowler, William C. Hanson, Robert L. TI Secular Trends in Treatment and Control of Type 2 Diabetes in an American Indian Population: A 30-Year Longitudinal Study SO DIABETES CARE LA English DT Article ID BLOOD-GLUCOSE CONTROL; PIMA-INDIANS; EXPERT COMMITTEE; RISK-FACTORS; MELLITUS; DISEASE; COMPLICATIONS; PRESSURE; ADULTS; CHOLESTEROL AB OBJECTIVE- Treatment guidelines for diabetes have become increasingly stringent as most research shows that more aggressive intervention reduces the risks for complications. Community data on the effect of these interventions are lacking. RESEARCH DESIGN AND METHODS- Changes in the pharmacologic treatment of diabetes, blood pressure, and cholesterol in adults with diabetes were analyzed in a longitudinal population-based study of American Indians from 10 independent 3-year time intervals between 1975 and 2004. Trends in drug use were assessed by logistic regression models and trends in glycemia, blood pressure, and cholesterol were assessed by linear models. RESULTS- Among the study participants, the use of any medicine for the treatment of diabetes increased from 53% in 1975-1978 to 67% in 2002-2004, P(trend) < 0.0001. The use of insulin as a single agent declined, and the use of combinations of insulin and oral agents increased. In 1990-1992, 23% of subjects had an A1C <7% and by 2002-2004, the proportion had increased to 33%, P(trend) < P 0.0001. The use of anti-hypertensive medicine increased from 21% in 1975-1977 to 58% in 2002-2004, P(trend) < 0.0001, coincident with a decline in mean systolic blood pressure from 137 mmHg in 1975-1977 to 123 mmHg in 2002-2004, P(trend) < 0.0001. The use of lipid-lowering medicine also increased with an accompanying increase in HDL and a decrease in non-HDL cholesterol concentration. CONCLUSIONS- Major changes in community treatment patterns for diabetes and related conditions coincided with improvements in glycemia, blood pressure, and cholesterol. C1 [Looker, Helen C.; Krakoff, Jonathan; Andre, Vickie; Kobus, Kathy; Nelson, Robert G.; Knowler, William C.; Hanson, Robert L.] NIDDK, NIH, Phoenix, AZ USA. [Looker, Helen C.] Mt Sinai Med Ctr, New York, NY 10029 USA. RP Hanson, RL (reprint author), NIDDK, NIH, Phoenix, AZ USA. EM rhanson@phx.niddk.nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 25 TC 6 Z9 6 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2010 VL 33 IS 11 BP 2383 EP 2389 DI 10.2337/dc10-0678 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683ZI UT WOS:000284516400017 PM 20855550 ER PT J AU Pavkov, ME Hanson, RL Knowler, WC Sievers, ML Bennett, PH Nelson, RG AF Pavkov, Meda E. Hanson, Robert L. Knowler, William C. Sievers, Maurice L. Bennett, Peter H. Nelson, Robert G. TI Effect of Intrauterine Diabetes Exposure on the Incidence of End-Stage Renal Disease in Young Adults With Type 2 Diabetes SO DIABETES CARE LA English DT Article AB OBJECTIVE- We examined the effect of intrauterine diabetes exposure (IDE) on the incidence of diabetic end-stage renal disease (ESRD) in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS- Individuals were followed from their first diabetic examination until December 2006, death, ESRD, or age of 45 years. RESULTS- Among the 1,850 diabetic participants, 102 had IDE. ESRD developed in 57, 5 of whom had IDE. Cumulative incidence of ESRD by age 45 was 19.3% in participants with IDE and 5.1% in those without; the age- and sex-adjusted incidence rate ratio was 4.12 (95% CI 1.54-11.02). After additional adjustment for age at diabetes onset, ESRD incidence was similar in the two groups (incidence rate ratio 1.38, 95% CI 0.45-4.24). CONCLUSIONS- IDE increases the age- and sex-adjusted incidence of ESRD fourfold in young adults with type 2 diabetes, mediated primarily by the earlier onset of type 2 diabetes in those with IDE. C1 [Hanson, Robert L.; Knowler, William C.; Sievers, Maurice L.; Bennett, Peter H.; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Pavkov, Meda E.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Nelson, RG (reprint author), NIDDK, NIH, Phoenix, AZ USA. EM rnelson@nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 9 TC 3 Z9 3 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2010 VL 33 IS 11 BP 2396 EP 2398 DI 10.2337/dc10-0811 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683ZI UT WOS:000284516400019 PM 20693350 ER PT J AU Cotsapas, C Prokunina-Olsson, L Welch, C Saxena, R Weaver, C Usher, N Guiducci, C Bonakdar, S Turner, N LaCroix, B Hall, JL AF Cotsapas, C. Prokunina-Olsson, L. Welch, C. Saxena, R. Weaver, C. Usher, N. Guiducci, C. Bonakdar, S. Turner, N. LaCroix, B. Hall, J. L. TI Expression analysis of loci associated with type 2 diabetes in human tissues SO DIABETOLOGIA LA English DT Article DE Colon; eQTL; HHEX; IDE; Liver; mRNA; Pancreas; SLC30A8; SNP; Type 2 diabetes ID GENOMICS; TCF7L2 AB Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues. We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling. Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver. This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined. C1 [Welch, C.; Weaver, C.; Usher, N.; Turner, N.; LaCroix, B.; Hall, J. L.] Lillehei Heart Inst, Dept Med, Minneapolis, MN 55455 USA. [Cotsapas, C.; Saxena, R.; Guiducci, C.; Bonakdar, S.] Broad Inst, Cambridge, MA USA. [Prokunina-Olsson, L.] NIH, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cotsapas, C.; Saxena, R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hall, J. L.] Univ Minnesota, Ctr Dev Biol, Minneapolis, MN USA. [Cotsapas, C.; Saxena, R.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, R.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Hall, JL (reprint author), Lillehei Heart Inst, Dept Med, 4-280 NHH,312 Church St SE, Minneapolis, MN 55455 USA. EM jlhall@umn.edu OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Cotsapas, Chris/0000-0002-7772-5910 FU NCI/NIH; NIH [1R21DK078029-01] FX We are grateful to S. Schmechel and S. Bowell for help with procurement of tissues from the University of Minnesota Tissue Procurement Facility. We would also like to thank M. Carlson for help in preparing samples for the analysis. The study was supported by an intramural research programme of NCI/NIH and by NIH grant 1R21DK078029-01 (to J. L. Hall). NR 10 TC 12 Z9 12 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2010 VL 53 IS 11 BP 2334 EP 2339 DI 10.1007/s00125-010-1861-2 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656HS UT WOS:000282320400011 PM 20703447 ER PT J AU Perantoni, AO AF Perantoni, A. O. TI STAT signaling in renal progenitor differentiation and tumorigenesis SO DIFFERENTIATION LA English DT Meeting Abstract C1 [Perantoni, A. O.] NCI, Frederick, MD 21701 USA. EM perantoa@mail.nih.gov 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 0301-4681 J9 DIFFERENTIATION JI Differentiation PD NOV PY 2010 VL 80 SU 1 BP S15 EP S16 DI 10.1016/j.diff.2010.09.176 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 672MT UT WOS:000283589700037 ER PT J AU Takase, Y Mukoyama, Y Takahashi, Y AF Takase, Yuta Mukoyama, Yosuke Takahashi, Yoshiko TI Reciprocal interactions between neural crest cells and dorsal aorta in developing embryos SO DIFFERENTIATION LA English DT Meeting Abstract C1 [Takase, Yuta; Takahashi, Yoshiko] Nara Inst Sci & Technol, Nara, Japan. [Mukoyama, Yosuke] NIH, Bethesda, MD 20892 USA. EM yu-takase@bs.naist.jp 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 0301-4681 J9 DIFFERENTIATION JI Differentiation PD NOV PY 2010 VL 80 SU 1 BP S47 EP S47 DI 10.1016/j.diff.2010.09.096 PG 1 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 672MT UT WOS:000283589700128 ER PT J AU Dawson, DA Goldstein, RB Moss, HB Li, TK Grant, BF AF Dawson, Deborah A. Goldstein, Rise B. Moss, Howard B. Li, Ting-Kai Grant, Bridget F. TI Gender differences in the relationship of internalizing and externalizing psychopathology to alcohol dependence: Likelihood, expression and course SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol dependence; Psychopathology; Gender; Externalizing; Internalizing ID DSM-IV ALCOHOL; NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; PSYCHIATRIC DIAGNOSTIC MODULES; SOCIAL DESIRABILITY BIASES; INTERVIEW SCHEDULE AUDADIS; DRUG-USE DISORDERS; UNITED-STATES; RISK-FACTORS AB Objective: To determine whether internalizing and externalizing psychopathology were differentially associated with alcohol dependence in men and women. Methods: Four categories of lifetime psychopathology were examined: neither internalizing nor externalizing (NINE), internalizing only (IO), externalizing only (EO) and both internalizing and externalizing (BIE). Multivariate models assessed gender differences in the adjusted associations of these categories with the odds of lifetime alcohol dependence in a representative sample of 43,093 U.S. adults 18 and older and with clinical course and expression in a subsample of 4781 lifetime alcoholics. Results: The excess odds of lifetime alcohol dependence associated with IO, EO and BIE were significantly greater for women than men, OR = 2.6, 8.8 and 10.7 versus 1.9, 4.0 and 6.5, respectively. Regardless of gender, the ORs were significantly higher for EO than IO and for BIE than EO. Gender differences in the expression and course of alcoholism were most pronounced for the categories of NINE and IO, with men having greater consumption, dependence severity and treatment but less familial alcoholism. Gender variation in the association of psychopathology with the expression and course of alcoholism was most evident in the BIE category, where the associations were stronger for women. Lifetime externalizing psychopathology was associated with an increased likelihood of treatment utilization, especially among women. Conclusions: Findings highlight the need to increase alcoholism screening, prevention and intervention among women with psychopathology, especially externalizing. The greater numbers of internalizing than externalizing alcoholics emphasize the need to treat symptoms of depression and anxiety in alcohol treatment settings. (C) 2010 Published by Elsevier Ireland Ltd. C1 [Dawson, Deborah A.; Goldstein, Rise B.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Moss, Howard B.] NIAAA, Off Director, NIH, Bethesda, MD 20892 USA. [Li, Ting-Kai] Duke Univ, Sch Med, Durham, NC 27710 USA. RP Dawson, DA (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Clin & Biol Res, NIH, Room 3071,5635 Fishers Lane,MSC9304, Bethesda, MD 20892 USA. EM ddawson@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; U.S. Department of Health and Human Services; National Institute on Drug Abuse FX The study on which this paper is based, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), is sponsored by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, U.S. Department of Health and Human Services, with supplemental support from the National Institute on Drug Abuse. This work was supported, in part, by the Intramural Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. None of the sources of funding had any influence on the design, results or interpretation of this analysis. NR 80 TC 27 Z9 27 U1 2 U2 19 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD NOV 1 PY 2010 VL 112 IS 1-2 BP 9 EP 17 DI 10.1016/j.drugalcdep.2010.04.019 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 690BQ UT WOS:000284975500002 PM 20558014 ER PT J AU Zhuang, XL Adipietro, KA Datta, S Northup, JK Ray, K AF Zhuang, Xiaolei Adipietro, Kaylin A. Datta, Shomik Northup, John K. Ray, Kausik TI Rab1 Small GTP-Binding Protein Regulates Cell Surface Trafficking of the Human Calcium-Sensing Receptor SO ENDOCRINOLOGY LA English DT Article ID METABOTROPIC GLUTAMATE-RECEPTOR; HUMAN CA2+ RECEPTOR; ENDOPLASMIC-RETICULUM; ANGIOTENSIN-II; SIGNAL-TRANSDUCTION; COUPLED RECEPTOR; CA-0(2+)-SENSING RECEPTOR; EXTRACELLULAR DOMAIN; VESICULAR TRANSPORT; CARDIAC MYOCYTES AB The human calcium-sensing receptor (hCaR) is a family-3/C G-protein-coupled receptor that regulates Ca(2+) homeostasis by controlling parathyroid hormone secretion. Here we investigated the role of Rab1, a small GTP-binding protein that specifically regulates protein transport from the endoplasmic reticulum to the Golgi, in cell surface transport of the hCaR. Cell surface expression of hCaR transiently expressed in human embryonic kidney 293 cells was strongly augmented by coexpression of Rab1 and attenuated by disruption of endogenous Rab1 function by expression of the dominant-negative Rab1N124I mutant or depletion of Rab1 with small interfering RNA. Rab1N124I expression also partially attenuated cell surface expression and signaling response to gain-of-function mutants of hCaR with truncated carboxyl-terminal sequences at positions 895 and 903. These carboxyl-tail truncations are similar to a deletion between residues S895 and V1075 found in a patient family causing autosomal dominant hypocalcemia. In addition, coexpression with wild-type Rab1 increased cell surface expression of the loss-of-function missense mutation R185Q, located on the hCaR amino-terminal extracellular ligand-binding domain (ECD), which causes familial hypocalciuric hypercalcemia. Truncated hCaR variants containing either the ECD with the first transmembrane helix or only the ECD also display Rab1-dependent cell surface expression or secretion into the culture medium, respectively. These data reveal a role for Rab1 in hCaR trafficking from the endoplasmic reticulum to the Golgi that regulates receptor cell surface expression and thereby cell signaling responsiveness to extracellular calcium. (Endocrinology 151: 5114-5123, 2010) C1 [Zhuang, Xiaolei; Adipietro, Kaylin A.; Datta, Shomik; Northup, John K.; Ray, Kausik] Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Ray, K (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court,Room 2A11, Rockville, MD 20850 USA. EM rayk@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders FX This work was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders. NR 35 TC 15 Z9 18 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2010 VL 151 IS 11 BP 5114 EP 5123 DI 10.1210/en.2010-0422 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667XY UT WOS:000283231700006 PM 20861236 ER PT J AU Gautam, D de Azua, IR Li, JH Guettier, JM Heard, T Cui, YH Lu, HY Jou, W Gavrilova, O Zawalich, WS Wess, J AF Gautam, Dinesh de Azua, Inigo Ruiz Li, Jian Hua Guettier, Jean-Marc Heard, Thomas Cui, Yinghong Lu, Huiyan Jou, William Gavrilova, Oksana Zawalich, Walter S. Wess, Juergen TI Beneficial Metabolic Effects Caused by Persistent Activation of beta-Cell M-3 Muscarinic Acetylcholine Receptors in Transgenic Mice SO ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; PANCREATIC B-CELLS; INSULIN-SECRETION; GLUCOSE-HOMEOSTASIS; NEUROBLASTOMA-CELLS; RANDOM MUTAGENESIS; DOWN-REGULATION; MOUSE PANCREAS; MESSENGER-RNA; RAT AB Previous studies have shown that beta-cell M-3 muscarinic acetylcholine receptors (M3Rs) play a key role in maintaining blood glucose homeostasis by enhancing glucose-dependent insulin release. In this study, we tested the hypothesis that long-term, persistent activation of beta-cell M3Rs can improve glucose tolerance and ameliorate the metabolic deficits associated with the consumption of a high-fat diet. To achieve the selective and persistent activation of beta-cell M3Rs in vivo, we generated transgenic mice that expressed the Q490L mutant M3R in their pancreatic beta-cells (beta-M3-Q490L Tg mice). The Q490L point mutation is known to render the M3R constitutively active. The metabolic phenotypes of the transgenic mice were examined in several in vitro and in vivo metabolic tests. In the presence of 15 mM glucose and the absence of M3R ligands, isolated perifused islets prepared from beta-M3-Q490L Tg mice released considerably more insulin than wild-type control islets. This effect could be completely blocked by incubation of the transgenic islets with atropine (10 mu M), an inverse muscarinic agonist, indicating that the Q490L mutant M3R exhibited ligand-independent signaling (constitutive activity) in mouse beta-cells. In vivo studies showed that beta-M3-Q490L Tg mice displayed greatly improved glucose tolerance and increased serum insulin levels as well as resistance to diet-induced glucose intolerance and hyperglycemia. These results suggest that chronic activation of beta-cell M3Rs may represent a useful approach to boost insulin output in the long-term treatment of type 2 diabetes. (Endocrinology 151: 5185-5194, 2010) C1 [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Lu, Huiyan] NIDDK, Bioorgan Chem Lab, Mouse Transgen Core Facil, Bethesda, MD 20892 USA. [Jou, William; Gavrilova, Oksana] NIDDK, Mouse Metab Core Facil, Bethesda, MD 20892 USA. [Zawalich, Walter S.] Yale Univ, Sch Nursing, New Haven, CT 06519 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Li, Jianhua/B-7671-2011 OI Li, Jianhua/0000-0002-5744-3182 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Basque Government FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. I. R. A. was the recipient of a Basque Government Fellowship. NR 44 TC 22 Z9 22 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2010 VL 151 IS 11 BP 5185 EP 5194 DI 10.1210/en.2010-0519 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667XY UT WOS:000283231700013 PM 20843999 ER PT J AU Guigon, CJ Kim, DW Zhu, XG Zhao, L Cheng, SY AF Guigon, Celine J. Kim, Dong Wook Zhu, Xuguang Zhao, Li Cheng, Sheue-Yann TI Tumor Suppressor Action of Liganded Thyroid Hormone Receptor beta by Direct Repression of beta-Catenin Gene Expression SO ENDOCRINOLOGY LA English DT Article ID EPITHELIAL-CELLS; C-ERBA; BINDING; TRANSCRIPTION; PROGRESSION; RESISTANCE; INTERACTS; PROMOTER; ISOFORMS; ELEMENT AB The abundance of beta-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that beta-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor beta (TR beta). By using hypothyroid mice supplemented or not with T(3), we showed that T(3) significantly repressed Ctnnb1 expression in vivo in the thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TR beta, we observed that T(3) induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5' deletion of the CTNNB1 promoter or with mutated thyroid hormone response element (TRE) binding sites, and EMSAs showed that this transrepression was mediated through an interaction between TR beta-retinoid X receptor beta complexes and TREs located in the human CTNNB1 promoter between -807 and -772 and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TR beta was further confirmed by chromatin immunoprecipitation assays showing TR beta recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the beta-catenin gene by liganded TR beta through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TR beta acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene. (Endocrinology 151: 5528-5536, 2010) C1 [Guigon, Celine J.; Kim, Dong Wook; Zhu, Xuguang; Zhao, Li; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 20 TC 14 Z9 15 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2010 VL 151 IS 11 BP 5528 EP 5536 DI 10.1210/en.2010-0475 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 667XY UT WOS:000283231700046 PM 20844001 ER PT J AU Cantor, KP Villanueva, CM Silverman, DT Figueroa, JD Real, FX Garcia-Closas, M Malats, N Chanock, S Yeager, M Tardon, A Garcia-Closas, R Serra, C Carrato, A Castano-Vinyals, G Samanic, C Rothman, N Kogevinas, M AF Cantor, Kenneth P. Villanueva, Cristina M. Silverman, Debra T. Figueroa, Jonine D. Real, Francisco X. Garcia-Closas, Monserrat Malats, Nuria Chanock, Stephen Yeager, Meredith Tardon, Adonina Garcia-Closas, Reina Serra, Consol Carrato, Alfredo Castano-Vinyals, Gemma Samanic, Claudine Rothman, Nathaniel Kogevinas, Manolis TI Polymorphisms in GSTT1, GSTZ1, and CYP2E1, Disinfection By-products, and Risk of Bladder Cancer in Spain SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE bladder cancer; CYP2E1; disinfection by-products; drinking water; GSTT1; GSTZ1; trihalomethanes ID GLUTATHIONE TRANSFERASE ZETA; DRINKING-WATER; DICHLOROACETIC ACID; LIFETIME EXPOSURE; POOLED-ANALYSIS; META-ANALYSIS; TRIHALOMETHANES; BROMODICHLOROMETHANE; SALMONELLA; INDUCTION AB BACKGROUND: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water. OBJECTIVES: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain. METHODS: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms. RESULTS: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0.8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (p(interaction) = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (p(interaction) = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively. CONCLUSIONS: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated. C1 [Cantor, Kenneth P.; Silverman, Debra T.; Figueroa, Jonine D.; Garcia-Closas, Monserrat; Chanock, Stephen; Yeager, Meredith; Samanic, Claudine; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. [Villanueva, Cristina M.; Castano-Vinyals, Gemma; Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona, Spain. [Villanueva, Cristina M.; Real, Francisco X.; Malats, Nuria; Castano-Vinyals, Gemma; Kogevinas, Manolis] Hosp del Mar, Inst Municipal Invest Med, Barcelona, Spain. [Villanueva, Cristina M.; Castano-Vinyals, Gemma; Kogevinas, Manolis] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Real, Francisco X.; Malats, Nuria] Ctr Nacl Invest Oncol, Madrid, Spain. [Real, Francisco X.; Serra, Consol] Univ Pompeu Fabra, Barcelona, Spain. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, Madrid, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. RP Cantor, KP (reprint author), NCI, Div Canc Epidemiol & Genet, 8109 EPS,6120 Execut Blvd, Bethesda, MD 20892 USA. EM cantork@nih.gov RI Serra, C/E-6879-2014; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Villanueva, Cristina/N-1942-2014; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Serra, C/0000-0001-8337-8356; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Villanueva, Cristina/0000-0002-0783-1259; Real, Francisco X/0000-0001-9501-498X; Castano-Vinyals, Gemma/0000-0003-4468-1816 FU National Institutes of Health, National Cancer Institute [N02-CP-11015]; Fondo de Investigacion Sanitaria [00/0745, G03/174, G03/160, C03/09, C03/90]; Instituto de Salud Carlos III, Spanish Health Ministry [CP06/00341] FX This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (N02-CP-11015), the Fondo de Investigacion Sanitaria (00/0745, G03/174, G03/160, C03/09, and C03/90), and the Instituto de Salud Carlos III, Spanish Health Ministry (CP06/00341). NR 42 TC 72 Z9 73 U1 3 U2 29 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2010 VL 118 IS 11 BP 1545 EP 1550 DI 10.1289/ehp.1002206 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 674CR UT WOS:000283711800024 PM 20675267 ER PT J AU Ramdhan, DH Kamijima, M Wang, D Ito, Y Naito, H Yanagiba, Y Hayashi, Y Tanaka, N Aoyama, T Gonzalez, FJ Nakajima, T AF Ramdhan, Doni Hikmat Kamijima, Michihiro Wang, Dong Ito, Yuki Naito, Hisao Yanagiba, Yukie Hayashi, Yumi Tanaka, Naoki Aoyama, Toshifumi Gonzalez, Frank J. Nakajima, Tamie TI Differential Response to Trichloroethylene-Induced Hepatosteatosis in Wild-Type and PPAR alpha-Humanized Mice SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE CYP2E1; fatty acid beta-oxidation; hepatotoxicity; PPAR alpha; steatosis; trichloroethylene ID ACTIVATED-RECEPTOR-ALPHA; HEPATIC PEROXISOME PROLIFERATION; NF-KAPPA-B; ALDEHYDE DEHYDROGENASE; METABOLIZING ENZYMES; RAT-LIVER; ACID; TOXICITY; HEPATOTOXICITY; EXPRESSION AB BACKGROUND: Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor alpha (PPAR) alpha, which is involved in lipid homeo-stasis and anti-inflammation. OBJECTIVE: We examined the role of mouse and human PPAR alpha in TRI-induced hepatic steatosis and toxicity. METHODS: Male wild-type (mPPAR alpha), Ppar alpha-null, and humanized PPAR alpha (hPPAR alpha) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements. RESULTS: Plasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Ppar alpha-null and hPPAR alpha mice. No differences were observed in TRI-mediated induction of hepatic PPAR alpha target genes except for a few genes that differed between mPPAR alpha and hPPAR alpha mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPAR gamma in Ppar alpha-null and hPPAR alpha mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NF kappa B) p52 mRNA and protein in all mice regardless of PPAR alpha genotype. CONCLUSIONS: NF kappa B-p52 is a candidate molecular marker for inflammation caused by TRI, and PPAR alpha may be involved in TRI-induced hepatosteatosis. However, human PPAR alpha may afford only weak protection against TRI-mediated effects compared with mouse PPAR alpha. C1 [Nakajima, Tamie] Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, Nagoya, Aichi 4668550, Japan. [Kamijima, Michihiro; Ito, Yuki] Nagoya City Univ, Grad Sch Med Sci, Dept Occupat & Environm Hlth, Nagoya, Aichi, Japan. [Tanaka, Naoki; Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Dept Metab Regulat, Matsumoto, Nagano 390, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp RI Ito, Yuki/C-3698-2008 FU Japan Society for the Promotion of Science [B18604020, B21406016] FX This study was supported in part by Grants-in-Aid for Scientific Research (B18604020, B21406016) from the Japan Society for the Promotion of Science. NR 42 TC 21 Z9 22 U1 1 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2010 VL 118 IS 11 BP 1557 EP 1563 DI 10.1289/ehp.1001928 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 674CR UT WOS:000283711800026 PM 20709644 ER PT J AU Galloway, T Cipelli, R Guralnik, J Ferrucci, L Bandinelli, S Corsi, AM Money, C McCormack, P Melzer, D AF Galloway, Tamara Cipelli, Riccardo Guralnik, Jack Ferrucci, Luigi Bandinelli, Stefania Corsi, Anna Maria Money, Cathryn McCormack, Paul Melzer, David TI Daily Bisphenol A Excretion and Associations with Sex Hormone Concentrations: Results from the InCHIANTI Adult Population Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE endocrine disruption; androgen; antiandrogen; bisphenol A; human biomonitoring; health effects; InCHIANTI ID ANDROGEN RECEPTOR; FREE TESTOSTERONE; HUMAN EXPOSURE; US POPULATION; NORMAL WOMEN; HUMAN HEALTH; IN-VITRO; URINARY; CELLS; SERUM AB BACKGROUND: Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited. OBJECTIVE: We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations. METHODS: We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography-mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17 beta-estradiol. RESULTS: Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42-3.77 ng/mL], and mean excretion was 5.63 mu g/day (5th population percentile, 2.1 mu g/day; 95th percentile, 16.4 mu g/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (beta = 0.046; 95% CI, 0.015-0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women. CONCLUSION: Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified. C1 [Galloway, Tamara; Melzer, David] Peninsula Coll Med & Dent, European Ctr Environm & Human Hlth, Exeter EX2 5DW, Devon, England. [Galloway, Tamara; Cipelli, Riccardo] Univ Exeter, Sch Biosci, Exeter, Devon, England. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Bandinelli, Stefania; Corsi, Anna Maria] Piero Palagi Hosp, InCHIANTI Grp, Florence, Italy. [Melzer, David] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. RP Melzer, D (reprint author), Peninsula Coll Med & Dent, European Ctr Environm & Human Hlth, Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Melzer, David/0000-0002-0170-3838 FU University of Exeter; U.K.-government; National Institute on Aging, U.S. National Institutes of Health; Peninsula College of Medicine and Dentistry FX R.C. was supported by University of Exeter internal funding. This project was supported in part by the (U.K.-government funded) Peninsula National Institute for Health Research (NIHR) Clinical Research Facility. It was also supported in part by the Intramural Research Program, National Institute on Aging, U.S. National Institutes of Health.; C.M. and P. M. are both employed by Brixham Environmental Laboratory, AstraZeneca UK Ltd., but their input was limited to conducting and documenting the bisphenol A (BPA) assays, and they were blind to the other data examined. The analysis of BPA samples on contract was funded from independent Peninsula College of Medicine and Dentistry sources. The remaining authors declare they have no actual or potential competing financial interests. NR 47 TC 77 Z9 78 U1 2 U2 25 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2010 VL 118 IS 11 BP 1603 EP 1608 DI 10.1289/ehp.1002367 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 674CR UT WOS:000283711800033 PM 20797929 ER PT J AU Shibata, T Solo-Gabriele, HM Sinigalliano, CD Gidley, ML Plano, LRW Fleisher, JM Wang, JD Elmir, SM He, GQ Wright, ME Abdelzaher, AM Ortega, C Wanless, D Garza, AC Kish, J Scott, T Hollenbeck, J Backer, LC Fleming, LE AF Shibata, Tomoyuki Solo-Gabriele, Helena M. Sinigalliano, Christopher D. Gidley, Maribeth L. Plano, Lisa R. W. Fleisher, Jay M. Wang, John D. Elmir, Samir M. He, Guoqing Wright, Mary E. Abdelzaher, Amir M. Ortega, Cristina Wanless, David Garza, Anna C. Kish, Jonathan Scott, Troy Hollenbeck, Julie Backer, Lorraine C. Fleming, Lora E. TI Evaluation of Conventional and Alternative Monitoring Methods for a Recreational Marine Beach with Nonpoint Source of Fecal Contamination SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID ESCHERICHIA-COLI CONCENTRATIONS; SOUTHERN LAKE-MICHIGAN; 16S RIBOSOMAL-RNA; WATER-QUALITY; SOURCE IDENTIFICATION; MICROBIAL INDICATORS; BACTERIA; URBAN; BACTEROIDALES; ENTEROCOCCI AB The objectives of this work were to compare enterococci (ENT) measurements based on the membrane filter, ENT(MF) with alternatives that can provide faster results including alternative enterococci methods (e.g., chromogenic substrate (CS), and quantitative polymerase chain reaction (qPCR)), and results from regression models based upon environmental parameters that can be measured in real-time. ENT(MF) were also compared to source tracking markers (Staphylococcus aureus, Bacteroidales human and dog markers, and Catellicoccus gull marker) in an effort to interpret the variability of the signal. Results showed that concentrations of enterococci based upon MF (<2 to 3320 CFU/100 mL) were significantly different from the CS and qPCR methods (p < 0.01). The correlations between MF and CS (r = 0.58, p < 0.01) were stronger than between MF and qPCR (r <= 0.36, p < 0.01). Enterococci levels by MF, CS, and qPCR methods were positively correlated with turbidity and tidal height Enterococci by MF and CS were also inversely correlated with solar radiation but enterococci by qPCR was not. The regression model based on environmental variables provided fair qualitative predictions of enterococci by ME in real-time, for daily geometric mean levels, but not for individual samples. Overall, ENT(ME) was not significantly correlated with source tracking markers with the exception of samples collected during one storm event. The inability of the regression model to predict ENT(MF) levels for individual samples is likely due to the different sources of ENT impacting the beach at any given time, making it particularly difficult to to predict short-term variability of ENT(MF) for environmental parameters. C1 [Shibata, Tomoyuki] No Illinois Univ, Sch Nursing & Hlth Studies, De Kalb, IL 60115 USA. [Shibata, Tomoyuki; Solo-Gabriele, Helena M.; Sinigalliano, Christopher D.; Gidley, Maribeth L.; Plano, Lisa R. W.; Fleisher, Jay M.; Wang, John D.; Elmir, Samir M.; He, Guoqing; Wright, Mary E.; Abdelzaher, Amir M.; Ortega, Cristina; Wanless, David; Garza, Anna C.; Kish, Jonathan; Hollenbeck, Julie; Fleming, Lora E.] Univ Miami, NSF, NIEHS, Oceans & Human Hlth Ctr,Rosenstiel Sch, Miami, FL USA. [Shibata, Tomoyuki; Sinigalliano, Christopher D.; Gidley, Maribeth L.] NOAA, Atlantic Oceanog & Meteorol Lab, Miami, FL 33149 USA. [Fleisher, Jay M.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Solo-Gabriele, Helena M.; Wright, Mary E.; Abdelzaher, Amir M.; Ortega, Cristina] Univ Miami, Coll Engn, Coral Gables, FL 33124 USA. [Plano, Lisa R. W.; Garza, Anna C.; Kish, Jonathan; Fleming, Lora E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Elmir, Samir M.] Miami Dade Cty Publ Hlth Dept, Miami, FL USA. [Scott, Troy] BCS Labs, Miami, FL USA. [Gidley, Maribeth L.; Wanless, David] Univ Miami, Cooperat Inst Marine & Atmospher Studies, Miami, FL USA. [Backer, Lorraine C.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Chamblee, GA USA. RP Shibata, T (reprint author), No Illinois Univ, Sch Nursing & Hlth Studies, Wirtz Hall 2091, De Kalb, IL 60115 USA. EM tshibata@niu.edu RI Sinigalliano, Christopher/A-8760-2014; gidley, maribeth/B-8335-2014; OI Sinigalliano, Christopher/0000-0002-9942-238X; gidley, maribeth/0000-0001-9583-8073; Fleisher, Jay/0000-0002-2553-2201 FU Centers for Disease Control and Prevention; Florida Department of Health through Florida Department of Environmental Protection; Environmental Protection Agency Internship Program; National Science Foundation (NSF); National Institute of Environmental Health Sciences (NIEHS) Oceans and Human Health Center at the University of Miami [NSF 0CE0432368/0911373, NIEHS P50 ES12736]; NSF REU in Oceans and Human Health; NSF SGER [NSF SGER 0743987]; Northern Gulf Institute, a NOAA Cooperative Institute [NA06OAR4320264] FX Funding was received from the Centers for Disease Control and Prevention; Florida Department of Health through monies from the Florida Department of Environmental Protection; the Environmental Protection Agency Internship Program; the National Science Foundation (NSF) and the National Institute of Environmental Health Sciences (NIEHS) Oceans and Human Health Center at the University of Miami [NSF 0CE0432368/0911373] and [NIEHS P50 ES12736] and NSF REU in Oceans and Human Health, and the NSF SGER (NSF SGER 0743987) in Oceans and Human Health. Development of the dog-host-specific Bacteroides and gull-host-specific Catellicoccus qPCR assays were funded in part by the Northern Gulf Institute, a NOAA Cooperative Institute (U.S. Department of Commerce award NA06OAR4320264). We would also like to thank IDEXX Corporation for the provision of supplies for the CS method. This study is dedicated to the memory of Ms. Seana Campbell, a very talented, hardworking and creative young researcher who died too young. NR 36 TC 29 Z9 30 U1 3 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD NOV 1 PY 2010 VL 44 IS 21 BP 8175 EP 8181 DI 10.1021/es100884w PG 7 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 671EV UT WOS:000283484000035 PM 20925349 ER PT J AU Carpentieri, A Ratner, DM Ghosh, SK Banerjee, S Bushkin, GG Cui, JK Lubrano, M Steffen, M Costello, CE O'Keefe, B Robbins, PW Samuelson, J AF Carpentieri, Andrea Ratner, Daniel M. Ghosh, Sudip K. Banerjee, Sulagna Bushkin, G. Guy Cui, Jike Lubrano, Michael Steffen, Martin Costello, Catherine E. O'Keefe, Barry Robbins, Phillips W. Samuelson, John TI The Antiretroviral Lectin Cyanovirin-N Targets Well-Known and Novel Targets on the Surface of Entamoeba histolytica Trophozoites SO EUKARYOTIC CELL LA English DT Article ID ASN-LINKED GLYCANS; PROTEOMIC ANALYSIS; POSTTRANSLATIONAL MODIFICATIONS; ENDOPLASMIC-RETICULUM; MONOCLONAL-ANTIBODY; QUALITY-CONTROL; PROTEIN; GLYCOPROTEINS; AMEBIASIS; HIV-1 AB Entamoeba histolytica, the protist that causes amebic dysentery and liver abscess, has a truncated Asn-linked glycan (N-glycan) precursor composed of seven sugars (Man(5)GlcNAc(2)). Here, we show that glycoproteins with unmodified N-glycans are aggregated and capped on the surface of E. histolytica trophozoites by the antiretroviral lectin cyanovirin-N and then replenished from large intracellular pools. Cyanovirin-N cocaps the Gal/GalNAc adherence lectin, as well as glycoproteins containing O-phosphodiester-linked glycans recognized by an anti-proteophosphoglycan monoclonal antibody. Cyanovirin-N inhibits phagocytosis by E. histolytica trophozoites of mucin-coated beads, a surrogate assay for amebic virulence. For technical reasons, we used the plant lectin concanavalin A rather than cyanovirin-N to enrich secreted and membrane proteins for mass spectrometric identification. E. histolytica glycoproteins with occupied N-glycan sites include Gal/GalNAc lectins, proteases, and 17 previously hypothetical proteins. The latter glycoproteins, as well as 50 previously hypothetical proteins enriched by concanavalin A, may be vaccine targets as they are abundant and unique. In summary, the antiretroviral lectin cyanovirin-N binds to well-known and novel targets on the surface of E. histolytica that are rapidly replenished from large intracellular pools. C1 [Carpentieri, Andrea; Ratner, Daniel M.; Ghosh, Sudip K.; Banerjee, Sulagna; Bushkin, G. Guy; Cui, Jike; Lubrano, Michael; Robbins, Phillips W.; Samuelson, John] Boston Univ, Dept Mol & Cell Biol, Goldman Sch Dent Med, Boston, MA 02118 USA. [Steffen, Martin] Boston Univ, Dept Pathol & Lab Med, Sch Med, Boston, MA 02118 USA. [Costello, Catherine E.] Boston Univ, Dept Biochem, Med Ctr, Boston, MA 02118 USA. [O'Keefe, Barry] NCI Frederick, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Samuelson, J (reprint author), Boston Univ, Dept Mol & Cell Biol, Goldman Sch Dent Med, 72 E Concord St,Evans 425, Boston, MA 02118 USA. EM jsamuels@bu.edu OI Costello, Catherine/0000-0003-1594-5122; Steffen, Martin/0000-0002-7853-7364; Samuelson, John/0000-0001-9533-3040; Carpentieri, Andrea/0000-0002-1944-5355 FU NIH [AI44070, GM31318, RR10888]; Training Program in Host Pathogen Interactions [T32 AI052070] FX This work was supported by NIH grants AI44070 (to J.S.), GM31318 (to P.W.R.), and RR10888 (to C.E.C.). Support for D.M.R. was provided by the Training Program in Host Pathogen Interactions (T32 AI052070). NR 56 TC 3 Z9 3 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD NOV PY 2010 VL 9 IS 11 BP 1661 EP 1668 DI 10.1128/EC.00166-10 PG 8 WC Microbiology; Mycology SC Microbiology; Mycology GA 674HF UT WOS:000283727500002 PM 20852023 ER PT J AU Hiemenz, JW Raad, II Maertens, JA Hachem, RY Saah, AJ Sable, CA Chodakewitz, JA Severino, ME Saddier, P Berman, RS Ryan, DM DiNubile, MJ Patterson, TF Denning, DW Walsh, TJ AF Hiemenz, J. W. Raad, I. I. Maertens, J. A. Hachem, R. Y. Saah, A. J. Sable, C. A. Chodakewitz, J. A. Severino, M. E. Saddier, P. Berman, R. S. Ryan, D. M. DiNubile, M. J. Patterson, T. F. Denning, D. W. Walsh, T. J. TI Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort SO EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES LA English DT Article ID LIPOSOMAL AMPHOTERICIN-B; LIVER-TRANSPLANT RECIPIENTS; ALTERNATIVE TRIAL DESIGNS; STEM-CELL TRANSPLANTATION; FUNGAL-INFECTIONS; HEMATOLOGIC MALIGNANCIES; PULMONARY ASPERGILLOSIS; COLLOIDAL DISPERSION; ANTIFUNGAL THERAPY; PROGNOSTIC-FACTORS AB In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of a parts per thousand yen1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy. C1 [Hiemenz, J. W.] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL 32610 USA. [Raad, I. I.; Hachem, R. Y.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Maertens, J. A.] Univ Hosp Gasthuisberg, Leuven, Belgium. [Saah, A. J.; Sable, C. A.; Chodakewitz, J. A.; Severino, M. E.; Saddier, P.; Berman, R. S.; Ryan, D. M.; DiNubile, M. J.] Merck Res Labs, West Point, PA USA. [Patterson, T. F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Patterson, T. F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Denning, D. W.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Walsh, T. J.] NCI, Bethesda, MD 20892 USA. RP Hiemenz, JW (reprint author), Univ Florida, Coll Med, Div Hematol Oncol, POB 100278, Gainesville, FL 32610 USA. EM john.hiemenz@medicine.ufl.edu OI Denning, David/0000-0001-5626-2251 FU Merck Co., Inc. FX Merck & Co., Inc., which markets caspofungin under the brand name Cancidas, sponsored and funded this study. Current and former employees of the sponsor (indicated on the title page) may own stock or stock options in the company. All non-Merck authors have served as investigators on Merck studies. The sponsor formally reviewed a penultimate draft. All co-authors approved an essentially final version of the manuscript. NR 45 TC 13 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0934-9723 J9 EUR J CLIN MICROBIOL JI Eur. J. Clin. Microbiol. Infect. Dis. PD NOV PY 2010 VL 29 IS 11 BP 1387 EP 1394 DI 10.1007/s10096-010-1013-0 PG 8 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 671LL UT WOS:000283507500009 PM 20703506 ER PT J AU Mueller, SC Ng, P Sinaii, N Leschek, EW Green-Golan, L VanRyzin, C Ernst, M Merke, DP AF Mueller, Sven C. Ng, Pamela Sinaii, Ninet Leschek, Ellen W. Green-Golan, Liza VanRyzin, Carol Ernst, Monique Merke, Deborah P. TI Psychiatric characterization of children with genetic causes of hyperandrogenism SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CONGENITAL ADRENAL-HYPERPLASIA; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CORTICOTROPIN-RELEASING-FACTOR; LUTEINIZING-HORMONE RECEPTOR; MALE PRECOCIOUS PUBERTY; TOURETTES-SYNDROME; ANDROGENIC STEROIDS; CONDUCT DISORDER; SEX-DIFFERENCES; K-SADS AB Objective: Very little is known about the mental health status in children with genetic causes of hyperandrogenism. This study sought to characterize psychiatric morbidity in this group. Design/methods: Children (8-18 years) with the diagnosis of classic congenital adrenal hyperplasia (CAH) or familial male precocious puberty (FMPP) underwent a semi-structured psychiatric interview, the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. According to sex and the literature, incidence of identified psychopathology was compared between the two endocrinological groups. We evaluated 72 patients: 54 CAH (21 females) and 18 FMPP. Results: Twenty-four (44.4%) CAH patients and 10 (55.6%) FMPP patients met the criteria for at least one lifetime psychiatric diagnosis. Attention-deficit hyperactivity disorder (ADHD) was present in 18.2% of CAH males, 44.4% of FMPP males, and one case (4.8%) in CAH females. A high rate of anxiety disorders was also found in all the three groups (17-21%). Relative to females with CAH, the FMPP patients exhibited higher rates of ADHD. Age at diagnosis and the treatment modalities were not associated with psychopathology. Rates of psychiatric disorder, specifically ADHD and anxiety disorders, were higher than in the general population. Conclusion: Although anxiety disorders may occur at an increased rate in children with chronic illness, androgens may contribute to higher risk for psychopathology in pediatric patients with genetic cause of excess androgen. Early diagnosis and treatment of childhood hyperandrogenism is essential for optimal development. The results suggest that assessment for psychiatric disorders should be part of the routine evaluation of these patients. C1 [Mueller, Sven C.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Ng, Pamela] NIMH, Unit Affect Cognit Neurosci, NIH, Bethesda, MD 20892 USA. [Sinaii, Ninet; Green-Golan, Liza; VanRyzin, Carol; Merke, Deborah P.] NIH, NIH Clin Ctr, Bethesda, MD 20892 USA. [Leschek, Ellen W.] NIDDKD, Diabet Endocrinol & Metab Dis Div, NIH, Bethesda, MD 20892 USA. [Merke, Deborah P.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Ng, Pamela] Univ New S Wales, Sch Psychiat, Sydney, NSW 2052, Australia. RP Mueller, SC (reprint author), NIMH, Sect Dev & Affect Neurosci, NIH, 15K North Dr, Bethesda, MD 20892 USA. EM msven@mail.nih.gov FU Phoqus Pharmaceuticals; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); National Institutes of Health Clinical Center; Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation FX D P Merke is a Commissioned Officer in the US Public Health Service. S C Mueller, P Ng, N Sinaii, E W Leschek, L Green-Golan, C VanRyzin, and M Ernst have nothing to declare. D P Merke received research funds from Phoqus Pharmaceuticals during 2007-2008.; This research was supported (in part) by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Mental Health (NIMH), and the National Institutes of Health Clinical Center and (in part) by the Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. NR 66 TC 23 Z9 23 U1 2 U2 7 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD NOV PY 2010 VL 163 IS 5 BP 801 EP 810 DI 10.1530/EJE-10-0693 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 662QR UT WOS:000282826900011 PM 20807778 ER PT J AU Singh, SP de Camargo, MM Zhang, HH Foley, JF Hedrick, MN Farber, JM AF Singh, Satya P. de Camargo, Maristela M. Zhang, Hongwei H. Foley, John F. Hedrick, Michael N. Farber, Joshua M. TI Changes in histone acetylation and methylation that are important for persistent but not transient expression of CCR4 in human CD4(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chemokines; Epigenetics; Histones; Human; T cells ID CHEMOKINE RECEPTOR EXPRESSION; DIFFERENTIAL EXPRESSION; GENE-TRANSCRIPTION; CYTOKINE GENES; HUMAN GENOME; CHROMATIN; MEMORY; LYMPHOCYTES; POLARIZATION; EPIGENETICS AB Although regulation of CXCR3 and CCR4 is related to Th1 and Th2 differentiation, respectively, many CXCR3(+) and CCR4(+) cells do not express IFN-gamma and/or IL-4, suggesting that the chemokine receptor genes might be inducible by mechanisms that are lineage-independent. We investigated the regulation of CXCR3 versus IFNG, and CCR4 versus IL4 in human CD4(+) T cells by analyzing modifications of histone H3. In naive cord-blood cells, under nonpolarizing conditions not inducing IL4, CCR4 was induced to high levels without many of the activation-associated changes in promoter histone H3 found for both IL4 and CCR4 in Th2 cells. Importantly, CCR4 expression was stable in Th2 cells, but fell in nonpolarized cells after the cells were rested; this decline could be reversed by increasing histone acetylation using sodium butyrate. Patterns of histone H3 modifications in CXCR3(+) CCR4(-) and CXCR3(-) CCR4(+) CD4(+) T-cell subsets from adult blood matched those in cells cultured under polarizing conditions in vitro. Our data show that high-level lineage-independent induction of CCR4 can occur following T-cell activation without accessibility-associated changes in histone H3, but that without such changes expression is transient rather than persistent. C1 [Singh, Satya P.; Zhang, Hongwei H.; Foley, John F.; Hedrick, Michael N.; Farber, Joshua M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [de Camargo, Maristela M.] Univ Sao Paulo, Inst Biomed Sci, Mol Immunoregulat Lab, Sao Paulo, Brazil. RP Farber, JM (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Rm 11N112,MSC 1886, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov RI Camargo, Maristela/G-8584-2011 OI Camargo, Maristela/0000-0003-2815-125X FU NIAID, NIH; FAPESP [01/02584-2] FX The authors are grateful to Lori Wilkinson and Brian De for assistance in ChIP assays, Calvin Eigsti and other members of the Research Technology Branch, NIAID, for their help with cell sorting, Keji Zhao for helpful discussions, and Philip Murphy and John O'Shea for critical review of the manuscript. The Intramural Research Program of NIAID, NIH, supported this research. M. M. C. was supported by the "Young Investigators Program" from FAPESP (01/02584-2). NR 40 TC 2 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD NOV PY 2010 VL 40 IS 11 BP 3183 EP 3197 DI 10.1002/eji.201040443 PG 15 WC Immunology SC Immunology GA 678FH UT WOS:000284059000023 PM 20963786 ER PT J AU Filbert, EL Nguyen, A Markiewicz, MA Fowlkes, BJ Huang, YNH Shaw, AS AF Filbert, Erin L. Nguyen, AnhCo Markiewicz, Mary A. Fowlkes, B. J. Huang, Yina H. Shaw, Andrey S. TI Kinase suppressor of Ras 1 is required for full ERK activation in thymocytes but not for thymocyte selection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE ERK; Kinase suppressor of Ras; Thymocyte development ID T-CELL DEVELOPMENT; SIGNAL-RELATED KINASE; KSR-1 GENE ENCODES; NEGATIVE SELECTION; PROTEIN-KINASE; TRANSGENIC MICE; LINEAGE COMMITMENT; POSITIVE SELECTION; ANTIGEN RECEPTOR; IN-VIVO AB The scaffold protein kinase suppressor of Ras 1 ( KSR1) is critical for efficient activation of ERK in a number of cell types. Consistent with this, we observed a defect in ERK activation in thymocytes that lack KSR1. Interestingly, we found that the defect was much greater after PMA stimulation than by CD3 activation. Since ERK activation is believed to be important for thymocyte development, we analyzed thymocyte selection in KSR1-deficient (KSR1(-/-)) mice. We found that positive selection in two different TCR transgenic models, HY and AND, was normal. On the other hand, negative selection in the HY model was slightly impaired in KSR1(-/-) mice. However, a defect in negative selection was not apparent in the AND TCR model system or in an endogenous superantigen-mediated model of negative selection. These results suggest that, despite a requirement for KSR1 for full ERK activation in thymocytes, full and efficient ERK activation is not essential for the majority of thymocyte selection events. C1 [Filbert, Erin L.; Nguyen, AnhCo; Markiewicz, Mary A.; Huang, Yina H.; Shaw, Andrey S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Fowlkes, B. J.] NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. [Shaw, Andrey S.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Shaw, AS (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. EM ashaw@wustl.edu OI Huang, Yina/0000-0002-0125-9351; Markiewicz, Mary/0000-0001-5685-8573 FU NIH [R37-AI57966-AS, T32-AI07163-EF]; Howard Hughes Medical Institute FX The authors thank Rob Lewis for providing KSR1-/- DBA1/LacJ mice. This work was supported by the NIH (R37-AI57966-AS and T32-AI07163-EF) and the Howard Hughes Medical Institute. NR 41 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD NOV PY 2010 VL 40 IS 11 BP 3226 EP 3234 DI 10.1002/eji.201040349 PG 9 WC Immunology SC Immunology GA 678FH UT WOS:000284059000027 PM 20865788 ER PT J AU Jauregui-Osoro, M Sunassee, K Weeks, AJ Berry, DJ Paul, RL Cleij, M Banga, J O'Doherty, MJ Marsden, PK Clarke, SEM Ballinger, JR Szanda, I Cheng, SY Blower, PJ AF Jauregui-Osoro, Maite Sunassee, Kavitha Weeks, Amanda J. Berry, David J. Paul, Rowena L. Cleij, Marcel Banga, Jasvinder Paul O'Doherty, Michael J. Marsden, Paul K. Clarke, Susan E. M. Ballinger, James R. Szanda, Istvan Cheng, Sheue-Yann Blower, Philip J. TI Synthesis and biological evaluation of [F-18]tetrafluoroborate: a PET imaging agent for thyroid disease and reporter gene imaging of the sodium/iodide symporter SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE F-18; PET; Tetrafluoroborate; Sodium/iodide symporter; Thyroid ID SODIUM-IODIDE SYMPORTER; POSITRON-EMISSION-TOMOGRAPHY; FLUOROBORATE IONS; MOUSE MODEL; TRANSGENE EXPRESSION; NA+/I-SYMPORTER; CANCER-THERAPY; I-124 PET; IN-VIVO; NIS AB Purpose The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters I-123-iodide, I-131-iodide and Tc-99m-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate F-18-labelled tetrafluoroborate ([F-18]TFB) for PET imaging of hNIS. Methods [F-18]TFB was prepared by isotopic exchange of BF (4) (-) with [F-18]fluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition. Results [F-18]TFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate. Conclusion [F-18]TFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans. C1 [Jauregui-Osoro, Maite; Sunassee, Kavitha; Weeks, Amanda J.; Berry, David J.; Paul, Rowena L.; Cleij, Marcel; O'Doherty, Michael J.; Marsden, Paul K.; Szanda, Istvan; Blower, Philip J.] Kings Coll London, St Thomas Hosp, Div Imaging Sci, London SE1 7EH, England. [Banga, Jasvinder Paul] Kings Coll London, Div Cell & Gene Based Therapy, London SE1 7EH, England. [Clarke, Susan E. M.; Ballinger, James R.] Guys & St Thomas NHS Trust, Dept Nucl Med, London, England. [Cheng, Sheue-Yann] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Blower, PJ (reprint author), Kings Coll London, St Thomas Hosp, Div Imaging Sci, 4th Floor Lambeth Wing, London SE1 7EH, England. EM Maite.Jauregui-Osoro@kcl.ac.uk; Philip.Blower@kcl.ac.uk FU Guy's & St Thomas' Charity; Cancer Research UK; EPSRC; Department of Health via the National Institute for Health Research (NIHR); MRC; DoH (UK) FX This work was supported by grants from Guy's & St Thomas' Charity, Cancer Research UK, and EPSRC. RLP acknowledges financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. This work was conducted within the King's College London-UCL Comprehensive Cancer Imaging Centre supported by Cancer Research UK & EPSRC, in association with MRC and DoH (UK). We thank Dr. M Upton for helpful advice on HPLC methods.; We acknowledge grants from Guy's & St Thomas' Charity, Cancer Research UK, EPSRC, MRC and Department of Health and the Wellcome Trust. NR 40 TC 36 Z9 36 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD NOV PY 2010 VL 37 IS 11 BP 2108 EP 2116 DI 10.1007/s00259-010-1523-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 657PI UT WOS:000282424400013 PM 20577737 ER PT J AU Bousquet, J Kiley, J Bateman, ED Viegi, G Cruz, AA Khaltaev, N Khaled, NA Baena-Cagnani, CE Barreto, ML Billo, N Canonica, GW Carlsen, KH Chavannes, N Chuchalin, A Drazen, J Fabbri, LM Gerbase, MW Humbert, M Joos, G Masjedi, MR Makino, S Rabe, K To, T Zhi, L AF Bousquet, J. Kiley, J. Bateman, E. D. Viegi, G. Cruz, A. A. Khaltaev, N. Khaled, N. Ait Baena-Cagnani, C. E. Barreto, M. L. Billo, N. Canonica, G. W. Carlsen, K-H Chavannes, N. Chuchalin, A. Drazen, J. Fabbri, L. M. Gerbase, M. W. Humbert, M. Joos, G. Masjedi, M. R. Makino, S. Rabe, K. To, T. Zhi, L. TI Prioritised research agenda for prevention and control of chronic respiratory diseases SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE Asthma; chronic obstructive pulmonary disease; chronic respiratory diseases; noncommunicable diseases; prevention; research ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; POSITIVE AIRWAY PRESSURE; MIDDLE-INCOME COUNTRIES; LUNG HEALTH; SLEEP-APNEA; PRACTICAL APPROACH; SMOKING-CESSATION; GLOBAL STRATEGY; ASTHMA AB The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention. C1 [Bousquet, J.] Hop Arnaud De Villeneuve, Serv Malad Resp, F-34295 Montpellier 5, France. [Bousquet, J.] INSERM, Montpellier, France. [Kiley, J.] NHLBI, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bateman, E. D.] Univ Cape Town, Fac Hlth Sci, ZA-7700 Rondebosch, South Africa. [Viegi, G.] CNR, Inst Clin Physiol, I-56100 Pisa, Italy. [Cruz, A. A.] Univ Fed Bahia, Fac Med Bahia, BR-41170290 Salvador, BA, Brazil. [Khaled, N. Ait; Billo, N.] Int Union TB & Lung Dis, Paris, France. [Baena-Cagnani, C. E.] Catholic Univ, Cordoba, Argentina. [Barreto, M. L.] Univ Fed Bahia, Inst Saude Coletiva, Salvador, BA, Brazil. [Canonica, G. W.] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Carlsen, K-H] Univ Oslo, Fac Med, Oslo, Norway. [Chavannes, N.; Rabe, K.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Chuchalin, A.] Pulmonol Res Inst, Moscow, Russia. [Chuchalin, A.] Russian Resp Soc, Moscow, Russia. [Drazen, J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Fabbri, L. M.] Univ Modena & Reggio Emilia, Modena, Italy. [Gerbase, M. W.] Univ Hosp Geneva, Geneva, Switzerland. [Humbert, M.] Univ Paris 11, Serv Pneumol, Hop Antoine Beclere, Clamart, France. [Joos, G.] Ghent Univ Hosp, B-9000 Ghent, Belgium. [Masjedi, M. R.] Shahid Beheshti Univ Med Sci, Tehran, Iran. [Makino, S.] Dokkyo Univ, Sch Med, Soka, Saitama, Japan. [To, T.] Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada. [Zhi, L.] Chinese Med Assoc, Beijing, Peoples R China. [Khaltaev, N.] Allerg Rhinitis & Its Impact Asthma ARIA, Global Alliance Chron Resp Dis GARD, Geneva, Switzerland. RP Bousquet, J (reprint author), Hop Arnaud De Villeneuve, Serv Malad Resp, F-34295 Montpellier 5, France. EM jean.bousquet@inserm.fr RI Chavannes, Niels/F-1148-2011; Fabbri, Leonardo/I-4055-2012; Cruz, Alvaro/I-1676-2012; OI Chavannes, Niels/0000-0002-8607-9199; Fabbri, Leonardo/0000-0001-8894-1689; Cruz, Alvaro/0000-0002-7403-3871; Barreto, Mauricio/0000-0002-0215-4930; Masjedi, Mohammadreza/0000-0003-4964-3851 NR 60 TC 43 Z9 45 U1 0 U2 7 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD NOV PY 2010 VL 36 IS 5 BP 995 EP 1001 DI 10.1183/09031936.00012610 PG 7 WC Respiratory System SC Respiratory System GA 673NH UT WOS:000283669700007 PM 20223919 ER PT J AU Zoppoli, G Cea, M Soncini, D Fruscione, F Rudner, J Moran, E Caffa, I Bedognetti, D Motta, G Ghio, R Ferrando, F Ballestrero, A Parodi, S Belka, C Patrone, F Bruzzone, S Nencioni, A AF Zoppoli, Gabriele Cea, Michele Soncini, Debora Fruscione, Floriana Rudner, Justine Moran, Eva Caffa, Irene Bedognetti, Davide Motta, Giulia Ghio, Riccardo Ferrando, Fabio Ballestrero, Alberto Parodi, Silvio Belka, Claus Patrone, Franco Bruzzone, Santina Nencioni, Alessio TI Potent synergistic interaction between the Nampt inhibitor AP0866 and the apoptosis activator TRAIL in human leukemia cells SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NAD BIOSYNTHESIS INHIBITOR; HEMATOLOGIC MALIGNANCIES; FK866; SENSITIVITY; AUTOPHAGY; SURVIVAL; LIGAND; RIBOSE; APO866 AB Objective The nicotinamide phosphoribosyltransferase (Nampt) inhibitor AP0866 depletes intracellular nicotinamide adenine dinucleotide (NAD(+)) and shows promising anticancer activity in preclinical studies Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and Induces apoptosis via caspase-8 and 10 Here we have explored the interaction between AP0866 and TRAIL in leukemia cell lines and in primary B cell chronic lymphocytic leukemia cells Materials and Methods Cells were treated with AP0866, TRAIL, or their combination Viability and mitochondrial transmembrane potential (Delta Psi(m)) were determined by cell staining with prom dium iodide and tetramethylrhodamine ethyl ester, respectively, and flow cytometry Nampt and gamma tubulin levels, as well as caspase 3 cleavage were detected by immunoblotting DR4 and DR5 expression were assessed by immunostaining and flow cytometry Caspases were inhibited with zVAD-FMK and zDEVD FMK, autophagy with 3-methyladenine, LY294002, and wortmannin Intracellular NAD(+) and adenosine triphosphate (ATP) were measured by cycling assays and high performance liquid chromatography (HPLC), respectively Results AP0866 induced NAD(+) depletion, Delta Psi(m), dissipation, and ATP shortage in leukemia cells, thereby leading to autophagic cell death TRAIL induced caspase dependent apoptosis TRAIL addition to AP0866 synergistically Increased its activity in leukemia cells by enhancing NAD(+) depletion, Delta Psi(m) dissipation, and ATP shortage No DR5 upregulation at the cell surface in response to AP0866 was observed Remarkably, in healthy leukocytes AP0866 and TRAIL were poorly active and failed to show any cooperation Conclusions Activation of the extrinsic apoptotic cascade with TRAIL selectively amplifies the sequelae of Nampt inhibition in leukemia cells, and appears as a promising strategy to enhance AP0866 activity in hematological malignancies (C) 2010 ISEH Society for Hematology and Stem Cells Published by Elsevier Inc C1 [Zoppoli, Gabriele; Moran, Eva; Caffa, Irene; Motta, Giulia; Ghio, Riccardo; Ferrando, Fabio; Patrone, Franco] Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy. [Zoppoli, Gabriele] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Adv Biotechnol Ctr, Genoa, Italy. [Rudner, Justine] Univ Tubingen, Dept Radiat Oncol, Tubingen, Germany. NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Belka, Claus] LMU Univ Munchen, Dept Radiat Oncol, Munich, Germany. [Bruzzone, Santina] Univ Genoa, Dept Expt Med, Biochem Sect, I-16132 Genoa, Italy. RP Nencioni, A (reprint author), Univ Genoa, Dept Internal Med, Room 221,Vle Benedetto XV 6, I-16132 Genoa, Italy. RI Bedognetti, Davide/A-9090-2012; Bruzzone, Santina/A-4264-2015; Zoppoli, Gabriele/B-6935-2016; Caffa, Irene/J-9835-2016 OI Bruzzone, Santina/0000-0003-2034-3716; Zoppoli, Gabriele/0000-0003-3890-5588; Caffa, Irene/0000-0003-1111-9915 NR 27 TC 30 Z9 32 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD NOV PY 2010 VL 38 IS 11 BP 979 EP 988 DI 10.1016/j.exphem.2010.07013 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 679AJ UT WOS:000284131500001 PM 20696207 ER PT J AU Wong, SS Keyvanfar, K Wan, ZH Kajigaya, S Young, NS Zhi, N AF Wong, Susan Keyvanfar, Keyvan Wan, Zhihong Kajigaya, Sachiko Young, Neal S. Zhi, Ning TI Establishment of an erythroid cell line from primary CD36(+) erythroid progenitor cells SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID EPITHELIAL-CELLS; PHILADELPHIA-CHROMOSOME; ERYTHROLEUKEMIA-CELLS; TELOMERASE ACTIVITY; HUMAN FIBROBLASTS; PARVOVIRUS B19; RED-CELLS; DIFFERENTIATION; ERYTHROPOIETIN; EXPRESSION AB Objective Most continuous cell lines with erythroid characteristics are derived from patients with myelogenous leukemia or erythroleukemia Among them, a few cell lines have been reported to be positive for CD36 We tried to establish a continuous erythroid cell line from the primary CD36(+) erythroid progenitor cells (EPCs) by the lentivirus mediated gene transduction system Materials and Methods A lentiviral vector carrying 5V40T, hTERT, or the human papillomavirus type 16 (HPV16) E6 and E7 (E6/E7) viral oncogenes, was Introduced Into CD36 EPCs, singularly or combined Transformed cells were characterized in terms of histology, phenotype, karyotype, and gene expression profile Results The lentiviral vector carrying HPV16 E6/E7 genes successfully transformed CD36(+) EPCs, creating a continuous cell line, CD36E Immunophenotype analysis revealed that the CD36E cells had characteristics of erythroid progenitors, among which about 27% of the cell population produced hemoglobin Colony forming cell assay demonstrated that the CD36E cells were capable of forming erythroid colonies Using cytokines or chemical agents, attempts were made to Induce differentiation of the CD36E cells but were ineffective, indicating the irreversible erythroid lineage commitment of the cells The gene expression profile of the CD36E cells displayed a marked difference from that of the CD36(+) EPCs Conclusions The continuous CD36E cell line is an erythroid progenitor cell line possessing the ability to produce hemoglobin The CD36E cell line would be an excellent tool for applied research involving erythroid lineage cells and comparative studies with primary CD36(+) EPCs Published by Elsevier Inc on behalf of the ISEH - Society for Hematology and Stem Cells C1 [Wong, Susan; Keyvanfar, Keyvan; Wan, Zhihong; Kajigaya, Sachiko; Young, Neal S.; Zhi, Ning] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Zhi, N (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Room 3 5272,10 Ctr Dr, Bethesda, MD 20892 USA. FU National Institutes of Health (NIH) (Bethesda MD USA) FX This work was supported by the National Institutes of Health (NIH) Intramural Research Program (Bethesda MD USA) We thank Andre Larochelle Hematology Branch National Heart Lung and Blood Institute (NHLBI) NIH for his helpful discussion We also thank the following people and facilities for their technical support Leigh Samsel and Phil McCoy at the NHLBI Flow Cytometry Core Facility NIH Sandra Burkett at National Cancer Institute Frederick SKY facility NIH (Frederick MD USA) Bey-Dih Chang and Thomas Primiano at CDI Technologies Madison WI USA and Rick Dreyfuss Medical Arts Photography Branch NIH (Bethesda MD USA) NR 52 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD NOV PY 2010 VL 38 IS 11 BP 994 EP 1005 DI 10.1016/j.exphem.2010.07.012 PG 12 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 679AJ UT WOS:000284131500003 PM 20696208 ER PT J AU Dimitrov, EL Petrus, E Usdin, TB AF Dimitrov, Eugene L. Petrus, Emily Usdin, Ted B. TI Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Pain; Nociception; Descending inhibition; Endocannabinoid; Knockout mouse; Supraspinal; Stress-induced analgesia ID STRESS-INDUCED ANALGESIA; ACID AMIDE HYDROLASE; HORMONE 2 RECEPTOR; CANNABINOID-INDUCED ANTINOCICEPTION; VESICULAR GLUTAMATE TRANSPORTERS; CENTRAL-NERVOUS-SYSTEM; PARATHYROID-HORMONE-2 RECEPTOR; NEUROPATHIC PAIN; BILATERAL LESIONS; DORSAL HORN AB Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55 C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icy, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CBI and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions. Published by Elsevier Inc. C1 [Dimitrov, Eugene L.; Petrus, Emily; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, 35 Convent Dr,Room 1B-215, Bethesda, MD 20892 USA. EM dimitrove@mail.nih.gov; petruse@umd.edu; usdint@mail.nih.gov FU National Institute of Mental Health, NIH FX This work was supported by the Intramural Program of the National Institute of Mental Health, NIH. Jonathan Kuo, Milan Rusnak, and Dean Choi made valuable contributions to the work. We thank Laurence Coutellier for comments on the manuscript. NR 72 TC 6 Z9 6 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2010 VL 226 IS 1 BP 68 EP 83 DI 10.1016/j.expneurol.2010.08.004 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 672XH UT WOS:000283619800011 PM 20696160 ER PT J AU Shurin, MR Gregory, M Morris, JC Malyguine, AM AF Shurin, Michael R. Gregory, Melissa Morris, John C. Malyguine, Anatoli M. TI Genetically modified dendritic cells in cancer immunotherapy: a better tomorrow? SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE cancer; clinical trial; dendritic cell; immunotherapy ID TUMOR-MESSENGER-RNA; REGULATORY T-CELLS; ANTITUMOR IMMUNE-RESPONSES; ACUTE MYELOID-LEUKEMIA; NATURAL-KILLER-CELLS; PHASE-I TRIAL; INTRATUMORAL INJECTION; MELANOMA PATIENTS; GENE-THERAPY; LUNG-CANCER AB Importance of the field: Dendritic cells (DC) are powerful antigen-presenting cells that induce and maintain primary cytotoxic T lymphocyte (CTL) responses directed against tumor antigens. Consequently, there has been much interest in their application as antitumor vaccines. Areas covered in this review: A large number of DC-based vaccine trials targeting a variety of cancers have been conducted; however, the rate of reported clinically significant responses remains low. Modification of DC to express tumor antigens or immunostimulatory molecules through the transfer of genes or mRNA transfection offers a logical alternative with potential advantages over peptide- or protein antigen-loaded DC. In this article, we review the current results and future prospects for genetically modified DC vaccines for the treatment of cancer. What the reader will gain: Genetically-modified dendritic cell-based vaccines represent a powerful tool for cancer therapy. Numerous preclinical and clinical studies have demonstrated the potential of dendritic cell vaccines alone or in combination with other therapeutic modalities. Take home message: Genetically modified DC-based anti-cancer vaccination holds promise, perhaps being best employed in the adjuvant setting with minimal residual disease after primary therapy, or in combination with other antitumor or immune-enhancing therapies. C1 [Gregory, Melissa; Malyguine, Anatoli M.] NCI, Appl & Dev Res Support Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Shurin, Michael R.] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. [Shurin, Michael R.] Univ Pittsburgh, Dept Immunol, Med Ctr, Pittsburgh, PA USA. [Morris, John C.] NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. RP Malyguine, AM (reprint author), NCI, Appl & Dev Res Support Program, SAIC Frederick Inc, Bldg 560 Room 12-79, Frederick, MD 21702 USA. EM malyguinea@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 103 TC 13 Z9 16 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD NOV PY 2010 VL 10 IS 11 BP 1539 EP 1553 DI 10.1517/14712598.2010.526105 PG 15 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 666QO UT WOS:000283132400004 PM 20955111 ER PT J AU Zhao, BZ He, YY AF Zhao, Baozhong He, Yu-Ying TI Recent advances in the prevention and treatment of skin cancer using photodynamic therapy SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE 5 aminolevulinic acid; ALA; MAL; methyl 5 aminolevulinate; PDT; photodynamic therapy; photosensitizers; skin cancer; topical PDT ID BASAL-CELL CARCINOMA; TOPICAL METHYL AMINOLEVULINATE; INDUCED PORPHYRIN FLUORESCENCE; ORGAN-TRANSPLANT RECIPIENTS; MULTIPLE ACTINIC KERATOSES; 5-AMINOLEVULINIC ACID; BOWENS-DISEASE; IN-VIVO; RANDOMIZED-TRIAL; CLINICAL-TRIAL AB Photodynamic therapy (PDT) is a noninvasive procedure that involves a photosensitizing drug and its subsequent activation by light to produce reactive oxygen species that specifically destroy target cells Recently PDT has been widely used in treating non-melanoma skin malignancies the most common cancer in the USA, with superior cosmetic outcomes compared with conventional therapies The topical photosensitizers commonly used are 5-aminolevulinic acid (ALA) and its esterified derivative methyl 5-aminolevulinate which are precursors of the endogenous photosensitizer protoporphyrin IX After treatment with ALA or methyl 5-aminolevulinate protoporphyrin IX preferentially accumulates in the lesion area of various skin diseases which allows not only PDT treatment but also fluorescence diagnosis with ALA-induced porphyrins Susceptible lesions include various forms of non-melanoma skin cancer such as actinic keratosis basal cell carcinoma and squamous cell carcinoma The most recent and promising developments in PDT include the discovery of new photosensitizers the exploitation of new drug delivery systems and the combination of other modalities which will all contribute to increasing PDT therapeutic efficacy and improving outcome This article summarizes the main principles of PDT and its current clinical use in the management of non-melanoma skin cancers as well as recent developments and possible future research directions C1 [He, Yu-Ying] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. [Zhao, Baozhong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP He, YY (reprint author), Univ Chicago, Dept Med, Dermatol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. RI Zhao, Baozhong/B-5865-2011 FU American Skin Association the University of Chicago Cancer Research Center [P30 CA014599]; NIH National Institute of Environmental Health Sciences FX Work in the authors laboratories was supported by the American Skin Association the University of Chicago Cancer Research Center (P30 CA014599) and the Intramural Research Program of the NIH National Institute of Environmental Health Sciences 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 This includes employment consultancies honoraria stock ownership or options expert testimony grants or patents received or pending or royalties NR 126 TC 56 Z9 61 U1 1 U2 16 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 EI 1744-8328 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD NOV PY 2010 VL 10 IS 11 BP 1797 EP 1809 DI 10.1586/ERA.10.154 PG 13 WC Oncology SC Oncology GA 683SQ UT WOS:000284495900017 PM 21080805 ER PT J AU Obican, SG Finnell, RH Mills, JL Shaw, GM Scialli, AR AF Obican, Sarah G. Finnell, Richard H. Mills, James L. Shaw, Gary M. Scialli, Anthony R. TI Folic acid in early pregnancy: a public health success story SO FASEB JOURNAL LA English DT Article DE folate; neural tube defects; congenital malformations; epidemiology; teratology ID NEURAL-TUBE DEFECTS; PERICONCEPTIONAL VITAMIN SUPPLEMENTATION; METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR; METHIONINE SYNTHASE REDUCTASE; CONOTRUNCAL HEART-DEFECTS; EMBRYONIC-DEVELOPMENT; AMNIOTIC-FLUID; BIRTH-DEFECTS; KNOCKOUT MICE; COLORECTAL ADENOMAS AB Folate is a water-soluble B vitamin that must be obtained in the diet or through supplementation. For >50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U. S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.-Obic. an, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. Folic acid in early pregnancy: a public health success story. FASEB J. 24, 4167-4174 (2010). www.fasebj.org C1 [Scialli, Anthony R.] Tetra Tech Sci, Arlington, VA 22201 USA. [Obican, Sarah G.; Scialli, Anthony R.] George Washington Univ, Sch Med, Dept Obstet & Gynecol, Washington, DC USA. [Finnell, Richard H.] Univ Texas Austin, Dept Nutr, Austin, TX 78712 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Shaw, Gary M.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. RP Scialli, AR (reprint author), Tetra Tech Sci, 2200 Wilson Blvd,Ste 400, Arlington, VA 22201 USA. EM ascialli@sciences.com FU National Institutes of Health (NIH), National Institute of Child Health and Human Development; NIH [DE016315, NS050249] FX This work was supported in part by the Intramural Research Program, National Institutes of Health (NIH), National Institute of Child Health and Human Development, and in part by funds from NIH grants DE016315 and NS050249. NR 83 TC 38 Z9 42 U1 0 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2010 VL 24 IS 11 BP 4167 EP 4174 DI 10.1096/fj.10-165084 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 675UA UT WOS:000283861100004 PM 20631328 ER PT J AU Wexler-Cohen, Y Ashkenazi, A Viard, M Blumenthal, R Shai, Y AF Wexler-Cohen, Yael Ashkenazi, Avraham Viard, Mathias Blumenthal, Robert Shai, Yechiel TI Virus-cell and cell-cell fusion mediated by the HIV-1 envelope glycoprotein is inhibited by short gp41 N-terminal membrane-anchored peptides lacking the critical pocket domain SO FASEB JOURNAL LA English DT Article DE membrane fusion; HIV-1 entry inhibitor; peptide-membrane interaction; viral envelope protein ID TRIMERIC COILED-COIL; IMMUNODEFICIENCY-VIRUS; POTENT INHIBITORS; CORE STRUCTURE; ENTRY; TYPE-1; SURFACE; DESIGN; REGION; STABILIZATION AB The interactions between the N- and C-terminal heptad repeat (NHR and CHR) regions of the human immunodeficiency virus (HIV-1) glycoprotein gp41 create a structure comprising a 6-helix bundle (SHB). A sequence in the SHB named the "pocket" is crucial for the SHB's stability and for the fusion inhibitory activity of 36-residue NHR peptide N36. We report that a short 27-residue peptide, N27, which lacks the pocket sequence, exhibits potent inhibitory activity in both cell-cell and virus-cell fusion assays when fatty acids were conjugated to its N but not C terminus. Furthermore, mutations in the positions that prevent interaction with the CHR but not with the NHR resulted in a dramatic reduction in N27 activity. These data support a mechanism in which N27 mainly targets the CHR rather than the internal NHR coiled-coil, reveal the N-terminal edge of the endogenous core structure in situ and hence complement our recent findings of the C-terminal edge of the core, and provide a new approach for designing short inhibitors from the NHR region of other lentiviruses due to similarities in their envelope proteins.-Wexler-Cohen, Y., Ashkenazi, A., Viard, M., Blumenthal, R., Shai, Y. Virus-cell and cell-cell fusion mediated by the HIV-1 envelope glycoprotein is inhibited by short gp41 N-terminal membrane-anchored peptides lacking the critical pocket domain. FASEB J. 24, 4196-4202 (2010). www.fasebj.org C1 [Wexler-Cohen, Yael; Ashkenazi, Avraham; Shai, Yechiel] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Viard, Mathias; Blumenthal, Robert] NCI, Nanobiol Program, Ctr Canc Res, Frederick, MD 21701 USA. [Viard, Mathias] SAIC Frederick Inc, Basic Res Program, NCI Frederick, Frederick, MD USA. RP Shai, Y (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. EM yechiel.shai@weizmann.ac.il FU Israel Science Foundation; National Cancer Institute, NIH [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Batya Zarmi for her valuable help with peptide purification, and Dr. Ayala Sharp and Eitan Ariel and the staff of the flow cytometry unit at the Weizmann Institute of Science for their valuable technical assistance and advice. This study was supported by the Israel Science Foundation and has been funded in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 19 Z9 20 U1 1 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2010 VL 24 IS 11 BP 4196 EP 4202 DI 10.1096/fj.09-151704 PG 7 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 675UA UT WOS:000283861100008 PM 20605950 ER PT J AU Gallazzini, M Yu, MJ Gunaratne, R Burg, MB Ferraris, JD AF Gallazzini, Morgan Yu, Ming-Jiun Gunaratne, Ruwan Burg, Maurice B. Ferraris, Joan D. TI c-Abl mediates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP SO FASEB JOURNAL LA English DT Article DE hypertonicity; kinase; NFAT5; signaling ID ENHANCER-BINDING PROTEIN; OSMOTIC RESPONSE ELEMENT; DAMAGE-INDUCIBLE KINASE; TYROSINE KINASE; DNA-DAMAGE; NUCLEAR-LOCALIZATION; PHOSPHOLIPASE C-GAMMA-1; IONIZING-RADIATION; ATM; CONTRIBUTES AB The transcription factor TonEBP/OREBP promotes cell survival during osmotic stress. High NaCl-induced phosphorylation of TonEBP/OREBP at tyrosine-143 was known to be an important factor in increasing its activity in cell culture. We now find that TonEBP/OREBP also is phosphorylated at tyrosine-143 in rat renal inner medulla, dependent on the interstitial osmolality. c-Abl seemed likely to be the kinase that phosphorylates TonEBP/OREBP because Y143 is in a consensus c-Abl phosphorylation site. We now confirm that, as follows. High NaCl increases c-Abl activity. Specific inhibition of c-Abl by imatinib, siRNA, or c-Abl kinase dead drastically reduces high NaCl-induced TonEBP/OREBP activity by reducing its nuclear location and transactivating activity. c-Abl associates with TonEBP/OREBP (coimmunoprecipitation) and phosphorylates TonEBP/OREBP-Y143 both in cell and in vitro. High NaCl-induced activation of ataxia telangiectasia mutated, previously known to contribute to activation of TonEBP/OREBP, depends on c-Abl activity. Thus, c-Abl is the kinase responsible for high NaCl-induced phosphorylation of TonEBP/OREBPY143, which contributes to its increased activity.-Gallazzini, M., Yu, M.-J., Gunaratne, R., Burg, M. B., Ferraris, J. D. c-Abl mediates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP. FASEB J. 24, 4325-4335 (2010). www.fasebj.org C1 [Gallazzini, Morgan; Yu, Ming-Jiun; Gunaratne, Ruwan; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Gallazzini, M (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gallazzinim@gmail.com RI Gallazzini, Morgan/E-5465-2011; OI YU, MING-JIUN/0000-0003-0393-4696 FU NHLBI FX The authors thank Dr. Martin Playford for suggestions on experimental design and Dr. Chris Combs and Dr. Daniela Malide of the National Heart, Lung, and Blood Institute (NHLBI) Light Microscopy Core Facility for help with microscopy. This research was supported by the Intramural Research Program of NHLBI. NR 31 TC 14 Z9 14 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2010 VL 24 IS 11 BP 4325 EP 4335 DI 10.1096/fj.10-157362 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 675UA UT WOS:000283861100020 PM 20585028 ER PT J AU Rudrabhatla, P Grant, P Jaffe, H Strong, MJ Pant, HC AF Rudrabhatla, Parvathi Grant, Philip Jaffe, Howard Strong, Michael J. Pant, Harish C. TI Quantitative phosphoproteomic analysis of neuronal intermediate filament proteins (NF-M/H) in Alzheimer's disease by iTRAQ SO FASEB JOURNAL LA English DT Article DE neurofilament-M/H; phosphorylation sites; iTRAQ; MS/MS mass spectrometry; TiO(2); proline-directed kinases ID PAIRED HELICAL FILAMENTS; WEIGHT NEUROFILAMENT PROTEIN; AMYOTROPHIC LATERAL SCLEROSIS; PHOSPHORYLATION SITES; CEREBROSPINAL-FLUID; AXONAL-TRANSPORT; MOTOR-NEURONS; ANTIBODIES; SUBUNIT; IDENTIFICATION AB Aberrant hyperphosphorylation of neuronal cytoskeletal proteins is one of the major pathological hallmarks of neurodegenerative disorders such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Human NFM/H display a large number of multiple KSP repeats in the carboxy-terminal tail domain, which are phosphorylation sites of proline-directed serine/threonine (pSer/Thr-Pro, KS/T-P) kinases. The phosphorylation sites of NF-M/H have not been characterized in AD brain. Here, we use quantitative phosphoproteomic methodology, isobaric tag for relative and absolute quantitation (iTRAQ), for the characterization of NFM/H phosphorylation sites in AD brain. We identified 13 hyperphosphorylated sites of NF-M; 9 Lys-Ser-Pro (KSP) sites; 2 variant motifs, Glu-Ser-Pro (ESP) Ser-736 and Leu-Ser-Pro (LSP) Ser-837; and 2 non-S/T-P motifs, Ser-783 and Ser-788. All the Ser/Thr residues are phosphorylated at significantly greater abundance in AD brain compared with control brain. Ten hyperphosphorylated KSP sites have been identified on the C-terminal tail domain of NF-H, with greater abundance of phosphorylation in AD brain compared with control brain. Our data provide the direct evidence that NFM/H are hyperphosphorylated in AD compared with control brain and suggest the role of both proline-directed and non-proline-directed protein kinases in AD. This study represents the first comprehensive iTRAQ analyses and quantification of phosphorylation sites of human NF-M and NF-H from AD brain and suggests that aberrant hyperphosphorylation of neuronal intermediate filament proteins is involved in AD.-Rudrabhatla, P., Grant, P., Jaffe, H., Strong, M. J., Pant, H. C. Quantitative phosphoproteomic analysis of neuronal intermediate filament proteins (NF-M/H) in Alzheimer's disease by iTRAQ. FASEB J. 24, 4396-4407 (2010). www.fasebj.org C1 [Pant, Harish C.] NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Jaffe, Howard] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. [Strong, Michael J.] Univ Western Ontario, Mol Brain Res Grp, Robarts Res Inst, London, ON, Canada. [Strong, Michael J.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. RP Pant, HC (reprint author), NINDS, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bldg 49,Rm 2A28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov RI Strong, Michael/H-9689-2012 FU National Institutes of Health of the National Institute of Neurological Diseases and Stroke FX This work was supported by the National Institutes of Health Intramural research programs of the National Institute of Neurological Diseases and Stroke. The authors thank the Harvard Brain Resource Center (Boston, MA, USA) and the National Institute of Child Health and Human Development Brain and Tissue Bank (Bethesda, MD, USA) for providing human brain tissue. NR 46 TC 39 Z9 41 U1 1 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2010 VL 24 IS 11 BP 4396 EP 4407 DI 10.1096/fj.10-157859 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 675UA UT WOS:000283861100026 PM 20624930 ER PT J AU Nagy, NT Sakamoto, T Takacs, B Gyimesi, M Hazai, E Bikadi, Z Sellers, JR Kovacs, M AF Nagy, Nikolett T. Sakamoto, Takeshi Takacs, Balazs Gyimesi, Mate Hazai, Eszter Bikadi, Zsolt Sellers, James R. Kovacs, Mihaly TI Functional adaptation of the switch-2 nucleotide sensor enables rapid processive translocation by myosin-5 SO FASEB JOURNAL LA English DT Article DE actomyosin; kinetics; nucleotide exchange; single molecule; sliding speed ID HAND-OVER-HAND; MUSCLE-CONTRACTION; KINETIC MECHANISM; STEP-SIZE; MOLECULAR-MECHANISM; TRYPTOPHAN RESIDUE; PHOSPHATE RELEASE; FLUORESCENT-PROBE; MOTOR-ACTIVITY; NECK LENGTH AB Active site loops that are conserved across superfamilies of myosins, kinesins, and G proteins play key roles in allosteric coupling of NTP hydrolysis to interaction with track filaments or effector proteins. In this study, we investigated how the class-specific natural variation in the switch-2 active site loop contributes to the motor function of the intracellular transporter myosin-5. We used single-molecule, rapid kinetic and spectroscopic experiments and semiempirical quantum chemical simulations to show that the class-specific switch-2 structure including a tyrosine (Y439) in myosin-5 enables rapid processive translocation along actin filaments by facilitating Mg2(+)-dependent ADP release. Using wild-type control and Y439 point mutant myosin-5 proteins, we demonstrate that the translocation speed precisely correlates with the kinetics of nucleotide exchange. Switch-2 variants can thus be used to fine-tune translocation speed while maintaining high processivity. The class-specific variation of switch-2 in various NTPase superfamilies indicates its general role in the kinetic tuning of Mg2(+)-dependent nucleotide exchange.-Nagy, N.T., Sakamoto, T., Takacs, B., Gyimesi, M., Hazai, E., Bikadi, Z., Sellers, J.R., Kovacs, M. Functional adaptation of the switch-2 nucleotide sensor enables rapid processive translocation by myosin-5. FASEB J. 24, 4480-4490 (2010). www.fasebj.org C1 [Nagy, Nikolett T.; Takacs, Balazs; Gyimesi, Mate; Kovacs, Mihaly] Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. [Sakamoto, Takeshi; Sellers, James R.] NHLBI, Lab Mol Physiol, Bethesda, MD 20892 USA. [Hazai, Eszter; Bikadi, Zsolt] VirtuaDrug Ltd, Budapest, Hungary. RP Kovacs, M (reprint author), Eotvos Lorand Univ, Dept Biochem, Pazmany P Stny 1-C, H-1117 Budapest, Hungary. EM kovacsm@elte.hu RI Kovacs, Mihaly/A-6841-2011 FU Fogarty International Center; National Heart, Lung, and Blood Institute [1 R01-TW007241]; Hungarian Scientific Research Fund (OTKA) [K71915, NNF78783]; European Molecular Biology Organization-Howard Hughes Medical Institute FX This work was supported by the Fogarty International Center and the National Heart, Lung, and Blood Institute (grant 1 R01-TW007241), Hungarian Scientific Research Fund (OTKA) grants K71915 and NNF78783, and a European Molecular Biology Organization-Howard Hughes Medical Institute startup grant to M.K.M.K. is a Bolyai Fellow of the Hungarian Academy of Sciences. The authors declare that they have no competing financial interests. NR 52 TC 8 Z9 8 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD NOV PY 2010 VL 24 IS 11 BP 4480 EP 4490 DI 10.1096/fj.10-163998 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 675UA UT WOS:000283861100033 PM 20631329 ER PT J AU Michalakis, KG Segars, JH AF Michalakis, Konstantinos G. Segars, James H. TI The role of adiponectin in reproduction: from polycystic ovary syndrome to assisted reproduction SO FERTILITY AND STERILITY LA English DT Article DE Adiponectin; hypothalamus; pituitary; gonads; reproduction; polycystic ovary syndrome; PCOS; pregnancy; embryo development; assisted reproduction ID ACTIVATED PROTEIN-KINASE; CHORIONIC-GONADOTROPIN TREATMENT; GESTATIONAL DIABETES-MELLITUS; COMPLEMENT-RELATED PROTEIN; ADIPOSE-SPECIFIC PROTEIN; IN-VITRO FERTILIZATION; MOLECULAR-WEIGHT FORM; FATTY-ACID OXIDATION; INSULIN-RESISTANCE; SERUM ADIPONECTIN AB Objective: To summarize the effects of the adipokine adiponectin on the reproductive endocrine system, from the hypothalamic-pituitary axis to the gonads and target tissues of the reproductive system. Design: A Medline computer search was performed to identify relevant articles. Setting: Research institution. Intervention(s): None. Result(s): Adiponectin is a hormone secreted by adipose tissue that acts to reduce insulin resistance and atherogenic damage, but it also exerts actions in other tissues. Adiponectin mediates its actions in the periphery mainly via two receptors, AdipoR1 and AdipoR2. Adiponectin receptors are present in many reproductive tissues, including the central nervous system, ovaries, oviduct, endometrium, and testes. Adiponectin influences gonadotropin release, normal pregnancy, and assisted reproduction outcomes. Conclusion(s): Adiponectin, a beneficial adipokine, represents a major link between obesity and reproduction. Higher levels of adiponectin are associated with improved menstrual function and better outcomes in assisted reproductive cycles. (Fertil Steril (R) 2010;94:1949-57. (C) 2010 by American Society for Reproductive Medicine.) C1 [Michalakis, Konstantinos G.; Segars, James H.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), NICHHD, NIH, 10 Ctr Dr,Bldg 10,CRC,1E-3140, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported in part by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 118 TC 46 Z9 51 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2010 VL 94 IS 6 BP 1949 EP 1957 DI 10.1016/j.fertnstert.2010.05.010 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 670QC UT WOS:000283441400005 PM 20561616 ER PT J AU Beydoun, HA Sicignano, N Beydoun, MA Matson, DO Bocca, S Stadtmauer, L Oehninger, S AF Beydoun, Hind A. Sicignano, Nicholas Beydoun, May A. Matson, David O. Bocca, Silvina Stadtmauer, Laurel Oehninger, Sergio TI A cross-sectional evaluation of the first cohort of young adults conceived by in vitro fertilization in the United States SO FERTILITY AND STERILITY LA English DT Article DE In vitro fertilization; cross-sectional; chronic disease; behavior ID HOSPITAL-CARE UTILIZATION; CHILDREN BORN; ASSISTED REPRODUCTION; INFANTS BORN; IVF; IVF/ICSI; EMBRYOS; WELL AB Objective: To assess the quality of life and susceptibility for chronic disease development of the oldest generation of young adults conceived by IVF in the U.S. Design: Cross-sectional. Setting: Single tertiary clinic. Patient(s): Young adults conceived by standard IVF between 1981 and 1990. Intervention(s): Self-administered questionnaire. Main Outcome Measure(s): Indicators of physical, psychologic, and behavioral health. Result(s): A total of 173 (31%) of 560 eligible young adults completed the questionnaire. Mean age was 21.2 years (range 18-26 years) and male-to-female ratio was 3:4. A limited number were conceived through gamete donation but none through oocyte/embryo micromanipulation. Prevalence rates of overweight and obesity were 35% and 10%, respectively. More than 65% were ever diagnosed with a chronic condition; most diagnoses were psychiatric, ocular, respiratory, and cardiometabolic in nature. Almost 40% of respondents were lifetime smokers, 62% reported binge drinking in the previous year, and >90% were physically active in the preceding month. Survey participants were mostly similar to a subsample of the 1999-2004 National Health and Nutrition Examination Survey on selected health indicators. Conclusion(s): Young adults conceived by IVF appear to be healthy and well adjusted, although the preponderance of psychologic health problems requires further investigation. (Fertil Steril (R) 2010;94:2043-9. (C) 2010 by American Society for Reproductive Medicine.) C1 [Bocca, Silvina; Stadtmauer, Laurel; Oehninger, Sergio] Eastern Virginia Med Sch, Jones Inst Reprod Med, Norfolk, VA 23507 USA. [Beydoun, Hind A.; Sicignano, Nicholas; Matson, David O.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23507 USA. [Beydoun, May A.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Oehninger, S (reprint author), Eastern Virginia Med Sch, Jones Inst Reprod Med, 601 Colley Ave,4th Floor, Norfolk, VA 23507 USA. EM oehninsc@evms.edu FU National Institute on Aging, National Institutes of Health, Baltimore, Maryland FX Supported in part by the intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. NR 25 TC 22 Z9 24 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2010 VL 94 IS 6 BP 2043 EP 2049 DI 10.1016/j.fertnstert.2009.12.023 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 670QC UT WOS:000283441400020 PM 20159654 ER PT J AU Norian, JM Levens, ED Richter, KS Widra, EA Levy, MJ AF Norian, John M. Levens, Eric D. Richter, Kevin S. Widra, Eric A. Levy, Michael J. TI Conversion from assisted reproductive technology to intrauterine insemination in low responders: Is it advantageous? SO FERTILITY AND STERILITY LA English DT Article DE ART; oocyte retrieval; intrauterine insemination; poor response ID FERTILIZATION; FOLLICLES; CYCLES; LESS AB Objective: To examine cycle outcomes among patients demonstrating an attenuated ovarian response that proceeded to oocyte retrieval to those converted to intrauterine insemination (IUI). Design: Retrospective cohort study. Setting: Large private fertility center. Patient(s): First planned autologous assisted reproductive technology (ART) cycles among women demonstrating a poor ovarian response to hyperstimulation (<= 4 follicles >= 14 mm, peak E-2 <1,000 IU/L at hCG administration). Intervention(s): Oocyte retrieval or IUI conversion. Main Outcome Measure(s): Live birth and clinical pregnancy. Result(s): A total of 269 IUI conversions and 167 oocyte retrievals followed a poor ovarian response to gonadotropins among first planned ART cycles. Number of follicles >= 14 mm (2.3 vs. 3.5) and peak E-2 levels (555 vs. 743 pg/mL) were lower for IUI conversions compared with those proceeding to ART. Peak E-2 was similar between groups after adjusting for follicle number (IUI: 611 pg/mL; ART: 652 pg/mL). Stimulation response was similar between treatment groups with equivalent follicle numbers. Undergoing oocyte retrieval was associated with significantly improved pregnancy (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.8-7.4) and live birth outcome (OR 3.5, 95% CI 1.7-8.0) after adjusting for age and follicle number. Conclusion(s): Among women demonstrating a poor ovarian response to gonadotropins, proceeding with planned ART resulted in significantly higher pregnancy rates than converting these cycles to IUI. (Fertil Steril (R) 2010; 94: 2073-7. (C) 2010 by American Society for Reproductive Medicine.) C1 [Norian, John M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Norian, John M.; Levens, Eric D.; Richter, Kevin S.; Widra, Eric A.; Levy, Michael J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Norian, JM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM norianjo@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported in part by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Health and Human Services. NR 16 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2010 VL 94 IS 6 BP 2073 EP 2077 DI 10.1016/j.fertnstert.2009.12.056 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 670QC UT WOS:000283441400026 PM 20171626 ER PT J AU Laughlin, SK Herring, AH Savitz, DA Olshan, AF Fielding, JR Hartmann, KE Baird, DD AF Laughlin, Shannon K. Herring, Amy H. Savitz, David A. Olshan, Andrew F. Fielding, Julia R. Hartmann, Katherine E. Baird, Donna D. TI Pregnancy-related fibroid reduction SO FERTILITY AND STERILITY LA English DT Editorial Material DE Leiomyoma; postpartum; pregnancy; ultrasound; uterine remodeling ID UTERINE LEIOMYOMATA; REPRODUCTIVE FACTORS; WHITE WOMEN; GROWTH; RISK; SIZE AB We tested the hypothesis that the protective effect of parity on fibroids is due to direct pregnancy-related effects by following women from early pregnancy to postpartum period with ultrasound. Of 171 women with one initial fibroid, 36% had no identifiable fibroid at the time of postpartum ultrasound, and 79% of the remaining fibroids decreased in size. (Fertil Steril (R) 2010;94:2421-3. (C)2010 by American Society for Reproductive Medicine.) C1 [Laughlin, Shannon K.; Baird, Donna D.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Laughlin, Shannon K.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Savitz, David A.; Olshan, Andrew F.] Mt Sinai Sch Med, Dis Prevent & Publ Hlth Inst, New York, NY USA. [Fielding, Julia R.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Hartmann, Katherine E.] Vanderbilt Univ, Inst Med & Publ Hlth, Nashville, TN USA. [Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA. RP Laughlin, SK (reprint author), Mayo Clin, Dept Obstet & Gynecol, 200 1st St SW, Rochester, MN 55905 USA. EM laughlin.shannon@mayo.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS; NICHD NIH HHS [HD049675, R01 HD043883, R01 HD043883-04, R01 HD049675, R24 HD050924]; NIEHS NIH HHS [P30 ES010126, P30ES10126] NR 19 TC 25 Z9 25 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2010 VL 94 IS 6 BP 2421 EP 2423 DI 10.1016/j.fertnstert.2010.03.035 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 670QC UT WOS:000283441400112 PM 20451187 ER PT J AU Ilinskaya, A Heidecker, G Jones, K AF Ilinskaya, Anna Heidecker, Gisela Jones, Kathryn TI Interaction between the HTLV-I envelope and cellular proteins: impact on virus infection and restriction SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID MURINE LEUKEMIA-VIRUS; RECEPTOR-BINDING DOMAIN; HEPARAN-SULFATE PROTEOGLYCANS; PFIZER MONKEY VIRUS; UBIQUITOUS GLUCOSE-TRANSPORTER; TROPICAL SPASTIC PARAPARESIS; HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-ENDOTHELIAL CELLS; CD4(+) T-CELLS; TYPE-1 ENVELOPE AB The first human retrovirus, human T-lymphotropic virus I (HTLV-I), was discovered 30 years ago Despite intensive study, the cell surface molecules involved in virus entry have only been identified over the past few years Three molecules form the receptor complex for HTLV-I glucose transporter I, neuropilin I and heparan sulfate proteoglycans Another molecule on the surface of dendritic cells, DC-SIGN, may play a role in dendntic cell-mediated infection of cells In addition to the cell surface molecules used for entry, the HTLV-I envelope interacts with cellular proteins, enabling the virus to traffic by exploiting cellular delivery pathways To facilitate both these steps, HTLV-I encodes motifs that mimic cellular binding partners for the trafficking system and ligands for the receptors Here we review the interactions between the HTLV-I envelope and cellular proteins C1 [Ilinskaya, Anna; Jones, Kathryn] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Ilinskaya, A (reprint author), NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. FU National Institutes of Health National Cancer Institute Center for Cancer Research; National Cancer Institute National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research This project has been funded in whole or in part with federal funds from the National Cancer Institute National Institutes of Health under contract HHSN261200800001E 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 163 TC 3 Z9 3 U1 1 U2 4 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 EI 1756-8927 J9 FUTURE MED CHEM JI Future Med. Chem. PD NOV PY 2010 VL 2 IS 11 BP 1651 EP 1668 DI 10.4155/FMC.10.255 PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 686XP UT WOS:000284733100012 PM 21428837 ER PT J AU Rahbari, R Zhang, LS Kebebew, E AF Rahbari, Reza Zhang, Lisa Kebebew, Electron TI Thyroid cancer gender disparity SO FUTURE ONCOLOGY LA English DT Review DE disparity; gender; genetics; molecular basis; papillary thyroid cancer; risk factors; thyroid cancer ID BRAF V600E MUTATION; POOLED ANALYSIS; REPRODUCTIVE FACTORS; RET/PTC ACTIVATION; RISK-FACTORS; ESTROGEN-RECEPTOR; POLISH POPULATION; PAPILLARY; CARCINOMA; RADIATION AB Cancer gender disparity in incidence, disease aggressiveness and prognosis has been observed in a variety of cancers. Thyroid cancer is one of the fastest growing cancer diagnoses worldwide. It is 2.9-times more common in women than men. The less aggressive histologic subtypes of thyroid cancer are more common in women, whereas the more aggressive histologic subtypes have similar gender distribution. The gender disparity in incidence, aggressiveness and prognosis is well established for thyroid cancer but the cause of the disparity is poorly understood. The aim of this article is to evaluate the current evidence on the cause of thyroid cancer gender disparity. Dietary and environmental factors do not appear to have a significant role in thyroid cancer gender disparity. Common somatic mutations in BRAF, rearranged in transformation/papillary thyroid carcinomas (RET/PTC) and neurotrophin receptor-tyrosine kinase (NTRK) also do not account for the gender disparity in thyroid cancer. While reproductive factors would seem a logical hypothesis to account for the gender disparity, there appears to be no conclusive effect on the risk of developing thyroid cancer. Recent studies on estrogen receptor status in thyroid cancer show a difference in the receptor subtypes expressed based on the histology of thyroid cancer. Moreover, the response to estrogen is dependent on the specific estrogen receptor expressed in thyroid cancer cells. However, what determines the tumor-specific sex hormone receptor expression is unclear. No established molecular factors appear to explain gender differences in thyroid cancer. Therefore, the application of high-throughput genomic and proteomic approaches to the study of thyroid cancer gender disparity could be helpful for better understanding the molecular basis for gender differences in thyroid and other cancers. C1 [Kebebew, Electron] CRC, Endocrine Oncol Sect, Surg Branch, NCI, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), CRC, Endocrine Oncol Sect, Surg Branch, NCI, Room 4-5952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU NIH [ZIA BC 011275] FX Electron Kebebew received funding from the NIH (grant ZIA BC 011275). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 60 TC 63 Z9 71 U1 2 U2 14 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD NOV PY 2010 VL 6 IS 11 BP 1771 EP 1779 DI 10.2217/FON.10.127 PG 9 WC Oncology SC Oncology GA 849BH UT WOS:000297099300011 PM 21142662 ER PT J AU Jatoi, I Anderson, WF AF Jatoi, Ismail Anderson, William F. TI Qualitative age interactions in breast cancer studies: a mini-review SO FUTURE ONCOLOGY LA English DT Review DE age; breast cancer; early onset; interaction; late onset; qualitative ID REPRODUCTIVE FACTORS; RANDOMIZED-TRIALS; UNITED-STATES; HAZARD RATES; RISK-FACTORS; MORTALITY; WOMEN; WHITE; DIAGNOSIS; HETEROGENEITY AB A qualitative age interaction is defined as the reversal of relative risks or rates according to age at onset, and is often evident in studies that examine the etiology, prognosis and treatment of breast cancer. For example, incidence rates (or risks) are higher for aggressive when compared with indolent breast cancers prior to age 40-50 years, after which rates are higher for indolent tumors. Nulliparity and obesity decrease breast cancer risk in younger women, but increase risk in older women. Curves depicting the annual hazard of breast cancer death are shaped differently for the early- and late-onset tumors. Clinical trials for mammography screening, fenretinide chemoprevention and neo-adjuvant chemotherapy show opposite effects in younger and older women. Finally, high-risk/early onset breast cancers are more common among African-American women than Caucasian women, and this may partly account for the racial survival disparities. Taken together, these examples imply that aging may modify breast cancer risk, prognosis and treatment. These qualitative age interactions (or effect modifications) are important because they suggest that high-risk/early-onset and low-risk/late-onset breast cancers are different diseases, derived from different carcinogenic pathways. When age interactions are suspected, breast cancer studies should be stratified by early versus late age of onset or analyzed age specifically. C1 [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, Div Surg Oncol, San Antonio, TX 78229 USA. [Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. RP Jatoi, I (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, Div Surg Oncol, San Antonio, TX 78229 USA. EM jatoi@uthscsa.edu FU NIH, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 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 48 TC 11 Z9 11 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD NOV PY 2010 VL 6 IS 11 BP 1781 EP 1788 DI 10.2217/FON.10.139 PG 8 WC Oncology SC Oncology GA 849BH UT WOS:000297099300012 PM 21142663 ER PT J AU Cotton, PB Durkalski, V Orrell, KB Brawman-Mintzer, O Drossman, DA Wilcox, CM Mauldin, PD Elta, GH Tarnasky, PR Fogel, EL Jagganath, SB Kozarek, RA Freeman, ML Romagnuolo, J Robuck, PR AF Cotton, Peter B. Durkalski, Valerie Orrell, Kyle B. Brawman-Mintzer, Olga Drossman, Douglas A. Wilcox, C. Mel Mauldin, Patrick D. Elta, Grace H. Tarnasky, Paul R. Fogel, Evan L. Jagganath, Sanjay B. Kozarek, Richard A. Freeman, Martin L. Romagnuolo, Joseph Robuck, Patricia R. TI Challenges in planning and initiating a randomized clinical study of sphincter of Oddi dysfunction SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID FINDINGS TYPE-I; ENDOSCOPIC SPHINCTEROTOMY; PAIN; PRESENTATIONS; DISORDERS; MANOMETRY AB Background: Sphincter of Oddi dysfunction (SOD) is a controversial topic, especially in patients with no objective findings on laboratory or imaging studies (SOD type III). The value of ERCP manometry with sphincterotomy is unproven and carries significant risks. Objective: To describe the process of planning and initiating a randomized sham-controlled study to establish whether patients with SOD respond to sphincter ablation, and whether the outcomes are predicted by the pain patterns, presence or absence of other functional GI or psychosocial problems, or the results of manometry. Design: Planning a trial to establish which patients with "suspected SOD" (if any) respond to endoscopic sphincter ablation. Setting: Meetings and correspondence by a planning group of gastroenterologists and clinical research specialists hosted at the Medical University of South Carolina. Patients: Clarifying subject characteristics and inclusion and exclusion criteria. Interventions: Defining the questionnaires, therapies, randomizations, and numbers of subjects required by outcome measures. Defining the metrics of success and failure. Results: The planning resulted in funding for the proposed study as a cooperative agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Limitations: Lack of data required several consensus decisions in designing the protocol. Conclusion: The planning process was challenging, and some changes were needed after initiation.* (Clinical trial registration number: NCT00688662.) (Gastrointest Endosc 2010;72:986-91.) C1 [Cotton, Peter B.; Orrell, Kyle B.; Romagnuolo, Joseph] Med Univ S Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Durkalski, Valerie] Med Univ S Carolina, Ctr Digest Dis, Div Biometry & Epidemiol, Dept Med, Charleston, SC 29425 USA. [Brawman-Mintzer, Olga] Med Univ S Carolina, Anxiety Disorders Program, Charleston, SC 29425 USA. [Mauldin, Patrick D.] Med Univ S Carolina, Dept Clin Pharm & Outcome Studies, S Carolina Coll Pharm, Charleston, SC 29425 USA. [Drossman, Douglas A.] Univ N Carolina, Ctr Funct GI & Motil Disorders, Chapel Hill, NC USA. [Wilcox, C. Mel] Univ Alabama, Div Gastroenterol, Birmingham, AL 35294 USA. [Elta, Grace H.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Tarnasky, Paul R.] Methodist Dallas Med Ctr, Dallas, TX USA. [Fogel, Evan L.] Indiana Univ, Med Ctr, Div Gastroenterol & Hepatol, Indianapolis, IN USA. [Jagganath, Sanjay B.] Johns Hopkins Univ Hosp, Div Gastroenterol, Baltimore, MD 21287 USA. [Kozarek, Richard A.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Freeman, Martin L.] Univ Minnesota, Med Ctr, Div Gastroenterol, Minneapolis, MN 55455 USA. [Robuck, Patricia R.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA. RP Cotton, PB (reprint author), Med Univ S Carolina, Div Gastroenterol & Hepatol, 25 Courtenay Dr,ART 7100A,MSC 290, Charleston, SC 29425 USA. EM cottonp@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK074739] FX All authors disclosed no financial relationships relevant to this publication. Research support for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, grant U01DK074739. NR 27 TC 9 Z9 9 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD NOV PY 2010 VL 72 IS 5 BP 986 EP 991 DI 10.1016/j.gie.2010.08.022 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 678SU UT WOS:000284101500013 PM 21034899 ER PT J AU Gaedcke, J Grade, M Jung, K Camps, J Jo, P Emons, G Gehoff, A Sax, U Schirmer, M Becker, H Beissbarth, T Ried, T Ghadimi, BM AF Gaedcke, Jochen Grade, Marian Jung, Klaus Camps, Jordi Jo, Peter Emons, Georg Gehoff, Anastasia Sax, Ulrich Schirmer, Markus Becker, Heinz Beissbarth, Tim Ried, Thomas Ghadimi, B. Michael TI Mutated KRAS Results in Overexpression of DUSP4, a MAP-Kinase Phosphatase, and SMYD3, a Histone Methyltransferase, in Rectal Carcinomas SO GENES CHROMOSOMES & CANCER LA English DT Article ID ADVANCED COLORECTAL-CANCER; HUMAN BREAST-CANCER; GENE-EXPRESSION; TUMOR PROGRESSION; LARYNGEAL-CANCER; COLON-CANCER; CETUXIMAB; CELLS; MUTATIONS; DEREGULATION AB Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas. (C) 2010 Wiley-Liss, Inc. C1 [Gaedcke, Jochen; Grade, Marian; Jo, Peter; Emons, Georg; Becker, Heinz; Ghadimi, B. Michael] Univ Med, Dept Gen & Visceral Surg, Gottingen, Germany. [Jung, Klaus; Beissbarth, Tim] Univ Med, Dept Med Stat, Gottingen, Germany. [Camps, Jordi; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gehoff, Anastasia] Inst Pathol, Kassel, Germany. [Sax, Ulrich] Univ Med, Dept Med Informat, Gottingen, Germany. [Schirmer, Markus] Univ Med, Dept Clin Pharmacol, Gottingen, Germany. RP Ghadimi, BM (reprint author), Univ Med Ctr, Dept Gen & Visceral Surg, Robert Koch Str 40, D-37075 Gottingen, Germany. EM riedt@mail.nih.gov; mghadim@gwdg.de RI Beissbarth, Tim/B-3129-2013; OI Beissbarth, Tim/0000-0001-6509-2143; Sax, Ulrich/0000-0002-8188-3495 FU National Institutes of Health; National Cancer Institute; Deutsche Forschungsgemeinschaft [KFO 179] FX Supported by the National Institutes of Health; National Cancer Institute; Deutsche Forschungsgemeinschaft, Grant number: KFO 179. NR 46 TC 59 Z9 61 U1 2 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD NOV PY 2010 VL 49 IS 11 BP 1024 EP 1034 DI 10.1002/gcc.20811 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 654SG UT WOS:000282188000006 PM 20725992 ER PT J AU So, JH Hong, SK Kim, HT Jung, SH Lee, MS Choi, JH Bae, YK Kudoh, T Kim, JH Kim, CH AF So, Ju-Hoon Hong, Sung-Kook Kim, Hyun-Taek Jung, Seung-Hyun Lee, Mi-Sun Choi, Jung-Hwa Bae, Young-Ki Kudoh, Tetsuhiro Kim, Ji-Hun Kim, Cheol-Hee TI Gicerin/Cd146 is involved in zebrafish cardiovascular development and tumor angiogenesis SO GENES TO CELLS LA English DT Article ID ANTI-CD146 MONOCLONAL-ANTIBODY; CELL-ADHESION MOLECULES; HUMAN ENDOTHELIAL-CELLS; IMMUNOGLOBULIN SUPERFAMILY; INHIBITS ANGIOGENESIS; VASCULAR DEVELOPMENT; GENE-EXPRESSION; VEGF RECEPTORS; CD146; IDENTIFICATION AB Angiogenesis plays an important role in vertebrate development and tumor growth. In this process, gicerin, which is known as a kind of cell adhesion molecule, has recently been reported to play an important role but its in vivo function is still unclear in developing vasculature. To address this issue, we used gain-of-function and loss-of-function analyses of gicerin in zebrafish. In the gain of function experiments using enforced expression of various domains of gicerin constructs, extracellular domain induced angiogenic sprouting defects, most notably in the intersegmental vessels, whereas the cytoplasmic domain of gicerin did not affect angiogenic sprouting. Moreover, morpholino-mediated knockdown of gicerin in embryos resulted in angiogenic sprouting defects in intersegmental vessels. Mechanistically, the angiogenic function of gicerin was found to be genetically linked to VEGF signaling in the knock-down experiments using vegf-a mRNA, VEGFR inhibitor and gicerin morpholino. In addition to the physiological angiogenesis during development, gicerin morphants efficiently blocked the tumor angiogenesis in zebrafish. Thus, knock-down of gicerin might have an important implication in controlling tumor angiogenesis. C1 [So, Ju-Hoon; Kim, Hyun-Taek; Jung, Seung-Hyun; Lee, Mi-Sun; Choi, Jung-Hwa; Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol & GRAST, Taejon 305764, South Korea. [Hong, Sung-Kook] NIH, NHGRI, Bethesda, MD 20892 USA. [Bae, Young-Ki] Natl Canc Ctr, Goyang 410769, South Korea. [Kudoh, Tetsuhiro] Univ Exeter, Sch Biosci, Exeter EX4 4PS, Devon, England. [Kim, Ji-Hun] Univ Ulsan, Coll Med, Dept Pathol, Seoul 138736, South Korea. RP Kim, CH (reprint author), Chungnam Natl Univ, Dept Biol & GRAST, Taejon 305764, South Korea. EM zebrakim@cnu.ac.kr RI Kim, Cheol-Hee/F-6278-2013 FU Korea government [MEST] [2009-0062785, 2009-008146] FX We sincerely thank Dr Hae-Chul Park and Dr Tao P. Zhong for providing of TG (olig2: DsRed2) and TG (kdr-like:gfp). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government [MEST] [No. 2009-0062785] and [No. 2009-008146] for GRAST. NR 43 TC 9 Z9 12 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1356-9597 J9 GENES CELLS JI Genes Cells PD NOV PY 2010 VL 15 IS 11 BP 1099 EP 1110 DI 10.1111/j.1365-2443.2010.01448.x PG 12 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 672OW UT WOS:000283596900001 PM 20977546 ER PT J AU Zaykin, DV Kozbur, DO AF Zaykin, Dmitri V. Kozbur, Damian O. TI P-Value Based Analysis for Shared Controls Design in Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE GWAS; shared controls; meta-analysis; multiple testing; combining correlated P-values ID LINKAGE DISEQUILIBRIUM; NORMAL VARIABLES; METAANALYSIS; MULTIPLE; TESTS; LOCI; DISTRIBUTIONS; PROBABILITY; REGIONS; NOTCH4 AB An appealing genome-wide association study design compares one large control group against several disease samples. A pioneering study by the Wellcome Trust Case Control Consortium that employed such a design has identified multiple susceptibility regions, many of which have been independently replicated. While reusing a control sample provides effective utilization of data, it also creates correlation between association statistics across diseases. An observation of a large association statistic for one of the diseases may greatly increase chances of observing a spuriously large association for a different disease. Accounting for the correlation is also particularly important when screening for SNPs that might be involved in a set of diseases with overlapping etiology. We describe methods that correct association statistics for dependency due to shared controls, and we describe ways to obtain a measure of overall evidence and to combine association signals across multiple diseases. The methods we describe require no access to individual subject data, instead, they efficiently utilize information contained in P-values for association reported for individual diseases. P-value based combined tests for association are flexible and essentially as powerful as the approach based on aggregating the individual subject data. Genet. Epidemiol. 34:725-738, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Zaykin, Dmitri V.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Kozbur, Damian O.] NIEHS, Student Internship Program, NIH, Res Triangle Pk, NC 27709 USA. RP Zaykin, DV (reprint author), NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. EM zaykind@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; Wellcome Trust [076113] FX Contract grant sponsors: NIH, National Institute of Environmental Health Sciences; Wellcome Trust 076113. NR 26 TC 14 Z9 14 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2010 VL 34 IS 7 BP 725 EP 738 DI 10.1002/gepi.20536 PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 677BZ UT WOS:000283965400009 PM 20976797 ER PT J AU Witkin, KL Friederichs, JM Cohen-Fix, O Jaspersen, SL AF Witkin, Keren L. Friederichs, Jennifer M. Cohen-Fix, Orna Jaspersen, Sue L. TI Changes in the Nuclear Envelope Environment Affect Spindle Pole Body Duplication in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID MICROTUBULE-ORGANIZING CENTER; DOMAIN PROTEIN MPS3; PORE COMPLEX; MOLECULAR ARCHITECTURE; NUCLEOPORINS NUP170P; MEMBRANE GROWTH; SPB DUPLICATION; MESSENGER-RNA; YEAST; COMPONENT AB The Saccharomyces cerevisiae nuclear membrane is part of a complex nuclear envelope environment also containing chromatin, integral and peripheral membrane proteins, and large structures such as nuclear pore complexes (NPCs) and the spindle pole body. To study how properties of the nuclear membrane affect nuclear envelope processes, we altered the nuclear membrane by deleting the SPO7 gene. We found that spo7 Delta cells were sickened by the mutation of genes coding for spindle pole body components and that spo7 Delta was synthetically lethal with mutations in the SUN domain gene MPS3. Mps3p is required for spindle pole body duplication and for a variety of other nuclear envelope processes. In spo7 Delta cells, the spindle pole body defect of mps3 mutants was exacerbated, suggesting that nuclear membrane composition affects spindle pole body function. The synthetic lethality between spo7 Delta and mps3 mutants was suppressed by deletion of specific nucleoporin genes. In fact, these gene deletions bypassed the requirement for Mps3p entirely, suggesting that under certain conditions spindle pole body duplication can occur via an Mps3p-independent pathway. These data point to an antagonistic relationship between nuclear pore complexes and the spindle pole body. We propose a model whereby nuclear pore complexes either compete with the spindle pole body for insertion into the nuclear membrane or affect spindle pole body duplication by altering the nuclear envelope environment. C1 [Witkin, Keren L.; Cohen-Fix, Orna] NIDDK, Lab Mol & Cell Biol, NIH, Bethesda, MD 20892 USA. [Friederichs, Jennifer M.; Jaspersen, Sue L.] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Friederichs, Jennifer M.; Jaspersen, Sue L.] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66160 USA. RP Cohen-Fix, O (reprint author), NIDDK, Lab Mol & Cell Biol, NIH, 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov; slj@stowers.org FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Stowers Institute for Medical Research FX We thank Mark Winey for strains and helpful discussions, Joseph Campbell for advice and technical support, and Kathryn Wagner for assistance with flow cytometry. We are grateful to Rhonda Trimble for assistance with EM and to Neal Freedman for help with statistical analysis. We thank Mark Rose for sharing unpublished data and for insightful suggestions on immunofluorescence data. We also thank Kevin O'Connell, Leslie Barbour, Micah Webster, Daphna Joseph-Strauss, and William Glassford for discussion and comments on the manuscript. K.L.W. is funded by a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) intramural Nancy Nossal fellowship award, O.C.F. is funded by an intramural NIDDK grant, and S.L.J. is supported by funds from the Stowers Institute for Medical Research. NR 77 TC 23 Z9 23 U1 0 U2 2 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD NOV PY 2010 VL 186 IS 3 BP 867 EP U191 DI 10.1534/genetics.110.119149 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA 677MI UT WOS:000283996100009 PM 20713690 ER PT J AU Scheuner, MT McNeel, TS Freedman, AN AF Scheuner, Maren T. McNeel, Timothy S. Freedman, Andrew N. TI Population prevalence of familial cancer and common hereditary cancer syndromes. The 2005 California Health Interview Survey SO GENETICS IN MEDICINE LA English DT Article DE family history; cancer; hereditary cancer syndrome; prevalence of familial risk ID NONPOLYPOSIS COLORECTAL-CANCER; LYNCH-SYNDROME; OVARIAN-CANCER; HISTORY; RISK; PREVENTION; REGISTRIES; CRITERIA AB Purpose: Family history guides cancer prevention and genetic testing. We sought to estimate the population prevalence of increased familial risk for breast, ovarian, endometrial, prostate, and colorectal cancers and hereditary cancer syndromes that include these cancers. Methods: Using the 2005 California Health Interview Survey data, a weak, moderate, or strong familial cancer risk was assigned to 33,187 respondents. Guidelines were applied to identify individuals with hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer. Results: Among respondents without a personal history of cancer, familial breast cancer was most prevalent; 7% had a moderate and 5% a strong familial risk. Older individuals and women were more likely to report family history of cancer. Generally, whites had the highest prevalence, and Asians and Latinos had the lowest prevalence. Among women without a personal history of breast or ovarian cancer, 2.5% met criteria for hereditary breast-ovarian cancer, and among individuals without a personal history of colorectal, endometrial or ovarian cancer, 1.1% met criteria for hereditary nonpolyposis colon cancer. Conclusions: We provide population-based prevalence estimates for moderate and strong familial risk for five common cancers and hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer. Such estimates are helpful in planning and evaluation of genetic services and prevention programs, and assessment of cancer surveillance and prevention strategies. Genet Med 2010:12(11):726-735. C1 [Scheuner, Maren T.] RAND Corp, Santa Monica, CA USA. [Scheuner, Maren T.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Scheuner, Maren T.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Silver Spring, MD USA. [Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Scheuner, MT (reprint author), 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM scheuner@rand.org FU National Cancer Institute at the National Institutes of Health FX This work was supported by a contract from the National Cancer Institute at the National Institutes of Health. NR 25 TC 30 Z9 30 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD NOV PY 2010 VL 12 IS 11 BP 726 EP 735 DI 10.1097/GIM.0b013e3181f30e9e PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 678UD UT WOS:000284105800010 PM 20921897 ER PT J AU Itsara, A Wu, H Smith, JD Nickerson, DA Romieu, I London, SJ Eichler, EE AF Itsara, Andy Wu, Hao Smith, Joshua D. Nickerson, Deborah A. Romieu, Isabelle London, Stephanie J. Eichler, Evan E. TI De novo rates and selection of large copy number variation SO GENOME RESEARCH LA English DT Article ID RARE CHROMOSOMAL DELETIONS; HUMAN-GENOME; 22Q11.2 DELETION; STRUCTURAL VARIATION; RECURRENT REARRANGEMENTS; SEGMENTAL DUPLICATIONS; MENTAL-RETARDATION; NORMAL INDIVIDUALS; ANGELMAN-SYNDROMES; PRADER-WILLI AB While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (> 100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of similar to 30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of mu = 1.2 X 10(-2) CNVs per genome per transmission (mu = 6.5 X 10(-3) for CNVs > 500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (> 500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 X 10(-3)) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied. [Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE23645.] C1 [Itsara, Andy; Smith, Joshua D.; Nickerson, Deborah A.; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Wu, Hao; London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Romieu, Isabelle] Natl Publ Hlth Inst, Cuernavaca 62100, Morelos, Mexico. [Eichler, Evan E.] Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Eichler, EE (reprint author), Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI Sincan, Murat /A-3794-2010; OI London, Stephanie/0000-0003-4911-5290 FU National Institute of Mental Health [1U24MH081810]; National Institute of Aging, National Institutes of Health, Department of Health and Human Services; Simons Foundation [SFARI 137578]; National Institute of Environmental Health Sciences (NIEHS) [ZIA ES049019, ZIA ES025045]; National Council of Science and Technology, Mexico [26206-M] FX We thank Huiling Li, NIEHS, for expert technical assistance. We thank Grace Chiu at Westat Inc. (Research Triangle Park, NC) and Shuangshuang Dai and John Grovenstein at the National Institute of Environmental Health Sciences for data management. We thank the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families for provided resources. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We also thank D. Fugman for technical support with the AGRE samples. We thank A. Singleton, L. Ferrucci, and investigators of the InCHIANTI study for sharing control genotype data generated with support from the Intramural Research Program of the National Institute of Aging, National Institutes of Health, Department of Health and Human Services. We also thank T. Brown, S. Girirajan, G.M. Cooper, and P. Green for critical review of the manuscript. This work was supported by a grant from the Simons Foundation (SFARI 137578 to E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute. Subject enrollment and Illumina genotyping of the Mexican asthma study were supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS; ZIA ES049019 and ZIA ES025045). Subject enrollment was supported in part by the National Council of Science and Technology, Mexico (grant 26206-M). NR 63 TC 151 Z9 155 U1 0 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD NOV PY 2010 VL 20 IS 11 BP 1469 EP 1481 DI 10.1101/gr.107680.110 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 673JF UT WOS:000283654800001 PM 20841430 ER PT J AU Hanover, J Keembiyehetty, C Wang, P Comly, M Dwyer, N Krause, M Love, D AF Hanover, John Keembiyehetty, Chithra Wang, Peng Comly, Marcy Dwyer, Nancy Krause, Michael Love, Dona TI Mouse O-Glcnacase Knockout Reveals Roles for O-Glcnac Cycling in Development, Metabolism and Epigenetics SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Hanover, John; Keembiyehetty, Chithra; Wang, Peng; Comly, Marcy; Dwyer, Nancy; Krause, Michael; Love, Dona] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 14 BP 1453 EP 1453 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300024 ER PT J AU Guan, Y Anderson, S Starost, M Despres, D Fritz, T Tabak, L AF Guan, Yu Anderson, Stasia Starost, Matthew Despres, Daryl Fritz, Timothy Tabak, Lawrence TI Normal Heart Development in Mice is Dependent on Mucin-Type O-Linked Glycosylation SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Guan, Yu; Anderson, Stasia; Starost, Matthew; Despres, Daryl; Tabak, Lawrence] NIH, Bethesda, MD 20892 USA. [Fritz, Timothy] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 26 BP 1457 EP 1457 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300036 ER PT J AU Huizing, M Yardeni, T Kakani, S Poling, J Ciccone, C Darvish, D Zerfas, P Tian, E Ten Hagen, K Ishihara, M Azadi, P Kopp, JB Gahl, WA AF Huizing, Marjan Yardeni, Tal Kakani, Sravan Poling, Justin Ciccone, Carla Darvish, Daniel Zerfas, Patricia Tian, E. Ten Hagen, Kelly Ishihara, Mayumi Azadi, Parastoo Kopp, Jeffrey B. Gahl, William A. TI The Gne M712T Mouse as a Model for Human Glomerulopathy: Treatment with N-Acetylmannosamine SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Huizing, Marjan; Yardeni, Tal; Kakani, Sravan; Poling, Justin; Ciccone, Carla; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Darvish, Daniel] HIBM Res Grp, Encino, CA USA. [Zerfas, Patricia] NIH, Div Vet Resources, ORS, Bethesda, MD 20892 USA. [Tian, E.; Ten Hagen, Kelly] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD USA. [Ishihara, Mayumi; Azadi, Parastoo] Univ Georgia, CCRC, Analyt Serv, Athens, GA 30602 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 32 BP 1459 EP 1459 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300042 ER PT J AU Rana, NA Nita-Lazar, A Kakuda, S Haltiwanger, RS AF Rana, Nadia A. Nita-Lazar, Aleksandra Kakuda, Shinako Haltiwanger, Robert S. TI Analysis of O-Glucosylation on Mouse Notch1 SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Rana, Nadia A.; Kakuda, Shinako; Haltiwanger, Robert S.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Nita-Lazar, Aleksandra] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 58 BP 1467 EP 1467 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300068 ER PT J AU Ghosh, SK Love, D Krause, M Hanover, J AF Ghosh, Salil K. Love, Dona Krause, Michael Hanover, John TI O-Glcnac Modification of the Carboxy Terminal Domain of RNA Polymerase II is Evolutionarily Conserved SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Ghosh, Salil K.; Love, Dona; Krause, Michael; Hanover, John] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 108 BP 1483 EP 1483 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300118 ER PT J AU Love, D Krause, M Hanover, J AF Love, Dona Krause, Michael Hanover, John TI O-Glcnac Cycling and Epigenetic Regulation in Drosophila melanogaster SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Love, Dona; Krause, Michael; Hanover, John] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 109 BP 1483 EP 1484 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300119 ER PT J AU Tran, D Ten Hagen, K AF Tran, Duy Ten Hagen, Kelly TI An O-Glycosyltransferase is Required for Proper Gut Development in Drosophila SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Tran, Duy; Ten Hagen, Kelly] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 112 BP 1484 EP 1485 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300122 ER PT J AU Kang, CS Riazuddin, S Mundorff, J Krasnewich, D Friedman, P Mullikin, J Drayna, D AF Kang, Changsoo Riazuddin, Sheikh Mundorff, Jennifer Krasnewich, Donna Friedman, Penelope Mullikin, James Drayna, Dennis TI Association of Mutations in the Lysosomal Enzyme-Targeting Pathway with Persistent Stuttering SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Kang, Changsoo; Drayna, Dennis] NIDCD, NIH, Rockville, MD USA. [Riazuddin, Sheikh] Natl Ctr Excellence Mol Biol, Lahor, Pakistan. [Mundorff, Jennifer] Hollins Commun Res Inst, Roanoke, VA USA. [Krasnewich, Donna] NHGRI, NIH, Bethesda, MD 20892 USA. [Friedman, Penelope] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Mullikin, James] Natl Human Genome Res, Genome Technol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 129 BP 1490 EP 1490 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300139 ER PT J AU Ciccone, C Yardeni, T Astiz-Martinez, A Vincent, L Lin, M Kakani, S Zerfas, P Gahl, WA Huizing, M AF Ciccone, Carla Yardeni, Tal Astiz-Martinez, Adrian Vincent, Lisa Lin, Maggie Kakani, Sravan Zerfas, Patricia Gahl, William A. Huizing, Marjan TI Evaluation of Oral Feeding of N-Acetylmannosamine-Related Sugars as Therapeutics for a Knock-In Mouse Model of Hereditary Inclusion Body Myopathy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Ciccone, Carla; Yardeni, Tal; Astiz-Martinez, Adrian; Vincent, Lisa; Lin, Maggie; Kakani, Sravan; Gahl, William A.; Huizing, Marjan] NHGRI, NIH, MGB, Bethesda, MD 20892 USA. [Zerfas, Patricia] NIH, Div Vet Resources, OD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 142 BP 1495 EP 1495 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300152 ER PT J AU Tran, D Lim, JM Liu, MA Wells, L Ten Hagen, K Live, D AF Tran, Duy Lim, Jae-Min Liu, Mian Wells, Lance Ten Hagen, Kelly Live, David TI Post-Translational Processing of Alpha-Dystroglycan SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Lim, Jae-Min; Liu, Mian; Wells, Lance; Live, David] Univ Georgia, CCRC, Athens, GA 30602 USA. [Tran, Duy; Ten Hagen, Kelly] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 148 BP 1497 EP 1497 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300158 ER PT J AU Yardeni, T Ciccone, C Jacobs, K Hoogstraten-Miller, S Darvish, D Anikster, Y Nemunaitis, J Maples, P Jay, CM Gahl, WA Huizing, M AF Yardeni, Tal Ciccone, Carla Jacobs, Katherine Hoogstraten-Miller, Shelley Darvish, Daniel Anikster, Yair Nemunaitis, John Maples, Phil Jay, Chris M. Gahl, William A. Huizing, Maejan TI Successful Delivery of Mannac and GNE in Lipoplex to Rescue Hyposialylation in a Mouse Model of Hereditary Inclusion Body Myopathy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Yardeni, Tal; Ciccone, Carla; Jacobs, Katherine; Gahl, William A.; Huizing, Maejan] MGB MHGRI NIH, Bethesda, MD USA. [Hoogstraten-Miller, Shelley] NHGRI, 2OLAM, NIH, Bethesda, MD 20892 USA. [Darvish, Daniel] HIBM Res Grp, Encino, CA USA. [Anikster, Yair] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Nemunaitis, John; Maples, Phil; Jay, Chris M.] Gradalis Inc, Dallas, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 160 BP 1501 EP 1501 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300170 ER PT J AU Boeggeman, E Ramakrishnan, B Qasba, PK AF Boeggeman, Elizabeth Ramakrishnan, Boopathy Qasba, Pradman K. TI Site-Specific Labeling of 5-Hydroxymethylcytosine Residues in DNA Via Modified Sugars Carrying Chemical Handles SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Boeggeman, Elizabeth; Ramakrishnan, Boopathy] SAIC Frederick Inc, BSP, SGS, CCR NP, Frederick, MD USA. [Qasba, Pradman K.] NCI Frederick, SGS, CCR NP, Frederick, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 194 BP 1511 EP 1512 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300204 ER PT J AU Guo, HJ Elnaiem, DE Novozhilova, NM Turco, SJ Sacks, DL Beverley, SM AF Guo, Hongjie Elnaiem, Dia-Eldin Novozhilova, Natalia M. Turco, Salvatore J. Sacks, David L. Beverley, Stephen M. TI Role of D-Arabinosylation of the Surface Lipophosphoglycan of Leishmania major in Infection of its Mammalian Host and Sand Fly Vector SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 07-10, 2010 CL St. Pete Beach, FL SP Soc Glycobiol C1 [Guo, Hongjie; Beverley, Stephen M.] Washington Univ, St Louis, MO USA. [Elnaiem, Dia-Eldin; Sacks, David L.] NIAID, Bethesda, MD 20892 USA. [Novozhilova, Natalia M.; Turco, Salvatore J.] Univ Kentucky, Med Ctr, Lexington, KY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2010 VL 20 IS 11 MA 233 BP 1525 EP 1525 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661TF UT WOS:000282750300243 ER PT J AU Jegalian, AG Buxbaum, NP Facchetti, F Raffeld, M Pittaluga, S Wayne, AS Jaffe, ES AF Jegalian, Armin G. Buxbaum, Nataliya P. Facchetti, Fabio Raffeld, Mark Pittaluga, Stefania Wayne, Alan S. Jaffe, Elaine S. TI Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE blastic plasmacytoid dendritic cell neoplasm; CD4(+)/CD56(+) hematodermic neoplasm; pediatric; acute myeloid leukemia; acute lymphoblastic leukemia; stem cell transplant; S-100; immunophenotyping; dendritic cells ID CD4(+)/CD56(+) HEMATODERMIC NEOPLASM; PERIPHERAL-BLOOD; ACUTE-LEUKEMIA; LYMPHOMA; EXPRESSION; LINEAGE; MALIGNANCIES; HOMEOSTASIS; MARKERS; ENTITY AB Background Blastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course in adults, whereas experience in children with this disease is very limited. Design and Methods This retrospective study analyzed the pathological and clinical findings of nine cases of blastic plasmactyoid dendritic cell neoplasm presenting in patients under the age of 18 years who were reviewed at our institution. We also identified 20 well-documented additional pediatric cases in the literature. Results In the combined analysis, the overall survival rate among the 25 patients with available follow-up, all having received chemotherapy, was 72% (follow-up ranging from 9 months to 13 years, with a median of 30 months). The event-free survival rate was 64%. Nine patients were alive 5 years after the original diagnosis, although only three of them had undergone hematopoietic stem cell transplantation one in first complete remission and two in second remission. Of the seven patients who lacked cutaneous disease at presentation, 100% survived, including five who were alive more than 5 years after diagnosis, although only two had undergone stem cell transplantation. Among the 18 patients who presented with cutaneous disease and for whom follow-up data were available, only 11 survived (61%). Detailed immunophenotypic characterization and clinical features of all cases are presented. Unexpectedly, three of four cases of blastic plasmacytoid dendritic cell neoplasm tested showed focal positivity for S-100. S-100 was negative in 28 cases of acute myeloid leukemia evaluated for this marker. Conclusions In contrast to adult cases, in which long-term survival depends on stem cell transplantation in first complete remission, blastic plasmacytoid dendritic cell neoplasms in children are clinically less aggressive. Treatment with high-risk acute lymphoblastic leukemia-type chemotherapy appears to be effective, and stem cell transplantation may be reserved for children who relapse and achieve a second remission. Outcomes were more favorable in cases that lacked cutaneous disease at presentation, although a comparison of cutaneous and non-cutaneous cases might be confounded by differences in treatment regimens. Focal expression of S-100 may be seen in concert with other markers of plasmacytoid dendritic cells. C1 [Jegalian, Armin G.; Raffeld, Mark; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Buxbaum, Nataliya P.; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Facchetti, Fabio] Univ Brescia, Dept Pathol, Brescia, Italy. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, 10 Ctr Dr,MSC 1500,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov RI FACCHETTI, Fabio/E-7190-2010; OI FACCHETTI, Fabio/0000-0003-4975-2388; Jaffe, Elaine/0000-0003-4632-0301; Buxbaum, Nataliya/0000-0002-5199-1997 FU Center for Cancer Research, National Cancer Institute, NIH FX this work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 40 TC 52 Z9 63 U1 0 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD NOV PY 2010 VL 95 IS 11 BP 1873 EP 1879 DI 10.3324/haematol.2010.026179 PG 7 WC Hematology SC Hematology GA 682YF UT WOS:000284438200013 PM 20663945 ER PT J AU Lee, K Hoots, WK AF Lee, K. Hoots, W. K. TI Human plasma-derived concentrates: preventing thrombosis and controlling haemorrhage SO HAEMOPHILIA LA English DT Editorial Material ID PROTHROMBIN COMPLEX CONCENTRATE; HEREDITARY ANTITHROMBIN-III; PROTEIN-S DEFICIENCY; INTRACEREBRAL HEMORRHAGE; ANTICOAGULANT TREATMENT; WARFARIN REVERSAL; P/N; PHARMACOKINETICS; THROMBOPHILIA; VOLUNTEERS C1 [Lee, K.] Columbia Univ, Med Ctr, Div Neurol Crit Care, Dept Neurol,Coll Phys & Surg, New York, NY 10032 USA. [Lee, K.] Columbia Univ, Coll Phys & Surg, Dept Neurosurg, New York, NY 10032 USA. [Hoots, W. K.] NHLBI, Bethesda, MD 20892 USA. RP Lee, K (reprint author), Columbia Univ, Med Ctr, Div Neurol Crit Care, Dept Neurol,Coll Phys & Surg, Milstein 8 Ctr 300, New York, NY 10032 USA. EM KL2356@columbia.edu NR 34 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD NOV PY 2010 VL 16 IS 6 BP 949 EP 951 DI 10.1111/j.1365-2516.2010.02331.x PG 3 WC Hematology SC Hematology GA 671MP UT WOS:000283510500015 PM 20546032 ER PT J AU Arvey, SR AF Arvey, Sarah R. TI Making the Immoral Moral: Consensual Unions and Birth Status in Cuban Law and Everyday Practice, 1940-1958 SO HAHR-HISPANIC AMERICAN HISTORICAL REVIEW LA English DT Article RP Arvey, SR (reprint author), Univ Texas, NCI Canc Educ & Career Dev Program, Sch Publ Hlth, Houston Hlth Sci Ctr, Houston, TX USA. FU NCI NIH HHS [R25 CA057712-17, R25 CA057712] NR 42 TC 1 Z9 1 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 0018-2168 J9 HAHR-HISP AM HIST R JI HAHR-Hisp. Am. Hist. Rev. PD NOV PY 2010 VL 90 IS 4 BP 627 EP 659 DI 10.1215/00182168-2010-044 PG 33 WC History SC History GA 658WV UT WOS:000282526000002 PM 21212853 ER PT J AU Rubin, DB AF Rubin, Daniel B. TI A Role for Moral Vision in Public Health SO HASTINGS CENTER REPORT LA English DT Article C1 [Rubin, Daniel B.] Univ Michigan, Ctr Eth Publ Life, Ann Arbor, MI 48109 USA. [Rubin, Daniel B.] Natl Inst Hlth, Dept Bioeth, Bethesda, MD USA. RP Rubin, DB (reprint author), Univ Michigan, Ctr Eth Publ Life, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD NOV-DEC PY 2010 VL 40 IS 6 BP 20 EP 22 PG 3 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 682IQ UT WOS:000284395000016 PM 21140742 ER PT J AU Keteyian, SJ Fleg, JL Brawner, CA Pina, IL AF Keteyian, Steven J. Fleg, Jerome L. Brawner, Clinton A. Pina, Ileana L. TI Role and benefits of exercise in the management of patients with heart failure SO HEART FAILURE REVIEWS LA English DT Article DE Exercise; Heart failure; Exercise capacity; Clinical events; Physiology ID QUALITY-OF-LIFE; LEFT-VENTRICULAR FUNCTION; RANDOMIZED CONTROLLED-TRIAL; SKELETAL-MUSCLE FUNCTION; TUMOR-NECROSIS-FACTOR; RESISTANCE EXERCISE; FUNCTIONAL-CAPACITY; HF-ACTION; ENDOTHELIAL DYSFUNCTION; ISCHEMIC CARDIOMYOPATHY AB Initial research established the feasibility of exercise training in patients with heart failure, as well as associated physiological benefits. This review summarizes the findings from over two dozen single-site studies that address the effect of exercise training on exercise capacity and cardiovascular and peripheral function. In addition, it incorporates the results from two meta-analyses and a recently completed multi-center trial, all of which studied the effects of exercise training on clinical outcomes. The major conclusions from these studies are that exercise training is safe; improves health status and exercise capacity; helps attenuate much of the abnormal pathophysiology that develops with heart failure; and yields a modest reduction in clinical events. The magnitude of the clinical benefits appears related to the volume of exercise completed. Future research is needed to identify which patient subgroups might benefit the most from exercise training, the optimal exercise dose or load needed to lessen disease-related symptoms and maximize clinical benefit, and the effects of exercise training in patients with heart failure and preserved left ventricular systolic function. C1 [Keteyian, Steven J.; Brawner, Clinton A.] Henry Ford Hosp, Dept Med, Detroit, MI 48202 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Pina, Ileana L.] Case Western Univ, Sch Med, Vet Adm Med Ctr, Cleveland, OH USA. RP Keteyian, SJ (reprint author), Henry Ford Hosp, Dept Med, 6525 2nd Ave, Detroit, MI 48202 USA. EM sketeyi1@hfhs.org OI Brawner, Clinton A./0000-0002-1705-6620 NR 81 TC 16 Z9 16 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 J9 HEART FAIL REV JI Heart Fail. Rev. PD NOV PY 2010 VL 15 IS 6 BP 523 EP 530 DI 10.1007/s10741-009-9157-7 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 657QD UT WOS:000282426500001 PM 20101456 ER PT J AU Yu, JH Zhu, BM Wickre, M Riedlinger, G Chen, WP Hosui, A Robinson, GW Hennighausen, L AF Yu, Ji Hoon Zhu, Bing-Mei Wickre, Mark Riedlinger, Gregory Chen, Weiping Hosui, Atsushi Robinson, Gertraud W. Hennighausen, Lothar TI The Transcription Factors Signal Transducer and Activator of Transcription 5A (STAT5A) and STAT5B Negatively Regulate Cell Proliferation Through the Activation of Cyclin-Dependent Kinase Inhibitor 2b (Cdkn2b) and Cdkn1a Expression SO HEPATOLOGY LA English DT Article ID GENE-EXPRESSION; SELF-RENEWAL; DIFFERENTIATION; CANCER; SENESCENCE; P15(INK4B); SURVIVAL; LEUKEMIA; INVASION; DELETION AB Although the cytokine-inducible transcription factor signal transducer and activator of transcription 5 (STAT5) promotes proliferation of a wide range of cell types, there are cell-specific and context-specific cases in which loss of STAT5 results in enhanced cell proliferation. Here, we report that loss of STAT5 from mouse embryonic fibroblasts (MEFs) leads to enhanced proliferation, which was linked to reduced levels of the cell cycle inhibitors p15(INK4B) and p21(CIPI). We further demonstrate that growth hormone, through the transcription factor STAT5, enhances expression of the Cdkn2b (cyclin-dependent kinase inhibitor 2B) gene and that STAT5A binds to interferon-gamma activated sequence sites within the promoter. We recently demonstrated that ablation of STAT5 from liver results in hepatocellular carcinoma upon CCl(4) treatment. We now establish that STAT5, like in MEFs, activates expression of the Cdkn2b gene in liver tissue. Loss of STAT5 led to diminished p15(INK4B) and increased hepatocyte proliferation. Conclusion: This study for the first time demonstrates that cytokines, through STAT5, induce the expression of a key cell cycle inhibitor. These experiments therefore shed mechanistic light on the context-specific role of STAT5 as tumor suppressor. (HEPATOLOGY 2010;52:1808-1818) C1 [Yu, Ji Hoon; Zhu, Bing-Mei; Wickre, Mark; Riedlinger, Gregory; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDKD, Genom Core Lab, NIH, Bethesda, MD 20892 USA. [Hosui, Atsushi] Osaka Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Suita, Osaka, Japan. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, 8 Ctr Dr,Room 101, Bethesda, MD 20892 USA. EM yujihoon@mail.nih.gov; lotharh@mail.nih.gov RI Robinson, Gertraud/I-2136-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases; Lothar Hennighausen at Chonnam National University Republic of Korea [R33-10059] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Lothar Hennighausen is a participant in the WCU program (R33-10059) at Chonnam National University Republic of Korea. NR 33 TC 14 Z9 18 U1 10 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD NOV PY 2010 VL 52 IS 5 BP 1808 EP 1818 DI 10.1002/hep.23882 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 674RH UT WOS:000283764800031 PM 21038417 ER PT J AU Kang, HS ZeRuth, G Lichti-Kaiser, K Vasanth, S Yin, ZY Kim, YS Jetten, AM AF Kang, Hong Soon ZeRuth, Gary Lichti-Kaiser, Kristin Vasanth, Shivakumar Yin, Zhengyu Kim, Yong-Sik Jetten, Anton M. TI Gli-similar (Glis) Kruppel-like zinc finger proteins: insights into their physiological functions and critical roles in neonatal diabetes and cystic renal disease SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE Diabetes; Polycystic kidney disease; Primary cilium; Pancreatic beta-cells; Glis Kruppel-like zinc finger protein ID INSULIN GENE-TRANSCRIPTION; POLYCYSTIC KIDNEY-DISEASE; STEM-CELL DIFFERENTIATION; BETA-CELL; PRIMARY CILIUM; REPRESSOR FUNCTIONS; CONGENITAL HYPOTHYROIDISM; INTRAFLAGELLAR TRANSPORT; PANCREAS DEVELOPMENT; ZIC GENES AB GLI-similar (Glis) 1-3 proteins constitute a subfamily of the Kruppel-like zinc finger transcription factors that are closely related to the Gli family. Glis 1-3 play critical roles in the regulation of a number of physiological processes and have been implicated in several pathologies. Mutations in GLIS2 have been linked to nephronophthisis, an autosomal recessive cystic kidney disease. Loss of Glis2 function leads to renal atrophy and fibrosis that involves epithelial-mesenchymal transition (EMT) of renal tubule epithelial cells. Mutations in human GLIS3 have been implicated in a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) and in some patients accompanied by polycystic kidney disease, glaucoma, and liver fibrosis. In addition, the GLIS3 gene has been identified as a susceptibility locus for the risk of type 1 and 2 diabetes. Glis3 plays a key role in pancreatic development, particularly in the generation of beta-cells and in the regulation of insulin gene expression. Glis2 and Glis3 proteins have been demonstrated to localize to the primary cilium, a signaling organelle that has been implicated in several pathologies, including cystic renal diseases. This association suggests that Glis2/3 are part of primary cilium-associated signaling pathways that control the activity of Glis proteins. Upon activation in the primary cilium, Glis proteins may translocate to the nucleus where they subsequently regulate gene transcription by interacting with Glis-binding sites in the promoter regulatory region of target genes. In this review, we discuss the current knowledge of the Glis signaling pathways, their physiological functions, and their involvement in several human pathologies. C1 [Kang, Hong Soon; ZeRuth, Gary; Lichti-Kaiser, Kristin; Vasanth, Shivakumar; Yin, Zhengyu; Kim, Yong-Sik; Jetten, Anton M.] NIEHS, Div Intramural Res, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Div Intramural Res, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov RI Yin, Zhengyu/H-9777-2012; OI Jetten, Anton/0000-0003-0954-4445 FU NIEHS, NIH [Z01-ES-100485] FX The authors would like to thank Drs. Christina Teng and Thomas Eling for their comments on the manuscript and Sue Edelstein for the artwork. This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-100485). NR 120 TC 21 Z9 22 U1 0 U2 4 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD NOV PY 2010 VL 25 IS 11 BP 1481 EP 1496 PG 16 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 653ZB UT WOS:000282136800012 PM 20865670 ER PT J AU Hammer, SM Ribaudo, H Bassett, R Mellors, JW Demeter, LM Coombs, RW Currier, J Morse, GD Gerber, JG Martinez, AI Spreen, W Fischl, MA Squires, KE AF Hammer, Scott M. Ribaudo, Heather Bassett, Roland Mellors, John W. Demeter, Lisa M. Coombs, Robert W. Currier, Judith Morse, Gene D. Gerber, John G. Martinez, Ana I. Spreen, William Fischl, Margaret A. Squires, Kathleen E. CA AIDS Clinical Trials Grp ACTG 372A TI A Randomized, Placebo-Controlled Trial of Abacavir Intensification in HIV-1-Infected Adults With Virologic Suppression on a Protease Inhibitor-Containing Regimen SO HIV CLINICAL TRIALS LA English DT Article DE abacavir; antiretroviral therapy; intensification ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; SEQUENTIAL 3-DRUG REGIMENS; HIV-1 LATENT RESERVOIR; RALTEGRAVIR INTENSIFICATION; MYOCARDIAL-INFARCTION; INITIAL TREATMENT; CLINICAL-TRIALS; INFECTION; VIREMIA AB Background and Objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation. Results: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm(3). Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/mL can be further reduced and what influence this may have on latent HIV reservoirs. C1 [Hammer, Scott M.] Columbia Univ, Div Infect Dis, New York, NY 10032 USA. [Ribaudo, Heather] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bassett, Roland] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Demeter, Lisa M.] Univ Rochester, Rochester, NY USA. [Coombs, Robert W.] Univ Washington, Seattle, WA 98195 USA. [Currier, Judith] Univ Calif Los Angeles, Los Angeles, CA USA. [Morse, Gene D.] SUNY Buffalo, Buffalo, NY 14260 USA. [Gerber, John G.] Univ Colorado, Denver, CO 80202 USA. [Martinez, Ana I.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Spreen, William] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. [Fischl, Margaret A.] Univ Miami, Miami, FL USA. [Squires, Kathleen E.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Hammer, SM (reprint author), Columbia Univ, Div Infect Dis, W 168th St, New York, NY 10032 USA. EM smh48@columbia.edu FU Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, National Institutes of Health; ACTG; Biocryst; Gilead Sciences; GlaxoSmithKline; Merck; Tibotec; Clinical Trials Unit (CTU) [AI069470, AI069494-03S1, AI068636]; Clinical and Translational Science Award (CTSA) [RR024156]; ACTG Pharmacology Specialty Laboratory [BRS-ACURE-Q-06-00140-T001] FX This study was performed by the AIDS Clinical Trials Group and was sponsored by the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, National Institutes of Health. Data management and analysis were performed under the auspices of the ACTG, and all authors had access to original datasets. Drugs were supplied by GlaxoSmithKline, Merck Research Laboratories, and Bristol-Myers Squibb through clinical trials agreements with DAIDS. This study is registered as NCT00000885 at ClinicalTrials.gov.; Dr. Hammer serves as consultant to Merck and Progenics and served on a Data Monitoring Committee for Bristol-Myers Squibb. Dr. Mellors is a consultant to Merck, Gilead Sciences, and RFS Pharma and is owner of stock options in RFS Pharma. Dr. Demeter's spouse receives royalty income from GlaxoSmithKline and Merck related to HPV vaccines. Dr. Demeter has no HIV-related conflicts. Dr. Coombs is a consultant to Merck. Dr. Gerber is a consultant to Merck. Dr. Spreen is a GlaxoSmithKline employee and shareholder. Dr. Squires receives grant support from Biocryst, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec and is consultant to and receives honoraria from Gilead Sciences, GlaxoSmithKline, Merck, Schering-Plough, Tibotec, and Tobira.; The authors have received the following support: Clinical Trials Unit (CTU) grant AI069470 and Clinical and Translational Science Award (CTSA) RR024156 (Dr. Hammer); CTU grant AI069494-03S1 (Dr. Mellors); CTU grant AI068636 (Dr. Morse); ACTG Pharmacology Specialty Laboratory grant BRS-ACURE-Q-06-00140-T001 (Social and Scientific Systems). NR 44 TC 11 Z9 11 U1 0 U2 2 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD NOV-DEC PY 2010 VL 11 IS 6 BP 312 EP 324 DI 10.1310/hct1105-312 PG 13 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 830HN UT WOS:000295648200002 PM 21239359 ER PT J AU Kerkar, SP Kemp, CD Avital, I AF Kerkar, Sid P. Kemp, Clinton D. Avital, Itzhak TI Liver resections in metastatic gastric cancer SO HPB LA English DT Review DE gastric cancer; liver metastases ID PHASE-II TRIAL; HEPATIC RESECTION; PROGNOSTIC-FACTORS; SURGICAL-TREATMENT; ADENOCARCINOMA; FLUOROURACIL; TUMORS; METHOTREXATE; SURVIVAL; OXALIPLATIN AB Background: The 5-year survival of patients receiving standard-of-care chemotherapy for metastatic gastric cancer (MGC) to the liver is <2%. This review examines the published data on liver resections for MGC and analyses the rationale for potentially aggressive surgical management. Methods: A search of the PubMed and Scopus databases was used to identify studies published in English from 1990 to 2009 that reported on 10 or more patients who underwent liver resections for MGC. All available clinicopathologic data were analysed. In particular, we examined longterm survival and the characteristics of individuals surviving for >5 years. Results: Nineteen studies reported on 436 patients. Median 5-year survival was 26.5% (range: 0-60%). Overall, 13.4% (48/358) of patients were alive at 5 years and studies with extended follow-up reported that 4.0% (7/174) of patients survived for >10 years. Overall in-hospital mortality was 3.5% (12/340 patients); however, the median mortality rate across the studies was 0%. No prognostic factor was found to be consistently statistically significant across these small studies. Conclusions: Despite the limitations of any analysis of retrospective data for highly selected groups of patients, it would appear that liver resections combined with systemic therapy for MGC can result in prolonged survival. C1 [Avital, Itzhak] Uniformed Serv Univ Hlth Sci, NCI, NIH, Surg Branch,Ctr Canc Res, Bethesda, MD 20892 USA. RP Avital, I (reprint author), Uniformed Serv Univ Hlth Sci, NCI, NIH, Surg Branch,Ctr Canc Res, Bldg 10 Hatfield CRC,Room 4-3961,10 Ctr Dr, Bethesda, MD 20892 USA. EM avitali@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA FX This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. NR 38 TC 26 Z9 27 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1365-182X J9 HPB JI HPB PD NOV PY 2010 VL 12 IS 9 BP 589 EP 596 DI 10.1111/j.1477-2574.2010.00224.x PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 709LE UT WOS:000286438700001 PM 20961366 ER PT J AU Gozzi, M Zamboni, G Krueger, F Grafman, J AF Gozzi, Marta Zamboni, Giovanna Krueger, Frank Grafman, Jordan TI Interest in Politics Modulates Neural Activity in the Amygdala and Ventral Striatum SO HUMAN BRAIN MAPPING LA English DT Article DE fMRI, social cognition, emotion, reward; brain imaging ID ORBITOFRONTAL CORTEX; FACIAL EXPRESSIONS; REWARD CIRCUITRY; FUNCTIONAL MRI; ROMANTIC LOVE; FMRI; BRAIN; STIMULI; EMOTION; CONSERVATISM AB Studies on political participation have found that a person's interest in politics contributes to the likelihood that he or she will be involved in the political process Here, we looked at whether or not interest in politics affects patterns of brain activity when individuals think about political matters Using functional magnetic resonance imaging (fMRI), we scanned individuals (either interested or uninterested in politics based on a self-report questionnaire) while they were expressing their agreement or disagreement with political opinions. After scanning, participants were asked to rate each political opinion presented in the scanner for emotional valence and emotional intensity. Behavioral results showed that those political opinions participants agreed with were perceived as more emotionally intense and more positive by individuals interested in politics relative to individuals uninterested in politics. In addition, individuals interested in politics showed greater activation in the amygdala and the ventral striatum (ventral putamen) relative to individuals uninterested in politics when reading political opinions in accordance with their own views. This study shows that having an interest in politics elicits activations in emotion- and reward-related brain areas even when simply agreeing with written political opinions. Hum Brain Mapp 31 1763-1771, 2010 (C) 2010 Wiley-Liss, Inc. C1 [Gozzi, Marta; Zamboni, Giovanna; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Gozzi, Marta] Univ Milano Bicocca, Dipartimento Psicol, Milan, Italy. [Zamboni, Giovanna] Univ Modena & Reggio Emilia, Dipartimento Neurosci, Modena, Italy. [Krueger, Frank] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. RI Zamboni, Giovanna/F-3583-2017; OI Zamboni, Giovanna/0000-0002-6133-3373; Grafman, Jordan H./0000-0001-8645-4457 FU Italian Ministry of University and Research (MIUR) FX Contract grant sponsors: National Institute of Neurological Disorders and Stroke Intramural Research Program, Italian Ministry of University and Research (MIUR). NR 48 TC 8 Z9 8 U1 0 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD NOV PY 2010 VL 31 IS 11 BP 1763 EP 1771 DI 10.1002/hbm.20976 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 673EE UT WOS:000283641100012 PM 20162603 ER PT J AU Wingert, JR Sinclair, RJ Dixit, S Damiano, DL Burton, H AF Wingert, Jason R. Sinclair, Robert J. Dixit, Sachin Damiano, Diane L. Burton, Harold TI Somatosensory-Evoked Cortical Activity in Spastic Diplegic Cerebral Palsy SO HUMAN BRAIN MAPPING LA English DT Article DE diplegia, cerebral palsy, magnetic resonance imaging, sensation; human ID HUMAN PARIETAL OPERCULUM; TACTILE OBJECT RECOGNITION; EARLY SENSORY DEPRIVATION; HUMAN BRAIN; 2-POINT DISCRIMINATION; FRONTOPARIETAL CIRCUIT; ASSOCIATION CORTEX; HEALTHY-VOLUNTEERS; FUNCTIONAL MRI; MACACA-MULATTA AB Somatosensory deficits have been identified in cerebral palsy (CP), but associated cortical brain activity in CP remains poorly understood Functional MRI was used to measure blood oxygenation level-dependent (BOLD) responses during three tactile tasks in 10 participants with spastic diplegia (mean age 18 70 years, SD 799 years, 5 females) and 10 age-matched controls (mean age 18 60 years, SD 3 86 years, 5 females). Tactile stimulation involved servo-controlled translation of smooth or embossed surfaces across the right index finger pad; the discrimination tasks with embossed surfaces involved judging whether (1) paired shapes were similar or different, and (2) a rougher set of horizontal gratings preceded or followed a smoother one Velocity and duration of surface translation was identical across all trials In addition, an event-related design revealed response dynamics per trial in both groups. Compared to controls, individuals with spastic diplegia had significantly reduced spatial extents in activated cortical areas and smaller BOLD response magnitudes in cortical areas for somato-sensation, motor, and goal-directed/attention behaviors These results provide mechanisms for the widespread somatosensory deficits in CP The reduced activation noted across multiple cortical areas might contribute to motor deficits in CP. Hum Brain Mapp 31 1772-1785, 2010 (C) 2010 Wiley-Liss, Inc C1 [Wingert, Jason R.] UNC Asheville, Weizenblatt Hlth Ctr, Dept Hlth & Wellness, Asheville, NC 28804 USA. [Sinclair, Robert J.; Burton, Harold] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Dixit, Sachin; Burton, Harold] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Ctr Clin, Bethesda, MD 20892 USA. RP Wingert, JR (reprint author), UNC Asheville, Weizenblatt Hlth Ctr, Dept Hlth & Wellness, CPO 2730,1 Univ Hts, Asheville, NC 28804 USA. RI Wingert, Jason/B-1528-2012; Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU National Institute of Neurological Disorders and Stroke [R01 N5054413, NS31005]; NIH Clinical Center; Foundation for Physical Therapy FX Contract grant sponsor National Institute of Neurological Disorders and Stroke, Contract grant numbers R01 N5054413, NS31005, Contract grant sponsor Intramural Program of the NIH Clinical Center; The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Additional support was provided by the Foundation for Physical Therapy PODS Scholarship. The authors would like to acknowledge Dr. Janice E. Brunstrom-Hernandez for her numerous contributions to this research. NR 90 TC 20 Z9 21 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD NOV PY 2010 VL 31 IS 11 BP 1772 EP 1785 DI 10.1002/hbm.20977 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 673EE UT WOS:000283641100013 PM 20205249 ER PT J AU He, CY Kraft, P Chasman, DI Buring, JE Chen, C Hankinson, SE Pare, G Chanock, S Ridker, PM Hunter, DJ AF He, Chunyan Kraft, Peter Chasman, Daniel I. Buring, Julie E. Chen, Constance Hankinson, Susan E. Pare, Guillaume Chanock, Stephen Ridker, Paul M. Hunter, David J. TI A large-scale candidate gene association study of age at menarche and age at natural menopause SO HUMAN GENETICS LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; GENOME-WIDE ASSOCIATION; BONE-MINERAL DENSITY; QUANTITATIVE TRAIT LOCI; ENDOMETRIAL CANCER-RISK; CAUCASIAN FEMALES; BREAST-CANCER; CARDIOVASCULAR-DISEASE; REPRODUCTIVE FACTORS; PREDICTIVE FACTORS AB Recent genome-wide association (GWA) studies have identified several novel genetic loci associated with age at menarche and age at natural menopause. However, the stringent significance threshold used in GWA studies potentially led to false negatives and true associations may have been overlooked. Incorporating biologically relevant information, we examined whether common genetic polymorphisms in candidate genes of nine groups of biologically plausible pathways and related phenotypes are associated with age at menarche and age at natural menopause. A total of 18,862 genotyped and imputed single nucleotide polymorphisms (SNPs) in 278 genes were assessed for their associations with these two traits among a total of 24,341 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 22,054). Linear regression was used to assess the marginal association of each SNP with each phenotype. We adjusted for multiple testing within each gene to identify statistically significant SNP associations at the gene level. To evaluate the overall evidence for an excess of statistically significant gene associations over the proportion expected by chance, we applied a one-sample test of proportion to each group of candidate genes. The steroid-hormone metabolism and biosynthesis pathway was found significantly associated with both age at menarche and age at natural menopause (P = 0.040 and 0.011, respectively). In addition, the group of genes associated with precocious or delayed puberty was found significantly associated with age at menarche (P = 0.013), and the group of genes involved in premature ovarian failure with age at menopause (P = 0.025). C1 [He, Chunyan] Indiana Univ, Sch Med, Dept Publ Hlth, Indianapolis, IN 46204 USA. [Kraft, Peter; Buring, Julie E.; Chen, Constance; Hankinson, Susan E.; Ridker, Paul M.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chasman, Daniel I.; Buring, Julie E.; Pare, Guillaume; Ridker, Paul M.] Harvard Univ, Brigham & Womens Hosp, Donald W Reynolds Ctr Cardiovasc Res, Sch Med, Boston, MA 02115 USA. [Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Sch Med, Boston, MA 02115 USA. [Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Hunter, David J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP He, CY (reprint author), Indiana Univ, Sch Med, Dept Publ Hlth, Indianapolis, IN 46204 USA. EM chunhe@iupui.edu FU National Heart Lung and Blood Institute [HL 043851, HL69757]; National Cancer Institute (Bethesda, MD, USA) [CA 047988]; Donald W. Reynolds Foundation (Las Vegas, NV, USA); Fondation Leducq (Paris, France); Amgen, Inc.; National Cancer Institute [CA 40356, CA 87969, U01-CA98233] FX We thank J. Miletich and A. Parker as well as the technical staff at Amgen, Inc (Cambridge, MA, USA) for their collaboration and scientific support in performing the genotyping for the WGHS. The NHS GWAS was performed as part of the Cancer Genetic Markers of Susceptibility initiative of the NCI. We particularly acknowledge the contributions of R. Hoover, A. Hutchinson, K. Jacobs and G. Thomas. We thank H. Ranu and P. Soule of the DF/HCC High Throughput Polymorphism Detection Laboratory for assistance. The WGHS is supported by HL 043851 and HL69757 from the National Heart Lung and Blood Institute and CA 047988 from the National Cancer Institute (Bethesda, MD, USA), the Donald W. Reynolds Foundation (Las Vegas, NV, USA), the Fondation Leducq (Paris, France), with collaborative scientific support and funding for genotyping provided by Amgen, Inc. The NHS is supported by CA 40356, CA 87969, and U01-CA98233 from the National Cancer Institute. We acknowledge the study participants in the NHS and the WGHS for their contribution in making this study possible. NR 74 TC 57 Z9 59 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD NOV PY 2010 VL 128 IS 5 BP 515 EP 527 DI 10.1007/s00439-010-0878-4 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 666EC UT WOS:000283094100005 PM 20734064 ER PT J AU O'Seaghdha, CM Yang, QO Glazer, NL Leak, TS Dehghan, A Smith, AV Kao, WHL Lohman, K Hwang, SJ Johnson, AD Hofman, A Uitterlinden, AG Chen, YDI Brown, EM Siscovick, DS Harris, TB Psaty, BM Coresh, J Gudnason, V Witteman, JC Liu, YM Kestenbaum, BR Fox, CS Kottgen, A AF O'Seaghdha, Conall M. Yang, Qiong Glazer, Nicole L. Leak, Tennille S. Dehghan, Abbas Smith, Albert V. Kao, W. H. Linda Lohman, Kurt Hwang, Shih-Jen Johnson, Andrew D. Hofman, Albert Uitterlinden, Andre G. Chen, Yii-Der Ida Brown, Edward M. Siscovick, David S. Harris, Tamara B. Psaty, Bruce M. Coresh, Josef Gudnason, Vilmundur Witteman, Jacqueline C. Liu, Yong Mei Kestenbaum, Bryan R. Fox, Caroline S. Koettgen, Anna CA GEFOS Consortium TI Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID BONE-MINERAL DENSITY; GENOME-WIDE ASSOCIATION; HYPOCALCIURIC HYPERCALCEMIA; A986S POLYMORPHISM; IONIZED CALCIUM; VITAMIN-D; DISEASE; DESIGN; PLASMA; KIDNEY AB Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for similar to 2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population. C1 [Kao, W. H. Linda; Coresh, Josef; Koettgen, Anna] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21287 USA. [O'Seaghdha, Conall M.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [Brown, Edward M.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Brown, Edward M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Johnson, Andrew D.; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Johnson, Andrew D.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA 01702 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Glazer, Nicole L.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Glazer, Nicole L.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Leak, Tennille S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Kao, W. H. Linda; Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Lohman, Kurt] Wake Forest Univ, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Liu, Yong Mei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Chen, Yii-Der Ida] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kestenbaum, Bryan R.] Univ Washington, Harborview Med Ctr, Div Nephrol, Seattle, WA 98195 USA. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, Dept Internal Med 4, D-79106 Freiburg, Germany. RP Kottgen, A (reprint author), Johns Hopkins Univ, Dept Epidemiol, 2024 E Monument St, Baltimore, MD 21287 USA. EM foxca@nhlbi.nih.gov; anna.koettgen@uniklinik-freiburg.de RI Kottgen, Anna/D-2920-2012; Johnson, Andrew/G-6520-2013; Yang, Qiong/G-5438-2014; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Dehghan, Abbas/0000-0001-6403-016X FU National Institutes of Health [N01-AG-12100, HHSN268200625226C, UL1RR025005]; Icelandic Heart Association; Althingi (the Icelandic Parliament); 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, R01HL087641, R01HL59367, R01HL086694, N01-HC-85079-86, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652, R01 AG027002]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; German Research Foundation; National Institutes of Health Career Development [K23 DK63274-01]; National Center for Research Resources [M01RR00425] FX AGES: The AGES-Reykjavik Study has been funded by National Institutes of Health contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). ARIC: The 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, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402 and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A. K. was supported by the Emmy Noether Programme of the German Research Foundation. CHS: The CHS research reported in this article was supported by contract numbers N01-HC-85079-86, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 and R01 AG027002 from the National Heart, Lung and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. In addition, funding was received from the National Institutes of Health Career Development Award K23 DK63274-01. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. FHS: This work was partially supported by the National Heart, Lung and Blood Institute's FraminghamHeart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the RobertDawson EvansEndowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. HEALTH ABC: This research was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The GWAS was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University and genotyping services were provided by the CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. RS: This 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 and the European Commission and the Municipality of Rotterdam. The genome-wide association database of the RS was funded through the Netherlands Organization of Scientific Research NWO (nos 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. A. D. is supported by an NWO grant (vici 918-76-619). GEFOS Consortium: The GEFOS Consortium (http://www.gefos.; org) have ben funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). NR 48 TC 47 Z9 47 U1 1 U2 16 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 NOV 1 PY 2010 VL 19 IS 21 BP 4296 EP 4303 DI 10.1093/hmg/ddq342 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 661TR UT WOS:000282751500017 PM 20705733 ER PT J AU Barenboim, M Zoltick, BJ Guo, YJ Weinberger, DR AF Barenboim, Maxim Zoltick, Brad J. Guo, Yongjian Weinberger, Daniel R. TI MicroSNiPer: A Web Tool for Prediction of SNP Effects on Putative microRNA Targets SO HUMAN MUTATION LA English DT Article DE microRNA; SNP; FASTA program; 3 ' UTR; gene expression; computational prediction ID BINDING-SITES; MESSENGER-RNAS; C. ELEGANS; SEQUENCE; GENE; POLYMORPHISMS; EXPRESSION; DATABASE; IDENTIFICATION; COMPLEMENTARY AB MicroRNAs are short, approximately 22 nucleotide noncoding RNAs binding to partially complementary sites in the 3'UTR of target mRNAs. This process generally results in repression of multiple targets by a particular microRNA. There is substantial interest in methods designed to predict the microRNA targets and effect of single nucleotide polymorphisms (SNPs) on microRNA binding, given the impact of microRNA on posttranscriptional regulation and its potential relation to complex diseases. We developed a web-based application, MicroSNiPer, which predicts the impact of a SNP on putative microRNA targets. This application interrogates the 30-untranslated region and predicts if a SNP within the target site will disrupt/eliminate or enhance/create a microRNA binding site. MicroSNiPer computes these sites and examines the effects of SNPs in real time. MicroSNiPer is a user-friendly Web-based tool. Its advantages include ease of use, flexibility, and straightforward graphical representation of the results. It is freely accessible at http://cbdb.nimh.nih.gov/microsniper. Hum Mutat 31: 1223-1232, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Barenboim, Maxim; Zoltick, Brad J.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Guo, Yongjian] NIAID, Bioinformat & Computat Biosci Branch, OCICB OSMO OD, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov FU National Institute of Mental Health, NIH FX M.B. conceived and designed the software. M. B., B.J.Z., and Y.G. implemented the software. D. R. W. developed requirements, planned and directed the project. All authors participated in writing the article and approved the final version. This work was supported by the Intramural Research Program of the National Institute of Mental Health, NIH. NR 52 TC 69 Z9 72 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2010 VL 31 IS 11 BP 1223 EP 1232 DI 10.1002/humu.21349 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 674XG UT WOS:000283783600013 PM 20809528 ER EF