FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Freiberg, AN Worthy, MN Lee, B Holbrook, MR AF Freiberg, Alexander N. Worthy, Melissa N. Lee, Benhur Holbrook, Michael R. TI Combined chloroquine and ribavirin treatment does not prevent death in a hamster model of Nipah and Hendra virus infection SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID SUBACUTE SCLEROSING-PANENCEPHALITIS; FLYING-FOXES; FATAL ENCEPHALITIS; BANGLADESH; HORSES; PARAMYXOVIRUS; MORBILLIVIRUS; TRANSMISSION; HUMANS; MALAYSIA AB Hendra virus (HeV) and Nipah virus (NiV) are recently emerged, closely related and highly pathogenic paramyxoviruses that cause severe disease such as encephalitis in animals and humans with fatality rates of up to 75 %. Due to their high case fatality rate following human infection and because of the lack of effective vaccines or therapy, they are classified as Biosafety Level 4 pathogens. A recent study reported that chloroquine, an anti-malarial drug, was effective in preventing NiV and HeV infection in cell culture experiments. In the present study, the antiviral efficacy of chloroquine was analysed, individually and in combination with ribavirin, in the treatment of NiV and HeV infection in in vivo experiments, using a golden hamster model. Although the results confirmed the strong antiviral activity of both drugs in inhibiting viral spread in vitro, they did not prove to be protective in the in vivo model. Ribavirin delayed death from viral disease in NiV-infected hamsters by approximately 5 days, but no significant effect in HeV-infected hamsters was observed. Chloroquine did not protect hamsters when administered either individually or in combination with ribavirin, the latter indicating the lack of a favourable drug-drug interaction. C1 [Freiberg, Alexander N.; Worthy, Melissa N.; Holbrook, Michael R.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Lee, Benhur] Univ Texas Med Branch, Dept Microbiol Immunol & Mol Genet, Galveston, TX 77555 USA. [Lee, Benhur] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90025 USA. [Lee, Benhur] Univ Calif Los Angeles, AIDS Inst, Los Angeles, CA 90025 USA. [Holbrook, Michael R.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Holbrook, Michael R.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. RP Holbrook, MR (reprint author), NIH, Integrated Res Facil, 8200 Res Plaza, Frederick, MD 21702 USA. EM Mike.Holbrook@utmb.edu RI Lee, Benhur/A-8554-2016 OI Lee, Benhur/0000-0003-0760-1709 FU NIH (NIAID) [U01 AI070495, U01 AI82100, UC7 AI070083]; Pacific South-west Regional Center of Excellence for Biodefense and Emerging Infectious Diseases [U54 AI065359] FX We would like to thank Terry Juelich, Allison Poussard, Lihong Zhang, Colette Keng and Stacy Agar for excellent technical assistance with the hamster studies. This work was supported by NIH (NIAID) grants U01 AI070495 and U01 AI82100 (B. L. and M. R. H.) and UC7 AI070083 (M. R. H.). B. L. was also supported by a grant from the Pacific South-west Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (U54 AI065359). NR 45 TC 20 Z9 20 U1 0 U2 7 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2010 VL 91 BP 765 EP 772 DI 10.1099/vir.0.017269-0 PN 3 PG 8 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 569HM UT WOS:000275587200021 PM 19889926 ER PT J AU Trimble, EL AF Trimble, Edward L. TI Global cooperation in gynecologic cancer SO JOURNAL OF GYNECOLOGIC ONCOLOGY LA English DT Editorial Material C1 NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM tt6m@nih.gov NR 0 TC 3 Z9 3 U1 0 U2 0 PU KOREAN SOC GYNECOLOGY ONCOLOGY & COLPOSCOPY PI SEOUL PA 102-HO, 55-5, NONHYEON-DONG, GANGNAM-GU, SEOUL, 135-010, SOUTH KOREA SN 2005-0380 J9 J GYNECOL ONCOL JI J. Gynecol. Oncol. PD MAR PY 2010 VL 21 IS 1 BP 1 EP 2 DI 10.3802/jgo.2010.21.1.1 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 576UR UT WOS:000276175400001 PM 20379440 ER PT J AU Semiletova, NV Shen, XD Baibakov, B Andakyan, A AF Semiletova, Natalya V. Shen, Xiu-Da Baibakov, Boris Andakyan, Arthur TI Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE MHC; peptide; T regulatory cells; chronic rejection; tolerance ID CHRONIC ALLOGRAFT-REJECTION; T-CELLS; TOLERANCE; PREVENTION; ACCOMMODATION; EXPRESSION; BLOOD; RATS AB BACKGROUND: The understanding of chronic rejection (transplant vascular sclerosis, or TVS) mechanisms is a major goal of transplantation. In this study we tested a cardiac transplant model for TVS development in connection with emerging T-regulatory cells (T-regs). We used 40-mer peptides derived from the donor MHC Class I alpha 1 helix of the alpha 1-domain to make recipients tolerant. METHODS: ACI recipients were transplanted with either RTI.A (WF), RTI.A(1) (LEW), RTI.A(c) (PVG), or RTI.A(b) (BUF) cardiac grafts. The grafts were analyzed 120 days later for TVS and development of T-regs. RESULTS: Donor MHC peptides were injected through the portal vein (0.1 mg) into ACI recipients of WF hearts in addition to sub-therapeutic cyclosporine (CsA, 10 mg/kg for 3 days post-operatively). Peptide treatment specifically prolonged graft survival for >100 days (n = 31). ACI recipients of WF or LEW hearts treated with PVG peptides promptly rejected the transplanted grafts (15 +/- 4 and 20 +/- I days, respectively). Presence of T-regs in tolerant recipients was confirmed by the adoptive transfer of T cells into a new cohort of syngeneic recipients (mean survival time [MST] >100 days, n = 3). CD4(+) and FoxP3(+) cells were detected in 70% of the chronically rejected grafts vs 38% (CD4) and 22% (FoxP3) in the well-preserved transplants. IgG and IgM deposits were found in only half of surviving cardiac grafts with a high level of TVS. Blood vessels in grafts with attenuated TVS were 80% IgG and IgM positive. Interleukin (IL)-4 and IL-2 were markedly down-regulated in the hearts with high TVS compared with well-preserved grafts. Long-term-surviving hearts demonstrated increased IL-10 expression. Interferon-gamma (IFN-gamma) was more evident in the grafts with a high TVS. CONCLUSIONS: Donor MHC Class I peptides can specifically prolong transplant survival and generate T-regs. The level of intragraft T-regs correlates with severity of TVS and IL-2/IL-4 down-regulation. J Heart Lung Transplant 2010;29:335-41 (C) 2010 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Semiletova, Natalya V.; Shen, Xiu-Da; Andakyan, Arthur] Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Baibakov, Boris] NIH, NIDDK, Bethesda, MD 20892 USA. RP Semiletova, NV (reprint author), Univ Calif Los Angeles, Sch Med, Div Gen Surg, 77-120 CHS,Box 957054, Los Angeles, CA 90095 USA. EM nsemiletova@mednet.ucla.edu FU American Heart Association [American Heart Association (0635221N]; American Society of Transplant Surgeons FX We thank Ana J. Coito, PhD, for helpful editorial comments and review of the manuscript.; Supported by a Scientist Development Grant from the American Heart Association (0635221N) and a Collaborative Scientist Award from the American Society of Transplant Surgeons.; The authors have no conflicts of interests to disclose. NR 19 TC 6 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD MAR PY 2010 VL 29 IS 3 BP 335 EP 341 DI 10.1016/j.healun.2009.08.003 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 574PX UT WOS:000276005200017 PM 20080050 ER PT J AU Ali, MM Bhattacharyya, P Olejniczak, AJ AF Ali, Mir M. Bhattacharyya, Partha Olejniczak, Anthony J. TI The Effects of Scholarly Productivity and Institutional Characteristics on the Distribution of Federal Research Grants SO JOURNAL OF HIGHER EDUCATION LA English DT Article ID FACULTY; FAVOR AB The Effects of Scholarly Productivity and Institutional Characteristics on the Distribution of Federal Research Grants. We estimate the effects of faculty scholarly productivity and institutional characteristics on the distribution of federally funded research grants. Although faculty with more publications and citations have a greater likelihood of securing competitive research grants than their less prolific peers, the benefit of having published papers in terms of improving one's ability to secure grants tapers as the number of papers published increases. Institutional characteristics (such as AAU membership and public/private status) act to modulate the impact of individual productivity such that otherwise equally productive faculties at private universities and AAU member institutions secure more grants (and more grant dollars) than public and non-AAU member institutions. Overall, institutional characteristics play a more significant role in determining the dollar amount of grants than the number of grants. C1 [Ali, Mir M.] Univ Toledo, Toledo, OH 43606 USA. [Bhattacharyya, Partha] NIA, NIH, Bethesda, MD 20892 USA. RP Ali, MM (reprint author), Univ Toledo, Toledo, OH 43606 USA. OI Olejniczak, Anthony/0000-0002-4666-8933 NR 11 TC 9 Z9 9 U1 1 U2 14 PU OHIO STATE UNIV PRESS PI COLUMBUS PA 1050 CARMACK RD, COLUMBUS, OH 43210 USA SN 0022-1546 J9 J HIGH EDUC JI J. High. Educ. PD MAR-APR PY 2010 VL 81 IS 2 BP 164 EP + PG 16 WC Education & Educational Research SC Education & Educational Research GA 575ZA UT WOS:000276111500003 ER PT J AU Kataoka, TR Kumanogoh, A Bandara, G Metcalfe, DD Gilfillan, AM AF Kataoka, Tatsuki R. Kumanogoh, Atsushi Bandara, Geethani Metcalfe, Dean D. Gilfillan, Alasdair M. TI CD72 Negatively Regulates KIT-Mediated Responses in Human Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TYROSINE-PHOSPHATASE SHP-1; FC-EPSILON-RI; MONOCLONAL ANTI-LYB-2 ANTIBODY; PROTOONCOGENE C-KIT; IV SEMAPHORIN CD100; B-CELL; GROWTH-FACTOR; NONREDUNDANT ROLES; ANTIGEN RECEPTOR; IMMUNE-SYSTEM AB KIT activation, through binding of its ligand, stem cell factor, is crucial for normal mast cell growth, differentiation, and survival. Furthermore, KIT may also contribute to mast cell homing and cytokine generation. Activating mutations in KIT lead to the dysregulated mast cell growth associated with the myeloproliferative disorder, mastocytosis. We investigated the potential of downregulating such responses through mast cell inhibitory receptor activation. In this study, we report that the B cell-associated ITIM-containing inhibitory receptor, CD72, is expressed in human mast cells. Ligation of CD72 with the agonistic Ab, BU40, or with recombinant human CD100 (rCD100), its natural ligand, induced the phosphorylation of CD72 with a resulting increase in its association with the tyrosine phosphatase SH2 domain-containing phosphatase-1. This, in turn, resulted in an inhibition of KIT-induced phosphorylation of Src family kinases and extracellular-regulated kinases (ERK1/2). As a consequence of these effects, KIT-mediated mast cell proliferation, chemotaxis, and chemokine production were significantly reduced by BU40 and rCD100. Furthermore, BU40 and rCD100 also downregulated the growth of the HMC1.2 human mast cell line. Thus, targeting CD72 may provide a novel approach to the suppression of mast cell disease such as mastocytosis. The Journal of Immunology, 2010, 184: 2468-2475. C1 [Kataoka, Tatsuki R.] Hyogo Coll Med, Dept Pathol, Nishinomiya, Hyogo 6638501, Japan. [Kataoka, Tatsuki R.; Bandara, Geethani; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Kumanogoh, Atsushi] Res Inst Microbial Dis, Dept Immunopathol, Osaka, Japan. [Kumanogoh, Atsushi] Osaka Univ, WPI Immunol Frontier Res Ctr, Osaka, Japan. RP Kataoka, TR (reprint author), Hyogo Coll Med, Dept Pathol, 1-1 Mukogawa, Nishinomiya, Hyogo 6638501, Japan. EM trkataoka@yahoo.co.jp RI Kumanogoh, Atsushi/C-7354-2009 FU National Institutes of Health, United States; Ministry of Education, Culture, Sports. Science and Technology, Japan FX This work was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research within the National Institutes of Health, United States, and by grants from the Ministry of Education, Culture, Sports. Science and Technology, Japan. NR 50 TC 15 Z9 17 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2010 VL 184 IS 5 BP 2468 EP 2475 DI 10.4049/jimmunol.0902450 PG 8 WC Immunology SC Immunology GA 558TG UT WOS:000274768900030 PM 20100931 ER PT J AU Biasin, M Piacentini, L Lo Caputo, S Naddeo, V Pierotti, P Borelli, M Trabattoni, D Mazzotta, F Shearer, GM Clerici, M AF Biasin, Mara Piacentini, Luca Lo Caputo, Sergio Naddeo, Valentina Pierotti, Piera Borelli, Manuela Trabattoni, Daria Mazzotta, Francesco Shearer, Gene M. Clerici, Mario TI TLR Activation Pathways in HIV-1-Exposed Seronegative Individuals SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC IMMUNE ACTIVATION; INTRAVASCULAR DRUG-USERS; HIV-INFECTION; UNINFECTED INDIVIDUALS; DENDRITIC CELLS; I INTERFERON; SEX WORKERS; IMMUNODEFICIENCY; RESISTANCE; EXPRESSION AB TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:Q, TLR4 (LIPS), TLR7 (imiquilmod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly 1:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1 beta, IL-6, TNF-alpha, and CCU; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1 alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1. The Journal of Immunology, 2010, 184: 2710-2717. C1 [Clerici, Mario] Univ Milan, Fac Med & Chirurg, DISPLITA Vialba, Cattedra Immunol, I-20157 Milan, Italy. [Clerici, Mario] IRCCS, Fdn Don Gnocchi, Milan, Italy. [Lo Caputo, Sergio; Pierotti, Piera; Mazzotta, Francesco] Osped SM Annunziata, Div Malattie Infett, Florence, Italy. [Shearer, Gene M.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Clerici, M (reprint author), Univ Milan, Fac Med & Chirurg, DISPLITA Vialba, Cattedra Immunol, Via GB Grassi, I-20157 Milan, Italy. EM mario.clerici@unimi.it RI Trabattoni, Daria/G-7424-2012; Piacentini, Luca/K-8908-2016; OI Piacentini, Luca/0000-0003-1022-4481; Clerici, Mario/0000-0001-5920-6191 FU Istituto Superiore di Sanita Programma Nazionale di Ricerca sull AIDS; European Community; Japan Health Science Foundation; Italian Ministry of Health; progetto Bando Futuro in Ricerca RETI, Rete Italiana Chimica Farmaceutica Ricerca e Sviluppo del Farmaco [RBPR05NWWC] FX This work was supported by grants from the Istituto Superiore di Sanita Programma Nazionale di Ricerca sull AIDS; the European Microbicides Project and AIDS Vaccine Integrated Project, European Community WP6 Projects; the Next Generation HIV-1 Immunogens inducing broadly reactive Neutralising antibodies European Community WP7 Project; the Japan Health Science Foundation; 2007 Ricerca Finalizzata (Italian Ministry of Health); 2007 Ricerca Corrente (Italian Ministry of Health) and progetto Bando Futuro in Ricerca RETI, Rete Italiana Chimica Farmaceutica Ricerca e Sviluppo del Farmaco (RBPR05NWWC). NR 36 TC 31 Z9 31 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2010 VL 184 IS 5 BP 2710 EP 2717 DI 10.4049/jimmunol.0902463 PG 8 WC Immunology SC Immunology GA 558TG UT WOS:000274768900057 PM 20124101 ER PT J AU Halvas, EK Wiegand, A Boltz, VF Kearney, M Nissley, D Wantman, M Hammer, SM Palmer, S Vaida, F Coffin, JM Mellors, JW AF Halvas, Elias K. Wiegand, Ann Boltz, Valerie F. Kearney, Mary Nissley, Dwight Wantman, Michael Hammer, Scott M. Palmer, Sarah Vaida, Florin Coffin, John M. Mellors, John W. TI Low Frequency Nonnucleoside Reverse-Transcriptase Inhibitor-Resistant Variants Contribute to Failure of Efavirenz-Containing Regimens in Treatment-Experienced Patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SINGLE-DOSE NEVIRAPINE; ANTIRETROVIRAL-DRUG-RESISTANCE; MULTIPLE SEQUENCE ALIGNMENT; HIV-1 INFECTION; IN-VIVO; THERAPY; MUTATIONS; POPULATIONS; TRANSMISSION AB Background. The contribution of low frequency drug-resistant human immunodeficiency virus type 1 (HIV1) variants to failure of antiretroviral therapy is not well defined in treatment-experienced patients. We sought to detect minor nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants at the initiation of multidrug efavirenz-containing therapy in both NNRTI-naive and NNRTI-experienced patients and to determine their association with virologic response. Methods. Plasma samples at entry and at time of virologic failure from patients enrolled in the AIDS Clinical Trials Group study 398 were analyzed by standard genotype, single-genome sequencing and allele-specific polymerase chain reaction (K103N and Y181C) to detect and quantify minor NNRTI-resistant variants. Results. Minor populations of NNRTI-resistant variants that were missed by standard genotype were detected more often at study entry in NNRTI-experienced patients than NNRTI-naive patients by both single-genome sequencing (8 of 12 vs 3 of 15; P = .022) and allele-specific polymerase chain reaction (>1% Y181C, 5 of 22 vs 3 of 72, respectively; P = .016). K103N variants at frequencies >1% were associated with inferior HIV-1 RNA response to efavirenz-containing therapy between entry and week 24 (change in HIV-1 RNA level, +0.5 vs -1.1 log(10) copies/mL; P<.001 Conclusions. Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens. C1 [Mellors, John W.] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. [Wiegand, Ann; Boltz, Valerie F.; Kearney, Mary; Palmer, Sarah; Coffin, John M.] NCI, HIV Drug Resistance Program, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Nissley, Dwight] NCI, Basic Res Program, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Wantman, Michael] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Hammer, Scott M.] Columbia Univ Coll Phys & Surg, Div Infect Dis, New York, NY 10032 USA. [Vaida, Florin] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Palmer, Sarah] Karolinska Inst, Swedish Inst Infect Dis Control, Dept Virol, Solna, Sweden. RP Mellors, JW (reprint author), Univ Pittsburgh, Dept Med, Div Infect Dis, 818 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM jwm1@pitt.edu FU NIAID; Division of AIDS University of Pittsburgh CTU [1U01 AI069494-01]; Virology Support Laboratory [204VC009]; ACTG Central Group [1U01AI068636-01] FX Financial support: NIAID, Division of AIDS (University of Pittsburgh CTU Grant 1U01 AI069494-01), and a Virology Support Laboratory subcontract (204VC009) of the ACTG Central Group Grant (1U01AI068636-01). NR 36 TC 63 Z9 65 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2010 VL 201 IS 5 BP 672 EP 680 DI 10.1086/650542 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552MW UT WOS:000274296600008 PM 20102272 ER PT J AU Minkoff, H Zhong, Y Burk, RD Palefsky, JM Xue, XN Watts, DH Levine, AM Wright, RL Colie, C D'Souza, G Massad, LS Strickler, HD AF Minkoff, Howard Zhong, Ye Burk, Robert D. Palefsky, Joel M. Xue, Xiaonan Watts, D. Heather Levine, Alexandra M. Wright, Rodney L. Colie, Christine D'Souza, Gypsyamber Massad, L. Stewart Strickler, Howard D. TI Influence of Adherent and Effective Antiretroviral Therapy Use on Human Papillomavirus Infection and Squamous Intraepithelial Lesions in Human Immunodeficiency Virus-Positive Women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL CYTOLOGIC CHANGES; HIV-SEROPOSITIVE WOMEN; HIV-1-INFECTED PATIENTS; NATURAL-HISTORY; SEXUAL-BEHAVIOR; CANCER; RISK; NEOPLASIA; COHORT; ERA AB Background. The impact of highly active antiretroviral therapy (HAART) on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients' adherence to their regimens or HAART effectiveness (viral suppression). Methods. Human immunodeficiency virus (HIV)-positive women (N = 286) who initiated HAART during follow-up in a prospective cohort were assessed semiannually for HPV infection (by polymerase chain reaction) and squamous intraepithelial lesions (SILs). Adherence was defined as use of HAART as prescribed >= 95% of the time, and effective HAART was defined as suppression of HIV replication. The prevalence, incident detection, and clearance of HPV infection and/or SILs before versus after HAART initiation were compared (using women as their own comparison group). Results. HAART initiation among adherent women was associated with a significant reduction in prevalence (odds ratio, 0.60 [95% confidence interval {CI}, 0.44-0.81]; P = .001), incident detection of oncogenic HPV infection (hazard ratio [HR], 0.49 [95% CI, 0.30-0.82]; P = .006), and decreased prevalence and more rapid clearance of oncogenic HPV-positive SILs (HR, 2.35 [95% CI, 1.07-5.18]; P = .03). Effects were smaller among nonadherent women. The associations of HPV infection and/or SILs with HAART effectiveness were fairly similar to those with HAART adherence. Conclusion. Effective and adherent HAART use is associated with a significantly reduced burden of HPV infection and SILs; this may help explain why rates of cervical cancer have not increased during the HAART era, despite greater longevity. C1 [Minkoff, Howard] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Minkoff, Howard] SUNY Downstate, Brooklyn, NY 11219 USA. [Zhong, Ye; Burk, Robert D.; Xue, Xiaonan; Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Wright, Rodney L.] Albert Einstein Coll Med, Dept Obstet & Gynecol, Bronx, NY 10467 USA. [Palefsky, Joel M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Levine, Alexandra M.] Univ So Calif, Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Watts, D. Heather] NIH, Bethesda, MD 20892 USA. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Colie, Christine] Georgetown Univ, Sch Med, Dept Med, Washington, DC USA. [Massad, L. Stewart] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. RP Minkoff, H (reprint author), Maimonides Hosp, Dept Obstet & Gynecol, 967 48th St, Brooklyn, NY 11219 USA. EM hminkoff@maimonidesmed.org FU NIH FX 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 (NIH). However, because this was an NIH-funded multicenter cohort study, the funding sources played a role in the WIHS study design; in the collection, analysis, and interpretation of data; and in the preparation, review, and approval of the manuscript. NR 30 TC 71 Z9 73 U1 1 U2 2 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 MAR 1 PY 2010 VL 201 IS 5 BP 681 EP 690 DI 10.1086/650467 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552MW UT WOS:000274296600009 PM 20105077 ER PT J AU Lucas, HR Lee, JC AF Lucas, Heather R. Lee, Jennifer C. TI Effect of dioxygen on copper(II) binding to alpha-synuclein SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Article; Proceedings Paper CT 2nd Georgian Bay International Conference on Bioinorganic Chemistry CY MAY 26-29, 2009 CL Parry Sound, CANADA SP Dockside Charles W Stockey Ctr DE Parkinson's disease; Amyloid; Tryptophan; Circular dichroism; Methionine oxidation; Cation-pi ID RAY-ABSORPTION SPECTROSCOPY; PARKINSONS-DISEASES; PRION PROTEIN; CATION-PI; ALZHEIMERS; SITES; COORDINATION; AGGREGATION; METHIONINE; STABILITY AB Using the fluorescent amino acid tryptophan (Trp), we have characterized the copper(II) binding of F4W alpha-synuclein in the presence and absence of dioxygen at neutral pH. Variations in Trp fluorescence indicate that copper(II) binding is enhanced by the presence of dioxygen, with the apparent dissociation constant (K(d(app))) changing from 100 nM (anaerobic) to 10 nM (aerobic). To investigate the possible role of methionine oxidation, complementary work focused on synthetic peptide models of the N-terminal Cu(II)-alpha-syn site, MDV(F/W) and M*DV(F/W), where M* = methionine sulfoxide. Furthermore, we employed circular dichroism (CD) spectroscopy to demonstrate that the phenyl-to-indole (F -> W) substitution does not alter copper(II) binding properties and to confirm the 1:1 metal-peptide binding stoichiometry. CD comparisons also revealed that Met1 oxidation does not affect the copper-peptide conformation and further suggested the possible existence of a Cu(II)-Trp/Phe (cation-pi) interaction. Published by Elsevier Inc. C1 [Lucas, Heather R.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural NIH HHS [ZIA HL001055-03] NR 30 TC 15 Z9 15 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD MAR PY 2010 VL 104 IS 3 BP 245 EP 249 DI 10.1016/j.jinorgbio.2009.12.010 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 560RY UT WOS:000274921100004 PM 20064662 ER PT J AU Yamaguchi, Y Hearing, VJ Maeda, A Morita, A AF Yamaguchi, Yuji Hearing, Vincent J. Maeda, Akira Morita, Akimichi TI NADPH:Quinone Oxidoreductase-1 as a New Regulatory Enzyme That Increases Melanin Synthesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID SKIN PIGMENTATION; MELANOMAS AB Most hypopigmenting reagents target the inhibition of tyrosinase, the key enzyme involved in melanin synthesis. In this issue, Choi et al. report that NADPH:quinone oxidoreductase-1 (NQO1) increases melanin synthesis, probably via the suppression of tyrosinase degradation. Because NQO1 was identified by comparing normally pigmented melanocytes with hypopigmented acral lentiginous melanoma cells, these results Suggest various hypotheses regarding the carcinogenic origin of the latter. C1 [Yamaguchi, Yuji] Nagoya City Univ, Dept Geriatr & Environm Dermatol, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yamaguchi, Y (reprint author), Nagoya City Univ, Dept Geriatr & Environm Dermatol, Grad Sch Med Sci, Mizuho Ku, 1 Kawasumi, Nagoya, Aichi 4678601, Japan. NR 10 TC 3 Z9 3 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2010 VL 130 IS 3 BP 645 EP 647 DI 10.1038/jid.2009.378 PG 3 WC Dermatology SC Dermatology GA 561ZC UT WOS:000275017600006 PM 20145642 ER PT J AU Mascia, F Cataisson, C Lee, TC Threadgill, D Mariani, V Amerio, P Chandrasekhara, C Adeva, GS Girolomoni, G Yuspa, SH Pastore, S AF Mascia, Francesca Cataisson, Christophe Lee, Tang-Cheng Threadgill, David Mariani, Valentina Amerio, Paolo Chandrasekhara, Chinmayi Adeva, Gema Souto Girolomoni, Giampiero Yuspa, Stuart H. Pastore, Saveria TI EGFR Regulates the Expression of Keratinocyte-Derived Granulocyte/Macrophage Colony-Stimulating Factor In Vitro and In Vivo SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASES; GROWTH-FACTOR RECEPTOR; HUMAN EPIDERMAL-KERATINOCYTES; CHEMOKINE EXPRESSION; FACTOR-ALPHA; HUMAN SKIN; TARGETED DISRUPTION; ATOPIC-DERMATITIS; CARCINOMA-CELLS; GM-CSF AB Recent advances in the knowledge of the EGFR pathway have revealed its contribution to distinct immune/inflammatory functions of the epidermis. The purpose of our study was to evaluate the role of EGFR in the regulation of keratinocyte GM-CSF expression. In cultured human keratinocytes, proinflammatory cytokines synergized with TGF-alpha to induce GM-CSF expression. Accordingly, high epidermal levels of EGFR activation are associated with enhanced expression of GM-CSF in lesional skin of patients with psoriasis or allergic contact dermatitis. In cultured keratinocytes, pharmacological inhibition of EGFR activity reduced GM-CSF promoter transactivation, whereas genetic inhibition of AP-1 reduced expression of GM-CSF. Furthermore, EGFR activation enhanced TNF-alpha-induced c-Jun phosphorylation and DNA binding, whereas c-Jun silencing reduced GM-CSF expression. Using two different mouse models, we showed that the lack of a functional EGFR pathway was associated with reduced cytokine-induced phosphorylation of ERK1/2, JNK1/2, c-Jun and reduced keratinocyte-derived GM-CSF expression both in vitro and in vivo. Finally, the analysis of CM-CSF expression in the skin of cancer patients treated with anti EGFR drugs showed an association between ERK activity, c-Jun phosphorylation, and epidermal GM-CSF expression. These data demonstrate that the EGFR pathway is critical for the upregulation of keratinocyte GM-CSF expression under conditions of cytokine stimulation. C1 [Mascia, Francesca] NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. [Lee, Tang-Cheng; Threadgill, David] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lee, Tang-Cheng; Threadgill, David] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC USA. [Mariani, Valentina; Pastore, Saveria] IRCCS, Lab Tissue Engn & Cutaneous Physiopathol, Ist Dermopat Immacolata, Rome, Italy. [Amerio, Paolo] Univ G dAnnunzio, Dermatol Clin, Chieti, Italy. [Girolomoni, Giampiero] Univ Verona, Dept Biomed & Surg Sci, Dermatol Sect, I-37100 Verona, Italy. RP Mascia, F (reprint author), NCI, Lab Canc Biol & Genet, CCR, NIH, 37 Convent Dr,Bldg 37 Rm 4066, Bethesda, MD 20892 USA. RI Threadgill, David/N-4425-2013; OI Threadgill, David/0000-0003-3538-1635; AMERIO, Paolo/0000-0003-1589-9672 FU Ministero della Salute; Ministero dell'Istruzione; dell'Universita e della Ricerca; Intramural Research Program of the Center for Cancer Research, NCI, NIH FX The authors thanks Marta Custer for her technical assistance with the mouse colony and the summer Students Susan Shen and Rachel Packer for their help in genotyping the mice The authors also acknowledge Professor Michele De Turst (Oncology Department of University of Chieti and Pescara) for providing skin samples from cetuximab-treated patients This work was supported by grants from the Ministero della Salute, Ministero dell'Istruzione, dell'Universita e della Ricerca (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN), and Fondo 60%) and from the Intramural Research Program of the Center for Cancer Research, NCI, NIH NR 45 TC 38 Z9 39 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2010 VL 130 IS 3 BP 682 EP 693 DI 10.1038/jid.2009.336 PG 12 WC Dermatology SC Dermatology GA 561ZC UT WOS:000275017600012 PM 19890352 ER PT J AU Elmariah, S O'Brien, KD Budoff, MJ Bluemke, D Delaney, JA Fuster, V Kronmal, RA Halperin, JL AF Elmariah, S. O'Brien, K. D. Budoff, M. J. Bluemke, D. Delaney, J. A. Fuster, V. Kronmal, R. A. Halperin, J. L. TI RELATIONSHIP BETWEEN LEFT VENTRICULAR MASS AND AORTIC VALVE CALCIFICATION: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research CY APR 05-06, 2010 CL Washington, DC SP Amer Federat Med Res, Eastern Reg C1 [Elmariah, S.; Fuster, V.; Halperin, J. L.] Mt Sinai Sch Med, Cardiovasc Inst, New York, NY USA. [O'Brien, K. D.; Delaney, J. A.; Kronmal, R. A.] Univ Washington, Seattle, WA 98195 USA. [Budoff, M. J.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Bluemke, D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bluemke, D.] NIH, Bethesda, MD 20892 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 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2010 VL 58 IS 3 BP 587 EP 587 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 572RQ UT WOS:000275850900017 ER PT J AU Miller, B McCardle, P Hernandez, R AF Miller, Brett McCardle, Peggy Hernandez, Ricardo TI Advances and Remaining Challenges in Adult Literacy Research SO JOURNAL OF LEARNING DISABILITIES LA English DT Article DE literacy; reading; adult basic education; adult learning AB Low literacy levels in adult learners pose an educational and public health challenge to practitioners and the scientific community. Increasing demands placed on literacy can limit opportunities in the workplace and access to health-related resources, negatively affecting public health. Current estimates from the National Center for Education Statistics suggest that more than 40 million adults in the United States possess only the most basic and concrete literacy skills. Despite the estimated number of learners possessing minimal literacy skills in English in the United States, there remains a paucity of research focused on adult learners to inform remediation efforts. This special issue of the Journal of Learning Disabilities represents an important step in highlighting the current scientific knowledge base and the implications for future directions and lines of inquiry with adult learners. C1 [Miller, Brett; McCardle, Peggy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Hernandez, Ricardo] US Dept Educ, Off Vocat & Adult Educ, Washington, DC USA. RP Miller, B (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,Suite 4B05,MSC 7510, Bethesda, MD 20892 USA. EM millerbre@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 20 TC 11 Z9 11 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-2194 J9 J LEARN DISABIL-US JI J. Learn. Disabil. PD MAR PY 2010 VL 43 IS 2 BP 101 EP 107 DI 10.1177/0022219409359341 PG 7 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 559SL UT WOS:000274847900002 PM 20179305 ER PT J AU Melillo, G AF Melillo, Giovanni TI T cells, not "immune" from HIF SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID HYPOXIA; CANCER C1 NCI, DTP Tumor Hypoxia Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Melillo, G (reprint author), NCI, DTP Tumor Hypoxia Lab, SAIC Frederick Inc, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillog@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 9 TC 1 Z9 1 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2010 VL 87 IS 3 BP 359 EP 361 DI 10.1189/jlb.1009678 PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 618FA UT WOS:000279335700003 PM 20194161 ER PT J AU Curcio, CA Johnson, M Huang, JD Rudolf, M AF Curcio, Christine A. Johnson, Mark Huang, Jiahn-Dar Rudolf, Martin TI Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration SO JOURNAL OF LIPID RESEARCH LA English DT Review DE retinal pigment epithelium; Bruch's membrane; drusen; basal deposits; cholesterol; retinyl ester ID PIGMENT EPITHELIAL-CELLS; HUMAN ATHEROSCLEROTIC LESIONS; TRIGLYCERIDE TRANSFER PROTEIN; LOW-DENSITY-LIPOPROTEIN; HUMAN BRUCHS MEMBRANE; BASAL LINEAR DEPOSIT; ATYPICAL RETINITIS-PIGMENTOSA; POLARIZING LIGHT-MICROSCOPY; AMERICAN-HEART-ASSOCIATION; ENDOTHELIAL GROWTH-FACTOR AB The largest risk factor for age-related macular degeneration (ARMD) is advanced age. With aging, there is a striking accumulation of neutral lipids in Bruch's membrane (BrM) of normal eye that continues through adulthood. This accumulation has the potential to significantly impact the physiology of the retinal pigment epithelium (RPE). It also ultimately leads to the creation of a lipid wall at the same locations where drusen and basal linear deposit, the pathognomonic extracellular, lipid-containing lesions of ARMD, subsequently form. Here, we summarize evidence obtained from light microscopy, ultrastructural studies, lipid histochemistry, assay of isolated lipoproteins, and gene expression analysis. These studies suggest that lipid deposition in BrM is at least partially due to accumulation of esterified cholesterol-rich, apolipoprotein B-containing lipoprotein particles produced by the RPE. Furthermore, we suggest that the formation of ARMD lesions and their aftermath may be a pathological response to the retention of a subendothelial apolipoprotein B lipoprotein, similar to a widely accepted model of atherosclerotic coronary artery disease (Tabas, I., K.J. Williams, and J. Boren. 2007. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 116: 1832-1844). This view provides a conceptual basis for the development of novel treatments that may benefit ARMD patients in the future.-Curcio, C. A., M. Johnson, J-D. Huang, and M. Rudolf. Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration. J. Lipid Res. 2010. 51: 451-467. C1 [Curcio, Christine A.] Univ Alabama, Sch Med, Dept Ophthalmol, Birmingham, AL USA. [Johnson, Mark] Northwestern Univ, Dept Biomed Engn, Evanston, IL USA. [Huang, Jiahn-Dar] NEI, NIH, Bethesda, MD 20892 USA. [Rudolf, Martin] Lubeck Univ Klinikum Schleswig Holstein, Lubeck, Germany. RP Curcio, CA (reprint author), Univ Alabama, Sch Med, Dept Ophthalmol, Birmingham, AL USA. EM curcio@uab.edu RI Johnson, Mark/B-6921-2009 FU National Institutes of Health [EY06109, EY014662]; International Retinal Research Foundation; American Health Assistance Foundation; EyeSight Foundation of Alabama; Research to Prevent Blindness, Inc.; Macula Vision Research Foundation; Roger Johnson Prize in Macular Degeneration Research; Deutsche Forschungsgemeinschaft FX This work was supported by the National Institutes of Health grants EY06109 and EY014662, the International Retinal Research Foundation, the American Health Assistance Foundation, the EyeSight Foundation of Alabama, Research to Prevent Blindness, Inc., the Macula Vision Research Foundation, the Roger Johnson Prize in Macular Degeneration Research, and Deutsche Forschungsgemeinschaft. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 200 TC 69 Z9 69 U1 2 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2010 VL 51 IS 3 BP 451 EP 467 DI 10.1194/jlr.R002238 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 555LW UT WOS:000274513300002 PM 19797256 ER PT J AU Kimmel, AR Brasaemle, DL McAndrews-Hill, M Sztalryd, C Londos, C AF Kimmel, Alan R. Brasaemle, Dawn L. McAndrews-Hill, Monica Sztalryd, Carole Londos, Constantine TI Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins SO JOURNAL OF LIPID RESEARCH LA English DT Review DE perilipin; adipocyte differentiation-related protein; adipophilin; tail-interacting protein of 47 kDa ID DIFFERENTIATION-RELATED PROTEIN; MESSENGER-RNA; DOMAIN; TIP47; ADIPOCYTES; DROSOPHILA; LIPOLYSIS; SEQUENCE; CLONING; ACCUMULATION AB The PAT family of proteins has been identified in eukaryotic species as diverse as vertebrates, insects, and amebazoa. These proteins share a highly conserved sequence organization and avidity for the surfaces of intra cellular, neutral lipid storage droplets. The current nomenclature of the various members lacks consistency and precision, deriving more from historic context than from recognition of evolutionary relationship and shared function. In consultation with the Mouse Genomic Nomenclature Committee, the Human Genome Organization Genomic Nomenclature Committee, and conferees at the 2007 FASEB Conference on Lipid Droplets: Metabolic Consequences of the Storage of Neutral Lipids, we have established a unifying nomenclature for the gene and protein family members. Each gene member will incorporate the root term PERILIPIN (PLIN), the founding gene of the PAT family, with the different genes/proteins numbered sequentially.-Kimmel, A. R., D. L. Brasaemle, M. McAndrews-Hill, C. Sztalryd, and C. Londos. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J. Lipid Res. 2010. 51: 468-471. C1 [Kimmel, Alan R.; Londos, Constantine] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Brasaemle, Dawn L.] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. [McAndrews-Hill, Monica] Jackson Lab, Bar Harbor, ME 04609 USA. [Sztalryd, Carole] Univ Maryland, Sch Med, Ctr Geriatr Res Educ & Clin, Vet Affairs Med Ctr,Dept Med, Baltimore, MD 21201 USA. RP Kimmel, AR (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov OI Brasaemle, Dawn/0000-0002-8553-8285 FU National Institutes of Health [R01 DK54797]; National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association [1-05-CD-17]; Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center; Clinical Nutrition Research Unit of Maryland [DK072488] FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases (A.R.K., C.L.), by the National Institutes of Health grant R01 DK54797 (D.L.B.), the American Diabetes Association career development award 1-05-CD-17 (C.S.), the Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center (C.S.), and the Clinical Nutrition Research Unit of Maryland DK072488 (C.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 35 TC 193 Z9 203 U1 3 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2010 VL 51 IS 3 BP 468 EP 471 DI 10.1194/jlr.R000034 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 555LW UT WOS:000274513300003 PM 19638644 ER PT J AU Matos, A Duque, V Beato, S da Silva, JP Major, E Melico-Silvestre, A AF Matos, Ana Duque, Vitor Beato, Silvia da Silva, Joao Poiares Major, Eugene Melico-Silvestre, Antonio TI Characterization of JC Human Polyomavirus Infection in a Portuguese Population SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE JC virus; epidemiology; seroprevalence; urinary excretion; Portugal ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; NON-HODGKIN-LYMPHOMA; COMPLETE GENOMES; BK VIRUS; URINARY-EXCRETION; IMMUNOCOMPETENT INDIVIDUALS; MOLECULAR EPIDEMIOLOGY; VIRAL EVOLUTION; BLOOD-DONORS; GENOTYPES AB JC virus (JCV) is ubiquitous in the human population, infecting children asymptomatically. After primary infection, JCV persists in the host-throughout life and is often excreted in the urine. Two hundred thirty-four urine samples and 78 serum samples, collected from 171 healthy individuals and 63 patients infected with HIV, were used to characterize JCV infection in a Portuguese population. Using PCR, JCV DNA was detected in 38% of the urine samples. A significant difference in the excretion rate was observed between patients infected with HIV (51%) and healthy individuals (33%). The frequency of JCV viruria increased with age in healthy individuals, but not in patients infected with HIV. JCV urinary load was determined by real-time quantitative PCR and was independent of gender, age, HIV infection, and CD4+ cell count. Overall, the JCV genotype detected most commonly was 113, followed by genotypes 2B and 4. The detection and quantitation of JCV-specific antibodies were performed in serum samples by an established enzyme immunoassay (EIA). Antibodies to JCV were observed in 91% of the patients tested, irrespective of HIV infection. A positive correlation between JCV urinary load and antibody titers was demonstrated. The present study provides the first characterization of seroprevalence and urinary excretion of JCV in a Portuguese population and revealed similar results to those observed in other European countries. A comparison between healthy individuals and patients infected with HIV, despite identical values of seroprevalence, showed some differences in the pattern of urinary excretion. J. Med Virol. 82:494-504, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Matos, Ana; da Silva, Joao Poiares] Univ Coimbra, Fac Farm, Microbiol Lab, P-3000548 Coimbra, Portugal. [Duque, Vitor] Coimbras Univ Hosp, Virol Lab, Dept Infect Dis, Coimbra, Portugal. [Beato, Silvia] IPCB, Dr Lopes Dias Sch Hlth, Castelo Branco, Portugal. [Major, Eugene] Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD USA. [Melico-Silvestre, Antonio] Coimbras Univ Hosp, Dept Infect Dis, Coimbra, Portugal. RP Matos, A (reprint author), Univ Coimbra, Fac Farm, Microbiol Lab, P-3000548 Coimbra, Portugal. EM anamatos@ci.uc.pt RI Beato, Silvia/L-2032-2015 OI Matos, Ana Miguel/0000-0001-5764-0023; Beato, Silvia/0000-0003-0683-0665 NR 45 TC 39 Z9 39 U1 2 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD MAR PY 2010 VL 82 IS 3 BP 494 EP 504 DI 10.1002/jmv.21710 PG 11 WC Virology SC Virology GA 548IP UT WOS:000273955000019 PM 20087944 ER PT J AU Wang, PS Patrick, AR Dormuth, C Maclure, M Avorn, J Canning, CF Schneeweiss, S AF Wang, Philip S. Patrick, Amanda R. Dormuth, Colin Maclure, Malcolm Avorn, Jerry Canning, Claire F. Schneeweiss, Sebastian TI Impact of Drug Cost Sharing on Service Use and Adverse Clinical Outcomes in Elderly Receiving Antidepressants SO JOURNAL OF MENTAL HEALTH POLICY AND ECONOMICS LA English DT Article ID CONVERTING-ENZYME-INHIBITORS; LATE-LIFE DEPRESSION; PATIENTS AGED 65; BRITISH-COLUMBIA; HEALTH-SERVICES; PRIMARY-CARE; ECONOMIC CONSEQUENCES; RECEPTOR ANTAGONISTS; BENEFITS; OLDER AB Background: Depression imposes enormous burdens on the elderly. Despite this, rates of initiation of and adherence to recommended pharmacotherapy are frequently low in this population. Although initiatives such as the Medicare Modernization Act (MMA) have improved seniors' access to antidepressants, there are concerns that the patient cost-sharing incorporated in the MMA may have unintended consequences if it reduces essential drug use. Age-related pharmacokinetic and pharmacodynamic changes could make seniors particularly vulnerable to antidepressant regimens used inappropriately to save costs, increasing their risks of morbidity, hospitalizations, and nursing home placements. Two sequential large-scale "natural experiments in British Columbia provide a unique opportunity to evaluate the effect of cost sharing on outcomes and mental health service use among seniors. In January 2002 the province introduced a $25 Canadian copay ($10 for low-income seniors). In May 2003 this copay policy was replaced by a second policy consisting of an income-based deductible, 25% coinsurance once the deductible was met, and full coverage once an out-of-pocket ceiling was met. The transition between the two policies is analogous to what many U.S. seniors experience when they transition from private insurance requiring copays to Medicare Part D requiring deductibles and coinsurance. Aims: To evaluate whether declines in antidepressant initiation after the introduction of two drug cost-sharing policies in British Columbia were associated with increased use of physician services, hospitalizations, and nursing home admissions among all British Columbia residents aged 65+. Methods: Records of physician service use, inpatient hospitalizations, and residential care admissions were obtained from administrative databases. Population-level patterns over time were plotted, and effects of implementing the cost-sharing policies examined in segmented linear regression models. Results: Neither policy affected the rates of visits to physicians or psychiatrists for depression, hospitalizations with a depression diagnosis, or long-term care admissions. Discussion: The cost-sharing policies studied may have contained non-essential antidepressant use without substantially increasing mental health service utilization. However, it is possible that the policies had effects that we were unable to detect, such as increasing rates of visits to social workers or psychologists or forcing patients to reduce other spending. Further, the sequential implementation of the policy changes, makes it difficult to estimate the effect of a direct change from full coverage to a coinsurance/income-based deductible policy. Implications for Health Policies: It may be possible to design policies to contain non-essential antidepressant use without substantially increasing other service utilization or adverse events. However, because undertreatment remains a serious problem among depressed elderly, well-designed prescription drug policies should be coupled with interventions to address under-treatment. C1 [Wang, Philip S.] NIMH, Bethesda, MD 20892 USA. [Patrick, Amanda R.; Avorn, Jerry; Canning, Claire F.; Schneeweiss, Sebastian] Harvard Univ, Dept Med, Brigham & Womens Hosp, Sch Med,Div Pharmacoepidemiol & Pharmacoecon, Cambridge, MA 02138 USA. [Maclure, Malcolm] Univ Victoria, Sch Hlth Informat Sci, Victoria, BC V8W 2Y2, Canada. [Dormuth, Colin] Univ British Columbia, Therapeut Initiat, Vancouver, BC V5Z 1M9, Canada. RP Wang, PS (reprint author), NIMH, 6001 Execut Blvd,Room 8229,MSC 9669, Bethesda, MD 20892 USA. EM wangphi@mail.nih.gov RI Schneeweiss, Sebastian/C-2125-2013 FU AHRQ HHS [5-R01-HS010881-07, R01 HS010881]; NIA NIH HHS [R01 AG021950, R01 AG021950-04]; NIMH NIH HHS [U01 MH069772, R01 MH069772, U01 MH069772-04] NR 44 TC 6 Z9 7 U1 2 U2 7 PU INT CTR MENTAL HEALTH POLICY & ECONOMICS-ICMPE PI MILANO PA VIA DANIELE CRESPI 7, MILANO, 20123, ITALY SN 1091-4358 J9 J MENT HEALTH POLICY JI J. Ment. Health Policy Econ. PD MAR PY 2010 VL 13 IS 1 BP 37 EP 44 PG 8 WC Health Policy & Services; Psychiatry SC Health Care Sciences & Services; Psychiatry GA 574AU UT WOS:000275961600005 PM 20571181 ER PT J AU Lu, CX Cheng, SY AF Lu, Changxue Cheng, Sheue-Yann TI Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Review ID INHIBITS CELL-GROWTH; PPAR-GAMMA AGONISTS; RESPONSE ELEMENT; GENE-EXPRESSION; RETINOIC ACID; CANCER CELLS; FATTY-ACIDS; CHOLESTEROL TRANSPORT; COLON CARCINOGENESIS; NUCLEAR RECEPTORS AB Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. C1 [Lu, Changxue; 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 The present research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 101 TC 22 Z9 22 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD MAR PY 2010 VL 44 IS 3 BP 143 EP 154 DI 10.1677/JME-09-0107 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 571SB UT WOS:000275774400001 PM 19741045 ER PT J AU Pan, YP Nussinov, R AF Pan, Yongping Nussinov, Ruth TI Preferred drifting along the DNA major groove and cooperative anchoring of the p53 core domain: mechanisms and scenarios SO JOURNAL OF MOLECULAR RECOGNITION LA English DT Article DE protein-DNA interactions; cooperativity; molecular dynamics simulations; DNA sliding; specific versus non-specific binding; binding mechanism ID TUMOR-SUPPRESSOR PROTEIN; BINDING DOMAIN; CRYSTAL-STRUCTURE; RESPONSE ELEMENT; STRUCTURAL BASIS; FOLDING FUNNELS; CONSENSUS DNA; WILD-TYPE; SITE; RECOGNITION AB While the importance of specific p53-DNA binding is broadly accepted, the recognition process is still not fully 0 understood. Figuring out the initial tetrameric p53-DNA association and the swift and cooperative search for specific binding sites is crucial for understanding the transactivation mechanism and selectivity. To gain insight into the p53-DNA binding process, here we have carried out explicit solvent molecular dynamic (MD) simulations of several p53 core domain-DNA conformations with the p53 and the DNA separated by varying distances. p53 approached the DNA, bound non-specifically, and quickly drifted along the DNA surface to find the major groove, cooperatively anchoring in a way similar to the specific binding observed in the crystal structure. Electrostatics was the major driving force behind the p53 movement. Mechanistically, this is a cooperative process: key residues, particularly Lys120 and Arg280 acted as sensors; upon finding their hydrogen-bonding partners, they lock in, anchoring p53 into the major groove. Concomitantly, the DNA adopted a conformation that facilitated p53 easy access. The initial non-specific core domain-DNA contacts assist in shifting the DNA and the p53 substrates toward conformations "ready" for specific major groove binding, with subsequent optimization of the interactions. This work is an invited contribution for the special issue of the Journal of Molecular Recognition dedicated to Professor Martin Karplus. Copyright (C) 2009 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this paper. C1 [Pan, Yongping; Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Mol Genet & Biochem, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Institutes of Health [N01-CO-12400] FX This research was supported (in part) by the Intramural Research Program of the NIH, 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 number N01-CO-12400. 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. This study utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 71 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3499 J9 J MOL RECOGNIT JI J. Mol. Recognit. PD MAR-APR PY 2010 VL 23 IS 2 SI SI BP 232 EP 240 DI 10.1002/jmr.990 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 570LC UT WOS:000275678100013 PM 19856322 ER PT J AU Fitch, RW Bewley, CA AF Fitch, Richard W. Bewley, Carole A. TI John W. Daly (1933-2008) SO JOURNAL OF NATURAL PRODUCTS LA English DT Biographical-Item C1 [Fitch, Richard W.] Indiana State Univ, Terre Haute, IN 47809 USA. [Bewley, Carole A.] NIDDKD, Bethesda, MD 20892 USA. RP Fitch, RW (reprint author), Indiana State Univ, Terre Haute, IN 47809 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 299 EP 300 DI 10.1021/np1000494 PG 2 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000001 PM 20141161 ER PT J AU Jones, TH Garraffo, HM Spande, TF Andriamaharavo, NR Gorman, JST Snyder, AJ Jeter, AW Torres, JA Snelling, RR Daly, JW AF Jones, Tappey H. Garraffo, H. Martin Spande, Thomas F. Andriamaharavo, Nirina R. Gorman, Jeffrey S. T. Snyder, Alexander J. Jeter, Andrew W. Torres, Juan A. Snelling, Roy R. Daly, John W. TI Caste-Specific Tyramides from Myrmicine Ants SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID VENOM ALKALOIDS; HYMENOPTERA; FORMICIDAE; CHEMISTRY; SOLENOPSIS; BEHAVIOR AB Analysis of the extracts of male ants of monomorium minimum and Monomorium ebeninum by GC-MS and GC-FTIR revealed the presence of tyramides 2 and 4c, for which the structures were established by comparison with synthetic samples. These compounds and their analogues 1 and 3 were also found in males of other Monomorium species, males of Myrmicaria opaciventris, and males of several Solenopsis (Diplorhoptrum) species. Vapor-phase FTIR spectra revealed critically important structural cities to two of the tyramides, which had methyl branching in the tyramide acyl moiety. Tyramide 4c exhibited a strong intramolecular amide NI-I hydrogen bond where an alpha-keto group was deduced to be present in the acyl moiety and also showed the overlap of this ketone group frequency with that of the amide nu(C=O). The biological function of these compounds is uncertain: however, their role in ant-mating behavior may be suggested by a large body of evidence. C1 [Jones, Tappey H.; Gorman, Jeffrey S. T.; Snyder, Alexander J.; Jeter, Andrew W.] Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. [Garraffo, H. Martin; Spande, Thomas F.; Andriamaharavo, Nirina R.; Daly, John W.] NIDDK, Bioorgan Chem Lab, NIH, HHS, Bethesda, MD 20892 USA. [Torres, Juan A.] Int Inst Trop Forestry, San Juan, PR 00928 USA. [Snelling, Roy R.] Los Angeles Cty Museum Nat Hist, Los Angeles, CA 90007 USA. RP Jones, TH (reprint author), Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. EM jonesth@vmi.edu FU NIDDK FX thank Lloyd Davis for the sample of M. pharaonis males and Gordon C. Snelling for the sample of Solenopsis nr. molesta males and a great deal of archival work in the collections at the Los Angeles County Museum of Natural History. We thank John Lloyd for Direct probe HRESIMS, Noel Whittaker for HRCIMS on synthetic 4a-4c, and Lewis Pannell (all of NIDDK) for the original HRMS of 2 and 4c. The research done at NIH was supported by the intramural research funds of NIDDK. NR 27 TC 5 Z9 6 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 313 EP 316 DI 10.1021/np900697s PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000005 PM 20102169 ER PT J AU Saporito, RA Donnelly, MA Madden, AA Garraffo, HM Spande, TF AF Saporito, Ralph A. Donnelly, Maureen A. Madden, Anne A. Garraffo, H. Martin Spande, Thomas F. TI Sex-Related Differences in Alkaloid Chemical Defenses of the Dendrobatid Frog Oophaga pumilio from Cayo Nancy, Bocas del Toro, Panama SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SNAKE RHABDOPHIS-TIGRINUS; STRAWBERRY POISON FROGS; GEOGRAPHIC-VARIATION; SKIN ALKALOIDS; BATRACHOTOXIN ALKALOIDS; ARTHROPOD SOURCE; PASSERINE BIRDS; DART FROGS; SEQUESTRATION; PATTERNS AB Poison frogs contain all alkaloid-based chemical defense that is sequestered directly from a diet of alkaloid-containing arthropods. Geographic and temporal variation in alkaloid defense is common in poison frogs and is generally attributed to differences in the availability of alkaloid-containing arthropods. Variable chemical defense in poison frogs may have important consequences for predator-prey interactions, requiring a full understanding of the factors involved in explaining such variation. In the Present study, we examine alkaloid variation in the dendrobatid poison frog Oophaga pumilio between males and females on Cayo Nancy (Isla Solarte), located in the Bocas del Toro archipelago of Panama. On average, females contained a significantly larger number and quantity of alkaloids when compared to males. Alkaloid composition varied significantly between males and females, illustrating that chemical defense in this population of O. pumilio is sex-dependent. The variation in alkaloids between sexes is attributed to differences in feeding and behavior between males and females. The majority of alkaloids present in the skin of O. pumilio appear to be of oribatid mite origin, supporting the importance of these dietary arthropods in file chemical defense of poison frogs. C1 [Saporito, Ralph A.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. [Donnelly, Maureen A.] Florida Int Univ, Coll Arts & Sci, Miami, FL 33199 USA. [Madden, Anne A.] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Garraffo, H. Martin; Spande, Thomas F.] NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Saporito, RA (reprint author), Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. EM ralph.saporito@gmail.com FU Environmental Protection Agency; Smithsonian Tropical Research Institute; NSF; NIH; NIDDK FX The authors dedicate this paper to our friend and colleague, the late John W. Daly, who continues to inspire research on the chemical ecology of poison frogs. We thank the Republic de Panama and Autoridad Nacional del Ambiente for permission to conduct this research (permit no. SE/A-23-M CITES permit no. SEX/A-129-06). We also thank the Smithsonian Tropical Research Institute (STRI) Bocas del Toro Research Station, G. Jacome. and O. Arosemena for their assistance with the logistics Of this study. We would like 10 especially thank C. S. Stephens and P. Stephens for permission to work Oil their private property and Cor their informative historical perspective oil Bocas del Toro. J. M. Snyder provided valuable comments oil the manuscript. The Institutional Animal Care and Use Committee of Florida International University approved the methods used in this study. An Environmental Protection Agency Fellowship and a Smithsonian Tropical Research Institute Fellowship awarded to R.A.S. funded the field component of this research. An NIH Courtesy Appointment and an NSF Postdoctoral Fellowship supported R.A.S. The work at NIH was funded by intramural funds of NIDDK. NR 48 TC 22 Z9 23 U1 4 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 317 EP 321 DI 10.1021/np900702d PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000006 PM 20030363 ER PT J AU Andriamaharavo, NR Garraffo, HM Saporito, RA Daly, JW Razafindrabe, CR Andriantsiferana, M Spande, TF AF Andriamaharavo, Nirina R. Garraffo, H. Martin Saporito, Ralph A. Daly, John W. Razafindrabe, Christian R. Andriantsiferana, Marta Spande, Thomas F. TI Roughing It: A Mantellid Poison Frog Shows Greater Alkaloid Diversity in Some Disturbed Habitats SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SKIN ALKALOIDS; MADAGASCAR; DECAHYDROQUINOLINES; COMMON AB Four five-skin alkaloid extracts of the Madagascan poison frog Mantella baroni from three disturbed collection sites were compared with four five-skin extracts from three undisturbed sites. the number of alkaloids (diversity) was significantly different in M. baroni between undisturbed and disturbed collection sites, with more alkaloids generally being found in frogs front disturbed Sites. TWO Undisturbed sites did not differ front two disturbed sites, but the third disturbed site (coded 6) had more than twice the alkaloid diversity found in frogs from the third undisturbed site (coded 5a/5b). There was no difference in the quantity of alkaloids in M. baroni between Undisturbed and disturbed collection sites. The hypothesis that all undisturbed habitat confers a benefit to poison frogs dwelling therein. in allowing for the sequestration of greater alkaloid diversity and amounts, is challenged by our results. In the Course of our Study, We found that collections of frogs separated by an interval of three months at all undisturbed site differed by Only 4%, in alkaloid composition over this period, whereas frogs collected at a distributed site and collected approximately three months later already had a 26% difference in alkaloid composition between the two collections. This constancy of skin alkaloid composition likely reflects a constancy of dietary prey items consumed by frogs at undistributed sites. C1 [Andriamaharavo, Nirina R.; Garraffo, H. Martin; Daly, John W.; Spande, Thomas F.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Saporito, Ralph A.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. [Razafindrabe, Christian R.; Andriantsiferana, Marta] Univ Antananarivo, Lab Chim Organ Prod Nat, Antananarivo 101, Madagascar. RP Spande, TF (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM thomassp@bdg8.niddk.nih.gov FU "Ministere de l'Educaiion Nationale et de la Recherche Scientifique"; NSF; NIDDK FX We thank the "Department de Biologie Animale, Universite d'Antananarivo" (DBAUA), staff for the fieldwork. The support of the "Ministere de l'Educaiion Nationale et de la Recherche Scientifique" through FADES funds is gratefully acknowledged. All NSF Postdoctoral Research Fellowship supported R.A.S. We thank the intramural program of NIDDK for funding this work. We thank the editor and both referees for important suggestions that have improved the readability of this paper. NR 21 TC 3 Z9 3 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 322 EP 330 DI 10.1021/np900721r PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000007 PM 20178326 ER PT J AU Fitch, RW Spande, TF Garraffo, HM Yeh, HJC Daly, JW AF Fitch, Richard W. Spande, Thomas F. Garraffo, H. Martin Yeh, Herman J. C. Daly, John W. TI Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; NEUROBLASTOMA CLONAL LINE; BINDING-SITES; SUBTYPE SELECTIVITY; SMOKING-CESSATION; 5-HT3 RECEPTOR; AGONIST; PHARMACOPHORE; AFFINITY; CELLS AB The skin of the Ecuadorian poison frog Epipedobates anthonyi contains the potent nicotinic agonists epibatidine (1) and N-methylepibatidine (3). In addition, a condensed tetracyclic epibatidine congener has been identified with activity at nicotinic acetylcholine receptors, but different selectivity than epibatidine. This rigid tetracycle has been named phantasmidine (4). Phantasmidine has a molecular formula of C(11)H(11)N(2)OCl, shares a chloropyridine moiety with 1, and also contains furan, pyrrolidine, and cyclobutane, rings. A combination of GC-MS and GC-FTIR analysis with on-column derivatization, 1D NMR spectroscopy with selective irradiation, and spectral simulation, along with 2D NMR, were used to elucidate file Structure from a total sample of similar to 20/mu g of HPLC-purified 4 an(] its corresponding acetamide (5). After synthesis, this novel rigid agonist may serve as a selective probe for beta 4-containing nicotinic receptors and Potentially lead 10 useful pharmaceuticals. C1 [Fitch, Richard W.; Spande, Thomas F.; Garraffo, H. Martin; Yeh, Herman J. C.; Daly, John W.] NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Fitch, RW (reprint author), Indiana State Univ, Dept Chem & Phys, 600 Chestnut St,Sci S35E, Terre Haute, IN 47802 USA. EM Richard.Fitch@indstate.edu FU NIDDK FX The authors wish to thank Mr. N. F. Whittaker (LBC, NIDDK) for obtaining, the FIRMS data. The passing of Dr. John W. Daly is deeply Mourned by the co-authors. His scientific insight and excellent mentorship Are gratefully appreciated, and his friendship is fondly remembered. This work was supported by intramural funds of NIDDK. NR 48 TC 14 Z9 14 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 331 EP 337 DI 10.1021/np900727e PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000008 PM 20337496 ER PT J AU Klausmeyer, P Van, QN Jato, J McCloud, TG Beutler, JA AF Klausmeyer, Paul Van, Que N. Jato, Johnson McCloud, Thomas G. Beutler, John A. TI Schweinfurthins I and j from Macaranga schweinfurthii SO JOURNAL OF NATURAL PRODUCTS LA English DT Article AB Demand for the experimental antineoplastic agent schweinfurthin A, for developmental testing, prompted it re-collection of leaf material of Macaranga schweinfurthii from the original collection site in Cameroon. During chromatographic purification of the organic solvent extract. analytical UPLC-PDA-TOFMS of stilbene-enriched fractions revealed the presence of six known schweinfurthins and two previously Unknown stilbenes. The structures of these new compounds, schweinfurthins I and J (1 and 2), were elucidated by 1D- and 2D-NMR techniques. C1 [Beutler, John A.] NCI Frederick, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. [Klausmeyer, Paul; McCloud, Thomas G.] NCI Frederick, SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. [Van, Que N.] NCI Frederick, SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. [Jato, Johnson] Bioresources Dev & Conservat Programme Cameroon, Yaounde, Cameroon. RP Beutler, JA (reprint author), NCI Frederick, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. EM beutlerj@mail.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU National Cancer Institue, National Institutes of Healt [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institue, National Institutes of Health, under Contract No. HHSN261200800001E. This rescarch was Supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This rcsoarch was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 7 TC 11 Z9 11 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 479 EP 481 DI 10.1021/np9006348 PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000035 PM 20000454 ER PT J AU Plaza, A Keffer, JL Lloyd, JR Colin, PL Bewley, CA AF Plaza, Alberto Keffer, Jessica L. Lloyd, John R. Colin, Patrick L. Bewley, Carole A. TI Paltolides A-C, Anabaenopeptin-Type Peptides from the Palau Sponge Theonella swinhoei SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID CONSTITUENT AMINO-ACIDS; ABSOLUTE-CONFIGURATION; CYCLIC-PEPTIDES; MARFEYS METHOD; MARINE SPONGE; GLYCOPEPTIDE; MOZAMBIQUE; SYMBIONTS; LC/MS AB Three new anabacnopeptin-like peptides, named paltolides A-C, were isolated from a deep-water specimen of the marine sponge Theonella swinhoei from Palau. Paltolides belong to a rare subgroup of sponge-derived anabaenopeptins, that have in common a C-terminal tryptophan residue linked 10 the epsilon-amine of' a lysine bearing, a i) configuration. The structures of paltolides A-C were determined by NMR and tandem MS techniques. Paltolide A is the first anabaenopeptin structures where a non-N-methylated amino acid precedes the C-terminal residue. C1 [Plaza, Alberto; Keffer, Jessica L.; Lloyd, John R.; Bewley, Carole A.] NIDDK, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov OI zaraat, javad/0000-0001-5341-7481; Keffer, Jessica/0000-0002-0302-3588 FU NIH FX This work was supported in part by the NIH Intramural Research Program (NIDDK) and the Intramural AIDS Targeted Antiviral Program. Office of the Director NIH (C.A.B). NR 22 TC 11 Z9 11 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2010 VL 73 IS 3 SI SI BP 485 EP 488 DI 10.1021/np900728x PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 573CC UT WOS:000275885000037 PM 20078073 ER PT J AU Son, TG Camandola, S Arumugam, TV Cutler, RG Telljohann, RS Mughal, MR Moore, TA Luo, WM Yu, QS Johnson, DA Johnson, JA Greig, NH Mattson, MP AF Son, Tae Gen Camandola, Simonetta Arumugam, Thiruma V. Cutler, Roy G. Telljohann, Richard S. Mughal, Mohamed R. Moore, Tyson A. Luo, Weiming Yu, Qian-Sheng Johnson, Delinda A. Johnson, Jeffrey A. Greig, Nigel H. Mattson, Mark P. TI Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE neuroprotection; Nrf2; ARE; phytochemicals; stroke ID ANTIOXIDANT RESPONSE ELEMENT; HUMAN NEUROBLASTOMA-CELLS; SIGNAL-REGULATED KINASE; STRESS-INDUCED DEATH; OXIDATIVE-STRESS; IN-VITRO; TRANSCRIPTION FACTOR; KEAP1/NRF2 PATHWAY; ADAPTIVE RESPONSE; EPITHELIAL-CELLS AB P>Many phytochemicals function as noxious agents that protect plants against insects and other damaging organisms. However, at subtoxic doses, the same phytochemicals may activate adaptive cellular stress response pathways that can protect cells against a variety of adverse conditions. We screened a panel of botanical pesticides using cultured human and rodent neuronal cell models, and identified plumbagin as a novel potent activator of the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. In vitro, plumbagin increases nuclear localization and transcriptional activity of Nrf2, and induces the expression of the Nrf2/ARE-dependent genes, such as heme oxygenase 1 in human neuroblastoma cells. Plumbagin specifically activates the Nrf2/ARE pathway in primary mixed cultures from ARE-human placental alkaline phosphatase reporter mice. Exposure of neuroblastoma cells and primary cortical neurons to plumbagin provides protection against subsequent oxidative and metabolic insults. The neuroprotective effects of plumbagin are abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo, administration of plumbagin significantly reduces the amount of brain damage and ameliorates-associated neurological deficits in a mouse model of focal ischemic stroke. Our findings establish precedence for the identification and characterization of neuroprotective phytochemicals based upon their ability to activate adaptive cellular stress response pathways. C1 [Son, Tae Gen; Camandola, Simonetta; Cutler, Roy G.; Telljohann, Richard S.; Mughal, Mohamed R.; Luo, Weiming; Yu, Qian-Sheng; Greig, Nigel H.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Arumugam, Thiruma V.; Moore, Tyson A.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. [Johnson, Delinda A.; Johnson, Jeffrey A.] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53706 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Camandola, S (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM camandolasi@mail.nih.gov RI Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012 FU National Institutes of Health (NIH); National Institute of Environmental Sciences (NIEHS) [ES 10042, ES08089] FX This research was supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health (NIH), and by grants from the National Institute of Environmental Sciences (NIEHS ES 10042 and ES08089) to J.A. Johnson. The authors declare no conflict of interest. NR 51 TC 82 Z9 93 U1 1 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2010 VL 112 IS 5 BP 1316 EP 1326 DI 10.1111/j.1471-4159.2009.06552.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 551VZ UT WOS:000274241900020 PM 20028456 ER PT J AU Oz, M Jaligam, V Galadari, S Petroianu, G Shuba, YM Shippenberg, TS AF Oz, Murat Jaligam, Vanaja Galadari, Sehamuddin Petroianu, George Shuba, Yaroslav M. Shippenberg, Toni S. TI The endogenous cannabinoid, anandamide, inhibits dopamine transporter function by a receptor-independent mechanism SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE anandamide; cannabinoids; dopamine transporter; HEK293 cells ID ARACHIDONIC-ACID; XENOPUS OOCYTES; SURFACE EXPRESSION; MEDIATED RESPONSES; NUCLEUS-ACCUMBENS; GLYCINE RECEPTORS; CYTOSOLIC CA2+; CURRENTS; FLUORESCENCE; MEMBRANES AB P>The endocannabinoid, anandamide (AEA), modulates the activity of the dopamine transporter (DAT) in heterologous cells and synaptosomal preparations. The cellular mechanisms mediating this effect are unknown. The present studies employed live cell imaging techniques and the fluorescent, high affinity DAT substrate, 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP+), to address this issue. AEA addition to EM4 cells expressing yellow fluorescent protein-tagged human DAT (hDAT) produced a concentration-dependent inhibition of ASP+ accumulation (IC(50): 3.2 +/- 0.8 mu M). This effect occurred within 1 min after AEA addition and persisted for 10 min thereafter. Pertussis toxin did not attenuate the effects of AEA suggesting a mechanism independent of G(i)/G(o) coupled receptors. The amidohydrolase inhibitor, phenylmethylsulfonyl fluoride (0.2 mM), failed to alter the AEA-evoked inhibition of ASP+ accumulation. Methanandamide (10 mu M), a metabolically stable analogue of AEA inhibited accumulation but arachidonic acid (10 mu M) was without effect suggesting that the effects of AEA are not mediated by its metabolic products. The extent of AEA inhibition of ASP+ accumulation was not altered in cells pre-treated with 1 mu M URB597, a specific and potent fatty acid amide hydrolase inhibitor, and the cyclooxygenase inhibitor, indomethacin (5 mu M) Live cell imaging revealed a significant redistribution of hDAT from the membrane to the cytosol in response to AEA treatment (10 mu M; 10 min). Similarly biotinylation experiments revealed that the decrease in DAT function was associated with a reduction in hDAT cell surface expression. These results demonstrate that AEA modulates DAT function via a cannabinoid receptor-independent mechanism and suggest that AEA may produces this effect, in part, by modulating DAT trafficking. C1 [Oz, Murat; Jaligam, Vanaja; Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, IRP, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Oz, Murat; Petroianu, George] UAE Univ, Dept Pharmacol, Labs Funct Lipid, Al Ain, U Arab Emirates. [Galadari, Sehamuddin] UAE Univ, Dept Biochem, Al Ain, U Arab Emirates. [Galadari, Sehamuddin] UAE Univ, Fac Med & Hlth Sci, Al Ain, U Arab Emirates. [Shuba, Yaroslav M.] Natl Acad Sci Ukraine, Bogomoletz Inst Physiol, Kiev, Ukraine. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, IRP, NIH,US Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tshippen@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 FU DHHS/NIH/NIDA FX This research was supported by the DHHS/NIH/NIDA Intramural Research Program. We thank Drs. V. I. Chefer and J. Meis for their help with statistical analysis and discussion of the data. NR 48 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2010 VL 112 IS 6 BP 1454 EP 1464 DI 10.1111/j.1471-4159.2009.06557.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 559GO UT WOS:000274811500007 PM 20050977 ER PT J AU Hsu, CH Chan, D Greggio, E Saha, S Guillily, MD Ferree, A Raghavan, K Shen, GC Segal, L Ryu, H Cookson, MR Wolozin, B AF Hsu, Cindy H. Chan, Diane Greggio, Elisa Saha, Shamol Guillily, Maria D. Ferree, Andrew Raghavan, Kesav Shen, Grace C. Segal, Lilach Ryu, Hoon Cookson, Mark R. Wolozin, Benjamin TI MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE C; elegans; c-Jun kinase; membrane; mitogen-activated protein kinase; p38; phosphorylation ID RICH REPEAT KINASE-2; DOPAMINERGIC-NEURONS; CAENORHABDITIS-ELEGANS; GTP-BINDING; CELL-DEATH; MUTATIONS; TOXICITY; NEURODEGENERATION; LRRK2/DARDARIN; LOCALIZATION AB P>Mutations in leucine-rich repeat kinase 2 (LRRK2) are prevalent causes of late-onset Parkinson's disease. Here, we show that LRRK2 binds to MAPK kinases (MKK) 3, 6, and 7, and that LRRK2 is able to phosphorylate MKK3, 6 and 7. Over-expression of LRRK2 and MKK6 increased the steady state levels of each protein beyond that observed with over-expression of either protein alone. Co-expression increased levels of MKK6 in the membrane more than in the cytoplasm. The increased expression of LRRK2 and MKK6 requires MKK6 activity. The disease-linked LRRK2 mutations, G2019S, R1441C and I2020T, enhance binding of LRRK2 to MKK6. This interaction was further supported by in vivo studies in C. elegans. RNAi knockdown in C. elegans of the endogenous orthologs for MKK6 or p38, sek-1 and pmk-1, abolishes LRRK2-mediated protection against mitochondrial stress. These results were confirmed by deletion of sek-1 in C. elegans. These data demonstrate that MKKs and LRRK2 function in similar biological pathways, and support a role for LRRK2 in modulating the cellular stress response. C1 [Hsu, Cindy H.; Chan, Diane; Saha, Shamol; Guillily, Maria D.; Ferree, Andrew; Raghavan, Kesav; Shen, Grace C.; Segal, Lilach; Wolozin, Benjamin] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Greggio, Elisa; Cookson, Mark R.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Wolozin, B (reprint author), Boston Univ, Sch Med, Dept Pharmacol, 715 Albany St,R-614, Boston, MA 02118 USA. EM bwolozin@bu.edu RI Greggio, Elisa/H-6119-2013 OI Greggio, Elisa/0000-0002-8172-3598 FU NIEHS [ES15567]; NINDS [NS41786]; Alzheimer Association and the Michael J. Fox Foundation; Intramural Research Program of the NIH; National Institute on Aging [Z01AG000948] FX We thank Roger Davis for his generosity in sharing the MKK plasmids, and Leonard Petrucelli for his valuable advice. We also thank Shelley Russek and Ramona Faris for their assistance with the luciferase assays. This work is supported by NIEHS ES15567, NINDS NS41786, the Alzheimer Association and the Michael J. Fox Foundation (B.W.). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Z01AG000948 (M.R.C.). NR 45 TC 57 Z9 60 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2010 VL 112 IS 6 BP 1593 EP 1604 DI 10.1111/j.1471-4159.2010.06568.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 559GO UT WOS:000274811500019 PM 20067578 ER PT J AU Lee, NR Pennington, BF Keenan, JM AF Lee, Nancy Raitano Pennington, Bruce F. Keenan, Janice M. TI Verbal short-term memory deficits in Down syndrome: phonological, semantic, or both? SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Article DE Down syndrome; Verbal short-term memory; Phonology; Semantics ID 3,000 MONOSYLLABIC WORDS; HIGH-RESOLUTION MRI; WORKING-MEMORY; PROACTIVE-INTERFERENCE; CHILDREN; SPAN; INDIVIDUALS; HEARING; SPEECH; NEUROPSYCHOLOGY AB The current study examined the phonological and semantic contributions to the verbal short-term memory (VSTM) deficit in Down syndrome (DS) by experimentally manipulating the phonological and semantic demands of VSTM tasks. The performance of 18 individuals with DS (ages 11-25) and 18 typically developing children (ages 3-10) matched pairwise on receptive vocabulary and gender was compared on four VSTM tasks, two tapping phonological VSTM (phonological similarity, nonword discrimination) and two tapping semantic VSTM (semantic category, semantic proactive interference). Group by condition interactions were found on the two phonological VSTM tasks (suggesting less sensitivity to the phonological qualities of words in DS), but not on the two semantic VSTM tasks. These findings suggest that a phonological weakness contributes to the VSTM deficit in DS. These results are discussed in relation to the DS neuropsychological and neuroanatomical phenotype. C1 [Lee, Nancy Raitano] NIMH, Unit Brain Imaging, Child Psychiat Branch, NIH, Bldg 10,Rm 4C110 MSC-1367,10 Ctr Dr, Bethesda, MD 20892 USA. [Lee, Nancy Raitano; Pennington, Bruce F.; Keenan, Janice M.] Univ Denver, Dept Psychol, Denver, CO 80208 USA. RP Lee, NR (reprint author), NIMH, Unit Brain Imaging, Child Psychiat Branch, NIH, Bldg 10,Rm 4C110 MSC-1367,10 Ctr Dr, Bethesda, MD 20892 USA. EM lnancy@mail.nih.gov RI Lee, Nancy Raitano/F-2565-2011; Lee, Nancy/M-7492-2016 OI Lee, Nancy/0000-0002-6663-0713 NR 74 TC 7 Z9 8 U1 5 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1866-1947 EI 1866-1955 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD MAR PY 2010 VL 2 IS 1 BP 9 EP 25 DI 10.1007/s11689-009-9029-4 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 567JT UT WOS:000275443600002 ER PT J AU Mehta, GU Asthagiri, AR Bakhtian, KD Auh, S Oldfield, EH Lonser, RR AF Mehta, Gautam U. Asthagiri, Ashok R. Bakhtian, Kamran D. Auh, Sungyoung Oldfield, Edward H. Lonser, Russell R. TI Functional outcome after resection of spinal cord hemangioblastomas associated with von Hippel-Lindau disease Clinical article SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE hemangioblastoma; outcome; spinal cord; von Hippel-Lindau disease ID CENTRAL-NERVOUS-SYSTEM; SURGICAL-MANAGEMENT; INTRAMEDULLARY HEMANGIOBLASTOMA; NATURAL-HISTORY; RADIOSURGERY AB Object. Spinal cord hemangioblastomas are a common protean manifestation of von Hippel-Lindau (VHL) disease and can be associated with significant morbidity. To better define expected outcome and optimal management of these tumors in the context of this neoplasia syndrome. the authors analyzed the findings from patients with VHL disease who underwent resection of spinal cord hemangioblastomas. Methods. Consecutive patients with VHL disease Who underwent surgery for spinal cord hemangioblastomas with > 6 months follow-up were included in the study. Serial clinical examinations. functional scores, imaging findings, and operative records were analyzed. Results. One hundred eight patients (57 male, 51 female) Underwent 156 operations for resection of 2 18 spinal cord hemangioblastomas. One hundred forty-six operations (94%) were performed for symptom-producing tumors. The most common presenting symptoms included hypesthesia (64% of resections), hyperreflexia (57%). dysesthesia (43%), and weakness (36%). Mean follow-up wits 7.0 +/- 5.0 years (range 0.5-20.9 years). Complete resection was achieved for 217 tumors (99.5%). At 6-months follow-up, patients were stable or improved after 149 operations (96%) and worse after 7 operations (4%). Ventral tumors (OR 15.66, 95% CI 2.54-96.45; p = 0.003) or completely intramedullary tumors (OR 10.74 95% CI 2.07-55.66; p = 0.005) were associated with an increased risk of postoperative worsening. The proportion of patients remaining functionally stable at 2, 5, 10 and 15 years' follow-up was 93, 86, 78, and 79%. Long-term functional decline was caused by extensive VHL-associated CNS disease (6 patients), VHL-associated visceral discase (1 patient). or non-VHL disease (2 patients). Conclusions. Resection of symptomatic spinal cord hemangioblastomas is a safe and effective means of preserving neurological function in patients with VHL disease. Tumor location (ventral or completely intramedullary) can be used to assess functional risk associated with surgery. Long-term decline in neurological function is usually caused by VHL-associated disease progression. (DOI: 10.3171/2009.10.SPINE09592) C1 [Mehta, Gautam U.; Asthagiri, Ashok R.; Bakhtian, Kamran D.; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Auh, Sungyoung] Natl Inst Neurol Disorders & Stroke, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov OI Mehta, Gautam/0000-0002-8009-6430 FU Intramural NIH HHS NR 30 TC 28 Z9 32 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD MAR PY 2010 VL 12 IS 3 BP 233 EP 242 DI 10.3171/2009.10.SPINE09592 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 562WG UT WOS:000275085400001 PM 20192620 ER PT J AU Sarnaik, AA Conley, YP Okonkwo, DO Barr, TL Fink, EL Szabo, C Kochanek, PM Clark, RSB AF Sarnaik, Ajit A. Conley, Yvette P. Okonkwo, David O. Barr, Taura L. Fink, Ericka L. Szabo, Csaba Kochanek, Patrick M. Clark, Robert S. B. TI Influence of PARP-1 Polymorphisms in Patients after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE ADP-ribosyltransferase; traumatic brain injury; poly(ADP-ribose) polymerase; poly-ADP-ribosylation ID POLY(ADP-RIBOSE) POLYMERASE INHIBITORS; NAD(+) DEPLETION; CELL-DEATH; ADP-RIBOSYLATION; OXIDATIVE STRESS; MICE; ACTIVATION; ISCHEMIA; PROTEINS; DAMAGE AB Poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the cellular response to stress and DNA damage. However, excessive activity of PARP-1 exacerbates brain injury via NAD(+) depletion and energy failure. The purpose of this study was to determine if tagging single nucleotide polymorphisms (tSNPs) covering multiple regions of the PARP-1 gene are related to outcome after traumatic brain injury (TBI) in humans. DNA from 191 adult patients with severe TBI was assayed for four tSNPs corresponding to haplotype blocks spanning the PARP-1 gene. Categorization as favorable or poor outcome was based on Glasgow Outcome Scale (GOS) score assigned at 6 months. PARP-1 enzyme activity was indirectly evaluated by quantifying poly-ADP-ribose (PAR)-modified proteins in cerebrospinal fluid (CSF) using an enzyme-linked immunosorbent assay. In multiple logistic regression analysis controlling for age, initial Glasgow Coma Scale score, and gender, the AA genotype of SNP rs3219119 was an independent predictor of favorable neurologic outcome. This SNP tags a haplotype block spanning the automodification and catalytic domains of the PARP-1 gene. SNP rs2271347 correlated with CSF PAR-modified protein level. This SNP, which did not correlate with outcome, tags a haplotype block spanning the promoter region of the PARP-1 gene. We conclude that after severe TBI in humans, a PARP-1 polymorphism within the automodification-catalytic domain is associated with neurological outcome, while a polymorphism within the promoter region was associated with CSF PAR-modified protein level. These findings must be replicated in a prospective study before the relevance of PARP-1 polymorphisms after TBI can be established. C1 [Sarnaik, Ajit A.; Fink, Ericka L.; Kochanek, Patrick M.; Clark, Robert S. B.] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Pittsburgh, PA 15260 USA. [Sarnaik, Ajit A.; Fink, Ericka L.; Kochanek, Patrick M.; Clark, Robert S. B.] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Pittsburgh, PA 15260 USA. [Okonkwo, David O.] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Conley, Yvette P.; Barr, Taura L.] Univ Pittsburgh, Dept Genet & Dev, Pittsburgh, PA 15260 USA. [Conley, Yvette P.; Barr, Taura L.] Univ Pittsburgh, Dept Hlth Promot, Pittsburgh, PA 15260 USA. [Szabo, Csaba] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX USA. [Sarnaik, Ajit A.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Barr, Taura L.] NINR, Tissue Injury Unit, Bethesda, MD 20892 USA. RP Clark, RSB (reprint author), Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, 3434 5th Ave, Pittsburgh, PA 15260 USA. EM clarkrs@ccm.upmc.edu RI Kochanek, Patrick/D-2371-2015; OI Kochanek, Patrick/0000-0002-2627-913X; Fink, Ericka/0000-0002-3683-4571 FU National Institute of Child Health and Human Development [T32 HD 40686]; National Institute of Neurological Disorders and Stroke [NS30318]; National Institute of Nursing Research [R01NR008424] FX The authors would like to thank the National Institute of Child Health and Human Development (T32 HD 40686), the National Institute of Neurological Disorders and Stroke (NS30318), and the National Institute of Nursing Research (R01NR008424). NR 30 TC 13 Z9 14 U1 3 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2010 VL 27 IS 3 BP 465 EP 471 DI 10.1089/neu.2009.1171 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 575PJ UT WOS:000276079100001 PM 19925161 ER PT J AU Durazo-Arvizu, RA Dawson-Hughes, B Sempos, CT Yetley, EA Looker, AC Cao, GC Harris, SS Burt, VL Carriquiry, AL Picciano, MF AF Durazo-Arvizu, Ramon A. Dawson-Hughes, Bess Sempos, Christopher T. Yetley, Elizabeth A. Looker, Anne C. Cao, Guichan Harris, Susan S. Burt, Vicki L. Carriquiry, Alicia L. Picciano, Mary Frances TI Three-Phase Model Harmonizes Estimates of the Maximal Suppression of Parathyroid Hormone by 25-Hydroxyvitamin D in Persons 65 Years of Age and Older SO JOURNAL OF NUTRITION LA English DT Article ID LOCALLY WEIGHTED REGRESSION; VITAMIN-D STATUS; HYPOVITAMINOSIS D; SERUM; WOMEN AB The concentration or threshold of 25-hydroxyvitamin D [25(OH)D] needed to maximally suppress intact serum parathyroid hormone (iPTH) has been suggested as a measure of optimal vitamin D status. Depending upon the definition of maximal suppression of iPTH and the 2-phase regression approach used, 2 distinct clusters for a single 25(OH)D threshold have been reported: 16-20 ng/mL (40-50 nmol/L) and 30-32 ng/mL (75-80 nmol/L). To rationalize the apparently disparate published results, we compared thresholds from several regression models including a 3-phase one to estimate simultaneously 2 thresholds before and after adjusting for possible confounding for age, BMI, glomerular filtration rate, dietary calcium, and season (April-September vs. October-March) within a single data set, i.e. data from the Tufts University Sites Testing Osteoporosis Prevention/Intervention Treatment study, consisting of 181 men and 206 women (total n = 387) ages 65-87 y. Plasma 25(OH)D and serum iPTH concentrations were (mean +/- SD) 22.1 +/- 7.44 ng/mL (55.25 +/- 18.6 nmol/L) and 36.6 +/- 16.03 pg/mL (3.88 +/- 1.7 pmol/L), respectively. The 3-phase model identified 2 thresholds of 12 ng/mL (30 nmol/L) and 28 ng/mL (70 nmol/L); similar results were found from the 2-phase models evaluated, i.e. 13-20 and 27-30 ng/mL (32.5-50 and 67.5-75 nmol/L) and with previous results. Adjusting for confounding did not change the results substantially. Accordingly, the 3-phase model appears to be superior to the 2-phase approach, because it simultaneously estimates the 2 threshold clusters found from the 2-phase approaches along with estimating confidence limits. If replicated, it may be of both clinical and public health importance. J. Nutr. 140: 595-599, 2010. C1 [Sempos, Christopher T.; Yetley, Elizabeth A.; Picciano, Mary Frances] Natl Inst Hlth, Off Dietary Supplements, Bethesda, MD 20816 USA. [Durazo-Arvizu, Ramon A.; Cao, Guichan] Loyola Univ Chicago, Dept Prevent Med & Epidemiol, Stritch Sch Med, Maywood, IL 60153 USA. [Dawson-Hughes, Bess; Harris, Susan S.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Bone Metab Lab, Boston, MA 02111 USA. [Looker, Anne C.; Burt, Vicki L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. RP Sempos, CT (reprint author), Natl Inst Hlth, Off Dietary Supplements, Bethesda, MD 20816 USA. EM semposch@mail.nih.gov FU National Institute on Aging, NIH, Bethesda, MD [AG10353]; Office of Dietary Supplements [5R37 HL045508-17] FX Supported by a grant from the National Institute on Aging, NIH, Bethesda, MD, grant number AG10353, and by an Office of Dietary Supplements administrative supplement to NIH grant number 5R37 HL045508-17. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC, the NIH, or the US Department of Health and Human Services. NR 23 TC 32 Z9 36 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAR PY 2010 VL 140 IS 3 BP 595 EP 599 DI 10.3945/jn.109.116681 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 559FJ UT WOS:000274807800023 PM 20089790 ER PT J AU Arenella, C Finke, B Domer, T Kaur, JS Merriman, MP Ousley, A AF Arenella, Cheryl Finke, Bruce Domer, Timothy Kaur, Judith S. Merriman, Melanie P. Ousley, Anita TI Adaptation, Dissemination, and Evaluation of a Cancer Palliative Care Curriculum for the Indian Health System SO JOURNAL OF PALLIATIVE CARE LA English DT Article AB In 2006, the Indian Health Service (IHS) and the National Cancer Institute (NCI) collaborated to develop an interdisciplinary palliative training program for health professionals in the Indian health system. Their goal was to improve clinician knowledge and skills in palliative care, to train future trainers, and to increase access to palliative care for American Indians and Alaska Natives. The combined program of participant self-study utilizing a multimedia CD-ROM and train-the-trainer seminars followed the curriculum entitled Education in Palliative and End-of-Life Care for Oncology (EPEC (TM)-O) with American Indian and Alaska Native Cultural Considerations. Three seminars trained 89 interdisciplinary health providers from throughout the Indian health system. Evaluations demonstrated increased clinician self-reported knowledge and confidence to train and high satisfaction with training. Forty-two of 67 participants completed an anonymous post-conference Web questionnaire. Nearly half had conducted or definitively planned palliative education sessions, and 57 percent started new palliative services at their practice sites. C1 [Arenella, Cheryl] NCI, Canc Educ Program Specialist, Off Commun & Educ, NIH, Rockville, MD 20852 USA. [Finke, Bruce] Indian Hlth Serv, Northampton, MA USA. [Domer, Timothy] Ft Defiance Indian Hosp, Home Based Care Program, Ft Defiance, AZ USA. [Kaur, Judith S.] Mayo Clin, Spirit Eagles Initiat, Rochester, MN USA. [Merriman, Melanie P.] Touchstone Consulting, N Bay Village, FL USA. [Ousley, Anita] NCI, Off Commun & Educ, NIH, Rockville, MD USA. RP Arenella, C (reprint author), NCI, Canc Educ Program Specialist, Off Commun & Educ, NIH, 6116 Execut Blvd,Suite 410,Room 4104, Rockville, MD 20852 USA. EM arenellac@mail.nih.gov NR 17 TC 4 Z9 4 U1 1 U2 5 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD SPR PY 2010 VL 26 IS 1 BP 15 EP 21 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 802BB UT WOS:000293483200004 PM 20402180 ER PT J AU Dishman, RK Dunn, AL Sallis, JF Vandenberg, RJ Pratt, CA AF Dishman, Rod K. Dunn, Andrea L. Sallis, James F. Vandenberg, Robert J. Pratt, Charlotte A. TI Social-Cognitive Correlates of Physical Activity in a Multi-Ethnic Cohort of Middle-School Girls: Two-year Prospective Study SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE accelerometry; African American; Hispanic; Latina; self-efficacy; social support; perceived barriers ID WHITE ADOLESCENT GIRLS; SELF-EFFICACY; ACTIVITY BEHAVIOR; FAMILY SUPPORT; 12TH GRADE; TRIAL; CHILDREN; DETERMINANTS; TAAG; DIET AB Objective The study examined social-cognitive correlates of physical activity in a multi-ethnic cohort of girls from six regions of the United States who participated in the Trial of Activity for Adolescent Girls during their 6th and 8th grade school years. Methods Girls completed validated questionnaires and wore accelerometers that measured weekly physical activity in the spring of 2002 and 2005. Results In 8th grade, self-efficacy and perceived social support had indirect relations with physical activity mediated through perceived barriers, which was inversely related to physical activity. Self-efficacy also had a direct relation with physical activity. Conclusions Correlations were smaller than those obtained in studies that measured physical activity by self-reports, suggesting that previous estimates were inflated by common method artifact. Nonetheless, physical activity trials among girls during early adolescence might focus on increasing self-efficacy for overcoming barriers to physical activity and on ways by which perceived barriers can otherwise be reduced. C1 [Dishman, Rod K.] Univ Georgia, Dept Kinesiol, Ramsey Student Ctr, Athens, GA 30602 USA. [Dunn, Andrea L.] Klein Buendel Inc, Golden, CO USA. [Sallis, James F.] San Diego State Univ, San Diego, CA 92182 USA. [Pratt, Charlotte A.] NHLBI, Bethesda, MD USA. RP Dishman, RK (reprint author), Univ Georgia, Dept Kinesiol, Ramsey Student Ctr, 330 River Rd, Athens, GA 30602 USA. EM rdishman@uga.edu FU NHLBI NIH HHS [UO1 HL066845, UO1HL066852, UO1HL066853, UO1HL066855, UO1HL066856, UO1HL066857, UO1HL066858] NR 55 TC 34 Z9 35 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD MAR PY 2010 VL 35 IS 2 BP 188 EP 198 DI 10.1093/jpepsy/jsp042 PG 11 WC Psychology, Developmental SC Psychology GA 555FU UT WOS:000274494700012 PM 19468040 ER PT J AU Stephens, BE Liu, J Lester, B Lagasse, L Shankaran, S Bada, H Bauer, C Das, A Higgins, R AF Stephens, Bonnie E. Liu, Jing Lester, Barry Lagasse, Linda Shankaran, Seetha Bada, Henrietta Bauer, Charles Das, Abhik Higgins, Rosemary TI Neurobehavioral Assessment Predicts Motor Outcome in Preterm Infants SO JOURNAL OF PEDIATRICS LA English DT Article ID LOW-BIRTH-WEIGHT; NEURODEVELOPMENTAL OUTCOMES; GESTATIONAL-AGE; CEREBRAL-PALSY; INTRAVENTRICULAR HEMORRHAGE; PREMATURE-INFANTS; NEWBORN NEUROBEHAVIOR; SUBSTANCE EXPOSURE; PREGNANCY; ULTRASOUND AB Objective To determine whether Neonatal Intensive Care Unit Network Neurobehavior Scales (NNNS) at 44 weeks predict motor outcome at 2 years in preterm infants from the Maternal Lifestyles Study (MLS). Study design Data were collected on all preterm infants (<36 weeks) in the MLS who underwent an NNNS at 44 weeks (n = 395) and neurologic examination at 12 to 36 months or Bayley Psychomotor Development Index (PDI) at 24 months (n = 270). Logistic regression analyzed NNNS summary scores associated with cerebral palsy (CP) or PDI <70, while controlling for birth weight <= 1250 g. Results Eighteen of 395 infants (5%) had CP; 24 of 270 infants (9%) had PDI <70. CP was associated with low quality of movement (odds ratio [OR], 1.95; 95% CI, 1.24-3.06; P = .004) and high lethargy (OR, 1.67; 95% CI, 1.01-2.76; P = .045). The model contributed 19% of the variance in CP diagnosis at 12 to 36 months (R(2) = .19, P<.001). Low PDI was associated with low handling ( OR, 1.83; 95% CI, 1.12-2.99; P = .017), low quality of movement (OR, 2.16; 95% CI, 1.38-3.38; P = .001), and hypotonia (OR, 1.63; 95% CI, 1.14-2.32; P = .007). The model contributed 26% of the variance in PDI <70 at 24 months (R(2) = 0.26, P < .001). Conclusions The neurobehavioral profile of under-arousal in 44-week-old preterm infants may predict poor motor outcome. (J Pediatr 2010;156:366-71). C1 [Stephens, Bonnie E.; Lester, Barry; Lagasse, Linda] Alpert Brown Med Sch, Dept Pediat, Providence, RI USA. [Liu, Jing; Lester, Barry; Lagasse, Linda; Shankaran, Seetha; Bada, Henrietta; Bauer, Charles; Das, Abhik; Higgins, Rosemary] NICHD Neonatal Res Network, Maternal Lifestyle Study MLS, Bethesda, MD USA. RP Stephens, BE (reprint author), Women & Infants Hosp Rhode Isl, 101 Dudley St, Providence, RI 02905 USA. EM bstephens@wihri.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Lifestyles Study FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Lifestyles Study. Presented in part at the annual meeting of the Society for Pediatric Research, May, 2007, Toronto, Canada. The authors declare no conflicts of interest. NR 50 TC 29 Z9 31 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2010 VL 156 IS 3 BP 366 EP 371 DI 10.1016/j.jpeds.2009.09.042 PG 6 WC Pediatrics SC Pediatrics GA 559XO UT WOS:000274863800007 PM 19880137 ER PT J AU Vaisbuch, E Romero, R Mazaki-Tovi, S Erez, O Kim, SK Chaiworapongsa, T Gotsch, F Than, NG Dong, Z Pacora, P Lamont, R Yeo, L Hassan, SS Kusanovic, JP AF Vaisbuch, Edi Romero, Roberto Mazaki-Tovi, Shali Erez, Offer Kim, Sun Kwon Chaiworapongsa, Tinnakorn Gotsch, Francesca Than, Nandor Gabor Dong, Zhong Pacora, Percy Lamont, Ronald Yeo, Lami Hassan, Sonia S. Kusanovic, Juan Pedro TI Retinol binding protein 4-a novel association with early-onset preeclampsia SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Adipokines; fetal death (FD); fetal demise; intrauterine fetal death (IUFD); pregnancy; RBP4; small-for-gestational age (SGA) neonate ID ENDOTHELIAL GROWTH-FACTOR; HEALTHY NULLIPAROUS WOMEN; ISCHEMIC-HEART-DISEASE; LONG-TERM MORTALITY; BED SPIRAL ARTERIES; INSULIN-RESISTANCE; NORMAL-PREGNANCY; ADIPONECTIN CONCENTRATIONS; SERUM ADIPONECTIN; GLUCOSE-TOLERANCE AB Objective: Dysregulation of maternal circulating adipokines has been implicated in several "great obstetrical syndromes" including preeclampsia (PE), small-for-gestational age (SGA) neonate and fetal death (FD). It has been suggested that adipokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. Retinol binding protein 4 (RBP4), a novel adipokine, plays a role in obesity-related disorders, as well as in the regulation of the immune response. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in patients with PE and in those with an SGA neonate or FD. Study design: This cross-sectional study included patients in the following groups: 1) normal pregnancy (n=134); 2) PE (n=104); 3) SGA neonate (n=28); and 4) FD (n=37). Maternal plasma RBP4 concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) The median maternal plasma RBP4 concentration was higher among patients with PE than in those with a normal pregnancy (P=0.03); 2) The median maternal plasma RBP4 concentrations of patients with preterm PE (<37 weeks) was higher than that of those with term PE (P=0.017) and than that of those with a normal pregnancy (P=0.002); 3) The median maternal plasma RBP4 concentration did not differ significantly between patients with a normal pregnancy and those with an SGA neonate or with an FD; 4) Among normal pregnant women, the maternal plasma RBP4 concentrations did not correlate with pre-pregnancy body mass index, gestational age at blood sampling and neonatal birthweight. Conclusions: 1) Preeclampsia, but not pregnancy with an SGA neonate or an FD, is associated with a higher median maternal plasma concentration of RBP4 than normal pregnancy; 2) Preterm PE, and specifically early-onset PE, is associated with higher median RBP4 concentrations in maternal plasma compared to term PE. These findings suggest a role for RBP4 in the pathogenesis of preterm PE, but not in SGA and FD. C1 [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kim, Sun Kwon; Chaiworapongsa, Tinnakorn; Gotsch, Francesca; Than, Nandor Gabor; Dong, Zhong; Pacora, Percy; Lamont, Ronald; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro] Hutzel Womens Hosp, Intramural Div, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kim, Sun Kwon; Chaiworapongsa, Tinnakorn; Gotsch, Francesca; Than, Nandor Gabor; Dong, Zhong; Pacora, Percy; Lamont, Ronald; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro] Hutzel Womens Hosp, Intramural Div, Perinatol Res Branch, NICHD,NIH,DHHS, Bethesda, MD USA. [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Chaiworapongsa, Tinnakorn; Lamont, Ronald; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Womens Hosp, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Romero, R (reprint author), Hutzel Womens Hosp, Intramural Div, Perinatol Res Branch, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 134 TC 32 Z9 36 U1 0 U2 5 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD MAR PY 2010 VL 38 IS 2 BP 129 EP 139 DI 10.1515/JPM.2009.140 PG 11 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 564DS UT WOS:000275194100004 PM 19708829 ER PT J AU Mazaki-Tovi, S Romero, R Vaisbuch, E Kusanovic, JP Chaiworapongsa, T Kim, SK Mittal, P Dong, Z Pacora, P Yeo, L Hassan, SS AF Mazaki-Tovi, Shali Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Kim, Sun Kwon Mittal, Pooja Dong, Zhong Pacora, Percy Yeo, Lami Hassan, Sonia S. TI Retinol-binding protein 4: a novel adipokine implicated in the genesis of LGA in the absence of gestational diabetes mellitus SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Adipokine; adipose tissue; appropriate-for-gestational-age (AGA); body mass index (BMI); cytokine; insulin resistance; insulin sensitivity; metabolism; obesity; overweight; pregnancy ID MATERNAL SERUM ADIPONECTIN; POLYCYSTIC-OVARY-SYNDROME; GLUCOSE-TOLERANCE TEST; INSULIN-RESISTANCE; METABOLIC SYNDROME; BIRTH-WEIGHT; NORMAL-PREGNANCY; AMNIOTIC-FLUID; ADIPOSE-TISSUE; PRETERM LABOR AB Objective: Adipokines (cytokines produced by adipose tissue) play a major role in the control of body weight and energy distribution. Retinol-binding protein 4 (RBP4), only recently recognized as an adipokine, has been proposed to modulate systemic insulin sensitivity. The goal of this study was to determine whether there is an association between maternal plasma RBP4 concentration and the birth of a large-for-gestational-age (LGA) newborn in women with and without gestational diabetes mellitus (GDM). Study design: This cross-sectional study included pregnant women at term in the following groups: 1) normal pregnancy with an appropriate-for-gestational-age (AGA) neonate (n=64); 2) normal pregnancy with an LGA neonate (n=44); 3) GDM with an AGA neonate (n=55); and 4) GDM with an LGA neonate (n=42). Maternal plasma RBP4 concentration was determined by ELISA. Parametric and non-parametric statistics were used for analyses. Results: 1) Patients with GDM, either with AGA or LGA neonates, had a higher median plasma concentration of RBP4 than normal pregnant women who delivered an AGA neonate (P=0.01 and P=0.008, respectively); 2) mothers without GDM but with LGA neonates had a higher median plasma concentration of RBP4 than those with normal pregnancy and AGA newborns (P=0.001); 3) these findings remained significant after adjusting for maternal age, body mass index and gestational age at blood sampling. Conclusion: GDM is characterized by alterations in maternal circulating RBP4 concentrations akin to those of Type 2 diabetes mellitus. RBP4 concentrations in maternal plasma may play a role in accelerated fetal growth in the absence of overt carbohydrate intolerance. C1 [Romero, Roberto] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Mazaki-Tovi, Shali; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Mittal, Pooja; Dong, Zhong; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Mazaki-Tovi, Shali; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Romero, R (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 104 TC 13 Z9 13 U1 0 U2 3 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD MAR PY 2010 VL 38 IS 2 BP 147 EP 155 DI 10.1515/JPM.2010.044 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 564DS UT WOS:000275194100006 PM 20146659 ER PT J AU Cruciani, L Romero, R Vaisbuch, E Kusanovic, JP Chaiworapongsa, T Mazaki-Tovi, S Mittal, P Ogge, G Gotsch, F Erez, O Kim, SK Dong, Z Pacora, P Lamont, RF Yeo, L Hassan, SS Di Renzo, GC AF Cruciani, Laura Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Mazaki-Tovi, Shali Mittal, Pooja Ogge, Giovanna Gotsch, Francesca Erez, Offer Kim, Sun Kwon Dong, Zhong Pacora, Percy Lamont, Ronald F. Yeo, Lami Hassan, Sonia S. Di Renzo, Gian Carlo TI Pentraxin 3 in amniotic fluid: a novel association with intra-amniotic infection and inflammation SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Amniocentesis; cytokines; microbial invasion of the amniotic cavity (MIAC); pattern recognition receptors (PRRs); pregnancy; preterm delivery; preterm labor (PTL); preterm prelabor rupture of membranes (PROM) ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION; RECOGNITION RECEPTOR PTX3; NECROSIS-FACTOR-ALPHA; ACUTE-PHASE PROTEINS; HUMORAL INNATE IMMUNITY; CALCIUM-BINDING PROTEIN; AMYLOID-P COMPONENT; LONG PENTRAXIN; PRETERM LABOR AB Objective: Pentraxin 3 (PTX3) is a soluble pattern recognition receptor (PRR) that has an important role in immunoregulation and vascular integrity. The aim of this study was to determine if PTX3 is present in amniotic fluid (AF) and whether its concentration changes with gestational age (GA), in the presence of preterm or term labor, and in cases of intra-amniotic infection/inflammation (IAI) associated with spontaneous preterm labor (PTL) or preterm prelabor rupture of membranes (PROM). Study design: This cross-sectional study included the following groups: 1) mid-trimester (n=45); 2) uncomplicated pregnancies at term with (n=48) and without (n=40) spontaneous labor; 3) women with PTL and intact membranes who: a) delivered at term (n=44); b) delivered preterm without IAI (n=40); or c) delivered preterm with IAI (n=62); 4) women with preterm PROM with (n=63) and without (n=36) IAI. PTX3 concentration in AF was determined by ELISA. Non-parametric statistics were used for analyses. Results: 1) Among women with PTL and intact membranes, the median AF PTX3 concentration was significantly higher in women with IAI than in those without IAI (7.95 ng/mL vs. 0.38 ng/mL; P<0.001) and than in those who delivered at term (0.55 ng/mL; P<0.001); 2) women with preterm PROM and IAI had a higher median AF PTX3 concentration than those without IAI (9.12 ng/mL vs. 0.76 ng/mL; P<0.001); 3) the median AF PTX3 concentration did not change with GA (mid-trimester: 0.79 ng/mL vs. term not in labor: 0.58 ng/mL; P=0.09); and 4) labor at term was not associated with a significant change of AF PTX 3 concentration (in labor: 0.54 ng/mL vs. not in labor: 0.58 ng/mL, P=0.9). Conclusions: PTX3 is a physiologic constituent of the AF, and its median concentration is elevated in the presence of IAI, suggesting that PTX3 may play a role in the innate immune response against IAI. C1 [Cruciani, Laura; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Mittal, Pooja; Ogge, Giovanna; Gotsch, Francesca; Erez, Offer; Kim, Sun Kwon; Dong, Zhong; Pacora, Percy; Lamont, Ronald F.; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Cruciani, Laura; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Mittal, Pooja; Ogge, Giovanna; Gotsch, Francesca; Erez, Offer; Kim, Sun Kwon; Dong, Zhong; Pacora, Percy; Lamont, Ronald F.; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Mittal, Pooja; Erez, Offer; Lamont, Ronald F.; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Di Renzo, Gian Carlo] Santa Maria della Misericordia Univ Hosp, Perugia, Italy. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 132 TC 27 Z9 27 U1 1 U2 3 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD MAR PY 2010 VL 38 IS 2 BP 161 EP 171 DI 10.1515/JPM.2009.141 PG 11 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 564DS UT WOS:000275194100008 PM 19792835 ER PT J AU Thomsen, M Conn, PJ Lindsley, C Wess, J Boon, JY Fulton, BS Fink-Jensen, A Caine, SB AF Thomsen, Morgane Conn, P. Jeffrey Lindsley, Craig Wess, Juergen Boon, Joon Y. Fulton, Brian S. Fink-Jensen, Anders Caine, S. Barak TI Attenuation of Cocaine's Reinforcing and Discriminative Stimulus Effects via Muscarinic M-1 Acetylcholine Receptor Stimulation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID VENTRAL TEGMENTAL AREA; ANTIPSYCHOTIC-LIKE ACTIVITY; NUCLEUS-LESIONED RATS; PEDUNCULOPONTINE NUCLEUS; DOPAMINE RELEASE; DEFICIENT MICE; ACCUMBENS; MORPHINE; BRAIN; AMPHETAMINE AB Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M-1 and/or M-4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M-1/M-4-preferring agonist xanomeline, the putative M-1-selective agonist (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novel M-1-selective agonist 1-(1-2-methylbenzyl)-1,4-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-one (TBPB) were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M-1 subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M-1 and M-4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M-1 receptor activation attenuates cocaine's abuse-related effects, whereas non-M-1/M-4 receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine effects of systemically applied, M-1 receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction. C1 [Thomsen, Morgane; Boon, Joon Y.; Fulton, Brian S.; Caine, S. Barak] Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. [Conn, P. Jeffrey; Lindsley, Craig] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. [Wess, Juergen] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Fink-Jensen, Anders] Copenhagen Univ Hosp, Rigshosp, Ctr Psychiat, Copenhagen, Denmark. [Fink-Jensen, Anders] Univ Copenhagen, Lab Neuropsychiat, Copenhagen, Denmark. RP Thomsen, M (reprint author), Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM mthomsen@mclean.harvard.edu RI Conn, Peter/D-7848-2012 FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health National Institute on Drug Abuse [DA007252, DA-012142]; National Institutes of Health National Institute of Mental Health [MH073676, MH-082867]; National Alliance for Research on Schizophrenia and Depression Young Investigator Award; Eleanor and Miles Shore/Harvard Medical School Fellowship FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; the National Institutes of Health National Institute on Drug Abuse [Grants DA007252, DA-012142]; the National Institutes of Health National Institute of Mental Health [Grants MH073676, MH-082867]; and by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award and a Eleanor and Miles Shore/Harvard Medical School Fellowship (to M.T.). NR 43 TC 19 Z9 20 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2010 VL 332 IS 3 BP 959 EP 969 DI 10.1124/jpet.109.162057 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 559DF UT WOS:000274800200030 PM 19996296 ER PT J AU Hayashi, T Justinova, Z Hayashi, E Cormaci, G Mori, T Tsai, SY Barnes, C Goldberg, SR Su, TP AF Hayashi, Teruo Justinova, Zuzana Hayashi, Eri Cormaci, Gianfrancesco Mori, Tomohisa Tsai, Shang-Yi Barnes, Chanel Goldberg, Steven R. Su, Tsung-Ping TI Regulation of sigma-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BINDING-SITES; LIGAND-BINDING; OLFACTORY-BULB; GUINEA-PIG; NEURONS; CELLS; ACTIVATION; EXPRESSION; DEATH AB sigma-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of sigma-1 receptors in the brain of drug-naive rats and then examined the dynamics of sigma-1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. sigma-1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the sigma-1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the sigma-1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in sigma-1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. sigma-1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and sigma-1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat. C1 [Hayashi, Teruo; Hayashi, Eri; Cormaci, Gianfrancesco; Mori, Tomohisa; Tsai, Shang-Yi; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Justinova, Zuzana; Barnes, Chanel; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Justinova, Zuzana] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Triad Suite 3304,333 Cassell Dr, Baltimore, MD 21224 USA. EM tsu@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU National Institutes of Health National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse.; T.H. and Z.J. contributed equally to this work. NR 44 TC 37 Z9 37 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2010 VL 332 IS 3 BP 1054 EP 1063 DI 10.1124/jpet.109.159244 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 559DF UT WOS:000274800200040 PM 19940104 ER PT J AU Kelly, EB Parra-Medina, D Pfeiffer, KA Dowda, M Conway, TL Webber, LS Jobe, JB Going, S Pate, RR AF Kelly, Evelyn B. Parra-Medina, Deborah Pfeiffer, Karin A. Dowda, Marsha Conway, Terry L. Webber, Larry S. Jobe, Jared B. Going, Scott Pate, Russell R. TI Correlates of Physical Activity in Black, Hispanic, and White Middle School Girls SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE black; Hispanic; white; race/ethnicity analysis; accelerometry ID ADOLESCENT GIRLS; CHILDREN; TRIAL; ACCELEROMETER; DETERMINANTS; PARENT; YOUTH; TAAG; US AB Background: A need exists to better understand multilevel influences on physical activity among diverse samples of girls. This study examined correlates of moderate-to-vigorous physical activity (MVPA) among adolescent girls from different racial/ethnic backgrounds. Methods: 1,180 6th grade girls (24.5% black, 15.7% Hispanic, and 59.8% white) completed a supervised self-administered questionnaire that measured hypothesized correlates of PA. MVPA data were collected for 6 days using the ActiGraph accelerometer. Hierarchical regression analysis was used to examine correlates of PA in each racial/ethnic group. Results: Hispanic girls (n = 185) engaged in 21.7 minutes of MVPA per day, black girls (n = 289) engaged in 19.5 minutes of MVPA per day, and white girls (n = 706) engaged in 22.8 minutes of MVPA per day. Perceived transportation barriers (+; P=.010) were significantly and positively related to MVPA for Hispanic girls. For black girls, Body Mass Index (BMI) (-; P=.005) and social support from friends (+; P=.006) were significant correlates of MVPA. For white girls, BMI (-; P<.001), barriers (-; P=.012), social support from friends (+; P=.010), participation in school sports (+; P=.009), and community sports (+; P=.025) were significant correlates of MVPA. Explained variance ranged from 30% to 35%. Conclusions: Correlates of MVPA varied by racial/ethnic groups. Effective interventions in ethnically diverse populations may require culturally tailored strategies. C1 [Kelly, Evelyn B.; Dowda, Marsha] Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Parra-Medina, Deborah] Univ Texas Hlth Sci Ctr San Antonio, Inst Hlth Promot Res, San Antonio, TX USA. [Pfeiffer, Karin A.] Michigan State Univ, Dept Kinesiol, E Lansing, MI 48824 USA. [Conway, Terry L.] San Diego State Univ, Dept Publ Hlth, San Diego, CA 92182 USA. [Webber, Larry S.] Tulane Univ, Dept Biostat, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Jobe, Jared B.] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Going, Scott] Univ Arizona, Dept Physiol & Nutr Sci, Tucson, AZ USA. [Pate, Russell R.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. RP Kelly, EB (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. FU NHLBI NIH HHS [U01 HL066852-02, U01 HL066852-06S1, U01 HL066852-05, U01 HL066852-04, U01 HL066852-01, 3U01HL066852-06S2, U01 HL066852, U01 HL066852-03, U01 HL066852-06, U01 HL066852-06S2] NR 29 TC 24 Z9 25 U1 1 U2 8 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 MAR PY 2010 VL 7 IS 2 BP 184 EP 193 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 636LT UT WOS:000280737900006 PM 20484757 ER PT J AU Jin, QC Chen, BS Li, YZ Peng, YL Deng, Y Dai, CE Luo, HM Zhao, D Chen, J Li, DB Dong, HT AF Jin, Qingchao Chen, Baoshan Li, Youzhi Peng, Youliang Deng, Ye Dai, Cheng'En Luo, Hongmei Zhao, Dong Chen, Jack Li, Debao Dong, Haitao TI Expression Profile During the Development of Appressoria Induced by Hydrophobic Surfaces in Magnaporthe grisea Y34 SO JOURNAL OF PHYTOPATHOLOGY LA English DT Article DE fungus; pathogenicity; morphogenesis; expressed sequence tag; cDNA array; quantitative real-time PCR ID RICE BLAST FUNGUS; PROTEIN-KINASE-A; GENE-EXPRESSION; SEQUENCE TAGS; ADENYLATE-CYCLASE; DNA-SEQUENCE; MAP KINASE; IDENTIFICATION; MORPHOGENESIS; PATHOGENICITY AB To study the gene expression profile during appressorium developmental process of Magnaphorthe grisea strain Y34 isolated from the rich area of Asia cultivated rice resources, expressed sequence tags (ESTs) and cDNA array analysis were performed. A total of 4756 tentative unique transcripts (TUTs) were obtained from 13 057 ESTs of the 3' ends of the strain, which was approximately 25% of the total M. grisea EST sequences deposited in the GenBank database. Approximately 84% of these TUTs matched with the published draft genome sequences of strain 70-15. Southern analyses with 12 TUT probes revealed no obvious DNA polymorphism among strains 70-15, Guy11 and Y34. A cDNA array with 4108 TUTs was used to monitor gene expression patterns during appressorium development of M. grisea. Compared with ungerminated conidia, the number of up-regulated and down-regulated genes was almost consistent at any time-points of 2, 8, 20 and 30 h during appressorium development. More genes were differentially expressed during appressorium maturation (20 and 30 h) than during appressorium induction (2 h) and formation (8 h). During appressorium maturation (20-30 h), genes generally seemed to be most actively expressed. C1 [Jin, Qingchao; Deng, Ye; Dai, Cheng'En; Luo, Hongmei; Zhao, Dong; Li, Debao; Dong, Haitao] Zhejiang Univ, Inst Biotechnol, Bioinformat & Gene Network Res Grp, Hangzhou 310029, Zhejiang, Peoples R China. [Chen, Baoshan; Li, Youzhi] Guangxi Univ, Lab Subtrop Bioresource Conservat & Utilizat, Nanning 530004, Peoples R China. [Peng, Youliang] China Agr Univ, Minist Agr, Key Lab Mol Plant Pathol, Beijing 100094, Peoples R China. [Jin, Qingchao] Zhejiang Univ, Ningbo Inst Technol, Dept Biol & Pharmaceut Engn, Ningbo 315100, Zhejiang, Peoples R China. [Chen, Jack] NICHD, Unit Biocomputat, NIH, Bethesda, MD 20892 USA. RP Dong, HT (reprint author), Zhejiang Univ, Inst Biotechnol, Bioinformat & Gene Network Res Grp, Hangzhou 310029, Zhejiang, Peoples R China. EM htdong@zjuem.zju.edu.cn OI ?, ?/0000-0002-7584-0632 FU National High Technology Research and Development Program of China [2002BA711A15]; National Natural Science Foundation of China [.30370919] FX This work was supported by the National High Technology Research and Development Program of China (grant No. 2002BA711A15) and the National Natural Science Foundation of China (grant No.30370919). We thank Kangle Zheng of the China National Rice Research Institute for critical reading of the manuscript and for many helpful suggestions. NR 53 TC 1 Z9 1 U1 1 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0931-1785 J9 J PHYTOPATHOL JI J. Phytopathol. PD MAR PY 2010 VL 158 IS 3 BP 143 EP 153 DI 10.1111/j.1439-0434.2009.01588.x PG 11 WC Plant Sciences SC Plant Sciences GA 551IO UT WOS:000274201100002 ER PT J AU Semba, RD Fink, JC Sun, K Windham, BG Ferrucci, L AF Semba, Richard D. Fink, Jeffrey C. Sun, Kai Windham, B. Gwen Ferrucci, Luigi TI Serum Carboxymethyl-Lysine, a Dominant Advanced Glycation End Product, Is Associated With Chronic Kidney Disease: The Baltimore Longitudinal Study of Aging SO JOURNAL OF RENAL NUTRITION LA English DT Article ID GLOMERULAR-FILTRATION-RATE; RENAL-FAILURE PATIENTS; CROSS-LINK BREAKER; DIABETIC-NEPHROPATHY; DIETARY GLYCOTOXINS; RISK-FACTOR; PENTOSIDINE; CREATININE; ATHEROSCLEROSIS; ACCUMULATION AB Objective: Advanced glycation end products (AGEs) are modifiable risk factors for renal disease that were primarily studied in persons with diabetes or endstage renal disease. Our objective was to characterize the relationship between AGEs and renal function in community-dwelling adults. Design: The presence of serum L-carboxymethyl-lysine (CML), a dominant AGE, was compared with renal function in a cross-sectional analysis. Setting: This study was part of the Baltimore Longitudinal Study of Aging in Baltimore, Maryland. Patients or Other Participants: Participants included community-dwelling men and women, aged 26 to 93 years, seen during a regular follow-up visit to the Baltimore Longitudinal Study of Aging between 2002 and 2007. Main Outcome Measures: The main outcome measures included chronic kidney disease (CKD) at stage >= 3 of the National Kidney Foundation classification (estimated glomerular filtration rate [eGFR] of, 60 mL/minute/1.73 m 2) and eGFR. Results: Of 750 adults, 121 (16.1%) had CKD. Serum CML was associated with CKD (odds ratio expressed per one standard deviation, 1.37; 95% confidence interval, 1.11 to 1.67; P = .003) in a multivariate logistic regression model adjusting for age, race, smoking, and chronic diseases. Serum CML was associated with eGFR (mL/minute/1.73 m(2)) (beta = -2.21, standard error = 0.57, P = .0001) in a multivariate linear regression model, adjusting for age, race, smoking, and chronic diseases. After excluding patients with diabetes, serum CML was associated with CKD (odds ratio per one standard deviation, 1.38; 95% confidence interval, 1.12 to 1.70; P = .003) and eGFR (beta = -2.09, standard error - 0.59, P - .0005), adjusting for the same covariates. Conclusion: Serum CML, a dominant AGE, is independently associated with CKD and eGFR. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved. C1 [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Fink, Jeffrey C.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Windham, B. Gwen; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, 550 N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institutes of Health [R01 AG027012] FX This work was supported by National Institute on Aging grant R01 AG027012 and by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. NR 43 TC 30 Z9 31 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD MAR PY 2010 VL 20 IS 2 BP 74 EP 81 DI 10.1053/j.jrn.2009.08.001 PG 8 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 559XU UT WOS:000274865300003 PM 19853477 ER PT J AU Chan, L Giardino, N Rubenfeld, G Baldwin, LM Fordyce, MA Hart, LG AF Chan, Leighton Giardino, Nicholas Rubenfeld, Gordon Baldwin, Laura-Mae Fordyce, Meredith A. Hart, L. Gary TI Geographic Differences in Use of Home Oxygen for Obstructive Lung Disease: A National Medicare Study SO JOURNAL OF RURAL HEALTH LA English DT Article DE durable medical equipment; health services accessibility; oxygen inhalation therapy; pulmonary disease (chronic obstructive); rural health services ID PHYSICIAN CARE; URBAN; QUALITY; THERAPY AB Rationale: Home oxygen is the most expensive equipment item that Medicare purchases ($1.7 billion/year). Objectives: To assess geographic differences in supplemental oxygen use. Methods: Retrospective cohort analysis of oxygen claims for a 20% random sample of Medicare patients hospitalized for obstructive lung disease in 1999 and alive at the end of 2000. Measurements and Main Results: While 33.7% of the 34,916 hospitalized patients used supplemental oxygen, there was more than a 4-fold difference between states and a greater than 6-fold difference between hospital referral regions with high/low utilization. Rocky Mountain States and Alaska had the highest utilization, while the District of Columbia and Louisiana had the lowest utilization. After adjusting for patient characteristics and elevation, high-utilization communities included low-lying areas in California, Florida, Michigan, Missouri, and Washington. Patients who were younger, male, white, and who had more comorbidities, more hospital admissions, and lived at higher altitudes and in areas of greater income also had higher odds of using supplemental oxygen. Residing in rural areas was associated with higher unadjusted oxygen use rates. After adjustment, patients living in large rural areas had higher odds of using oxygen than patients living in urban areas or in small rural areas. Conclusions: There is significant geographic variation in supplemental oxygen use, even after controlling for patient and contextual factors. The Centers for Medicare & Medicaid Services should examine these issues further and enact changes that ensure patient health and fiscal responsibility. C1 [Chan, Leighton] NIH, Dept Rehabil Med, CRC, Ctr Clin, Bethesda, MD 20892 USA. [Giardino, Nicholas] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Rubenfeld, Gordon] Univ Washington, Sch Med, Div Pulm Crit Care Med, Seattle, WA USA. [Baldwin, Laura-Mae; Fordyce, Meredith A.] Univ Washington, Sch Med, Dept Family Med, Seattle, WA 98195 USA. [Hart, L. Gary] Univ Arizona, Arizona Rural Hlth Off, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. RP Chan, L (reprint author), NIH, Dept Rehabil Med, CRC, Ctr Clin, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM chanle@cc.nih.gov FU Intramural NIH HHS [ZIA CL060073-03]; PHS HHS [5U1CRH00035-02).] NR 26 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD SPR PY 2010 VL 26 IS 2 BP 139 EP 145 DI 10.1111/j.1748-0361.2010.00275.x PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 578DJ UT WOS:000276273400005 PM 20447000 ER PT J AU Affonso, DD Mayberry, L Shibuya, JY Archambeau, OG Correa, M Deliramich, AN Frueh, BC AF Affonso, Dyanne D. Mayberry, Linda Shibuya, June Y. Archambeau, Olga G. Correa, Mary Deliramich, Aimee N. Frueh, B. Christopher TI Cultural Context of School Communities in Rural Hawaii to Inform Youth Violence Prevention* SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE violence; organization and administration of school health program; safety education; research; public health; health policy ID QUALITATIVE RESEARCH; HEALTH-CARE; PERSPECTIVES; PTSD; RISK AB METHODS: Eight focus groups involving 86 community stakeholders included 51 adults (parent, teachers, school staff, community leaders) and 35 children aged 8-15 years old (3rd- to 10-th grade). Qualitative narrative analysis elicited major themes. RESULTS: Five themes emerged: (1) School-community violence takes on many forms that become entrenched in local culture. (2) Disintegration of community resources and a sense of learned helplessness underlie the escalation of youth violence. (3) Inadequate role modeling coupled with behavioral ambivalence among adults has sustained a climate of local cultural acceptance with youth violence. (4) Connection to cultural values has diminished, leading to a sense of loss in cultural identity among students. (5) Cultural values and practices are potential strategies for youth violence prevention. CONCLUSIONS: Cultural and community contextual factors contributed to youth violence in rural Hawaiian communities. Study implications include the need to further investigate the impact of vigilant, community involvement of stakeholders in school-based youth violence prevention program development. Cultural revitalization at family, school, and community levels may be critical success factors of such programs. C1 [Affonso, Dyanne D.] NIH, Res Infrastruct Minor Inst, RIMI, NCMHD, Bethesda, MD 20892 USA. [Affonso, Dyanne D.] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. [Mayberry, Linda] NYU, Coll Nursing, New York, NY 10003 USA. [Shibuya, June Y.] Univ Hawaii, Res Infrastruct Minor Inst, Hilo, HI 96720 USA. [Correa, Mary] State Hawaii Dept Educ, Sch Complex Area, Hilo, HI 96720 USA. [Deliramich, Aimee N.] Univ S Dakota, Vermillion, SD 57069 USA. [Frueh, B. Christopher] Univ Hawaii, Social Sci Div, Hilo, HI 96720 USA. [Frueh, B. Christopher] Univ Hawaii, Masters Program Counseling Psychol, Hilo, HI 96720 USA. RP Affonso, DD (reprint author), NIH, Res Infrastruct Minor Inst, RIMI, NCMHD, Bethesda, MD 20892 USA. EM daffonso@hawaii.edu; linda.mayberry@nyu.edu; shibuyaj@hawaii.edu; Lozhkina@hawaii.edu; mary_correa@notes.k12.hi.us; ames13_83@yahoo.com; Frueh@hawaii.edu NR 33 TC 8 Z9 9 U1 0 U2 13 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD MAR PY 2010 VL 80 IS 3 BP 146 EP 152 PG 7 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 557KW UT WOS:000274669000007 PM 20236417 ER PT J AU Smith, SM Dawson, DA Goldstein, RB Grant, BE AF Smith, Sharon M. Dawson, Deborah A. Goldstein, Rise B. Grant, Bridget E. TI Examining Perceived Alcoholism Stigma Effect on Racial-Ethnic Disparities in Treatment and Quality of Life Among Alcoholics SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID PSYCHIATRIC DIAGNOSTIC MODULES; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; MENTAL-ILLNESS STIGMA; IV AUDADIS-IV; SELF-ESTEEM; RELIABILITY; PEOPLE; DEPRESSION; SEVERITY AB Objective: The aim of this study was to examine racial-ethnic differences in perceived stigmatization of former alcoholics and their effect on associations of race-ethnicity with treatment history and psychological function among lifetime alcoholics. Method: Logistic regression analyses were conducted using data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of U.S. adults 18 years or older. Results: Stigma scores were lowest for Whites and Native Americans, higher for Blacks, and highest for Asians and Hispanics, both in the total population and among lifetime alcoholics. Neither race-ethnicity nor stigma was associated with treatment utilization. Psychological function was negatively associated with stigma, but the impact of stigma on racial-ethnic differences in psychological function fell short of statistical significance. Conclusions: Stigma may reduce quality of life among those with alcohol dependence, but there is no clear evidence that it affects racial-ethnic differences in quality of life. (J. Stud. Alcohol Drugs, 71, 231-236, 2010) C1 [Smith, Sharon M.; Dawson, Deborah A.; Goldstein, Rise B.; Grant, Bridget E.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Smith, SM (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM smithsh1@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is funded by the National Institute on Alcohol Abuse and Alcoholism, with supplemental support from the National Institute on Drug Abuse. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of sponsoring organizations, agencies, or the U.S. government. NR 43 TC 12 Z9 13 U1 2 U2 10 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAR PY 2010 VL 71 IS 2 BP 231 EP 236 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 578FJ UT WOS:000276278700009 PM 20230720 ER PT J AU Kastenmayer, RJ Moak, HB Jeffress, EJ Elkins, WR AF Kastenmayer, Robin J. Moak, Hannah B. Jeffress, Erin J. Elkins, William R. TI Management and Care of African Dormice (Graphiurus kelleni) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID SMALL MAMMALS; MURINUS; PREFERENCES; GLIRIDAE; RODENTIA AB African dormice (Graphittrus spp.) are small nocturnal rodents that currently are uncommon in laboratory settings. Their use may increase as they have recently been shown to develop an infection with monkeypox virus and may prove to be a valuable animal model for infectious disease research. Because African dormice are not commercially available, an extensive breeding colony is required to produce the animals needed for research use. Husbandry modifications that increased the production of offspring were the use of a high-protein diet, increased cage enrichment, and decreased animal density. To optimize consumption of a high-protein diet, we tested the palatability of several high-protein foods in a series of preference trials. Dormice preferred wax worm larva, cottage cheese, roasted soy nuts, and canned chicken. Issues related to medical management of Graphittrus kelleni include potential complications from traumatic injury. The development of a program for the husbandry and care of African dormice at our institution typifies the experiences of many laboratory animal facilities that are asked to support the development of animal models using novel species. C1 [Kastenmayer, Robin J.; Moak, Hannah B.; Jeffress, Erin J.; Elkins, William R.] NIAID, Comparat Med Branch, Bethesda, MD 20892 USA. RP Kastenmayer, RJ (reprint author), NIAID, Comparat Med Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rkastenmayer@niaid.nih.gov FU NIH, National Institute for Allergy and Infectious Diseases FX We would like to thank Dr Gerald Shea for statistical analysis and the staff of the Comparative Medicine Branch for their care of the animals. This research was supported by the Intramural Research Program of the NIH, National Institute for Allergy and Infectious Diseases. NR 12 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2010 VL 49 IS 2 BP 173 EP 176 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 573AZ UT WOS:000275882100008 PM 20353691 ER PT J AU Whiteside, TE Thigpen, JE Kissling, GE Grant, MG Forsythe, DB AF Whiteside, Tanya E. Thigpen, Julius E. Kissling, Grace E. Grant, Mary G. Forsythe, Diane B. TI Endotoxin, Coliform, and Dust Levels in Various Types of Rodent Bedding SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID GRAIN DUST; INFLAMMATION; EXPOSURE; ASTHMA; ASSAY; LAL AB Endotoxins in grain dust, household dust, and animal bedding may induce respiratory symptoms in rodents and humans. We assayed the endotoxin, coliform, and dust levels in 20 types of rodent bedding. Endotoxin concentrations were measured by using a commercial test kit, coliform counts were determined by using conventional microbiologic procedures, and dust content was evaluated by using a rotating-tapping shaker. Paper bedding types contained significantly less endotoxin than did other bedding types; the highest levels of endotoxin were detected in hardwood and corncob beddings. The range of endotoxin content for each bedding type was: corncob bedding, 1913 to 4504 endotoxin units per gram (EU/g); hardwood bedding, 3121 to 5401 EU/g; corncob-paper mixed bedding, 1586 to 2416 EU/g; and paper bedding, less than 5 to 105 EU/g. Coliform counts varied from less than 10 to 7591 cfu/g in corncob beddings, 90 to 4010 cfu/g in corncob-paper mixed beddings, less than 10 to 137 cfu/g in hardwood beddings, and less than 10 cfu/g in paper beddings. Average dust content was less than 0.15% in all commercial bedding types. We conclude that paper bedding is the optimal bedding type for conducting LPS inhalation studies and that rodent bedding containing high levels of endotoxin may alter the results of respiratory and immunologic studies in rodents. C1 [Whiteside, Tanya E.; Thigpen, Julius E.; Grant, Mary G.; Forsythe, Diane B.] Natl Inst Environm Hlth Sci, Comparat Med Branch, NIH, US Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, US Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Whiteside, TE (reprint author), Natl Inst Environm Hlth Sci, Comparat Med Branch, NIH, US Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM whitesi1@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX The authors thank Drs John Hollingsworth, Michael Fessler and Donald Cook for their assistance in reviewing and editing the manuscript and Gordon Caviness, Jacqueline Locklear, Patricia Deese, and Margaret Fender for their technical support. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 20 TC 7 Z9 7 U1 2 U2 6 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2010 VL 49 IS 2 BP 184 EP 189 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 573AZ UT WOS:000275882100010 PM 20353693 ER PT J AU Kuczmarski, MF Sees, AC Hotchkiss, L Cotugna, N Evans, MK Zonderman, AB AF Kuczmarski, Marie Fanelli Sees, Alexandra Cremer Hotchkiss, Lawrence Cotugna, Nancy Evans, Michele K. Zonderman, Alan B. TI Higher Healthy Eating Index-2005 Scores Associated with Reduced Symptoms of Depression in an Urban Population: Findings from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) Study SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; MULTIPLE-PASS METHOD; SELF-RATED HEALTH; DIETARY PATTERNS; OLDER-ADULTS; ELDERLY-MEN; MORTALITY; PREVALENCE; NUTRITION; WOMEN AB Background Depression affects more than 15 million Americans in a given year. Compared to physical health, less is known about the affect of diet quality on symptoms of depression. Objective This study investigated the relationship between diet quality and reported symptoms of depression in a low-income urban population. Subjects/setting Subjects included 1,118 African-American and white adults, aged 30 to 64 years, living in Baltimore, MD, and represented a subsample of the initial examination and recruitment phase of the Healthy Aging in Neighborhoods of Diversity across the Life Span study. Methods Nutrition data were based on two 24-hour dietary recalls collected by trained interviewers using the US Department of Agriculture Automated Multiple Pass Method. Diet quality was calculated using the US Department of Agriculture Healthy Eating Index (HEI)-2005. Depressive symptoms were assessed by a trained interviewer using the Center for Epidemiologic Studies Depression scale. Statistical analysis Both linear and logistic regression analyses were used to examine whether or not diet quality was associated with depressive symptoms. The dependent variable was depressive symptoms and independent variables included HEI-2005, race, sex, age, education, income, and food-assistance program participation. Results Mean HEI-2005 score was 52.17 +/- 0.40 (out of 100). Mean Center for Epidemiologic Studies Depression scale score was 11.64 +/- 0.25 (out of 40). Diet quality was significantly associated with reported symptoms of depression. However, income was a significantly stronger predictor of depression compared to diet quality, education, and sex. Conclusions Registered dietitians should be aware of relationships between psychological status and nutritional health when assisting clients to better manage their food choices to improve their overall health and quality of life. J Am Diet Assoc. 2010;110:383-389. C1 [Kuczmarski, Marie Fanelli; Sees, Alexandra Cremer; Cotugna, Nancy] Univ Delaware, Dept Hlth Nutr & Exercise Sci, Newark, DE 19716 USA. [Evans, Michele K.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Hlth Disparities Res Sect, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. RP Cotugna, N (reprint author), Univ Delaware, Dept Hlth Nutr & Exercise Sci, 301 E Willard Hall, Newark, DE 19716 USA. EM ncotugna@udel.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute of Aging, National Institute of Health FX This research was funded by the Intramural Research Program of the National Institute of Aging, National Institute of Health. NR 53 TC 50 Z9 51 U1 1 U2 12 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAR PY 2010 VL 110 IS 3 BP 383 EP 389 DI 10.1016/j.jada.2009.11.025 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 587LO UT WOS:000276994100009 PM 20184988 ER PT J AU Frank, LH Yu, Q Francis, R Tian, X Samtani, R Sahn, DJ Leatherbury, L Lo, CW AF Frank, Lowell H. Yu, Qing Francis, Richard Tian, Xin Samtani, Rajeev Sahn, David J. Leatherbury, Linda Lo, Cecilia W. TI Ventricular Rotation Is Independent of Cardiac Looping: A Study in Mice With Situs Inversus Totalis Using Speckle-Tracking Echocardiography SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Ventricular twist; Rotation; Speckle tracking; Situs inversus; High-frequency ultrasound ID PRIMARY CILIARY DYSKINESIA; MYOCARDIAL-FUNCTION; FIBER ORIENTATION; APEX ROTATION; TORSION; TWIST; ULTRASOUND; VALIDATION; HUMANS; HEART AB Background: The authors conducted an ultrasound interrogation of a mutant mouse model with a Dnah5 mutation to determine whether cardiac mechanics may be affected by reversal of cardiac situs. This mutant is a bona fide model of primary ciliary dyskinesia, with surviving homozygous mice showing either situs solitus (SS) or situs inversus totalis (SI). Methods: High-frequency ultrasound interrogations of 27 neonatal and infant Dnah5 mutant mice, 16 with SS and 11 with SI, were conducted using an ultra-high-frequency biomicroscope. Electrocardiographic and respiratory gating were used to reconstruct high-resolution two-dimensional cines at 1,000 Hz, with speckle-tracking echocardiography used to further analyze midchamber and apical rotation. Results: All SS mice exhibited the expected counterclockwise apical rotation as viewed caudocranially, and surprisingly, the same counterclockwise motion was also observed in SI mice. Speckle-tracking analysis confirmed counterclockwise systolic rotation in both SS and SI mice, and this increased in magnitude from the subepicardium to the endocardium and from the papillary muscles to the apex. The magnitude of apical endocardial rotation was not different for SS and SI mice (5.64 +/- 0.75 degrees and 5.76 +/- 1.90 degrees, respectively, P = .93). The anatomic segments responsible for the largest components of apical endocardial systolic rotation differed between the SS and SI hearts (P = .004). In both, the two largest contributors to rotation were offset 180 degrees from each other, but the anatomic regions differed between them. In SS hearts, maximal regional rotation occurred at the anterior mid-septum and posterolateral free wall, while in SI hearts, it was derived from the posterior septum and the anterolateral free wall. Analysis by episcopic fluorescence image capture histology of representative SI and SS mice showed normal intracardiac and segmental anatomy ({S, D, S} or {I, L, I}) without intracardiac defects. Conclusions: These results show that mirror-image cardiac looping did not result in mirror-image rotation of the morphologic left ventricle. These findings suggest that further studies are warranted to evaluate whether fiber orientation and cardiac mechanics may be abnormal in individuals with reversal of cardiac situs. The results of this study indicate that cardiac looping and myofiber orientation may be independently regulated. (J Am Soc Echocardiogr 2010;23:315-23.) C1 [Frank, Lowell H.; Leatherbury, Linda] Childrens Natl Med Ctr, Div Cardiol, Childrens Natl Heart Inst, Washington, DC 20010 USA. [Frank, Lowell H.; Yu, Qing; Francis, Richard; Samtani, Rajeev; Leatherbury, Linda; Lo, Cecilia W.] NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Sahn, David J.] Oregon Hlth & Sci Univ, Dept Pediat Cardiol, Portland, OR 97201 USA. [Lo, Cecilia W.] Univ Pittsburgh, Dept Dev Biol, Sch Med, Pittsburgh, PA USA. RP Frank, LH (reprint author), Childrens Natl Med Ctr, Div Cardiol, Childrens Natl Heart Inst, 111 Michigan Ave NW, Washington, DC 20010 USA. EM lfrank@cnmc.org RI Francis, Richard/P-2524-2015 FU Division of Intramural Research, National Heart, Lung, and Blood Institute (Bethesda, MD) [ZO1-HL005701] FX This work was supported by grant ZO1-HL005701 from the Division of Intramural Research, National Heart, Lung, and Blood Institute (Bethesda, MD). NR 41 TC 8 Z9 8 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAR PY 2010 VL 23 IS 3 BP 315 EP 323 DI 10.1016/j.echo.2009.11.024 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 564NO UT WOS:000275221900012 PM 20097527 ER PT J AU Ishwaran, H Kogalur, UB Gorodeski, EZ Minn, AJ Lauer, MS AF Ishwaran, Hemant Kogalur, Udaya B. Gorodeski, Eiran Z. Minn, Andy J. Lauer, Michael S. TI High-Dimensional Variable Selection for Survival Data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Forest; Maximal subtree; Minimal depth; Random survival forest; Tree; VIMP ID GENE-EXPRESSION PROFILES; BREAST-CANCER; PREDICT SURVIVAL; RANDOM FORESTS; CELL LYMPHOMA; CLASSIFICATION; MODELS; CHEMOTHERAPY; SIGNATURE AB The minimal depth of a maximal subtree IN a dimensionless order statistic measuring the predictiveness of a variable in a survival tree We derive the distribution of the minimal depth and use it lot high-dimensional variable selection using random survival forests In big p and small n problems (where p is the dimension and n Is the sample size). the distribution of the minimal depth reveals a "ceiling effect" in which a tree simply cannot be grown deep enough to properly identify predictive variables Motivated by this limitation. we develop a new regularized algorithm. termed RSF-Variable Hunting This algorithm exploits maximal subtrees for effective variable selection under such scenarios Several applications are presented demonstrating the methodology. including the problem of gene selection using microarray data In this work we focus only on survival settings. although out methodology also applies to other random forests applications. including regression and classification settings All examples presented here use the R-software package randomSurvivalForest C1 [Ishwaran, Hemant; Kogalur, Udaya B.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Gorodeski, Eiran Z.] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44195 USA. [Minn, Andy J.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Ishwaran, H (reprint author), Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. RI Gorodeski, Eiran/D-5384-2009; Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Gorodeski, Eiran/0000-0003-3756-8831 FU National Heart. Lung. and Blood Institute [CAN 8324207]; Department of Defense [BC085325] FX Hemant Ishwaran is Staff (E-mail lupin:tit ishwaran@gmail com) and Udaya B Kogalur is Adjunct Staff. Department of Quantitative Health Sciences Cleveland Clinic. Cleveland OH 44195 Eiran Z Gorodeski is Fellow. Heart and Vascular Institute. Cleveland Clinic. Cleveland. OH 44195 Andy J Minn is Assistant Professor. Department of Radiation Oncology, University of Pennsylvania. Philadelphia. PA 19104 Michael S Lauer is Director. Division of Cardiovascular Sciences National Heart. Lung. and Blood Institute. Bethesda. MD 20892 This work was partially funded by the National Heart. Lung. and Blood Institute (CAN 8324207) and by Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (BC085325) NR 47 TC 68 Z9 70 U1 1 U2 15 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD MAR PY 2010 VL 105 IS 489 BP 205 EP 217 DI 10.1198/jasa.2009.tm08622 PG 13 WC Statistics & Probability SC Mathematics GA 584XD UT WOS:000276786500021 ER PT J AU Bekker, V Chanock, SJ Yeager, M Hutchinson, AA von Hahn, T Chen, S Xiao, N Dotrang, M Brown, M Busch, MP Edlin, BR Rice, CM O'Brien, TR AF Bekker, V. Chanock, S. J. Yeager, M. Hutchinson, A. A. von Hahn, T. Chen, S. Xiao, N. Dotrang, M. Brown, M. Busch, M. P. Edlin, B. R. Rice, C. M. O'Brien, T. R. TI Genetic variation in CLDN1 and susceptibility to hepatitis C virus infection SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE claudin-1; epidemiology; genetic; susceptibility; viral receptor ID INJECTION-DRUG USERS; SAN-FRANCISCO; CLAUDIN-1; ENTRY; SEROPREVALENCE; ASSOCIATIONS; DISEASE; RISK; HCV AB Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a 'whole gene association study' among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n = 658) to those in IDUs who had cleared HCV (n = 199) or remained HCV-uninfected (n = 68). Analyses were controlled for racial ancestry (African-American or European-American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; P = 0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; P = 0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; P = 0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; P = 0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African-American and European-American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection. C1 [Chanock, S. J.; Yeager, M.; Hutchinson, A. A.; Xiao, N.; Brown, M.; O'Brien, T. R.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Bekker, V.; Chanock, S. J.] NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [von Hahn, T.; Rice, C. M.] Rockefeller Univ, Ctr Study Hepatitis C, New York, NY 10021 USA. [Chen, S.] Informat Management Serv Inc, Silver Spring, MD USA. [Dotrang, M.] CSC, Rockville, MD USA. [Edlin, B. R.] Univ Calif San Francisco, Urban Hlth Study, San Francisco, CA 94143 USA. [Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Edlin, B. R.] Cornell Univ, Weill Med Coll, Ctr Study Hepatitis C, New York, NY 10021 USA. [Yeager, M.; Hutchinson, A. A.; Xiao, N.; Brown, M.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Gaithersburg, MD USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS 5052,MSC 7246, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov OI Edlin, Brian/0000-0001-8172-8797 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Cancer Institute, National Institutes of Health [N01-CO-12400]; PHS [AI072613]; Greenberg Medical Research Institute; Starr Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. T.V.H and C.M.R were supported by PHS grant AI072613, the Greenberg Medical Research Institute, and the Starr Foundation. NR 26 TC 11 Z9 11 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD MAR PY 2010 VL 17 IS 3 BP 192 EP 200 DI 10.1111/j.1365-2893.2009.01166.x PG 9 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 545ID UT WOS:000273724800006 PM 19674288 ER PT J AU Witko, SE Johnson, JE Kalyan, NK Felber, BK Pavlakis, GN Sidhu, MK Hendry, RM Udem, SA Parks, CL AF Witko, Susan E. Johnson, J. Erik Kalyan, Narender K. Felber, Barbara K. Pavlakis, George N. Sidhu, Maninder K. Hendry, R. Michael Udem, Stephen A. Parks, Christopher L. TI Refined methods for propagating vesicular stomatitis virus vectors that are defective for G protein expression SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Negative-strand RNA virus; VSV; Vero cells; Electroporation; Heat shock; Non-propagating ID RESPIRATORY SYNCYTIAL VIRUS; ATTENUATED RECOMBINANT VACCINE; REPLICATION-COMPETENT VECTOR; MESSENGER-RNA DEGRADATION; IMMEDIATE-EARLY GENE; STRUCTURAL FEATURES; NONHUMAN-PRIMATES; ENDOGENOUS VIRUS; MAMMALIAN-CELLS; REV DEPENDENCE AB Propagation-defective vesicular stomatitis virus (VSV) vectors that encode a truncated G protein (VSV-Gstem) or lack the G gene entirely (VSV-Delta G) are attractive vaccine vectors because they are immunogenic, cannot replicate and spread after vaccination, and do not express many of the epitopes that elicit neutralizing anti-VSV immunity. To consider advancing non-propagating VSV vectors towards clinical assessment, scalable technology that is compliant with human vaccine manufacturing must be developed to produce clinical trial material. Accordingly, two propagation methods were developed for VSV-Gstem and VSV-Delta G vectors encoding HIV gag that have the potential to support large-scale production. One method is based on transient expression of G protein after electroporating plasmid DNA into Vero cells and the second is based on a stable Vero cell line that contains a G gene controlled by a heat shock-inducible transcription unit. Both methods reproducibly supported production of 1 x 10(7) to 1 x 10(8) infectious units (I.U.s) of vaccine vector per milliliter. Results from these studies also showed that optimization of the G gene is necessary for abundant G protein expression from electroporated plasmid DNA or from DNA integrated in the genome of a stable cell line, and that the titers of VSV-Gstem vectors generally exceeded VSV-Delta G. (C) 2009 Elsevier B.V. All rights reserved. C1 [Witko, Susan E.; Johnson, J. Erik; Kalyan, Narender K.; Sidhu, Maninder K.; Hendry, R. Michael; Udem, Stephen A.; Parks, Christopher L.] Pfizer Vaccine Res, Pearl River, NY 10965 USA. [Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Hendry, R. Michael] Ctr Dis Control, Div HIV AIDS Prevent, Atlanta, GA 30329 USA. [Parks, Christopher L.] Int AIDS Vaccine Initiat, Vaccine Design & Dev Lab, Brooklyn, NY 11220 USA. RP Kalyan, NK (reprint author), Pfizer Vaccine Res, 401 N Middletown Rd, Pearl River, NY 10965 USA. EM kalyann@wyeth.com FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [HVDDT NO1-A1-25458]; National Cancer Institute, Center for Cancer Research FX This work was sponsored in part by an HIV-1 Vaccine Design and Development Team contract from the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (HVDDT NO1-A1-25458), and the National Cancer Institute Intramural Research Program at the Center for Cancer Research. We thank Julia Li for performing statistical analysis, Alan Gordon for insightful comments and suggestions and Ellen Murphy and Yury Matsuka for critical review of the manuscript. NR 82 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD MAR PY 2010 VL 164 IS 1-2 BP 43 EP 50 DI 10.1016/j.jviromet.2009.11.023 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 585JD UT WOS:000276820500008 PM 19941901 ER PT J AU Boltz, VF Maldarelli, F Martinson, N Morris, L McIntyre, JA Gray, G Hopley, MJ Kimura, T Mayers, DL Robinson, P Mellors, JW Coffin, JM Palmer, SE AF Boltz, Valerie F. Maldarelli, Frank Martinson, Neil Morris, Lynn McIntyre, James A. Gray, Glenda Hopley, Mark J. Kimura, Toshio Mayers, Douglas L. Robinson, Patrick Mellors, John W. Coffin, John M. Palmer, Sarah E. TI Optimization of allele-specific PCR using patient-specific HIV consensus sequences for primer design SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; Allele-specific PCR; Low frequency variants; Subtype consensus sequence; Patient-specific HIV-1 consensus sequence ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; SINGLE-DOSE NEVIRAPINE; RESISTANT HIV-1; ANTIRETROVIRAL THERAPY; DRUG-RESISTANCE; TRANSMISSION; POPULATIONS; PERSISTENCE; MUTATIONS AB Allele-specific PCR based on subtype consensus sequences is a powerful technique for detecting low frequency drug resistant mutants in HIV-1 infected patients. However, this approach can be limited by genetic variation in the region complementary to the primers, leading to variability in allele detection. The goals of this study were to quantify this effect and then to improve assay performance. (C) 2009 Elsevier B.V. All rights reserved. C1 [Palmer, Sarah E.] Karolinska Inst, Dept Virol, Swedish Inst Infect Dis & Control, S-17182 Solna, Sweden. [Boltz, Valerie F.; Maldarelli, Frank; Coffin, John M.; Palmer, Sarah E.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Martinson, Neil; McIntyre, James A.; Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Morris, Lynn] Natl Inst Communicable Dis, Johannesburg, South Africa. [Martinson, Neil] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hopley, Mark J.; Kimura, Toshio] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Mayers, Douglas L.; Robinson, Patrick] Boehringer Ingelheim Pharmaceut, Ridgefield, CT USA. [Mayers, Douglas L.] Idenix Pharmaceut, Cambridge, MA USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Palmer, SE (reprint author), Karolinska Inst, Dept Virol, Swedish Inst Infect Dis & Control, Nobels Vag 18, S-17182 Solna, Sweden. EM sarah.palmer@smi.se OI , Lynn/0000-0003-3961-7828 FU National Cancer Institute Science Applications International Corporation (SAIC) [20Xs190A]; NIH; National Institute of Allergy and Infectious Disease [U01AI38858]; George Kirby Foundation; Boehringer Ingelheim ZA, Johannesburg, South Africa; Swedish Research Council FX We wish to thank Mary Kearney and Ann Wiegand for valuable scientific discussion and Sarah Cohen for sample management. This work was supported in part, by grants to John Mellors from the National Cancer Institute Science Applications International Corporation (SAIC) contract 20Xs190A, and by the Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Disease (Virology Support Subcontract of the Adult AIDS Clinical Trials central Group U01AI38858). John Coffin was a Research Professor of the American Cancer Society with support from the George Kirby Foundation. The parent studies were funded by the National Department of Health of South Africa and Boehringer Ingelheim ZA, Johannesburg, South Africa. Sarah Palmer was funded in part by Swedish Research Council. All participants in these studies have provided written informed consent for viral resistance testing. NR 19 TC 11 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD MAR PY 2010 VL 164 IS 1-2 BP 122 EP 126 DI 10.1016/j.jviromet.2009.11.025 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 585JD UT WOS:000276820500020 PM 19948190 ER PT J AU Nayak, B Kumar, S DiNapoli, JM Paldurai, A Perez, DR Collins, PL Samal, SK AF Nayak, Baibaswata Kumar, Sachin DiNapoli, Joshua M. Paldurai, Anandan Perez, Daniel R. Collins, Peter L. Samal, Siba K. TI Contributions of the Avian Influenza Virus HA, NA, and M2 Surface Proteins to the Induction of Neutralizing Antibodies and Protective Immunity SO JOURNAL OF VIROLOGY LA English DT Article ID NEWCASTLE-DISEASE VIRUS; EXPRESSING H5 HEMAGGLUTININ; A VIRUS; EXTRACELLULAR DOMAIN; LETHAL INFLUENZA; PLASMID DNAS; VACCINE; CHICKENS; NEURAMINIDASE; MICE AB Highly pathogenic avian influenza virus (HPAIV) subtype H5N1 causes severe disease and mortality in poultry. Increased transmission of H5N1 HPAIV from birds to humans is a serious threat to public health. We evaluated the individual contributions of each of the three HPAIV surface proteins, namely, the hemagglutinin (HA), the neuraminidase (NA), and the M2 proteins, to the induction of HPAIV-neutralizing serum antibodies and protective immunity in chickens. Using reverse genetics, three recombinant Newcastle disease viruses (rNDVs) were engineered, each expressing the HA, NA, or M2 protein of H5N1 HPAIV. Chickens were immunized with NDVs expressing a single antigen (HA, NA, and M2), two antigens (HA+NA, HA+M2, and NA+M2), or three antigens (HA+NA+M2). Immunization with HA or NA induced high titers of HPAIV-neutralizing serum antibodies, with the response to HA being greater, thus identifying HA and NA as independent neutralization antigens. M2 did not induce a detectable neutralizing serum antibody response, and inclusion of M2 with HA or NA reduced the magnitude of the response. Immunization with HA alone or in combination with NA induced complete protection against HPAIV challenge. Immunization with NA alone or in combination with M2 did not prevent death following challenge, but extended the time period before death. Immunization with M2 alone had no effect on morbidity or mortality. Thus, there was no indication that M2 is immunogenic or protective. Furthermore, inclusion of NA in addition to HA in a vaccine preparation for chickens may not enhance the high level of protection provided by HA. C1 [Nayak, Baibaswata; Kumar, Sachin; Paldurai, Anandan; Perez, Daniel R.; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [DiNapoli, Joshua M.; Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016; OI Perez, Daniel/0000-0002-6569-5689 FU Avian Influenza Coordinated Agricultural Project (AICAP) [2005-05523, 2007-04981]; NIAID [N01A060009]; NIAID-NIH [HHSN266200700010C] FX This research was supported by Avian Influenza Coordinated Agricultural Project (AICAP) grants 2005-05523 and 2007-04981, NIAID contract N01A060009 (85% support), and NIAID, NIH Intramural Research Program (15% support). D. R. P. is funded by NIAID-NIH HHSN266200700010C. NR 42 TC 29 Z9 32 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 5 BP 2408 EP 2420 DI 10.1128/JVI.02135-09 PG 13 WC Virology SC Virology GA 552YD UT WOS:000274330300020 PM 20032181 ER PT J AU Su, HP Singh, K Gittis, AG Garboczi, DN AF Su, Hua-Poo Singh, Kavita Gittis, Apostolos G. Garboczi, David N. TI The Structure of the Poxvirus A33 Protein Reveals a Dimer of Unique C-Type Lectin-Like Domains SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINIA VIRUS A33R; ACTIVATING IMMUNORECEPTOR NKG2D; ACTIN-CONTAINING MICROVILLI; SMALLPOX DNA VACCINE; TO-CELL SPREAD; CRYSTAL-STRUCTURE; ENVELOPE GLYCOPROTEIN; TYROSINE PHOSPHORYLATION; EXTRACELLULAR VIRIONS; MONOCLONAL-ANTIBODIES AB The current vaccine against smallpox is an infectious form of vaccinia virus that has significant side effects. Alternative vaccine approaches using recombinant viral proteins are being developed. A target of subunit vaccine strategies is the poxvirus protein A33, a conserved protein in the Chordopoxvirinae subfamily of Poxviridae that is expressed on the outer viral envelope. Here we have determined the structure of the A33 ectodomain of vaccinia virus. The structure revealed C-type lectin-like domains (CTLDs) that occur as dimers in A33 crystals with five different crystal lattices. Comparison of the A33 dimer models shows that the A33 monomers have a degree of flexibility in position within the dimer. Structural comparisons show that the A33 monomer is a close match to the Link module class of CTLDs but that the A33 dimer is most similar to the natural killer (NK)-cell receptor class of CTLDs. Structural data on Link modules and NK-cell receptor-ligand complexes suggest a surface of A33 that could interact with viral or host ligands. The dimer interface is well conserved in all known A33 sequences, indicating an important role for the A33 dimer. The structure indicates how previously described A33 mutations disrupt protein folding and locates the positions of N-linked glycosylations and the epitope of a protective antibody. C1 [Su, Hua-Poo; Singh, Kavita; Gittis, Apostolos G.; Garboczi, David N.] NIAID, Struct Biol Sect, RTB, NIH, Rockville, MD 20852 USA. RP Garboczi, DN (reprint author), NIAID, Struct Biol Sect, RTB, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM dgarboczi@niaid.nih.gov FU U. S. Department of Energy; Office of Science; Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH; NIAID FX Use of the Advanced Photon Source beam lines was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 78 TC 18 Z9 19 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 5 BP 2502 EP 2510 DI 10.1128/JVI.02247-09 PG 9 WC Virology SC Virology GA 552YD UT WOS:000274330300028 PM 20032175 ER PT J AU O'Keefe, BR Giomarelli, B Barnard, DL Shenoy, SR Chan, PKS McMahon, JB Palmer, KE Barnett, BW Meyerholz, DK Wohlford-Lenane, CL McCray, PB AF O'Keefe, Barry R. Giomarelli, Barbara Barnard, Dale L. Shenoy, Shilpa R. Chan, Paul K. S. McMahon, James B. Palmer, Kenneth E. Barnett, Brian W. Meyerholz, David K. Wohlford-Lenane, Christine L. McCray, Paul B., Jr. TI Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae SO JOURNAL OF VIROLOGY LA English DT Article ID ACUTE RESPIRATORY SYNDROME; SARS-CORONAVIRUS; CARBOHYDRATE-BINDING; INACTIVATING PROTEIN; REPLICATION CYCLE; AIRWAY EPITHELIA; PLANT-LECTINS; CYANOVIRIN-N; BALB/C MICE; INFECTION AB Viruses of the family Coronaviridae have recently emerged through zoonotic transmission to become serious human pathogens. The pathogenic agent responsible for severe acute respiratory syndrome (SARS), the SARS coronavirus (SARS-CoV), is a member of this large family of positive-strand RNA viruses that cause a spectrum of disease in humans, other mammals, and birds. Since the publicized outbreaks of SARS in China and Canada in 2002-2003, significant efforts successfully identified the causative agent, host cell receptor(s), and many of the pathogenic mechanisms underlying SARS. With this greater understanding of SARS-CoV biology, many researchers have sought to identify agents for the treatment of SARS. Here we report the utility of the potent antiviral protein griffithsin (GRFT) in the prevention of SARS-CoV infection both in vitro and in vivo. We also show that GRFT specifically binds to the SARS-CoV spike glycoprotein and inhibits viral entry. In addition, we report the activity of GRFT against a variety of additional coronaviruses that infect humans, other mammals, and birds. Finally, we show that GRFT treatment has a positive effect on morbidity and mortality in a lethal infection model using a mouse-adapted SARS-CoV and also specifically inhibits deleterious aspects of the host immunological response to SARS infection in mammals. C1 [O'Keefe, Barry R.; Giomarelli, Barbara; McMahon, James B.] NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. [Barnard, Dale L.] Utah State Univ, Logan, UT 84322 USA. [Shenoy, Shilpa R.] SAIC Frederick, Frederick, MD 21702 USA. [Chan, Paul K. S.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Palmer, Kenneth E.; Barnett, Brian W.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA. [Palmer, Kenneth E.; Barnett, Brian W.] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. [Palmer, Kenneth E.] Owensboro Canc Res Program, Owensboro, KY 42303 USA. [Meyerholz, David K.; Wohlford-Lenane, Christine L.] Univ Iowa, Dept Pathol, Carver Coll Med, Iowa City, IA 52242 USA. [McCray, Paul B., Jr.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [McCray, Paul B., Jr.] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. RP O'Keefe, BR (reprint author), NCI, Mol Targets Dev Program, Ctr Canc Res, Bldg 562,Rm 201, Frederick, MD 21702 USA. EM okeefeba@mail.nih.gov; paul-mccray@uiowa.edu RI Chan, Paul/J-9360-2013; OI Palmer, Kenneth/0000-0002-2811-1111 FU NIH [N01-CO-12400, HHSN261200800001E, PO1 A1060699]; National Cancer Institute; Center for Cancer Research; Roy J. Carver Trust; Executive Vice President of the University of Louisville FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (B. R. O., B. G., and J. B. M.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and HHSN261200800001E (S. R. S.). P. B. M. is supported in part by NIH PO1 A1060699 and the Roy J. Carver Trust; K. E. P. is supported by a Pilot Project grant from the Executive Vice President of the University of Louisville. NR 38 TC 51 Z9 52 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 5 BP 2511 EP 2521 DI 10.1128/JVI.02322-09 PG 11 WC Virology SC Virology GA 552YD UT WOS:000274330300029 PM 20032190 ER PT J AU Cheng, F Chen, AY Best, SM Bloom, ME Pintel, D Qiu, JM AF Cheng, Fang Chen, Aaron Yun Best, Sonja M. Bloom, Marshall E. Pintel, David Qiu, Jianming TI The Capsid Proteins of Aleutian Mink Disease Virus Activate Caspases and Are Specifically Cleaved during Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN PARVOVIRUS B19; MINUTE VIRUS; CANINE PARVOVIRUS; TRANSCRIPTION PROFILE; VIRAL REPLICATION; UNIQUE FEATURES; INTERSTITIAL PNEUMONIA; NUCLEOTIDE-SEQUENCE; MOLECULAR CLONE; CYTOCHROME-C AB Aleutian mink disease virus (AMDV) is currently the only known member of the genus Amdovirus in the family Parvoviridae. It is the etiological agent of Aleutian disease of mink. We have previously shown that a small protein with a molecular mass of approximately 26 kDa was present during AMDV infection and following transfection of capsid expression constructs (J. Qiu, F. Cheng, L. R. Burger, and D. Pintel, J. Virol. 80: 654-662, 2006). In this study, we report that the capsid proteins were specifically cleaved at aspartic acid residue 420 (D420) during virus infection, resulting in the previously observed cleavage product. Mutation of a single amino acid residue at D420 abolished the specific cleavage. Expression of the capsid proteins alone in Crandell feline kidney (CrFK) cells reproduced the cleavage of the capsid proteins in virus infection. More importantly, capsid protein expression alone induced active caspases, of which caspase-10 was the most active. Active caspases, in turn, cleaved capsid proteins in vivo. Our results also showed that active caspase-7 specifically cleaved capsid proteins at D420 in vitro. These results suggest that viral capsid proteins alone induce caspase activation, resulting in cleavage of capsid proteins. We also provide evidence that AMDV mutants resistant to caspase-mediated capsid cleavage increased virus production approximately 3-to 5-fold in CrFK cells compared to that produced from the parent virus AMDV-G at 37 degrees C but not at 31.8 degrees C. Collectively, our results indicate that caspase activity plays multiple roles in AMDV infection and that cleavage of the capsid proteins might have a role in regulating persistent infection of AMDV. C1 [Cheng, Fang; Chen, Aaron Yun; Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. [Best, Sonja M.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Pintel, David] Univ Missouri, Life Sci Ctr, Columbia, MO USA. RP Qiu, JM (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Mail Stop 3029,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM jqiu@kumc.edu FU NIAID [RO1 AI070723, AI46458, AI56310]; NCRR [P20 RR016443]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by PHS grant RO1 AI070723 from NIAID and grant P20 RR016443 from the NCRR COBRE program to J. Q. and PHS grants AI46458 and AI56310 from NIAID to D. P. S. M. B. and M. E. B. were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 52 TC 15 Z9 20 U1 1 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 6 BP 2687 EP 2696 DI 10.1128/JVI.01917-09 PG 10 WC Virology SC Virology GA 565VG UT WOS:000275322300006 PM 20042496 ER PT J AU Ofek, G McKee, K Yang, YP Yang, ZY Skinner, J Guenaga, FJ Wyatt, R Zwick, MB Nabel, GJ Mascola, JR Kwong, PD AF Ofek, Gilad McKee, Krisha Yang, Yongping Yang, Zhi-Yong Skinner, Jeff Guenaga, F. Javier Wyatt, Richard Zwick, Michael B. Nabel, Gary J. Mascola, John R. Kwong, Peter D. TI Relationship between Antibody 2F5 Neutralization of HIV-1 and Hydrophobicity of Its Heavy Chain Third Complementarity-Determining Region SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; TRANSITION-STATE ANALOG; MONOCLONAL-ANTIBODIES; VENOM PHOSPHOLIPASE-A2; ENVELOPE GLYCOPROTEIN; ECTODOMAIN REGION; CRYSTAL-STRUCTURE; GP41 ECTODOMAIN; ANTI-GP41 2F5; MEMBRANE AB The membrane-proximal external region (MPER) of the HIV-1 gp41 transmembrane glycoprotein is the target of the broadly neutralizing antibody 2F5. Prior studies have suggested a two-component mechanism for 2F5-mediated neutralization involving both structure-specific recognition of a gp41 protein epitope and nonspecific interaction with the viral lipid membrane. Here, we mutationally alter a hydrophobic patch on the third complementarity-determining region of the heavy chain (CDR H3) of the 2F5 antibody and assess the abilities of altered 2F5 variants to bind gp41 and to neutralize diverse strains of HIV-1. CDR H3 alterations had little effect on the affinity of 2F5 variants for a peptide corresponding to its gp41 epitope. In contrast, strong effects and a high degree of correlation (P < 0.0001) were found between virus neutralization and CDR H3 hydrophobicity, as defined by predicted free energies of transfer from water to a lipid bilayer interface or to octanol. The effect of CDR H3 hydrophobicity on neutralization was independent of isolate sensitivity to 2F5, and CDR H3 variants with tryptophan substitutions were able to neutralize HIV-1 similar to 10-fold more potently than unmodified 2F5. A threshold was observed for increased hydrophobicity of the 2F5 CDR H3 loop beyond which effects on 2F5-mediated neutralization leveled off. Together, the results provide a more complete understanding of the 2F5 mechanism of HIV-1 neutralization and indicate ways to enhance the potency of MPER-directed antibodies. C1 [Ofek, Gilad; McKee, Krisha; Yang, Yongping; Yang, Zhi-Yong; Guenaga, F. Javier; Wyatt, Richard; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Skinner, Jeff] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Zwick, Michael B.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Kwong, PD (reprint author), 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov OI Skinner, Jeff/0000-0001-5697-0442 FU NIH; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative (IAVI) FX We thank the members of the Structural Biology Section, VRC, and S. H. White for discussions and comments on the manuscript, W. R. Schief for comments on the CDR H3 mutants, G. M. Shaw for providing HIV-2 strains 7312a and 7312aC1, and J. Stuckey for assistance with figures and tables.; O., F. J. G., R. W., M. B. Z., J. R. M., and P. D. K. designed research; G. O., K. M., Y. Y., and Z.- Y. Y. performed research; Z.- Y. Y. and G. J. N. contributed new reagents; G. O., K. M., J. S., J. R. M., and P. D. K. analyzed data; G. O. and P. D. K. wrote the paper.; Support for this work was provided by the Intramural Research Program of the NIH, by a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Health Initiative, and by the International AIDS Vaccine Initiative (IAVI). NR 48 TC 73 Z9 74 U1 2 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 6 BP 2955 EP 2962 DI 10.1128/JVI.02257-09 PG 8 WC Virology SC Virology GA 565VG UT WOS:000275322300030 PM 20042512 ER PT J AU Hood, CL Abraham, J Boyington, JC Leung, K Kwong, PD Nabel, GJ AF Hood, Chantelle L. Abraham, Jonathan Boyington, Jeffrey C. Leung, Kwanyee Kwong, Peter D. Nabel, Gary J. TI Biochemical and Structural Characterization of Cathepsin L-Processed Ebola Virus Glycoprotein: Implications for Viral Entry and Immunogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID ENDOSOMAL CATHEPSINS; FILOVIRUS ENTRY; INFLUENZA-VIRUS; CELLULAR ENTRY; BINDING; RESIDUES; IDENTIFICATION; PROTEOLYSIS; RECEPTOR; MARBURG AB Ebola virus (EBOV) cellular attachment and entry is initiated by the envelope glycoprotein (GP) on the virion surface. Entry of this virus is pH dependent and associated with the cleavage of GP by proteases, including cathepsin L (CatL) and/or CatB, in the endosome or cell membrane. Here, we characterize the product of CatL cleavage of Zaire EBOV GP (ZEBOV-GP) and evaluate its relevance to entry. A stabilized recombinant form of the EBOV GP trimer was generated using a trimerization domain linked to a cleavable histidine tag. This trimer was purified to homogeneity and cleaved with CatL. Characterization of the trimeric product by N-terminal sequencing and mass spectrometry revealed three cleavage fragments, with masses of 23, 19, and 4 kDa. Structure-assisted modeling of the cathepsin L-cleaved ZEBOV-GP revealed that cleavage removes a glycosylated glycan cap and mucin-like domain (MUC domain) and exposes the conserved core residues implicated in receptor binding. The CatL-cleaved ZEBOV-GP intermediate bound with high affinity to a neutralizing antibody, KZ52, and also elicited neutralizing antibodies, supporting the notion that the processed intermediate is required for viral entry. Together, these data suggest that CatL cleavage of EBOV GP exposes its receptor-binding domain, thereby facilitating access to a putative cellular receptor in steps that lead to membrane fusion. C1 [Hood, Chantelle L.; Abraham, Jonathan; Boyington, Jeffrey C.; Leung, Kwanyee; Kwong, Peter D.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Room 4502,Bldg 40,MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural Research Program, Vaccine Research Center; NIAID; NIH FX We thank Ati Tislerics for manuscript preparation, Brenda Hartman and Michael Cichanowski for the preparation of figures, and members of the Virological Laboratory, Vaccine Research Center, for helpful advice and discussions. We acknowledge Cammi Bittner, Ralph Hopkins, and James Hartley of the Advanced Technology Program, SAICFrederick, Inc., National Cancer Institute at Frederick, MD, for recombinant baculovirus protein production. We thank Mary Ann Gawinowicz for performing the mass spectrometry and N-terminal sequencing analyses. We also thank Young Do Kwon for help performing the surface plasmon resonance measurements.; This research was supported by the Intramural Research Program, Vaccine Research Center, NIAID, NIH. NR 22 TC 55 Z9 58 U1 1 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 6 BP 2972 EP 2982 DI 10.1128/JVI.02151-09 PG 11 WC Virology SC Virology GA 565VG UT WOS:000275322300032 PM 20053739 ER PT J AU Gordon, SN Weissman, AR Cecchinato, V Fenizia, C Ma, ZM Lee, TH Zaffiri, L Andresen, V Parks, RW Jones, KS Heraud, JM Ferrari, MG Chung, HK Venzon, D Mahieux, R Murphy, EL Jacobson, S Miller, CJ Ruscetti, FW Franchini, G AF Gordon, Shari N. Weissman, Anna R. Cecchinato, Valentina Fenizia, Claudio Ma, Zhong-Min Lee, Tzong-Hae Zaffiri, Lorenzo Andresen, Vibeke Parks, Robyn Washington Jones, Kathryn S. Heraud, Jean Michel Ferrari, Maria Grazia Chung, Hye Kyung Venzon, David Mahieux, Renaud Murphy, Edward L. Jacobson, Steven Miller, Christopher J. Ruscetti, Francis W. Franchini, Genoveffa TI Preexisting Infection with Human T-Cell Lymphotropic Virus Type 2 neither Exacerbates nor Attenuates Simian Immunodeficiency Virus SIVmac251 Infection in Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID II HTLV-II; DISEASE PROGRESSION; UP-REGULATION; COINFECTED INDIVIDUALS; CLINICAL-FEATURES; HIV-1 REPLICATION; DENDRITIC CELLS; DRUG-USERS; SUBTYPE-B; LEUKEMIA AB Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIVmac251-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naive macaques to SIVmac251 demonstrated comparable levels of SIVmac251 viral replication, similar rates of mucosal and peripheral CD4(+) T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIVmac251 coinfected animals versus SIVmac251 singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIVmac251 infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIVmac251 infection. C1 [Gordon, Shari N.; Weissman, Anna R.; Cecchinato, Valentina; Fenizia, Claudio; Zaffiri, Lorenzo; Andresen, Vibeke; Parks, Robyn Washington; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Jones, Kathryn S.; Ruscetti, Francis W.] NCI, Basic Res Program, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. [Ferrari, Maria Grazia; Chung, Hye Kyung] Adv BioSci Labs Inc, Kensington, MD 20895 USA. [Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Heraud, Jean Michel] Inst Pasteur Madagascar, WHO, Natl Influenza Lab, Antananarivo, Madagascar. [Ma, Zhong-Min; Mahieux, Renaud] Ecole Normale Super, INSERM, U758, F-69364 Lyon 07, France. [Ma, Zhong-Min; Mahieux, Renaud] IFR BioSci Lyon Gerland 128, F-69364 Lyon 07, France. [Miller, Christopher J.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Murphy, Edward L.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94118 USA. [Murphy, Edward L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Lee, Tzong-Hae; Murphy, Edward L.] Blood Syst Res Inst, San Francisco, CA 94118 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, NIH, 9000 Rockville Pike,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI HERAUD, Jean-Michel/O-1464-2013 OI HERAUD, Jean-Michel/0000-0003-1107-0859 NR 58 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 6 BP 3043 EP 3058 DI 10.1128/JVI.01655-09 PG 16 WC Virology SC Virology GA 565VG UT WOS:000275322300039 PM 20071587 ER PT J AU Waheed, AA Ablan, SD Sowder, RC Roser, JD Schaffner, CP Chertova, E Freed, EO AF Waheed, Abdul A. Ablan, Sherimay D. Sowder, Raymond C. Roser, James D. Schaffner, Carl P. Chertova, Elena Freed, Eric O. TI Effect of Mutations in the Human Immunodeficiency Virus Type 1 Protease on Cleavage of the gp41 Cytoplasmic Tail SO JOURNAL OF VIROLOGY LA English DT Article ID CHOLESTEROL-BINDING COMPOUND; B METHYL-ESTER; LIPID RAFTS; ENVELOPE GLYCOPROTEINS; HIV-1 REPLICATION; MOLECULAR CLONE; DOMAIN; RESISTANT; VIRIONS; MATRIX AB We previously reported that human immunodeficiency virus type 1 (HIV-1) develops resistance to the cholesterol-binding compound amphotericin B methyl ester (AME) by acquiring mutations (P203L and S205L) in the cytoplasmic tail of the transmembrane envelope glycoprotein gp41 that create cleavage sites for the viral protease (PR). In the present study, we observed that a PR inhibitor-resistant (PIR) HIV-1 mutant is unable to efficiently cleave the gp41 cytoplasmic tail in P203L and S205L virions, resulting in loss of AME resistance. To define the pathway to AME resistance in the context of the PIR PR, we selected for resistance with an HIV-1 isolate expressing the mutant enzyme. We identified a new gp41 mutation, R236L, that results in cleavage of the gp41 tail by the PIR PR. These results highlight the central role of gp41 cleavage as the primary mechanism of AME resistance. C1 [Waheed, Abdul A.; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Sowder, Raymond C.; Roser, James D.; Chertova, Elena] NCI, AIDS & Canc Virus Program, SAIC, Frederick, MD 21702 USA. [Schaffner, Carl P.] Rutgers State Univ, Waksman Inst, Dept Microbiol & Biochem, New Brunswick, NJ 08903 USA. RP Waheed, AA (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535,Rm 108, Frederick, MD 21702 USA. EM awaheed@ncifcrf.gov FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute; NIH; Intramural AIDS Targeted Antiviral Program FX We thank members of the Freed laboratory for helpful discussions and critical reviews of the manuscript and K. Felton and K. Waki for assistance with DNA cloning. The HIV-1 gp41 monoclonal antibody 2F5 and TZM-bl cells were obtained from the NIH AIDS Research and Reference Reagent Program. AME; This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. NR 32 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2010 VL 84 IS 6 BP 3121 EP 3126 DI 10.1128/JVI.02002-09 PG 6 WC Virology SC Virology GA 565VG UT WOS:000275322300048 PM 20042499 ER PT J AU Espeland, MA Shumaker, SA Limacher, M Rapp, SR Bevers, TB Barad, DH Coker, LH Gaussoin, SA Stefanick, ML Lane, DS Maki, PM Resnick, SM AF Espeland, Mark A. Shumaker, Sally A. Limacher, Marian Rapp, Stephen R. Bevers, Therese B. Barad, David H. Coker, Laura H. Gaussoin, Sarah A. Stefanick, Marcia L. Lane, Dorothy S. Maki, Pauline M. Resnick, Susan M. CA WHIMS Study Grp CoSTAR Study Grp TI Relative Effects of Tamoxifen, Raloxifene, and Conjugated Equine Estrogens on Cognition SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HEALTH INITIATIVE MEMORY; POSTMENOPAUSAL HORMONE-THERAPY; RANDOMIZED CONTROLLED-TRIAL; BREAST-CANCER; WHIMS-MRI; WOMEN; DEMENTIA; IMPAIRMENT; 17-BETA-ESTRADIOL; HIPPOCAMPUS AB Objective: To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged >= 65 years. Methods: Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n=6211, CoSTAR n=250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors. Results: At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of <= 0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p=0.001) and less marked for raloxifene (p=0.06) and CEE (p=0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p=0.009 (tamoxifen), p=0.08 (raloxifene), and p=0.03 (CEE). Conclusions: Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown. C1 [Espeland, Mark A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Limacher, Marian] Univ Florida, Gainesville, FL USA. [Bevers, Therese B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Barad, David H.] Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. [Stefanick, Marcia L.] Stanford Univ, Ctr Res Dis Prevent, Palo Alto, CA 94304 USA. [Lane, Dorothy S.] SUNY Stony Brook, Sch Med, Dept Prevent Med, Stony Brook, NY 11794 USA. [Maki, Pauline M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit 03, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Espeland, MA (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mespelan@wfubmc.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [N01-WH-4-4221]; U.S. Department of Health and Human Services; Wyeth Pharmaceuticals, Inc., St. Davids, PA; Wake Forest University Health Sciences; National Cancer Institute; AstraZeneca Pharmaceuticals; Eli Lilly and Co; National Institute on Aging [NO1-AG-2106] FX This work was supported by the following sources. The Women's Health Initiative was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services. WHIMS was funded by Wyeth Pharmaceuticals, Inc., St. Davids, PA, Wake Forest University Health Sciences, and by the National Heart, Lung, and Blood Institute (N01-WH-4-4221). STAR was supported by Public Health Service grants U10-CA-37377, U10-CA-69974, U10CA-12027, and U10CA-69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, AstraZeneca Pharmaceuticals, and Eli Lilly and Co. CoSTAR was funded by the National Institute on Aging (NO1-AG-2106). S.M.R. is supported by the Intramural Research Program, National Institute on Aging, and National Institutes of Health. NR 38 TC 15 Z9 15 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 BP 371 EP 379 DI 10.1089/jwh.2009.1605 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200002 PM 20136553 ER PT J AU Augustson, EM Bahde, AL Hunt, YM Taylor, SC Pilsner, AM AF Augustson, Erik M. Bahde, Ami L. Hunt, Yvonne M. Taylor, Shani C. Pilsner, Alison M. TI The Integration of Web 2.0 and Online Social Networking into Web-Based Smoking Cessation Resources Targeted to Women: The National Cancer Institute Smokefree Women Project SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Hunt, Yvonne M.; Taylor, Shani C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 08 BP 605 EP 606 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200036 ER PT J AU Beydoun, HA Al-Sahab, B Beydoun, MA Tamim, H AF Beydoun, Hind A. Al-Sahab, Ban Beydoun, May A. Tamim, Hala TI Intimate Partner Violence as a Risk Factor for Postpartum Depression among Canadian Women in the Maternity Experience Survey SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Al-Sahab, Ban; Tamim, Hala] York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON M3J 2R7, Canada. [Beydoun, May A.] NIA, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 11 BP 606 EP 607 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200039 ER PT J AU Bondy, C AF Bondy, Carolyn TI Turner Syndrome (TS): A Neglected Disorder of Women SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Bondy, Carolyn] NICHHD, Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 14 BP 608 EP 608 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200042 ER PT J AU Gould, HN Bakalov, VK Bondy, CA AF Gould, Harley N. Bakalov, Vladimir K. Bondy, Carolyn A. TI Life Outcome Measures in Women with Turner Syndrome SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Gould, Harley N.; Bakalov, Vladimir K.; Bondy, Carolyn A.] NICHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 33 BP 614 EP 615 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200061 ER PT J AU Hunt, YM Augustson, EA Bahde, AL Taylor, SC Pilsner, AM AF Hunt, Y. M. Augustson, E. A. Bahde, A. L. Taylor, S. C. Pilsner, A. M. TI Use of Social Networking Sites by Pregnant Smokers SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Hunt, Y. M.; Augustson, E. A.; Bahde, A. L.; Taylor, S. C.; Pilsner, A. M.] NCI, Tobacco Control Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 40 BP 617 EP 617 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200068 ER PT J AU Merz, A Bakalov, V Bondy, C AF Merz, Alexa Bakalov, Vladimir Bondy, Carolyn TI Estrogen Replacement Therapy and Aortic Dilation in Women with Turner Syndrome SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Merz, Alexa; Bakalov, Vladimir; Bondy, Carolyn] NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 62 BP 625 EP 625 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200090 ER PT J AU Taylor, TJ St John, LJ Martino, AC Shankar, R Henderson, WA AF Taylor, Tara J. St John, Lena J. Martino, Angela C. Shankar, Ravi Henderson, Wendy A. TI Association of IL-6, TNF-Alpha, and Body Mass Index in Women After Gastrointestinal Test Solution Ingestion SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Taylor, Tara J.; St John, Lena J.; Martino, Angela C.; Shankar, Ravi; Henderson, Wendy A.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 MA 92 BP 635 EP 636 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200120 ER PT J AU Patel, KV Semba, RD Ferrucci, L Newman, AB Fried, LP Wallace, RB Bandinelli, S Phillips, CS Yu, BB Connelly, S Shlipak, MG Chaves, PHM Launer, LJ Ershler, WB Harris, TB Longo, DL Guralnik, JM AF Patel, Kushang V. Semba, Richard D. Ferrucci, Luigi Newman, Anne B. Fried, Linda P. Wallace, Robert B. Bandinelli, Stefania Phillips, Caroline S. Yu, Binbing Connelly, Stephanie Shlipak, Michael G. Chaves, Paulo H. M. Launer, Lenore J. Ershler, William B. Harris, Tamara B. Longo, Dan L. Guralnik, Jack M. TI Red Cell Distribution Width and Mortality in Older Adults: A Meta-analysis SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Erythrocyte Indices; Mortality; Risk Factors ID SIZE DISTRIBUTION CURVES; COMPLETE BLOOD-COUNT; ICSH RECOMMENDATIONS; UNEXPLAINED ANEMIA; UNITED-STATES; WHITE CELL; DISEASE; RISK; ERYTHROPOIETIN; PREVALENCE AB Background. Red cell distribution width (RDW) is a quantitative measure of variability in the size of circulating erythrocytes with higher values reflecting greater heterogeneity in cell sizes. Recent studies have shown that higher RDW is associated with increased mortality risk in patients with clinically significant cardiovascular disease (CVD). Whether RDW is prognostic in more representative community-based populations is unclear. Methods. Seven relevant community-based studies of older adults with RDW measurement and mortality ascertainment were identified. Cox proportional hazards regression and meta-analysis on individual participant data were performed. Results. Median RDW values varied across studies from 13.2% to 14.6%. During 68,822 person-years of follow-up of 11,827 older adults with RDW measured, there was a graded increased risk of death associated with higher RDW values (p < .001). For every 1% increment in RDW. total mortality risk increased by 14% (adjusted hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.11-1.17). In addition, RDW was strongly associated with deaths from CVD (adjusted HR: 1.15; 95% CI: 1.12-1.25), cancer (adjusted HR: 1.13; 95% CI: 1.07-1.20). and other causes (adjusted HR: 1.13; 95% CI: 1.07-1.18). Furthermore, the RDW-mortality association occurred in all major demographic, disease, and nutritional risk factor subgroups examined. Among the subset of 1,603 older adults without major age-associated diseases, RDW remained strongly associated with total mortality (adjusted HR: 1.32; 95% CI: 1.21-1.44). Conclusions. RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases. The biologic mechanisms underlying this association merit investigation. C1 [Patel, Kushang V.; Phillips, Caroline S.; Yu, Binbing; Launer, Lenore J.; Harris, Tamara B.; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ferrucci, Luigi; Ershler, William B.; Longo, Dan L.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Wallace, Robert B.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Connelly, Stephanie] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Shlipak, Michael G.] Univ Calif San Francisco, Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Patel, KV (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM kushang.patel@nih.gov RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging, National Institutes of Health [R01 AG029148, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, N01-AG12112, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, and by the following grants and contracts from the National Institute on Aging: R01 AG029148, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, N01-AG12112, N01-AG-6-2101. N01-AG-6-2103. and N01-AG-6-2106. NR 28 TC 164 Z9 173 U1 2 U2 15 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2010 VL 65 IS 3 BP 258 EP 265 DI 10.1093/gerona/glp163 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 567CV UT WOS:000275420800008 PM 19880817 ER PT J AU Weiss, CO Hoenig, HH Varadhan, R Simonsick, EA Fried, LP AF Weiss, Carlos O. Hoenig, Helen H. Varadhan, Ravi Simonsick, Eleanor A. Fried, Linda P. TI Relationships of Cardiac, Pulmonary, and Muscle Reserves and Frailty to Exercise Capacity in Older Women SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Frailty; Exercise capacity ID HEART-FAILURE; HEALTH; ADULTS; TOLERANCE; PHENOTYPE; STRENGTH AB Background. A decline in exercise capacity (EC) is a characteristic of frailty. We hypothesized that decline is the effect of decrements in several physiological systems. We assessed whether the relationship of three main physiological systems-cardiac, pulmonary, and musculoskeletal-to EC is independent or interactive and whether their effect on EC varies with respect to frailty status. Methods. Observational study of 547 disabled women aged 65 years and older (Women's Health and Aging Study 1) including 131 frail who participated in a test of EC. EC (seated step test), cardiac function (chronotropic index). pulmonary function (forced vital capacity, FVC), musculoskeletal function (quadriceps strength, QS), and frailty status were measured and interactive effects were modeled using linear regression and differentiation. Results. Each physiological system had a direct relationship with EC, which was lower in frail compared with nonfrail. The relationship between FVC and EC was positive and increased with increasing QS in nonfrail subjects. The effect of QS on EC was positive and increased with increasing FVC regardless of frailty. In subjects with low QS, frailty status was associated with lower EC and this effect became stronger with increasing FVC. Discussion. Findings suggest but do not show that frailty status modifies the effects of physiological function in several systems oil EC. Approaches to understanding emergent properties Such its vulnerability to illness and death and clinical efforts to prevent and treat frailty should evaluate and possibly intervene on several physiological systems to be maximally effective. C1 [Weiss, Carlos O.; Simonsick, Eleanor A.] Johns Hopkins Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA. [Weiss, Carlos O.; Varadhan, Ravi] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Hoenig, Helen H.] Duke Univ, Med Ctr, Dept Med, Div Geriatr, Durham, NC 27710 USA. [Hoenig, Helen H.] Durham Vet Adm Med Ctr, Phys Med & Rehabil Serv, Durham, NC USA. [Varadhan, Ravi] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Simonsick, Eleanor A.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Weiss, CO (reprint author), Johns Hopkins Sch Med, Dept Med, Div Geriatr Med & Gerontol, 5200 Eastern Ave,Mason F Lord Ctr Tower 711, Baltimore, MD 21224 USA. EM cweiss9@jhmi.edu FU National Institute on Aging [N01AG12112]; National Institutes of Health [NCPR M01-RR00052]; Robert Wood Johnson Harold Amos Medical Faculty Development; NIA [P30AG021334-04, 5R37AG019905-08] FX The original study for this research was funded by the National Institute on Aging grant N01AG12112 and was supported by the National Institutes of Health grant NCPR M01-RR00052. C.O.W. was funded by the Robert Wood Johnson Harold Amos Medical Faculty Development Program and by NIA P30AG021334-04. L.P.F. was funded by NIA 5R37AG019905-08. NR 29 TC 6 Z9 8 U1 0 U2 5 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2010 VL 65 IS 3 BP 287 EP 294 DI 10.1093/gerona/glp147 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 567CV UT WOS:000275420800012 PM 19822621 ER PT J AU Zoico, E Rossi, A Di Francesco, V Sepe, A Olioso, D Pizzini, F Fantin, F Bosello, O Cominacini, L Harris, TB Zamboni, M AF Zoico, Elena Rossi, Andrea Di Francesco, Vincenzo Sepe, Anna Olioso, Debora Pizzini, Francesca Fantin, Francesco Bosello, Ottavio Cominacini, Luciano Harris, Tamara B. Zamboni, Mauro TI Adipose Tissue Infiltration in Skeletal Muscle of Healthy Elderly Men: Relationships With Body Composition, Insulin Resistance, and Inflammation at the Systemic and Tissue Level SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE IMAT; Body composition; Insulin resistance; Inflammation; Aging ID DIABETES-MELLITUS; WOMEN; SARCOPENIA; MASS; DEPOSITION; STRENGTH; LEPTIN; SIZE AB Background. Association between inflammatory markers and intermuscular adipose tissue (IMAT) has been reported. we hypothesized that subclinical inflammation of adipose tissue surrounding and infiltrating muscle could be related to the metabolic and functional abnormalities of the "aging muscle." Methods. In 20 healthy elderly men undergoing elective vertebral Surgery, IMAT within erector spinae was evaluated by magnetic resonance imaging and body composition by dual-energy x-ray absorptiometry. Fasting glucose, insulin, high-sensitive C-reactive protein (hs-CRP), leptin, adiponectin, and interleukin 6 (IL-6) were measured, and insulin resistance was estimated by homeostasis model assessment (HOMA) index. In subcutaneous adipose tissue (SAT) biopsies near the erector spinae, quantification of gene expression was performed. Results. IMAT showed a significant association with body mass index and total and regional body fat, even after adjustment for age. Insulin, HOMA, and leptin were significantly correlated with IMAT, whereas hs-CRP presented an association of borderline significance. IL-6 expression in SAT was significantly associated with IMAT; IL-6 messenger RNA (mRNA) was negatively associated with adiponectin and peroxisome proliferator-activated receptor gamma expression. In multivariate regression analysis, 68% of IMAT variance was explained by fat mass and age, independent of waist circumference, leptin, HOMA, and IL-6 mRNA. Conclusion. IMAT was primarily related to age and total body adiposity: subclinical inflammation in fat significantly contributes to IMAT. C1 [Zoico, Elena; Rossi, Andrea; Di Francesco, Vincenzo; Sepe, Anna; Olioso, Debora; Fantin, Francesco; Bosello, Ottavio; Zamboni, Mauro] Univ Verona, Div Geriatr Med, I-37126 Verona, Italy. [Pizzini, Francesca] Borgo Trento City Hosp, Serv Neuroradiol, Verona, Italy. [Cominacini, Luciano] Univ Verona, Div Internal Med, I-37126 Verona, Italy. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Zamboni, M (reprint author), Univ Verona, Osped Maggiore, Div Geriatr Med, Piazzale Stefani 1, I-37126 Verona, Italy. EM mauro.zamboni@univr.it RI Pizzini, Francesca Bendetta/O-5291-2016; OI Pizzini, Francesca Bendetta/0000-0002-6285-0989; Olioso, Debora/0000-0002-9048-0364; ZAMBONI, Mauro/0000-0001-6961-9483; ZOICO, Elena/0000-0002-5235-1545 FU Ministero dell'Istruzione dell'Universita e della Ricerca [2007BRR57M_003] FX This work was supported by grants from Ministero dell'Istruzione dell'Universita e della Ricerca project (COFIN no. 2007BRR57M_003). NR 22 TC 51 Z9 51 U1 2 U2 9 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2010 VL 65 IS 3 BP 295 EP 299 DI 10.1093/gerona/glp155 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 567CV UT WOS:000275420800013 PM 19864639 ER PT J AU Tolea, MI Costa, PT Terracciano, A Griswold, M Simonsick, EM Najjar, SS Scuteri, A Deiana, B Orru, M Masala, M Uda, M Schlessinger, D Ferrucci, L AF Tolea, Magdalena I. Costa, Paul T. Terracciano, Antonio Griswold, Michael Simonsick, Eleanor M. Najjar, Samer S. Scuteri, Angelo Deiana, Barbara Orru, Marco Masala, Marco Uda, Manuela Schlessinger, David Ferrucci, Luigi TI Sex-Specific Correlates of Walking Speed in a Wide Age-Ranged Population SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Cross-sectional design; Personality; Walking speed ID DISABLED OLDER WOMEN; PHYSICAL PERFORMANCE; INFLAMMATORY MARKERS; MOBILITY LIMITATION; REFERENCE VALUES; GAIT SPEED; HEALTH; PERSONALITY; DISABILITY; ADULTS AB The goals of this cross-sectional study were to explore correlates of walking speed in a large wide age-ranged population and to identify factors affecting lower walking speed at older ages. Participants were 3,872 community-dwelling adults in the first follow-up of the SardiNIA study who completed a 4-m walking test. Sex-specific correlates of walking speed included marital status, height, waist circumference, pulse wave velocity, comorbidity, subjective health, strength, and personality. Effect modifiers of the age-walking speed association included extraversion (< 55 years, p = .019) and education (< 55 years, p = .021; >= 55 years, p = .012) in women, and openness (< 55 years, p = .005), waist circumference (< 55 years, p = .010), and subjective health (< 55 years, p = .014) in men. The strong impact of personality suggests that certain personality traits may be associated with behaviors that affect physical performance and condition the reduced mobility mostly at younger ages. If these patterns are confirmed in longitudinal studies, personality may be an important target for prevention. C1 [Tolea, Magdalena I.] NIA, Clin Res Branch, Harbor Hosp, Longitudinal Studies Sect, Baltimore, MD 21225 USA. [Costa, Paul T.; Terracciano, Antonio] NIA, Lab Personal & Cognit, Intramural Res Program, Baltimore, MD 21225 USA. [Griswold, Michael] Univ Mississippi, Med Ctr, Ctr Biostat, Oxford, England. [Najjar, Samer S.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21225 USA. [Scuteri, Angelo] INRCA, Unita Operat Geriatria, Rome, Italy. [Scuteri, Angelo] IRCCS, Rome, Italy. [Deiana, Barbara; Orru, Marco] Osped Microcitemico, CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Masala, Marco; Uda, Manuela] Cittadella Univ Monserrato, CNR, Ist Neurogenet & Neurofarmacol, Monserrato, Italy. [Schlessinger, David] NIA, Genet Lab, Intramural Res Program, Baltimore, MD 21225 USA. RP Tolea, MI (reprint author), NIA, Clin Res Branch, Harbor Hosp, Longitudinal Studies Sect, 3001 S Hanover St, Baltimore, MD 21225 USA. EM toleam@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU National Institutes of Health, National Institute on Aging [N01-AG-1-2109] FX This research and the SardiNIA team were supported (in part) by the Intramural research Program of the National Institutes of Health, National Institute on Aging (contract N01-AG-1-2109). P. T. C. receives royalties from the revised NEO Personality Inventory. NR 51 TC 28 Z9 28 U1 0 U2 5 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAR PY 2010 VL 65 IS 2 BP 174 EP 184 DI 10.1093/geronb/gbp130 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 558WT UT WOS:000274780100005 PM 20051464 ER PT J AU Eisner, C Faulhaber-Walter, R Wang, YH Leelahavanichkul, A Yuen, PST Mizel, D Star, RA Briggs, JP Levine, M Schnermann, J AF Eisner, Christoph Faulhaber-Walter, Robert Wang, Yaohui Leelahavanichkul, Asada Yuen, Peter S. T. Mizel, Diane Star, Robert A. Briggs, Josephine P. Levine, Mark Schnermann, Jurgen TI Major contribution of tubular secretion to creatinine clearance in mice SO KIDNEY INTERNATIONAL LA English DT Article DE creatinine clearance; drug transporter; gender difference; glomerular filtration rate; ion transport ID GLOMERULAR-FILTRATION-RATE; CONTRALUMINAL ORGANIC ANION; CATION-TRANSPORT SYSTEMS; ENDOGENOUS CREATININE; RENAL EXCRETION; FITC-INULIN; CIMETIDINE; PLASMA; KIDNEY; RAT AB This study was performed to quantify the fraction of excreted creatinine not attributable to creatinine filtration for accurately determining the glomerular filtration rate in mice. To measure this we compared creatinine filtration with the simultaneous measurement of inulin clearance using both single-bolus fluorescein isothiocyanate (FITC)-inulin elimination kinetics and standard FITC-inulin infusion. During anesthesia, creatinine filtration was found to be systematically higher than inulin clearance in both male and female C57BL/6J mice. The secretion fraction was significantly less in female mice. Administration of either cimetidine or para-aminohippuric acid, competitors of organic cation and anion transport respectively, significantly reduced the secretion fraction in male and female mice and both significantly increased the plasma creatinine level. Creatinine secretion in both genders was not mediated by the organic cation transporters OCT1 or OCT2 since secretion fraction levels were identical in FVB wild-type and OCT1/2 knockout mice. Thus, secretion accounts for about 50 and 35% of excreted creatinine in male and female mice, respectively. Increasing plasma creatinine threefold by infusion further increased the secretion fraction. Renal organic anion transporter 1 mRNA expression was higher in male than in female mice, reflecting the gender difference in creatinine secretion. Hence we show that there is a major secretory contribution to creatinine excretion mediated through the organic anion transport system. This feature adds to problems associated with measuring endogenous creatinine filtration in mice. Kidney International (2010) 77, 519-526; doi: 10.1038/ki. 2009.501; published online 23 December 2009 C1 [Eisner, Christoph; Faulhaber-Walter, Robert; Wang, Yaohui; Leelahavanichkul, Asada; Yuen, Peter S. T.; Mizel, Diane; Star, Robert A.; Levine, Mark; Schnermann, Jurgen] NIDDKD, NIH, Bethesda, MD 20892 USA. [Faulhaber-Walter, Robert] Hannover Med Sch, Dept Nephrol, D-3000 Hannover, Germany. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Room 4D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov RI Yuen, Peter/B-1954-2008; Briggs, Josephine/B-9394-2009 OI Yuen, Peter/0000-0001-9557-3909; Briggs, Josephine/0000-0003-0798-1190 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 31 TC 80 Z9 82 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2010 VL 77 IS 6 BP 519 EP 526 DI 10.1038/ki.2009.501 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 561RP UT WOS:000274996700009 PM 20032962 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2010 VL 39 IS 3 BP 68 EP 68 DI 10.1038/laban0310-68b PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 564TX UT WOS:000275241600008 PM 20164942 ER PT J AU Lee, SJ Tsang, PS Diaz, TM Wei, BY Stetler-Stevenson, WG AF Lee, Seo-Jin Tsang, Patricia S. Diaz, Tere M. Wei, Bei-Yang Stetler-Stevenson, William George TI TIMP-2 modulates VEGFR-2 phosphorylation and enhances phosphodiesterase activity in endothelial cells SO LABORATORY INVESTIGATION LA English DT Article DE angiogenesis; endothelial cells; protein tyrosine phosphatase; phosphodiesterase; tissue inhibitors of metalloproteinases ID NITRIC-OXIDE SYNTHASE; TISSUE INHIBITOR; MACULAR DEGENERATION; TUMOR ANGIOGENESIS; METALLOPROTEINASE-2; ACTIVATION; MECHANISM; DOMAIN; PHOSPHOLIPASE-C-GAMMA-1; AUTOPHOSPHORYLATION AB In this study, we examine the effects of tissue inhibitor of metalloproteinases-2 (TIMP-2) on the phosphorylation status of specific phosphotyrosine residues on the vascular endothelial cell growth factor receptor-2 (VEGFR-2) cytoplasmic tail and examine the effects on associated downstream signaling pathways. To focus on metalloproteinase-independent mechanisms, we used the TIMP-2 analog known as Ala + TIMP-2 that is deficient in matrix metalloproteinase-inhibitory activity. Our experiments are designed to compare the effects of VEGF-A stimulation with or without Ala + TIMP-2 pretreatment, as well as basal responses in human microvascular endothelial cells. Our results show that Ala + TIMP-2 selectively alters the phosphorylation pattern of VEGFR-2 after VEGF-A stimulation and disrupts the downstream activation of PLC-gamma, Ca(+2) flux, Akt, and eNOS, as well as decreasing cGMP levels. Moreover, we observed an Ala + TIMP-2-induced reduction in cGMP levels typically elevated by exogenous NO donors implicating Ala + TIMP-2 in the direct activation of an isobutylmethylxanthine (IBMX)-sensitive cGMP phosphodiesterase activity. TIMP-2 suppression of endothelial mitogenesis and angiogenesis involves at least two mechanisms, one mediated by protein tyrosine phosphatase inhibition of VEGFR-2 activation as well as downstream signaling and a second mechanism involving direct activation of an IBMX-sensitive phosphodiesterase activity. C1 [Lee, Seo-Jin; Diaz, Tere M.; Wei, Bei-Yang; Stetler-Stevenson, William George] NCI, Radiat Oncol Branch, CCR, Adv Technol Ctr, Bethesda, MD 20892 USA. [Tsang, Patricia S.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Radiat Oncol Branch, CCR, Adv Technol Ctr, 8-1 Grovemont Circle,Room 115, Bethesda, MD 20892 USA. EM sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU National Cancer Institute, Center for Cancer Research [Z01SC 009179] FX We thank Drs Jensen-Taubman and Guedez for their critical reading of the paper. This study was supported by intramural research funds from the National Cancer Institute, Center for Cancer Research Project # Z01SC 009179. NR 36 TC 14 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD MAR PY 2010 VL 90 IS 3 BP 374 EP 382 DI 10.1038/labinvest.2009.136 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 561RV UT WOS:000274997300003 PM 20084057 ER PT J AU Castle, PE Katki, HA AF Castle, Philip E. Katki, Hormuzd A. TI Benefits and risks of HPV testing in cervical cancer screening SO LANCET ONCOLOGY LA English DT Editorial Material C1 [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Dept Hlth & Human Serv, Bethesda, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS NR 8 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2010 VL 11 IS 3 BP 214 EP 215 DI 10.1016/S1470-2045(09)70385-7 PG 2 WC Oncology SC Oncology GA 568MA UT WOS:000275525300004 PM 20089448 ER PT J AU Shanafelt, TD Ghia, P Lanasa, MC Landgren, O Rawstron, AC AF Shanafelt, T. D. Ghia, P. Lanasa, M. C. Landgren, O. Rawstron, A. C. TI Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management SO LEUKEMIA LA English DT Review DE monoclonal B-cell lymphocytosis (MBL); chronic lymphocytic leukemia (CLL); prognosis; biology; management; non-Hodgkin lymphoma ID SPONSORED-WORKING-GROUP; QUALITY-OF-LIFE; DIAGNOSTIC-CRITERIA; FLOW-CYTOMETRY; LEUKEMIA; BLOOD; RISK; TRANSPLANTATION; GUIDELINES; CLL AB Chronic lymphocytic leukemia (CLL) and the other low-grade non-Hodgkin lymphomas are among the most common lymphoid malignancies. Recent studies suggest that more than 4% of the general population over age 40 harbor a population of clonal B cells with the phenotype of either CLL or another B-cell malignancy, a condition now designated monoclonal B-cell lymphocytosis (MBL). Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a hematologic malignancy. The biologic characteristics and clinical implications of MBL appear to differ based on whether it is identified during the diagnostic evaluation of lymphocytosis or incidentally discovered through screening of individuals with normal lymphocyte counts as part of research studies using highly sensitive detection methods. In this paper, we provide a state of the art review on the prevalence, nomenclature, biology, natural history and clinical management of MBL. Leukemia (2010) 24, 512-520; doi:10.1038/leu.2009.287; published online 21 January 2010 C1 [Shanafelt, T. D.] Mayo Clin, Div Hematol, Dept Med, Rochester, MN 55905 USA. [Ghia, P.] Univ Vita Salute San Raffaele, Lab Cell Neoplasia B, Div Mol Oncol, Milan, Italy. [Ghia, P.] Univ Vita Salute San Raffaele, Lymphoma Unit, Dept Oncol, Milan, Italy. [Ghia, P.] Ist Sci San Raffaele, Milan, Italy. [Lanasa, M. C.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Landgren, O.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Rawstron, A. C.] Leeds Teaching Hosp, St Jamess Inst Oncol, Hematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England. RP Shanafelt, TD (reprint author), Mayo Clin, Div Hematol, Dept Med, Rochester, MN 55905 USA. EM shanafelt.tait@mayo.edu RI Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Rawstron, Andy/0000-0003-0798-9790 FU National Cancer Institute (NCI) [CA 113408]; Italian Association for Cancer Research - AIRC, Milano, Italy; Leukaemia Research Fund, UK FX This work was supported by grants from the National Cancer Institute (NCI CA 113408; T Shanafelt), Italian Association for Cancer Research - AIRC, Milano, Italy (P Ghia), Leukaemia Research Fund, UK (A Rawstron). NR 44 TC 106 Z9 111 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2010 VL 24 IS 3 BP 512 EP 520 DI 10.1038/leu.2009.287 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 566UV UT WOS:000275399600003 PM 20090778 ER PT J AU Williams, ME Dreyling, MH Kahl, BS Leonard, JP O'Connor, OA Press, OW Wilson, WH AF Williams, Michael E. Dreyling, Martin H. Kahl, Brad S. Leonard, John P. O'Connor, Owen A. Press, Oliver W. Wilson, Wyndham H. TI Mantle cell lymphoma: Report of the 2009 Mantle Cell Lymphoma Consortium Workshop SO LEUKEMIA & LYMPHOMA LA English DT Review DE Mantle cell lymphoma; minimal residual disease (MRD); cell cycle and apoptosis; antibody-based immunotherapy; adoptive cellular therapy ID S-TRANSFERASE-PI; EXPRESSION; CANCER; EEYARESTATIN; INHIBITION; RITUXIMAB; LEUKEMIA; THERAPY; BINDING AB Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by cyclin D1 overexpression as a result of the t(11;14) chromosomal translocation, and by biological and clinical heterogeneity with frequent extranodal dissemination. There is no consensus or standard for initial therapy or for treatment of relapsed disease, and no proven curative therapy exists. Nonetheless, considerable progress in treatment response and survival has been realized over the past several years, and the disease remains an important focus of preclinical and clinical research. Advances in the biologic understanding of MCL, new molecular targets and therapeutic strategies, and the applications of biomarkers for risk stratification and molecular targeting were reviewed at a recent MCL Workshop. These are summarized herein, and are intended as both a status report on areas of active investigation and to serve as a template for future research.1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR-191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization. Mol Cancer Ther; 9(3); 581-93. (C) 2010 AACR. C1 [Giovannetti, Elisa] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam CCA 1 52, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. [Smit, Egbert F.] Vrije Univ Amsterdam Med Ctr, Dept Pneumol, NL-1081 HV Amsterdam, Netherlands. [Burgers, Jacobus A.] Nederlands Kanker Inst, Dept Thorac Oncol, Amsterdam, Netherlands. [Giovannetti, Elisa; Danesi, Romano] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, Pisa, Italy. [Zucali, Paolo A.; Santoro, Armando] IRCCS, Ist Clin Humanitas, Dept Med Oncol & Hematol, Milan, Italy. [D'Incecco, Armida; Falcone, Alfredo; Tibaldi, Carmelo] Azienda USL 6 Livorno, Dept Oncol, Div Oncol, Livorno, Italy. [Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giovannetti, E (reprint author), Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam CCA 1 52, Dept Med Oncol, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM elisa.giovannetti@gmail.com RI Giovannetti, Elisa/F-4261-2011; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504 FU Fondazione A.R.C.O. FX Grant Support; Fondazione A.R.C.O. (C. Tibaldi). NR 50 TC 45 Z9 47 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2010 VL 9 IS 3 BP 581 EP 593 DI 10.1158/1535-7163.MCT-09-0665 PG 13 WC Oncology SC Oncology GA 607GO UT WOS:000278487300006 PM 20159991 ER PT J AU Quintela-Fandino, M Le Tourneau, C Duran, I Chen, EX Wang, L Tsao, M Bandarchi-Chamkhaleh, B Pham, NA Do, T MacLean, M Nayyar, R Tusche, MW Metser, U Wright, JJ Mak, TW Siu, LL AF Quintela-Fandino, Miguel Le Tourneau, Christophe Duran, Ignacio Chen, Eric X. Wang, Lisa Tsao, Ming Bandarchi-Chamkhaleh, Bizhan Pham, Nhu-Ann Do, Trevor MacLean, Martha Nayyar, Rakesh Tusche, Michael W. Metser, Ur Wright, John J. Mak, Tak W. Siu, Lillian L. TI Phase I Combination of Sorafenib and Erlotinib Therapy in Solid Tumors: Safety, Pharmacokinetic, and Pharmacodynamic Evaluation from an Expansion Cohort SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; ADVANCED HEPATOCELLULAR-CARCINOMA; POSITRON-EMISSION-TOMOGRAPHY; CLINICAL-TRIALS GROUP; DAYS ON/7 DAYS; BREAST-CANCER; RAF KINASE; EARLY PREDICTION AB The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >= 4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. Mol Cancer Ther; 9(3); 751-60. (C) 2010 AACR. C1 [Quintela-Fandino, Miguel; Le Tourneau, Christophe; Duran, Ignacio; Chen, Eric X.; Wang, Lisa; Tsao, Ming; Bandarchi-Chamkhaleh, Bizhan; Pham, Nhu-Ann; Do, Trevor; MacLean, Martha; Metser, Ur; Siu, Lillian L.] Univ Toronto, Princess Margaret Hosp, Phase Consortium 2, Toronto, ON M5G 2M, Canada. [Quintela-Fandino, Miguel; Nayyar, Rakesh; Tusche, Michael W.; Mak, Tak W.] Univ Toronto, Ontario Canc Inst, Toronto, ON M5G 2M, Canada. [Wright, John J.] NCI, Bethesda, MD 20892 USA. RP Siu, LL (reprint author), Univ Toronto, Princess Margaret Hosp, Div Med Oncol & Hematol, 610 Univ Ave,Suite 5-718, Toronto, ON M5G 2M, Canada. EM lillian.siu@uhn.on.ca OI quintela-fandino, miguel/0000-0003-1648-1964 FU Bayer Pharmaceuticals; Roche Pharmaceuticals; NCI-CTEP [NOI-CM-62203]; Translational Research Initiative [P7178/22XS108-Task order 17]; Fondation de France; OCRN [05NOV00203]; Spanish Society of Medical Oncology; Rafael Hervada Biomedical Research Award FX M. Quintela-Fandino and L. L. Siu: research funded by Bayer Pharmaceuticals; E. X. Chen: honoraria and research funded by Roche Pharmaceuticals; M. Tsao: honoraria and compensated advisory role for Roche Pharmaceuticals.r Grant Supportr NCI-CTEP grant NOI-CM-62203 and the Translational Research Initiative grant P7178/22XS108-Task order 17. C. Le Tourneau is in part supported by a grant of the Fondation de France. T. Mak is recipient of OCRN 2006 grant number 05NOV00203. M. Quintela-Fandino received the 2005 Spanish Society of Medical Oncology-Young Investigators Grant and the Rafael Hervada Biomedical Research Award in November 2008 in La Coruna, Spain, for this work. NR 55 TC 13 Z9 14 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2010 VL 9 IS 3 BP 751 EP 760 DI 10.1158/1535-7163.MCT-09-0868 PG 10 WC Oncology SC Oncology GA 607GO UT WOS:000278487300021 PM 20197396 ER PT J AU Carrillo-Carrasco, N Chandler, RJ Chandrasekaran, S Venditti, CP AF Carrillo-Carrasco, Nuria Chandler, Randy J. Chandrasekaran, Suma Venditti, Charles P. TI RESCUE AND LONG-TERM OUTCOME OF A MURINE MODEL OF METHYLMALONIC ACIDEMIA FOLLOWING LIVER-DIRECTED, AAV-MEDIATED GENE THERAPY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Carrillo-Carrasco, Nuria; Chandler, Randy J.; Chandrasekaran, Suma; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Chandler, Randy J.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 200 EP 200 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900015 ER PT J AU Chandler, RJ Phillips, D Boja, ES Carrillo-Carrasco, N Caldovic, L Morizono, H Balaban, RS Venditti, CP AF Chandler, Randy J. Phillips, Darci Boja, Emily S. Carrillo-Carrasco, Nuria Caldovic, Ljubica Morizono, Hioki Balaban, Robert S. Venditti, Charles P. TI PROTEOMICS REVEALS NEW INSIGHTS INTO THE CAUSES OF HYPERAMMONEMIA IN METHYLMALONIC ACIDEMIA SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Chandler, Randy J.; Carrillo-Carrasco, Nuria; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Chandler, Randy J.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. [Phillips, Darci; Boja, Emily S.; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Phillips, Darci; Boja, Emily S.; Balaban, Robert S.] NHLBI, Prote Core Facil, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Caldovic, Ljubica; Morizono, Hioki] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 200 EP 201 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900016 ER PT J AU Hauser, NS Paul, SM Gropman, AL Hanna, G Sloan, J Venditti, CP AF Hauser, Natalie S. Paul, Scott M. Gropman, Andrea L. Hanna, Glenn Sloan, Jennifer Venditti, Charles P. TI THE FUNCTIONAL PHENOTYPE OF AN INBORN ERROR OF METABOLISM: OUTLINING IMPAIRMENT AND DISABILITY IN METHYLMALONIC ACIDEMIA SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Hauser, Natalie S.; Sloan, Jennifer; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Paul, Scott M.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Hanna, Glenn] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 202 EP 202 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900019 ER PT J AU Donsante, A Johnson, P Holmes, CS Jansen, LA Kaler, SG AF Donsante, Anthony Johnson, Paul Holmes, Courtney S. Jansen, Laura A. Kaler, Stephen G. TI TISSUE-SPECIFIC SOMATIC MOSAICISM ASSOCIATED WITH CLASSICAL MENKES DISEASE SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Donsante, Anthony; Johnson, Paul; Kaler, Stephen G.] NICHD, Unit Pediat Genet, Program Mol Med, Bethesda, MD USA. [Holmes, Courtney S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Jansen, Laura A.] Univ Washington, Seattle Childrens Hosp Res Inst, Div Pediat Neurol, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 212 EP 212 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900041 ER PT J AU Introne, WJ Perry, MB Kayser, MA Suwannarat, P O'Brien, KE Bryant, J Troendle, J Tsilou, E Sachdev, V Reynolds, JC Moylan, E Bernardini, I Gahl, WA AF Introne, W. J. Perry, M. B. Kayser, M. A. Suwannarat, P. O'Brien, K. E. Bryant, J. Troendle, J. Tsilou, E. Sachdev, V. Reynolds, J. C. Moylan, E. Bernardini, I. Gahl, W. A. TI NITISINONE USE IN ALKAPTONURIA: RESULTS OF A THREE YEAR TRIAL SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Introne, W. J.; O'Brien, K. E.; Bryant, J.; Gahl, W. A.] NHGRI, NIH, Off Clin Director, Bethesda, MD 20892 USA. [Perry, M. B.; Moylan, E.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kayser, M. A.] Warren Clin Ctr Genet, Tulsa, OK USA. [Kayser, M. A.] Ctr Genet Testing St Francis, Tulsa, OK USA. [Suwannarat, P.] Kaiser Permanente, San Francisco, CA USA. [Suwannarat, P.; Bernardini, I.; Gahl, W. A.] NHGRI, MGB, NIH, Bethesda, MD 20892 USA. [O'Brien, K. E.] Off Rare Dis OD, Bethesda, MD USA. [Troendle, J.] NICHD, NIH, Bethesda, MD USA. [Tsilou, E.] NEI, NIH, Bethesda, MD 20892 USA. [Sachdev, V.] NHLBI, NIH, Bethesda, MD 20892 USA. [Reynolds, J. C.] NIH, DNM, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 218 EP 218 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900056 ER PT J AU James, PM Hecht, L Kaler, SG Berry, GT AF James, P. M. Hecht, L. Kaler, S. G. Berry, G. T. TI PARENTERAL COPPER CHLORIDE TREATMENT IN A FEMALE WITH A POSSIBLE MENKES DISEASE PHENOCOPY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applied Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [James, P. M.; Hecht, L.; Berry, G. T.] Childrens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. [James, P. M.; Berry, G. T.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kaler, S. G.] NIH, Unit Pediat Genet, Lab Clin Genom, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 219 EP 219 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900058 ER PT J AU Manoli, I Sloan, J Sysol, JR Chandler, RJ Cusmano-Ozog, K Zerfas, P Hoffmann, V Abu-Asab, M Tsokos, M Enns, GM Venditti, CP AF Manoli, I. Sloan, J. Sysol, J. R. Chandler, R. J. Cusmano-Ozog, K. Zerfas, P. Hoffmann, V. Abu-Asab, M. Tsokos, M. Enns, G. M. Venditti, C. P. TI THE RENAL DISEASE OF METHYLMALONIC ACIDEMIA: INSIGHTS INTO PATHOPHYSIOLOGY USING MOUSE MODELS AND HUMAN STUDIES SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Manoli, I.; Sloan, J.; Sysol, J. R.; Chandler, R. J.; Venditti, C. P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Cusmano-Ozog, K.; Enns, G. M.] Stanford Univ, Div Med Genet, Stanford, CA 94305 USA. [Zerfas, P.; Hoffmann, V.] NIH, Div Vet Resources, ORS, Bethesda, MD 20892 USA. [Abu-Asab, M.; Tsokos, M.] NIH, Ultrastruct Pathol Sect, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 224 EP 224 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900070 ER PT J AU Hirschfeld, S Samavedam, R Keller, M Smith, D Ohira, R Srivastava, R Johnson, K Bordonaro, T AF Hirschfeld, Steven Samavedam, Rajni Keller, Michael Smith, Daniela Ohira, Riki Srivastava, Ranjana Johnson, Kelly Bordonaro, Tina TI ADVANCING CHILD HEALTH RESEARCH THROUGH HARMONIZED PEDIATRIC TERMINOLOGY SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 33rd Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2010) CY MAR 28-31, 2010 CL Albuquerque, NM SP Soc Inherited Metabol Disorders, Genzyme, Abbott Metabol, Shire, ARUP Labs, Cytonet LLC, GeneDx, Hyperion Therapeut, Nautricia N Amer, Vitaflo, Ucyclyd Pharma, RDT, BIOMARIN, Applid Nutr Corp, CamBrooke Foods, Hitachi, Mead Johnson, PreventionGenetics, Canadian PKU & Allied Disorders Inc, Transgenomic, Emory Genet Lab, FOD, Kakkis EveryLife Fdn, Natl PKU Alliance, Organ Acidemia Assoc C1 [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Samavedam, Rajni; Keller, Michael; Smith, Daniela; Ohira, Riki; Srivastava, Ranjana; Johnson, Kelly; Bordonaro, Tina] Booz Allen Hamilton, Rockville, MD USA. RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 229 EP 229 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900080 ER PT J AU Blech-Hermoni, YN Ziegler, SG Hruska, KS Stubblefield, BK LaMarca, ME Portnoy, ME Green, ED Sidransly, E AF Blech-Hermoni, Yotam N. Ziegler, Shira G. Hruska, Kathleen S. Stubblefield, Barbara K. LaMarca, Mary E. Portnoy, Matthew E. Green, Eric D. Sidransly, Ellen CA NISC Comparative Sequencing TI In silico and functional studies of the regulation of the glucocerebrosidase gene SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Multi-species sequence comparisons; Glucocerebrosidase; Gaucher disease; Transcriptional regulation; Luciferase assays ID ACID BETA-GLUCOSIDASE; GAUCHER-DISEASE; CELL-TYPES; IDENTIFICATION; COMPLEXITY; EXPRESSION; SEQUENCES; DISORDER; MUTATION; PATIENT AB in Gaucher disease (GD), the inherited deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within lysosomes. Although almost 300 mutations in the glucocerebrosidase gene (GBA) have been identified, the ability to predict phenotype from genotype is quite limited. in this study, we sought to examine potential GBA transcriptional regulatory elements for variants that contribute to phenotypic diversity. Specifically, we generated the genomic sequence for the orthologous genomic region (similar to 39.4 kb) encompassing GBA in eight non-human mammals. Computational comparisons of the resulting sequences, using human sequence as the reference, allowed the identification of multi-species conserved sequences (MCSs). Further analyses predicted the presence of two putative clusters of transcriptional regulatory elements upstream and downstream of GBA, containing five and three transcription factor-binding sites (TFBSs), respectively. A firefly luciferase (Fluc) reporter construct containing sequence flanking the GBA gene was used to test the functional consequences of altering these conserved sequences. The predicted TFBSs were individually altered by targeted mutagenesis, resulting in enhanced Fluc expression for one site and decreased expression for seven others sites. Gel-shift assays confirmed the loss of nuclear-protein binding for several of the mutated constructs. These identified conserved non-coding sequences flanking GBA could play a role in the transcriptional regulation of the gene contributing to the complexity underlying the phenotypic diversity seen in GD. Published by Elsevier Inc. C1 [Blech-Hermoni, Yotam N.; Ziegler, Shira G.; Hruska, Kathleen S.; Stubblefield, Barbara K.; LaMarca, Mary E.; Sidransly, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Portnoy, Matthew E.; Green, Eric D.] NHGRI, Phys Mapping Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; NISC Comparative Sequencing] NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Sidransly, 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 and National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute and National Institutes of Health. NR 22 TC 6 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 275 EP 282 DI 10.1016/j.ymgme.2009.10.189 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900106 PM 20004604 ER PT J AU Giannini, EH Mehta, AB Hilz, MJ Beck, M Bichet, DG Brady, RO West, M Germain, DP Wanner, C Waldek, S Clarke, JTR Mengel, E Strotmann, JM Warnock, DG Linhart, A AF Giannini, Edward H. Mehta, Atul B. Hilz, Max J. Beck, Michael Bichet, Daniel G. Brady, Roscoe O. West, Michael Germain, Dominique P. Wanner, Christoph Waldek, Stephen Clarke, Joe T. R. Mengel, Eugen Strotmann, Joerg M. Warnock, David G. Linhart, Ales TI A validated disease severity scoring system for Fabry disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Fabry disease; Severity scoring; Inherited metabolic disorder; DS3; alpha-Galactosidase A ID ENZYME REPLACEMENT THERAPY; OUTCOME SURVEY; NATURAL-HISTORY; FEMALES; ALPHA; MANIFESTATIONS; NEPHROPATHY; INVOLVEMENT; PREVALENCE; MANAGEMENT AB Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument's total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument's domains was estimated and the DS3's quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R(2) = 0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts. (C) 2009 Elsevier Inc. All rights reserved. C1 [Giannini, Edward H.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Dept Pediat,Div Rheumatol, Cincinnati, OH 45220 USA. [Mehta, Atul B.] Royal Free Hosp, Dept Acad Haematol, London NW3 2QG, England. [Mehta, Atul B.] UCL, Sch Med, London W1N 8AA, England. [Hilz, Max J.] Univ Erlangen Nurnberg, Dept Neurol, Erlangen, Germany. [Hilz, Max J.] NYU, Dept Neurol, New York, NY 10016 USA. [Hilz, Max J.] NYU, Dept Med, New York, NY 10016 USA. [Hilz, Max J.] NYU, Dept Psychiat, New York, NY 10016 USA. [Beck, Michael; Mengel, Eugen] Univ Med Mainz, Ctr Pediat, Mainz, Germany. [Bichet, Daniel G.] Univ Montreal, Hop Sacre Coeur Montreal, Montreal, PQ, Canada. [Brady, Roscoe O.] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [West, Michael] Dalhousie Univ, Dept Med, Div Nephrol, Halifax, NS, Canada. [Germain, Dominique P.] Univ Versailles St Quentin Yvelines, Garches, France. [Germain, Dominique P.] Hop Raymond Poincare, AP HP, Div Med Genet, Garches, France. [Wanner, Christoph] Univ Wurzburg, Dept Med, Div Nephrol, Wurzburg, Germany. [Waldek, Stephen] Salford Royal NHS Fdn Trust, Adult Inherited Metab Dis Dept Metab Dis, Manchester, Lancs, England. [Clarke, Joe T. R.] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Clarke, Joe T. R.] Univ Toronto, Toronto, ON, Canada. [Clarke, Joe T. R.] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Pediat, Serv Genet, Sherbrooke, PQ J1K 2R1, Canada. [Strotmann, Joerg M.] Univ Wurzburg, Dept Med 1, Ctr Cardiovasc Med, Wurzburg, Germany. [Warnock, David G.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Linhart, Ales] Charles Univ Prague, Fac Med 1, Dept Internal Med 2, Prague, Czech Republic. RP Giannini, EH (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Dept Pediat,Div Rheumatol, Cincinnati, OH 45220 USA. EM edward.giannini@cchmc.org NR 39 TC 25 Z9 29 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2010 VL 99 IS 3 BP 283 EP 290 DI 10.1016/j.ymgme.2009.10.178 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 563OB UT WOS:000275140900107 PM 19951842 ER PT J AU Klaschik, S Tross, D Shirota, H Klinman, DM AF Klaschik, Sven Tross, Debra Shirota, Hidekazu Klinman, Dennis M. TI Short- and long-term changes in gene expression mediated by the activation of TLR9 SO MOLECULAR IMMUNOLOGY LA English DT Article DE Rodent; Gene regulation; Signal transduction; Molecular biology ID IMMUNOSTIMULATORY CPG-OLIGODEOXYNUCLEOTIDES; TOLL-LIKE RECEPTORS; BACTERIAL-DNA; CUTTING EDGE; CELL ACTIVATION; T-CELLS; IN-VIVO; PHASE-I; MURINE; MOTIFS AB CpG DNA binds to Toll-like receptor 9 to stimulate a strong innate immune response. The magnitude, duration and scope of CpG-inducecl changes in gene expression are incompletely understood despite extensive studies of TLR9 mediated signal transduction pathways. In particular, the prolonged effects of CpG DNA on gene activation have not been investigated despite evidence that a single dose of CpG DNA alters immune reactivity for several weeks. This study used gene expression analysis to monitor changes in mRNA levels for 14 days, and identified the genes, pathways and functional groups triggered in vivo following CpG DNA administration. Two discrete peaks of gene activation (at 3 h and 5 days) were observed after CpG injection. Both the behavior and function of genes activated during the second peak differed from those triggered shortly after CpG administration. Initial gene up-regulation corresponded to a period when TLR9 ligation stimulated genes functionally associated with the generation of innate and adaptive immune responses (e.g. the NF-kappa B and B-cell receptor pathways). The second peak reflected processes associated with cell division (e.g. cell cycle and DNA replication and repair). The complex bimodal pattern of gene expression elicited by CpG DNA administration provides novel insights into the long-term effects of TLR9 engagement on genes associated with immunity and cell proliferation. Published by Elsevier Ltd. C1 [Klaschik, Sven; Tross, Debra; Shirota, Hidekazu; Klinman, Dennis M.] NCI, Expt Immunol Lab, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, NIH, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural NIH HHS [ZIA BC010852-03] NR 53 TC 22 Z9 24 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD MAR PY 2010 VL 47 IS 6 BP 1317 EP 1324 DI 10.1016/j.molimm.2009.11.014 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 578NN UT WOS:000276300600018 PM 20005572 ER PT J AU Pastar, I Stojadinovic, O Krzyzanowska, A Barrientos, S Stuelten, C Zimmerman, K Blumenberg, M Brem, H Tomic-Canic, M AF Pastar, Irena Stojadinovic, Olivera Krzyzanowska, Agata Barrientos, Stephan Stuelten, Christina Zimmerman, Karen Blumenberg, Miroslav Brem, Harold Tomic-Canic, Marjana TI Attenuation of the Transforming Growth Factor beta-Signaling Pathway in Chronic Venous Ulcers SO MOLECULAR MEDICINE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; DIABETIC FOOT ULCERS; P38 MAP KINASE; TGF-BETA; CHRONIC WOUNDS; EPIDERMAL-KERATINOCYTES; HUMAN SKIN; GENE-EXPRESSION; II RECEPTOR; LEG ULCERS AB Transforming growth factor beta (TGF beta) is important in inflammation, angiogenesis, reepithelialization and connective tissue regeneration during wound healing. We analyzed components of TGF beta signaling pathway in biopsies from 10 patients with nonhealing venous ulcers (VUs). Using comparative genomics of transcriptional profiles of VUs and TGF beta-treated keratinocytes, we found deregulation of TGF beta target genes in VUs. Using quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis, we found suppression of TGF beta RI, TGWU and TGF beta 3RIII, and complete absence of phosphorylated Smad2 (pSmad2) in VU epidermis. In contrast, pSmad2 was induced in the cells of the migrating epithelial tongue of acute wounds. TGF beta-inducible transcription factors (GADD45 beta, ATF3 and ZFP36L1) were suppressed in VUs. Likewise, genes suppressed by TGF beta (FABP5, CSTA and S100A8) were induced in nonhealing VUs. An inhibitor of Smad signaling, Smad7 was also downregulated in VUs. We conclude that TGF beta signaling is functionally blocked in VUs by downregulation of TGF beta receptors and attenuation of Smad signaling resulting in deregulation of TGF beta target genes and consequent hyperproliferation. These data suggest that application of exogenous TGF beta may not be a beneficial treatment for VUs. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2009.00149 C1 [Pastar, Irena; Stojadinovic, Olivera; Tomic-Canic, Marjana] Univ Miami, Miller Sch Med, Dept Dermatol & Cutaneous Surg, Wound Healing & Regenerat Med Res Program, Miami, FL 33136 USA. [Krzyzanowska, Agata] Hosp Special Surg, Tissue Engn Regenerat & Repair Program, New York, NY 10021 USA. [Barrientos, Stephan] Univ Rochester, Sch Med, Dept Med, Rochester, NY USA. [Stuelten, Christina] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Zimmerman, Karen; Brem, Harold] NYU, Sch Med, Dept Surg, Helen & Martin Kimmel Div Wound Healing & Regener, New York, NY USA. [Blumenberg, Miroslav] NYU, Sch Med, Dept Dermatol, New York, NY USA. [Blumenberg, Miroslav] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. [Blumenberg, Miroslav] NYU, Sch Med, Inst Canc, New York, NY 10016 USA. RP Tomic-Canic, M (reprint author), Univ Miami, Miller Sch Med, Dept Dermatol & Cutaneous Surg, Wound Healing & Regenerat Med Res Program, NW 10th Ave,RMSB 2023A, Miami, FL 33136 USA. EM mtcanic@med.miami.edu FU National Institutes of Health Grant [RO1NR008029]; Rudolph Rupert Scleroderma Research Program; National Institutes of Health, National Cancer Institute, Bethesda, MD FX We are grateful to M Goldring and members of her laboratory (Hospital for Special Surgery) and G Guasch (Fuchs Lab, Rockefeller University) for helpful advice and technical assistance. We are also grateful to members of Tomic and Brem Laboratories for helpful suggestions and critical review. This work was supported by National Institutes of Health Grant RO1NR008029 (M Tomic-Canic), Rudolph Rupert Scleroderma Research Program (M Tomic-Canic), Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD (C Stuelten). NR 63 TC 36 Z9 36 U1 1 U2 5 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD MAR-APR PY 2010 VL 16 IS 3-4 BP 92 EP 101 DI 10.2119/molmed.2009.00149 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 575DA UT WOS:000276044300002 PM 20069132 ER PT J AU Durand, S Storz, G AF Durand, Sylvain Storz, Gisela TI Reprogramming of anaerobic metabolism by the FnrS small RNA SO MOLECULAR MICROBIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; ARC 2-COMPONENT SYSTEM; ESCHERICHIA-COLI; GENE-EXPRESSION; OUTER-MEMBRANE; TRANSCRIPTIONAL ACTIVATION; DIFFERENTIAL REGULATION; MEDIATING REPRESSION; SUPEROXIDE-DISMUTASE; AEROBIC PATHWAYS AB P>Small RNAs (sRNAs) that act by base pairing with trans-encoded mRNAs modulate metabolism in response to a variety of environmental stimuli. Here, we describe an Hfq-binding sRNA (FnrS) whose expression is induced upon a shift from aerobic to anaerobic conditions and which acts to downregulate the levels of a variety of mRNAs encoding metabolic enzymes. Anaerobic induction in minimal medium depends strongly on FNR but is also affected by the ArcA and CRP transcription regulators. Whole genome expression analysis showed that the levels of at least 32 mRNAs are downregulated upon FnrS overexpression, 15 of which are predicted to base pair with FnrS by TargetRNA. The sRNA is highly conserved across its entire length in numerous Enterobacteria, and mutational analysis revealed that two separate regions of FnrS base pair with different sets of target mRNAs. The majority of the target genes were previously reported to be downregulated in an FNR-dependent manner but lack recognizable FNR binding sites. We thus suggest that FnrS extends the FNR regulon and increases the efficiency of anaerobic metabolism by repressing the synthesis of enzymes that are not needed under these conditions. C1 [Durand, Sylvain; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH-CNRS Research Career Transition Award FX We thank P. Valentin-Hansen and P. Kiley for sharing unpublished information, S. Gottesman, P. Mandin and P. Kiley for advice and strains and F. Barras for helpful discussions. We also are grateful to C. Beisel, S. Gottesman, E. Hobbs and P. Kiley for comments on the manuscript. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. S.D. was the recipient of an NIH-CNRS Research Career Transition Award. NR 76 TC 72 Z9 74 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2010 VL 75 IS 5 BP 1215 EP 1231 DI 10.1111/j.1365-2958.2009.07044.x PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 559FR UT WOS:000274808800014 PM 20070527 ER PT J AU Wang, TTY Schoene, NW Kim, YS Mizuno, CS Rimando, AM AF Wang, Thomas T. Y. Schoene, Norberta W. Kim, Young S. Mizuno, Cassia S. Rimando, Agnes M. TI Differential effects of resveratrol and its naturally occurring methylether analogs on cell cycle and apoptosis in human androgen-responsive LNCaP cancer cells SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Androgen; Cancer prevention; Estrogen; Phytochemicals; Stilbenes ID PROSTATE-CANCER; IN-VIVO; EXPRESSION; RECEPTOR; PROGRESSION; STILBENES; ARREST; GENES; LINES; P21(WAF1/CIP1) AB Stilbenes are phytoalexins that become activated when plants are stressed. These compounds exist in foods and are widely consumed. Resveratrol is a grape-derived stilbene, which possesses a wide range of health-promoting activities, including anticancer properties. Several other stilbenes structurally similar to resveratrol are also available in food, but their biological activities remain largely unknown. In this study, we compared the effects of resveratrol and its natural derivatives pterostilbene, trans-resveratrol trimethylether, trans-pinostilbene and trans-desoxyrhapontigenin on androgen-responsive human prostate cancer LNCaP cells. We found that these compounds exert differential effects on LNCaP cell growth, cell cycle and apoptosis. Trans-resveratrol trimethylether appeared to be the most potent compound among the stilbenes tested. Treatment of LNCaP cells with trans-resveratrol trimethylether resulted in G2/M blockage while other compounds, including resveratrol, induced G1/S arrest. Moreover, different from other compounds, trans-resveratrol trimethylether induced apoptosis. At the molecular level, the effects of these compounds on cell cycle correlated with induction of the cyclin-dependent kinase inhibitor 1A and B mRNA levels. Additionally, these compounds also inhibited both androgen- as well as estrogen-mediated pathways. These results provide mechanistic information on how resveratrol and its methylether analogs may act to contribute to potential antiprostate cancer activity. C1 [Wang, Thomas T. Y.; Schoene, Norberta W.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Kim, Young S.] Natl Canc Inst, Nutrit Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD USA. [Mizuno, Cassia S.; Rimando, Agnes M.] ARS, Nat Prod Utilizat Res Unit, USDA, University, MS USA. RP Wang, TTY (reprint author), ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, 10300 Baltimore Ave,Bldg 307C,Room 132, Beltsville, MD 20705 USA. EM tom.wang@ars.usda.gov FU US appropriated funds [1235-51530-052-00, 6408-41000-006-00]; National Cancer Institute FX This work was supported by US appropriated funds to USDA project numbers 1235-51530-052-00 (TTYWN. WS), 6408-41000-006-00 (CSM, AMR) and the National Cancer Institute (YSK). NR 47 TC 52 Z9 53 U1 1 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1613-4125 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD MAR PY 2010 VL 54 IS 3 BP 335 EP 344 DI 10.1002/mnfr.200900143 PG 10 WC Food Science & Technology SC Food Science & Technology GA 575JS UT WOS:000276063900003 PM 20077416 ER PT J AU Baca-Garcia, E Perez-Rodriguez, MM Keyes, KM Oquendo, MA Hasin, DS Grant, BF Blanco, C AF Baca-Garcia, E. Perez-Rodriguez, M. M. Keyes, K. M. Oquendo, M. A. Hasin, D. S. Grant, B. F. Blanco, C. TI Suicidal ideation and suicide attempts in the United States: 1991-1992 and 2001-2002 SO MOLECULAR PSYCHIATRY LA English DT Article DE attempted suicide; epidemiology; prevalence; health surveys; ethnic groups; age groups ID NATIONAL EPIDEMIOLOGIC SURVEY; MAJOR DEPRESSIVE DISORDER; IV PSYCHIATRIC-DISORDERS; DELIBERATE SELF-HARM; NON-HISPANIC WHITES; OF-THE-LITERATURE; ANTIDEPRESSANT TREATMENT; COMORBIDITY SURVEY; RISK-FACTORS; PREVALENCE AB The aim of the study is to compare the prevalence of suicidal ideation and attempts in the United States in 1991-1992 and 2001-2002, and identify sociodemographic groups at increased risk for suicidal ideation and attempts. Data were drawn from the National Institute on Alcohol Abuse and Alcoholism 1991-1992 National Longitudinal Alcohol Epidemiologic Survey (n = 42 862) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43 093), two nationally representative household surveys of non-institutionalized civilians aged 18 years and older, residing in the United States. The lifetime prevalence of suicide attempts remained unchanged in the United States between 1991-1992 and 2001-2002. Specific groups, namely 18- to 24-year-old white and black women, 25- to 44-year-old white women and 45- to 64-year-old Native American men were identified as being at high risk for suicide attempts. Despite prevention and treatment efforts, the lifetime prevalence of suicide attempts remains unchanged. Given the morbidity and mortality associated with suicide attempts, urgent action is needed to decrease the prevalence of suicide attempts in the United States. Molecular Psychiatry ( 2010) 15, 250-259; doi: 10.1038/mp.2008.98; published online 9 September 2008 C1 [Grant, B. F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Baca-Garcia, E.; Oquendo, M. A.; Hasin, D. S.; Blanco, C.] New York State Psychiat Inst & Hosp, Dept Psychiat, New York, NY 10032 USA. [Baca-Garcia, E.; Oquendo, M. A.; Hasin, D. S.; Blanco, C.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Baca-Garcia, E.] Univ Autonoma Madrid, Fdn Jimenez Diaz Hosp, Dept Psychiat, Madrid, Spain. [Perez-Rodriguez, M. M.] Hosp Ramon & Cajal, Dept Psychiat, E-28034 Madrid, Spain. [Perez-Rodriguez, M. M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Keyes, K. M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov RI Perez Rodriguez, Maria/B-9410-2013; Baca-Garcia, Enrique/F-4106-2015 OI Perez Rodriguez, Maria/0000-0001-5137-1993; Baca-Garcia, Enrique/0000-0002-6963-6555 FU NIH [DA019606, DA020783, DA023200, MH076051, AA014223]; American Foundation for Suicide Prevention; New York State Psychiatric Institute; Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM; National Institute on Drug Abuse (NIDA); Intramural Program of the National Institutes of Health, NIAAA FX This study has been financially supported by NIH Grants DA019606, DA020783, DA023200 and MH076051 (Dr Blanco) and AA014223 (Dr Hasin), grants from the American Foundation for Suicide Prevention ( Dr Blanco and Dr Oquendo), the New York State Psychiatric Institute ( Dr Blanco, Dr Hasin and Dr Oquendo) and the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM (Dr BacaGarcia and Dr Perez-Rodriguez). The NESARC was funded by the NIAAA with supplemental support from the National Institute on Drug Abuse (NIDA). This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. Dr Bridget Grant had full access to all of the data in this study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Dr Blanco takes responsibility for the integrity of the data and the accuracy of the data analysis, and that all authors had full access to all the data in the study. NR 42 TC 41 Z9 43 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2010 VL 15 IS 3 BP 250 EP 259 DI 10.1038/mp.2008.98 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 558FO UT WOS:000274726700007 PM 18779820 ER PT J AU Simonelli, F Maguire, AM Testa, F Pierce, EA Mingozzi, F Bennicelli, JL Rossi, S Marshall, K Banfi, S Surace, EM Sun, JW Redmond, TM Zhu, XS Shindler, KS Ying, GS Ziviello, C Acerra, C Wright, JF McDonnell, JW High, KA Bennett, J Auricchio, A AF Simonelli, Francesca Maguire, Albert M. Testa, Francesco Pierce, Eric A. Mingozzi, Federico Bennicelli, Jeannette L. Rossi, Settimio Marshall, Kathleen Banfi, Sandro Surace, Enrico M. Sun, Junwei Redmond, T. Michael Zhu, Xiaosong Shindler, Kenneth S. Ying, Gui-Shuang Ziviello, Carmela Acerra, Carmela Wright, J. Fraser McDonnell, Jennifer Wellman High, Katherine A. Bennett, Jean Auricchio, Alberto TI Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration SO MOLECULAR THERAPY LA English DT Article ID PHASE-I TRIAL; CHILDHOOD BLINDNESS; MOLECULAR-GENETICS; RPE65 MUTATIONS; CANINE MODEL; VISION; DISEASE; VARIABILITY; HEMOPHILIA; NYSTAGMUS AB The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases. C1 [Simonelli, Francesca; Testa, Francesco; Rossi, Settimio; Acerra, Carmela] Univ Naples 2, Dept Ophthalmol, I-80131 Naples, Italy. [Simonelli, Francesca; Banfi, Sandro; Surace, Enrico M.; Ziviello, Carmela; Acerra, Carmela; Auricchio, Alberto] Telethon Inst Genet & Med TIGEM, Naples, Italy. [Maguire, Albert M.; Pierce, Eric A.; Bennicelli, Jeannette L.; Shindler, Kenneth S.; Ying, Gui-Shuang; Bennett, Jean] Univ Penn, Sch Med, FM Kirby Ctr Mol Ophthalmol, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Maguire, Albert M.; Mingozzi, Federico; Marshall, Kathleen; Sun, Junwei; Zhu, Xiaosong; Acerra, Carmela; Wright, J. Fraser; McDonnell, Jennifer Wellman; High, Katherine A.; Bennett, Jean] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA. [Redmond, T. Michael] NEI, NIH, Bethesda, MD 20892 USA. [Ziviello, Carmela] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. [High, Katherine A.] Childrens Hosp Philadelphia, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Auricchio, Alberto] Univ Naples Federico 2, Dept Pediat, Naples, Italy. RP Simonelli, F (reprint author), Univ Naples 2, Dept Ophthalmol, Via S Pansini 5, I-80131 Naples, Italy. EM franctes@tin.it; jebennet@mail.med.upenn.edu; auricchio@tigem.it RI Testa, Francesco/J-3185-2012; Rossi, Settimio/J-4922-2012; mingozzi, federico/I-2332-2013; OI Simonelli, Francesca/0000-0001-8520-6769; AURICCHIO, Alberto/0000-0002-0832-2472; Testa, Francesco/0000-0002-1482-1577; Redmond, T. Michael/0000-0002-1813-5291; Surace, Enrico Maria/0000-0002-2975-942X; BANFI, Sandro/0000-0002-6541-8833; Pierce, Eric/0000-0002-2354-4102 FU Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia; Foundation Fighting Blindness; Research to Prevent Blindness; Macula Vision Foundation; Paul and Evanina Mackall Foundation Trust; Scheie Eye Institute; F. M. Kirby Foundation [TIGEM-P21, GGP07180]; Italian Telethon Foundation; Regione Campania Convenzione [018933]; European Community [223445]; Institutional Clinical and Translational Science Award Research Center [UL1-RR-024134]; Rosanne H. Silbermann Foundation; Associazione Italiana Amaurosi Congenita di Leber; Howard Hughes Medical Institute FX This work was supported by the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, the Foundation Fighting Blindness which sponsors the CHOP-Penn Pediatric Center for Retinal Degenerations, Research to Prevent Blindness senior scientist award (J.B.) and departmental award, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust, the Scheie Eye Institute, the F. M. Kirby Foundation, grants (TIGEM-P21, to A. A., E. M. S., and S. B., and GGP07180, to F. S.) from the Italian Telethon Foundation, Regione Campania Convenzione, grants 018933 Clinigene and 223445 AAVEYE from the European Community to A. A., a grant (UL1-RR-024134) from the Institutional Clinical and Translational Science Award Research Center, the Rosanne H. Silbermann Foundation, the Associazione Italiana Amaurosi Congenita di Leber, and the Howard Hughes Medical Institute (to K. A. H.). We thank the subjects and their families for their continuous support of the study; the medical, operating-room, anesthesia, and nursing staff at Children's Hospital of Philadelphia and the physicians and staff in the Division of Ophthalmology; Barbara Konkle and Giovanni Cucchiaro for lending their clinical expertise; the members of the hospital's institutional review board and its chair, Mark Schreiner, along with David Brint, Richard Hurwitz, Mark Blumenkranz, and David Birch, for their invaluable guidance; Robert Nelson, Andrea Ballabio, Alfredo Ciccodicola, Ernesto Rinaldi, and Valder Arruda for their helpful discussions; Stuart Fine and Monte Mills for their support; Daniel Chung, Fred Letterio, Randall Toy, Matthew Canver, Sohani Amarasekera, Mohammed Toure, Nicholas Volpe, Jr., Katherine H. Maguire, Armida Faella, Anna Nesti, Angelo Torre, Valentina Di Iorio, Vito de Novellis and Ida Marabese for their technical and clinical assistance. NR 26 TC 263 Z9 277 U1 4 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2010 VL 18 IS 3 BP 643 EP 650 DI 10.1038/mt.2009.277 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 567NS UT WOS:000275454500025 PM 19953081 ER PT J AU Winkler, C AF Winkler, Cheryl TI Is There a Genetic Basis for Health Disparities in Human Immunodeficiency Virus Disease? SO MOUNT SINAI JOURNAL OF MEDICINE LA English DT Article DE acquired immune deficiency syndrome (AIDS); health disparities; human immunodeficiency virus (HIV); human immunodeficiency virus-associated nephropathy (HIVAN); genetic alleles; genetic predisposition; myosin; heavy chain 9; non-muscle (MYH9); nephropathy; chromosome 22 renal susceptibility alleles ID DUFFY ANTIGEN RECEPTOR; STAGE RENAL-DISEASE; GENOME-WIDE ASSOCIATION; CHRONIC KIDNEY-DISEASE; AFRICAN-AMERICANS; HIV-1 INFECTION; SEGMENTAL GLOMERULOSCLEROSIS; RESISTANCE ALLELE; NATURAL-SELECTION; PLASMODIUM-VIVAX AB The highest global prevalence rates for human immunodeficiency virus and acquired immune deficiency syndrome have been recorded in southern Africa; in the United States, individuals of African descent are disproportionately affected by human immunodeficiency virus infection. Human immunodeficiency virus infected individuals with African ancestry are also estimated to have a 17-fold or greater risk for developing human immunodeficiency virus associated nephropathy in comparison with their counterparts of non-African descent. Several recent studies have implicated genetic alleles that are more frequent in populations of African descent and increase the risk of human immunodeficiency virus infection and the risk of human immunodeficiency virus associated neuropathy (HIVAN). The supposition that persons of African descent are more susceptible to human immunodeficiency virus infection because of an underlying genetic predisposition is not supported by available evidence. However, strong, replicated data show that the increased risk for human immunodeficiency-virus associated nephropathy, as well as other major forms of kidney disease in individuals of African descent, is due in part to MYH9 (myosin, heavy chain 9, nonmuscle) renal disease susceptibility alleles that are very frequent throughout sub-Saharan Africa but are infrequent or absent in non-Africans. Selection, drift, and demographic events shape the allelic architecture of the human genome: it is expected that these events will be reflected in geographic-specific differentiation in allele frequencies for a small subset of alleles that may be associated with either increased or reduced risk for complex and infectious diseases. Mt Sinai J Med 77:149-159, 2010. (C) 2010 Mount Sinai School of Medicine C1 NCI, Lab Genome Divers, Frederick, MD 21701 USA. RP Winkler, C (reprint author), NCI, Lab Genome Divers, Frederick, MD 21701 USA. EM winklerc@mail.nih.gov FU National Cancer Institute (National Institutes of Health) [HHSN26120080001E]; Center for Cancer Research (National Cancer Institute, National Institutes of Health) FX The author thanks Dr. George Nelson, Dr. Bert Gold, Dr. Ping An, and Dr. leffrey Kopp for insightful discussions and the participants who made these studies possible. This project has been funded in whole or in part with federal funds from the National Cancer Institute (National Institutes of Health) under contract HHSN26120080001E. This research was supported by the Intramural Research Program of the Center for Cancer Research (National Cancer Institute, National Institutes of Health). NR 62 TC 3 Z9 3 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0027-2507 J9 MT SINAI J MED JI Mt. Sinai J. Med. PD MAR-APR PY 2010 VL 77 IS 2 BP 149 EP 159 DI 10.1002/msj.20172 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 580GW UT WOS:000276437000004 PM 20309925 ER PT J AU Ciccone, EJ Read, SW Mannon, PJ Yao, MD Hodge, JN Dewar, R Chairez, CL Proschan, MA Kovacs, JA Sereti, I AF Ciccone, E. J. Read, S. W. Mannon, P. J. Yao, M. D. Hodge, J. N. Dewar, R. Chairez, C. L. Proschan, M. A. Kovacs, J. A. Sereti, I. TI Cycling of gut mucosal CD4+T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels SO MUCOSAL IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-INFECTED PATIENTS; CD4(+) T-CELLS; MICROBIAL TRANSLOCATION; GASTROINTESTINAL-TRACT; LYMPHOID-TISSUE; IMMUNE RECONSTITUTION; PERIPHERAL-BLOOD; SIV INFECTION; LYMPHOCYTES AB The gut mucosa is an important site of HIV immunopathogenesis with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with beta 7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV-RNA. These data suggest that gut T-cell activation and microbial translocation may be interconnected whereas prolonged ART may decrease activation and restore gut CD4+ T cells. C1 [Ciccone, E. J.; Hodge, J. N.; Chairez, C. L.; Sereti, I.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Read, S. W.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Mannon, P. J.] Univ Alabama, Div Gastroenterol & Hepatol, Birmingham, AL USA. [Yao, M. D.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Dewar, R.] SAIC Frederick Inc, Frederick, MD USA. [Proschan, M. A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Kovacs, J. A.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU NIH; NIAID; Critical Care Medicine Department; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX We acknowledge Andrew Redd, Vitaly Ganusov and Michele Di Mascio for their helpful comments and discussion, Jason Brenchley and Danny Douek for their advice regarding the LPS assay, and the staff of the OP8 clinic and the GI suite at the NIH Clinical Center for their assistance with patient recruitment and care. Special thanks to all study participants who volunteered for research gut biopsy procedures. This research was supported in part by the Intramural Program of the NIH, NIAID and Critical Care Medicine Department. In addition, 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 it mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 37 TC 53 Z9 53 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAR PY 2010 VL 3 IS 2 BP 172 EP 181 DI 10.1038/mi.2009.129 PG 10 WC Immunology SC Immunology GA 554PH UT WOS:000274446400009 PM 19956090 ER PT J AU Lovas, G Nielsen, JA Johnson, KR Hudson, LD AF Lovas, G. Nielsen, J. A. Johnson, K. R. Hudson, L. D. TI Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE axonal transection; experimental demyelination; injury response; microarray; rat ID LYSOLECITHIN-INDUCED DEMYELINATION; MAGNETIC-RESONANCE-SPECTROSCOPY; THYROTROPIN-RELEASING-HORMONE; MULTIPLE-SCLEROSIS; SPINAL-CORD; AXOTOMIZED NEURONS; GANGLION NEURONS; NERVOUS-SYSTEM; MESSENGER-RNAS; RAT-BRAIN AB The main pathological features of multiple sclerosis, demyelination and axonal transection, are considered to cause reversible and irreversible neurological deficits, respectively. This study aimed to separately analyze the effects of these pathological hallmarks on neuronal gene expression in experimental paradigms. The pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or a complete pathway transection (axonal transection) in rats. Transcriptional changes in the pontocerebellar neurons were investigated with microarrays at days 4, 10 and 37 post-intervention, which was confirmed by immunohistochemistry on protein level. A common as well as unique set of injury-response genes was identified. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. The expression of Atf3 in a patient with Marburg's variant of multiple sclerosis was also detected, also confirming the activation of the Atf3 pathway in a human disease sample. It was concluded that this experimental approach may be useful for the identification of pathways that could be targeted for remyelinative or neuroprotective drug development. C1 [Lovas, G.] Semmelweis Univ, Dept Neurol, H-1083 Budapest, Hungary. [Lovas, G.; Nielsen, J. A.; Hudson, L. D.] NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. [Johnson, K. R.] NINDS, Bioinformat Neurosci Grp, Div Intramural Res, Informat Technol Program,NIH, Bethesda, MD 20892 USA. [Nielsen, J. A.] US FDA, Div Gen Restorat & Neurol Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Lovas, G (reprint author), Semmelweis Univ, Dept Neurol, Balassa Str 6, H-1083 Budapest, Hungary. EM lovasgab@hotmail.com RI Messier, Claude/A-2322-2008 OI Messier, Claude/0000-0002-4791-1763 FU NINDS FX We thank Andras Boros (Richter Inc.) for assistance with the animal surgeries, tissue isolation, and RNA preparation and Gabor G Kovacs (Department of Neuropathology, National Institute of Psychiatry and Neurology) for providing the Marburg's samples. We thank Abdel Elkahloun, (Genome Technologies Branch, NHGRI) for his help with the microarrays. This work was supported by NINDS intramural funds. NR 48 TC 2 Z9 2 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD MAR PY 2010 VL 16 IS 3 BP 303 EP 316 DI 10.1177/1352458509357063 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 563ZF UT WOS:000275179200005 PM 20086029 ER PT J AU Golan, G Ishchenko, AA Khassenov, B Shoham, G Saparbaev, MK AF Golan, Gali Ishchenko, Alexander A. Khassenov, Bekbolat Shoham, Gil Saparbaev, Murat K. TI Coupling of the nucleotide incision and 3 ' -> 5 ' exonuclease activities in Escherichia coli endonuclease IV: Structural and genetic evidences SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 1st Russian-European Workshop on DNA Repair and Epigenetic Regulation of Genome Stability CY JUN 24-26, 2008 CL St Petersburg, RUSSIA SP RAS Siberian Div, Inst Chem Biol & Fundamental Med, RAS, Inst Cytol DE Oxidative DNA damage; Cluster DNA lesion; Nucleotide incision repair; Base excision repair; AP endonuclease; 3 ' -> 5 ' exonuclease ID ELECTRON-DENSITY MAPS; DNA-POLYMERASE-V; REPAIR PATHWAY; IONIZING-RADIATION; PROTEIN STRUCTURES; HYDROGEN-PEROXIDE; BASE EXCISION; DAMAGE; ENZYME; SITES AB Aerobic respiration generates reactive oxygen species (ROS) as a by-product of cellular metabolism which can damage DNA. The complex nature of oxidative DNA damage requires actions of several repair pathways. Oxidized DNA bases are substrates for two overlapping pathways: base excision repair (BER) and nucleotide incision repair (NIR). In the BER pathway a DNA glycosylase cleaves the N-glycosylic bond between the abnormal base and deoxyribose, leaving either an abasic site or single-stranded DNA break. Alternatively, in the NIR pathway, an apurinic/apyrimidinic (AP) endonuclease incises duplex DNA 5 ' next to oxidatively damaged nucleotide. The multifunctional Escherichia coli endonuclease IV (Nfo) is involved in both BER and NIR pathways. Nfo incises duplex DNA 5' of a damaged residue but also possesses an intrinsic 3' -> 5' exonuclease activity. Herein. we demonstrate that Nfo-catalyzed NIR and exonuclease activities can generate a single-strand gap at the 5' side of 5,6-dihydrouracil residue. Furthermore, we show that Nfo mutants carrying amino acid substitutions H69A and G149D are deficient in both NIR and exonuclease activities, suggesting that these two functions are genetically linked and governed by the same amino acid residues. The crystal structure of Nfo-H69A mutant reveals the loss of one of the active site zinc atoms (Zn1) and rearrangements of the catalytic site, but no gross changes in the overall enzyme conformation. We hypothesize that these minor changes strongly affect the DNA binding of Nfo. Decreased affinity may lead to a different kinking angle of the DNA helix and this in turn thwart nucleotide incision and exonuclease activities of Nfo mutants but to lesser extent of their AP endonuclease function. Based on the biochemical and genetic data we propose a model where nucleotide incision coupled to 3' -> 5' exonuclease activity prevents formation of lethal double-strand breaks when repairing bi-stranded clustered DNA damage. (C) 2009 Elsevier B.V. All rights reserved. C1 [Golan, Gali; Shoham, Gil] Hebrew Univ Jerusalem, IL-91904 Jerusalem, Israel. [Ishchenko, Alexander A.; Saparbaev, Murat K.] Univ Paris 11, Inst Cancerol Gustave Roussy, CNRS, UMR 8126,Grp Reparat ADN, F-94805 Villejuif, France. [Khassenov, Bekbolat] Natl Ctr Biotechnol, Astana, Kazakhstan. RP Shoham, G (reprint author), Hebrew Univ Jerusalem, IL-91904 Jerusalem, Israel. EM gil2@vms.huji.ac.il; smurat@igr.fr RI Ishchenko, Alexander/E-4914-2012; Ishchenko, Alexander/D-4133-2013; Saparbaev, Murat/N-3225-2015; OI Saparbaev, Murat/0000-0002-4630-1074; Khassenov, Bekbolat/0000-0003-4572-948X NR 42 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAR 1 PY 2010 VL 685 IS 1-2 SI SI BP 70 EP 79 DI 10.1016/j.mrfmmm.2009.08.017 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 569JA UT WOS:000275591200010 PM 19751747 ER PT J AU Rotskaya, UN Rogozin, IB Vasyunina, EA Malyarchuk, BA Nevinsky, GA Sinitsyna, OI AF Rotskaya, Ulyana N. Rogozin, Igor B. Vasyunina, Elena A. Malyarchuk, Boris A. Nevinsky, Georgy A. Sinitsyna, Olga I. TI High frequency of somatic mutations in rat liver mitochondrial DNA SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 1st Russian-European Workshop on DNA Repair and Epigenetic Regulation of Genome Stability CY JUN 24-26, 2008 CL St Petersburg, RUSSIA SP RAS Siberian Div, Inst Chem Biol & Fundamental Med, RAS, Inst Cytol DE Mitochondrial DNA; Displacement loop; Nucleotide substitutions; Age-related somatic mutagenesis; Wistar rats ID D-LOOP REGION; POINT MUTATIONS; POLYMERASE-GAMMA; MTDNA MUTATIONS; REPAIR; MUTAGENESIS; REPLICATION; MICE; APOPTOSIS; FIDELITY AB Somatic mutations in mitochondrial DNA (mtDNA) are thought to play an important role in both aging and neurodegenerative diseases although their specific contributions remain a subject of intense debate. We analyzed somatic mutations in the mtDNA control regions in the liver of Wistar rats. The mutation rate was found to be high and increased with age from 5.3 x 10(-4) mutations per position to 4.48 x 10(-3) mutations per position at 3 and 12 months of age, respectively. The vast majority of nucleotide substitutions are transitions (similar to 95%) with A:T>G:C transitions being the most frequent type of substitution (>50%). In 3-month-old Wistar rats, approximately 40% of somatic mutations in the control region of mtDNA are significantly consistent with the model of dislocation mutagenesis which is a signature of error-prone DNA synthesis by mtDNA polymerase gamma. The results are consistent with the previous hypothesis that normal intramitochondrial dNTP pool asymmetries, which have been shown to reduce the fidelity of mtDNA polymerase gamma, substantially contribute to somatic mutagenesis of the rat mtDNA. (C) 2009 Elsevier B.V. All rights reserved. C1 [Rotskaya, Ulyana N.; Rogozin, Igor B.; Vasyunina, Elena A.; Nevinsky, Georgy A.; Sinitsyna, Olga I.] Russian Acad Sci, Siberian Div, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Rogozin, Igor B.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Malyarchuk, Boris A.] Russian Acad Sci, Far Eastern Div, Inst Biol Problems N, Magadan 685000, Russia. [Nevinsky, Georgy A.] Russian Acad Sci, Siberian Div, Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia. RP Sinitsyna, OI (reprint author), Russian Acad Sci, Siberian Div, Inst Cytol & Genet, Pr Lavrentyeva 10, Novosibirsk 630090, Russia. EM olgasin1@yandex.ru RI Nevinsky, Georgy/E-6053-2012 FU Intramural NIH HHS NR 40 TC 4 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAR 1 PY 2010 VL 685 IS 1-2 SI SI BP 97 EP 102 DI 10.1016/j.mrfmmm.2009.12.010 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 569JA UT WOS:000275591200013 PM 20036675 ER PT J AU Ramot, Y Steiner, M Morad, V Leibovitch, S Amouyal, N Cesta, MF Nyska, A AF Ramot, Yuval Steiner, Michal Morad, Vered Leibovitch, Sigalit Amouyal, Netanel Cesta, Mark F. Nyska, Abraham TI Pulmonary thrombosis in the mouse following intravenous administration of quantum dot-labeled mesenchymal cells SO NANOTOXICOLOGY LA English DT Article ID STEM-CELLS; IN-VIVO; EPIDERMAL-KERATINOCYTES; LONG-TERM; TOXICITY; MICE; NANOPARTICLES; CYTOTOXICITY; IMPACT AB Quantum dots (QDs) are emerging as novel diagnostic agents. Yet, only a few studies have examined the possible deleterious effects of QD-labeled stem cells. We assessed the potential toxic effects of QD-labeled human embryonic palatal mesenchymal (QD-HEPM) cells in male NOD/SCID mice for six months, following the administration of a single intravenous injection. Control animals were administered with non-labeled HEPM cells. No treatment-related clinical signs, hematological, or biochemical parameters were found in the QD-HEPM animals in comparison to control animals. Histologically, multifocal organizing thrombi were noted in the pulmonary arteries of all QD-HEPM animals from the one-week study group and in one animal from the one-month group. Additionally, increased severity of perivascular inflammation was noted at the injection sites of QD-HEPM animals from the one-week group. This is the first study reporting histopathological evidence for pro-thrombotic adverse effects mediated by QD labeling. C1 [Ramot, Yuval] Hadassah Hebrew Univ Med Ctr, Jerusalem, Israel. [Steiner, Michal; Morad, Vered; Leibovitch, Sigalit; Amouyal, Netanel] Harlan Biotech Israel Ltd, Rehovot, Israel. [Cesta, Mark F.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. [Nyska, Abraham] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel. RP Nyska, A (reprint author), Haharuv 18,POB 184, IL-36576 Timrat, Israel. EM anyska@bezeqint.net FU Intramural Research Program of the NIH; National Institutes of Environmental Health Sciences; Genesis Cell Therapy Consortium FX The authors wish to thank Dr Yona Grunfeld from Harlan Biotech Ltd, Israel for the excellent comments. This research was supported [in part] by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences and by Genesis Cell Therapy Consortium (A. R.), operated by the Chief Scientist Office of the Israeli Ministry of Industry, Trade and Labor (MIT). NR 35 TC 21 Z9 22 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 J9 NANOTOXICOLOGY JI Nanotoxicology PD MAR PY 2010 VL 4 IS 1 BP 98 EP 105 DI 10.3109/17435390903470093 PG 8 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA 562OF UT WOS:000275061000007 PM 20795905 ER PT J AU Min, JY Subbarao, K AF Min, Ji-Young Subbarao, Kanta TI Cellular targets for influenza drugs SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID WEST-NILE-VIRUS; SCREEN; REPLICATION; INFECTION; REVEALS C1 [Min, Ji-Young; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Min, JY (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000933-06] NR 13 TC 12 Z9 12 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 2010 VL 28 IS 3 BP 239 EP 240 DI 10.1038/nbt0310-239 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 565JT UT WOS:000275288300019 PM 20212486 ER PT J AU Petersen, GM Amundadottir, L Fuchs, CS Kraft, P Stolzenberg-Solomon, RZ Jacobs, KB Arslan, AA Bueno-de-Mesquita, HB Gallinger, S Gross, M Helzlsouer, K Holly, EA Jacobs, EJ Klein, AP LaCroix, A Li, DH Mandelson, MT Olson, SH Risch, HA Zheng, W Albanes, D Bamlet, WR Berg, CD Boutron-Ruault, MC Buring, JE Bracci, PM Canzian, F Clipp, S Cotterchio, M de Andrade, M Duell, EJ Gaziano, JM Giovannucci, EL Goggins, M Hallmans, G Hankinson, SE Hassan, M Howard, B Hunter, DJ Hutchinson, A Jenab, M Kaaks, R Kooperberg, C Krogh, V Kurtz, RC Lynch, SM McWilliams, RR Mendelsohn, JB Michaud, DS Parikh, H Patel, AV Peeters, PHM Rajkovic, A Riboli, E Rodriguez, L Seminara, D Shu, XO Thomas, G Tjonneland, A Tobias, GS Trichopoulos, D Van Den Eeden, SK Virtamo, J Wactawski-Wende, J Wang, ZM Wolpin, BM Yu, H Yu, K Zeleniuch-Jacquotte, A Fraumeni, JF Hoover, RN Hartge, P Chanock, SJ AF Petersen, Gloria M. Amundadottir, Laufey Fuchs, Charles S. Kraft, Peter Stolzenberg-Solomon, Rachael Z. Jacobs, Kevin B. Arslan, Alan A. Bueno-de-Mesquita, H. Bas Gallinger, Steven Gross, Myron Helzlsouer, Kathy Holly, Elizabeth A. Jacobs, Eric J. Klein, Alison P. LaCroix, Andrea Li, Donghui Mandelson, Margaret T. Olson, Sara H. Risch, Harvey A. Zheng, Wei Albanes, Demetrius Bamlet, William R. Berg, Christine D. Boutron-Ruault, Marie-Christine Buring, Julie E. Bracci, Paige M. Canzian, Federico Clipp, Sandra Cotterchio, Michelle de Andrade, Mariza Duell, Eric J. Gaziano, J. Michael Giovannucci, Edward L. Goggins, Michael Hallmans, Goran Hankinson, Susan E. Hassan, Manal Howard, Barbara Hunter, David J. Hutchinson, Amy Jenab, Mazda Kaaks, Rudolf Kooperberg, Charles Krogh, Vittorio Kurtz, Robert C. Lynch, Shannon M. McWilliams, Robert R. Mendelsohn, Julie B. Michaud, Dominique S. Parikh, Hemang Patel, Alpa V. Peeters, Petra H. M. Rajkovic, Aleksandar Riboli, Elio Rodriguez, Laudina Seminara, Daniela Shu, Xiao-Ou Thomas, Gilles Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Van Den Eeden, Stephen K. Virtamo, Jarmo Wactawski-Wende, Jean Wang, Zhaoming Wolpin, Brian M. Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Fraumeni, Joseph F., Jr. Hoover, Robert N. Hartge, Patricia Chanock, Stephen J. TI A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33 SO NATURE GENETICS LA English DT Article ID BASE-LINE CHARACTERISTICS; RECOMBINATION HOTSPOTS; WOMENS HEALTH; BREAST-CANCER; RISK; GENE; VARIANTS; TELOMERASE; CELLS; LUNG AB We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies. C1 [Amundadottir, Laufey; Parikh, Hemang; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Petersen, Gloria M.; Bamlet, William R.; de Andrade, Mariza; McWilliams, Robert R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Michaud, Dominique S.; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Jacobs, Kevin B.; Hutchinson, Amy; Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Gross, Myron] Univ Minnesota, Dept Lab Med & Pathol, Sch Med, Minneapolis, MN 55455 USA. [Helzlsouer, Kathy] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Holly, Elizabeth A.; Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Johns Hopkins Med Inst, Sol Goldman Pancreat Res Ctr, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [LaCroix, Andrea; Mandelson, Margaret T.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Li, Donghui; Hassan, Manal] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Mandelson, Margaret T.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Risch, Harvey A.; Yu, Herbert] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Berg, Christine D.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Boutron-Ruault, Marie-Christine] Univ Paris Sud, INSERM, Inst Gustave Roussy, Villejuif, France. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Dept Aging, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Canzian, Federico] German Canc Res Ctr, Heidelberg, Germany. [Clipp, Sandra] George W Comstock Ctr Publ Hlth Res & Prevent, Johns Hopkins Bloomberg Sch Publ Hlth, Hagerstown, MD USA. [Cotterchio, Michelle] Univ Toronto, Canc Care Ontario & Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Duell, Eric J.] Catalan Inst Oncol, Barcelona, Spain. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Aging, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Cardiovasc Dis, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Prevent Med, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Howard, Barbara] Georgetown Univ, MedStar Res Inst, Hyattsville, MD USA. [Krogh, Vittorio] Fdn IRCCS, Ist Nazl Tumoridi Milano, Nutr Epidemiol Unit, Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Lynch, Shannon M.; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Michaud, Dominique S.; Peeters, Petra H. M.; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Rajkovic, Aleksandar] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Biol, Pittsburgh, PA USA. [Rodriguez, Laudina] Hlth & Hlth Care Serv Council, Publ Hlth & Participat Directorate, Asturias, Spain. [Thomas, Gilles] Ctr Leon Berard, INSERM, F-69373 Lyon, France. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Boutron Ruault, Marie-Christine/G-3705-2013; Gallinger, Steven/E-4575-2013; Boutron, Marie-Christine/K-8168-2013; Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Krogh, Vittorio/K-2628-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Krogh, Vittorio/0000-0003-0122-8624; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Duell, Eric J/0000-0001-5256-0163 FU Intramural NIH HHS [ZIA CP010193-03]; NCI NIH HHS [P50 CA062924-140011, K07 CA140790, P50 CA062924, P50 CA062924-130011, P50 CA062924-150011, P50 CA062924-160011, P50 CA102701, R01 CA082729, R01 CA097193, R01 CA124908, R37 CA070867] NR 63 TC 274 Z9 278 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2010 VL 42 IS 3 BP 224 EP U29 DI 10.1038/ng.522 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400010 PM 20101243 ER PT J AU Van Deerlin, VM Sleiman, PMA Martinez-Lage, M Chen-Plotkin, A Wang, LS Graff-Radford, NR Dickson, DW Rademakers, R Boeve, BF Grossman, M Arnold, SE Mann, DMA Pickering-Brown, SM Seelaar, H Heutink, P van Swieten, JC Murrell, JR Ghetti, B Spina, S Grafman, J Hodges, J Spillantini, MG Gilman, S Lieberman, AP Kaye, JA Woltjer, RL Bigio, EH Mesulam, M al-Sarraj, S Troakes, C Rosenberg, RN White, CL Ferrer, I Llado, A Neumann, M Kretzschmar, HA Hulette, CM Welsh-Bohmer, KA Miller, BL Alzualde, A de Munain, AL McKee, AC Gearing, M Levey, AI Lah, JJ Hardy, J Rohrer, JD Lashley, T Mackenzie, IRA Feldman, HH Hamilton, RL Dekosky, ST van der Zee, J Kumar-Singh, S Van Broeckhoven, C Mayeux, R Vonsattel, JPG Troncoso, JC Kril, JJ Kwok, JBJ Halliday, GM Bird, TD Ince, PG Shaw, PJ Cairns, NJ Morris, JC McLean, CA DeCarli, C Ellis, WG Freeman, SH Frosch, MP Growdon, JH Perl, DP Sano, M Bennett, DA Schneider, JA Beach, TG Reiman, EM Woodruff, BK Cummings, J Vinters, HV Miller, CA Chui, HC Alafuzoff, I Hartikainen, P Seilhean, D Galasko, D Masliah, E Cotman, CW Tunon, MT Martinez, MCC Munoz, DG Carroll, SL Marson, D Riederer, PF Bogdanovic, N Schellenberg, GD Hakonarson, H Trojanowski, JQ Lee, VMY AF Van Deerlin, Vivianna M. Sleiman, Patrick M. A. Martinez-Lage, Maria Chen-Plotkin, Alice Wang, Li-San Graff-Radford, Neill R. Dickson, Dennis W. Rademakers, Rosa Boeve, Bradley F. Grossman, Murray Arnold, Steven E. Mann, David M. A. Pickering-Brown, Stuart M. Seelaar, Harro Heutink, Peter van Swieten, John C. Murrell, Jill R. Ghetti, Bernardino Spina, Salvatore Grafman, Jordan Hodges, John Spillantini, Maria Grazia Gilman, Sid Lieberman, Andrew P. Kaye, Jeffrey A. Woltjer, Randall L. Bigio, Eileen H. Mesulam, Marsel al-Sarraj, Safa Troakes, Claire Rosenberg, Roger N. White, Charles L., III Ferrer, Isidro Llado, Albert Neumann, Manuela Kretzschmar, Hans A. Hulette, Christine Marie Welsh-Bohmer, Kathleen A. Miller, Bruce L. Alzualde, Ainhoa Lopez de Munain, Adolfo McKee, Ann C. Gearing, Marla Levey, Allan I. Lah, James J. Hardy, John Rohrer, Jonathan D. Lashley, Tammaryn Mackenzie, Ian R. A. Feldman, Howard H. Hamilton, Ronald L. Dekosky, Steven T. van der Zee, Julie Kumar-Singh, Samir Van Broeckhoven, Christine Mayeux, Richard Vonsattel, Jean Paul G. Troncoso, Juan C. Kril, Jillian J. Kwok, John B. J. Halliday, Glenda M. Bird, Thomas D. Ince, Paul G. Shaw, Pamela J. Cairns, Nigel J. Morris, John C. McLean, Catriona Ann DeCarli, Charles Ellis, William G. Freeman, Stefanie H. Frosch, Matthew P. Growdon, John H. Perl, Daniel P. Sano, Mary Bennett, David A. Schneider, Julie A. Beach, Thomas G. Reiman, Eric M. Woodruff, Bryan K. Cummings, Jeffrey Vinters, Harry V. Miller, Carol A. Chui, Helena C. Alafuzoff, Irina Hartikainen, Paivi Seilhean, Danielle Galasko, Douglas Masliah, Eliezer Cotman, Carl W. Tunon, M. Teresa Martinez, M. Cristina Caballero Munoz, David G. Carroll, Steven L. Marson, Daniel Riederer, Peter F. Bogdanovic, Nenad Schellenberg, Gerard D. Hakonarson, Hakon Trojanowski, John Q. Lee, Virginia M-Y TI Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GLOBAL GENE-EXPRESSION; GENOTYPE DATA; DEMENTIA; PROGRANULIN; MUTATIONS; CONSENSUS; DISEASE; ONSET; FAMILIES AB Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP) 1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism. C1 [Van Deerlin, Vivianna M.; Martinez-Lage, Maria; Chen-Plotkin, Alice; Wang, Li-San; Schellenberg, Gerard D.; Trojanowski, John Q.; Lee, Virginia M-Y] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Univ Penn, Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet,Sch Med, Philadelphia, PA 19104 USA. [Martinez-Lage, Maria] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain. [Chen-Plotkin, Alice; Grossman, Murray; Arnold, Steven E.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Graff-Radford, Neill R.] Mayo Coll Med, Dept Neurol, Jacksonville, FL USA. [Dickson, Dennis W.; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Arnold, Steven E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Arnold, Steven E.] Univ Penn, Sch Med, Penn Memory Ctr, Philadelphia, PA 19104 USA. [Mann, David M. A.; Pickering-Brown, Stuart M.] Univ Manchester, Sch Community Based Med, Manchester, Lancs, England. [Seelaar, Harro; van Swieten, John C.] Erasmus MC, Rotterdam, Netherlands. [Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA. [Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA. [Spina, Salvatore] Univ Siena, Dept Neurol Neurosurg & Behav Sci, I-53100 Siena, Italy. [Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA. [Spillantini, Maria Grazia] Univ Cambridge, Cambridge Ctr Brain Repair, Dept Clin Neurosci, Cambridge, England. [Gilman, Sid] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Lieberman, Andrew P.] Univ Michigan, Dept Pathol, Ann Arbor, MI USA. [Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Dept Neurol & Biomed Engn, Portland, OR 97201 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Bigio, Eileen H.] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Bigio, Eileen H.; Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Cognit Neurol & Alzheimer Dis Ctr, Chicago, IL 60611 USA. [al-Sarraj, Safa] Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England. [Troakes, Claire] Kings Coll Hosp London, MRC, London Neurodegenerat Dis Brain Bank, Inst Psychiat, London, England. [Rosenberg, Roger N.] Univ Texas SW Med Ctr Dallas, Rush Alzheimers Dis Ctr, Dallas, TX 75390 USA. [White, Charles L., III] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Ferrer, Isidro] Hosp Univ Bellvitge, Inst Neuropatol, Inst Invest Biomed Bellvitge IDIBELL, Barcelona, Spain. [Llado, Albert] Hosp Clin Barcelona, Alzheimers Dis & Cognit Disorders Unit, Serv Neurol, Inst Clin Neurociencies, Barcelona, Spain. [Neumann, Manuela] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland. [Kretzschmar, Hans A.] Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany. [Hulette, Christine Marie] Duke Univ, Dept Pathol, Hlth Sci Ctr, Durham, NC 27706 USA. [Welsh-Bohmer, Kathleen A.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Welsh-Bohmer, Kathleen A.] Duke Univ, Med Ctr, Bryan Alzheimers Dis Res Ctr, Durham, NC 27710 USA. [Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Alzualde, Ainhoa] Hosp Donostia, Neurogenet Unit, Inst Biodonostia, San Sebastian, Spain. [Lopez de Munain, Adolfo] Hosp Donostia, Serv Neurol, San Sebastian, Spain. [McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.] Ctr Geriatr Res Educ & Clin, Bedford Vet Adm Med Ctr, Bedford, MA USA. [Gearing, Marla] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Gearing, Marla; Levey, Allan I.] Emory Univ, Sch Med, Alzheimers Dis Res Ctr, Atlanta, GA 30322 USA. [Gearing, Marla; Levey, Allan I.] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Levey, Allan I.; Lah, James J.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Hardy, John] UCL, Inst Neurol, Reta Lila Labs, London, England. [Hardy, John; Lashley, Tammaryn] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Rohrer, Jonathan D.] UCL, Inst Neurol, Dementia Res Ctr, London, England. [Lashley, Tammaryn] UCL, Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England. [Mackenzie, Ian R. A.] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Mackenzie, Ian R. A.; Feldman, Howard H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Feldman, Howard H.] Vancouver Gen Hosp, Div Neurol, Vancouver, BC, Canada. [Feldman, Howard H.] Bristol Myers Squibb Co, Neurosci, Wallingford, CT 06492 USA. [Hamilton, Ronald L.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Dekosky, Steven T.] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA. [van der Zee, Julie; Kumar-Singh, Samir; Van Broeckhoven, Christine] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, Antwerp, Belgium. [van der Zee, Julie; Kumar-Singh, Samir; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium. [Mayeux, Richard; Vonsattel, Jean Paul G.] Columbia Univ, Taub Inst Res Alzheimers Dis, New York, NY USA. [Vonsattel, Jean Paul G.] Columbia Univ, New York Brain Bank, New York, NY USA. [Vonsattel, Jean Paul G.] Columbia Univ, Dept Pathol, New York, NY USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Kril, Jillian J.] Univ Sydney, Discipline Med, Sydney, NSW 2006, Australia. [Kril, Jillian J.] Univ Sydney, Discipline Pathol, Sydney, NSW 2006, Australia. [Kwok, John B. J.; Halliday, Glenda M.] Univ New S Wales, Prince Wales Med Res Inst, Sydney, NSW, Australia. [Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Ince, Paul G.; Shaw, Pamela J.] Univ Sheffield, Dept Neurosci, Sheffield, S Yorkshire, England. [Cairns, Nigel J.; Morris, John C.] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, St Louis, MO USA. [Cairns, Nigel J.; Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO USA. [McLean, Catriona Ann] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Alzheimers Dis Ctr, Imaging Dementia & Aging Lab,Ctr Neurosci, Sacramento, CA 95817 USA. [Ellis, William G.] Univ Calif Davis, Dept Pathol, Sacramento, CA 95817 USA. [Freeman, Stefanie H.; Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Freeman, Stefanie H.; Frosch, Matthew P.; Growdon, John H.] Harvard Univ, Sch Med, Boston, MA USA. [Growdon, John H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Perl, Daniel P.] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Sano, Mary] James J Peters Vet Affairs Med Ctr, New York, NY USA. [Bennett, David A.; Schneider, Julie A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Beach, Thomas G.] Sun Hlth Res Inst, Sun City, AZ USA. [Reiman, Eric M.] Univ Arizona, Banner Alzheimers Inst, Translat Genom Res Inst, Phoenix, AZ USA. [Reiman, Eric M.] Arizona Alzheimers Consortium, Phoenix, AZ USA. [Woodruff, Bryan K.] Mayo Clin, Scottsdale, AZ USA. [Cummings, Jeffrey] Univ Calif Los Angeles, David Geffen Sch Med, Mary S Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Miller, Carol A.; Chui, Helena C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Alafuzoff, Irina] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Alafuzoff, Irina] Univ Kuopio, Dept Clin Med, FIN-70211 Kuopio, Finland. [Hartikainen, Paivi] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland. [Seilhean, Danielle] Univ Paris 06, Paris, France. [Seilhean, Danielle] AP HP, Paris, France. [Galasko, Douglas; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Masliah, Eliezer] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Cotman, Carl W.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Tunon, M. Teresa] Hosp Navarra Pathol Dept, Navarra, Spain. [Tunon, M. Teresa; Martinez, M. Cristina Caballero] Brain Bank Navarra, Navarra, Spain. [Martinez, M. Cristina Caballero] Navarra Hlth Serv Osasunbidea, Biomed Res Ctr, Navarra, Spain. [Munoz, David G.] Univ Toronto, St Michaels Hosp, Dept Lab Med & Pathobiol, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Carroll, Steven L.] Univ Alabama, Dept Pathol, Tuscaloosa, AL 35487 USA. [Marson, Daniel] Univ Alabama, Dept Neurol, Tuscaloosa, AL 35487 USA. [Marson, Daniel] Univ Alabama, Alzheimers Dis Res Ctr, Tuscaloosa, AL 35487 USA. [Riederer, Peter F.] Univ Wurzburg, Clin & Policlin Psychiat Psychosomat & Psychother, Wurzburg, Germany. [Bogdanovic, Nenad] Karolinska Univ Hosp, Dept Geriatr Med, Stockholm, Sweden. [Hakonarson, Hakon] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Div Pulm Med,Dept Pediat, Philadelphia, PA 19104 USA. RP Van Deerlin, VM (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM vivianna@mail.med.upenn.edu; trojanow@mail.med.upenn.edu RI Shaw, Pamela/A-7620-2010; Pickering-Brown, Stuart/D-4008-2009; Lashley, Tammaryn/D-2583-2009; Shaw, Pamela/E-6193-2010; Ince, Paul/A-5064-2009; Morris, John/A-1686-2012; Neumann, Manuela/F-6558-2011; Hardy, John/C-2451-2009; Kumar-Singh, Samir/G-6280-2012; Arnold, Steven/J-7546-2012; Halliday, Glenda/E-8555-2011; Troakes, Claire/K-4346-2015; Tunon, Teresa/B-2525-2017; OI Rohrer, Jonathan/0000-0002-6155-8417; Dickson, Dennis W/0000-0001-7189-7917; Kaye, Jeffrey/0000-0002-9971-3478; Grafman, Jordan H./0000-0001-8645-4457; Kwok, John/0000-0001-9574-6195; Munoz, David/0000-0003-0957-6244; Martinez-Lage, Maria/0000-0002-5859-7562; Feldman, Howard/0000-0002-9258-4538; Kril, Jillian/0000-0001-9407-8674; Pickering-Brown, Stuart/0000-0003-1561-6054; Ince, Paul/0000-0001-6677-8753; Kumar-Singh, Samir/0000-0001-9466-6732; Halliday, Glenda/0000-0003-0422-8398; Tunon, Teresa/0000-0001-6589-1084; Carroll, Steven/0000-0001-6714-4373 FU National Health and Medical Research Council of Australia; Biobank at the Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; French clinical and genetic research network FX This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the study subjects and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger and C. Kim and study coordination was provided by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: S. Weintraub, N. Johnson, C. Shaw, V. Haroutunian, R. C. Petersen, D. S. Knopman, K. A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Re e, J. R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J. D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P. P. De Deyn, W. S. Brooks, T. Chow, V. Meininger, L. Lacomblez and E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: D. Clark, A. King, I. Bodi, D. Purohit, L. Kwong, J. E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.-J. Martin, R. Highley and C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: J. Kirby, E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R. M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P. R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch and I. Volkmann. We also thank the Brain Bank of University of Barcelona, Hospital Clinic, Clinic for Alzheimer's Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium and the French clinical and genetic research network on FTD/FTD-motor neuron disease (MND). Many grant funding agencies provided financial support for this study, including the US National Institutes of Health (NIH) (grant numbers AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG010133, AG08671, NS044233, NS15655, AG008017, AG13854, AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG16573, AG033101 and NIH Intramural Program). Additional funds were provided by Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, the Pacific Alzheimer's disease Research Foundation (PARF) grant #C06-01, the Alzheimer's Research Trust, Alzheimer's Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte (07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (0060204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputacion Foral de Gipuzkoa (DFG 0876/08), ILUNDAIN Fundazioa, Centro de Investigaciones Biomedicas en Red en Enfermededades Neurodegenerativas (CIBERNED), Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWOV), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.; Z receves a postdoctoral fellowship from the FWOV, the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran's Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05901 to the Arizona Parkinson's Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, Ministerio de Ciencia y Tecnologia, Ref Saud y Farmacia 2001-4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'. NR 29 TC 193 Z9 194 U1 3 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2010 VL 42 IS 3 BP 234 EP U34 DI 10.1038/ng.536 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400012 PM 20154673 ER PT J AU Ellinor, PT Lunetta, KL Glazer, NL Pfeufer, A Alonso, A Chung, MK Sinner, MF de Bakker, PIW Mueller, M Lubitz, SA Fox, E Darbar, D Smith, NL Smith, JD Schnabel, RB Soliman, EZ Rice, KM Van Wagoner, DR Beckmann, BM van Noord, C Wang, K Ehret, GB Rotter, JI Hazen, SL Steinbeck, G Smith, AV Launer, LJ Harris, TB Makino, S Nelis, M Milan, DJ Perz, S Esko, T Kottgen, A Moebus, S Newton-Cheh, C Li, M Moehlenkamp, S Wang, TJ Kao, WHL Vasan, RS Nothen, MM MacRae, CA Stricker, BHC Hofman, A Uitterlinden, AG Levy, D Boerwinkle, E Metspalu, A Topol, EJ Chakravarti, A Gudnason, V Psaty, BM Roden, DM Meitinger, T Wichmann, HE Witteman, JCM Barnard, J Arking, DE Benjamin, EJ Heckbert, SR Kaab, S AF Ellinor, Patrick T. Lunetta, Kathryn L. Glazer, Nicole L. Pfeufer, Arne Alonso, Alvaro Chung, Mina K. Sinner, Moritz F. de Bakker, Paul I. W. Mueller, Martina Lubitz, Steven A. Fox, Ervin Darbar, Dawood Smith, Nicholas L. Smith, Jonathan D. Schnabel, Renate B. Soliman, Elsayed Z. Rice, Kenneth M. Van Wagoner, David R. Beckmann, Britt-M van Noord, Charlotte Wang, Ke Ehret, Georg B. Rotter, Jerome I. Hazen, Stanley L. Steinbeck, Gerhard Smith, Albert V. Launer, Lenore J. Harris, Tamara B. Makino, Seiko Nelis, Mari Milan, David J. Perz, Siegfried Esko, Tonu Koettgen, Anna Moebus, Susanne Newton-Cheh, Christopher Li, Man Moehlenkamp, Stefan Wang, Thomas J. Kao, W. H. Linda Vasan, Ramachandran S. Noethen, Markus M. MacRae, Calum A. Stricker, Bruno H. Ch Hofman, Albert Uitterlinden, Andre G. Levy, Daniel Boerwinkle, Eric Metspalu, Andres Topol, Eric J. Chakravarti, Aravinda Gudnason, Vilmundur Psaty, Bruce M. Roden, Dan M. Meitinger, Thomas Wichmann, H-Erich Witteman, Jacqueline C. M. Barnard, John Arking, Dan E. Benjamin, Emelia J. Heckbert, Susan R. Kaeaeb, Stefan TI Common variants in KCNN3 are associated with lone atrial fibrillation SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CA2+-ACTIVATED K+ CHANNEL; SMALL-CONDUCTANCE; FAMILIAL AGGREGATION; FUNCTIONAL ROLES; CHROMOSOME 4Q25; BLOOD-PRESSURE; HEART-DISEASE; RISK; EXPRESSION AB Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization. C1 [Ellinor, Patrick T.; Lubitz, Steven A.; Makino, Seiko; Milan, David J.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lunetta, Kathryn L.; Wang, Ke] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lunetta, Kathryn L.; Schnabel, Renate B.; Wang, Thomas J.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Glazer, Nicole L.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne; Meitinger, Thomas] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Chung, Mina K.; Van Wagoner, David R.; Hazen, Stanley L.] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Lerner Res Inst, Cleveland, OH 44106 USA. [Sinner, Moritz F.; Mueller, Martina; Beckmann, Britt-M; Steinbeck, Gerhard; Kaeaeb, Stefan] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.; Newton-Cheh, Christopher] Harvard & Massachusetts Inst Technol, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Mueller, Martina; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Mueller, Martina; Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Fox, Ervin] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Darbar, Dawood] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Smith, Nicholas L.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44106 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [van Noord, Charlotte; Stricker, Bruno H. Ch; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [van Noord, Charlotte; Stricker, Bruno H. Ch; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging, Leiden, Netherlands. [Ehret, Georg B.; Chakravarti, Aravinda; Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Nelis, Mari; Esko, Tonu; Metspalu, Andres] Estonian Bioctr, Genotyping Core Facil, Tartu, Estonia. [Nelis, Mari; Esko, Tonu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Koettgen, Anna; Li, Man; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Moebus, Susanne] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Newton-Cheh, Christopher; Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Moehlenkamp, Stefan] Univ Duisburg Essen, W German Heart Ctr Essen, Dept Cardiol, Essen, Germany. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Dept Med, Boston, MA 02118 USA. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Noethen, Markus M.] Life & Brain Ctr Bonn, Dept Genom, Bonn, Germany. [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Stricker, Bruno H. Ch; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Stricker, Bruno H. Ch] Inspectorate Hlth Care, The Hague, Netherlands. [Stricker, Bruno H. Ch] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Topol, Eric J.] Scripps Res Inst, Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth, Res Inst, Seattle, WA USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Barnard, John] Cleveland Clin, Dept Quantitat Hlth Sci, Lerner Res Inst, Cleveland, OH 44106 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Cardiol & Prevent Med Div,Evans Dept Med, Boston, MA 02118 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM pellinor@partners.org; stefan.kaab@med.uni-muenchen.de RI Smith, Albert/K-5150-2015; Darbar, Dawood/C-9079-2015; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Van Wagoner, David/C-6783-2008; Alonso, Alvaro/A-4917-2010; Soliman, Elsayed/D-8124-2011; EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Kaab, Stefan/H-3915-2012; Rice, Kenneth/A-4150-2013; Pfeufer, Arne/B-6634-2013; de Bakker, Paul/B-8730-2009; Schnabel, Renate/F-6527-2014 OI Smith, Albert/0000-0003-1942-5845; Lunetta, Kathryn/0000-0002-9268-810X; Esko, Tonu/0000-0003-1982-6569; Topol, Eric/0000-0002-1478-4729; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Nothen, Markus/0000-0002-8770-2464; Darbar, Dawood/0000-0002-4103-5977; Gudnason, Vilmundur/0000-0001-5696-0084; Van Wagoner, David/0000-0001-8250-9828; Alonso, Alvaro/0000-0002-2225-8323; Soliman, Elsayed/0000-0001-5632-8150; EHRET, Georg/0000-0002-5730-0675; Rice, Kenneth/0000-0001-5779-4495; de Bakker, Paul/0000-0001-7735-7858; FU CCR NIH HHS [RC1 HL101056-01]; NCRR NIH HHS [CTSA 1UL-RR024989, M01 RR000069, M01 RR000069-43, M01RR00069, RR025774, UL1 RR024989, UL1 RR024989-03, UL1 RR025005, UL1 RR025005-01, UL1 RR025005-025914, UL1 RR025774, UL1 RR025774-01, UL1RR025005]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01, U01HG004402]; NHLBI NIH HHS [RC1HL101056, HL076784, N01 HC-55222, N01 HC015103, N01 HC025195, N01 HC035129, N01 HC045133, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01 HC055222, N01 HC075150, N01 HC085079, N01 HC085080, N01 HC085081, N01 HC085082, N01 HC085083, N01 HC085084, N01 HC085085, N01 HC085086, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, N02 HL64278, N02-HL-6-4278, P01 HL 076491, P01 HL076491, P01 HL076491-01, P50 HL077107, P50 HL077107-03, R01 HL059367, R01 HL059367-02, R01 HL068986, R01 HL068986-05A2, R01 HL076784, R01 HL076784-01, R01 HL086694, R01 HL086694-01A1, R01 HL087641, R01 HL087641-01, R01 HL087652, R01 HL087652-01, R01 HL090620, R01 HL090620-01A1, R01 HL092217, R01 HL092217-01A2, R01 HL092577, R01 HL092577-01A1, R01 HL104156, R01HL086694, R01HL087641, R01HL092217, R01HL092577, R01HL59367, RC1 HL101056, RC1 HL101056-01, T32 HL007575, T32 HL007575-25, U01 HL065962, U01 HL065962-01A1, U01 HL065962-09, U01 HL080295, U01 HL080295-01, U01HL65962, U10 HL054512-05, U10HL054512]; NIA NIH HHS [1R01AG028321, N01 AG012100, N01-AG-12100, R01 AG028321, R01 AG028321-01]; NIDA NIH HHS [1R21DA027021, R21 DA026982, R21 DA027021, R21 DA027021-01]; NIDDK NIH HHS [DK063491, P30 DK063491, P30 DK063491-02, P30 DK063491-07, R01 DK033651]; PHS HHS [HHSN268200625226C] NR 33 TC 229 Z9 236 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2010 VL 42 IS 3 BP 240 EP U36 DI 10.1038/ng.537 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400013 PM 20173747 ER PT J AU Mu, JB Myers, RA Jiang, HY Liu, SF Ricklefs, S Waisberg, M Chotivanich, K Wilairatana, P Krudsood, S White, NJ Udomsangpetch, R Cui, LW Ho, M Ou, FZ Li, HB Song, JP Li, GQ Wang, XH Seila, S Sokunthea, S Socheat, D Sturdevant, DE Porcella, SF Fairhurst, RM Wellems, TE Awadalla, P Su, XZ AF Mu, Jianbing Myers, Rachel A. Jiang, Hongying Liu, Shengfa Ricklefs, Stacy Waisberg, Michael Chotivanich, Kesinee Wilairatana, Polrat Krudsood, Srivicha White, Nicholas J. Udomsangpetch, Rachanee Cui, Liwang Ho, May Ou, Fengzhen Li, Haibo Song, Jianping Li, Guoqiao Wang, Xinhua Seila, Suon Sokunthea, Sreng Socheat, Duong Sturdevant, Daniel E. Porcella, Stephen F. Fairhurst, Rick M. Wellems, Thomas E. Awadalla, Philip Su, Xin-zhuan TI Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs SO NATURE GENETICS LA English DT Article ID QUININE RESISTANCE; ARTESUNATE-MEFLOQUINE; POPULATION-STRUCTURE; MALARIA; CHLOROQUINE; MUTATIONS; ASSOCIATION; THAILAND; CAMBODIA; PROTEIN AB Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome(1,2); screening for genes under selection may suggest potential drug or immune targets(3). Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of similar to 1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome. C1 [Mu, Jianbing; Jiang, Hongying; Liu, Shengfa; Fairhurst, Rick M.; Wellems, Thomas E.; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Myers, Rachel A.; Awadalla, Philip] Univ Montreal, Dept Pediat, Fac Med, St Justine Res Ctr, Montreal, PQ H3C 3J7, Canada. [Myers, Rachel A.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Liu, Shengfa] Xiamen Univ, Sch Life Sci, Xiamen, Fujian, Peoples R China. [Ricklefs, Stacy; Sturdevant, Daniel E.; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Res Technol Branch,Rocky Mt Labs,NIH, Hamilton, MT USA. [Waisberg, Michael] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Chotivanich, Kesinee; Wilairatana, Polrat] Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok, Thailand. [Krudsood, Srivicha] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok, Thailand. [White, Nicholas J.] Mahidol Univ, Wellcome Trust Mahidol Univ Oxford Trop Med Res P, Bangkok, Thailand. [Udomsangpetch, Rachanee] Mahidol Univ, Fac Sci, Dept Pathobiol, Bangkok 10400, Thailand. [Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Ho, May] Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB, Canada. [Ou, Fengzhen; Li, Haibo; Song, Jianping; Li, Guoqiao] Res Ctr Qinghao, Guangzhou, Guangdong, Peoples R China. [Wang, Xinhua] Guangzhou Univ Chinese Med, Guangzhou, Guangdong, Peoples R China. [Seila, Suon; Sokunthea, Sreng; Socheat, Duong] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmu@niaid.nih.gov; philip.awadalla@umontreal.ca; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research, NIAID, NIH (USA); Canadian Institute of Health Research [11284, 200183]; US National Academies Keck Genome Initiative; Human Frontiers in Science Program [RGP54/2006]; Wellcome Trust; 973 National Basic Research Program of China [2007CB513103] FX This work was supported by the Division of Intramural Research, NIAID, NIH (USA), funds from the Canadian Institute of Health Research #11284 and #200183, the US National Academies Keck Genome Initiative, and the Human Frontiers in Science Program #RGP54/2006 for P. A. K. C. and N.J.W. are supported by the Wellcome Trust. S. L. was supported by the 973 National Basic Research Program of China, #2007CB513103. We also thank J. Sattabongkot for help in parasite shipping, J. Dunn and L. Zhang for assistance in parasite culture and NIAID intramural editor B. R. Marshall for assistance. NR 31 TC 111 Z9 114 U1 4 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2010 VL 42 IS 3 BP 268 EP U113 DI 10.1038/ng.528 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400019 PM 20101240 ER PT J AU Park, JH Adoro, S Guinter, T Erman, B Alag, AS Catalfamo, M Kimura, MY Cui, YZ Lucas, PJ Gress, RE Kubo, M Hennighausen, L Feigenbaum, L Singer, A AF Park, Jung-Hyun Adoro, Stanley Guinter, Terry Erman, Batu Alag, Amala S. Catalfamo, Marta Kimura, Motoko Y. Cui, Yongzhi Lucas, Philip J. Gress, Ronald E. Kubo, Masato Hennighausen, Lothar Feigenbaum, Lionel Singer, Alfred TI Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells SO NATURE IMMUNOLOGY LA English DT Article ID DOUBLE-POSITIVE THYMOCYTES; TRANSCRIPTION FACTORS; LYMPHOCYTE DEVELOPMENT; NEGATIVE SELECTION; DISTINCT FUNCTIONS; RUNX PROTEINS; COMMITMENT; THPOK; EXPRESSION; IL-7 AB Immature CD4(+) CD8(+) (double-positive (DP)) thymocytes are signaled via T cell antigen receptors (TCRs) to undergo positive selection and become responsive to intrathymic cytokines such as interleukin 7 (IL-7). We report here that cytokine signaling is required for positively selected thymocytes to express the transcription factor Runx3, specify CD8 lineage choice and differentiate into cytotoxic-lineage T cells. In DP thymocytes genetically engineered to be cytokine responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into mature CD8(+) T cells, completely circumventing positive selection. We conclude that TCR-mediated positive selection converts DP cells into cytokine-responsive thymocytes, but it is subsequent signaling by intrathymic cytokines that specifies CD8 lineage choice and promotes differentiation into cytotoxic-lineage T cells. C1 [Park, Jung-Hyun; Adoro, Stanley; Guinter, Terry; Alag, Amala S.; Kimura, Motoko Y.; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Erman, Batu] Sabanci Univ, Biol Sci & Bioengn Program, Fac Engn & Nat Sci, Istanbul, Turkey. [Catalfamo, Marta] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Cui, Yongzhi; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD USA. [Lucas, Philip J.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kubo, Masato] RIKEN, Yokohama Inst, Lab Signal Network, Res Ctr Allergy & Immunol, Kanagawa, Japan. [Feigenbaum, Lionel] NCI, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Kubo, Masato/A-5918-2016 OI Park, Jung Hyun /0000-0002-9547-9055; FU US National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank R. Bosselut, N. El Kassar, R. Hodes, D. Singer and N. Taylor for critical reading of the manuscript; S. Habu (Tokai University) for mouse Runx3 cDNA; A. Weiss (University of California San Francisco) for fluorescein isothiocyanate-conjugated monoclonal antibody to Syk (5F5); J. Ihle (St. Jude Children's Research Hospital) for Socs1+/- Ifng-/- mice; and S. Sharrow, A. Adams and L. Granger for flow cytometry. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute and the Center for Cancer Research. NR 50 TC 117 Z9 118 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2010 VL 11 IS 3 BP 257 EP U10 DI 10.1038/ni.1840 PG 9 WC Immunology SC Immunology GA 556QI UT WOS:000274605800014 PM 20118929 ER PT J AU Santra, S Liao, HX Zhang, RJ Muldoon, M Watson, S Fischer, W Theiler, J Szinger, J Balachandran, H Buzby, A Quinn, D Parks, RJ Tsao, CY Carville, A Mansfield, KG Pavlakis, GN Felber, BK Haynes, BF Korber, BT Letvin, NL AF Santra, Sampa Liao, Hua-Xin Zhang, Ruijin Muldoon, Mark Watson, Sydeaka Fischer, Will Theiler, James Szinger, James Balachandran, Harikrishnan Buzby, Adam Quinn, David Parks, Robert J. Tsao, Chun-Yen Carville, Angela Mansfield, Keith G. Pavlakis, George N. Felber, Barbara K. Haynes, Barton F. Korber, Bette T. Letvin, Norman L. TI Mosaic vaccines elicit CD8(+) T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELL RESPONSES; RHESUS-MONKEYS; AIDS AB An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses(1,2). It must generate CD8(+) T lymphocytes that control HIV replication and CD4(+) T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus(3-5). Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine(6,7). Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates(8). Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8(+) T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8(+) T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes. C1 [Santra, Sampa; Balachandran, Harikrishnan; Buzby, Adam; Quinn, David; Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Liao, Hua-Xin; Zhang, Ruijin; Parks, Robert J.; Tsao, Chun-Yen; Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC USA. [Muldoon, Mark] Univ Manchester, Sch Math, Manchester, Lancs, England. [Watson, Sydeaka; Fischer, Will; Theiler, James; Szinger, James; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Watson, Sydeaka] Baylor Univ, Dept Stat Sci, Waco, TX 76798 USA. [Carville, Angela; Mansfield, Keith G.] New England Reg Primate Res Ctr, Southborough, MA 01772 USA. [Pavlakis, George N.; Felber, Barbara K.] NCI, NIH, Frederick, MD 21701 USA. [Korber, Bette T.] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM nletvin@bidmc.harvard.edu RI Muldoon, Mark/C-7505-2009; Fischer, Will/B-1323-2013; OI Fischer, Will/0000-0003-4579-4062; Korber, Bette/0000-0002-2026-5757 FU US National Institutes of Health [AI-0678501]; HIV Research and Design (HIVRAD) [P01 AI-61734]; National Institute of Allergy and Infectious Diseases [N01 AI-50010]; Los Alamos National Laboratory FX We thank G. Tomaras for generous advice and assistance with reagents and antibody data. We also thank C. Lord for assistance with reagents. This work was supported by US National Institutes of Health grant AI-0678501 (Center for HIV AIDS Vaccine Immunology), HIV Research and Design (HIVRAD) P01 AI-61734, National Institute of Allergy and Infectious Diseases contract N01 AI-50010 and a Los Alamos National Laboratory-directed research grant to B. T. K., W. F. and S. W. NR 18 TC 124 Z9 125 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2010 VL 16 IS 3 BP 324 EP U122 DI 10.1038/nm.2108 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500039 PM 20173754 ER PT J AU Akahata, W Yang, ZY Andersen, H Sun, SY Holdaway, HA Kong, WP Lewis, MG Higgs, S Rossmann, MG Rao, S Nabel, GJ AF Akahata, Wataru Yang, Zhi-Yong Andersen, Hanne Sun, Siyang Holdaway, Heather A. Kong, Wing-Pui Lewis, Mark G. Higgs, Stephen Rossmann, Michael G. Rao, Srinivas Nabel, Gary J. TI A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection SO NATURE MEDICINE LA English DT Article ID IMMUNOGENICITY; GLYCOPROTEIN; ORGANIZATION; EXPRESSION; DISEASE; VECTOR AB Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia(1,2) since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alpha-viruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans. C1 [Akahata, Wataru; Yang, Zhi-Yong; Kong, Wing-Pui; Rao, Srinivas; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sun, Siyang; Holdaway, Heather A.; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Andersen, Hanne; Lewis, Mark G.] Bioqual Inc, Rockville, MD USA. [Higgs, Stephen] Univ Texas Med Branch, Dept Pathol, Galveston, TX USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX We thank K. Nagashima for help with electron microscopy and J. D. Yoder for initiating cryoelectron microscopy reconstruction. We also thank A. Tislerics and J. Stein for help with manuscript preparation, B. Hartman for graphic arts and members of the Nabel lab for helpful discussions. We thank R. Seder and D. D. Pinschewer (Department of Pathology and Immunology, University of Geneva) for their kind gift of Ifnar1-/- mice, A. Ault, J.-P. Todd, A. Zajac, C. Chiedi (Vaccine Research Center) and D. Gordon (Bioqual) for plaque assay and processed animal blood samples, J. Greenhouse for RT-PCR assay, B. W. Finneyfrock, T. Jenkins and A. Dodson for animal sampling and care, K. Foulds, M. Donaldson and M. Roederer for monkey sample procedures and J. Lee for preparing 293F cells for VLP production. This research was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 35 TC 189 Z9 195 U1 1 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2010 VL 16 IS 3 BP 334 EP U134 DI 10.1038/nm.2105 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500041 PM 20111039 ER PT J AU Flatz, L Hegazy, AN Bergthaler, A Verschoor, A Claus, C Fernandez, M Gattinoni, L Johnson, S Kreppel, F Kochanek, S van den Broek, M Radbruch, A Levy, F Lambert, PH Siegrist, CA Restifo, NP Lohning, M Ochsenbein, AF Nabel, GJ Pinschewer, DD AF Flatz, Lukas Hegazy, Ahmed N. Bergthaler, Andreas Verschoor, Admar Claus, Christina Fernandez, Marylise Gattinoni, Luca Johnson, Susan Kreppel, Florian Kochanek, Stefan van den Broek, Maries Radbruch, Andreas Levy, Frederic Lambert, Paul-Henri Siegrist, Claire-Anne Restifo, Nicholas P. Loehning, Max Ochsenbein, Adrian F. Nabel, Gary J. Pinschewer, Daniel D. TI Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity SO NATURE MEDICINE LA English DT Article ID DENDRITIC CELLS; LISTERIA-MONOCYTOGENES; CYTOLYTIC ACTIVITY; ANTIBODIES; MICE; RESPONSES; ADENOVIRUS; IMMUNIZATION; PREVALENCE; PROTECTION AB Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4(+) T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer. C1 [Flatz, Lukas; Bergthaler, Andreas; Fernandez, Marylise; Johnson, Susan; Siegrist, Claire-Anne; Pinschewer, Daniel D.] Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland. [Flatz, Lukas; Hegazy, Ahmed N.; Bergthaler, Andreas; Verschoor, Admar; van den Broek, Maries; Loehning, Max; Pinschewer, Daniel D.] Univ Zurich Hosp, Inst Expt Immunol, CH-8091 Zurich, Switzerland. [Flatz, Lukas; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hegazy, Ahmed N.; Radbruch, Andreas; Loehning, Max] Charite, Dept Rheumatol & Clin Immunol, D-13353 Berlin, Germany. [Hegazy, Ahmed N.; Radbruch, Andreas; Loehning, Max] Deutsch Rheuma Forschungszentrum, Berlin, Germany. [Bergthaler, Andreas] Inst Syst Biol, Seattle, WA USA. [Verschoor, Admar] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, Munich, Germany. [Claus, Christina; Ochsenbein, Adrian F.] Univ Bern, Dept Clin Res, Bern, Switzerland. [Fernandez, Marylise; Johnson, Susan; Lambert, Paul-Henri; Siegrist, Claire-Anne; Pinschewer, Daniel D.] Univ Geneva, World Hlth Org Collaborating Ctr Neonatal Vaccino, Geneva, Switzerland. [Gattinoni, Luca; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kreppel, Florian; Kochanek, Stefan] Univ Ulm, Div Gene Therapy, Ulm, Germany. [van den Broek, Maries] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Levy, Frederic] Ludwig Inst Canc Res, CH-1066 Epalinges, Switzerland. [Siegrist, Claire-Anne] Univ Geneva, Dept Pediat, Geneva, Switzerland. RP Pinschewer, DD (reprint author), Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland. EM lukas.flatz@gmail.com; daniel.pinschewer@gmx.ch RI Gattinoni, Luca/A-2281-2008; Restifo, Nicholas/A-5713-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Bergthaler, Andreas/0000-0003-0597-1976; Restifo, Nicholas P./0000-0003-4229-4580 FU Schweizerische Stiftung fur medizinisch-biologische Stipendien; German Research Foundation [GRAKO1121]; Volkswagen Foundation; Boehringer Ingelheim Fonds; Roche Research Foundation; Swiss National Science Foundation [PP00A-114913, 3100A0-104067/1] FX We thank H. Hengartner and R. Zinkernagel for critical comments, suggestions, discussions and long-term support; E. Horvath for technical assistance; S. A. Rosenberg and J. R. Wunderlich for samples from patients with melanoma; M. Roederer and K. Foulds for reagents and flow cytometry support; A. Oxenius, R. Sprri and N. Joller for providing access to their flow cytometry facility; A. Pegu, R. Roychoudhuri and C. Cheng for discussions and advice on human DC cultures; D. von Laer (Georg-Speyer-Haus) for plasmid M369 and GP-expressing 293T cells; H. Shen (University of Pennsylvania School of Medicine) for rLM-OVA; M. Groettrup (University of Constance) for VACC-OVA, originally generated by J. Yewdell (National Institute of Allergy and Infectious Diseases); and R. Schirmbeck (University of Ulm) for StT-OVA-G cDNA. L. F. was supported by a fellowship of the Schweizerische Stiftung fur medizinisch-biologische Stipendien. A. N. H. is a fellow of GRAKO1121 of the German Research Foundation. M. L. is a Lichtenberg fellow funded by the Volkswagen Foundation. A. B. was supported by a PhD scholarship of the Boehringer Ingelheim Fonds and by a post-doctoral fellowship of the Roche Research Foundation. D. D. P. holds a stipendiary professorship of the Swiss National Science Foundation (PP00A-114913) and was supported by grant 3100A0-104067/1 of the Swiss National Science Foundation. NR 40 TC 58 Z9 58 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2010 VL 16 IS 3 BP 339 EP U142 DI 10.1038/nm.2104 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500042 PM 20139992 ER PT J AU Ji, YY Lu, Y Yang, F Shen, WH Tang, TTT Feng, LY Duan, SM Lu, B AF Ji, Yuanyuan Lu, Yuan Yang, Feng Shen, Wanhua Tang, Tina Tze-Tsang Feng, Linyin Duan, Shumin Lu, Bai TI Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons SO NATURE NEUROSCIENCE LA English DT Article ID NERVE GROWTH-FACTOR; HIGH-FREQUENCY STIMULATION; NEUROTROPHIC FACTOR BDNF; LONG-TERM POTENTIATION; SYNAPTIC-TRANSMISSION; HIPPOCAMPAL-NEURONS; DIFFERENTIAL REGULATION; KINASE ACTIVATION; ADULT HIPPOCAMPUS; PC12 CELLS AB Extracellular factors may act on cells in two distinct modes: an acute increase in concentration as a result of regulated secretion, or a gradual increase in concentration when secreted constitutively or from a distant source. We found that cellular responses to brain-derived neurotrophic factor ( BDNF) differed markedly depending on how BDNF was delivered. In cultured rat hippocampal neurons, acute and gradual increases in BDNF elicited transient and sustained activation of TrkB receptor and its downstream signaling, respectively, leading to differential expression of Homer1 and Arc. Transient TrkB activation promoted neurite elongation and spine head enlargement, whereas sustained TrkB activation facilitated neurite branch and spine neck elongation. In hippocampal slices, fast and slow increases in BDNF enhanced basal synaptic transmission and LTP, respectively. Thus, the kinetics of TrkB activation is critical for cell signaling and functions. This temporal dimension in cellular signaling may also have implications for the therapeutic drug design. C1 [Ji, Yuanyuan; Lu, Yuan; Yang, Feng; Lu, Bai] NIMH, Gene Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Ji, Yuanyuan; Shen, Wanhua; Feng, Linyin; Duan, Shumin] Chinese Acad Sci, Inst Neurosci, Shanghai, Peoples R China. [Tang, Tina Tze-Tsang] Natl Inst Neurol Disorders & Stroke, Receptor Biol Unit, Bethesda, MD USA. [Tang, Tina Tze-Tsang] Univ Bristol, Sch Med Sci, Dept Anat, MRC,Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. [Ji, Yuanyuan; Lu, Yuan; Yang, Feng; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. RP Lu, B (reprint author), GlaxoSmithKline Inc, R&D China, Shanghai, Peoples R China. EM bai.b.lu@gsk.com RI Yang, Feng/C-9530-2011; Shen, Wanhua/B-5554-2011; Lu, Bai/A-4018-2012 OI Shen, Wanhua/0000-0002-5178-9561; FU National Institute on Child Health and Human Development; National Institute of Mental Health FX We thank the National Cancer Institute, Center for Cancer Research Fellows Editorial Board and G. Nagappan for the thoughtful comments and suggestions. We thank W. H. Wilson for his innovative research in cancer therapy that helped us conceive this work. This work was supported by the Intramural Research Programs of the National Institute on Child Health and Human Development and the National Institute of Mental Health. NR 37 TC 137 Z9 147 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2010 VL 13 IS 3 BP 302 EP U7 DI 10.1038/nn.2505 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 559WW UT WOS:000274860100011 PM 20173744 ER PT J AU Suh, YH Terashima, A Petralia, RS Wenthold, RJ Isaac, JTR Roche, KW Roche, PA AF Suh, Young Ho Terashima, Akira Petralia, Ronald S. Wenthold, Robert J. Isaac, John T. R. Roche, Katherine W. Roche, Paul A. TI A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking SO NATURE NEUROSCIENCE LA English DT Article ID SYNAPTOSOMAL-ASSOCIATED PROTEIN; MEMBRANE-FUSION; NMDA RECEPTORS; SYNAPTIC PLASTICITY; MAST-CELLS; EXOCYTOSIS; AMPA; INTERNALIZATION; MECHANISMS; COMPLEX AB Regulated exocytosis is essential for many biological processes and many components of the protein trafficking machinery are ubiquitous. However, there are also exceptions, such as SNAP-25, a neuron-specific SNARE protein that is essential for synaptic vesicle release from presynaptic nerve terminals. In contrast, SNAP-23 is a ubiquitously expressed SNAP-25 homolog that is critical for regulated exocytosis in non-neuronal cells. However, the role of SNAP-23 in neurons has not been elucidated. We found that SNAP-23 was enriched in dendritic spines and colocalized with constituents of the postsynaptic density, whereas SNAP-25 was restricted to axons. In addition, loss of SNAP-23 using genetically altered mice or shRNA targeted to SNAP-23 led to a marked decrease in NMDA receptor surface expression and NMDA receptor currents, whereas loss of SNAP-25 did not. SNAP-23 is therefore important for the functional regulation of postsynaptic glutamate receptors. C1 [Suh, Young Ho; Roche, Katherine W.] Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, Bethesda, MD 20824 USA. [Suh, Young Ho; Roche, Paul A.] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Terashima, Akira; Isaac, John T. R.] Natl Inst Neurol Disorders & Stroke, Dev Synapt Plast Sect, Bethesda, MD USA. [Petralia, Ronald S.; Wenthold, Robert J.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Roche, KW (reprint author), Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, Bethesda, MD 20824 USA. EM rochek@ninds.nih.gov; paul.roche@nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU National Cancer Institute Intramural Research Program; National Institute of Neurological Disorders and Stroke Intramural Research Program; Integrative Neural Immune Program; National Institute on Deafness and other Communication Disorders FX We thank Y.-X. Wang for help with immunogold labeling, J.D. Badger II for preparing primary neuron cultures and M. Park ( Stanford University) for helpful technical comments. We also thank the National Institute of Neurological Disorders and Stroke Light Imaging Facility, particularly C. Smith. In addition, we would like to acknowledge the National Institute of Neurological Disorders and Stroke sequencing facility. This research was supported by the National Cancer Institute Intramural Research Program (P. A. R.), the National Institute of Neurological Disorders and Stroke Intramural Research Program (Y.H.S. and K. W. R.), the Integrative Neural Immune Program (Y.H.S. fellowship), and the intramural program of the National Institute on Deafness and other Communication Disorders (R. S. P. and R.J.W.). NR 48 TC 54 Z9 54 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2010 VL 13 IS 3 BP 338 EP U16 DI 10.1038/nn.2488 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 559WW UT WOS:000274860100016 PM 20118925 ER PT J AU Imamura, CK Takebe, N Nakamura, S Saya, H Ueno, NT AF Imamura, Chiyo K. Takebe, Naoko Nakamura, Seigo Saya, Hideyuki Ueno, Naoto T. TI EXPERIMENTAL THERAPIES Investigator-initiated cancer trials with INDs for approval in Japan SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material C1 [Ueno, Naoto T.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Imamura, Chiyo K.] Keio Univ, Dept Clin Pharmacokinet & Pharmacodynam, Sch Med, Shinjuku Ku, Tokyo 1608582, Japan. [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD 20852 USA. [Nakamura, Seigo] St Lukes Int Hosp, Dept Breast Surg Oncol, Chuo Ku, Tokyo 1048560, Japan. [Saya, Hideyuki] Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan. RP Ueno, NT (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Holcombe Blvd,Unit 1354, Houston, TX 77030 USA. EM nueno@mdanderson.org RI Saya, Hideyuki/J-4325-2013 NR 6 TC 3 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2010 VL 7 IS 3 BP 127 EP 128 DI 10.1038/nrclinonc.2010.13 PG 2 WC Oncology SC Oncology GA 562LX UT WOS:000275053500003 PM 20190792 ER PT J AU Barry, CE Boshoff, HI Dartois, V Dick, T Ehrt, S Flynn, J Schnappinger, D Wilkinson, RJ Young, D AF Barry, Clifton E., III Boshoff, Helena I. Dartois, Veronique Dick, Thomas Ehrt, Sabine Flynn, JoAnne Schnappinger, Dirk Wilkinson, Robert J. Young, Douglas TI Spectrum of latent tuberculosis - existing tests cannot resolve the underlying phenotypes Reply SO NATURE REVIEWS MICROBIOLOGY LA English DT Letter C1 [Wilkinson, Robert J.; Young, Douglas] Natl Inst Med Res, MRC, Div Mycobacterial Res, London NW7 1AA, England. [Wilkinson, Robert J.; Young, Douglas] Univ London Imperial Coll Sci Technol & Med, Ctr Mol Microbiol & Infect, London SW7 2AZ, England. [Wilkinson, Robert J.; Young, Douglas] Univ London Imperial Coll Sci Technol & Med, Div Med, London SW7 2AZ, England. [Wilkinson, Robert J.] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Observatory, South Africa. [Flynn, JoAnne] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. [Ehrt, Sabine; Schnappinger, Dirk] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Dartois, Veronique; Dick, Thomas] Novartis Inst Trop Dis, Singapore 138670, Singapore. [Barry, Clifton E., III; Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Young, D (reprint author), Natl Inst Med Res, MRC, Div Mycobacterial Res, Mill Hill, London NW7 1AA, England. EM d.young@imperial.ac.uk RI Barry, III, Clifton/H-3839-2012 NR 2 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD MAR PY 2010 VL 8 IS 3 DI 10.1038/nrmicro2236-c2 PG 1 WC Microbiology SC Microbiology GA 556CM UT WOS:000274565400016 ER PT J AU Scher, AI Launer, LJ AF Scher, Ann I. Launer, Lenore J. TI MIGRAINE Migraine with aura increases the risk of stroke SO NATURE REVIEWS NEUROLOGY LA English DT Editorial Material ID CARDIOVASCULAR-DISEASE; WOMEN AB Migraine-in particular, migraine with aura-seems to confer an increased risk of ischemic stroke and might also be linked with other cardiovascular events. Findings from a new meta-analysis support the former association; however, insufficient data exist to conclude whether this type of headache increases the risk of nonstroke cardiovascular disease. C1 [Scher, Ann I.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Scher, AI (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ascher@usuhs.mil FU Intramural NIH HHS [ZIA AG007260-04] NR 9 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD MAR PY 2010 VL 6 IS 3 BP 128 EP 129 DI 10.1038/nrneurol.2010.14 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 565KE UT WOS:000275290200003 PM 20212428 ER PT J AU Kim, HW Rapoport, SI Rao, JS AF Kim, Hyung-Wook Rapoport, Stanley I. Rao, Jagadeesh S. TI Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Bipolar disorder; Apoptosis; Caspase; BDNF; Synaptophysin; Drebrin ID CYTOSOLIC PHOSPHOLIPASE A(2); RAT FRONTAL-CORTEX; POSITRON-EMISSION-TOMOGRAPHY; ARACHIDONIC-ACID CASCADE; MOOD STABILIZERS; ADMINISTRATION INCREASES; ALZHEIMERS-DISEASE; BINDING PROTEIN; GENE-EXPRESSION; LITHIUM AB Bipolar disorder (BD) is a progressive psychiatric disorder characterized by recurrent changes of mood and is associated with cognitive decline. There is evidence of excitotoxicity, neuroinflammation, upregulated arachidonic acid (AA) cascade signaling and brain atrophy in BD patients. These observations suggest that BD pathology may be associated with apoptosis as well as with disturbed synaptic function. To test this hypothesis, we measured mRNA and protein levels of the pro-apoptotic (Bax, BAD, caspase-9 and caspase-3) and anti-apoptotic factors (BDNF and Bcl-2) and of pre- and post-synaptic markers (synaptophysin and drebrin), in postmortem prefrontal cortex (Brodmann area 9) from 10 BD patients and 10 age-matched controls. Consistent with the hypothesis, BID brains showed significant increases in protein and mRNA levels of the pro-apoptotic factors and significant decreases of levels of the anti-apoptotic factors and the synaptic markers, synaptophysin and drebrin. These differences may contribute to brain atrophy and progressive cognitive changes in BD. (C) Published by Elsevier Inc. C1 [Kim, Hyung-Wook; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov FU Harvard Brain Bank, Boston, MA [R24MH068855]; Intramural Research Programs of the National Institute on Aging; National Institute of Environmental Health Sciences, National Institutes of Health Bethesda, MD 20892 FX We thank the Harvard Brain Bank, Boston, MA, for providing the postmortem brain samples under PHS grant R24MH068855. This research was entirely supported by the Intramural Research Programs of the National Institute on Aging and the National Institute of Environmental Health Sciences, National Institutes of Health Bethesda, MD 20892. We thank the NIH Fellows Editorial Board and Dr. Eugene Streicher for proofreading the manuscripts. NR 59 TC 86 Z9 92 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2010 VL 37 IS 3 SI SI BP 596 EP 603 DI 10.1016/j.nbd.2009.11.010 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 560PH UT WOS:000274914100012 PM 19945534 ER PT J AU Lu, HB Demny, S Zuo, YT Rea, W Wang, LM Chefer, SI Vaupel, DB Yang, YH Stein, EA AF Lu, Hanbing Demny, Steven Zuo, Yantao Rea, William Wang, Leiming Chefer, Svetlana I. Vaupel, D. Bruce Yang, Yihong Stein, Elliot A. TI Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: A novel method for dynamic manganese-enhanced MRI SO NEUROIMAGE LA English DT Article DE Blood-brain barrier; Manganese-enhanced MRI; Endothelial barrier antigen; Mannitol; Manganese ID RESONANCE-IMAGING MEMRI; IN-VIVO; ACTIVATION; PROTEIN; MICE; PATHWAY; ANTIGEN AB Manganese (Mn(2+)) has limited permeability through the blood-brain barrier (BBB). Opening the BBB such that a sufficient amount of Mn(2+) enters the extracellular space is a critical step for dynamic manganese-enhanced magnetic resonance imaging (ME-MRI) experiments. The traditional BBB opening method uses intracarotid hyperosmolar stress which results in suboptimal BBB opening, and practically is limited to nonsurvival experiments due to substantial surgical trauma. In the present ME-MRI study, we investigate the feasibility of opening the BBB with an antibody that targets the endothelial barrier antigen (EBA) specifically expressed by rat endothelial cells. Results demonstrate that intravenous infusion of the anti-EBA agent SMI-71 leads to BBB disruption of the whole brain as detected by ME-MRI and confirmed by Evans blue dye staining. Physiologically, injection of SMI-71 leads to a hypertensive response followed by a sustained hypotensive response in animals anesthetized with urethane alone. Incorporating isoflurane partially mitigated both pressor responses. In general, BBB disruption via intravenous infusion of SMI-71 is straightforward and obviates technical difficulties associated with intracarotid hyperosmolar stress, opening new possibilities for in vivo neuroimaging with ME-MRI. The data also suggest that ME-MRI may be used as an imaging method to assess BBB integrity complementary to the Evans blue dye method, a classical but highly invasive technique, permitting longitudinal assessment of the integrity of the BBB on the same animal. Published by Elsevier Inc. C1 [Lu, Hanbing; Demny, Steven; Zuo, Yantao; Rea, William; Wang, Leiming; Chefer, Svetlana I.; Vaupel, D. Bruce; Yang, Yihong; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Stein, EA (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,Rm 7A711, Baltimore, MD 21224 USA. EM estein@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX We would like to thank Michael A. Eckhaus, V.M.D, chief of Pathology Service at the Division of Veterinary Resources, ORS, OD, National Institutes of Health for performing pathological examinations; we would also like to thank Drs. Marisela Morales and Hui Shen for technical support in histological preparation and Thomas J. Ross for discussions on statistical analysis. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 30 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 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2010 VL 50 IS 1 BP 7 EP 14 DI 10.1016/j.neuroimage.2009.12.053 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 559GC UT WOS:000274810100002 PM 20026228 ER PT J AU Munoz, KE Meyer-Lindenberg, A Hariri, AR Mervis, CB Mattay, VS Morris, CA Berman, KF AF Munoz, Karen E. Meyer-Lindenberg, Andreas Hariri, Ahmad R. Mervis, Carolyn B. Mattay, Venkata S. Morris, Colleen A. Berman, Karen Faith TI Abnormalities in neural processing of emotional stimuli in Williams syndrome vary according to social vs. non-social content SO NEUROIMAGE LA English DT Article ID MATERIAL-SPECIFIC LATERALIZATION; SUPRAVALVULAR AORTIC STENOSIS; NEONATAL AMYGDALA LESIONS; PERSONALITY-CHARACTERISTICS; COGNITIVE NEUROSCIENCE; GENETIC INFLUENCES; BEHAVIOR; LANGUAGE; PHENOTYPE; BRAIN AB Williams syndrome (WS) is a rare genetic disorder caused by the deletion of similar to 25 genes on chromosome 7q11.23 and is characterized by both hypersociability and increases in specific phobia and anticipatory anxiety regarding non-social entities or circumstances. Alterations in amygdala reactivity and prefrontal regulation consistent with the observed behavioral pattern of social versus non-social abnormalities have been previously demonstrated in individuals with WS ( Meyer-Lindenberg et al., 2005). However, in that study, the social stimulus (faces) matching task was more difficult than the non-social scene (IAPS stimuli) matching task, making it impossible to disambiguate the relative contributions of task difficulty and stimulus type (social versus non-social). In the present study, we examined the performance of the same group of participants with WS and normal IQs during a more cognitively demanding task using the same scene stimuli as in the prior study. Confirming previous findings, the results indicated (a) a differential response of prefrontal regions as a function of task difficulty and (b) a persistently increased activation of the amygdala to non-social scenes by individuals with WS regardless of cognitive load. These data provide further evidence of disruption in amygdala-prefrontal circuitry in individuals with WS. (C) 2009 Published by Elsevier Inc. C1 [Munoz, Karen E.; Meyer-Lindenberg, Andreas; Berman, Karen Faith] NIMH, Sect Integrat Neuroimaging, NIH, DHHS, Bethesda, MD 20892 USA. [Munoz, Karen E.; Meyer-Lindenberg, Andreas; Hariri, Ahmad R.; Mattay, Venkata S.; Berman, Karen Faith] NIMH, Genes Cognit & Psychosis Program, NIH, DHHS, Bethesda, MD 20892 USA. [Mervis, Carolyn B.] Univ Louisville, Neurodev Sci Lab, Dept Psychol & Brain Sci, Louisville, KY 40292 USA. [Morris, Colleen A.] Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89102 USA. RP Berman, KF (reprint author), 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov RI Hariri, Ahmad/D-5761-2011; Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU DHHS/NIH/NIMH/IRP; NINDS [NS35102]; Multimodal Neuroimaging Training Program [1T90DA022761]; National Institute of Mental Health [MH072837]; National Alliance for Research on Schizophrenia and Depression; Bundesministerium fur Bildung und Forschung (Nationales Genomforschungsnetz plus MooDs); Deutsche Forschungsgemeinschaft [SFB 636-B7]; NARSAD FX We thank Neha Dixit, Aaron-Bonner Jackson, Rosanna Olsen, John Holt, and Yunxia Tong for research assistance and Daniel Weinberger for helpful discussion of this manuscript. This work was supported by DHHS/NIH/NIMH/IRP and NINDS grant no NS35102 (C.B.M., principal investigator). K.E.M. is supported by the Multimodal Neuroimaging Training Program Fellowship: 1T90DA022761. A.R.H is supported by the National Institute of Mental Health: MH072837 and the National Alliance for Research on Schizophrenia and Depression. A.M.L. acknowledges support during the preparation of the manuscript by Bundesministerium fur Bildung und Forschung (Nationales Genomforschungsnetz plus MooDs), Deutsche Forschungsgemeinschaft (SFB 636-B7) and NARSAD (2009 Distinguished Investigator Award). NR 60 TC 23 Z9 24 U1 1 U2 11 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 MAR PY 2010 VL 50 IS 1 BP 340 EP 346 DI 10.1016/j.neuroimage.2009.11.069 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 559GC UT WOS:000274810100035 PM 20004252 ER PT J AU Lucas, BC Bogovic, JA Carass, A Bazin, PL Prince, JL Pham, DL Landman, BA AF Lucas, Blake C. Bogovic, John A. Carass, Aaron Bazin, Pierre-Louis Prince, Jerry L. Pham, Dzung L. Landman, Bennett A. TI The Java Image Science Toolkit (JIST) for Rapid Prototyping and Publishing of Neuroimaging Software SO NEUROINFORMATICS LA English DT Article DE Parallel processing; Pipeline; Rapid prototyping; Image processing; MRI ID IMPLICIT SURFACE EVOLUTION; ENVIRONMENT; DESIGN; MRI AB Non-invasive neuroimaging techniques enable extraordinarily sensitive and specific in vivo study of the structure, functional response and connectivity of biological mechanisms. With these advanced methods comes a heavy reliance on computer-based processing, analysis and interpretation. While the neuroimaging community has produced many excellent academic and commercial tool packages, new tools are often required to interpret new modalities and paradigms. Developing custom tools and ensuring interoperability with existing tools is a significant hurdle. To address these limitations, we present a new framework for algorithm development that implicitly ensures tool interoperability, generates graphical user interfaces, provides advanced batch processing tools, and, most importantly, requires minimal additional programming or computational overhead. Java-based rapid prototyping with this system is an efficient and practical approach to evaluate new algorithms since the proposed system ensures that rapidly constructed prototypes are actually fully-functional processing modules with support for multiple GUI's, a broad range of file formats, and distributed computation. Herein, we demonstrate MRI image processing with the proposed system for cortical surface extraction in large cross-sectional cohorts, provide a system for fully automated diffusion tensor image analysis, and illustrate how the system can be used as a simulation framework for the development of a new image analysis method. The system is released as open source under the Lesser GNU Public License (LGPL) through the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC). C1 [Prince, Jerry L.; Landman, Bennett A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Lucas, Blake C.; Bogovic, John A.; Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Lucas, Blake C.] NIA, NIH, Baltimore, MD 21224 USA. [Bazin, Pierre-Louis; Prince, Jerry L.; Pham, Dzung L.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Landman, Bennett A.] Vanderbilt Univ, Dept Elect Engn, Nashville, TN 37235 USA. [Landman, Bennett A.] Vanderbilt Univ, Dept Radiol & Radiol Sci, Nashville, TN 37235 USA. RP Landman, BA (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. EM bennett.landman@vanderbilt.edu RI Prince, Jerry/A-3281-2010; OI Prince, Jerry/0000-0002-6553-0876; Bazin, Pierre-Louis/0000-0002-0141-5510; Carass, Aaron/0000-0003-4939-5085 FU NIH/NINDS [5R01NS037747, 1R01NS056307]; NIH/NIA [N01-AG-4-0012]; NINDS [5R01NS054255] FX We greatly appreciate the unwavering support of Matt McAuliffe and Evan McCreedy of the NIH Center for Information Technology and the dedication of our undergraduate interns (Yufeng Guo, Robert Kim, Meenal Patel, Heba Mustufa, Hanlin Wan, and Jie Zhang). This work was supported by NIH/NINDS 5R01NS037747, 1R01NS056307, NIH/NIA N01-AG-4-0012 and NINDS 5R01NS054255. NR 29 TC 67 Z9 67 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD MAR PY 2010 VL 8 IS 1 BP 5 EP 17 DI 10.1007/s12021-009-9061-2 PG 13 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 579CJ UT WOS:000276344300002 PM 20077162 ER PT J AU Chow, VW Mattson, MP Wong, PC Gleichmann, M AF Chow, Vivian W. Mattson, Mark P. Wong, Philip C. Gleichmann, Marc TI An Overview of APP Processing Enzymes and Products SO NEUROMOLECULAR MEDICINE LA English DT Review DE Amyloid beta; alpha-secretase; beta-secretase; gamma-secretase; APP; AICD ID AMYLOID-PRECURSOR-PROTEIN; ALZHEIMERS-DISEASE THERAPEUTICS; BETA-SECRETASE CLEAVAGE; CELLULAR PRION PROTEIN; TRANS-GOLGI NETWORK; NEURAL STEM-CELLS; ALPHA-SECRETASE; GAMMA-SECRETASE; A-BETA; CATHEPSIN-B AB The generation of amyloid beta-peptide (A beta) by enzymatic cleavages of the beta-amyloid precursor protein (APP) has been at the center of Alzheimer's disease (AD) research. While the basic process of beta- and gamma-secretase-mediated generation of Ab is text book knowledge, new aspects of Ab and other cleavage products have emerged in recent years. Also our understanding of the enzymes involved in APP proteolysis has increased dramatically. All of these discoveries contribute to a more complete understanding of APP processing and the physiologic and pathologic roles of its secreted and intracellular protein products. Understanding APP processing is important for any therapeutic strategy aimed at reducing Ab levels in AD. In this review, we provide a concise description of the current state of understanding the enzymes involved in APP processing, the cleavage products generated by different processing patterns, and the potential functions of those cleavage products. C1 [Mattson, Mark P.; Gleichmann, Marc] NIA, Neurosci Lab, Baltimore, MD 21224 USA. [Chow, Vivian W.; Wong, Philip C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. RP Gleichmann, M (reprint author), NIA, Neurosci Lab, 5th Floor Suite 100 BRC,251 Bayview Blvd, Baltimore, MD 21224 USA. EM gleichmannma@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU NIH, National Institute on Aging FX This study was in part supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 113 TC 113 Z9 118 U1 2 U2 21 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2010 VL 12 IS 1 SI SI BP 1 EP 12 DI 10.1007/s12017-009-8104-z PG 12 WC Neurosciences SC Neurosciences & Neurology GA 572IB UT WOS:000275821100001 PM 20232515 ER PT J AU Gleichmann, M Mattson, MP AF Gleichmann, Marc Mattson, Mark P. TI Alzheimer's Disease and Neuronal Network Activity SO NEUROMOLECULAR MEDICINE LA English DT Review DE Alzheimer's Disease; Amyloid beta; Presenilin; Neurofibrillary tangles; Seizures; Neuronal networks ID AMYLOID-PRECURSOR PROTEIN; TRIPLE-TRANSGENIC MODEL; A-BETA; NEURODEGENERATIVE DISEASES; CALCIUM HOMEOSTASIS; SYNAPTIC PLASTICITY; CORTICAL-NEURONS; LINKED MUTATIONS; TAU PATHOLOGY; MOUSE MODEL AB The amyloid beta-peptide theory of Alzheimer's Disease has helped to advance our understanding of the disease tremendously. A new area of research focuses on the changes in neuronal network activity that take place and may contribute to the clinical and pathological picture of Alzheimer's Disease. An apparent symptom of altered neuronal network activity in Alzheimer's Disease is an increased frequency in epileptic seizures that is observed both in human patients and in mouse models of Alzheimer's Disease. A root cause for altered network activity may be amyloid beta itself by its ability to alter synaptic (glutamatergic) transmission and to impair the induction of long-term potentiation. It is on this aspect of Alzheimer's Disease research that the current issue of NeuroMolecular Medicine will focus. Reviews will discuss the basic research and clinical aspects of the issue such as the effects of amyloid b on synaptic transmission and neuronal networks, as well as the changes in functional MRI activation patterns observed in early stages of Alzheimer's Disease and the frequency and relevance of epileptic seizures in Alzheimer's Disease patients. C1 [Gleichmann, Marc; Mattson, Mark P.] NIA, Neurosci Lab, BRC, Baltimore, MD 21224 USA. RP Gleichmann, M (reprint author), NIA, Neurosci Lab, BRC, 5th Floor,Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM gleichmannma@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU NIH, National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 14 Z9 14 U1 0 U2 18 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2010 VL 12 IS 1 SI SI BP 44 EP 47 DI 10.1007/s12017-009-8100-3 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 572IB UT WOS:000275821100004 PM 19885650 ER PT J AU Rothman, SM Mattson, MP AF Rothman, Sarah M. Mattson, Mark P. TI Adverse Stress, Hippocampal Networks, and Alzheimer's Disease SO NEUROMOLECULAR MEDICINE LA English DT Review DE Alzheimer's disease; Chronic stress; Glucocorticoids; Hippocampal plasticity ID MILD COGNITIVE IMPAIRMENT; AMYLOID-BETA-PEPTIDE; CHRONIC PSYCHOSOCIAL STRESS; TRANSGENIC MOUSE MODEL; LONG-TERM POTENTIATION; PITUITARY-ADRENOCORTICAL AXIS; MEMBRANE-LIPID PEROXIDATION; CA3 PYRAMIDAL NEURONS; NEUROTROPHIC-FACTOR; SLEEP-DEPRIVATION AB Recent clinical data have implicated chronic adverse stress as a potential risk factor in the development of Alzheimer's disease (AD) and data also suggest that normal, physiological stress responses may be impaired in AD. It is possible that pathology associated with AD causes aberrant responses to chronic stress, due to potential alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Recent study in rodent models of AD suggests that chronic adverse stress exacerbates the cognitive deficits and hippocampal pathology that are present in the AD brain. This review summarizes recent findings obtained in experimental AD models regarding the influence of chronic adverse stress on the underlying cellular and molecular disease processes including the potential role of glucocorticoids. Emerging findings suggest that both AD and chronic adverse stress affect hippocampal neural networks in a similar fashion. We describe alterations in hippocampal plasticity, which occur in both chronic stress and AD including dendritic remodeling, neurogenesis, and long-term potentiation. Finally, we outline potential roles for oxidative stress and neurotrophic factor signaling as the key determinants of the impact of chronic stress on the plasticity of neural networks and AD pathogenesis. C1 [Rothman, Sarah M.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Rothman, SM (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM sarah.rothman@nih.gov RI Mattson, Mark/F-6038-2012 FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 177 TC 81 Z9 82 U1 4 U2 12 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2010 VL 12 IS 1 SI SI BP 56 EP 70 DI 10.1007/s12017-009-8107-9 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 572IB UT WOS:000275821100006 PM 19943124 ER PT J AU Sarkozy, A McKenna, C Straub, V Lochmuller, H Goldfarb, LG Bushby, K AF Sarkozy, A. McKenna, C. Straub, V. Lochmuller, H. Goldfarb, L. G. Bushby, K. TI Recurrent BAG3 gene mutation in a British family with two siblings with severe myofibrillar myopathy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT United Kingdom Neuromuscular Translational Research Conference 2010 CY MAR 25-26, 2010 CL Oxford, ENGLAND SP London Newcastle MRC Ctr Neuromuscular Dis, Muscular Dystrophy Campaign, Genzyme C1 [Sarkozy, A.; McKenna, C.; Straub, V.; Lochmuller, H.; Bushby, K.] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Goldfarb, L. G.] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Bethesda, MD USA. 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 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD MAR PY 2010 VL 20 SU 1 BP S28 EP S28 DI 10.1016/S0960-8966(10)70100-0 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 584NL UT WOS:000276759200100 ER PT J AU Mori, T Ito, S Kuwaki, T Yanagisawa, M Sakurai, T Sawaguchi, T AF Mori, Tomohisa Ito, Shinobu Kuwaki, Tomoyuki Yanagisawa, Masashi Sakurai, Takeshi Sawaguchi, Toshiko TI Monoaminergic neuronal changes in orexin deficient mice SO NEUROPHARMACOLOGY LA English DT Article DE Orexin; Orexin knockout mice; Orexin/ataxin-3 mice; Dopamine; Serotonin; Narcolepsy ID VENTRAL TEGMENTAL AREA; LOCOMOTOR-ACTIVITY; HUMAN NARCOLEPSY; DOPAMINERGIC SYSTEM; SEROTONIN; RECEPTORS; INVOLVEMENT; ENVIRONMENT; PEPTIDES; MORPHINE AB Orexin knockout (KO) mice and orexin/ataxin-3 mice (which have a different pathophysiological background in orexin deficiency) exhibit a phenotype that is similar to human narcolepsy. Although the interactions between the monoaminergic and orexinergic systems are not entirely clear, indirect monoamine-receptor agonists (especially psychostimulants) may contribute to the treatment of narcolepsy. The present study was designed to investigate the interaction between brain orexinergic and monoaminergic neurons as measured by the status of monoaminergic systems and monoamine-related behaviors using orexin-deficient mice. Previous studies have shown that a reduction of monoaminergic tone is related to wakefulness. In the present study, locomotor activity in a novel environment and dopamine turnover was significantly decreased in orexin-deficient mice compared to WT mice, which suggests that psychostimulants may be useful for maintaining wakefulness in orexin deficiency. We also examined the effects of orexin deficiency on psychostimulant-induced hyperlocomotion. The hyperlocomotion induced by methamphetamine and methylphenidate was lower, whereas that induced by MDMA was higher in orexin KO mice compared to WT mice. The sensitivities against psychostimulants in orexin/ataxin-3 mice differed from those in orexin KO mice. These results indicate that the effectiveness of each psychostimulant, which is closely related to its monoaminergic function, was influenced by orexin deficiency itself as well as by the different pathophysiological background in orexin deficiency. (C) 2009 Published by Elsevier Ltd. C1 [Sawaguchi, Toshiko] Fukuoka Jo Gakuin Univ, Early Childhood Dev Dept, Fac Human Relat, Minami Ku, Fukuoka 8111313, Japan. [Mori, Tomohisa] NIDA, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Ito, Shinobu] Tokyo Womens Med Univ, Inst Adv Biomed Engn & Sci, Shinjuku Ku, Tokyo 1628666, Japan. [Kuwaki, Tomoyuki] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Physiol, Kagoshima 8908544, Japan. [Yanagisawa, Masashi] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Sakurai, Takeshi] Kanazawa Univ, Fac Med, Dept Mol Neurosci & Integrat Physiol, Kanazawa, Ishikawa 9208640, Japan. RP Sawaguchi, T (reprint author), Fukuoka Jo Gakuin Univ, Early Childhood Dev Dept, Fac Human Relat, Minami Ku, 3-42-1 Hisa, Fukuoka 8111313, Japan. EM tsawagu@gmail.com OI ITO, SHINOBU/0000-0003-1108-1371 NR 31 TC 15 Z9 15 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD MAR-APR PY 2010 VL 58 IS 4-5 BP 826 EP 832 DI 10.1016/j.neuropharm.2009.08.009 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 568TA UT WOS:000275544500017 PM 19703479 ER PT J AU Farrell, M Roth, BL AF Farrell, Martilias Roth, Bryan L. TI Allosteric Antipsychotics: M4 Muscarinic Potentiators as Novel Treatments for Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID RECEPTOR AGONIST; DRUGS; MICE; XANOMELINE; SITES C1 [Farrell, Martilias; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH Psychoact Drug Screening Program,Div Med Che, Chapel Hill, NC 27759 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, NIMH Psychoact Drug Screening Program,Div Med Che, 8032 Burnett Womack Bldg, Chapel Hill, NC 27759 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [U19 MH082441] NR 11 TC 6 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2010 VL 35 IS 4 BP 851 EP 852 DI 10.1038/npp.2009.206 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 554HA UT WOS:000274424900001 PM 20145632 ER PT J AU Benninghoff, J Gritti, A Rizzi, M LaMorte, G Schloesser, RJ Schmitt, A Robel, S Genius, J Moessner, R Riederer, P Manji, HK Grunze, H Rujescu, D Moeller, HJ Lesch, KP Vescovi, AL AF Benninghoff, Jens Gritti, Angela Rizzi, Matteo LaMorte, Giuseppe Schloesser, Robert J. Schmitt, Angelika Robel, Stefanie Genius, Just Moessner, Rainald Riederer, Peter Manji, Husseini K. Grunze, Heinz Rujescu, Dan Moeller, Hans-Juergen Lesch, Klaus-Peter Vescovi, Angelo Luigi TI Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE neurogenesis; neural progenitors; TPH; serotonin; brain; hippocampus ID TRANSPORTER-DEFICIENT MICE; FIBROBLAST-GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; HIPPOCAMPAL NEUROGENESIS; DENTATE GYRUS; PROGENITOR CELLS; ANTIDEPRESSANT TREATMENT; SUBVENTRICULAR ZONE; 5-HT1A RECEPTORS; KNOCKOUT MICE AB Serotonin (5-HT) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis. In this study, we evaluated the role of 5-HT on the functional features in neurospheres derived from adult neural stem cells (ANSC). We cultured neurospheres derived from mouse hippocampus in serum-free medium containing epidermal (EGF) and type-2 fibroblast growth factor (FGF2). Under these conditions ANSC expressed both isoforms of tryptophane-hydroxylase (TPH) and produced 5-HT. Blocking TPH function by para-chlorophenylalanine (PCPA) reduced ANSC proliferation, which was rescued by exogenous 5-HT. 5-HT action on ANSC was mediated predominantly by the serotonin receptor subtype 5-HT1A and, to a lesser extent, through the 5-HT2C (receptor) subtype, as shown by selectively antagonizing these receptors. Finally, we documented a 5-HT-induced increase of ANSC migration activity. In summary, we demonstrated a powerful serotonergic impact on ANSC functional features, which was mainly mediated by 5-HT1A receptors. Neuropsychopharmacology (2010) 35, 893-903; doi:10.1038/npp.2009.181; published online 9 December 2009 C1 [Benninghoff, Jens; Gritti, Angela; Rizzi, Matteo; LaMorte, Giuseppe; Vescovi, Angelo Luigi] Ist Sci San Raffaele, Stem Cell Res Inst, I-20132 Milan, Italy. [Benninghoff, Jens; Robel, Stefanie; Genius, Just; Grunze, Heinz; Rujescu, Dan; Moeller, Hans-Juergen] Univ Munich, Dept Psychiat, D-80336 Munich, Bavaria, Germany. [Schmitt, Angelika; Moessner, Rainald; Riederer, Peter; Lesch, Klaus-Peter] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Schloesser, Robert J.; Manji, Husseini K.] Univ Wurzburg, Dept Psychiat, Wurzburg, Germany. [Moessner, Rainald] Univ Bonn, Dept Psychiat & Psychotherapy, D-5300 Bonn, Germany. RP Benninghoff, J (reprint author), Univ Munich, Dept Psychiat Mol & Clin Neurobiol, Nussbaumstr 7, D-80336 Munich, Bavaria, Germany. EM jens.benninghoff@med.uni-muenchen.de RI Gritti, Angela/K-2729-2016; Robel, Stefanie/G-2924-2011; Lesch, Klaus-Peter/J-4906-2013; OI Vescovi, Angelo Luigi/0000-0002-1742-4112; Gritti, Angela/0000-0002-9845-0370; Grunze, Heinz/0000-0003-4712-8979; Robel, Stefanie/0000-0001-6716-3670; Lesch, Klaus-Peter/0000-0001-8348-153X; Genius, Just/0000-0003-3270-3491 FU Deutsche Forschungsgemeinschaft (DFG) [Be2530]; University of Munich; [SFB 531] FX This work was supported by Deutsche Forschungsgemeinschaft (DFG) Be2530 to JB, Forderprogramm Forschung und Lehre (FoFoLe) of University of Munich to JB, and SFB 531 to JB/KPL. None of the authors declare any conflict of interest. NR 73 TC 24 Z9 26 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2010 VL 35 IS 4 BP 893 EP 903 DI 10.1038/npp.2009.181 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 554HA UT WOS:000274424900006 PM 20010549 ER PT J AU Sambataro, F Blasi, G Fazio, L Caforio, G Taurisano, P Romano, R Di Giorgio, A Gelao, B Lo Bianco, L Papazacharias, A Popolizio, T Nardini, M Bertolino, A AF Sambataro, Fabio Blasi, Giuseppe Fazio, Leonardo Caforio, Grazia Taurisano, Paolo Romano, Raffaella Di Giorgio, Annabella Gelao, Barbara Lo Bianco, Luciana Papazacharias, Apostolos Popolizio, Teresa Nardini, Marcello Bertolino, Alessandro TI Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE default mode network; schizophrenia; antipsychotics; working memory; ventromedial prefrontal cortex; fMRI ID MEDIAL PREFRONTAL CORTEX; CEREBRAL BLOOD-FLOW; RESTING-STATE; WORKING-MEMORY; FUNCTIONAL CONNECTIVITY; BRAIN-FUNCTION; ANTIPSYCHOTIC MEDICATIONS; INDEPENDENT COMPONENTS; DOPAMINE MODULATION; GLOBAL SIGNAL AB Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN. Neuropsychopharmacology (2010) 35, 904-912; doi:10.1038/npp.2009.192; published online 2 December 2009 C1 [Sambataro, Fabio; Blasi, Giuseppe; Fazio, Leonardo; Caforio, Grazia; Taurisano, Paolo; Romano, Raffaella; Di Giorgio, Annabella; Gelao, Barbara; Lo Bianco, Luciana; Papazacharias, Apostolos; Nardini, Marcello; Bertolino, Alessandro] Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, I-70124 Bari 9, Italy. [Popolizio, Teresa; Bertolino, Alessandro] IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, FG, Italy. [Sambataro, Fabio] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Bertolino, A (reprint author), Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Piazza Giulio Cesare, I-70124 Bari 9, Italy. EM a.bertolino@psichiat.uniba.it RI Sambataro, Fabio/E-3426-2010; Fazio, Leonardo/J-4570-2012; Bertolino, Alessandro/O-6352-2016; Di Giorgio, Annabella /D-7353-2017; OI Sambataro, Fabio/0000-0003-2102-416X; Fazio, Leonardo/0000-0003-4000-974X; Bertolino, Alessandro/0000-0002-1251-1380; Di Giorgio, Annabella /0000-0001-7876-3495; Papazacharias, Apostolos/0000-0001-5470-1601 NR 67 TC 74 Z9 77 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2010 VL 35 IS 4 BP 904 EP 912 DI 10.1038/npp.2009.192 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 554HA UT WOS:000274424900007 PM 19956088 ER PT J AU Silverman, JL Tolu, SS Barkan, CL Crawley, JN AF Silverman, Jill L. Tolu, Seda S. Barkan, Charlotte L. Crawley, Jacqueline N. TI Repetitive Self-Grooming Behavior in the BTBR Mouse Model of Autism is Blocked by the mGluR5 Antagonist MPEP SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE autism; social behavior; repetitive behavior; mouse models; mGluR5; BTBR ID FRAGILE-X-SYNDROME; METABOTROPIC GLUTAMATE-RECEPTOR-5 MGLUR5; HUMAN FMR1 TRANSGENE; SPECTRUM DISORDERS; ANXIOLYTIC-LIKE; RECEPTOR ANTAGONIST; MENTAL-RETARDATION; IN-VIVO; INBRED STRAINS; ANIMAL-MODELS AB Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T + tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism. Neuropsychopharmacology (2010) 35, 976-989; doi:10.1038/npp.2009.201; published online 23 December 2009 C1 [Silverman, Jill L.] NIMH, Lab Behav Neurosci, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Silverman, JL (reprint author), NIMH, Lab Behav Neurosci, NIH, Porter Neurosci Res Ctr, Bldg 35,Room 1C-707,9000 Rockville Pike,MSC 3730, Bethesda, MD 20892 USA. EM silvermanj@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX The present research was supported by the National Institute of Mental Health Intramural Research Program. We thank Dr Mu Yang and Ms Sarah M Turner for assistance in paper preparation. NR 109 TC 154 Z9 157 U1 5 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2010 VL 35 IS 4 BP 976 EP 989 DI 10.1038/npp.2009.201 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 554HA UT WOS:000274424900014 PM 20032969 ER PT J AU Conforto, AB Ferreiro, KN Tomasi, C dos Santos, RL Moreira, VL Marie, SKN Baltieri, SC Scaff, M Cohen, LG AF Conforto, Adriana Bastos Ferreiro, Karina Nocelo Tomasi, Camilla dos Santos, Renata Laurenti Moreira, Viviane Loureiro Nagahashi Marie, Suely Kazue Baltieri, Silvia Cristina Scaff, Milberto Cohen, Leonardo G. TI Effects of Somatosensory Stimulation on Motor Function After Subacute Stroke SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE stroke; rehabilitation; somatosensory stimulation; motor training; hand function; nerve stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; PERIPHERAL-NERVE STIMULATION; ELECTRICAL-STIMULATION; NEUROMUSCULAR STIMULATION; SENSORY STIMULATION; ACUTE HEMIPLEGIA; CONTROLLED-TRIAL; PINCH STRENGTH; RECOVERY; HAND AB Background. Previous works showed potentially beneficial effects of a single session of peripheral nerve sensory stimulation (PSS) on motor function of a paretic hand in patients with subacute and chronic stroke. Objective. To investigate the influence of the use of different stimulus intensities over multiple sessions (repetitive PSS [RPSS]) paired with motor training. Methods. To address this question, 22 patients were randomized within the second month after a single hemispheric stroke in a parallel design to application of 2-hour RPSS at 1 of 2 stimulus intensities immediately preceding motor training, 3 times a week, for 1 month. Jebsen-Taylor test (JTT, primary endpoint measure), pinch force, Functional Independence Measure (FIM), and corticomotor excitability to transcranial magnetic stimulation were measured before and after the end of the treatment month. JTT, FIM scores, and pinch force were reevaluated 2 to 3 months after the end of the treatment. Results. Baseline motor function tests were comparable across the 2 RPSS intensity groups. JTT improved significantly in the lower intensity RPSS group but not in the higher intensity RPSS group at month 1. This difference between the 2 groups reduced by months 2 to 3. Conclusions. These results indicate that multiple sessions of RPSS could facilitate training effects on motor function after subacute stroke depending on the intensity of stimulation. It is proposed that careful dose-response studies are needed to optimize parameters of RPSS stimulation before designing costly, larger, double-blind, multicenter clinical trials. C1 [Conforto, Adriana Bastos] Univ Sao Paulo, Clin Hosp, Div Neurol, BR-05403000 Sao Paulo, Brazil. [Conforto, Adriana Bastos] Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil. [Cohen, Leonardo G.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Conforto, AB (reprint author), Univ Sao Paulo, Clin Hosp, Div Neurol, Av Dr Eneas C Aguiar 255-5084, BR-05403000 Sao Paulo, Brazil. EM abconf@yahoo.com RI Marie, Suely/D-1870-2012 FU Fogarty International Center, National Institutes of Health [1 R21 TW006706]; NINDS, NIH FX This work was partially supported by grant 1 R21 TW006706 from the Fogarty International Center, National Institutes of Health, and by the Intramural Research Program of the NINDS, NIH. NR 60 TC 50 Z9 53 U1 1 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD MAR PY 2010 VL 24 IS 3 BP 263 EP 272 DI 10.1177/1545968309349946 PG 10 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 556JI UT WOS:000274586500006 PM 19884642 ER PT J AU Rodriguez, JS Morris, SM Hotchkiss, CE Doerge, DR Allen, RR Mattison, DR Paule, MG AF Rodriguez, J. S. Morris, S. M. Hotchkiss, C. E. Doerge, D. R. Allen, R. R. Mattison, D. R. Paule, M. G. TI The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Methylphenidate; Juvenile; Operant; Learning; Memory; Attention ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; NMDA RECEPTOR ANTAGONISTS; BEHAVIORAL-TEST BATTERY; NONHUMAN-PRIMATES; PERIADOLESCENT RATS; DEVELOPMENTAL ASPECTS; BRAIN-FUNCTION; DOUBLE-BLIND; CHILDREN; ADHD AB Methylphenidate (MPH) is an amphetamine derivative widely prescribed for the treatment of attention deficit-hyperactivity disorder. Recent concern over its genotoxic potential in children [11] spurred a study on the effects of chronic MPH treatment in a nonhuman primate population and the studies reported here were conducted in conjunction with that study in the same animals. Here, the focus was on the ability of juvenile rhesus monkeys to learn how to perform a battery of operant behavioral tasks while being treated chronically with MPH. Performance of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB) was used to quantify the learning of tasks thought to model specific aspects of cognitive function including learning, motivation, color and position discrimination, and short-term memory. The OTB tasks designed to assess these specific behaviors included Incremental Repeated Acquisition (IRA), Progressive Ratio (PR), Conditioned Position Responding (CPR), and Delayed Matching-to-Sample (DMTS), respectively. juvenile males (n =10/group) pressed levers and press-plates for banana-flavored food pellets. Subjects were treated orally, twice a day, five days per week (M-F) for 66 weeks with escalating doses (0.15 mg/kg initially, increased to 2.5 mg/kg for the low dose group and to 12.5 mg/kg for the high dose group) and tested in OTB tasks 30 to 60 min after the morning dose. The findings indicate that MPH at doses up to 2.5 mg/kg twice per day were well tolerated (performance was no different than controls) but at doses of 12.5 mg/kg twice per day there was a significant decrement in OTB performance, characterized by decreases in both percent task completed and response rates for all tasks. These effects of MPH seem primarily due to decreases in motivation to perform for food, which is not surprising given the well known appetite suppressing effects of amphetamine-like stimulants. Thus, the current data do not strongly suggest cognitive impairments following chronic MPH administration. (C) 2009 Elsevier Inc. All rights reserved. C1 [Rodriguez, J. S.; Paule, M. G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Morris, S. M.] US FDA, Div Genet & Reprod Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Hotchkiss, C. E.] US FDA, Bionet Corp, Natl Ctr Toxicol Res, Jefferson, AR USA. [Doerge, D. R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Allen, R. R.] Peak Stat Serv, Evergreen, CO USA. [Mattison, D. R.] NICHHD, Obstet & Pediat Pharmacol Branch, NIH, Bethesda, MD 20892 USA. RP Rodriguez, JS (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. EM rodriguezj13@uthscsa.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU National Institute on Child Health and Human Development; National Center for Toxicological Research [224-05-0003]; Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA FX Funding: These studies were supported through an interagency agreement between the National Institute on Child Health and Human Development and the National Center for Toxicological Research, 224-05-0003 and a postdoctoral fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA (to J. Rodriguez). NR 44 TC 18 Z9 18 U1 3 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2010 VL 32 IS 2 BP 142 EP 151 DI 10.1016/j.ntt.2009.08.011 PG 10 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 583TJ UT WOS:000276702500004 PM 19737611 ER PT J AU David, SP Mezuk, B Zandi, PP Strong, D Anthony, JC Niaura, R Uhl, GR Eaton, WW AF David, Sean P. Mezuk, Briana Zandi, Peter P. Strong, David Anthony, James C. Niaura, Raymond Uhl, George R. Eaton, William W. TI Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE REPLACEMENT THERAPY; GENOME-WIDE ASSOCIATION; GENETIC-VARIATION; RECEPTOR GENE; TAQ1A POLYMORPHISM; BIPOLAR DISORDER; CLINICAL-TRIALS; BUPROPION SR; FOLLOW-UP; CESSATION AB The 11q23.1 genomic region has been associated with nicotine dependence in Black and White Americans. By conducting linkage disequilibrium analyses of 7 informative single nucleotide polymorphisms (SNPs) within the tetratricopeptide repeat domain 12 (TTC12)/ankyrin repeat and kinase containing 1 (ANKK1)/dopamine (D2) receptor gene cluster, we identified haplotype block structures in 270 Black and 368 White (n = 638) participants, from the Baltimore Epidemiologic Catchment Area cohort study, spanning the TTC12 and ANKK1 genes consisting of three SNPs (rs2303380-rs4938015-rs11604671). Informative haplotypes were examined for sex-specific associations with daily tobacco smoking initiation and cessation using longitudinal data from 1993-1994 and 2004-2005 interviews. There was a Haplotype x Sex interaction such that Black men possessing the GTG haplotype who were smokers in 1993-2004 were more likely to have stopped smoking by 2004-2005 (55.6% GTG vs. 22.0% other haplotypes), while Black women were less likely to have quit smoking if they possessed the GTG (20.8%) versus other haplotypes (24.0%; p = .028). In Whites, the GTG haplotype (vs. other haplotypes) was associated with lifetime history of daily smoking (smoking initiation; odds ratio = 1.6; 95% CI = 1.1-2.4; p = .013). Moreover, there was a Haplotype x Sex interaction such that there was higher prevalence of smoking initiation with GTG (77.6%) versus other haplotypes (57.0%; p = .043). In 2 different ethnic American populations, we observed man-woman variation in the influence of the rs2303380-rs4938015-rs11604671 GTG haplotype on smoking initiation and cessation. These results should be replicated in larger cohorts to establish the relationship among the rs2303380-rs4938015-rs11604671 haplotype block, sex, and smoking behavior. C1 [David, Sean P.] Stanford Univ, Dept Med, Ctr Educ Family & Community Med, Div Family & Community Med,Sch Med, Stanford, CA 94305 USA. [Mezuk, Briana] Virginia Commonwealth Univ, Sch Med, Dept Epidemiol & Community Hlth, Richmond, VA USA. [Zandi, Peter P.; Eaton, William W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Strong, David; Niaura, Raymond] Brown Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Anthony, James C.] Michigan State Univ, Coll Human Med, Dept Epidemiol, E Lansing, MI 48824 USA. [Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP David, SP (reprint author), Stanford Univ, Dept Med, Ctr Educ Family & Community Med, Div Family & Community Med,Sch Med, 1215 Welch Rd, Stanford, CA 94305 USA. EM spdavid@stanford.edu OI David, Sean/0000-0002-4922-2603; Mezuk, Briana/0000-0003-1798-2285 FU NIMH [U01-33870]; NIDA [K05-DA015799]; Michigan State University FX We are also grateful to the ECA's principal collaborators (D. Regier, B. Locke, W. E., and J. Burke) and to Drs. M. Kramer, E. Gruenberg, and S. Shapiro from the Johns Hopkins site, supported by NIMH grant U01-33870. JCA directed the original Baltimore ECA sampling, recruitment, and assessment and was Co-Principal Investigator with WWE for the ECA follow-up research; his recent research is supported by a NIDA Senior Scientist award (K05-DA015799) and Michigan State University research funds. We are also grateful to G. Sullivan for editorial assistance. NR 56 TC 14 Z9 15 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAR PY 2010 VL 12 IS 3 BP 251 EP 262 DI 10.1093/ntr/ntp201 PG 12 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 558WE UT WOS:000274778400009 PM 20133381 ER PT J AU Yi, J Chang, N Liu, XW Guo, G Xue, LX Tong, TJ Gorospe, M Wang, WG AF Yi, Jie Chang, Na Liu, Xinwen Guo, Gaier Xue, Lixiang Tong, Tanjun Gorospe, Myriam Wang, Wengong TI Reduced nuclear export of HuR mRNA by HuR is linked to the loss of HuR in replicative senescence SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BINDING PROTEIN HUR; INCREASED CYCLOOXYGENASE-2 EXPRESSION; ELAV-LIKE PROTEIN; CYTOPLASMIC HUR; CELL-PROLIFERATION; OVARIAN-CARCINOMA; PROGNOSTIC-FACTOR; BREAST-CARCINOMA; STABILITY FACTOR; CD83 EXPRESSION AB The RNA-binding protein, HuR, associates with the HuR mRNA, but the consequences of this interaction are unknown. Here, we use human diploid fibroblasts (HDFs) and cervical carcinoma cells to study this regulatory paradigm. Ectopic overexpression of HuR potently enhanced the translation and cytoplasmic levels of endogenous HuR, but did not affect HuR mRNA levels. Inhibition of CRM1 function by Lemptomycin B or by knockdown of CRM1 greatly diminished the cytoplasmic levels of endogenous HuR mRNA and hence blocked the induction of endogenous HuR by exogenous HuR. Further studies showed that HuR interacted with the 3'-untranslated region (UTR) of HuR and that overexpression of HuR increased the cytoplasmic levels of a chimeric luciferase-HuR 3'-UTR reporter transcript, as well as luciferase activity; conversely, HuR knockdown reduced both parameters. Moreover, the loss of HuR in senescent, late-passage HDFs was accompanied by a reduced cytoplasmic presence of endogenous HuR mRNA, ectopic Luc-HuR-3'UTR reporter transcript, and luciferase activity relative to what was observed in young, early-passage cells. Our results reveal a positive feedback mechanism for the regulation of HuR, which may play an important role in the regulation of HuR during replicative senescence. C1 [Yi, Jie; Chang, Na; Liu, Xinwen; Xue, Lixiang; Tong, Tanjun; Wang, Wengong] Peking Univ, Hlth Sci Ctr, Res Ctr Aging, Dept Biochem & Mol Biol, Beijing 100083, Peoples R China. [Guo, Gaier] Changzhi Med Coll, Dept Biochem, Changzhi 046000, Shanxi, Peoples R China. [Gorospe, Myriam] NIA, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. RP Wang, WG (reprint author), Peking Univ, Hlth Sci Ctr, Res Ctr Aging, Dept Biochem & Mol Biol, 38 Xueyuan Rd, Beijing 100083, Peoples R China. EM wwg@bjmu.edu.cn FU Major State Basic Research Development Program of China [2007CB507400]; National Science Foundation of China [30672202, 30621002]; Ministry of Education of People's Republic of China [B07001]; National Institute on Aging-IRP, National Institutes of Health FX Funding for open access charges: The Major State Basic Research Development Program of China (Grant 2007CB507400); the National Science Foundation of China (Grants 30672202 and 30621002); the Ministry of Education of People's Republic of China (Grant B07001, 111 project); and the National Institute on Aging-IRP, National Institutes of Health (to M. G.). NR 36 TC 32 Z9 32 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2010 VL 38 IS 5 BP 1547 EP 1558 DI 10.1093/nar/gkp1114 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 578PA UT WOS:000276304500018 PM 20007147 ER PT J AU Potrykus, K Murphy, H Chen, XF Epstein, JA Cashel, M AF Potrykus, Katarzyna Murphy, Helen Chen, Xiongfong Epstein, Jonathan A. Cashel, Michael TI Imprecise transcription termination within Escherichia coli greA leader gives rise to an array of short transcripts, GraL SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CLEAVAGE FACTORS GREA; RNA-POLYMERASE; SECONDARY CHANNEL; IN-VIVO; INTRINSIC TERMINATION; CRYSTAL-STRUCTURE; GENE-EXPRESSION; PPGPP; DKSA; MECHANISM AB We report that greA expression is driven by two strong, overlapping P1 and P2 promoters. The P1 promoter is Sigma(70)-dependent and P2 is Sigma(E)-dependent. Two-thirds of transcripts terminate within the leader region and the remaining third comprises greA mRNA. Termination efficiency seems to be unaffected by growth phase. Two collections of small 40-50 (initiating from P2) and 50-60 nt (from P1) RNA chains, termed GraL, are demonstrable in vivo and in vitro. We document that GraL arrays arise from an intrinsic terminator with an 11 bp stem followed by an AU(7)GCU(2) sequence. Atypical chain termination occurs at multiple sites; the 3'-ends differ by 1 nt over a range of 10 nt. Transcripts observed are shown to be insensitive to Gre factors and physically released from RNAP-DNA complexes. The abundance of individual chains within each cluster displays a characteristic pattern, which can be differentially altered by oligonucleotide probes. Multiple termination sites are particularly sensitive to changes at the bottom of the stem. Evolutionarily conserved GraL stem structures and fitness assays suggest a biological function for the RNA clusters themselves. Although GraL overexpression induces >= 3-fold transcriptional changes of over 100 genes, a direct target remains elusive. C1 [Potrykus, Katarzyna; Murphy, Helen; Cashel, Michael] Eunice Kennedy Shriver NICHD, Mol Genet Lab, Program Genom Dev, OSD,NIH, Bethesda, MD 20892 USA. [Chen, Xiongfong; Epstein, Jonathan A.] Eunice Kennedy Shriver NICHD, Unit Biol Computat, OSD, NIH, Bethesda, MD 20892 USA. RP Potrykus, K (reprint author), Eunice Kennedy Shriver NICHD, Mol Genet Lab, Program Genom Dev, OSD,NIH, Bethesda, MD 20892 USA. EM potrykuk@mail.nih.gov; cashelm@mail.nih.gov FU National Institute of Child Health; National Institutes of Health FX Funding for open access charge: this work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program of the National Institutes of Health. NR 48 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2010 VL 38 IS 5 BP 1636 EP 1651 DI 10.1093/nar/gkp1150 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 578PA UT WOS:000276304500025 PM 20008510 ER PT J AU Shukla, A Yuspa, SH AF Shukla, Anjali Yuspa, Stuart H. TI CLIC4 and Schnurri-2 A dynamic duo in TGF beta signaling with broader implications in cellular homeostasis and disease SO NUCLEUS-AUSTIN LA English DT Article DE TGF beta; CLIC4; Schnurri-2; cancer; p53; signaling AB CLIC4 is a highly conserved, multifunctional member of the chloride intracellular channel family of proteins. The protein is largely cytoplasmic but translocates to the nucleus upon a variety of stimuli including TGF beta, TNF alpha and etoposide. Nuclear resident CLIC4 causes growth arrest, terminal differentiation and apoptosis. Recently, it was discovered that TGF beta causes CLIC4 to associate with Schnurri-2 and together they translocate to the nucleus and dissociate thereafter. The nuclear function of CLIC4 was further illuminated by the discovery that CLIC4 enhances TGF beta signaling by associating with phospho-Smad2 and 3 and preventing their dephosphorylation. Enhanced TGF beta dependent gene expression and growth inhibition are downstream consequences of this activity of CLIC4. In this article, we speculate on other consequences of the CLIC4 relation to TGF beta signaling and the potential for CLIC4 to participate in other cellular functions related to normal homeostasis and disease. C1 [Shukla, Anjali; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov RI Shukla, Anjali/G-4046-2014 FU Intramural NIH HHS [Z01 BC005445-23] NR 51 TC 8 Z9 8 U1 1 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD MAR-APR PY 2010 VL 1 IS 2 BP 144 EP 149 DI 10.1038/ncb1885 PG 6 WC Cell Biology SC Cell Biology GA V28GC UT WOS:000208668300004 PM 20617112 ER PT J AU Cheng, CY Reich, D Coresh, J Boerwinkle, E Patterson, N Li, M North, KE Tandon, A Bailey-Wilson, JE Wilson, JG Kao, WHL AF Cheng, Ching-Yu Reich, David Coresh, Josef Boerwinkle, Eric Patterson, Nick Li, Man North, Kari E. Tandon, Arti Bailey-Wilson, Joan E. Wilson, James G. Kao, W. H. Linda TI Admixture Mapping of Obesity-related Traits in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study SO OBESITY LA English DT Article ID BODY-FAT DISTRIBUTION; SERUM LEPTIN LEVELS; PROOPIOMELANOCORTIN GENE; LINKAGE-DISEQUILIBRIUM; UNITED-STATES; VISCERAL FAT; WHITE WOMEN; MASS INDEX; ASSOCIATION; LOCUS AB Obesity is an important cause of morbidity and mortality worldwide. In the United States, the prevalence of obesity is higher in African Americans than whites, even after adjustment for socioeconomic status (SES). This leads to the hypothesis that differences in genetic background may contribute to racial/ethnic differences in obesity-related traits. We tested this hypothesis by conducting a genome-wide admixture mapping scan using 1,350 ancestry-informative single-nucleotide polymorphisms (SNPs) in 3,531 self-identified blacks from the Atherosclerosis Risk in Communities (ARIC) study. We used these markers to estimate the overall proportions of European ancestry (PEAs) for each individual and then scanned for the association between PEA and obesity-related traits (both continuous and dichotomous) at each locus. The median (interquartile range) PEA was 0.151 (0.115). PEA was inversely correlated with continuous BMI, weight, and subscapular skinfold thickness, even after adjusting for socioeconomic factors. In contrast, PEA was positively correlated with BMI-adjusted waist circumference. Using admixture mapping on dichotomized traits, we identified a locus on 2p23.3 to be suggestively associated with BMI (locus-specific lod = 4.11) and weight (locus-specific lod = 4.07). After adjusting for global PEA, each additional copy of a European ancestral allele at the 2p23.3 peak was associated with a BMI decrease of similar to 0.92 kg/m(2) (P = 2.9 x 10(-5)). Further mapping in this region on chromosome 2 may be able to uncover causative variants underlying obesity, which may offer insights into the control of energy homeostasis. C1 [Cheng, Ching-Yu; Coresh, Josef; Li, Man; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cheng, Ching-Yu; Bailey-Wilson, Joan E.] Natl Human Genome Res Inst, Inherited Dis Res Branch, Baltimore, MD USA. [Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Dept Opthalmol, Taipei 112, Taiwan. [Cheng, Ching-Yu] Natl Yang Ming Univ, Sch Med, Taipei Vet Gen Hosp, Taipei 112, Taiwan. [Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Reich, David; Patterson, Nick; Tandon, Arti] Broad Inst Harvard, Program Med & Populat Genet, Boston, MA USA. [Reich, David; Patterson, Nick; Tandon, Arti] MIT, Boston, MA USA. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Wilson, James G.] VA Med Ctr, Jackson, MS USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Kao, WHL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM wkao@jhsph.edu RI Cheng, Ching-Yu/K-7017-2013; OI Cheng, Ching-Yu/0000-0003-0655-885X; Bailey-Wilson, Joan/0000-0002-9153-2920 FU National Institute of Diabetes and Digestive and Kidney Diseases [R21DK073482, K01DK067207]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022]; Burroughs Wellcome Career Development Award; NIH [U01-HG004168, N01-HG-65403]; Johns Hopkins University [N01-HV-48195]; Center for Inherited Disease Research (CDIR); [UL1RR025005] FX We thank the staff and participants of the Atherosclerosis Risk in Communities (ARIC) study for their important contributions. This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants R21DK073482 and K01DK067207 (W. H. L. K.). The ARIC study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, N01HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, and N01-HC-55022 and infrastructure is partly supported by grant UL1RR025005, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. D. R. is supported by a Burroughs Wellcome Career Development Award in the Biomedical Sciences and D. R., N. P. and A. T. are supported by the NIH grant U01-HG004168. Genotyping services were provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from the NHLBI and by the Center for Inherited Disease Research (CDIR). CDIR is fully funded through a federal contract from the NIH to the Johns Hopkins University, contract number N01-HG-65403. NR 53 TC 25 Z9 25 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAR PY 2010 VL 18 IS 3 BP 563 EP 572 DI 10.1038/oby.2009.282 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 562BO UT WOS:000275024100020 PM 19696751 ER PT J AU Doumatey, AP Lashley, KS Huang, HX Zhou, J Chen, GJ Amoah, A Agyenim-Boateng, K Oli, J Fasanmade, O Adebamowo, CA Adeyemo, AA Rotimi, CN AF Doumatey, Ayo P. Lashley, Kerrie S. Huang, Hanxia Zhou, Jie Chen, Guanjie Amoah, Albert Agyenim-Boateng, Kofi Oli, Johnnie Fasanmade, Olufemi Adebamowo, Clement A. Adeyemo, Adebowale A. Rotimi, Charles N. TI Relationships Among Obesity, Inflammation, and Insulin Resistance in African Americans and West Africans SO OBESITY LA English DT Article ID C-REACTIVE PROTEIN; ACUTE-PHASE REACTION; ADIPOSE-TISSUE; METABOLIC SYNDROME; ADIPOKINES; ASSOCIATION; ADOLESCENTS; CHILDREN; FEATURES; ADULTS AB Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist-to-hip ratio (WHR)), inflammatory markers (high-sensitivity C-reactive protein (hsCRP), haptoglobin, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha), and IR (homeostasis model assessment of insulin resistance (HOMA(IR))) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL-6 (but not TNF-alpha level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMA(IR), and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL-6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity. C1 [Doumatey, Ayo P.; Huang, Hanxia; Zhou, Jie; Chen, Guanjie; Adeyemo, Adebowale A.; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Natl Inst Hlth, Bethesda, MD 20892 USA. [Lashley, Kerrie S.] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. [Amoah, Albert] Univ Ghana, Sch Med, Dept Med, Accra, Ghana. [Agyenim-Boateng, Kofi] Univ Sci & Technol Kumasi, Dept Med, Kumasi, Ghana. [Oli, Johnnie] Univ Nigeria, Teaching Hosp, Dept Med, Enugu, Nigeria. [Fasanmade, Olufemi] Univ Lagos, Coll Med, Endocrine & Metab Unit, Lagos, Nigeria. [Adebamowo, Clement A.] Univ Ibadan, Coll Med, Ibadan, Nigeria. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Natl Inst Hlth, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Adebamowo, Clement/0000-0002-6571-2880; Adeyemo, Adebowale/0000-0002-3105-3231 FU NIGMS/MBRS/SCORE Program [S06GM008016320107]; National Center for Research Resources (NCRR) [2M01RR010284]; National Institutes of Health (NIH); Office of Research on Minority Health [3T37TW00041-03S2]; National Institute of Diabetes and Digestive and Kidney Diseases [DK-54001]; Intramural Research Program of the National Human Genome Research Institute; Center for Research in Genomics and Global Health FX The Howard University Family Study was supported by grant S06GM008016320107 to CR from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center, which is supported by grant number 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Support for the Africa America Diabetes Mellitus study is provided by NIH grant no. 3T37TW00041-03S2 from the Office of Research on Minority Health and also in part by the NCRR, National Human Genome Research Institute, and by the National Institute of Diabetes and Digestive and Kidney Diseases grant DK-54001. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research in Genomics and Global Health. NR 40 TC 18 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAR PY 2010 VL 18 IS 3 BP 598 EP 603 DI 10.1038/oby.2009.322 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 562BO UT WOS:000275024100025 PM 19798069 ER PT J AU Taha, TE Kumwenda, J Cole, SR Hoover, DR Kafulafula, G Fowler, MG Thigpen, MC Li, Q Kumwenda, NI Mofenson, L AF Taha, Taha E. Kumwenda, Johnstone Cole, Stephen R. Hoover, Donald R. Kafulafula, George Fowler, Mary Glenn Thigpen, Michael C. Li, Qing Kumwenda, Newton I. Mofenson, Lynne TI Postnatal Human Immunodeficiency Virus-1 Transmission After Cessation of Infant Extended Antiretroviral Prophylaxis and Effect of Maternal Highly Active Antiretroviral Therapy EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Taha, Taha E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Kennedy Shriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Rutgers State Univ, Piscataway, NJ USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIVAIDS Viral Hepatitis STD & TB Prevent, Atlanta, GA USA. Univ Malawi, Coll Med, Blantyre, Malawi. RP Taha, TE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. OI Mofenson, Lynne/0000-0002-2818-9808 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 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAR PY 2010 VL 65 IS 3 BP 150 EP 151 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 575UQ UT WOS:000276095000004 ER PT J AU Horton, AL Momirova, V Dizon-Townson, D Wenstrom, K Wendel, G Samuels, P Sibai, B Spong, CY Cotroneo, M Sorokin, Y Miodovnik, M O'Sullivan, MJ Conway, D Wapner, RJ AF Horton, Amanda L. Momirova, Valerija Dizon-Townson, Donna Wenstrom, Katharine Wendel, George Samuels, Philip Sibai, Baha Spong, Catherine Y. Cotroneo, Margaret Sorokin, Yoram Miodovnik, Menachem O'Sullivan, Mary J. Conway, Deborah Wapner, Ronald J. CA NICHD TI Family History of Venous Thromboembolism and Identifying Factor V Leiden Carriers During Pregnancy SO 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 ID ORAL-CONTRACEPTION; COST-EFFECTIVENESS; RISK; THROMBOPHILIA; MUTATION; WOMEN; THROMBOSIS; POSTPARTUM; DISEASE AB OBJECTIVE: To estimate whether there is a correlation between family history of venous thromboembolism and factor V Leiden mutation carriage in gravid women without a personal history of venous thromboembolism. METHODS: This is a secondary analysis of a prospective observational study of the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden mutation. Family history of venous thromboembolism in either first-or second-degree relatives was self-reported. Sensitivity, specificity, and positive and negative predictive values of family history to predict factor V Leiden mutation carrier status were calculated. RESULTS: Women without a personal venous thromboembolism history and with available DNA were included (n=5,168). One hundred forty women (2.7% [95% confidence interval (CI) 2.3-3.2%]) were factor V Leiden mutation-positive. Four hundred twelve women (8.0% [95% CI 7.3-8.7%]) reported a family history of venous thromboembolism. Women with a positive family history were twofold more likely to be factor V Leiden mutation carriers than those with a negative family history (23 of 412 [5.6%] compared with 117 of 4,756 [2.5%], P<.001). The sensitivity, specificity, and positive predictive value of a family history of a first-or second-degree relative for identifying factor V Leiden carriers were 16.4% (95% CI 10.7-23.6%), 92.3% (95% CI 91.5-93.0%), and 5.6% (95% CI 3.6-8.3%), respectively. CONCLUSION: Although a family history of venous thromboembolism is associated with factor V Leiden mutation in thrombosis-free gravid women, the sensitivity and positive predictive values are too low to recommend screening women for the factor V Leiden mutation based solely on a family history. (Obstet Gynecol 2010;115:521-5) C1 Univ N Carolina, Dept Obstet, Chapel Hill, NC USA. Univ N Carolina, Dept Gynecol, Chapel Hill, NC USA. Univ Utah, Salt Lake City, UT USA. Univ Alabama, Birmingham, AL USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Pittsburgh, PA USA. Wayne State Univ, Detroit, MI USA. Univ Cincinnati, Cincinnati, OH USA. Univ Miami, Miami, FL USA. Univ Texas San Antonio, San Antonio, TX USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Horton, AL (reprint author), NorthShore Univ Hlth Syst, 2650 Ridge Ave, Evanston, IL 60201 USA. EM horton.alm@gmail.com RI Samuels, Philip/E-4011-2011 FU NICHD NIH HHS [U10 HD027905-09, HD27860, HD34116, HD34136, HD34208, U01 HD036801-02, U10 HD027860, U10 HD027860-09, U10 HD027869-11, U10 HD027905, U10 HD027915-08, U10 HD034116, U10 HD034122-04, U10 HD034136, U10 HD034208, U10 HD034210-04, U10 HD040500, UG1 HD027869, UG1 HD027915, U10 HD021410-14, HD21410, HD21414, HD27861, HD27869, HD27915, HD27917, HD34210, HD36801, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD021414-09S1, U10 HD027861-09, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD027917-09, U10 HD034116-04, U10 HD034122, U10 HD034136-08, U10 HD034208-04, U10 HD036801, UG1 HD034116, UG1 HD034208] NR 16 TC 3 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2010 VL 115 IS 3 BP 521 EP 525 DI 10.1097/AOG.0b013e3181d018a8 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 563LA UT WOS:000275132300007 PM 20177282 ER PT J AU Aagaard-Tillery, K Spong, CY Thom, E Sibai, B Wendel, G Wenstrom, K Samuels, P Simhan, H Sorokin, Y Miodovnik, M Meis, P O'Sullivan, MJ Conway, D Wapner, RJ AF Aagaard-Tillery, Kjersti Spong, Catherine Y. Thom, Elizabeth Sibai, Baha Wendel, George, Jr. Wenstrom, Katharine Samuels, Philip Simhan, Hyagriv Sorokin, Yoram Miodovnik, Menachem Meis, Paul O'Sullivan, Mary J. Conway, Deborah Wapner, Ronald J. CA Eunice Kennedy Shriver Natl Inst C TI Pharmacogenomics of Maternal Tobacco Use Metabolic Gene Polymorphisms and Risk of Adverse Pregnancy Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INFANT BIRTH-WEIGHT; GESTATIONAL-AGE; CIGARETTE-SMOKING; NICOTINE METABOLISM; HUMAN-PLACENTA; FETAL-GROWTH; DNA-DAMAGE; PRETERM; ASSOCIATION; DELIVERY AB OBJECTIVE: To assess whether functional maternal or fetal genotypes along well-characterized metabolic pathways (ie, CYP1A1, GSTT1, and CYP2A6) may account for varying associations with adverse outcomes among pregnant women who smoke. METHODS: DNA samples from 502 smokers and their conceptuses, alongside women in a control group, were genotyped for known functional allelic variants of CYP1A1 (Ile(462)Val AA>AG/GG), GSTT1(del), and CYP2A6 (Lys(160)His T>A). Modification of the association between smoking and outcome by genotype was evaluated. Outcomes included birth weight, pregnancy loss, preterm birth, small for gestational age, and a composite outcome composed of the latter four components plus abruption. RESULTS: No interaction between maternal or fetal genotype of any of the polymorphisms and smoking could be demonstrated. In contrast, the association of smoking with gestational age-adjusted birth weight (birth weight ratio) was modified by fetal GSTT1 genotype (P for interaction=.02). Fetuses with GSTT1(del) had a mean birth weight reduction among smokers of 262 g (P=.01), whereas in fetuses without the GSTT1(del) the effect of tobacco exposure was nonsignificant (mean reduction 87 g, P=.16). After adjusting for confounding, results were similar. CONCLUSION: Fetal GSTT1 deletion significantly and specifically modifies the effect of smoking on gestational age-corrected birth weight. (Obstet Gynecol 2010;115:568-77) C1 Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. Univ Tennessee, Memphis, TN USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Alabama, Birmingham, AL USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wayne State Univ, Detroit, MI USA. Univ Cincinnati, Cincinnati, OH USA. Wake Forest Univ, Hlth Serv, Winston Salem, NC 27109 USA. Univ Miami, Miami, FL USA. Univ Texas San Antonio, San Antonio, TX USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Aagaard-Tillery, K (reprint author), Baylor Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, 1 Baylor Plaza, Houston, TX 77030 USA. EM aagaardt@bcm.tmc.edu RI Samuels, Philip/E-4011-2011 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HD27869, U10-HD21414, U01-HD36801, U10-HD34208, U10-HD27860, U10-HD34116, U10-HD34136, U10-HD27861, U10-HD34122, U10-HD21410, U10-HD27915, U10-HD34210, U10-HD27905, U10-HD27917]; National Institutes of Health FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Maternal-Fetal Medicine Units Network (U10HD27869, U10-HD21414, U01-HD36801, U10-HD34208, U10-HD27860, U10-HD34116, U10-HD34136, U10-HD27861, U10-HD34122, U10-HD21410, U10-HD27915, U10-HD34210, U10-HD27905, and U10-HD27917) and the National Institutes of Health's Office of Research on Women's Health. NR 41 TC 15 Z9 16 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2010 VL 115 IS 3 BP 568 EP 577 DI 10.1097/AOG.0b013e3181d06faf PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 563LA UT WOS:000275132300013 PM 20177288 ER PT J AU Richter, HE Burgio, KL Brubaker, L Nygaard, IE Ye, W Weidner, A Bradley, CS Handa, VL Borello-France, D Goode, PS Zyczynski, H Lukacz, ES Schaffer, J Barber, M Meikle, S Spino, C AF Richter, Holly E. Burgio, Kathryn L. Brubaker, Linda Nygaard, Ingrid E. Ye, Wen Weidner, Alison Bradley, Catherine S. Handa, Victoria L. Borello-France, Diane Goode, Patricia S. Zyczynski, Halina Lukacz, Emily S. Schaffer, Joseph Barber, Matthew Meikle, Susan Spino, Cathie CA Pelvic Floor Disorders Network TI Continence Pessary Compared With Behavioral Therapy or Combined Therapy for Stress Incontinence A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the International-Continence-Society CY SEP 29-OCT 03, 2009 CL San Francisco, CA SP Int Continence Soc ID URINARY-INCONTINENCE; ELECTRICAL-STIMULATION; MUSCLE EXERCISE; WOMEN; MANAGEMENT; VALIDATION AB OBJECTIVE: To compare the effectiveness of a continence pessary to evidence-based behavioral therapy for stress incontinence and to assess whether combined pessary and behavioral therapy is superior to single-modality therapy. METHODS: This was a multisite, randomized clinical trial (Ambulatory Treatments for Leakage Associated with Stress Incontinence [ATLAS]) that randomly assigned 446 women with stress incontinence to pessary, behavioral therapy, or combined treatment. Primary outcome measures, at 3 months, were Patient Global Impression of Improvement and the stress incontinence subscale of the Pelvic Floor Distress Inventory. A priori, to be considered clinically superior, combination therapy had to be better than both single-modality therapies. Outcome measures were repeated at 6 and 12 months. Primary analyses used an intention-to-treat approach. RESULTS: At 3 months, scores from 40% of the pessary group and 49% of the behavioral group were "much better" or "very much better" on the Patient Global Impression of Improvement (P=.10). Compared with the pessary group, more women in the behavioral group reported having no bothersome incontinence symptoms (49% compared with 33%, P=.006) and treatment satisfaction (75% compared with 63%, P=.02). Combination therapy was significantly better than pessary as shown on the Patient Global Impression of Improvement (53%, P=.02) and Pelvic Floor Distress Inventory (44%, P=.05) but not better than behavioral therapy; it was therefore not superior to single-modality therapy. Group differences were not sustained to 12 months on any measure, and patient satisfaction remained above 50% for all treatment groups. CONCLUSION: Behavioral therapy resulted in greater patient satisfaction and fewer bothersome incontinence symptoms than pessary at 3 months, but differences did not persist to 12 months. Combination therapy was not superior to single-modality therapy. C1 [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Birmingham VA Med Ctr, Birmingham, AL USA. Loyola Univ, Maywood, IL 60153 USA. Univ Utah, Salt Lake City, UT USA. Univ Michigan, Ann Arbor, MI 48109 USA. Duke Univ, Durham, NC USA. Univ Iowa, Iowa City, IA USA. Johns Hopkins Sch Med, Baltimore, MD USA. Duquesne Univ, Pittsburgh, PA 15219 USA. Magee Womens Hosp, Pittsburgh, PA USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Texas SW, Dallas, TX USA. Cleveland Clin, Cleveland, OH 44106 USA. NIH, Bethesda, MD 20892 USA. RP Richter, HE (reprint author), Univ Alabama, Dept Obstet & Gynecol, 618 20th St,NHB 219, Birmingham, AL 35233 USA. EM hrichter@uabmc.edu FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U10 HD41261, U01 HD041249, U01 HD041249-09, U10 HD 41250, U10 HD041248, U10 HD041250, U10 HD041261, U10 HD041263, U10 HD041267, U10 HD041268, U10 HD054136, U10 HD054214, U10 HD054215, U10 HD054241, U10 HD41248, U10 HD41249, U10 HD41263, U10 HD41267, U10 HD41268, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, UG1 HD054214] NR 23 TC 40 Z9 42 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2010 VL 115 IS 3 BP 609 EP 617 DI 10.1097/AOG.0b013e3181d055d4 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 563LA UT WOS:000275132300019 PM 20177294 ER PT J AU Haukka, E Pehkonen, I Leino-Arjas, P Viikari-Juntura, E Takala, EP Malmivaara, A Hopsu, L Mutanen, P Ketola, R Virtanen, T Holtari-Leino, M Nykanen, J Stenholm, S Ojajarvi, A Riihimaki, H AF Haukka, Eija Pehkonen, Irmeli Leino-Arjas, Paivi Viikari-Juntura, Eira Takala, Esa-Pekka Malmivaara, Antti Hopsu, Leila Mutanen, Pertti Ketola, Ritva Virtanen, Tuija Holtari-Leino, Merja Nykanen, Jaana Stenholm, Sari Ojajarvi, Anneli Riihimaki, Hilkka TI Effect of a participatory ergonomics intervention on psychosocial factors at work in a randomised controlled trial SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID MUSCULOSKELETAL DISORDERS; RISK-FACTORS; METHODOLOGICAL ISSUES; TRAINING-PROGRAM; BACK-PAIN; HEALTH; IMPLEMENTATION; REDUCTION; INCREASE; NECK AB Objectives To study the effect of a participatory ergonomics intervention on psychosocial factors among kitchen workers. Design A cluster randomised controlled trial. Setting Four cities in Finland, 2002-2005. Participants 504 workers in 119 municipal kitchens. Intervention Kitchens were randomised to intervention (n = 59) and control (n = 60) groups. The intervention lasted 11-14 months and was based on the workers' active participation in work analysis, planning and implementing the ergonomic changes aimed at decreasing the physical and mental workload. Main outcome measures Mental stress, mental strenuousness of work, hurry, job satisfaction, job control, skill discretion, co-worker relationships and supervisor support. Data were collected by questionnaire at baseline, at the end of the intervention, and at a 12-month follow-up (PI(12)). Results At the end of the intervention, the OR of job dissatisfaction for the intervention group as compared with the control group was 3.0 (95% CI 1.1 to 8.5), of mental stress 2.3 (1.2 to 4.7) and of poor co-worker relationships 2.3 (1.0 to 5.2). At the PI(12), the OR of job dissatisfaction was 3.0 (1.2 to 7.8). Analysis of the independent and joint effects of the intervention and unconnected organisational reforms showed that adverse changes were accentuated among those with exposure to both. Conclusions No favourable effects on psychosocial factors at work were found. The adverse changes were due to a joint effect of the intervention and the unconnected organisational reforms. The findings do not support the usefulness of this kind of intervention in changing unsatisfactory psychosocial working conditions. C1 [Haukka, Eija; Pehkonen, Irmeli; Leino-Arjas, Paivi; Viikari-Juntura, Eira; Takala, Esa-Pekka; Hopsu, Leila; Mutanen, Pertti; Ketola, Ritva; Virtanen, Tuija; Nykanen, Jaana; Ojajarvi, Anneli; Riihimaki, Hilkka] Finnish Inst Occupat Hlth, FI-00250 Helsinki, Finland. [Malmivaara, Antti; Stenholm, Sari] Natl Inst Hlth & Welf, Helsinki, Finland. [Holtari-Leino, Merja] Occupat Safety & Hlth Inspectorate Turku & Pori, Turku, Finland. [Stenholm, Sari] NIA, Baltimore, MD 21224 USA. RP Haukka, E (reprint author), Finnish Inst Occupat Hlth, Topeliuksenkatu 41 A A, FI-00250 Helsinki, Finland. EM Eija.Haukka@ttl.fi RI Stenholm, Sari/G-6940-2011; OI Haukka, Eija/0000-0001-9638-2047 FU Academy of Finland (Health Promotion Research Programme); Finnish Work Environment Fund; Ministry of Labour; Local Government Pensions Institution FX The Academy of Finland (Health Promotion Research Programme), the Finnish Work Environment Fund, the Ministry of Labour and the Local Government Pensions Institution supported the study. NR 40 TC 10 Z9 11 U1 3 U2 21 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD MAR PY 2010 VL 67 IS 3 BP 170 EP 177 DI 10.1136/oem.2008.043786 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 567LG UT WOS:000275447500007 PM 19737735 ER PT J AU Massip, L Garand, C Labbe, A Perreault, E Turaga, RVN Bohr, VA Lebel, M AF Massip, L. Garand, C. Labbe, A. Perreault, E. Turaga, R. V. N. Bohr, V. A. Lebel, M. TI Depletion of WRN protein causes RACK1 to activate several protein kinase C isoforms SO ONCOGENE LA English DT Article DE Werner syndrome; mass spectrometry; RACK1; PKC activation ID WERNER-SYNDROME PROTEIN; DNA-DAMAGE; BETA-II; FUNCTIONAL INTERACTION; OXIDATIVE STRESS; RAT-BRAIN; S-PHASE; PHOSPHORYLATION; EPSILON; BREAKS AB Werner's syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in patients with WS (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and telomere maintenance. In this study, we show that a knock down of the WRN protein in normal human fibroblasts induces phosphorylation and activation of several protein kinase C (PKC) enzymes. Using a tandem affinity purification strategy, we found that WRN physically and functionally interacts with receptor for activated C-kinase 1 (RACK1), a highly conserved anchoring protein involved in various biological processes, such as cell growth and proliferation. RACK1 binds strongly to the RQC domain of WRN and weakly to its acidic repeat region. Purified RACK1 has no impact on the helicase activity of WRN, but selectively inhibits WRN exonuclease activity in vitro. Interestingly, knocking down RACK1 increased the cellular frequency of DNA breaks. Depletion of the WRN protein in return caused a fraction of nuclear RACK1 to translocate out of the nucleus to bind and activate PKC delta and PKC beta II in the membrane fraction of cells. In contrast, different DNA-damaging treatments known to activate PKCs did not induce RACK1/PKCs association in cells. Overall, our results indicate that a depletion of the WRN protein in normal fibroblasts causes the activation of several PKCs through translocation and association of RACK1 with such kinases. Oncogene (2010) 29, 1486-1497; doi:10.1038/onc.2009.443; published online 7 December 2009 C1 [Massip, L.; Garand, C.; Labbe, A.; Perreault, E.; Turaga, R. V. N.; Lebel, M.] Univ Laval, Hop Hotel Dieu, Dept Mol Biol Med Biochem & Pathol, Ctr Rech Cancerol, Quebec City, PQ G1R 2J6, Canada. [Bohr, V. A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Lebel, M (reprint author), Univ Laval, Hop Hotel Dieu, Dept Mol Biol Med Biochem & Pathol, Ctr Rech Cancerol, 9 McMahon St, Quebec City, PQ G1R 2J6, Canada. EM michel.lebel@crhdq.ulaval.ca RI Perreault, Eric/B-7632-2009 FU Canadian Institutes of Health Research; National Institute on Aging, NIH; Fonds de la Recherche en Sante du Quebec FX We are grateful to Mrs N Roberge for the FACS analyses (Centre de Recherche en Cancerologie, Quebec City, Qc). This study was supported by the Canadian Institutes of Health Research to ML and in part by funds from the intramural Program of the National Institute on Aging, NIH to VAB. ML is a senior scholar from the Fonds de la Recherche en Sante du Quebec. NR 53 TC 9 Z9 9 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR PY 2010 VL 29 IS 10 BP 1486 EP 1497 DI 10.1038/onc.2009.443 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 566SD UT WOS:000275392400007 PM 19966859 ER PT J AU Gottlieb, C Li, ZQ Uzel, G Nussenblatt, RB Sen, HN AF Gottlieb, Chloe Li, Zhuqing Uzel, Gulbu Nussenblatt, Robert B. Sen, H. Nida TI Uveitis in DiGeorge syndrome: a case of autoimmune ocular inflammation in a patient with deletion 22q11.2 SO OPHTHALMIC GENETICS LA English DT Article DE DiGeorge syndrome; Uveitis; Deletion 22q11.2; Velocardiofacial syndrome; Sarcoidosis ID JUVENILE RHEUMATOID-ARTHRITIS; SARCOIDOSIS; CELLS AB Methods: We describe a case of a 25-year-old male with bilateral granulomatous panuveitis who after initial investigation and treatment for an infectious cause was determined to have autoimmune-related uveitis with evidence on clinical, laboratory and imaging assessments suggestive of ocular sarcoidosis. Results: The patient was found to have a normal T cell count and T cell proliferative response that was compared to a control patient, and phenotypes determined by flow cytometry were normal. However, the CD4/CD8 ratio in this patient was slightly lower than normal and the number of CD28 negative T cells, in both CD4 and CD8 populations, were significantly higher than a control. Conclusions: The significance of these T cell abnormalities is unknown in the context of this patient's uveitis but is suggestive of a role in autoimmunity, which is a known phenomenon in del22q11.2 syndrome, although autoimmune-related uveitis is not a previously described feature. C1 [Gottlieb, Chloe; Li, Zhuqing; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, NIH, Bethesda, MD 20892 USA. RP Gottlieb, C (reprint author), NEI, NIH, Immunol Lab, 10 Ctr Dr,Bldg 10,Rm 10D45, Bethesda, MD 20892 USA. EM gottliebc@nei.nih.gov FU Intramural NIH HHS [ZIE EY000482-02] NR 21 TC 5 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1381-6810 J9 OPHTHALMIC GENET JI Ophthalmic Genet. PD MAR PY 2010 VL 31 IS 1 BP 24 EP 29 DI 10.3109/13816810903426249 PG 6 WC Genetics & Heredity; Ophthalmology SC Genetics & Heredity; Ophthalmology GA 560CU UT WOS:000274880400004 PM 20141355 ER PT J AU Zhao, JL Ellwein, LB Cui, H Ge, J Guan, HJ Lv, JH Ma, XZ Yin, JL Yin, ZQ Yuan, YS Liu, H AF Zhao, Jialiang Ellwein, Leon B. Cui, Hao Ge, Jian Guan, Huaijin Lv, Jianhua Ma, Xianzhi Yin, Jinglin Yin, Zheng Qin Yuan, Yuansheng Liu, Hu TI Prevalence of Vision Impairment in Older Adults in Rural China The China Nine-Province Survey SO OPHTHALMOLOGY LA English DT Article ID CATARACT-SURGERY; VISUAL IMPAIRMENT; EYE SURVEY; BLINDNESS; POPULATION; DISTRICT; COUNTY AB Purpose: Describe the prevalence of visual impairment/blindness among older adults in rural populations in China. Design: Population-based, cross-sectional study. Participants: We evaluated 45 747 adults >= 50 years of age. Methods: Geographically defined cluster sampling was used in randomly selecting a cross-section of residents from a representative rural county within each of 9 provinces in mainland China. Participants were enumerated through village registers followed by door-to-door household visits. Eligible persons were invited to local examination sites for visual acuity (VA) testing and eye examination. Main Outcome Measures: Presenting and best-corrected distance VA. Results: Of 50 395 enumerated eligible persons, 45 747 (90.8%) were examined and tested for VA. The prevalence of presenting visual impairment < 20/ 63 to >= 20/400 in the better eye was 10.8% and blindness (< 20/400) was 2.29%. Across the 9 provinces, presenting visual impairment ranged from 6.89% to 15.8%, and blindness from 1.27% to 5.40%. With best-corrected VA, the prevalence of visual impairment was 5.30%, and 1.93% for blindness. The ranges across the 9 provinces were 3.13% to 9.51% for visual impairment and 0.74% to 4.95% for blindness. Visual impairment and blindness were associated with older age, female gender, lack of education, and geographic area ( province) with both presenting and best-corrected VA. Conclusions: Visual impairment and blindness are important public health problems in rural China, with significant regional variations in prevalence. Blindness prevention programs targeting the rural elderly should be expanded, particularly in areas with limited access and affordability of eye care services. Special emphasis should be given to reaching women and those without education. Greater attention should also be given to correction of refractive error. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2010; 117:409-416 (C) 2010 by the American Academy of Ophthalmology. C1 [Zhao, Jialiang; Liu, Hu] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Beijing 100730, Peoples R China. [Ellwein, Leon B.] NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Cui, Hao] Harbin Med Coll, Affiliated Hosp 1, Harbin, Peoples R China. [Ge, Jian] Sun Yat Sen Univ, Zhongshan Eye Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Guan, Huaijin] Nantong Univ, Affiliated Hosp, Nantong, Peoples R China. [Lv, Jianhua] Xingtai Eye Hosp, Xingtai, Peoples R China. [Ma, Xianzhi] Peoples Hosp, Xinjiang, Peoples R China. [Yin, Jinglin] Jiangxi Peoples Hosp, Nanchang, Peoples R China. [Yin, Zheng Qin] Third Mil Med Univ, Southwest Hosp, Chongqing, Peoples R China. [Yuan, Yuansheng] Yunnan Med Coll, Kunming, Peoples R China. RP Zhao, JL (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, 1 Shuai Fu Yuan, Beijing 100730, Peoples R China. EM zhaojialiang@medmail.com.cn FU Chinese Ministry of Health, Beijing, China; World Health Organization, Geneva, Switzerland [N01-EY-2103]; Lions Clubs International Foundation, Oak Brook, Illinois FX Supported by the Chinese Ministry of Health, Beijing, China; the World Health Organization, Geneva, Switzerland (under National Institutes of Health [Bethesda, Maryland] contract no. N01-EY-2103); and the Lions Clubs International Foundation, Oak Brook, Illinois. The sponsor or funding organizations participated in the design of the study. NR 13 TC 58 Z9 88 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2010 VL 117 IS 3 BP 409 EP U27 DI 10.1016/j.ophtha.2009.11.023 PG 9 WC Ophthalmology SC Ophthalmology GA 563BQ UT WOS:000275101000002 PM 20079923 ER PT J AU Cukras, C Agron, E Klein, ML Ferris, FL Chew, EY Gensler, G Wong, WT AF Cukras, Catherine Agron, Elvira Klein, Michael L. Ferris, Frederick L., III Chew, Emily Y. Gensler, Gary Wong, Wai T. CA Age Related Eye Dis Study Res Grp TI Natural History of Drusenoid Pigment Epithelial Detachment in Age-Related Macular Degeneration: Age-Related Eye Disease Study Report No. 28 SO OPHTHALMOLOGY LA English DT Article ID GEOGRAPHIC ATROPHY; SEVERITY SCALE; CLASSIFICATION; MACULOPATHY AB Objective: To describe the natural history of eyes with drusenoid pigment epithelial detachments (DPEDs) associated with age-related macular degeneration (AMD). Design: Multicenter, clinic-based, prospective cohort study. Participants: Among 4757 participants enrolled in the Age-Related Eye Disease Study (AREDS), 255 were identified as having DPED in at least 1 eye and having 5 or more years of follow-up after the initial detection of the DPED. Methods: Baseline and annual fundus photographs were evaluated for the evolution of the fundus features and the development of advanced AMD in the forms of central geographic atrophy (CGA) or neovascular (NV) AMD. Kaplan-Meier analyses of progression to advanced AMD and of moderate vision loss (>= 15 letters compared with baseline) were performed. Main Outcome Measures: Rate of progression to advanced AMD and change in visual acuity from baseline (in terms of mean letters lost and proportion losing >= 15 letters). Results: A total of 311 eyes (from 255 participants) with DPED were followed for a median follow-up time of 8 years subsequent to the initial detection of a DPED. Of the 282 eyes that did not have advanced AMD at baseline, advanced AMD developed within 5 years in 119 eyes (42%) (19% progressing to CGA and 23% progressing to NV-AMD). In the remaining eyes that did not develop advanced AMD (n = 163), progressive fundus changes, typified by the development of calcified drusen and pigmentary changes, were detected. Visual decline was prominent among study eyes, with approximately 40% of all eyes decreasing in visual acuity by >= 15 letters at 5 years follow-up. Mean visual acuity decreased from 76 letters (similar to 20/30) at baseline to 61 letters (similar to 20/60) at 5 years. Five-year decreases in mean visual acuity averaged 26 letters for eyes progressing to advanced AMD and 8 letters for non-progressing eyes. Conclusions: The natural history of eyes containing DPED is characterized by a high rate of progression to both CGA and NV-AMD. Among eyes not progressing to advanced AMD, progressive development of pigmentary changes and calcified drusen were observed. Decline of visual acuity is a common outcome, with or without progression to advanced forms of AMD. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 489-499 (C) 2010 by the American Academy of Ophthalmology. C1 [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Cukras, Catherine; Agron, Elvira; Ferris, Frederick L., III; Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Legacy Good Samaritan Hosp & Med Ctr, Devers Eye Inst, Portland, OR USA. [Gensler, Gary] EMMES Corp, AREDS Coordinating Ctr, Rockville, MD 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 National Eye Institute Intramural Research Program FX Supported by funding from the National Eye Institute Intramural Research Program. NR 16 TC 38 Z9 41 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2010 VL 117 IS 3 BP 489 EP 499 DI 10.1016/j.ophtha.2009.12.002 PG 11 WC Ophthalmology SC Ophthalmology GA 563BQ UT WOS:000275101000013 PM 20079925 ER PT J AU Kacmaz, RO Kempen, JH Newcomb, C Daniel, E Gangaputra, S Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Jabs, DA Levy-Clarke, GA Foster, CS AF Kacmaz, R. Oktay Kempen, John H. Newcomb, Craig Daniel, Ebenezer Gangaputra, Sapna Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Levy-Clarke, Grace A. Foster, C. Stephen TI Cyclosporine for Ocular Inflammatory Diseases SO OPHTHALMOLOGY LA English DT Article ID LOW-DOSE CYCLOSPORINE; TERM-FOLLOW-UP; BIRDSHOT RETINOCHOROIDOPATHY; IMMUNOMODULATORY THERAPY; ENDOGENOUS UVEITIS; BEHCETS-SYNDROME; MASKED TRIAL; CYCLOPHOSPHAMIDE; CHOROIDITIS; ARTHRITIS AB Purpose: To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation. Design: Retrospective cohort study. Participants: A total of 373 patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007 inclusive. Methods: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures: Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity. Results: Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone <= 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 250 mg/day tended to be more successful than lower doses and were not associated with a higher discontinuation for toxicity rate; higher doses did not seem to offer a therapeutic advantage. Conclusions: Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2010; 117: 576-584 (C) 2010 by the American Academy of Ophthalmology. C1 [Kacmaz, R. Oktay; Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Daniel, Ebenezer; Gangaputra, Sapna; Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photog Reading Ctr, Madison, WI USA. [Nussenblatt, Robert B.; Levy-Clarke, Grace A.] NEI, Immunol Lab, Bethesda, MD USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Internal Med, Dept Ophthalmol, Portland, OR USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Internal Med, Div Rheumatol, Portland, OR USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kempen, JH (reprint author), Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute [EY014943]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; RPB James S. Adams Special Scholar Award; National Eye Institute; Department of Veterans' Affairs FX Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Dr. Kempen is an RPB James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is an RPB Harrington Special Scholar Award recipient. Dr. Levy-Clarke was previously supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. Dr. Suhler was supported in part by the Department of Veterans' Affairs. NR 41 TC 80 Z9 82 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2010 VL 117 IS 3 BP 576 EP 584 DI 10.1016/j.ophtha.2009.08.010 PG 9 WC Ophthalmology SC Ophthalmology GA 563BQ UT WOS:000275101000025 PM 20031223 ER PT J AU Tsilou, ET Giri, N Weinstein, S Mueller, C Savage, SA Alter, BP AF Tsilou, Ekaterini T. Giri, Neelam Weinstein, Sarah Mueller, Christine Savage, Sharon A. Alter, Blanche P. TI Ocular and Orbital Manifestations of the Inherited Bone Marrow Failure Syndromes: Fanconi Anemia and Dyskeratosis Congenita SO OPHTHALMOLOGY LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; COLE-ENGMAN SYNDROME; GENETIC-HETEROGENEITY; RETINAL VASCULOPATHY; APLASTIC-ANEMIA; GLAUCOMA; PATIENT; EYE; RETINOPATHY; CHILDREN AB Purpose: The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). All 4 syndromes have been associated with various physical abnormalities. As part of a genotype/phenotype/cancer susceptibility study, we determined the prevalence of ophthalmic manifestations in these 4 syndromes. Design: Cross-sectional study of a patient cohort. Participants: Seventy-five patients with an IBMFS and 121 of their first-degree relatives were seen in the National Eye Institute, National Institutes of Health, from 2001 to 2007. The patient group included 22 with FA, 28 with DC, 19 with DBA, and 6 with SDS. Methods: Every participant underwent a complete ophthalmic evaluation and digital facial photography with an adhesive paper ruler on the patient's forehead for an internal measure of scale. Interpupillary distance (IPD), inner canthal distance (ICD), outer canthal distance (OCD), palpebral fissure length (PFL), and corneal diameter (CD) were measured. Thirteen of the 22 patients with FA underwent axial length (AL) measurements by A-scan ultrasonography. Main Outcome Measures: Type and prevalence of ophthalmic manifestations. Results: Ninety-five percent of patients with FA had at least 1 abnormal parameter, and 25% of patients had at least 4 abnormal parameters. Eighty-two percent of patients had small palpebral fissures, 69% of patients had simple microphthalmia, 64% of patients had small OCD, 55% of patients had microcornea, 28% of patients had ptosis, and 6% of patients had epicanthal folds. In patients with DC, abnormalities of the lacrimal drainage system (29%) were the most prevalent findings, followed by retinal abnormalities (pigmentary changes, retinal neovascularization, retinal detachment, exudative retinopathy) in 21%, cicatricial entropion with trichiasis and blepharitis in 7% each, and sparse eyelashes and congenital cataract in 3.5% each. No significant ophthalmic abnormalities were seen in patients with DBA or SDS. Conclusions: Syndrome-specific ocular findings are associated with FA and DC and may antedate diagnosis of the specific syndrome. Early recognition of these abnormalities is important for optimal management. C1 [Tsilou, Ekaterini T.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Giri, Neelam; Weinstein, Sarah; Mueller, Christine; Savage, Sharon A.; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tsilou, ET (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10 Ctr Dr,MSC 1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. EM tsiloue@nei.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural NIH HHS [Z99 HD999999]; NCI NIH HHS [N02CP65504, N02CP11019] NR 47 TC 22 Z9 23 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2010 VL 117 IS 3 BP 615 EP 622 DI 10.1016/j.ophtha.2009.08.023 PG 8 WC Ophthalmology SC Ophthalmology GA 563BQ UT WOS:000275101000030 PM 20022637 ER PT J AU Wu, PH Nelson, N Tseng, Y AF Wu, Pei-Hsun Nelson, Nathaniel Tseng, Yiider TI A general method for improving spatial resolution by optimization of electron multiplication in CCD imaging SO OPTICS EXPRESS LA English DT Article ID PML NUCLEAR-BODIES; PARTICLE TRACKING; MICRORHEOLOGY; CAMERA; SPECTROSCOPY; DYNAMICS AB The electron-multiplying charge-coupled device (EMCCD) camera possesses an electron multiplying function that can effectively convert the weak incident photon signal to amplified electron output, thereby greatly enhancing the contrast of the acquired images. This device has become a popular photon detector in single-cell biophysical assays to enhance subcellular images. However, the quantitative relationship between the resolution in such measurements and the electron multiplication setting in the EMCCD camera is not well-understood. We therefore developed a method to characterize the exact dependence of the signal-to-noise-ratio (SNR) on EM gain settings over a full range of incident light intensity. This information was further used to evaluate the EMCCD performance in subcellular particle tracking. We conclude that there are optimal EM gain settings for achieving the best SNR and the best spatial resolution in these experiments. If it is not used optimally, electron multiplication can decrease the SNR and increases spatial error. (C) 2010 Optical Society of America C1 [Wu, Pei-Hsun; Nelson, Nathaniel; Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. [Wu, Pei-Hsun; Tseng, Yiider] NCI, Phys Sci Oncol Ctr, Gainesville, FL 32611 USA. RP Wu, PH (reprint author), Univ Florida, Dept Chem Engn, Museum Rd, Gainesville, FL 32611 USA. EM ytseng@che.ufl.edu FU National Institutes of Health [U54CA143868, EB004416] FX The authors are grateful for Dr. Tanmay Lele and Mr. Stephen Hugo Arce for their thoughtful discussion. This research was partially funded by National Institutes of Health grants U54CA143868 and EB004416. NR 25 TC 10 Z9 11 U1 1 U2 8 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD MAR 1 PY 2010 VL 18 IS 5 BP 5199 EP 5212 DI 10.1364/OE.18.005199 PG 14 WC Optics SC Optics GA 567NO UT WOS:000275454100008 PM 20389533 ER PT J AU Mezey, E Mayer, B Nemeth, K AF Mezey, E. Mayer, B. Nemeth, K. TI Unexpected roles for bone marrow stromal cells (or MSCs): a real promise for cellular, but not replacement, therapy SO ORAL DISEASES LA English DT Review DE biochemistry; physiology; cell; immunology and microbiology; medicine ID MESENCHYMAL STEM-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; VERSUS-HOST-DISEASE; REGULATORY T-CELLS; LUNG INJURY; RAT MODEL; IN-VIVO; HEMATOPOIETIC ORGANS; DENDRITIC CELLS; LIVER FIBROSIS AB Adult and embryonic stem cells have drawn a lot of attention in the last decade as new tools in regenerative medicine. A variety of such cells have been discovered and put forward as candidates for use in cell replacement therapy. Investigators hope that some, if not all, of our organs can be replaced or restored to function; that new livers, kidneys, and brain cells can be produced. Many reviews have already been written about stem cells and their potential use in regenerating tissues. In this study, we would like to call attention to a different application of a special group of adult stem cells, the stromal cells in the bone marrow (also called mesenchymal stem cells or MSCs). These cells have been discovered to modulate immune function. They can easily be expanded in culture and surprisingly, they also seem not to be immunogenic. Thus, they can be removed from donors, expanded, stored in freezers, and used as allogeneic transplants in a variety of diseases in everyday medicine. C1 [Mezey, E.; Mayer, B.; Nemeth, K.] NIDCR, Adult Stem Cell Unit, NIH, CSDB, Bethesda, MD 20892 USA. RP Mezey, E (reprint author), NIDCR, Adult Stem Cell Unit, NIH, CSDB, 49 Convent Dr,5A76, Bethesda, MD 20892 USA. EM mezeye@mail.nih.gov RI Mayer, Balazs/B-7864-2013 OI Mayer, Balazs/0000-0003-3577-3823 FU DIR; NIDCR of the IRP; NIH FX The work was supported by the DIR, NIDCR of the IRP, NIH. NR 88 TC 5 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD MAR PY 2010 VL 16 IS 2 BP 129 EP 135 DI 10.1111/j.1601-0825.2009.01605.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 558AW UT WOS:000274713400002 PM 19656313 ER PT J AU McDermott, NE Barrett, J Hipp, J Merino, MJ Lee, CCR Waterman, P Domingo, DL Walsh, TJ AF McDermott, Nancy E. Barrett, John Hipp, Jason Merino, Maria J. Lee, Chyi-Chia Richard Waterman, Paige Domingo, Demetrio L. Walsh, Thomas J. TI Successful treatment of periodontal mucormycosis: report of a case and literature review SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTOLOGY LA English DT Review ID CALCOFLUOR WHITE STAIN; MUCOR-INDICUS; CUTANEOUS MUCORMYCOSIS; ZYGOMYCOSIS; FUNGI; EPIDEMIOLOGY; INFECTIONS; SPECIMENS; DIAGNOSIS; LEUKEMIA AB Mucormycosis is an aggressive and potentially devastating fungal infection which typically manifests in pulmonary, rhinocerebral, or disseminated forms in patients with hematologic malignancy. Mucormycosis confined to the periodontium is uncommon, and to our knowledge only 6 cases have been reported in the English-language literature. This case report describes a patient with acute leukemia and periodontal mucormycosis. Calcofluor fluorescence microscopy is also proposed as a method for establishing a prompt diagnosis and guiding extent of intraoperative surgical debridement. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: e64-e69) C1 [McDermott, Nancy E.; Domingo, Demetrio L.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Barrett, John] NHLBI, Bethesda, MD 20892 USA. [Merino, Maria J.; Lee, Chyi-Chia Richard] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP McDermott, NE (reprint author), Natl Inst Dent & Craniofacial Res, Bldg 10,Room 1N117,Mailstop 1191, Bethesda, MD 20892 USA. EM mcdermottn@nidcr.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 NR 30 TC 11 Z9 11 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD MAR PY 2010 VL 109 IS 3 BP E64 EP E69 DI 10.1016/j.tripleo.2009.11.012 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 561DT UT WOS:000274956600035 PM 20219588 ER PT J AU Alter, BP Olson, SB AF Alter, Blanche P. Olson, Susan B. TI Wilms Tumor, AML, and Medulloblastoma in a Child With Cancer Prone Syndrome of Total Premature Chromatid Separation and Fanconi Anemia SO PEDIATRIC BLOOD & CANCER LA English DT Letter ID ANEUPLOIDY C1 [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Olson, Susan B.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Rm 7020, Rockville, MD 20852 USA. EM alterb@mail.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2010 VL 54 IS 3 BP 488 EP 488 DI 10.1002/pbc.22333 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 554FR UT WOS:000274421400033 PM 19856400 ER PT J AU Casella, JF King, AA Barton, B White, DA Noetzel, MJ Ichord, RN Terrill, C Hirtz, D McKinstry, RC Strouse, JJ Howard, TH Coates, TD Minniti, CP Campbell, AD Vendt, BA Lehmann, H DeBaun, MR AF Casella, James F. King, Allison A. Barton, Bruce White, Desiree A. Noetzel, Michael J. Ichord, Rebecca N. Terrill, Cindy Hirtz, Deborah McKinstry, Robert C. Strouse, John J. Howard, Thomas H. Coates, Thomas D. Minniti, Caterina P. Campbell, Andrew D. Vendt, Bruce A. Lehmann, Harold DeBaun, Michael R. TI DESIGN OF THE SILENT CEREBRAL INFARCT TRANSFUSION (SIT) TRIAL SO PEDIATRIC HEMATOLOGY AND ONCOLOGY LA English DT Article ID SICKLE-CELL-DISEASE; CHILDREN; STROKE; ANEMIA; THERAPY; RISK AB Background: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. Procedure: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12-18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. Conclusion: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.= 15 degrees, a positive apprehension test, patellar lateral hypermobility (>= 10 mm), or a positive "J sign." Methods. Each knee underwent 2 randomly ordered testing conditions (untaped and taped). A full fast-phase contrast (PC) magnetic resonance image set was acquired for each condition while the participants volitionally extended and flexed their knee. Three-dimensional displacements and rotations were calculated through integration of the fast-PC velocity data. Statistical comparisons between baseline patellofemoral kinematics and the change in kinematics clue to taping were performed using a 2-tailed paired Student t test. Correlations between baseline patellofemoral kinematics and the change in kinematics due to taping also were quantified. Results. Patellar taping resulted in a significant patellofemoral inferior shift. The strongest correlation existed between the change in lateral-medial displacement with taping and baseline (r=.60). Conclusions. The inferior shift in patellar displacement with taping partially explains the previously documented decrease in pain due to increases in contact area. The lack of alteration in 5 of the 6 kinematic variables with taping may have been due to the fact that post-taping kinematic alterations are sensitive to the baseline kinematic values. C1 [Brindle, Timothy J.; Alter, Katharine E.; Sheehan, Frances T.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Rehabil Programs, Baltimore, MD USA. [Alter, Katharine E.] Johns Hopkins Hlth Syst Corp, Baltimore, MD USA. RP Sheehan, FT (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10,CRC Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 FU Howard Hughes Foundation; National Institutes of Health FX This research was supported, in part, by the Howard Hughes Foundation and the Intramural Research Program of the National Institutes of Health (Clinical Center and National Institute of Child Health and Human Development). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Institutes of Health or the US Public Health Service. NR 45 TC 23 Z9 24 U1 0 U2 6 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD MAR PY 2010 VL 90 IS 3 BP 411 EP 419 DI 10.2522/ptj.20080365 PG 9 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 574YP UT WOS:000276030400013 PM 20110340 ER PT J AU Moralejo, DH Hansen, CT Treuting, P Hessner, MJ Fuller, JM Van Yserloo, B Jensen, R Osborne, W Kwitek, AE Lernmark, A AF Moralejo, Daniel H. Hansen, Carl T. Treuting, Piper Hessner, Martin J. Fuller, Jessica M. Van Yserloo, Brian Jensen, Richard Osborne, William Kwitek, Anne E. Lernmark, Ake TI Differential effects of leptin receptor mutation on male and female BBDR.(Gimap5-/Gimap5-) spontaneously diabetic rats SO PHYSIOLOGICAL GENOMICS LA English DT Article DE obesity; diabetes; islet inflammation; lymphopenia ID T-CELL DEVELOPMENT; BB RAT; LYMPHOCYTE SURVIVAL; GENETIC DISSECTION; IMMUNE-RESPONSES; BODY-WEIGHT; IAN5 GENE; FATTY RAT; F344 RAT; EXPRESSION AB Moralejo DH, Hansen CT, Treuting P, Hessner MJ, Fuller JM, Van Yserloo B, Jensen R, Osborne W, Kwitek AE, Lernmark angstrom. Differential effects of leptin receptor mutation on male and female BBDR.(Gimap5-/Gimap5-) spontaneously diabetic rats. Physiol Genomics 41: 9-20, 2010. First published December 8, 2009; doi:10.1152/physiolgenomics.00186.2009.-Rodents homozygous for autosomal leptin receptor gene mutations not only become obese, insulin resistant, and hyperleptinemic but also develop a dysregulated immune system. Using marker-assisted breeding to introgress the Koletsky rat leptin receptor mutant (lepr(-)/lepr(-)), we developed a novel congenic BBDR.(lepr-/lepr-) rat line to study the development of obesity and type 2 diabetes (T2D) in the BioBreeding ( BB) diabetes-resistant (DR) rat. While heterozygous lepr (-/+) or homozygous (+/+) BBDR rats remained lean and metabolically normal, at 3 wk of age all BBDR.(lepr-/lepr-) rats were obese without hyperglycemia. Between 45 and 70 days of age, male but not female obese rats developed T2D. We had previously developed congenic BBDR.(Gimap5-/Gimap5-) rats, which carry an autosomal frameshift mutation in the Gimap5 gene linked to lymphopenia and spontaneous development of type 1 diabetes (T1D) without sex differences. Because the autoimmune-mediated destruction of pancreatic islet beta-cells may be affected not only by obesity but also by the absence of leptin receptor signaling, we next generated BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) double congenic rats carrying the mutation for Gimap5 and T1D as well as the Lepr mutation for obesity and T2D. The hyperleptinemia rescued end-stage islets in BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats and induced an increase in islet size in both sexes, while T1D development was delayed and reduced only in females. These results demonstrate that obesity and T2D induced by introgression of the Koletsky leptin receptor mutation in the BBDR rat result in islet expansion associated with protection from T1D in female but not male BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats. BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats should prove valuable to study interactions between lack of leptin receptor signaling, obesity, and sex-specific T2D and T1D. C1 [Moralejo, Daniel H.; Treuting, Piper] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Fuller, Jessica M.; Jensen, Richard; Lernmark, Ake] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Osborne, William] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Van Yserloo, Brian; Osborne, William] Univ Washington, Dept Diabet, Seattle, WA 98195 USA. Univ Washington, Endocrinol Res Ctr, Seattle, WA 98195 USA. [Kwitek, Anne E.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Kwitek, Anne E.] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Hansen, Carl T.] NIH, Bethesda, MD 20892 USA. [Hessner, Martin J.] Med Coll Wisconsin, Dept Pediat, Max McGee Natl Res Ctr Juvenile Diabet, Milwaukee, WI 53226 USA. [Hessner, Martin J.] Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53201 USA. RP Moralejo, DH (reprint author), Univ Washington, Dept Comparat Med, HSB K-165,Box 357710,1959 NE Pacific St, Seattle, WA 98195 USA. EM moralejo@u.washington.edu FU Junior Faculty Award [1-05-JF-32]; Mentor Based Postdoctoral Fellowship Award; American Diabetes Association; National Institutes of Health [AI-42380]; Virus Molecular Biology and Cell Core; University of Washington Diabetes and Endocrinology Research Center [DK-17047]; Robert H. Williams Endowment FX This work was supported by a Junior Faculty Award (1-05-JF-32) ( D. H. Moralejo) and a Mentor Based Postdoctoral Fellowship Award (angstrom. Lernmark) from the American Diabetes Association, the National Institutes of Health (AI-42380), the Virus Molecular Biology and Cell Core ( W. Osborne and B. Van Yserloo) of the University of Washington Diabetes and Endocrinology Research Center (DK-17047), as well as by the Robert H. Williams Endowment at the University of Washington. NR 52 TC 6 Z9 6 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAR PY 2010 VL 41 IS 1 BP 9 EP 20 DI 10.1152/physiolgenomics.00186.2009 PG 12 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 563TY UT WOS:000275158700002 PM 19996157 ER PT J AU Hoi, Y Wasserman, BA Xie, YYJ Najjar, SS Ferruci, L Lakatta, EG Gerstenblith, G Steinman, DA AF Hoi, Yiemeng Wasserman, Bruce A. Xie, Yuanyuan J. Najjar, Samer S. Ferruci, Luigi Lakatta, Edward G. Gerstenblith, Gary Steinman, David A. TI Characterization of volumetric flow rate waveforms at the carotid bifurcations of older adults SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE volumetric flow rate; carotid bifurcation; magnetic resonance imaging; human studies; augmentation index ID VERTEBRAL ARTERIES; HEMODYNAMICS; AGE AB While it is widely appreciated that volumetric blood flow rate (VFR) dynamics change with age, there has been no detailed characterization of the typical shape of carotid bifurcation VFR waveforms of older adults. Toward this end, retrospectively gated phase contrast magnetic resonance imaging was used to measure time-resolved VFR waveforms proximal and distal to the carotid bifurcations of 94 older adults (age 68 +/- 8 years) with little or no carotid artery disease, recruited from the BLSA cohort of the VALIDATE study of factors in vascular aging. Timings and amplitudes of well-defined feature points from these waveforms were extracted automatically and averaged to produce representative common, internal and external carotid artery (CCA, ICA and ECA) waveform shapes. Relative to young adults, waveforms from older adults were found to exhibit a significantly augmented secondary peak during late systole, resulting in significantly higher resistance index (RI) and flow augmentation index (FAI). Cycle-averaged VFR at the CCA, ICA and ECA were 389 +/- 74, 245 +/- 61 and 125 +/- 49 mL min(-1), respectively, reflecting a significant cycle-averaged outflow deficit of 5%, which peaked at around 10% during systole. A small but significant mean delay of 13 ms between arrivals of ICA versus CCA/ECA peak VFR suggested differential compliance of these vessels. Sex and age differences in waveform shape were also noted. The characteristic waveforms presented here may serve as a convenient baseline for studies of VFR waveform dynamics or as suitable boundary conditions for models of blood flow in the carotid arteries of older adults. C1 [Hoi, Yiemeng; Xie, Yuanyuan J.; Steinman, David A.] Univ Toronto, Dept Mech & Ind Engn, Biomed Simulat Lab, Toronto, ON, Canada. [Wasserman, Bruce A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Najjar, Samer S.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ferruci, Luigi] NIA, Clin Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gerstenblith, Gary] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. RP Hoi, Y (reprint author), Univ Toronto, Dept Mech & Ind Engn, Biomed Simulat Lab, Toronto, ON, Canada. EM steinman@mie.utoronto.ca RI Steinman, David/A-4258-2008 OI Steinman, David/0000-0002-7963-1168 FU Canadian Institutes of Health Research [MOP-62934]; NIH, National Institute on Aging [NO1-AG-3-1003]; Heart & Stroke Foundation Career Investigator Award FX This study was supported by grant MOP-62934 from the Canadian Institutes of Health Research. The VALIDATE study is supported by Contract NO1-AG-3-1003 from the National Institute on Aging, and, in part, by the Intramural Research Program of the NIH, National Institute on Aging. DAS also acknowledges the support of a Heart & Stroke Foundation Career Investigator Award. NR 16 TC 36 Z9 36 U1 0 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 J9 PHYSIOL MEAS JI Physiol. Meas. PD MAR PY 2010 VL 31 IS 3 BP 291 EP 302 DI 10.1088/0967-3334/31/3/002 PG 12 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA 559SQ UT WOS:000274848400002 PM 20086276 ER PT J AU Shearin, AL Ostrander, EA AF Shearin, Abigail L. Ostrander, Elaine A. TI Canine Morphology: Hunting for Genes and Tracking Mutations SO PLOS BIOLOGY LA English DT Article ID ROD-CONE DEGENERATION; DOMESTIC DOG; LINKAGE DISEQUILIBRIUM; GENOME SEQUENCE; COAT COLOR; EVOLUTION; INSERTION; CANIDAE; TRAITS; BREEDS C1 [Shearin, Abigail L.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Shearin, Abigail L.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. RP Shearin, AL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU National Human Genome Research Institute; Howard Hughes Scholars Program FX Funding: This work is supported by the intramural Program of the National Human Genome Research Institute and the Howard Hughes Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 19 Z9 19 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2010 VL 8 IS 3 AR e1000310 DI 10.1371/journal.pbio.1000310 PG 6 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 602GB UT WOS:000278125400001 PM 20209140 ER PT J AU Daigle, BJ Deng, A McLaughlin, T Cushman, SW Cam, MC Reaven, G Tsao, PS Altman, RB AF Daigle, Bernie J., Jr. Deng, Alicia McLaughlin, Tracey Cushman, Samuel W. Cam, Margaret C. Reaven, Gerald Tsao, Philip S. Altman, Russ B. TI Using Pre-existing Microarray Datasets to Increase Experimental Power: Application to Insulin Resistance SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID DIFFERENTIALLY EXPRESSED GENES; SINGULAR-VALUE DECOMPOSITION; INTEGRATIVE ANALYSIS; REGULATORY MODULES; OBESE INDIVIDUALS; DNA MICROARRAY; ADIPOSE-TISSUE; BREAST-CANCER; NETWORK; DISEASE AB Although they have become a widely used experimental technique for identifying differentially expressed (DE) genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources; thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT), a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes' expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58%) of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a freely available software package that is immediately applicable to any human microarray study. C1 [Daigle, Bernie J., Jr.; Altman, Russ B.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [McLaughlin, Tracey; Reaven, Gerald; Tsao, Philip S.] Stanford Univ, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. [McLaughlin, Tracey] Stanford Univ, Div Endocrinol, Sch Med, Stanford, CA 94305 USA. [Cushman, Samuel W.; Cam, Margaret C.] NIDDK, NIH, Bethesda, MD USA. [Altman, Russ B.] Stanford Univ, Dept Bioengn, Sch Med, Stanford, CA 94305 USA. RP Daigle, BJ (reprint author), Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. EM russ.altman@stanford.edu FU NIH [GM61374, DK071333, DK071309]; HHMI; NLM FX This study was funded by NIH grants GM61374, DK071333, and DK071309, and a gift from Microsoft. BJD is supported by an HHMI predoctoral fellowship and an NLM training fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2010 VL 6 IS 3 AR e1000718 DI 10.1371/journal.pcbi.1000718 PG 15 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 602FZ UT WOS:000278125200026 PM 20361040 ER PT J AU Li, CY Zhang, Y Wang, ZB Zhang, Y Cao, CM Zhang, PW Lu, SJ Li, XM Yu, Q Zheng, XF Du, Q Uhl, GR Liu, QR Wei, LP AF Li, Chuan-Yun Zhang, Yong Wang, Zhanbo Zhang, Yan Cao, Chunmei Zhang, Ping-Wu Lu, Shu-Juan Li, Xiao-Mo Yu, Quan Zheng, Xiaofeng Du, Quan Uhl, George R. Liu, Qing-Rong Wei, Liping TI A Human-Specific De Novo Protein-Coding Gene Associated with Human Brain Functions SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID DROSOPHILA-MELANOGASTER; MOLECULAR-GENETICS; NONCODING DNA; BDNF GENES; EVOLUTION; SEQUENCE; DATABASE; DISEASE; LINKAGE; JINGWEI AB To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203). Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions. C1 [Li, Chuan-Yun; Lu, Shu-Juan; Li, Xiao-Mo; Wei, Liping] Peking Univ, Ctr Bioinformat, Natl Lab Prot Engn & Plant Genet Engn, Coll Life Sci, Beijing 100871, Peoples R China. [Zhang, Yong] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. [Wang, Zhanbo] Chinese Peoples Liberat Army Gen Hosp, Dept Pathol, Beijing, Peoples R China. [Zhang, Yan; Cao, Chunmei; Du, Quan] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Zhang, Ping-Wu; Uhl, George R.] NIDA, Mol Neurobiol Branch, Baltimore, MD USA. [Yu, Quan; Zheng, Xiaofeng] Peking Univ, Dept Biochem & Mol Biol, Natl Lab Prot Engn & Plant Genet Engn, Coll Life Sci, Beijing 100871, Peoples R China. [Liu, Qing-Rong] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. RP Li, CY (reprint author), Peking Univ, Ctr Bioinformat, Natl Lab Prot Engn & Plant Genet Engn, Coll Life Sci, Beijing 100871, Peoples R China. EM qrliu1@verizon.net; weilp@mail.cbi.pku.edu.cn RI Zhang, Yan/B-2831-2012; Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 FU China National High-tech 863 Programs [2006AA02Z334, 2006AA02Z314, 2006AA02A312, 2007AA02Z165]; 973 Programs [2006CB910404, 2007CB946904]; China Postdoctoral Science Foundation [20090460160]; National Institutes of Health (NIH), National Institute on Drug Abuse FX This study was supported by the China National High-tech 863 Programs (2006AA02Z334, 2006AA02Z314, 2006AA02A312, 2007AA02Z165) and 973 Programs (2006CB910404, 2007CB946904), the China Postdoctoral Science Foundation (20090460160) and the National Institutes of Health (NIH)-Intramural Research Program, National Institute on Drug Abuse. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 52 Z9 54 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2010 VL 6 IS 3 AR e1000734 DI 10.1371/journal.pcbi.1000734 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 602FZ UT WOS:000278125200032 PM 20376170 ER PT J AU Alur, RP Vijayasarathy, C Brown, JD Mehtani, M Onojafe, IF Sergeev, YV Boobalan, E Jones, M Tang, K Liu, HQ Xia, CH Gong, XH Brooks, BP AF Alur, Ramakrishna P. Vijayasarathy, Camasamudram Brown, Jacob D. Mehtani, Mohit Onojafe, Ighovie F. Sergeev, Yuri V. Boobalan, Elangovan Jones, MaryPat Tang, Ke Liu, Haiquan Xia, Chun-hong Gong, Xiaohua Brooks, Brian P. TI Papillorenal Syndrome-Causing Missense Mutations in PAX2/Pax2 Result in Hypomorphic Alleles in Mouse and Human SO PLOS GENETICS LA English DT Article ID RENAL-COLOBOMA SYNDROME; ASTROCYTE PRECURSOR CELLS; OPTIC-NERVE COLOBOMAS; DOMAIN-DNA COMPLEX; PAX2 GENE; TRANSCRIPTION ACTIVATION; VESICOURETERAL REFLUX; CRYSTAL-STRUCTURE; PROTEIN; EXPRESSION AB Papillorenal syndrome (PRS, also known as renal-coloboma syndrome) is an autosomal dominant disease characterized by potentially-blinding congenital optic nerve excavation and congenital kidney abnormalities. Many patients with PRS have mutations in the paired box transcription factor gene, PAX2. Although most mutations in PAX2 are predicted to result in complete loss of one allele's function, three missense mutations have been reported, raising the possibility that more subtle alterations in PAX2 function may be disease-causing. To date, the molecular behaviors of these mutations have not been explored. We describe a novel mouse model of PRS due to a missense mutation in a highly-conserved threonine residue in the paired domain of Pax2 (p.T74A) that recapitulates the ocular and kidney findings of patients. This mutation is in the Pax2 paired domain at the same location as two human missense mutations. We show that all three missense mutations disrupt potentially critical hydrogen bonds in atomic models and result in reduced Pax2 transactivation, but do not affect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind its DNA consensus sequence. Moreover, these mutations show reduced steady-state levels of Pax2 protein in vitro and ( for p.T74A) in vivo, likely by reducing protein stability. These results suggest that hypomorphic alleles of PAX2/Pax2 can lead to significant disease in humans and mice. C1 [Alur, Ramakrishna P.; Brown, Jacob D.; Mehtani, Mohit; Onojafe, Ighovie F.; Sergeev, Yuri V.; Boobalan, Elangovan] NIH, Ophthalm Genet & Visual Funct Branch, Natl Eye Inst, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram; Brooks, Brian P.] Natl Inst Deafness & Other Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Brown, Jacob D.; Brooks, Brian P.] Georgetown Univ, Sch Med, Dept Biochem Mol & Cellular Biol, Washington, DC USA. [Jones, MaryPat] NIH, Natl Human Genome Res Inst, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tang, Ke] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Liu, Haiquan; Xia, Chun-hong; Gong, Xiaohua] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. [Liu, Haiquan; Xia, Chun-hong; Gong, Xiaohua] Univ Calif Berkeley, Vis Sci Program, Berkeley, CA 94720 USA. RP Alur, RP (reprint author), NIH, Ophthalm Genet & Visual Funct Branch, Natl Eye Inst, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov FU National Eye Institute; National Institutes of Health [EY013849] FX This work was supported by the intramural program at the National Eye Institute, National Institutes of Health, and by NIH grant EY013849. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 9 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2010 VL 6 IS 3 AR e1000870 DI 10.1371/journal.pgen.1000870 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 578RE UT WOS:000276311400024 PM 20221250 ER PT J AU Moshkovich, N Lei, EP AF Moshkovich, Nellie Lei, Elissa P. TI HP1 Recruitment in the Absence of Argonaute Proteins in Drosophila SO PLOS GENETICS LA English DT Article ID POSITION-EFFECT VARIEGATION; RNA INTERFERENCE; HETEROCHROMATIN FORMATION; CHROMATIN INSULATOR; MESSENGER-RNAS; CELL-FORMATION; SOMATIC-CELLS; MELANOGASTER; PIWI; GENE AB Highly repetitive and transposable element rich regions of the genome must be stabilized by the presence of heterochromatin. A direct role for RNA interference in the establishment of heterochromatin has been demonstrated in fission yeast. In metazoans, which possess multiple RNA-silencing pathways that are both functionally distinct and spatially restricted, whether RNA silencing contributes directly to heterochromatin formation is not clear. Previous studies in Drosophila melanogaster have suggested the involvement of both the AGO2-dependent endogenous small interfering RNA (endo-siRNA) as well as Piwi-interacting RNA (piRNA) silencing pathways. In order to determine if these Argonaute genes are required for heterochromatin formation, we utilized transcriptional reporters and chromatin immunoprecipitation of the critical factor Heterochromatin Protein 1 (HP1) to monitor the heterochromatic state of piRNA clusters, which generate both endo-siRNAs and the bulk of piRNAs. Surprisingly, we find that mutation of AGO2 or piwi increases silencing at piRNA clusters corresponding to an increase of HP1 association. Furthermore, loss of piRNA production from a single piRNA cluster results in genome-wide redistribution of HP1 and reduction of silencing at a distant heterochromatic site, suggesting indirect effects on HP1 recruitment. Taken together, these results indicate that heterochromatin forms independently of endo-siRNA and piRNA pathways. C1 [Moshkovich, Nellie; Lei, Elissa P.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Moshkovich, Nellie] Univ Maryland, Grad Program Mol & Cell Biol, College Pk, MD 20742 USA. RP Moshkovich, N (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 43 Z9 46 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2010 VL 6 IS 3 AR e1000880 DI 10.1371/journal.pgen.1000880 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 578RE UT WOS:000276311400018 PM 20300658 ER PT J AU Clark, DB Moss, HB AF Clark, Duncan B. Moss, Howard B. TI Providing Alcohol-Related Screening and Brief Interventions to Adolescents through Health Care Systems: Obstacles and Solutions SO PLOS MEDICINE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; USE DISORDERS; SUBSTANCE-ABUSE; YOUNG-ADULTS; AGE; REDUCTION; DRINKING; AUDIT; ONSET C1 [Clark, Duncan B.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. [Moss, Howard B.] NIAAA, NIH, Bethesda, MD USA. RP Clark, DB (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. EM clarkdb@upmc.edu FU NIAAA NIH HHS [U01 AA016482, R01 AA016482, U01 AA016482-04, U01AA016482]; NIDA NIH HHS [P50 DA005605, P50 DA005605-19A28741, P50DA05605] NR 37 TC 19 Z9 19 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD MAR PY 2010 VL 7 IS 3 AR e1000214 DI 10.1371/journal.pmed.1000214 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 578RF UT WOS:000276311600004 PM 20231870 ER PT J AU Souza, AP Andrade, BB Aquino, D Entringer, P Miranda, JC Alcantara, R Ruiz, D Soto, M Teixeira, CR Valenzuela, JG de Oliveira, CI Brodskyn, CI Barral-Netto, M Barral, A AF Souza, Ana Paula Andrade, Bruno Bezerril Aquino, Dorlene Entringer, Petter Miranda, Jose Carlos Alcantara, Ruan Ruiz, Daniel Soto, Manuel Teixeira, Clarissa R. Valenzuela, Jesus G. de Oliveira, Camila Indiani Brodskyn, Claudia Ida Barral-Netto, Manoel Barral, Aldina TI Using Recombinant Proteins from Lutzomyia longipalpis Saliva to Estimate Human Vector Exposure in Visceral Leishmaniasis Endemic Areas SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID PHLEBOTOMINE SANDFLIES; BRAZILIENSIS INFECTION; IMMUNE-RESPONSE; PSYCHODIDAE; ANTIGENS; ANTIBODY; CHAGASI; DIPTERA; GLANDS; MARKER AB Background: Leishmania is transmitted by female sand flies and deposited together with saliva, which contains a vast repertoire of pharmacologically active molecules that contribute to the establishment of the infection. The exposure to vector saliva induces an immune response against its components that can be used as a marker of exposure to the vector. Performing large-scale serological studies to detect vector exposure has been limited by the difficulty in obtaining sand fly saliva. Here, we validate the use of two sand fly salivary recombinant proteins as markers for vector exposure. Methodology/principal findings: ELISA was used to screen human sera, collected in an area endemic for visceral leishmaniasis, against the salivary gland sonicate (SGS) or two recombinant proteins (rLJM11 and rLJM17) from Lutzomyia longipalpis saliva. Antibody levels before and after SGS seroconversion (n=26) were compared using the Wilcoxon signed rank paired test. Human sera from an area endemic for VL which recognize Lu. longipalpis saliva in ELISA also recognize a combination of rLJM17 and rLJM11. We then extended the analysis to include 40 sera from individuals who were seropositive and 40 seronegative to Lu. longipalpis SGS. Each recombinant protein was able to detect anti-saliva seroconversion, whereas the two proteins combined increased the detection significantly. Additionally, we evaluated the specificity of the anti-Lu. longipalpis response by testing 40 sera positive to Lutzomyia intermedia SGS, and very limited (2/40) cross-reactivity was observed. Receiver-operator characteristics (ROC) curve analysis was used to identify the effectiveness of these proteins for the prediction of anti-SGS positivity. These ROC curves evidenced the superior performance of rLJM17+rLJM11. Predicted threshold levels were confirmed for rLJM17+rLJM11 using a large panel of 1,077 serum samples. Conclusion: Our results show the possibility of substituting Lu. longipalpis SGS for two recombinant proteins, LJM17 and LJM11, in order to probe for vector exposure in individuals residing in endemic areas. C1 [Souza, Ana Paula; Andrade, Bruno Bezerril; Aquino, Dorlene; Entringer, Petter; Miranda, Jose Carlos; Alcantara, Ruan; de Oliveira, Camila Indiani; Brodskyn, Claudia Ida; Barral-Netto, Manoel; Barral, Aldina] Fiocruz MS, Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Aquino, Dorlene] Univ Fed Maranhao, Dept Enfermagem, Sao Luis, Brazil. [Ruiz, Daniel; Soto, Manuel] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, Dept Biol Mol, Madrid, Spain. [Teixeira, Clarissa R.; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [de Oliveira, Camila Indiani; Brodskyn, Claudia Ida; Barral-Netto, Manoel; Barral, Aldina] INCT, Inst Invest Imunol, Sao Paulo, Brazil. RP Souza, AP (reprint author), Fiocruz MS, Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. EM abarral@bahia.fiocruz.br RI de Oliveira, Camila/B-4358-2009; Barral Netto, Manoel/B-3904-2009; Barral, Aldina/B-4191-2009; Andrade, Bruno/J-9111-2012; Imunologia, Inct/I-2124-2013; OI de Oliveira, Camila/0000-0002-7868-5164; Barral Netto, Manoel/0000-0002-5823-7903; Barral, Aldina/0000-0002-7177-464X; Andrade, Bruno/0000-0001-6833-3811; Soto Alvarez, Manuel/0000-0001-6825-841X FU CNPq; CYTED; CAPES; Renorbio/CNPq; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; FIOCRUZ; FAPESB FX This work was supported by grants from CNPq, CYTED, CAPES, and Renorbio/CNPq. This work was partially supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. BBA was supported by CNPq. APS and RA were supported by CAPES fellowships. PE was supported by a FIOCRUZ fellowship. DR was supported by a FAPESB fellowship. CIdO, CIB, MBN, and AB are senior investigators from CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 17 TC 37 Z9 37 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAR PY 2010 VL 4 IS 3 AR e649 DI 10.1371/journal.pntd.0000649 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 578RG UT WOS:000276312200015 PM 20351785 ER PT J AU Teixeira, C Gomes, R Collin, N Reynoso, D Jochim, R Oliveira, F Seitz, A Elnaiem, DE Caldas, A de Souza, AP Brodskyn, CI de Oliveira, CI Mendonca, I Costa, CHN Volf, P Barral, A Kamhawi, S Valenzuela, JG AF Teixeira, Clarissa Gomes, Regis Collin, Nicolas Reynoso, David Jochim, Ryan Oliveira, Fabiano Seitz, Amy Elnaiem, Dia-Eldin Caldas, Arlene de Souza, Ana Paula Brodskyn, Claudia I. de Oliveira, Camila Indiani Mendonca, Ivete Costa, Carlos H. N. Volf, Petr Barral, Aldina Kamhawi, Shaden Valenzuela, Jesus G. TI Discovery of Markers of Exposure Specific to Bites of Lutzomyia longipalpis, the Vector of Leishmania infantum chagasi in Latin America SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CANINE VISCERAL LEISHMANIASIS; ANTITICK SALIVA ANTIBODY; SAND FLIES; EPIDEMIOLOGIC MARKER; IMMUNE-RESPONSE; TICK BITE; FLY; TRANSCRIPTOME; PROTEINS; ANTIGENS AB Background: Sand flies deliver Leishmania parasites to a host alongside salivary molecules that affect infection outcomes. Though some proteins are immunogenic and have potential as markers of vector exposure, their identity and vector specificity remain elusive. Methodology/Principal Findings: We screened human, dog, and fox sera from endemic areas of visceral leishmaniasis to identify potential markers of specific exposure to saliva of Lutzomyia longipalpis. Human and dog sera were further tested against additional sand fly species. Recombinant proteins of nine transcripts encoding secreted salivary molecules of Lu. longipalpis were produced, purified, and tested for antigenicity and specificity. Use of recombinant proteins corresponding to immunogenic molecules in Lu. longipalpis saliva identified LJM17 and LJM11 as potential markers of exposure. LJM17 was recognized by human, dog, and fox sera; LJM11 by humans and dogs. Notably, LJM17 and LJM11 were specifically recognized by humans exposed to Lu. longipalpis but not by individuals exposed to Lu. intermedia. Conclusions/Significance: Salivary recombinant proteins are of value as markers of vector exposure. In humans, LJM17 and LJM11 emerged as potential markers of specific exposure to Lu. longipalpis, the vector of Leishmania infantum chagasi in Latin America. In dogs, LJM17, LJM11, LJL13, LJL23, and LJL143 emerged as potential markers of sand fly exposure. Testing these recombinant proteins in large scale studies will validate their usefulness as specific markers of Lu. longipalpis exposure in humans and of sand fly exposure in dogs. C1 [Teixeira, Clarissa; Gomes, Regis; Collin, Nicolas; Reynoso, David; Jochim, Ryan; Oliveira, Fabiano; Seitz, Amy; Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Elnaiem, Dia-Eldin] Univ Maryland Eastern Shore, Dept Nat Sci, Princess Anne, MD USA. [Caldas, Arlene] Univ Fed Maranhao, Sao Luis, Maranhao, Brazil. [de Souza, Ana Paula; Brodskyn, Claudia I.; de Oliveira, Camila Indiani; Barral, Aldina] Fiocruz MS, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Mendonca, Ivete; Costa, Carlos H. N.] Inst Doencas Tropicais Natan Portella, Teresina, Piaui, Brazil. [Mendonca, Ivete; Costa, Carlos H. N.] Univ Fed Piaui, Teresina, Piaui, Brazil. [Volf, Petr] Charles Univ Prague, Dept Parasitol, Fac Sci, Prague, Czech Republic. RP Teixeira, C (reprint author), NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM jvalenzuela@niaid.nih.gov RI de Oliveira, Camila/B-4358-2009; Oliveira, Fabiano/B-4251-2009; Volf, Petr/C-4300-2012; Jochim, Ryan/C-6756-2013; Imunologia, Inct/I-2124-2013; Barral, Aldina/B-4191-2009 OI de Oliveira, Camila/0000-0002-7868-5164; Oliveira, Fabiano/0000-0002-7924-8038; Volf, Petr/0000-0003-1790-1123; Barral, Aldina/0000-0002-7177-464X FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US 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, US National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 52 Z9 52 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAR PY 2010 VL 4 IS 3 AR e638 DI 10.1371/journal.pntd.0000638 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 578RG UT WOS:000276312200011 PM 20351786 ER PT J AU Chesebro, B Race, B Meade-White, K LaCasse, R Race, R Klingeborn, M Striebel, J Dorward, D McGovern, G Jeffrey, M AF Chesebro, Bruce Race, Brent Meade-White, Kimberly LaCasse, Rachel Race, Richard Klingeborn, Mikael Striebel, James Dorward, David McGovern, Gillian Jeffrey, Martin TI Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring SO PLOS PATHOGENS LA English DT Article ID STRAUSSLER-SCHEINKER-DISEASE; SCRAPIE-INFECTED MICE; CHRONIC WASTING DISEASE; INCUBATION PERIOD; TRANSGENIC MICE; SPONGIFORM ENCEPHALOPATHY; ELECTRON-MICROSCOPY; PRP ACCUMULATION; RESISTANT STATE; DEXTRAN SULFATE AB Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease. C1 [Chesebro, Bruce; Race, Brent; Meade-White, Kimberly; LaCasse, Rachel; Race, Richard; Klingeborn, Mikael; Striebel, James] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. [Dorward, David] NIAID, Rocky Mt Labs, Electron Microscopy Sect, Res Technol Branch, Hamilton, MT 59840 USA. [McGovern, Gillian; Jeffrey, Martin] VLA Lasswade, Penicuik, Midlothian, Scotland. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM bchesebro@nih.gov RI Jeffrey, Martin/D-2251-2009; McGOVERN, GILLIAN/C-3441-2011; APHA, Staff publications/E-6082-2010 OI McGOVERN, GILLIAN/0000-0001-5344-5909; FU NIAID FX Funded by the Intramural program of NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 67 Z9 68 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2010 VL 6 IS 3 AR e1000800 DI 10.1371/journal.ppat.1000800 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 596XY UT WOS:000277720400011 PM 20221436 ER PT J AU Zheng, SL Hsing, AW Sun, J Chu, LW Yu, K Li, G Gao, ZR Kim, ST Isaacs, WB Shen, MC Gao, YT Hoover, RN Xu, JF AF Zheng, Siqun Lilly Hsing, Ann W. Sun, Jielin Chu, Lisa W. Yu, Kai Li, Ge Gao, Zhengrong Kim, Seong-Tae Isaacs, William B. Shen, Ming-Chang Gao, Yu-Tang Hoover, Robert N. Xu, Jianfeng TI Association of 17 Prostate Cancer Susceptibility Loci With Prostate Cancer Risk in Chinese Men SO PROSTATE LA English DT Article DE prostate cancer; association; Asian; Chinese; 8q24 ID GENOME-WIDE ASSOCIATION; AFRICAN-AMERICANS; HAPLOTYPE MAP; 8Q24; VARIANTS; MULTIPLE; POPULATION; GENE; SIZE AB BACKGROUND. Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk. METHODS. To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls. RESULTS. After adjustment for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rsl016343: OR=2.07, 95% CI: 1.35-3.20, P=9.4 x 10(-4)) and 8q24 Region 1 (rs10090154: OR = 2.07, 95% CI: 1.31-3.28, P = 0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (OR(Region2) = 1.92-2.05, P = 9.4 x 10(-4) to 0.003, and OR(Region1) = 1.77-1.81, P = 0.01 for all SNPs). CONCLUSIONS. Our study shows that multiple prostate cancer risk loci identified in European populations by GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men. Prostate 70: 425-432, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Hsing, Ann W.; Chu, Lisa W.; Yu, Kai; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zheng, Siqun Lilly; Sun, Jielin; Li, Ge; Gao, Zhengrong; Kim, Seong-Tae; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Zheng, Siqun Lilly; Sun, Jielin; Li, Ge; Gao, Zhengrong; Kim, Seong-Tae; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Isaacs, William B.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Shen, Ming-Chang] Shanghai Canc Hosp, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM hsinga@mail.nih.gov RI Kim, Seong-Tae/E-4474-2017 OI Kim, Seong-Tae/0000-0001-7436-1405 FU Intramural Research Program; Division of Cancer Epidemiology and Genetics; National Cancer Institute, National Institutes of Health [CA105055, CA106523, CA95052]; Cancer Prevention Fellowship Program; Office of Preventive Oncology, National Cancer Institute FX Grant sponsor: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Grant sponsor: National Cancer Institute; Grant numbers: CA105055, CA106523, CA95052; Grant sponsor: Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute. NR 32 TC 29 Z9 36 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAR 1 PY 2010 VL 70 IS 4 BP 425 EP 432 DI 10.1002/pros.21076 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 566OS UT WOS:000275382600008 PM 19866473 ER PT J AU Anishkin, A Milac, AL Guy, HR AF Anishkin, Andriy Milac, Adina L. Guy, H. Robert TI Symmetry-restrained molecular dynamics simulations improve homology models of potassium channels SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE symmetry annealing; ion channels; structure prediction; structure refinement ID MECHANOSENSITIVE CHANNEL; ENERGY LANDSCAPES; STRUCTURAL MODELS; PROTEIN-STRUCTURE; FORCE-FIELD; K+ CHANNEL; CRYSTAL-STRUCTURE; GATING MECHANISM; LIPID-BILAYERS; ION-CHANNEL AB Most crystallized homo-oligomeric ion channels are highly symmetric, which dramatically decreases conformational space and facilitates building homology models (HMs). However, in molecular dynamics (MD) simulations channels deviate from ideal symmetry and accumulate thermal defects, which complicate the refinement of HMs using MD. In this work we evaluate the ability of symmetry constrained MD simulations to improve HMs accuracy, using an approach conceptually similar to Critical Assessment of techniques for protein Structure Prediction (CASP) competition: build HMs of channels with known structure and evaluate the efficiency of proposed methods in improving HMs accuracy (measured as deviation from experimental structure). Results indicate that unrestrained MD does not improve the accuracy of HMs, in stantaneous symmetrization improves accuracy but not stability of HMs during subsequent unrestrained MD, while gradually imposing symmetry constraints improves both accuracy (by 5-50%) and stability of HMs. Moreover, accuracy and stability are strongly correlated, making stability a reliable criterion in predicting the accuracy of new HMs. C1 [Milac, Adina L.; Guy, H. Robert] NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Anishkin, Andriy] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Milac, Adina L.] Romanian Acad, Inst Biochem, Dept Bioinformat & Struct Biochem, Bucharest 060031 17, Romania. RP Guy, HR (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM guyh@mail.nih.gov RI Milac, Adina/C-1070-2011 OI Milac, Adina/0000-0003-1845-4281 FU National Cancer Institute, Center for Cancer Research FX Grant sponsors: NIH (Intramural Research Program), National Cancer Institute, Center for Cancer Research. NR 61 TC 11 Z9 11 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2010 VL 78 IS 4 BP 932 EP 949 DI 10.1002/prot.22618 PG 18 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559LG UT WOS:000274825700010 PM 19902533 ER PT J AU Ishima, R Gong, QG Tie, YF Weber, IT Louis, JM AF Ishima, Rieko Gong, Qingguo Tie, Yunfeng Weber, Irene T. Louis, John M. TI Highly conserved glycine 86 and arginine 87 residues contribute differently to the structure and activity of the mature HIV-1 protease SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE NMR; X-ray; crystal; AIDS; retrovirus; protease; HIV-1 ID RESOLUTION CRYSTAL-STRUCTURES; HUMAN-IMMUNODEFICIENCY; SUBSTRATE COMPLEX; DRUG-RESISTANCE; INHIBITOR; MUTATIONS; DYNAMICS; MUTANTS; MONOMER; PROTEINASES AB The structural and functional role of conserved residue G86 in HIV-1 protease (PR) was investigated by NMR and crystallographic analyses of substitution mutations of glycine to alanine and serine (PRG86A and PRG86S). While PRG86S had undetectable catalytic activity, PRG86A exhibited similar to 6000-fold lower catalytic activity than PR. H-1-N-15 NMR correlation spectra revealed that PRG86A and PRG86S are dimeric, exhibiting dimer dissociation constants (K-d) of similar to 0.5 and similar to 3.2 mu M, respectively, which are significantly lower than that seen for PR with R87K mutation (K-d > 1 mM. Thus, the G86 mutants, despite being partially dimeric under the assay conditions, are defective in catalyzing substrate hydrolysis. NMR spectra revealed no changes in the chemical shifts even in the presence of excess substrate, indicating very poor binding of the substrate. Both NMR chemical shift data and crystal structures of PRG86A and PRG86S in the presence of active-site inhibitors indicated high structural similarity to previously described PR/inhibitor complexes, except for specific perturbations within the active site loop and around the mutation site. The crystal structures in the presence of the inhibitor showed that the region around residue 86 was connected to the active site by a conserved network of hydrogen bonds, and the two regions moved further apart in the mutants. Overall, in contrast to the role of R87 in contributing significantly to the dimer stability of PR, G86 is likely to play an important role in maintaining the correct geometry of the active site loop in the PR dimer for substrate binding and hydrolysis. C1 [Ishima, Rieko; Gong, Qingguo] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Tie, Yunfeng; Weber, Irene T.] Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. [Louis, John M.] NIDDKD, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Ishima, R (reprint author), Rm 1037,Biomed Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15260 USA. EM ishima@pitt.edu FU NIH [GM062920]; NIDDK, NIH; University of Pittsburgh; Georgia State University Molecular Basis of Disease Program; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Grant sponsor: NIH; Grant number: GM062920; Grant sponsor: The Intramural Research program of the NIDDK, NIH; Grant sponsor: The University of Pittsburgh; Grant sponsor: The Georgia State University Molecular Basis of Disease Program.; The authors thank the staff at the SER-CAT beamline at the Advanced Photon Source, Argonne National Laboratory, for assistance during X-ray data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. NR 41 TC 10 Z9 10 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2010 VL 78 IS 4 BP 1015 EP 1025 DI 10.1002/prot.22625 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 559LG UT WOS:000274825700016 PM 19899162 ER PT J AU Oyelaran, O Gildersleeve, JC AF Oyelaran, Oyindasola Gildersleeve, Jeffrey C. TI Evaluation of human antibody responses to keyhole limpet hemocyanin on a carbohydrate microarray SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Antibody; Antigen array; Glycan array; Keyhole limpet hemocyanin; Tumor-associated carbohydrate antigen ID IMMUNOLOGICAL ADJUVANT QS-21; BLADDER-CANCER; VACCINE DEVELOPMENT; IN-VITRO; MONOCLONAL-ANTIBODIES; CONJUGATE VACCINE; SERUM ANTIBODIES; N-GLYCANS; ANTIGEN; KLH AB Purpose: Keyhole limpet hemocyanin (KLH) is used as a vaccine adjuvant, as a carrier protein for small haptens, and as a treatment for bladder cancer. Immunization with KLH produces antibodies to tumor-associated carbohydrate antigens (TACAs) in animals, and these antibodies have been postulated as the basis of efficacy for bladder cancer treatment. The purpose of this study was to evaluate antibody responses to KLH in humans. Experimental design: A carbohydrate microarray was used to profile antibody responses in 14 individuals immunized with KLH plus alum adjuvant. Results: Eight out of fourteen individuals produced antibodies to at least one TACA. Increases to Lewis X, Lewis Y, GA1di, GM3, and sialyl Lewis A were observed in certain individuals, but, in general, antibody profiles were highly variable. Pre-immunization antibody levels to a subset of array antigens had a statistically significant correlation with the magnitude of the antibody response to KLH. Conclusions and clinical relevance: Antibodies to TACAs can be produced in humans, but antibody profiles differ considerably from person to person, which may contribute to variable clinical responses with KLH. Pre-treatment antibody levels to certain antigens may be useful for predicting which patients will respond favorably to KLH. C1 [Gildersleeve, Jeffrey C.] NCI Frederick, Med Chem Lab, Ctr Canc Res, Frederick, MD USA. RP Gildersleeve, JC (reprint author), NCI Frederick, Med Chem Lab, Ctr Canc Res, 376 Boyles St,Bldg 376,Rm 208, Frederick, MD USA. EM gildersleevej@ncifcrf.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU NIH, NCI FX The authors thank Dr. Monika Fleshner (University of Colorado) for the generous gift of serum samples. This research was supported by the Intramural Research Program of the NIH, NCI. NR 53 TC 14 Z9 14 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD MAR PY 2010 VL 4 IS 3 BP 285 EP 294 DI 10.1002/prca.200900130 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 575HU UT WOS:000276058900003 PM 21137049 ER PT J AU Schulze, TG AF Schulze, Thomas G. TI Genetic Research into Bipolar Disorder: The Need for a Research Framework that Integrates Sophisticated Molecular Biology and Clinically Informed Phenotype Characterization SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Manic-depressive illness; Schizophrenia; Depression; Classification; Linkage; Association ID GENOME-WIDE ASSOCIATION; STAR-ASTERISK-D; PSYCHIATRIC-DISORDERS; ANTIDEPRESSANT TREATMENT; SUSCEPTIBILITY LOCI; MAJOR DEPRESSION; LUNG-CANCER; MACULAR DEGENERATION; CITALOPRAM TREATMENT; LINKAGE ANALYSIS AB Research into the genetic basis of bipolar disorder (BD) has reached a turning point. Genome-wide association studies (GWAS), encompassing several thousand samples, have produced replicated evidence for some novel susceptibility genes; however, the genetic variants implicated so far account for only a fraction of disease liability, a phenomenon not limited to psychiatric phenotypes but characteristic of all complex genetic traits studied to date. It appears that pure genomic approaches, such as GWAS alone, will not suffice to unravel the genetic basis of a complex illness like BD. Genomic approaches will need to be complemented by a variety of strategies, including phenomics, epigenomics, pharmacogenomics, and neurobiology, as well as the study of environmental factors. This review highlights the most promising findings from recent GWAS and candidate gene studies in BD. It furthermore sketches out a potential research framework integrating various lines of research into the molecular biological basis of BD. C1 [Schulze, Thomas G.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Schulze, Thomas G.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Schulze, Thomas G.] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. RP Schulze, TG (reprint author), NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, 35 Convent Dr,Bldg 35,Rm 1A205,MSC 3719, Bethesda, MD 20892 USA. EM schulzet@mail.nih.gov RI Schulze, Thomas/H-2157-2013 FU Intramural NIH HHS [Z99 MH999999] NR 129 TC 41 Z9 42 U1 0 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 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD MAR PY 2010 VL 33 IS 1 BP 67 EP + DI 10.1016/j.psc.2009.10.005 PG 17 WC Psychiatry SC Psychiatry GA 601KQ UT WOS:000278058400006 PM 20159340 ER PT J AU Comulada, WS Rotheram-Borus, MJ Pequegnat, W Weiss, RE Desmond, KA Arnold, EM Remien, RH Morin, SF Weinhardt, LS Johnson, MO Chesney, MA AF Comulada, W. Scott Rotheram-Borus, Mary Jane Pequegnat, Willo Weiss, Robert E. Desmond, Katherine A. Arnold, Elizabeth Mayfield Remien, Robert H. Morin, Stephen F. Weinhardt, Lance S. Johnson, Mallory O. Chesney, Margaret A. TI Relationships Over Time Between Mental Health Symptoms and Transmission Risk Among Persons Living With HIV SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE HIV; mental health; substance abuse; sexual behavior ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTION-DRUG USERS; SUBSTANCE USE; PSYCHIATRIC-DISORDERS; SEXUAL-BEHAVIOR; UNITED-STATES; EPIDEMIOLOGY; THERAPY; ANXIETY; WOMEN AB Relationships between mental health symptoms (anxiety and depression) or a positive state of mind and behavior associated with HIV transmission (substance use and risky sexual behavior) were explored in a longitudinal study of persons living with HIV (PLH; N = 936) who were participants in a transmission-prevention trial. Bivariate longitudinal regressions were used to estimate the correlations between mental health symptoms and HIV-related transmission acts for 3 time frames: at the baseline interview, over 25 months, and from assessment to assessment. At baseline, mental health symptoms were associated with transmission acts. Elevated levels of mental health symptoms at baseline were associated with decreasing alcohol or marijuana use over 25 months. Over 25 months, an increasingly positive state of mind was associated with decreasing alcohol or marijuana use; an increasingly positive state of mind in the immediate intervention condition and increasing depressive symptoms in the lagged condition were related to increasing risky sexual behavior. Our findings suggest that mental health symptoms precede a decrease in substance use and challenge self-medication theories. Changes in mental health symptoms and sexual behavior occur more in tandem. C1 [Comulada, W. Scott; Rotheram-Borus, Mary Jane; Desmond, Katherine A.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Weiss, Robert E.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. [Remien, Robert H.] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Remien, Robert H.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Weinhardt, Lance S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI USA. [Pequegnat, Willo] NIH, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. [Arnold, Elizabeth Mayfield] Wake Forest Univ, Dept Psychiat & Behav Med, Winston Salem, NC 27109 USA. [Morin, Stephen F.; Johnson, Mallory O.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Chesney, Margaret A.] NIH, Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Comulada, WS (reprint author), 10920 Wilshire Blvd,Suite 350, Los Angeles, CA 90024 USA. EM scomulad@ucla.edu FU NIMH NIH HHS [U10MH057636, P30 MH043520, R01 MH057615, R01 MH057615-01A1, U10 MH057615, U10 MH057616, U10 MH057631, U10 MH057636, U10MH057615, U10MH057616, U10MH057631] NR 41 TC 21 Z9 22 U1 1 U2 12 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2010 VL 24 IS 1 BP 109 EP 118 DI 10.1037/a0018190 PG 10 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 576KB UT WOS:000276142100011 PM 20307117 ER PT J AU Thorsell, A Schank, JR Singley, E Hunt, SP Heilig, M AF Thorsell, Annika Schank, Jesse R. Singley, Erick Hunt, Stephen P. Heilig, Markus TI Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Neurokinin-1 receptor; Substance P; Alcohol escalation; Conditioned place preference ID SUBSTANCE-P RECEPTORS; ELEVATED PLUS-MAZE; PHARMACOLOGICAL BLOCKADE; C57BL/6J MICE; GUINEA-PIGS; ANTAGONIST; BEHAVIOR; ANXIETY; STRESS; ANTIDEPRESSANT AB Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects. The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders. The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors. L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors. Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism. C1 [Thorsell, Annika; Schank, Jesse R.; Singley, Erick; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Hunt, Stephen P.] UCL, Dept Cell & Dev Biol, London, England. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,10 CRC 1-5330, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 FU NIAAA Intramural budget FX Funding for this study was provided by the NIAAA Intramural budget. NR 56 TC 36 Z9 36 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2010 VL 209 IS 1 BP 103 EP 111 DI 10.1007/s00213-010-1775-1 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 553YZ UT WOS:000274404000010 PM 20112009 ER PT J AU Peng, XQ Gardner, EL Xi, ZX AF Peng, Xiao-Qing Gardner, Eliot L. Xi, Zheng-Xiong TI Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters SO PSYCHOPHARMACOLOGY LA English DT Article DE gamma-Vinyl GABA; GABA; Glutamate; Anion channel; GABA transporter; Nucleus accumbens ID PLASMA-MEMBRANE; AMINO-ACIDS; COCAINE ADDICTION; BRAIN; NEUROTRANSMISSION; VIGABATRIN; INHIBITION; DOPAMINE; TRANSAMINASE; ASTROCYTES AB gamma-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc). Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc. In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats. Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na(+)-channel blocker, failed to alter GVG-enhanced GABA and glutamate. These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition. C1 [Peng, Xiao-Qing; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU Intramural NIH HHS [Z99 DA999999] NR 51 TC 5 Z9 5 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2010 VL 208 IS 4 BP 511 EP 519 DI 10.1007/s00213-009-1753-7 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 550BD UT WOS:000274100200001 PM 20033132 ER PT J AU Shin, R Ikemoto, S AF Shin, Rick Ikemoto, Satoshi TI The GABA(B) receptor agonist baclofen administered into the median and dorsal raphe nuclei is rewarding as shown by intracranial self-administration and conditioned place preference in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Intracranial self-administration; Conditioned place preference; Reward; Reinforcement; Baclofen; GABA(B) receptors; Median and dorsal raphe nuclei ID VENTRAL TEGMENTAL AREA; SEROTONERGIC NEURONS; PHARMACOLOGICAL-TREATMENT; ASCENDING PROJECTIONS; AFFECTIVE-DISORDERS; LOCOMOTOR-ACTIVITY; B RECEPTORS; MUSCIMOL; STIMULATION; TOXIN AB The midbrain raphe regions have long been implicated in affective processes and disorders. There is increasing evidence to suggest that the median (MR) and dorsal raphe nuclei (DR) tonically inhibit reward-related processes. Stimulation of GABA(B) receptors in the midbrain raphe nuclei is known to inhibit local neurons, especially serotonergic neurons. We sought to determine if injections of the GABA(B) receptor agonist baclofen into the MR or DR are rewarding, using intracranial self-administration and conditioned place preference. Rats quickly learned to lever press for infusions of baclofen (0.1-2.5 mM) into the MR, but not the ventral tegmental area or central linear nucleus. Rats increased lever pressing associated with intra-DR baclofen infusions, but not readily. Baclofen self-administration into the MR or DR was attenuated by coadministration of the GABA(B) receptor antagonist SCH 50911 (1 mM) or systemic pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). In addition, intra-DR and intra-MR injections of baclofen induced conditioned place preference; injection into DR was more effective. Baclofen injections into the midbrain raphe nuclei are rewarding. Baclofen was more readily self-administered into the MR than into the DR, while baclofen injections into the DR more readily induced conditioned place preference than those into the MR. These sites may be differentially involved in aspects of reward. These findings suggest that MR or DR neurons containing GABA(B) receptors are involved in tonic inhibitory control over reward processes. C1 [Shin, Rick; Ikemoto, Satoshi] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM Satoshi.Ikemoto@nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 47 TC 12 Z9 13 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2010 VL 208 IS 4 BP 545 EP 554 DI 10.1007/s00213-009-1757-3 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 550BD UT WOS:000274100200004 PM 20054525 ER PT J AU Rowland, LM Beason-Held, L Tamminga, CA Holcomb, HH AF Rowland, Laura M. Beason-Held, Lori Tamminga, Carol A. Holcomb, Henry H. TI The interactive effects of ketamine and nicotine on human cerebral blood flow SO PSYCHOPHARMACOLOGY LA English DT Article DE Nicotine; Glutamate; Dopamine; PET; NMDA receptor; Cingulate; Schizophrenia; Blood flow; Frontal cortex ID RAT PREFRONTAL CORTEX; METHYL-D-ASPARTATE; EXCITATORY SYNAPTIC-TRANSMISSION; NMDA RECEPTOR ANTAGONIST; VENTRAL TEGMENTAL AREA; DOPAMINE RELEASE; NUCLEUS-ACCUMBENS; INTRAVENOUS (H2O)-O-15; COGNITIVE DEFICITS; GLUTAMATE RELEASE AB The purpose of this study was to determine if acute nicotine attenuated ketamine-induced regional cerebral blood flow (rCBF). Following 2-4 h of nicotine abstinence, healthy chronic smokers participated in four sets of rCBF studies, H (2) (15) O positron emission tomography, during a simple sensory motor control task. The four drug conditions studied were placebo, ketamine alone, nicotine alone, and ketamine + nicotine. Intravenous ketamine increased rCBF in frontal, orbital-frontal, and anterior cingulate areas. Nicotine alone induced marked rCBF elevations in the lateral occipital cortex and rCBF suppressions in the basal ganglia and anterior cingulate cortex. Nicotine added to ketamine attenuated the ketamine-induced elevated rCBF in the anterior cingulate cortex but caused a marked rCBF increase in the orbital frontal region. This study illustrates the interactive effects of ketamine, an NMDA receptor antagonist, and nicotine in multiple brain regions. Nicotine substantially ameliorated the effects of ketamine on anterior cingulate rCBF and, when given alone, markedly suppressed anterior cingulate rCBF. The enhanced, synergistic orbitofrontal effects observed with ketamine and nicotine together suggest a marked increase in excitatory neurotransmission in a brain region often linked to psychosis, reward, and addictive behaviors. C1 [Rowland, Laura M.; Holcomb, Henry H.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat,Funct Neuroimaging Lab, Baltimore, MD 21228 USA. [Beason-Held, Lori] NIA, Baltimore, MD 21224 USA. [Tamminga, Carol A.] Univ Texas SW Med Sch, Dept Psychiat, Dallas, TX USA. [Holcomb, Henry H.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. RP Holcomb, HH (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat,Funct Neuroimaging Lab, 55 Wade Ave, Baltimore, MD 21228 USA. EM hholcomb@mprc.umaryland.edu FU Novartis Pharmaceuticals, Basel, Switzerland; NIMH [K01MH077230]; Intramural Research Program, National Institute on Aging (Baltimore, MD), National Institutes of Health FX We thank Robert F. Dannals, David Clough, Hayden Ravert, Robert Smoot, and Karen Edmonds of the Johns Hopkins Cyclotron Facility, and Nancy Kakoyannis, Ning Ma, and Adrienne Lahti of the University of Maryland School of Medicine, Department of Psychiatry for their valuable help. This study was funded by a research grant from Novartis Pharmaceuticals, Basel, Switzerland, to William T. Carpenter and the University of Maryland School of Medicine, and an NIMH grant (K01MH077230) to Laura M. Rowland. We also thank the volunteers for participating in the study. Lori Beason-Held is supported by the Intramural Research Program, National Institute on Aging (Baltimore, MD), National Institutes of Health. NR 68 TC 12 Z9 13 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2010 VL 208 IS 4 BP 575 EP 584 DI 10.1007/s00213-009-1758-2 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 550BD UT WOS:000274100200007 PM 20066400 ER PT J AU Dieperink, E Ho, SB Heit, S Durfee, JM Thuras, P Willenbring, ML AF Dieperink, Eric Ho, Samuel B. Heit, Sara Durfee, Janet M. Thuras, Paul Willenbring, Mark L. TI Significant Reductions in Drinking Following Brief Alcohol Treatment Provided in a Hepatitis C Clinic SO PSYCHOSOMATICS LA English DT Article ID VIRUS-INFECTION; UNITED-STATES; PSYCHIATRIC-DISORDERS; ANTIVIRAL TREATMENT; INTERFERON THERAPY; LIVER-DISEASE; SUBSTANCE USE; PRIMARY-CARE; VETERANS; MULTICENTER AB Background: Although the hepatitis C virus (HCV) alone increases the risk of cirrhosis, alcohol use is thought to act synergistically with HCV to significantly hasten the development of fibrosis. Objective: The authors assessed the impact of brief medical counseling or integrated-care approaches to lessen or eliminate alcohol use in these vulnerable patients. Method: This retrospective study describes the effect of brief alcohol treatment delivered in a hepatitis clinic on drinking outcomes and antiviral treatment eligibility: 47 heavy-drinking chronic hepatitis C patients received a brief intervention performed by medical clinicians, with follow-up by a psychiatric nurse-specialist. Results: At the last follow-up, 62% of patients reported >50% drinking reduction; these included 36% who achieved abstinence. Only 6% of patients were excluded from antiviral therapy. Discussion: Brief treatment addressing heavy drinking delivered by hepatitis clinicians with psychiatric-specialist follow-up was associated with abstinence or a significant reduction in alcohol consumption in over 50% of patients. (Psychosomatics 2010; 51:149-156) C1 Minneapolis VA Med Ctr, Minneapolis Hepatitis Resource Ctr C, Minneapolis, MN USA. Minneapolis VA Med Ctr, Dept Psychiat, Minneapolis, MN USA. Minneapolis VA Med Ctr, Dept Med, Minneapolis, MN USA. Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. RP Willenbring, ML (reprint author), NIAAA, NIH, 5635 Fishers Lane,Rm 2047, Bethesda, MD 20892 USA. EM mlw@niaaa.nih.gov FU Hepatitis C Resource Center FX This work was supported by the Hepatitis C Resource Center. NR 39 TC 13 Z9 13 U1 0 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2010 VL 51 IS 2 BP 149 EP 156 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 573FZ UT WOS:000275895200008 PM 20332290 ER PT J AU Jacobson, KA AF Jacobson, Kenneth A. TI New frontiers for ligands of adenosine and P2Y receptors SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Jacobson, Kenneth A.] NIDDKD, NIH, Bethesda, MD 20902 USA. EM kajacobs@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2010 VL 6 IS 1 BP 49 EP 50 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 568SV UT WOS:000275543900008 ER PT J AU Costanzi, S Ferino, G Vilar, S AF Costanzi, Stefano Ferino, Giulio Vilar, Santiago TI Homology models of G-protein-coupled receptors as a tool for structure-based drug discovery SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Costanzi, Stefano; Ferino, Giulio; Vilar, Santiago] NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2010 VL 6 IS 1 BP 67 EP 68 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 568SV UT WOS:000275543900037 ER PT J AU Pastorin, G Federico, S Cateni, F Cacciari, B Klotz, KN Gao, ZG Jacobson, KA Corradino, M Paoletta, S Moro, S Spalluto, G AF Pastorin, Giorgia Federico, Stephanie Cateni, Francesca Cacciari, Barbara Klotz, Karl-Norbert Gao, Zhan-Guo Jacobson, Kenneth A. Corradino, Marta Paoletta, Silvia Moro, Stefano Spalluto, Giampiero TI Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: a preliminary receptor-driven SAR profile SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Pastorin, Giorgia] Natl Univ Singapore, Dept Pharm, Singapore 117548, Singapore. [Federico, Stephanie; Cateni, Francesca; Spalluto, Giampiero] Univ Trieste, Dipartimento Sci Farmaceut, I-34127 Trieste, Italy. [Cacciari, Barbara] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Klotz, Karl-Norbert] Univ Wurzburg, Inst Pharmakol & Toxikol, D-97078 Wurzburg, Germany. [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, MRS, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Corradino, Marta; Paoletta, Silvia; Moro, Stefano] Univ Padua, Dipartimento Sci Farmaceut, MMS, I-35131 Padua, Italy. EM stephanie.federico@phd.units.it RI Moro, Stefano/A-2979-2012; Pastorin, Giorgia/B-5907-2015 OI Moro, Stefano/0000-0002-7514-3802; NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2010 VL 6 IS 1 BP 80 EP 80 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 568SV UT WOS:000275543900055 ER PT J AU Das, A Zhou, YX Ivanov, AA Carter, RL Harden, TK Jacobson, KA AF Das, Arijit Zhou, Yixing Ivanov, Andrei A. Carter, Rhonda L. Harden, T. Kendall Jacobson, Kenneth A. TI Enhanced potency of nucleotide-dendrimer conjugates as agonists of the P2Y(14) receptor: multivalent effect in G-protein-coupled receptor recognition SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Das, Arijit; Ivanov, Andrei A.; Jacobson, Kenneth A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Yixing; Carter, Rhonda L.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM kajacobs@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2010 VL 6 IS 1 BP 88 EP 88 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 568SV UT WOS:000275543900067 ER PT J AU Einstein, AJ Elliston, CD Arai, AE Chen, MY Mather, R Pearson, GDN DeLaPaz, RL Nickoloff, E Dutta, A Brenner, DJ AF Einstein, Andrew J. Elliston, Carl D. Arai, Andrew E. Chen, Marcus Y. Mather, Richard Pearson, Gregory D. N. DeLaPaz, Robert L. Nickoloff, Edward Dutta, Ajoy Brenner, David J. TI Radiation Dose from Single-Heartbeat Coronary CT Angiography Performed with a 320-Detector Row Volume Scanner SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ARTERY-DISEASE; LENGTH PRODUCT; IMAGE QUALITY; CARDIAC CT; DIAGNOSIS AB Purpose: To determine radiation doses from coronary computed tomographic (CT) angiography performed by using a 320-detector row volume scanner and evaluate how the effective dose depends on scan mode and the calculation method used. Materials and Methods: Radiation doses from coronary CT angiography performed by using a volume scanner were determined by using metaloxide-semiconductor field-effect transistor detectors positioned in an anthropomorphic phantom physically and radiographically simulating a male or female human. Organ and effective doses were determined for six scan modes, including both 64-row helical and 280-row volume scans. Effective doses were compared with estimates based on the method most commonly used in clinical literature: multiplying dose-length product (DLP) by a general conversion coefficient (0.017 or 0.014 mSv . mGy(-1) . cm(-1)), determined from Monte Carlo simulations of chest CT by using single-section scanners and previous tissue-weighting factors. Results: Effective dose was reduced by up to 91% with volume scanning relative to helical scanning, with similar image noise. Effective dose, determined by using International Commission on Radiological Protection publication 103 tissue-weighting factors, was 8.2 mSv, using volume scanning with exposure permitting a wide reconstruction window, 5.8 mSv with optimized exposure and 4.4 mSv for optimized 100-kVp scanning. Estimating effective dose with a chest conversion coefficient resulted in a dose as low as 1.8 mSv, substantially underestimating effective dose for both volume and helical coronary CT angiography. Conclusion: Volume scanning markedly decreases coronary CT angiography radiation doses compared with those at helical scanning. When conversion coefficients are used to estimate effective dose from DLP, they should be appropriate for the scanner and scan mode used and reflect current tissue-weighting factors. (C) RSNA, 2010. C1 [Einstein, Andrew J.] Columbia Univ, Med Ctr, Dept Med, Div Cardiol, New York, NY 10032 USA. [Einstein, Andrew J.; Pearson, Gregory D. N.; DeLaPaz, Robert L.; Nickoloff, Edward; Dutta, Ajoy] Columbia Univ, Med Ctr, Dept Radiol, New York, NY 10032 USA. [Elliston, Carl D.; Brenner, David J.] Columbia Univ, Med Ctr, Ctr Radiol Res, New York, NY 10032 USA. New York Presbyterian Hosp, New York, NY 10032 USA. [Arai, Andrew E.; Chen, Marcus Y.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Mather, Richard] Toshiba Amer Med Syst, Tustin, CA USA. RP Einstein, AJ (reprint author), Columbia Univ, Med Ctr, Dept Med, Div Cardiol, 622 W 168th St,PH 10-203A, New York, NY 10032 USA. EM andrew.einstein@columbia.edu FU National Institutes of Health [5 KL2 RR024157-03] FX This research was supported by the National Institutes of Health (grant 5 KL2 RR024157-03). A.E.A. and M.C. are employees of National Heart, Lung, and Blood Institute. NR 23 TC 96 Z9 104 U1 0 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2010 VL 254 IS 3 BP 698 EP 706 DI 10.1148/radiol.09090779 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 559CA UT WOS:000274796200010 PM 20177085 ER PT J AU Avila, NA Dwyer, AJ Rabel, A Darling, T Hong, CH Moss, J AF Avila, Nilo A. Dwyer, Andrew J. Rabel, Antoinette Darling, Thomas Hong, Chien-Hui Moss, Joel TI CT of Sclerotic Bone Lesions: Imaging Features Differentiating Tuberous Sclerosis Complex with Lymphangioleiomyomatosis from Sporadic Lymphangioleiomymatosis SO RADIOLOGY LA English DT Article AB Purpose: To determine if sclerotic bone lesions evident at body computed tomography (CT) are of value as a diagnostic criterion of tuberous sclerosis complex (TSC) and in the differentiation of TSC with lymphangioleiomyomatosis (LAM) from sporadic LAM. Materials and Methods: Informed consent was signed by all patients in this HIPAA-compliant study approved by the institutional review board. Retrospective analysis was performed of the body CT studies of 472 patients: 365 with sporadic LAM, 82 with TSC/LAM, and 25 with TSC. The images were reviewed by using a picture archiving and communication system workstation with bone settings (window width, 1500 HU; window level, 300 HU) and fit-to-screen option. CT image characteristics assessed included shape, size, and distribution of sclerotic bone lesions with subsequent calculation of differences in the frequency of these lesions. Results: Most commonly the sclerotic bone lesions were round, measured 0.3 cm (range, 0.2-3.2), and were distributed throughout the spine. The frequencies differed among the three patient groups Four or more sclerotic bone lesions were detected in all 25 (100%) of those with TSC, with a sensitivity of .89 (72 of 82) and specificity of .97 (355 of 367) in the differentiation of sporadic LAM from TSC/LAM (P<.01). Conclusion: The number of sclerotic bone lesions at body CT is of potential value in the diagnosis of TSC and in the differentiation of patients with sporadic LAM from those with TSC/LAM. (C)RSNA, 2010 C1 [Avila, Nilo A.] Washington DC Vet Affairs Med Ctr, Serv Radiol, Washington, DC 20422 USA. [Avila, Nilo A.; Dwyer, Andrew J.] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Rabel, Antoinette; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Darling, Thomas] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Hong, Chien-Hui] Tainan Hosp, Dept Hlth, Tainan, Taiwan. RP Avila, NA (reprint author), Washington DC Vet Affairs Med Ctr, Serv Radiol, 50 Irving St NW,Room BH 223, Washington, DC 20422 USA. EM nilo.avila@va.gov OI Darling, Thomas/0000-0002-5161-1974 FU National Heart, Lung, and Blood Institute FX A. R. and J. M. are employees of the National Heart, Lung, and Blood Institute. NR 18 TC 20 Z9 22 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2010 VL 254 IS 3 BP 851 EP 857 DI 10.1148/radiol.09090227 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 559CA UT WOS:000274796200027 PM 20177097 ER PT J AU Dittfeld, C Dietrich, A Peickert, S Hering, S Baumann, M Grade, M Ried, T Kunz-Schughart, LA AF Dittfeld, Claudia Dietrich, Antje Peickert, Susann Hering, Sandra Baumann, Michael Grade, Marian Ried, Thomas Kunz-Schughart, Leoni A. TI CD133 expression is not selective for tumor-initiating or radioresistant cell populations in the CRC cell line HCT-116 SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Cancer stem/tumor-initiating cells (CSC/TIC); Colorectal carcinoma (CRC) cell lines; HCT-116; 2-D culture; 3-D culture; Radioresponse ID CANCER STEM-CELLS; HEPATOCELLULAR-CARCINOMA CELLS; COLORECTAL-CANCER; COLON-CANCER; STEM/PROGENITOR CELLS; PROGENITOR CELLS; PLASMA-MEMBRANE; BRAIN-TUMORS; IDENTIFICATION; MARKER AB Background and purpose: CD133 is controversially discussed as putative (surrogate) marker for cancer stem/tumor-initiating cell populations (CSC/TIC) in epithelial tumors including colorectal carcinomas (CRCs). We studied CD133 expression in established CRC cell lines and examined in vitro behavior, radioresponse and in vivo tumor formation of CD133(+/-) subpopulations of one cell line of interest. Materials and methods: Ten CRC cell lines were analyzed for CD 133 expression using flow cytometry and Western blotting. CD133(+) and CD133(-) HCF-116 subpopulations were separated by FACS and studied in 2-D and 3-D culture and colony formation assays after irradiation. Subcutaneous xenograft formation was monitored in NMRI (nu/nu) mice. Results and conclusions: CRC cell lines could be classified into three groups: (i) CD133, (ii) CD133(+) and (iii) those with two distinct CD133(+) and CD133(-) subpopulations. Isolated CD133(+/) HCT-116 subpopulations were studied relative to the original fraction. No difference was found in 2-D growth, spheroid formation or radioresponse in vitro. Also, tumor formation and growth rate did not differ for the sorted subpopulations. However, a subset of xenografts originated from CD133 HCT-116 showed a striking enrichment in the CD133(+) fraction. Our data show that CD133 expression is not selective for sphere forming, tumor-initiating or radioresistant subpopulations in the HCT-116 CRC cell line. This implies that CD133 cannot be regarded as a CSC/TIC marker in all CRC cell lines and that functional measurements of tumor formation have to generally accompany CSC/TIC-directed mechanistic or therapeutic studies. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 94 (2010) 375-383 C1 [Kunz-Schughart, Leoni A.] Tech Univ Dresden, OncoRay Ctr Radiat Res Oncol, Fac Med Carl Gustav Carus, D-01307 Dresden, Germany. [Hering, Sandra] Tech Univ Dresden, Inst Legal Med, D-01307 Dresden, Germany. [Baumann, Michael] Univ Hosp Dresden, Dept Radiat Oncol, Dresden, Germany. [Grade, Marian] Univ Med Goettingen, Dept Gen & Visceral Surg, Gottingen, Germany. [Ried, Thomas] NCI, NIH, Bethesda, MD 20892 USA. RP Kunz-Schughart, LA (reprint author), Tech Univ Dresden, OncoRay Ctr Radiat Res Oncol, Fac Med Carl Gustav Carus, Fetscherstr 74,PF 86, D-01307 Dresden, Germany. EM leoni.kunz-schughart@oncoray.de FU German Federal Ministry of Education and Research (BMBF) [01ZZ0502]; German Research Foundation (DFG) [KU 971/7-1, GR 3376/2-1, KFO 179] FX The authors gratefully acknowledge the excellent technical assistance of Ms. Marit Wondrak and Ms. Melanie Huether. This work was supported in part by the German Federal Ministry of Education and Research (BMBF) through Grant 01ZZ0502 and the German Research Foundation (DFG) through Grants KU 971/7-1 and GR 3376/2-1, and the KFO 179. OncoRay is funded by the BMBF in the program "Center for Innovation Competence". NR 69 TC 21 Z9 23 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD MAR PY 2010 VL 94 IS 3 BP 375 EP 383 DI 10.1016/j.radonc.2009.10.010 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 582SQ UT WOS:000276619500019 PM 20344822 ER PT J AU Costantine, M AF Costantine, M. TI Cord Blood Biomarkers and the Risk of Cerebral Palsy or Death. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Costantine, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 7 BP 68A EP 69A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600009 ER PT J AU Dong, Z Meng, H Sivalogan, S Wang, RN McLuckie, L Xu, Y Tarquini, F Kim, CJ Kim, JS Mittal, P Shynlova, O Lye, S Romero, R AF Dong, Zhong Meng, Hong Sivalogan, Sivasakthy Wang, Rona McLuckie, Lorri Xu, Yi Tarquini, Federica Kim, Chong Jai Kim, Jung-Sun Mittal, Pooja Shynlova, Oksana Lye, Stephen Romero, Roberto TI Human Myometrial Cells Are a Source of Chemokines That Recruit Monocytes and Granulocytes and Generate a Myometrial Inflammatory Phenotype. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Dong, Zhong; Meng, Hong; Sivalogan, Sivasakthy; Wang, Rona; McLuckie, Lorri; Xu, Yi; Tarquini, Federica; Kim, Chong Jai; Kim, Jung-Sun; Mittal, Pooja; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kim, Chong Jai; Kim, Jung-Sun; Mittal, Pooja; Romero, Roberto] Wayne State Univ, Sch Med, Detroit, MI USA. [Shynlova, Oksana; Lye, Stephen] Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S BP 80A EP 80A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600051 ER PT J AU Pulanic, TK Turner, M Gemmill, J Pavletic, S Barret, J Childs, R Khachykian, I Kaushal, S Stratton, P AF Pulanic, Tajana Klepac Turner, Maria Gemmill, Julie Pavletic, Steven Barret, John Childs, Richard Khachykian, Isabella Kaushal, Suhasini Stratton, Pamela TI Female Genital Chronic Graft Versus Host Disease SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Pulanic, Tajana Klepac; Gemmill, Julie; Khachykian, Isabella; Stratton, Pamela] NICHD, PRAE, Bethesda, MD USA. [Turner, Maria] NCI, DB, Bethesda, MD 20892 USA. [Pavletic, Steven] NCI, CCR, Bethesda, MD 20892 USA. [Barret, John; Childs, Richard; Kaushal, Suhasini] NHLBI, HB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 74 BP 87A EP 87A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600076 ER PT J AU Stratton, P Giri, N Alter, BP AF Stratton, Pamela Giri, Neelam Alter, Blanche P. TI Fanconi Anemia Has a Different Gynecologic Natural History Than Other Inherited Bone Marrow Failure Syndromes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Stratton, Pamela] NICHD, PRAE, Bethesda, MD USA. [Giri, Neelam; Alter, Blanche P.] NCI, CGB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 77 BP 87A EP 87A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600078 ER PT J AU Gemmill, JAL Sinaii, N Hsu, AL Segars, J Stratton, P AF Gemmill, Julie Anne L. Sinaii, Ninet Hsu, Albert L. Segars, James Stratton, Pamela TI Intraperitoneal Bupivacaine for Pain Relief after Operative Laparoscopy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Gemmill, Julie Anne L.; Hsu, Albert L.; Segars, James; Stratton, Pamela] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Sinaii, Ninet] CC NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 91 BP 91A EP 91A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600092 ER PT J AU Hsu, AL Sinaii, N Segars, JH Nieman, LK Stratton, P AF Hsu, Albert L. Sinaii, Ninet Segars, James H. Nieman, Lynnette K. Stratton, Pamela TI Relating Pelvic Pain Location with Surgical Findings of Endometriosis SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Sinaii, Ninet] CC NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD USA. [Hsu, Albert L.; Sinaii, Ninet; Segars, James H.; Nieman, Lynnette K.; Stratton, Pamela] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 96 BP 93A EP 93A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600097 ER PT J AU Muneyyirei-Delale, O Jiang, XC Dalloul, M Fan, YF Charles, C Nacharaju, V Fleisher, J Stratton, P AF Muneyyirei-Delale, Ozgul Jiang, Xian-Cheng Dalloul, Mudar Fan, Yi-Fan Charles, Cassandra Nacharaju, Vijaya Fleisher, Jay Stratton, Pamela TI F11R/JAM and SM Levels in Women with Endometriosis on Treatment with Lupron-Depot vs. Norethindrone Acetate. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Muneyyirei-Delale, Ozgul; Jiang, Xian-Cheng; Dalloul, Mudar; Fan, Yi-Fan; Charles, Cassandra; Nacharaju, Vijaya] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Muneyyirei-Delale, Ozgul] Kings Cty Hosp Ctr, Brooklyn, NY USA. [Fleisher, Jay] Nova SE Univ, Coll Osteopath Med, Ft Lauderdale, FL 33314 USA. [Stratton, Pamela] NICHD, Gynecol Serv, NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 102 BP 94A EP 94A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600103 ER PT J AU Kaushal, S Merideth, M Pulanic, TK Sereti, I Mican, JM Stratton, P AF Kaushal, Suhasini Merideth, Melissa Pulanic, Tajana K. Sereti, Irini Mican, JoAnn M. Stratton, Pamela TI Successful Treatment of Extensive, Multifocal Bowen's Disease in Two HIV-Infected Women with Topical Imiquimod SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Kaushal, Suhasini] NHLBI, HB, Bethesda, MD 20892 USA. [Merideth, Melissa] NHGRI, MGB, Bethesda, MD 20892 USA. [Pulanic, Tajana K.; Stratton, Pamela] NICHD, PRAE, Bethesda, MD USA. [Sereti, Irini] NIAID, LIR, Bethesda, MD 20892 USA. [Mican, JoAnn M.] NIAID, DCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 188 BP 118A EP 118A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600188 ER PT J AU Driggers, PH Guo, XXC Segars, JH AF Driggers, Paul H. Guo, Xiaoxiao C. Segars, James H. TI Hormone-Dependent Signaling by the LH Receptor Is Mediated, in Part, by AKAP-Brx. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Driggers, Paul H.; Guo, Xiaoxiao C.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 253 BP 136A EP 136A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600252 ER PT J AU Moon, KS Maguire, M Segars, JH Browne, HN Abel, B Armstrong, AY AF Moon, Kimberly S. Maguire, Marcy Segars, James H. Browne, Hyacinth N. Abel, Brent Armstrong, Alicia Y. TI Is Anti-Mullerian Hormone a Marker of Cyclophosphamide-Induced Primordial Follicular Destruction in Mice Pretreated with Cetrorelix? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Moon, Kimberly S.; Maguire, Marcy; Segars, James H.; Browne, Hyacinth N.; Abel, Brent; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 255 BP 136A EP 136A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600254 ER PT J AU Yu, B Sullivan, S Vanderhoof, VH Troendle, JF Koziol, DE Nelson, LM AF Yu, Bo Sullivan, Shannon Vanderhoof, Vien H. Troendle, James F. Koziol, Deloris E. Nelson, Lawrence M. TI Serum Free Testosterone Levels Are Significantly Associated with Metabolic Risk Factors for Cardiovascular Disease (CVD) in Women with 46, XX Spontaneous Primary Ovarian Insufficiency (POI) SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Yu, Bo; Sullivan, Shannon; Vanderhoof, Vien H.; Troendle, James F.; Koziol, Deloris E.; Nelson, Lawrence M.] NICHD IRP, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 280 BP 143A EP 144A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600279 ER PT J AU Yu, B Michalakis, KG Brayboy, LM Richter, KS Levy, M Widra, E Segars, JH AF Yu, Bo Michalakis, Konstantinos G. Brayboy, Lynae M. Richter, Kevin S. Levy, Michael Widra, Eric Segars, James H. TI Subclinical Hypothyroidism Does Not Adversely Affect Pregnancy Outcomes after Assisted Reproduction SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Yu, Bo; Michalakis, Konstantinos G.; Brayboy, Lynae M.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Richter, Kevin S.; Levy, Michael; Widra, Eric] Shady Grove Fertil Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 284 BP 145A EP 145A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600283 ER PT J AU Shynlova, O Kwong, R Dorogin, A Romero, R Lye, S AF Shynlova, Oksana Kwong, Ruth Dorogin, Anna Romero, Roberto Lye, Stephen TI Role of Stretch in Induction of Myometrial Inflammatory Response in Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Shynlova, Oksana; Kwong, Ruth; Dorogin, Anna; Lye, Stephen] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, New York, NY USA. [Lye, Stephen] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A1, Canada. [Lye, Stephen] Univ Toronto, Dep Ob Gyn, Toronto, ON M5S 1A1, Canada. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 319 BP 155A EP 155A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600318 ER PT J AU Saade, GR AF Saade, George R. TI Thrombophilia and Stillbirth: A Population-Based Study SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Saade, George R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SCRN, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 339 BP 160A EP 161A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600338 ER PT J AU Morgan, TK Tolosa, JE AF Morgan, Terry K. Tolosa, Jorge E. TI Placental Villous Hypermaturation Is Associated with Idiopathic Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Invest C1 [Morgan, Terry K.; Tolosa, Jorge E.] Eunice Kennedy Shriver NICHD MFMUN, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 414 BP 183A EP 183A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600413 ER PT J AU Ehrenberg, HM AF Ehrenberg, Hugh M. TI Is the Indication for Cesarean Delivery Affected by Maternal Body Habitus? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Ehrenberg, Hugh M.] Eunice Kennedy Shriver NICHD, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S BP 191A EP 191A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600443 ER PT J AU Fejzo, MS Jalil, S MacGibbon, K Opper, N Romero, R Goodwn, TM Mullin, P AF Fejzo, Marlena S. Jalil, Shemi MacGibbon, Kimber Opper, Neisha Romero, Roberto Goodwn, T. Murphy Mullin, Patrick TI Recurrence Risk of Hyperemesis Gravidarum. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Fejzo, Marlena S.; Jalil, Shemi; Opper, Neisha; Goodwn, T. Murphy; Mullin, Patrick] USC, Los Angeles, CA USA. [MacGibbon, Kimber] Www Helper Org, Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Romero, Roberto] NICHD, Perinatol Res Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S BP 191A EP 192A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600444 ER PT J AU Gyamfi, C AF Gyamfi, Cynthia TI The Cesarean Registry: The Risk of Uterine Rupture and Placenta Accreta in Women with a Prior Myomectomy. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Gyamfi, Cynthia] Eunice Kennedy Shriver NICHD MFMU Network, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S BP 193A EP 193A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600450 ER PT J AU Tita, A AF Tita, A. TI Timing of Delivery and Pregnancy Outcomes among Laboring Nulliparous Women. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Tita, A.] Eunice Kennedy Shriver NICHD, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S BP 207A EP 208A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600499 ER PT J AU Myatt, L AF Myatt, Leslie TI Do First Trimester Serum Biomarkers Predict Different Phenotypes of Preeclampsia? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Myatt, Leslie] Eunice Kennedy Shriver Inst Child Hlth & Human De, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 602 BP 239A EP 239A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601079 ER PT J AU McCarthy-Keith, D Norian, J Hill, M Millo, C Armstrong, A AF McCarthy-Keith, Desiree' Norian, John Hill, Micah Millo, Corina Armstrong, Alicia TI Use of FDG-Positron Emission Tomography (PET)/Computerized Tomography (CT) to Localize an Androgen Secreting Lesion in a Patient with Severe Hirsutism SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Invest C1 [McCarthy-Keith, Desiree'; Norian, John; Hill, Micah; Armstrong, Alicia] NICHD, NIH, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Millo, Corina] NIH, PET Dept, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 646 BP 251A EP 251A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601122 ER PT J AU Sullivan, SD Popat, V Calis, KA Vanderhoof, V Koziol, DE Troendle, JF Nelson, LM AF Sullivan, Shannon D. Popat, Vaishali Calis, Karim A. Vanderhoof, Vien Koziol, Debris E. Troendle, James F. Nelson, Lawrence M. TI Treatment with Transdermal Physiologic Testosterone Replacement Improves Insulin Sensitivity in Women with 46,XX Primary Ovarian Insufficiency (POI). SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Sullivan, Shannon D.; Popat, Vaishali; Calis, Karim A.; Vanderhoof, Vien; Troendle, James F.; Nelson, Lawrence M.] NICHD IRP, NIH, Bethesda, MD USA. [Koziol, Debris E.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 692 BP 264A EP 264A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601168 ER PT J AU Catherino, WH Britten, J Malik, M AF Catherino, William H. Britten, Joy Malik, Minnie TI Modifying the Leiomyoma Transcriptome To Dissolve Fibrosis Using GnRH Analogues. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Catherino, William H.; Britten, Joy; Malik, Minnie] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Catherino, William H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 709 BP 269A EP 269A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601184 ER PT J AU Feng, LP Leikin, S Leppert, P AF Feng, Liping Leikin, Sergey Leppert, Phyllis TI Pattern of Collagen Types in Uterine Fibroids. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Feng, Liping; Leppert, Phyllis] Duke Univ, OB GYN, Durham, NC USA. [Leikin, Sergey] NICHD, Sect Phys Biochem, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 711 BP 270A EP 270A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601186 ER PT J AU Pulanic, TK Venkatesan, A Segars, J Locklin, J Sokka, S Wood, B Stratton, P AF Pulanic, Tajana Klepac Venkatesan, Aradhana Segars, James Locklin, Julia Sokka, Sham Wood, Bradford Stratton, Pamela TI Novel Use of a Vaginal Pessary To Optimize the Position the Uterus for Magnetic Resonance Imaging-Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Pulanic, Tajana Klepac; Segars, James; Stratton, Pamela] NICHD, PRAE, NIH, Bethesda, MD USA. [Venkatesan, Aradhana; Locklin, Julia; Wood, Bradford] NIH, Bethesda, MD 20892 USA. [Sokka, Sham] Philips Healthcare, Cleveland, OH USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 716 BP 271A EP 271A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601191 ER PT J AU Anderson, BL AF Anderson, Brenna L. TI The Impact of Antibiotic Therapy on Vaginal Flora among Women with a Positive Fetal Fibronectin SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Anderson, Brenna L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 736 BP 277A EP 277A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601211 ER PT J AU Carreno, CA Segel, SY AF Carreno, Carlos A. Segel, Sally Y. TI Relationship between Fetal Station and Successful Vaginal Delivery in Nulliparous Women SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Carreno, Carlos A.; Segel, Sally Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 740 BP 278A EP 278A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601215 ER PT J AU Welsh, T Tan, HQ Yi, LJ Mattison, D Caritis, S Mesiano, S AF Welsh, Toni Tan, Huiqing Yi, Lijuan Mattison, Donald Caritis, Steve Mesiano, Sam TI Prophylactic 17 alpha-Hydroxyprogesterone Caproate Treatment Does Not Affect Gestation Length of in the Guinea Pig SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Welsh, Toni; Tan, Huiqing; Yi, Lijuan; Mesiano, Sam] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Mattison, Donald] NICHD, Obstet & Pediat Pharmacol Branch, Bethesda, MD USA. [Caritis, Steve] Univ Pittsburgh, Pittsburgh, PA USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 758 BP 283A EP 283A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601233 ER PT J AU Robinson, BK AF Robinson, Barrett K. TI The Relationship between Increasing Maternal BMI and Characteristics of the Second Stage of Labor SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Robinson, Barrett K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 764 BP 285A EP 285A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601239 ER PT J AU Hogue, CJ AF Hogue, Carol J. TI Association of Significant Life Events with Risk of Stillbirth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Hogue, Carol J.] Emory Univ, Rollins Sch Publ Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Stillbirth Collaborat Res Network SCRN, Atlanta, GA 30322 USA. RI Hogue, Carol/H-5442-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 784 BP 290A EP 290A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601259 ER PT J AU Jessmon, P Kilburn, BA Leach, RE Armant, DR AF Jessmon, Philip Kilburn, Brian A. Leach, Richard E. Armant, D. Randall TI Post-Transcriptional Regulation of Heparin-Binding EGF-Like Growth Factor in Human Trophoblast Cells. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Jessmon, Philip; Kilburn, Brian A.; Armant, D. Randall] Wayne State Univ, Sch Med, Detroit, MI USA. [Jessmon, Philip; Armant, D. Randall] NICHHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD 20892 USA. [Leach, Richard E.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 891 BP 321A EP 322A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601364 ER PT J AU Roberts, JM AF Roberts, James M. TI Body Mass Index and Waist/Hip Ratio as Predictors of Preeclampsia and Response to Antioxidant Therapy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Roberts, James M.] NICHHD, Maternal Fetal Med Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 927 BP 331A EP 332A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601400 ER PT J AU Brenner, CA Dupont, C Armant, DR AF Brenner, Carol A. Dupont, Catherine Armant, D. Randall TI Expression Profiles of Cohesins, Shugoshins and Spindle Assembly Checkpoint Genes in Rhesus Macaque Oocytes Predict Their Susceptibility for Aneuploidy during Embryonic Development. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Brenner, Carol A.; Dupont, Catherine; Armant, D. Randall] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 965 BP 343A EP 343A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601438 ER PT J AU Chandramouli, GVR Jessmon, P Risinger, J Armant, DR Leach, RE AF Chandramouli, G. V. R. Jessmon, Philip Risinger, John Armant, D. Randall Leach, Richard E. TI Gene Expression Analysis Does Not Support the Use of Cobalt Chloride (CoCl2) as a Surrogate for Hypoxia in the Study of Trophoblast Biology. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Invest C1 [Chandramouli, G. V. R.; Risinger, John; Leach, Richard E.] Michigan State Univ, Grand Rapids, MI USA. [Jessmon, Philip; Armant, D. Randall] Wayne State Univ, Sch Med, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 966 BP 343A EP 343A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601439 ER PT J AU Cooper, AR Sullivan, SD Allsworth, JE Vanderhoof, VH Bosworth, T Remaley, A Nelson, LM AF Cooper, Amber R. Sullivan, Shannon D. Allsworth, Jenifer E. Vanderhoof, Vien H. Bosworth, Tracey Remaley, Alan Nelson, Lawrence M. TI Women with Primary Ovarian Insufficiency (POI) Have Significantly Lower Serum DHEAS Levels Than Age-Matched Fertile Controls. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Cooper, Amber R.; Allsworth, Jenifer E.] Washington Univ, St Louis, MO USA. [Sullivan, Shannon D.; Vanderhoof, Vien H.; Nelson, Lawrence M.] NICHD IRP, NIH, Bethesda, MD USA. [Bosworth, Tracey; Remaley, Alan] NIH, Ctr Clin, Lab Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 978 BP 346A EP 346A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601450 ER PT J AU Wolff, EF Kaushal, S Childs, RW Stratton, P AF Wolff, E. F. Kaushal, S. Childs, R. W. Stratton, P. TI Fertility Sparing Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Case Series of 11 Subsequent Pregnancy Outcomes. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Wolff, E. F.; Kaushal, S.; Stratton, P.] NICHD, NIH, Bethesda, MD USA. [Childs, R. W.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 977 BP 346A EP 346A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601449 ER PT J AU Chason, RJ Beall, SA Csokmay, JM Benne, MB Segars, JH AF Chason, Rebecca J. Beall, Stephanie A. Csokmay, John M. Benne, Melinda B. Segars, James H. TI Oocyte Maturation Failure: Incidence and Prognosis for Pregnancy at Assisted Reproduction SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Beall, Stephanie A.] Vanderbilt Univ, Nashville, TN USA. [Chason, Rebecca J.; Csokmay, John M.; Benne, Melinda B.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Chason, Rebecca J.; Csokmay, John M.; Segars, James H.] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 989 BP 349A EP 349A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601461 ER PT J AU Manuck, TA AF Manuck, Tracy A. TI Admixture Mapping Identifies a Region of Chromosome 7 with Potential Spontaneous Preterm Birth (SPTB) Risk Susceptibility Genes in African American (AA) Women SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Manuck, Tracy A.] NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 999 BP 352A EP 352A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601471 ER PT J AU Myatt, L AF Myatt, Leslie TI First Trimester Serum Biomarkers for Prediction of Preeclampsia in a Low Risk Population. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Myatt, Leslie] Eunice Kennedy Shriver Inst Child Hlth & Human De, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 1021 BP 359A EP 359A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601493 ER PT J AU Black, DL Gorospe, M AF Black, Douglas L. Gorospe, Myriam TI Tapas and RNA in Renaissance Spain SO RNA BIOLOGY LA English DT Article DE RNA-binding proteins; splicing; RNA transport; mRNA turnover; microRNA; translational control ID MESSENGER-RNA; TRANSLATION; PROTEIN C1 [Black, Douglas L.] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Black, DL (reprint author), Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. EM dougb@microbio.ucla.edu; myriam-gorospe@nih.gov NR 16 TC 0 Z9 0 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD MAR-APR PY 2010 VL 7 IS 2 BP 130 EP 132 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 661VV UT WOS:000282761300004 PM 20534974 ER PT J AU Winkler, CA Nelson, G Oleksyk, TK Nava, MB Kopp, JB AF Winkler, Cheryl A. Nelson, George Oleksyk, Taras K. Nava, M. Berenice Kopp, Jeffrey B. TI Genetics of Focal Segmental Glomerulosclerosis and Human Immunodeficiency Virus-Associated Collapsing Glomerulopathy: The Role of MYH9 Genetic Variation SO SEMINARS IN NEPHROLOGY LA English DT Review DE Health disparities; glomerulosclerosis; end-stage kidney disease; podocyte; myosin ID STAGE RENAL-DISEASE; ADMIXTURE LINKAGE DISEQUILIBRIUM; PREGNANCY-RELATED MORTALITY; TYPE-2 DIABETES-MELLITUS; GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; AFRICAN-AMERICANS; MACULAR DEGENERATION; NATURAL-SELECTION; KIDNEY-DISEASE AB Until recently, knowledge of genetic causes of glomerular disease was limited to certain rare or uncommon inherited diseases, and to genes, either rare or with small effect, identified in candidate gene studies. These genetic factors accounted for only a very small fraction of kidney disease. However, the striking differences in frequency of many forms of kidney disease between African Americans and European Americans, which could not be explained completely by cultural or economic factors, pointed to a large unidentified genetic influence. Because focal segmental glomerulosclerosis (FSGS) and human immunodeficiency virus-associated collapsing glomerulopathy have striking racial disparities, we performed an admixture mapping study to identify contributing genetic factors. Admixture mapping identified genetic variants in the nonmuscle myosin heavy chain 9 gene (MYH9) as having a major influence on both FSGS and human immunodeficiency virus-associated collapsing glomerulopathy, with odds ratios from 4 to 8 and attributable fractions of 70% to 100%. Previously identified, rare, inherited MYH9 disorders point to a mechanism by which MYH9 variation disrupts the actin-myosin filaments responsible for maintaining the structure of podocytes, the cells that provide one of three filtration barriers in the glomeruli. MYH9 variation has a smaller but still highly significant effect on nondiabetic kidney disease, and a weaker but significant effect on diabetic kidney disease; it is unclear whether underlying cryptic FSGS is responsible for the MYH9 association with these diseases. The strong predicted power of MYH9 variation for disease indicates a clear role for genetic testing for these variants in personalized medicine, for assessment of genetic risk, and potentially for diagnosis. Semin Nephrol 30:111-125 Published by Elsevier Inc. C1 [Nava, M. Berenice; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.; Nelson, George] NCI, Sci Applicat Int Corp Frederick Inc, Lab Genom Divers, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Oleksyk, Taras K.] Univ Puerto Rico, Dept Biol, Mayaguez, PR USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, 10 Ctr Dr,MSC 1268, Bethesda, MD 20892 USA. EM jbkopp@nih.gov RI Rinaldi2, Carlos/D-4479-2011; Taras, Oleksyk/J-8805-2013; OI Taras, Oleksyk/0000-0002-8148-3918; Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; National Institute of Diabetes and Digestive and Kidney Disease; National Cancer Institute, National Institutes of Health [HHSN2612008001E] FX This research was supported in part by the Intramural Research Programs of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and of the National Institute of Diabetes and Digestive and Kidney Disease. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health under contract HHSN2612008001E. NR 60 TC 14 Z9 14 U1 0 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAR PY 2010 VL 30 IS 2 BP 111 EP 125 DI 10.1016/j.semnephrol.2010.01.003 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 582CY UT WOS:000276574400003 PM 20347641 ER PT J AU Kaphingst, KA McBride, CM AF Kaphingst, Kimberly A. McBride, Colleen M. TI Patient Responses to Genetic Information: Studies of Patients With Hereditary Cancer Syndromes Identify Issues for Use of Genetic Testing in Nephrology Practice SO SEMINARS IN NEPHROLOGY LA English DT Review DE Hereditary cancer syndromes; genetic counseling; risk perception; screening behaviors; health literacy ID NONPOLYPOSIS COLORECTAL-CANCER; BREAST-OVARIAN CANCER; RANDOMIZED CONTROLLED-TRIAL; BRCA2 MUTATION CARRIERS; RISK-REDUCING SURGERY; DECISION-MAKING; KIDNEY CANCER; RENAL-CANCER; PSYCHOLOGICAL IMPACT; SCREENING PRACTICES AB Advances in the genetic basis of kidney disease may mean that genetic testing is increasingly important in reducing disease morbidity and mortality among patients. However, there is little research examining patient responses to genetic information for Mendelian and common kidney diseases. Existing research on kidney and other hereditary cancer syndromes can inform three major issues relevant to the nephrology context as follows: (1) how patients understand their risk of disease after genetic counseling and testing, (2) their emotional responses to the information, and (3) their uptake of recommended risk-reducing strategies. Prior research suggests that genetic counseling and testing may improve patient understanding of genetics, but patients still might not fully understand the meaning of their results for disease risk. Genetic counseling and testing does not appear to result in long-term negative emotional effects among patients who carry mutations or those who do not. Finally, although genetic counseling and testing may improve adherence to recommended screening strategies, adherence varies substantially across different risk-reduction options. Previous research also suggests that computer-based interventions might be a useful adjunct to genetic counseling approaches. Examining whether and how these prior findings relate to the context of hereditary kidney disease is an important area for future research. Semin Nephrol 30:203-214 (C) 2010 Elsevier Inc. All rights reserved. C1 [Kaphingst, Kimberly A.; McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Kaphingst, KA (reprint author), Washington Univ, Hlth Commun Res Lab, 700 Rosedale Ave,Campus Box 1009, St Louis, MO 63112 USA. EM kkaphingst@gwbmail.wustl.edu FU National Human Genuine Research Institute, National Institutes a Health FX Supported by the Intramural Research Program of the National Human Genuine Research Institute, National Institutes a Health. NR 70 TC 7 Z9 7 U1 2 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAR PY 2010 VL 30 IS 2 BP 203 EP 214 DI 10.1016/j.semnephrol.2010.01.011 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 582CY UT WOS:000276574400011 PM 20347649 ER PT J AU Klebanoff, MA Andrews, WW Zhang, J Brotman, RM Nansel, TR Yu, KF Schwebke, JR AF Klebanoff, Mark A. Andrews, William W. Zhang, Jun Brotman, Rebecca M. Nansel, Tonja R. Yu, Kai-Fun Schwebke, Jane R. TI Race of Male Sex Partners and Occurrence of Bacterial Vaginosis SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; RISK-FACTORS; VAGINAL FLORA; METRONIDAZOLE PLUS; RANDOMIZED-TRIAL; WOMEN; ASSOCIATION; PREVALENCE; ACQUISITION; INFECTIONS AB Background: Whether bacterial vaginosis (BV) is sexually transmitted is uncertain. Also it is unknown why BV is approximately twice as prevalent among black as among white women. An association of BV with a characteristic of the male sex partner, such as race, might support sexual transmission as well as account for the observed ethnic disparity in BV. Methods: Three thousand six hundred twenty nonpregnant women 15 to 44 years of age were followed quarterly for 1 year. At each visit, extensive questionnaire data and vaginal swabs for Gram's staining were obtained. The outcome was transition from BV-negative to positive (Nugent's score >= 7) in an interval of 2 consecutive visits. Results: BV occurred in 12.8% of 906 sexually active intervals to white women-24.8% of intervals when the woman reported a black partner and 10.7% when all partners were white. Among white women, there was a 2-fold increased risk for BV incidence with a black, compared with a white partner (risk ratio [RR] 2.3, 95% confidence interval 1.6-3.4; adjusted RR 2.2, 95% confidence interval 1.5-3.4), but differed according to condom use. In the presence of consistent condom use, the adjusted RR was 0.7 (0.3-2.4); it was 2.4 (1.0-6.2) in the presence of inconsistent use; and 2.7 (1.7-4.2) in the absence of condom use. Black women could not be studied, as there were insufficient numbers who reported only white male sex partners. Conclusion: The association of BV occurrence with partner's race, and its blunting by condom use, suggests that BV may have a core group component and may be sexually transmitted. C1 [Klebanoff, Mark A.; Zhang, Jun; Nansel, Tonja R.; Yu, Kai-Fun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Andrews, William W.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Brotman, Rebecca M.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Schwebke, Jane R.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, 6100 Bldg Room 7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov RI Brotman, Rebecca/H-5442-2011; OI Brotman, Rebecca/0000-0001-8762-6214; Nansel, Tonja/0000-0002-8298-7595 FU Intramural funds [NO-1-HD-8-3293]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [Z01 HD002535-10] FX Supported by contract NO-1-HD-8-3293 and by Intramural funds (Z01 HD002535-10) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 38 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAR PY 2010 VL 37 IS 3 BP 184 EP 190 DI 10.1097/OLQ.0b013e3181c04865 PG 7 WC Infectious Diseases SC Infectious Diseases GA 565CC UT WOS:000275265600011 PM 19959972 ER PT J AU Wang, SN Zhou, YF Seavey, CN Singh, AK Xu, XL Hunt, T Hoyt, RF Horvath, KA AF Wang, Suna Zhou, Yifu Seavey, Caleb N. Singh, Avneesh K. Xu, Xiuli Hunt, Timothy Hoyt, Robert F., Jr. Horvath, Keith A. TI Rapid and dynamic alterations of gene expression profiles of adult porcine bone marrow-derived stem cell in response to hypoxia SO STEM CELL RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; NUCLEAR ANTIGEN; ADIPOSE-TISSUE; STROMAL CELLS; FIBROBLASTS; CANCER; MODEL; GADD45-BETA; RECEPTORS; RELEVANCE AB This study sought to identify the gene expression patterns of porcine bone marrow-derived MSC in response to hypoxia and to investigate novel specific hypoxic targets that may have a role in determining MSC proliferation/survival and differentiation. MSC from 15 animals were incubated in 1% oxygen and 8% carbon dioxide for 6, 12, and 24 h. RNA samples were isolated and assayed with Affymetrix porcine arrays and quantitative reverse-transcription PCR. Significant gene expression levels among the four groups of normoxia, 6-, 12-, and 24-h hypoxia were identified. The pattern in the 12-h hypoxia group was similar to that of the 24-h group. Of 23,924 probes, 377 and 210 genes were regulated in the 6- and 24-h hypoxia groups, respectively. Functional classification of the hypoxic regulated genes was mainly clustered in cell proliferation and response to stress. However, the major upregulated genes in the 6-h group were activated in cell cycle phases; the genes in the 24-h hypoxia were evenly separated into cell differentiation, apoptosis, and cellular metabolic processes. Twenty-eight genes were upregulated in all hypoxia groups; these genes are considered as hypoxic targets. Our results identified a genome-wide hypoxia-induced gene expression pattern in porcine MSC. This study provides a global view of molecular events in the cells during exposure to hypoxia and revealed a set of novel candidate hypoxic targets. Published by Elsevier B.V. C1 [Wang, Suna; Zhou, Yifu; Seavey, Caleb N.; Singh, Avneesh K.; Xu, Xiuli; Hunt, Timothy; Hoyt, Robert F., Jr.; Horvath, Keith A.] NHLBI, Cellular Biol Sect, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RP Wang, SN (reprint author), NHLBI, Cellular Biol Sect, Cardiothorac Surg Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 2N246, Bethesda, MD 20892 USA. EM wangs3@mail.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank the NHLBI Core Facilities for processing microarray hybridization and data normalization; this work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 45 TC 8 Z9 8 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 J9 STEM CELL RES JI Stem Cell Res. PD MAR PY 2010 VL 4 IS 2 BP 117 EP 128 DI 10.1016/j.scr.2009.12.002 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 578MK UT WOS:000276297600004 PM 20172499 ER PT J AU Barr, TL Latour, LL Lee, KY Schaewe, TJ Luby, M Chang, GS El-Zammar, Z Alam, S Hallenbeck, JM Kidwell, CS Warach, S AF Barr, Taura L. Latour, Lawrence L. Lee, Kyung-Yul Schaewe, Timothy J. Luby, Marie Chang, George S. El-Zammar, Ziad Alam, Shaista Hallenbeck, John M. Kidwell, Chelsea S. Warach, Steven TI Blood-Brain Barrier Disruption in Humans Is Independently Associated With Increased Matrix Metalloproteinase-9 SO STROKE LA English DT Article DE acute cerebrovascular event; blood-brain barrier; matrix metalloproteinase-9 ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE ISCHEMIC-STROKE; MATRIX-METALLOPROTEINASE EXPRESSION; ATTENUATED INVERSION-RECOVERY; FOCAL CEREBRAL-ISCHEMIA; HEMORRHAGIC TRANSFORMATION; MULTIPLE-SCLEROSIS; THROMBOLYTIC THERAPY; TEMPORAL PROFILE; REPERFUSION AB Background and Purpose-Matrix metalloproteinases (MMP) may play a role in blood-brain barrier (BBB) disruption after ischemic stroke. We hypothesized that plasma concentrations of MMP-9 are associated with a marker of BBB disruption in patients evaluated for acute stroke. Methods-Patients underwent MRI on presentation and approximate to 24 hours later. The MRI marker, termed hyperintense acute reperfusion injury marker (HARM), is gadolinium enhancement of cerebrospinal fluid on fluid-attenuated inversion recovery MRI. Plasma MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were measured by enzyme-linked immunosorbent assay. Logistic regression models tested for predictors of HARM on 24-hour follow-up scans separately for MMP-9 and the ratio of MMP-9 to TIMP-1. Results-For the 41 patients enrolled, diagnoses were: acute ischemic cerebrovascular syndrome, 33 (80.6%); intracerebral hemorrhage, 6 (14.6%); stroke mimic, 1 (2.4%); and no stroke, 1 (2.4%). HARM was present in 17 (41.5%) patients. In model 1, HARM was associated with baseline plasma MMP-9 concentration (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.001-1.019; P=0.033). In model 2, HARM was associated with the ratio of MMP-9 to tissue inhibitor of matrix metalloproteinase-1 (OR, 4.94; 95% CI, 1.27-19.14; P=0.021). Conclusions-Baseline MMP-9 was a significant predictor of HARM at 24-hour follow-up, supporting the hypothesis that MMP-9 is associated with BBB disruption. If the association between MMP-9 and BBB disruption is confirmed in future studies, HARM may be a useful imaging marker to evaluate MMP-9 inhibition in ischemic stroke and other populations with BBB disruption. (Stroke. 2010; 41: e123-e128.) C1 [Barr, Taura L.] NINR, Bethesda, MD 20892 USA. [Latour, Lawrence L.; Luby, Marie; Hallenbeck, John M.; Kidwell, Chelsea S.; Warach, Steven] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Lee, Kyung-Yul] Yonsei Univ, Coll Med, Dept Neurol, Seoul, South Korea. [Schaewe, Timothy J.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [El-Zammar, Ziad] SUNY Upstate Med Univ, Syracuse, NY USA. [Alam, Shaista] NIMH, Bethesda, MD 20892 USA. [Kidwell, Chelsea S.] Georgetown Univ, Dept Neurol, Washington, DC USA. Washington Hosp Ctr, Stroke Ctr, Washington, DC 20010 USA. RP Barr, TL (reprint author), Hatfield Clin Res Ctr, Tissue Injury Unit, 10 Ctr Dr,Bldg 10,Room 2-1339, Bethesda, MD 20812 USA. EM barrt@mail.nih.gov OI Lee, Kyung-Yul/0000-0001-5585-7739 FU pre-doctoral Intramural Research Training Award via the Graduate Partnerships Program through the National Institute of Nursing Research, National Institutes of Health; Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX Taura Barr's contributions were supported by a pre-doctoral Intramural Research Training Award via the Graduate Partnerships Program through the National Institute of Nursing Research, National Institutes of Health. This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 48 TC 68 Z9 73 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2010 VL 41 IS 3 BP E123 EP E128 DI 10.1161/STROKEAHA.109.570515 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 559DA UT WOS:000274799600031 PM 20035078 ER PT J AU Taylor, M Grundt, P Griffin, SA Newman, AH Luedtke, RR AF Taylor, Michelle Grundt, Peter Griffin, Suzy A. Newman, Amy Hauck Luedtke, Robert R. TI Dopamine D3 Receptor Selective Ligands With Varying Intrinsic Efficacies at Adenylyl Cyclase Inhibition and Mitogenic Signaling Pathways SO SYNAPSE LA English DT Article DE dopamine receptors; D2-like dopamine receptors; D3 receptors; D3 selective compounds; intrinsic efficacy; functional selectivity ID ABNORMAL INVOLUNTARY MOVEMENTS; ABUSE THERAPEUTIC AGENTS; DRUG-SEEKING BEHAVIOR; D-3 RECEPTOR; FUNCTIONAL SELECTIVITY; INDUCED REINSTATEMENT; PARTIAL AGONISTS; SUBSTANCE-ABUSE; RHESUS-MONKEYS; CELL-LINE AB A panel of structurally related substituted 4-phenylpiperazines with nanomolar affinity and selectivity at D3 dopamine receptors has been synthesized. Compounds in which a heterocyclic (2-phenyl pyridyl, 3-phenyl pyridyl, benzothiophene, or benzofuran) moiety is adjacent to the amide was varied and/or a double bond (trans-butenyl) replaced the four-carbon aliphatic chain linking the arylamide with the 4-phenylpiperazine moiety were compared for (a) affinity at human D2 and D3 dopamine receptors, (b) intrinsic efficacy using an adenylyl cyclase inhibition assay, and (c) intrinsic efficacy using a mitogenic assay. All 16 compounds were (a) more efficacious for the D3 receptor cyclase inhibition assay than for the D3 receptor mitogenic assay and (b) exhibited the same or greater efficacy at D3 compared to D2 receptor (with the exception of one compound). Although the heterocyclic amide moiety appears to be the pivotal structural element determining the intrinsic efficacy of our D3 receptor selective compounds, the magnitude of the efficacy is modulated by the (a) substituent(s) on the phenyl piperazine and (b) the saturation of the four-carbon chain that links the arylamide and the phenylpiperazine. In addition, our ligands are functionally selective, because they can have differing intrinsic efficacies for the cyclase inhibition and the mitogenic activation signaling pathways. Compounds that are essentially full agonists at the cyclase assay appear to be only partial agonists in the mitogenic assay and compounds that are partial agonists in our cyclase assay are partial agonists or antagonists in the mitogenic assay. Synapse 64:251-266, 2010. (C)2009 Wiley-Liss, Inc. C1 [Taylor, Michelle; Griffin, Suzy A.; Luedtke, Robert R.] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. [Grundt, Peter; Newman, Amy Hauck] NIDA, Med Chem Sect, IRP, NIH, Baltimore, MD 21224 USA. RP Luedtke, RR (reprint author), Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, 3500 Camp Bowie, Ft Worth, TX 76107 USA. EM rluedtke@hsc.unt.edu FU NIDA-IRP [R-01 DA13584-01, R-01 DA13584-03S1]; Michael J. Fox Foundation for Parkinson's Disease Research FX NIDA-IRP; Contract grant numbers: R-01 DA13584-01, R-01 DA13584-03S1; Contract grant sponsor: Michael J. Fox Foundation for Parkinson's Disease Research. NR 66 TC 13 Z9 13 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAR PY 2010 VL 64 IS 3 BP 251 EP 266 DI 10.1002/syn.20725 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 544RU UT WOS:000273677600009 PM 19924694 ER PT J AU Gourraud, PA Feolo, M AF Gourraud, P. A. Feolo, M. TI The Babel Tower revisited: SNPs - Indels - CNVs. Confusion in naming sequence variant always rises from ashes SO TISSUE ANTIGENS LA English DT Article DE CNV; indel; MHC region; nomenclature; SNP ID NOMENCLATURE C1 [Gourraud, P. A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Feolo, M.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Gourraud, PA (reprint author), Univ Calif San Francisco, Dept Neurol, 513 Parnassus Ave, San Francisco, CA 94143 USA. EM pierreantoine.gourraud@ucsf.edu RI Gourraud, Pierre-Antoine/O-3024-2015 NR 10 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAR PY 2010 VL 75 IS 3 BP 199 EP 200 DI 10.1111/j.1399-0039.2009.01424.x PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 553AE UT WOS:000274336000001 PM 20030785 ER PT J AU Schecter, A Colacino, J Patel, K Kannan, K Yun, SH Haffner, D Harris, TR Birnbaum, L AF Schecter, Arnold Colacino, Justin Patel, Keyur Kannan, Kurunthachalam Yun, Se Hun Haffner, Darrah Harris, T. Robert Birnbaum, Linda TI Polybrominated diphenyl ether levels in foodstuffs collected from three locations from the United States SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE United States food; PBDE intake; Texas; New York; California ID BROMINATED FLAME RETARDANTS; DIETARY PBDE INTAKE; BREAST-MILK; HUMAN EXPOSURE; POLYCHLORINATED-BIPHENYLS; MARKET-BASKET; 2,2',4,4',5-PENTABROMODIPHENYL ETHER; DEVELOPMENTAL EXPOSURE; FOOD; CONSUMPTION AB Objectives: The objectives of this study were to provide updated measurements of PBDEs in US food, to estimate possible difference in levels from differing geographical regions, and to provide an improved estimate of current dietary intake. Methods: Thirty matched food samples for a total of 90 samples were collected from each of three cities (Los Angeles, California; Dallas, Texas; and Albany, New York) and were analyzed for 13 polybrominated diphenyl ether congeners (BDE 28, 47, 49, 66, 85, 99, 100, 138, 153, 154, 183, 203, and 209). Dietary intake of PBDEs was estimated by food type, age, and sex. Results: In this pilot Study, we did not note a statistically significant difference in total PBDE levels in food collected from the three locations. The median total PBDE levels (estimating non-detected values as half of the detection limit) in meat, dairy, eggs, and fish were 267 pg/g wet weight (ww) (range 102-3156 pg/g ww), 176 pg/g ww (range 41-954 pg/g ww), 637 pg/g ww (range 193-932 pg/g ww), and 243 pg/g ww (range 36-2161 pg/g ww). PBDE intake from food was estimated to range from 2.7 ng/kg/day for children 2 through 5 years of age to 0.8 ng/kg/day for women aged 60 years and older. This compares closely with our previous study where the intake estimate was 2.7 ng/kg/day for children 2 through 5 years of age and 0.9 ng/kg/day for women aged 60 years and older. Conclusion: We did not find a decrease of PBDEs in food since our previous studies which we expected to find due to the declining use of PBDEs in the USA. These findings could be consistent with food contamination from depot sources of PBDEs. A larger, more representative sampling of the US food supply is indicated based on our findings. (C) 2009 Elsevier Inc. All rights reserved. C1 [Schecter, Arnold; Patel, Keyur; Harris, T. Robert] Univ Texas Sch Publ Hlth Dallas, Dallas, TX 75309 USA. [Colacino, Justin] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Kannan, Kurunthachalam; Yun, Se Hun] SUNY Albany, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12222 USA. [Kannan, Kurunthachalam; Yun, Se Hun] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12222 USA. [Haffner, Darrah] Univ Texas SW Med Sch, Dallas, TX USA. [Birnbaum, Linda] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Schecter, A (reprint author), Univ Texas Sch Publ Hlth Dallas, 5323 Harry Hines,V8-112, Dallas, TX 75309 USA. EM arnold.schecter@utsouthwestern.edu FU Gustavus and Louise Pfeiffer Foundation FX The authors would like to acknowledge the Gustavus and Louise Pfeiffer Foundation for their generous grant which funded this research. NR 45 TC 32 Z9 34 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 1 PY 2010 VL 243 IS 2 SI SI BP 217 EP 224 DI 10.1016/j.taap.2009.10.004 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 565NS UT WOS:000275301400010 PM 19835901 ER PT J AU Mills, LA Kagaayi, J Shott, JP Newell, K Bwanika, JB Ssempijja, V Aluma, S Quinn, TC Reynolds, SJ Gray, RH AF Mills, Lisa A. Kagaayi, Joseph Shott, Joseph P. Newell, Kevin Bwanika, John Baptist Ssempijja, Victor Aluma, Simon Quinn, Thomas C. Reynolds, Steven J. Gray, Ronald H. TI Performance of a prototype malaria rapid diagnostic test versus thick film microscopy among HIV-positive subjects in rural Rakai, Uganda SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE Malaria; HIV/AIDS; Diagnosis; Rapid diagnostic test; Africa; Uganda AB In this study, we report the performance of a prototype malaria rapid diagnostic test, Malaria F-test (MET), compared with thick blood films from HIV-positive Ugandans undergoing malaria testing. In total, 21/154 samples (13.6%) were concordantly positive by both thick film and MET and 129/154 samples (83.8%) were concordantly negative; 1 sample (0.6%) was thick film-positive but MET-negative and 3 samples (1.9%) were thick film-negative but MET-positive. The sensitivity of MET was 95.5% (95% CI 77.2-99.9%) compared with thick film microscopy and the specificity was 97.7% (95% CI 93.5-99.5%). MFT was simple, rapid and effective for detection of Plasmodium falciparum among HIV-positive subjects in a rural, malaria-endemic African setting. Published by Elsevier Ltd on behalf of Royal Society of Tropical Medicine and Hygiene. C1 [Mills, Lisa A.] Johns Hopkins Med Inst, Div Infect Dis, Baltimore, MD 21287 USA. [Mills, Lisa A.; Kagaayi, Joseph; Bwanika, John Baptist; Ssempijja, Victor; Aluma, Simon; Gray, Ronald H.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Shott, Joseph P.; Newell, Kevin] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Quinn, Thomas C.; Reynolds, Steven J.; Gray, Ronald H.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Mills, LA (reprint author), Johns Hopkins Med Inst, Div Infect Dis, 1830 E Monument St 401, Baltimore, MD 21287 USA. EM LisaAMills@Hotmail.com FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases, and the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; BD Diagnostics (Sparks, MD, USA) FX Funding: This project was funded in whole or in part with federal funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. Research support and test kits were provided by BD Diagnostics (Sparks, MD, USA). NR 6 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0035-9203 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD MAR PY 2010 VL 104 IS 3 BP 237 EP 239 DI 10.1016/j.trstmh.2009.07.030 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 574OJ UT WOS:000276000000012 PM 19765788 ER PT J AU Hallenbeck, JM AF Hallenbeck, John M. TI Introduction of a New Journal SO TRANSLATIONAL STROKE RESEARCH LA English DT Editorial Material C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Hallenbeck, JM (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM HallenbJ@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD MAR PY 2010 VL 1 IS 1 BP 1 EP 1 DI 10.1007/s12975-010-0013-9 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V23EP UT WOS:000208326400001 PM 24323448 ER PT J AU Wu, DQ Pan, WJ AF Wu, Dianqing Pan, Weijun TI GSK3: a multifaceted kinase in Wnt signaling SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID GLYCOGEN-SYNTHASE KINASE-3; RECEPTOR-RELATED PROTEIN-5; BETA-CATENIN; CORECEPTOR LRP6; XENOPUS EMBRYOS; NEGATIVE REGULATOR; STABILIZES AXIN; PPPSP MOTIFS; WILMS-TUMOR; PHOSPHORYLATION AB GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated beta-catenin phosphorylation is known to be the key event in Wnt-beta-catenin signaling, the mechanisms that underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-beta-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations. C1 [Wu, Dianqing] Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA. [Wu, Dianqing] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. [Pan, Weijun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Wu, DQ (reprint author), Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA. EM dan.wu@yale.edu FU NIH [CA139395, CA132317, AR051476] FX We thank Matthew C. Jones for reading and commenting on the manuscript. D.W. is supported by NIH grants (CA139395, CA132317, AR051476). Due to space limitations, we apologize for the many references that we had to omit. NR 74 TC 97 Z9 100 U1 3 U2 29 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2010 VL 35 IS 3 BP 161 EP 168 DI 10.1016/j.tibs.2009.10.002 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 573KQ UT WOS:000275912600006 ER PT J AU An, P Winkler, CA AF An, Ping Winkler, Cheryl A. TI Host genes associated with HIV/AIDS: advances in gene discovery SO TRENDS IN GENETICS LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 DISEASE PROGRESSION; DUFFY ANTIGEN RECEPTOR; NUMBER VARIANT ASSAYS; T-CELL COUNTS; AIDS PROGRESSION; AFRICAN-AMERICANS; PROMOTER VARIANT; GENOMEWIDE ASSOCIATION; ANTIRETROVIRAL THERAPY AB Twenty-five years after the discovery of HIV as the cause of AIDS there is still no effective vaccine and no cure for this disease. HIV susceptibility shows a substantial degree of individual heterogeneity, much of which can be conferred by host genetic variation. In an effort to discover host factors required for HIV replication, identify crucial pathogenic pathways, and reveal the full armament of host defenses, there has been a shift from candidate-gene studies to unbiased genome-wide genetic and functional studies. However, the number of securely identified host factors involved in HIV disease remains small, explaining only similar to 15-20% of the observed heterogeneity - most of which is attributable to human lymphocyte antigen (HLA) variants. Multidisciplinary approaches integrating genetic epidemiology to systems biology will be required to fully understand virus-host interactions to effectively combat HIV/AIDS. C1 [An, Ping; Winkler, Cheryl A.] NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Winkler, CA (reprint author), NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. EM winklerc@mail.nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX We are in debt to Dr. George Nelson for many discussions and for critical reading of the manuscript. This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health (NIH), 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 107 TC 50 Z9 51 U1 0 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD MAR PY 2010 VL 26 IS 3 BP 119 EP 131 DI 10.1016/j.tig.2010.01.002 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 565ES UT WOS:000275272600006 PM 20149939 ER PT J AU Ahlers, JD Belyakov, IM AF Ahlers, Jeffrey D. Belyakov, Igor M. TI Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS SO TRENDS IN IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL REPLICATION CAPACITY; LONG-TERM NONPROGRESSORS; MUCOSAL AIDS VACCINE; CLASS-I ALLELES; RHESUS-MONKEYS; IMMUNE ESCAPE; ELITE CONTROLLERS; HIV-1 INFECTION; LYMPHOCYTE RESPONSES AB CD8(+) cytotoxic T lymphocyte (CTL) responses are crucial in establishing the control of persistent virus infections. Population studies of HIV-1-infected individuals suggest that CD8(+) CTL responses targeting epitopes that take the greatest toll on virus replication are instrumental in immune control. A major question for vaccine design is whether incorporating epitopes responsible for controlling a persistent virus will translate into protection from natural infection or serve solely as a fail-safe mechanism to prevent overt disease in infected individuals. Here, we discuss qualitative parameters of the CD8(+) CTL response and mechanisms operative in the control of persistent virus infections and suggest new strategies for design and delivery of HIV vaccines. C1 [Ahlers, Jeffrey D.] NIAID, NIH, Bethesda, MD 20817 USA. [Belyakov, Igor M.] Midwest Res Inst, Frederick, MD 21702 USA. RP Ahlers, JD (reprint author), NIAID, NIH, Bethesda, MD 20817 USA. NR 116 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD MAR PY 2010 VL 31 IS 3 BP 120 EP 130 DI 10.1016/j.it.2009.12.003 PG 11 WC Immunology SC Immunology GA 580GT UT WOS:000276436700007 PM 20089450 ER PT J AU Miller, LH AF Miller, Louis H. TI The Multilateral Initiative on Malaria: looking back and looking ahead SO TRENDS IN PARASITOLOGY LA English DT Editorial Material AB The Multilateral Initiative on Malaria (MIM) started in 1997 with the aim of giving African scientists an equal voice with Northern scientists in making decisions about malaria research in Africa. Is there a need for MIM today with the large increase in funding for malaria research from governments and foundations? I conclude that MIM is still needed today to support African scientists' investigator-initiated research and training. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM lmiller@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000241-26] NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD MAR PY 2010 VL 26 IS 3 BP 110 EP 113 DI 10.1016/j.pt.2009.12.009 PG 4 WC Parasitology SC Parasitology GA 572CP UT WOS:000275804700003 PM 20097134 ER PT J AU Vail, DM Michels, GM Khanna, C Selting, KA London, CA AF Vail, D. M. Michels, G. M. Khanna, C. Selting, K. A. London, C. A. CA Vet Cooperative Oncology Grp TI Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)-a veterinary cooperative oncology group (VCOG) consensus document SO VETERINARY AND COMPARATIVE ONCOLOGY LA English DT Article DE comparative oncology; dog; hematology; lymphoma; oncology ID POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMA; CELL LYMPHOMA; REARRANGEMENT; REMISSION; DIAGNOSIS; PATIENT; RELAPSE; CATS; GENE AB Standardized assessment of response to therapy for lymphoma in dogs is lacking, making critical comparisons of treatment protocols difficult. This Veterinary Cooperative Oncology Group (VCOG) consensus document, based on the recommendations of a subcommittee of ACVIM board-certified veterinary oncologists, was unanimously adopted at the 29th Annual Conference of the Veterinary Cancer Society (VCS) by the VCOG membership. It has integrated guidance from the response assessment criteria established for lymphoma in human patients using standards available in routine veterinary oncology practices that are simple, repeatable and consistently applicable. These guidelines are intended only for use in dogs, where peripheral lymphadenopathy represents the principal component of their disease and as such do not critically assess extranodal disease (e.g., primary cutaneous, central nervous system, gastrointestinal). It is hoped these guidelines will be widely adopted and serve to facilitate the comparison of current and future treatment protocols used in the therapy of dogs. C1 [Vail, D. M.] Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. [Vail, D. M.] Univ Wisconsin, Carbone Comprehens Canc Ctr, Madison, WI 53706 USA. [Michels, G. M.] Pfizer Anim Hlth, Kalamazoo, MI USA. [Khanna, C.] NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Selting, K. A.] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 65211 USA. [London, C. A.] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA. RP Vail, DM (reprint author), Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. EM vaild@svm.vetmed.wisc.edu RI London, Cheryl/E-6561-2012 NR 26 TC 53 Z9 53 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1476-5810 EI 1476-5829 J9 VET COMP ONCOL JI Vet. Comp. Oncol. PD MAR PY 2010 VL 8 IS 1 BP 28 EP 37 DI 10.1111/j.1476-5829.2009.00200.x PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 547TL UT WOS:000273912000004 PM 20230579 ER PT J AU Fredrickson, TN Hartley, JW Morse, HC AF Fredrickson, T. N. Hartley, J. W. Morse, H. C., III TI Citrobacter-Induced Colitis in Mice With Murine Acquired Immunodeficiency Syndrome SO VETERINARY PATHOLOGY LA English DT Article DE Citrobacter; colitis; murine acquired immunodeficiency syndrome ID HYPERPROLIFERATING COLONIC EPITHELIA; RETROVIRUS-INDUCED IMMUNODEFICIENCY; LEUKEMIA VIRUSES; LEISHMANIA-MAJOR; HOST-DEFENSE; RODENTIUM; HYPERPLASIA; INFECTION; LP-BM5; MAIDS AB Over the period of a year, colitis was observed in 44 mice raised in a conventional nonspecific pathogen free colony, 41 of these having concomitant retrovirus induced murine acquired immunodeficiency syndrome (MAIDS). The lesions varied from bacterial colonization to hyperplasia of colonic mucosa to severe, often fatal, ulceration. Citrobacter rodentium was isolated from the colon and/or liver of 2 mice with colitis. When C57BL/6 mice with or without MAIDS were given graded doses of the bacterium, only those with MAIDS developed colitis, and C rodentium was reisolated from their livers. Thus, mice with MAIDS can develop severe disease following opportunistic infection with an environmental contaminant of the colony that is nonpathogenic for normal adult mice. C1 [Fredrickson, T. N.; Hartley, J. W.; Morse, H. C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, NIH, Twinbrook 1,5640 Fishers Lane,Room 1421, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 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 32 TC 1 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2010 VL 47 IS 2 BP 312 EP 317 DI 10.1177/0300985809358605 PG 6 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 572LQ UT WOS:000275834300014 PM 20118320 ER PT J AU Chen, GL Lamirande, EW Jin, H Kemble, G Subbarao, K AF Chen, Grace L. Lamirande, Elaine W. Jin, Hong Kemble, George Subbarao, Kanta TI Safety, immunogencity, and efficacy of a cold-adapted A/Ann Arbor/6/60 (H2N2) vaccine in mice and ferrets SO VIROLOGY LA English DT Article DE Live attenuated influenza vaccines; A/Ann Arbor/6/60 (H2N2) ID INFLUENZA-VIRUS VACCINE; A VIRUSES; LIVE; PROTECTION; ORIGIN; A/ANN-ARBOR/6/60; TRANSMISSION; EVOLUTION; SUBTYPES; HUMANS AB We studied the attenuation, immunogenicity and efficacy of the cold-adapted A/Ann Arbor/6/60 (AA ca) (H2N2) virus in mice and ferrets to evaluate its use in the event of an H2 influenza pandemic. The AA ca virus was restricted in replication in the respiratory tract of mice and ferrets. In mice, 2 doses of vaccine elicited a >4-fold rise in hemagglutination-inhibition (HAI) titer and resulted in complete inhibition of viral replication following lethal homologous wild-type virus challenge. In ferrets, a single dose of the vaccine elicited a >4-fold rise in HAI titer and conferred complete protection against homologous wild-type virus challenge in the upper respiratory tract. In both mice and ferrets, the AA ca virus provided significant protection from challenge with heterologous H2 virus challenge in the respiratory tract. The AA ca vaccine is safe, immunogenic, and efficacious against homologous and heterologous challenge in mice and ferrets, supporting the evaluation of this vaccine in clinical trials. Published by Elsevier Inc. C1 [Chen, Grace L.; Lamirande, Elaine W.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Jin, Hong; Kemble, George] Medimmune, Mountain View, CA 94043 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 33,Room 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM chengra@niaid.nih.gov; elamirande@niaid.nih.gov; jinh@medimmune.com; kembleg@medimmune.com; ksubbarao@niaid.nih.gov FU National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). This research was performed as part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID and MedImmune. H.J. and G.K. are employees of MedImmune, the manufacturer of seasonal live attenuated influenza virus vaccine (LAIV). NR 35 TC 18 Z9 18 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 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2010 VL 398 IS 1 BP 109 EP 114 DI 10.1016/j.virol.2009.12.003 PG 6 WC Virology SC Virology GA 557KX UT WOS:000274669100011 PM 20034647 ER PT J AU Portnoy, DB Smoak, ND Marsh, KL AF Portnoy, David B. Smoak, Natalie D. Marsh, Kerry L. TI Perceiving interpersonally-mediated risk in virtual environments SO VIRTUAL REALITY LA English DT Article DE Presence; Sexual risk; Embodiment; Interpersonal risk ID REALITY; BEHAVIOR; PREDICTORS; INTERNET; THERAPY; FUTURE; REASON AB Using virtual reality (VR) to examine risky behavior that is mediated by interpersonal contact, such as agreeing to have sex, drink, or smoke with someone, offers particular promise and challenges. Social contextual stimuli that might trigger impulsive responses can be carefully controlled in virtual environments (VE), and yet manipulations of risk might be implausible to participants if they do not feel sufficiently immersed in the environment. The current study examined whether individuals can display adequate evidence of presence in a VE that involved potential interpersonally-induced risk: meeting a potential dating partner. Results offered some evidence for the potential of VR for the study of such interpersonal risk situations. Participants' reaction to the scenario and risk-associated responses to the situation suggested that the embodied nature of virtual reality override the reality of the risk's impossibility, allowing participants to experience adequate situational embedding, or presence. C1 [Portnoy, David B.; Smoak, Natalie D.; Marsh, Kerry L.] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT 06269 USA. [Portnoy, David B.] NCI, NIH, Bethesda, MD 20892 USA. [Smoak, Natalie D.] Illinois Wesleyan Univ, Dept Psychol, Bloomington, IL 61701 USA. RP Marsh, KL (reprint author), Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT 06269 USA. EM portnoydb@mail.nih.gov; kerry.l.marsh@uconn.edu OI Portnoy, David/0000-0003-2175-9457 FU University of Connecticut, Center for Health, Intervention, and Prevention; National Institute of Mental Health FX This research was supported by grants to Kerry L. Marsh and David B. Portnoy from the University of Connecticut, Center for Health, Intervention, and Prevention. This article was written while the third author was supported by a grant from the National Institute of Mental Health. We would like to thank our research assistants for help with data collection and the two volunteers who recorded Blair's voice. NR 32 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1359-4338 J9 VIRTUAL REAL-LONDON JI Virtual Real. PD MAR PY 2010 VL 14 IS 1 SI SI BP 67 EP 76 DI 10.1007/s10055-009-0120-7 PG 10 WC Computer Science, Interdisciplinary Applications; Computer Science, Software Engineering; Imaging Science & Photographic Technology SC Computer Science; Imaging Science & Photographic Technology GA 838HU UT WOS:000296279400007 PM 20228871 ER PT J AU Hayes, BK Heit, E Swendsen, H AF Hayes, Brett K. Heit, Evan Swendsen, Haruka TI Inductive reasoning SO WILEY INTERDISCIPLINARY REVIEWS-COGNITIVE SCIENCE LA English DT Review ID CATEGORY-BASED INDUCTION; PROPERTY GENERALIZATION; UNCERTAIN CATEGORIES; CROSS-CLASSIFICATION; NATURAL CATEGORIES; MENTAL MODELS; SIMILARITY; DIVERSITY; PROBABILITY; TYPICALITY AB Inductive reasoning entails using existing knowledge or observations to make predictions about novel cases. We review recent findings in research on category-based induction as well as theoretical models of these results, including similarity-based models, connectionist networks, an account based on relevance theory, Bayesian models, and other mathematical models. A number of touchstone empirical phenomena that involve taxonomic similarity are described. We also examine phenomena involving more complex background knowledge about premises and conclusions of inductive arguments and the properties referenced. Earlier models are shown to give a good account of similarity-based phenomena but not knowledge-based phenomena. Recent models that aim to account for both similarity-based and knowledge-based phenomena are reviewed and evaluated. Among the most important new directions in induction research are a focus on induction with uncertain premise categories, the modeling of the relationship between inductive and deductive reasoning, and examination of the neural substrates of induction. A common theme in both the well-established and emerging lines of induction research is the need to develop well-articulated and empirically testable formal models of induction. (C) 2010 John Wiley&Sons, Ltd. WIREs Cogn Sci 2010 1 278-292 C1 [Hayes, Brett K.] Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. [Heit, Evan] Univ Calif Merced, Sch Social Sci Humanities & Arts, Merced, CA USA. [Swendsen, Haruka] NIH, Mood & Anxiety Disorder Res Program, Bethesda, MD 20892 USA. RP Hayes, BK (reprint author), Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. EM B.Hayes@unsw.edu.au RI Heit, Evan/B-1551-2010; OI Heit, Evan/0000-0003-3457-1816; Hayes, Brett/0000-0003-1415-0088 NR 89 TC 26 Z9 27 U1 4 U2 15 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1939-5078 J9 WIRES COGN SCI JI Wiley Interdiscip. Rev.-Cogn. Sci. PD MAR-APR PY 2010 VL 1 IS 2 BP 278 EP 292 DI 10.1002/wcs.44 PG 15 WC Psychology, Experimental SC Psychology GA 863NQ UT WOS:000298171700013 PM 26271241 ER PT J AU Muljo, SA Kanellopoulou, C Aravind, L AF Muljo, S. A. Kanellopoulou, C. Aravind, L. TI MicroRNA targeting in mammalian genomes: genes and mechanisms SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID ALGA CHLAMYDOMONAS-REINHARDTII; PIWI-INTERACTING RNAS; C-ELEGANS; CAENORHABDITIS-ELEGANS; MESSENGER-RNA; TRANSCRIPTION FACTORS; REGULATORY RNA; POSTTRANSCRIPTIONAL REGULATION; TETRAHYMENA-THERMOPHILA; CELL DIFFERENTIATION AB We briefly review the history of microRNA (miRNA) research and some of the lessons learnt. To provide some insights as to how and why miRNAs came into existence, we consider the evolution of the RNA interference machinery, miRNA genes, and their targets. We highlight the importance of systems biology approaches to integrate miRNAs as an essential subnetwork for modulating gene expression programs. Building accurate computational models that can simulate highly complex cell-specific gene expression patterns in mammals will lead to a better understanding of miRNAs and their targets in physiological and pathological situations. The impact of miRNAs on medicine, either as potential disease predisposing factors, biomarkers, or therapeutics, is highly anticipated and has started to reveal itself. (C) 2010 John Wiley & Sons, Inc. WIREs Syst Biol Med 2010 2 148-161 C1 [Muljo, S. A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kanellopoulou, C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM muljos@niaid.nih.gov RI Muljo, Stefan/F-5671-2015 OI Muljo, Stefan/0000-0003-1013-446X FU US NIH; NIAID; NCBI, NLM FX We thank anonymous reviewers for their helpful suggestions and apologize in advance that we could not cite all the relevant papers. S.A.M. and L.A. are supported by the Intramural Research Program of the US NIH, NIAID and NCBI, NLM respectively. C.K. is a Claudia Adams Barr Fellow in David Livingston's laboratory (DFCI). NR 119 TC 15 Z9 15 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD MAR-APR PY 2010 VL 2 IS 2 BP 148 EP 161 DI 10.1002/wsbm.53 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674CQ UT WOS:000283711700004 PM 20836019 ER PT J AU Kronman, AC Freund, KM Hanchate, A Emanuel, EJ Ash, AS AF Kronman, Andrea C. Freund, Karen M. Hanchate, Amresh Emanuel, Ezekiel J. Ash, Arlene S. TI NURSING HOME RESIDENCE CONFOUNDS GENDER DIFFERENCES IN MEDICARE UTILIZATION An Example of Simpson's Paradox SO WOMENS HEALTH ISSUES LA English DT Article ID LAST YEAR; INTENSIVE-CARE; HEALTH-CARE; LIFE; END; BENEFICIARIES; EXPENDITURES; DISPARITIES; PREFERENCES; COSTS AB Background. Gender differences in health care utilization in older Americans may be confounded by nursing home residence. Medicare data contain several files that can be used to create a measure of nursing home residence, but prior work has not addressed which best account for potential confounding. Simpson's paradox occurs when aggregated data support a different conclusion from what the disaggregated data show. We describe such a paradox that appeared when we sharpened our definition of "nursing home residence" while examining gender differences in Medicare utilization at the end of life. Methods. To understand gender-specific health care utilization at the end of life, we conducted a retrospective analysis of a national random sample of Medicare beneficiaries aged 66 or older who died in 2001 with Parts A and B data for 18 months before death. We sought to associate each of total hospital days and costs during the final 6 months of life with numbers of primary care physician visits in the 12 preceding months. In addition to demographics, comorbidities, and geography, "nursing home residence" was a potential confounder, which we imputed in two ways: 1) from skilled nursing facility bills in the Part A Medicare Provider Analysis and Review (MedPAR) file; and 2) from Berenson-Eggers-Type-of-Service codes indicating widely spaced doctor visits in nursing homes obtained from Medicare's carrier file. Conclusion. Gender differences in Medicare utilization are strongly confounded by nursing home resident status, which can be imputed well from Medicare's carrier file, but not MedPAR. C1 [Kronman, Andrea C.; Freund, Karen M.; Hanchate, Amresh; Ash, Arlene S.] Boston Univ, Med Ctr, Womens Hlth Unit, Sect Gen Internal Med,Evans Dept Med,Sch Med, Boston, MA 02118 USA. [Kronman, Andrea C.; Freund, Karen M.; Hanchate, Amresh; Ash, Arlene S.] Boston Univ, Med Ctr, Hlth Care Res Unit, Sect Gen Internal Med,Evans Dept Med, Boston, MA 02118 USA. [Emanuel, Ezekiel J.] NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kronman, Andrea C.; Freund, Karen M.] Boston Univ, Sch Med, Womens Hlth Interdisciplinary Res Ctr, Boston, MA 02118 USA. RP Kronman, AC (reprint author), Boston Univ, Med Ctr, Womens Hlth Unit, Sect Gen Internal Med,Evans Dept Med,Sch Med, 801 Massachusetts Ave,Suite 470, Boston, MA 02118 USA. EM Andrea.Kronman@bmc.org OI Hanchate, Amresh/0000-0002-7038-4463; Freund, Karen/0000-0002-9049-5574 FU NICHD NIH HHS [K12 HD043444] NR 33 TC 6 Z9 6 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2010 VL 20 IS 2 BP 105 EP 113 DI 10.1016/j.whi.2009.11.016 PG 9 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 610TQ UT WOS:000278760400004 PM 20149970 ER PT J AU Siluk, D Mager, DE Kim, HS Wang, Y Furimsky, AM Ta, A Iyer, LV Green, CE Wainer, IW AF Siluk, D. Mager, D. E. Kim, H. S. Wang, Y. Furimsky, A. M. Ta, A. Iyer, L. V. Green, C. E. Wainer, I. W. TI Pharmacokinetics and metabolism of (R,R)-methoxyfenoterol in rat SO XENOBIOTICA LA English DT Article DE Hepatocytes; liver microsomes; intestinal microsomes; high-performance liquid chromatography (HPLC); mass spectrometry; pharmacokinetics; phase II drug metabolism ID FENOTEROL DERIVATIVES; PLASMA; SPECTROMETRY AB 1. (R,R)-fenoterol (Fen), a beta(2)-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results from the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen. 2. The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3 min x nmol ml(-1)), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146 ml min(-1) kg(-1), the T(1/2) was significantly longer, 152.9 versus 108.9 min, and the area under the curve (AUC) was significantly increased, 300 versus 119 min x nmol ml(-1). 3. (R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6%, while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation. 4. The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G. C1 [Siluk, D.] Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, PL-80416 Gdansk, Poland. [Siluk, D.; Kim, H. S.; Wang, Y.; Wainer, I. W.] NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Furimsky, A. M.; Ta, A.; Iyer, L. V.; Green, C. E.] SRI Int, Menlo Pk, CA 94025 USA. [Mager, D. E.] SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. RP Siluk, D (reprint author), Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, Gen J Hallera 107, PL-80416 Gdansk, Poland. EM dsiluk@amg.gda.pl FU National Institutes of Health (National Institute on Aging) FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging). NR 17 TC 5 Z9 5 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD MAR PY 2010 VL 40 IS 3 BP 195 EP 206 DI 10.3109/00498250903434533 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 560DT UT WOS:000274882900004 PM 20039779 ER PT J AU Foreman, JE Sharma, AK Amin, S Gonzalez, FJ Peters, JM AF Foreman, Jennifer E. Sharma, Arun K. Amin, Shantu Gonzalez, Frank J. Peters, Jeffrey M. TI Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) inhibits cell growth in a mouse mammary gland cancer cell line SO CANCER LETTERS LA English DT Article DE Peroxisome proliferator-activated receptor-beta/delta; Mammary gland cancer; Cell proliferation; Apoptosis ID BREAST-CANCER; DELTA; DIFFERENTIATION; MICE; PROGRESSION; EXPRESSION; AGONISTS; TARGET; ALPHA; BETA AB The effects of ligand activation of PPAR beta/delta were examined in the mouse mammary tumor cell line (C20). Expression of PPAR beta/delta was markedly lower in C20 cells as compared to the human non-tumorigenic mammary gland derived cell line (MCF10A) and mouse keratinocytes. Ligand activation of PPAR beta/delta in C20 cells caused upregulation of the PPAR beta/delta target gene angiopoietin-like 4 (Angptl4). Inhibition of C20 cell proliferation and clonogenicity was observed following treatment with GW0742 or GW501516, two highly specific PPAR beta/delta ligands. In addition, an increase in apoptosis was observed in C20 cells cultured with 10 mu M GW501516 that preceded the observed inhibition of cell proliferation. Results from this study show that proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPAR beta/delta due in part to increased apoptosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Foreman, Jennifer E.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Foreman, Jennifer E.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Sharma, Arun K.; Amin, Shantu] Penn State Univ, Milton S Hershey Med Ctr, Penn State Canc Inst, Dept Pharmacol, Hershey, PA 17033 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU [CA124533] FX The authors gratefully acknowledge Drs. Timothy Hla and Mallika Ghosh for providing the C20 cell line, Drs. Andrew Billin and Timothy Willson for providing GW0742 and Elaine Kunze, Susan Magargee, and Nicole Bern from the Center for Quantitative Cell Analysis at the Huck Institutes of Life Sciences of The Pennsylvania State University for their technical support with flow cytometry and data analysis. This work supported in part by CA124533 (J.M.P.). NR 33 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD FEB 28 PY 2010 VL 288 IS 2 BP 219 EP 225 DI 10.1016/j.canlet.2009.07.006 PG 7 WC Oncology SC Oncology GA 563RJ UT WOS:000275150800011 PM 19660859 ER PT J AU Sospedra, M Zhao, YD Giulianotti, M Simon, R Pinilla, C Martin, R AF Sospedra, Mireia Zhao, Yingdong Giulianotti, Marc Simon, Richard Pinilla, Clemencia Martin, Roland TI Combining positional scanning peptide libraries, HLA-DR transfectants and bioinformatics to dissect the epitope spectrum of HLA class II cross-restricted CD4+T cell clones SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE T cells; Specificity; MHC; Antigen presentation; Combinatorial peptide libraries ID MULTIPLE-SCLEROSIS; STRUCTURAL BASIS; MOLECULAR-BASIS; ANTIGEN; TCR; RECOGNITION; SPECIFICITY; RECEPTOR; COMPLEX AB The use of positional scanning peptide libraries in combination with biometrical analysis is one of the few approaches, which allows the identification of stimulatory peptides for T cells of unknown specificity. Despite the successful application of this strategy in different studies, not every T cell is suited for analysis. For as yet unknown reasons some T cells do not recognize these highly complex libraries, and even more importantly the predictive capacity of the current approach shows high variability among individual T cell clones and their TCRs. A number of factors probably contribute to differences in T cell recognition and have to be taken into account in order to overcome these difficulties. Our results Suggest that the ability of some T cells to recognize peptides in the context of more than one HLA class II molecule expressed by autologous APCs could diminish the predictive capacity of the approach. in contrast, the use of B cell lines expressing single HLA class II molecules as APCs instead of autologous peripheral blood mononuclear cells markedly improves the capacity to identify target peptides for this type of T cells. (C) 2010 Elsevier B.V. All rights reserved. C1 [Zhao, Yingdong; Martin, Roland] Univ Med Ctr Hamburg Eppendorf, Inst Neuroimmunol & Clin MS Res, D-20251 Hamburg, Germany. [Sospedra, Mireia; Martin, Roland] NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Yingdong; Simon, Richard] NCI, Computat & Syst Biol Grp, Biometr Res Branch, NIH, Rockville, MD 20852 USA. [Giulianotti, Marc; Pinilla, Clemencia] Mixture Sci, San Diego, CA 92121 USA. [Pinilla, Clemencia] Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. RP Martin, R (reprint author), Ctr Mol Neurobiol, Inst Neuroimmunol & Clin MS Res Inims, Falkenried 94, D-20251 Hamburg, Germany. EM roland.martin@zmnh.uni.hamburg.de FU Gemeinnutzige Hertie Stiftung; NIH [HHSN266200400080C/N01-AI-40080]; MSNRI FX The Institute for Neuroimmunology and Clinical MS Research, University Medical Center Hamburg-Eppendorf is supported by the Gemeinnutzige Hertie Stiftung. C. Pinilla was awarded a funding from NIH HHSN266200400080C/N01-AI-40080 and MSNRI. NR 13 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 28 PY 2010 VL 353 IS 1-2 BP 93 EP 101 DI 10.1016/j.jim.2009.12.006 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 568DU UT WOS:000275503100012 PM 20036243 ER PT J AU Smith, EP Specker, B Korach, KS AF Smith, Eric P. Specker, Bonny Korach, Kenneth S. TI Recent experimental and clinical findings in the skeleton associated with loss of estrogen hormone or estrogen receptor activity SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 9th International Aromatase Conference CY OCT 13-16, 2008 CL Shanghai, PEOPLES R CHINA DE Estrogen; Androgen; Estrogen receptor; Bone; Epiphysis; Osteoporosis; Aromatase ID CONGENITAL AROMATASE DEFICIENCY; BONE-MINERAL DENSITY; ANDROGEN-INSENSITIVITY SYNDROME; GROWTH-PLATE SENESCENCE; ADULT MALE-MICE; REPLACEMENT THERAPY; SEX STEROIDS; G-PROTEIN; TESTOSTERONE REPLACEMENT; ACTIVATION-FUNCTION AB Studies on rodent models and rare human disorders of estrogen production or response have revealed an increased complexity of the actions of estrogen on bone. ER alpha disruption in human males results in delayed epiphyseal maturation, tall stature, trabecular thinning, marked cortical thinning, genu valgum and significantly reduced cortical vBMD, but trabecular number is preserved and there is normal to increased periosteal expansion. Aromatase deficiency results overall in a similar phenotype, although less is known about skeletal architecture. Importantly, estrogen replacement in these individuals, even if provided late in the third decade, may normalize aBMD. Less certain is whether there is complete recovery of normal skeletal architecture and strength. Rodent models, in general, are consistent with the human phenotype but are confounded by inherent differences between mouse and human physiology and issues regarding the completeness of the different knock-out lines. Both human and rodent studies suggest that residual effects of estrogen through ER beta, truncated ER alpha forms or nonclassical estrogen receptors might account for different phenotypes in the hERKO man, aromatase deficient subjects and rodents. Importantly, androgen, particularly by preserving trabecular number and augmenting both periosteal and epiphyseal growth, also has significant actions on bone. (C) 2010 Published by Elsevier Ltd. C1 [Smith, Eric P.] Univ Cincinnati, Coll Med, Dept Internal Med, Div Endocrinol Diabet & Metab, Cincinnati, OH 45267 USA. [Specker, Bonny] S Dakota State Univ, Ethel Austin Martin Program Human Nutr, Brookings, SD 57007 USA. [Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Smith, EP (reprint author), Univ Cincinnati, Coll Med, Dept Internal Med, Div Endocrinol Diabet & Metab, Cincinnati, OH 45267 USA. EM smithep@email.uc.edu OI Korach, Kenneth/0000-0002-7765-418X; Specker, Bonny/0000-0003-4759-9957 FU Intramural NIH HHS [Z01 ES070065-31]; NIEHS NIH HHS [Z01 ES070065] NR 125 TC 11 Z9 12 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD FEB 28 PY 2010 VL 118 IS 4-5 SI SI BP 264 EP 272 DI 10.1016/j.jsbmb.2009.10.016 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 574QV UT WOS:000276008300013 PM 19900547 ER PT J AU Coker, LH Espeland, MA Rapp, SR Legault, C Resnick, SM Hogan, P Gaussoin, S Dailey, M Shumaker, SA AF Coker, Laura H. Espeland, Mark A. Rapp, Stephen R. Legault, Claudine Resnick, Susan M. Hogan, Patricia Gaussoin, Sarah Dailey, Maggie Shumaker, Sally A. TI Postmenopausal hormone therapy and cognitive outcomes: The Women's Health Initiative Memory Study (WHIMS) SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 9th International Aromatase Conference CY OCT 13-16, 2008 CL Shanghai, PEOPLES R CHINA DE Hormone therapy; Cognition; Brain MRI; Cerebrovascular disease ID ESTROGEN-REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; CEREBRAL-BLOOD-FLOW; WHITE-MATTER HYPERINTENSITIES; CONJUGATED EQUINE ESTROGENS; SURGICALLY MENOPAUSAL WOMEN; ALZHEIMERS-DISEASE; PLUS PROGESTIN; OLDER WOMEN; RISK AB This review discusses major findings from the Women's Health Initiative Memory Study (WHIMS). WHIMS reported hormone therapy (HT) - conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) - increased the risk for dementia (HR 1.76 [95% CI, 1.19-2.60]; P=0.005) and global cognitive decline, with a mean decrement relative to placebo of 0.21 points on the Modified Mini Mental State Examination (3MS) (P=0.006) in women age 65 and older. A subset of WHIMS participants joined the ancillary WHI Study of Cognitive Aging (WHISCA) trials, in which domain-specific cognitive tests and mood were measured annually. Compared with placebo, CEE+ MPA had a negative impact on verbal memory over time (P=0.01); and CEE-Alone was associated with lower spatial rotational ability (P <= 0.01) at the initial assessment, but the difference diminished over time. The ancillary WHIMS-MRI study measured subclinical cerebrovascular disease to possibly explain the negative cognitive findings reported by WHIMS and the increased clinical stroke in older women reported by the WHI. WHIMS-MRI reported that while CEE+ MPA and CEE-Alone were not associated with increased ischemic brain lesion volume relative to placebo; both CEE+ MPA and CEE-Alone were associated with lower mean brain volumes in the hippocampus (P=0.05); frontal lobe (P=0.004); and total brain (P=0.07). HT-associated reductions in hippocampal volumes were greatest in women with baseline 3MS scores <= 90. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Coker, Laura H.; Espeland, Mark A.; Legault, Claudine; Hogan, Patricia; Gaussoin, Sarah] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Coker, Laura H.; Dailey, Maggie; Shumaker, Sally A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC 27157 USA. [Rapp, Stephen R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Psychiat & Behav Sci, Winston Salem, NC 27157 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Coker, LH (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM lcoker@wfubmc.edu FU Intramural NIH HHS [ZIA AG000190-02] NR 58 TC 46 Z9 48 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD FEB 28 PY 2010 VL 118 IS 4-5 SI SI BP 304 EP 310 DI 10.1016/j.jsbmb.2009.11.007 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 574QV UT WOS:000276008300020 PM 19932751 ER PT J AU von Leupoldt, A Keil, A Chan, PYS Bradley, MM Lang, PJ Davenport, PW AF von Leupoldt, Andreas Keil, Andreas Chan, Pei-Ying S. Bradley, Margaret M. Lang, Peter J. Davenport, Paul W. TI Cortical sources of the respiratory-related evoked potential SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Cortex; EEG; Perception; Respiratory-related evoked potential; Minimum-norm estimate ID COMPONENTS; OCCLUSION; EEG; HUMANS AB The respiratory-related evoked potential (RREP) is increasingly used to study the neural processing of respiratory signals. However, little is known about the cortical origins of early (Nf, P1, N1) and later RREP components (P2, P3). By using high-density EEG, we studied cortical sources of RREP components elicited by short inspiratory occlusions in 18 healthy volunteers (6 female, mean age 20.0 +/- 1.8 years). Topographical maps for Nf and P1 showed bilateral maximum EEG voltages over the frontal and centro-parietal cortex, respectively. Cortical source analyses (minimum-norm estimates) in addition to topographical maps demonstrated bilateral sensorimotor cortex origins for N1 and P2 which were paralleled by an additional frontal cortex source (p's < 0.05). The source of the P3 was located at the parietal cortex (p < 0.05). The results support previous findings on the cortical Sources of early RREP components Nf, P1 and N1 and demonstrate the cortical sources of later RREP components P2 and P3. (C) 2009 Elsevier B.V. All Fights reserved. C1 [von Leupoldt, Andreas] Univ Hamburg, Dept Psychol, D-20146 Hamburg, Germany. [von Leupoldt, Andreas; Chan, Pei-Ying S.; Davenport, Paul W.] Univ Florida, Dept Physiol Sci, Gainesville, FL 32610 USA. [von Leupoldt, Andreas] Univ Med Ctr Hamburg Eppendorf, Dept Syst Neurosci, Hamburg, Germany. [von Leupoldt, Andreas; Keil, Andreas; Bradley, Margaret M.; Lang, Peter J.] Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL USA. RP von Leupoldt, A (reprint author), Univ Hamburg, Dept Psychol, Von Melle Pk 5, D-20146 Hamburg, Germany. EM andreas.vonleupoldt@uni-hamburg.de RI Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 FU National Institute of Mental Health [P50 MH 72850]; German Research Society (Deutsche Forschungsgemeinschaft, DFG) [DFG LE 1843/9-1] FX This study was supported in part by a grant from the National Institute of Mental Health (P50 MH 72850) to Peter J. Lang, and by a stipend (Heisenberg-Stipendium, DFG LE 1843/9-1) from the German Research Society (Deutsche Forschungsgemeinschaft, DFG) to Andreas von Leupoldt. The funding sources had no impact on the study design, data collection/interpretation or preparation of the present manuscript. NR 14 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD FEB 28 PY 2010 VL 170 IS 2 BP 198 EP 201 DI 10.1016/j.resp.2009.12.006 PG 4 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 565AD UT WOS:000275259400009 PM 20036344 ER PT J AU Li, Y Graubard, BI Korn, EL AF Li, Yan Graubard, Barry I. Korn, Edward L. TI Application of nonparametric quantile regression to body mass index percentile curves from survey data SO STATISTICS IN MEDICINE LA English DT Article DE bandwidth selection; conditional percentile; kernel estimator; local linear regression; National Health and Nutrition Examination Survey; National Health Examination Survey ID LEAST-SQUARES REGRESSION; GROWTH CHARTS; ADOLESCENTS; CHILDREN; SCATTERPLOTS AB Increasing rates of overweight among children in the U.S. stimulated interest in obtaining national percentile curves of body size to serve as a benchmark in assessing growth development in clinical and population settings. In 2000, the U.S. Centers for Disease Control and Prevention (CDC) developed conditional percentile curves for body mass index (BMI) for ages 2-20 years. The 2000 CDC BMI-for-age curves are partially parametric and only partially incorporated the survey sample weights in the curve estimation. As a result, they may not fully reflect the underlying pattern of BMI-for-age in the population. This motivated us to develop a nonparametric double-kernel-based method and automatic bandwidth selection procedure. We include sample weights in the bandwidth selection, conduct median correction to reduce small-sample smoothing bias, and rescale the bandwidth to make it scale invariant. Using this procedure we re-estimate the national percentile BMI-for-age curves and the prevalence of high-BMI children in the U.S. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Li, Yan] Univ Texas Arlington, Dept Math, Arlington, TX 76019 USA. [Li, Yan; Graubard, Barry I.] NCI, Biostat Branch, Bethesda, MD 20892 USA. [Korn, Edward L.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Univ Texas Arlington, Dept Math, Room 436,Pickard Hall, Arlington, TX 76019 USA. EM liyanno@uta.edu FU Intramural NIH HHS [NIH0012815804]; PHS HHS [NIH0012815804] NR 23 TC 8 Z9 8 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2010 VL 29 IS 5 BP 558 EP 572 DI 10.1002/sim.3810 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 569FZ UT WOS:000275583300004 PM 20013898 ER PT J AU Schisterman, EF Vexler, A Mumford, SL Perkins, NJ AF Schisterman, Enrique F. Vexler, Albert Mumford, Sunni L. Perkins, Neil J. TI Hybrid pooled-unpooled design for cost-efficient measurement of biomarkers SO STATISTICS IN MEDICINE LA English DT Article DE maximum likelihood; measurement error; pooling; random sampling; receiver operating characteristics; sampling design ID RANDOM MEASUREMENT ERROR; ROC CURVE ANALYSIS; DIAGNOSTIC MARKERS; BIOSPECIMENS; INFERENCE; SUBJECT; ASSESSMENTS; MODELS; LIMIT; AREA AB Evaluating biomarkers in epidemiological studies can be expensive and time consuming. Many investigators use techniques such as random sampling or pooling biospecimens in order to cut costs and save time on experiments. Commonly, analyses based on pooled data are strongly restricted by distributional assumptions that are challenging to validate because of the pooled biospecimens. Random sampling provides data that can be easily analyzed. However, random sampling methods are not optimal cost-efficient designs for estimating means. We propose and examine a cost-efficient hybrid design that involves taking a sample of both pooled and unpooled data in an optimal proportion in order to efficiently estimate the unknown parameters of the biomarker distribution. In addition, we find that this design can be used to estimate and account for different types of measurement and pooling error, without the need to collect validation data or repeated measurements. We show an example where application of the hybrid design leads to minimization of a given loss function based on variances of the estimators of the unknown parameters. Monte Carlo simulation and biomarker data from a study on coronary heart disease are used to demonstrate the proposed methodology. Published in 2010 by John Wiley & Sons, Ltd. C1 [Schisterman, Enrique F.; Vexler, Albert; Mumford, Sunni L.; Perkins, Neil J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Execut Blvd, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Contract/grant sponsors: National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development NR 28 TC 19 Z9 19 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2010 VL 29 IS 5 BP 597 EP 613 DI 10.1002/sim.3823 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 569FZ UT WOS:000275583300007 PM 20049693 ER PT J AU Nicodemus, KK Malley, JD Strobl, C Ziegler, A AF Nicodemus, Kristin K. Malley, James D. Strobl, Carolin Ziegler, Andreas TI The behaviour of random forest permutation-based variable importance measures under predictor correlation SO BMC BIOINFORMATICS LA English DT Article AB Background: Random forests (RF) have been increasingly used in applications such as genome-wide association and microarray studies where predictor correlation is frequently observed. Recent works on permutation-based variable importance measures (VIMs) used in RF have come to apparently contradictory conclusions. We present an extended simulation study to synthesize results. Results: In the case when both predictor correlation was present and predictors were associated with the outcome (H(A)), the unconditional RF VIM attributed a higher share of importance to correlated predictors, while under the null hypothesis that no predictors are associated with the outcome (H(0)) the unconditional RF VIM was unbiased. Conditional VIMs showed a decrease in VIM values for correlated predictors versus the unconditional VIMs under H(A) and was unbiased under H(0). Scaled VIMs were clearly biased under H(A) and H(0). Conclusions: Unconditional unscaled VIMs are a computationally tractable choice for large datasets and are unbiased under the null hypothesis. Whether the observed increased VIMs for correlated predictors may be considered a "bias" - because they do not directly reflect the coefficients in the generating model - or if it is a beneficial attribute of these VIMs is dependent on the application. For example, in genetic association studies, where correlation between markers may help to localize the functionally relevant variant, the increased importance of correlated predictors may be an advantage. On the other hand, we show examples where this increased importance may result in spurious signals. C1 [Nicodemus, Kristin K.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Nicodemus, Kristin K.] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England. [Nicodemus, Kristin K.] NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Bethesda, MD USA. [Malley, James D.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Strobl, Carolin] Univ Munich, Dept Stat, D-80539 Munich, Germany. [Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, D-23562 Lubeck, Germany. RP Nicodemus, KK (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM kristin.nicodemus@well.ox.ac.uk OI Ziegler, Andreas/0000-0002-8386-5397 FU Wellcome Trust FX We are grateful to Dr. Yan Meng for her insightful comments on our manuscript. The Wellcome Trust provided support for KKN. 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. NR 11 TC 66 Z9 66 U1 3 U2 16 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 FEB 27 PY 2010 VL 11 AR 110 DI 10.1186/1471-2105-11-110 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 578LS UT WOS:000276295700002 PM 20187966 ER PT J AU Aleksic, M Dushek, O Zhang, H Shenderov, E Chen, JL Cerundolo, V Coombs, D van der Merwe, PA AF Aleksic, Milos Dushek, Omer Zhang, Hao Shenderov, Eugene Chen, Ji-Li Cerundolo, Vincenzo Coombs, Daniel van der Merwe, P. Anton TI Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time SO IMMUNITY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; LIGAND INTERACTIONS; BINDING-KINETICS; TCR-BINDING; ACTIVATION; AFFINITY; FLEXIBILITY; VACCINES; DESIGN; IMMUNOGENICITY AB T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1134 TCR-pMHC binding properties measured in solution. We found that both the on rate (k(on)) and off rate (k(off)) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or "confinement time" of a TCR-pMHC interaction. This confinement time model clarifies the role of k(on) in T cell activation and reconciles apparently contradictory repo on the role of TCR-pMHC binding kinetics and affinity in T cell activation. C1 [Aleksic, Milos; Dushek, Omer; Zhang, Hao; van der Merwe, P. Anton] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Dushek, Omer] Univ Oxford, Ctr Math Biol, Oxford OX1 3LB, England. [Shenderov, Eugene; Chen, Ji-Li; Cerundolo, Vincenzo] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Shenderov, Eugene] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Coombs, Daniel] Univ British Columbia, Dept Math, Vancouver, BC V6T 1Z2, Canada. [Coombs, Daniel] Univ British Columbia, Inst Appl Math, Vancouver, BC V6T 1Z2, Canada. RP van der Merwe, PA (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM anton.vandermerwe@path.ox.ac.uk RI van der Merwe, P. Anton/F-8539-2011; OI Cerundolo, Vincenzo/0000-0003-0040-3793; Coombs, Daniel/0000-0002-8038-6278 FU Cancer Research UK, the Medical Research Council (UK); National Sciences and Engineering Research Council (Canada); Mathematics of Information Technology and Complex Systems National Centre of Excellence (Canada) FX We thank D. Shepherd for the supply of the 1G4 TCR expression plasmid and J. Byrne for the help with protein expression. We would also like to thank the reviewers for their constructive criticism. This work was supported by Cancer Research UK, the Medical Research Council (UK), the National Sciences and Engineering Research Council (Canada), and the Mathematics of Information Technology and Complex Systems National Centre of Excellence (Canada). NR 44 TC 94 Z9 94 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 26 PY 2010 VL 32 IS 2 BP 163 EP 174 DI 10.1016/j.immuni.2009.11.013 PG 12 WC Immunology SC Immunology GA 566BX UT WOS:000275346000007 PM 20137987 ER PT J AU Kim, HS Das, A Gross, CC Bryceson, YT Long, EO AF Kim, Hun Sik Das, Asmita Gross, Catharina C. Bryceson, Yenan T. Long, Eric O. TI Synergistic Signals for Natural Cytotoxicity Are Required to Overcome Inhibition by c-Cbl Ubiquitin Ligase SO IMMUNITY LA English DT Article ID NK-CELL CYTOTOXICITY; KILLER-CELLS; T-CELLS; NEGATIVE REGULATION; RECEPTOR SIGNALS; VAV PROTEINS; ACTIVATION; NKG2D; PATHWAYS; POLARIZATION AB Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-gamma 2, Ca(2+), mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-CbI. c-CbI inhibited Vav1-dependent signals, given that c-CbI knockdown did not rescue the Vav1 defect. Moreover, c-CbI knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2134 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-CbI. Inhibition of NK cell cytotoxicity by CD94NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-CbI knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms. C1 [Kim, Hun Sik; Das, Asmita; Gross, Catharina C.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Bryceson, Yenan T.] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Ctr Infect Med,Dept Med, S-14186 Huddinge, Sweden. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM elong@nih.gov RI Long, Eric/G-5475-2011; OI Long, Eric/0000-0002-7793-3728; Bryceson, Yenan/0000-0002-7783-9934 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank M. March for useful discussions; G. Cohen, D. Geraghty, J. Gumperz, P. Parham, H.G. Klingemann, J. Kornbluth, and M. Robertson for cell lines; and L. Samelson and D. Bohman for plasmids. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 50 TC 53 Z9 54 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 26 PY 2010 VL 32 IS 2 BP 175 EP 186 DI 10.1016/j.immuni.2010.02.004 PG 12 WC Immunology SC Immunology GA 566BX UT WOS:000275346000008 PM 20189481 ER PT J AU Cannons, JL Qi, H Lu, KT Dutta, M Gomez-Rodriguez, J Cheng, J Wakeland, EK Germain, RN Schwartzberg, PL AF Cannons, Jennifer L. Qi, Hai Lu, Kristina T. Dutta, Mala Gomez-Rodriguez, Julio Cheng, Jun Wakeland, Edward K. Germain, Ronald N. Schwartzberg, Pamela L. TI Optimal Germinal Center Responses Require a Multistage T Cell:B Cell Adhesion Process Involving Integrins, SLAM-Associated Protein, and CD84 SO IMMUNITY LA English DT Article ID FOLLICULAR-HELPER-CELLS; RESTING NK CELLS; HUMORAL IMMUNITY; MOLECULAR DISSECTION; CUTTING EDGE; B-CELLS; SAP; FAMILY; AUTOIMMUNITY; RECEPTORS AB CD4(+) T cells deficient in signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) exhibit a selective impairment in adhesion to antigen-presenting B cells but not dendritic cells (DCs), resulting in defective germinal center formation. However, the nature of this selective adhesion defect remained unclear. We found that whereas T cell:DC interactions were primarily integrin dependent, T cell:B cell interactions had both an early integrin-dependent phase and a sustained phase that also required SAP. We further found that the SLAM family member CD84 was required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. Moreover, both CD84 and another SLAM member, Ly108, mediated T cell adhesion and participated in stable T cell:B cell interactions in vitro. Our results reveal insight into the dynamic regulation of T cell:B cell interactions and identify SLAM family members as critical components of sustained T cell:B cell adhesion required for productive humoral immunity. C1 [Cannons, Jennifer L.; Lu, Kristina T.; Dutta, Mala; Gomez-Rodriguez, Julio; Cheng, Jun; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Qi, Hai; Germain, Ronald N.] NIAID, NIH, Bethesda, MD 20892 USA. [Dutta, Mala] George Washington Univ, Inst Biomed Sci, Washington, DC 20052 USA. [Wakeland, Edward K.] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@nhgri.nih.gov FU NHGRI; MAID; NIH, USA FX We thank R. Handon and A. Venegas for invaluable technical assistance; M. Kirby and S. Anderson for cell sorting; J. Fekecs for graphics assistance; and K. Nichols and S.-H. Hwang for mouse reagents. This work was funded by the intramural research programs of the NHGRI and MAID, NIH, USA. NR 41 TC 176 Z9 189 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 26 PY 2010 VL 32 IS 2 BP 253 EP 265 DI 10.1016/j.immuni.2010.01.010 PG 13 WC Immunology SC Immunology GA 566BX UT WOS:000275346000014 PM 20153220 ER PT J AU Milman, G Barnes, AJ Lowe, RH Huestis, MA AF Milman, Garry Barnes, Allan J. Lowe, Ross H. Huestis, Marilyn A. TI Simultaneous quantification of cannabinoids and metabolites in oral fluid by two-dimensional gas chromatography mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Tetrahydrocannabinol; Cannabinoids; Oral fluid; Two-dimensional chromatography; 11-Nor-9-carboxy-tetrahydrocannabinol ID SOLID-PHASE EXTRACTION; DELTA(9)-TETRAHYDROCANNABINOL THC; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; HUMAN PLASMA; VALIDATED METHOD; GC-MS; CANNABIDIOL; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL; INGESTION; SPECIMENS AB Development and validation of a method for simultaneous identification and quantification of Delta 9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and metabolites 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) in oral fluid. Simultaneous analysis was problematic due to different physicochemical characteristics and concentration ranges. Neutral analytes, such as THC and CBD, are present in ng/mL, rather than pg/mL concentrations, as observed for the acidic THCCOOH biomarker in oral fluid. THCCOOH is not present in cannabis smoke, definitively differentiating cannabis use from passive smoke exposure. THC, 11-OH-THC, THCCOOH, CBD, and CBN quantification was achieved in a single oral fluid specimen collected with the Quantisal (TM) device. One nil. oral fluid/buffer solution (0.25 mL oral fluid and 0.75 mL buffer) was applied to conditioned CEREX (R) Polycrom (TM) THC solid-phase extraction (SPE) columns. After washing, THC, 11-OH-THC, CBD, and CBN were eluted with hexane/acetone/ethyl acetate (60:30:20, v/v/v), derivatized with N,O-bis-(trimethylsilyl)trifluoroacetamide and quantified by two-dimensional gas chromatography electron ionization mass spectrometry (2D-GCMS) with cold trapping. Acidic THCCOOH was separately eluted with hexane/ethyl acetate/acetic acid (75:25:2.5, v/v/v), derivatized with trifluoroacetic anhydride and hexafluoroisopropanol, and quantified by the more sensitive 2D-GCMS-electron capture negative chemical ionization (NCI-MS). Linearity was 0.5-50 ng/mL for THC, 11-OH-THC, CBD and 1-50 ng/mL for CBN. The linear dynamic range for THCCOOH was 7.5-500 pg/mL. Intra- and inter-assay imprecision as percent RSD at three concentrations across the linear dynamic range were 0.3-6.6%. Analytical recovery was within 13.8% of target. This new SPE 2D-GCMS assay achieved efficient quantification of five cannabinoids ill Oral fluid, including pg/mL concentrations of THCCOOH by combining differential elution, 2D-GCMS with electron ionization and negative chemical ionization. This method will be applied to quantification of cannabinoids in oral fluid specimens from individuals participating in controlled cannabis and Sativex (R) (50% THC and 50% CBD) administration studies, and during cannabis withdrawal. Published by Elsevier B.V. C1 [Huestis, Marilyn A.] NIDA, NIH, Ctr Biomed Res, Intramural Res Program, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, NIH, Ctr Biomed Res, Intramural Res Program, 251 Bayview Blvd,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX Funding for this research was provided by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 35 TC 53 Z9 53 U1 6 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 26 PY 2010 VL 1217 IS 9 BP 1513 EP 1521 DI 10.1016/j.chroma.2009.12.053 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 561CQ UT WOS:000274953500013 PM 20083251 ER PT J AU Fromm, G Adelman, K AF Fromm, George Adelman, Karen TI Taking MLL through the MudPIT: Identification of Novel Complexes that Bring Together MLL-Fusion Proteins and Transcription Elongation Factors SO MOLECULAR CELL LA English DT Editorial Material ID MIXED-LINEAGE LEUKEMIA; CHROMATIN; REGULATORS; TEFB C1 [Fromm, George; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Adelman, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov FU Intramural NIH HHS NR 10 TC 4 Z9 4 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 26 PY 2010 VL 37 IS 4 BP 449 EP 450 DI 10.1016/j.molcel.2010.02.005 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 566CZ UT WOS:000275349000001 PM 20188661 ER PT J AU Androutsellis-Theotokis, A Rueger, MA Park, DM Boyd, JD Padmanabhan, R Campanati, L Stewart, CV LeFranc, Y Plenz, D Walbridge, S Lonser, RR McKay, RDG AF Androutsellis-Theotokis, Andreas Rueger, Maria A. Park, Deric M. Boyd, Justin D. Padmanabhan, Raji Campanati, Loraine Stewart, Craig V. LeFranc, Yann Plenz, Dietmar Walbridge, Stuart Lonser, Russell R. McKay, Ronald D. G. TI Angiogenic Factors Stimulate Growth of Adult Neural Stem Cells SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SUBVENTRICULAR ZONE; IN-VIVO; DENTATE GYRUS; PROGENITOR PROLIFERATION; MAMMALIAN FOREBRAIN; ISCHEMIC-STROKE; MOUSE BRAIN; NEUROGENESIS; NEURONS AB Background: The ability to grow a uniform cell type from the adult central nervous system (CNS) is valuable for developing cell therapies and new strategies for drug discovery. The adult mammalian brain is a source of neural stem cells (NSC) found in both neurogenic and non-neurogenic zones but difficulties in culturing these hinders their use as research tools [1,2,3,4,5,6]. Methodology/Principal Findings: Here we show that NSCs can be efficiently grown in adherent cell cultures when angiogenic signals are included in the medium. These signals include both anti-angiogenic factors (the soluble form of the Notch receptor ligand, DII4) and pro-angiogenic factors (the Tie-2 receptor ligand, Angiopoietin 2). These treatments support the self renewal state of cultured NSCs and expression of the transcription factor Hes3, which also identifies the cancer stem cell population in human tumors. In an organotypic slice model, angiogenic factors maintain vascular structure and increase the density of dopamine neuron processes. Conclusions/Significance: We demonstrate new properties of adult NSCs and a method to generate efficient adult NSC cultures from various central nervous system areas. These findings will help establish cellular models relevant to cancer and regeneration. C1 [Androutsellis-Theotokis, Andreas; Rueger, Maria A.; Park, Deric M.; Boyd, Justin D.; Campanati, Loraine; McKay, Ronald D. G.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Walbridge, Stuart; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Stewart, Craig V.; LeFranc, Yann; Plenz, Dietmar] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. [Padmanabhan, Raji] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Androutsellis-Theotokis, A (reprint author), Acad Athens, Biomed Res Fdn, Athens, Greece. EM AndreasTheotokis@gmail.com RI Park, Deric/C-5675-2013; Neurociencia, Inct/I-1011-2013 FU National Institute of Neurological Disorders; Stroke at the National Institutes of Health; Michael J. Fox Foundation; National Parkinson's Foundation; Tuchman Foundation FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, the Michael J. Fox Foundation, the National Parkinson's Foundation, and the Tuchman Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 30 Z9 31 U1 1 U2 3 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 FEB 26 PY 2010 VL 5 IS 2 AR e9414 DI 10.1371/journal.pone.0009414 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RS UT WOS:000274997000007 PM 20195471 ER PT J AU Arbab, AS Janic, B Jafari-Khouzani, K Iskander, ASM Kumar, S Varma, NRS Knight, RA Soltanian-Zadeh, H Brown, SL Frank, JA AF Arbab, Ali S. Janic, Branislava Jafari-Khouzani, Kourosh Iskander, A. S. M. Kumar, Sanath Varma, Nadimpalli R. S. Knight, Robert A. Soltanian-Zadeh, Hamid Brown, Stephen L. Frank, Joseph A. TI Differentiation of Glioma and Radiation Injury in Rats Using In Vitro Produce Magnetically Labeled Cytotoxic T-Cells and MRI SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MESENCHYMAL STEM-CELLS; DENDRITIC CELLS; TUMOR RECURRENCE; RESONANCE-SPECTROSCOPY; IMMUNE-RESPONSES; MALIGNANT GLIOMA; GRADE GLIOMAS; SPINAL-CORD; F-18 FDG AB Background: A limitation with current imaging strategies of recurrent glioma undergoing radiotherapy is that tumor and radiation injury cannot be differentiated with post contrast CT or MRI, or with PET or other more complex parametric analyses of MRI data. We propose to address the imaging limitation building on emerging evidence indicating that effective therapy for recurrent glioma can be attained by sensitized T-cells following vaccination of primed dendritic cells (DCs). The purpose of this study was to determine whether cord blood T-cells can be sensitized against glioma cells (U-251) and if these sensitized cytotoxic T-cells (CTLs) can be used as cellular magnetic resonance imaging probes to identify and differentiate glioma from radiation necrosis in rodent models. Methodology/Principal Findings: Cord blood T and CD14+ cells were collected. Isolated CD14+ cells were then converted to dendritic cells (DCs), primed with glioma cell lysate and used to sensitize T-cells. Phenotypical expression of the generated DCs were analyzed to determine the expression level of CD14, CD86, CD83 and HLA-DR. Cells positive for CD25, CD4, CD8 were determined in generated CTLs. Specificity of cytotoxicity of the generated CTLs was also determined by lactate dehydrogenase (LDH) release assay. Secondary proliferation capacity of magnetically labeled and unlabeled CTLs was also determined. Generated CTLs were magnetically labeled and intravenously injected into glioma bearing animals that underwent MRI on days 3 and 7 post-injection. CTLs were also administered to animals with focal radiation injury to determine whether these CTLs accumulated non-specifically to the injury sites. Multi-echo T2- and T2*-weighted images were acquired and R2 and R2* maps created. Our method produced functional, sensitized CTLs that specifically induced U251 cell death in vitro. Both labeled and unlabeled CTLs proliferated equally after the secondary stimulation. There were significantly higher CD25 positive cells (p = <0.006) in CTLs. In addition, T2- and T2*-weighted MR images showed increased low signal intensity areas in animals that received labeled CTLs as compared to the images from animals that received control cells. Histological analysis confirmed the presence of iron positive cells in sites corresponding to MRI low signal intensity regions. Significant differences (p = <0.001) in tumor R2 and R2* values were observed among the groups of animals. Animals with radiation injury exhibited neither MRI hypointense areas nor presence of iron positive cells. Conclusion: Our results indicate that T-cells can be effectively sensitized by in vitro methods and used as cellular probes to identify and differentiate glioma from radiation necrosis. C1 [Arbab, Ali S.; Janic, Branislava; Jafari-Khouzani, Kourosh; Iskander, A. S. M.; Varma, Nadimpalli R. S.; Soltanian-Zadeh, Hamid] Henry Ford Hosp, Dept Radiol, Cellular & Mol Imaging Lab, Detroit, MI 48202 USA. [Knight, Robert A.] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [Kumar, Sanath; Brown, Stephen L.] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [Frank, Joseph A.] NIH, Frank Lab Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Frank Lab, NIH, Bethesda, MD USA. RP Arbab, AS (reprint author), Henry Ford Hosp, Dept Radiol, Cellular & Mol Imaging Lab, Detroit, MI 48202 USA. EM saali@rad.hfh.edu RI Soltanian-Zadeh, Hamid/K-2903-2016 OI Soltanian-Zadeh, Hamid/0000-0002-7302-6856 FU National Institutes of Health (NIH) [R21NS058589, R01CA122031, 1R21CA129801] FX The work is supported by National Institutes of Health (NIH) grants R21NS058589, R01CA122031 and 1R21CA129801. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 8 Z9 9 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 FEB 26 PY 2010 VL 5 IS 2 AR e9365 DI 10.1371/journal.pone.0009365 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RS UT WOS:000274997000005 PM 20195476 ER PT J AU Bansal, S Pourbohloul, B Hupert, N Grenfell, B Meyers, LA AF Bansal, Shweta Pourbohloul, Babak Hupert, Nathaniel Grenfell, Bryan Meyers, Lauren Ancel TI The Shifting Demographic Landscape of Pandemic Influenza SO PLOS ONE LA English DT Article ID HONG-KONG INFLUENZA; TRANSMISSION PARAMETERS; INFECTIOUS AGENTS; ASIAN INFLUENZA; EPIDEMIC; VIRUS; MORTALITY; SPREAD; IMMUNITY; VACCINE AB Background: As Pandemic (H1N1) 2009 influenza spreads around the globe, it strikes school-age children more often than adults. Although there is some evidence of pre-existing immunity among older adults, this alone may not explain the significant gap in age-specific infection rates. Methods and Findings: Based on a retrospective analysis of pandemic strains of influenza from the last century, we show that school-age children typically experience the highest attack rates in primarily naive populations, with the burden shifting to adults during the subsequent season. Using a parsimonious network-based mathematical model which incorporates the changing distribution of contacts in the susceptible population, we demonstrate that new pandemic strains of influenza are expected to shift the epidemiological landscape in exactly this way. Conclusions: Our analysis provides a simple demographic explanation for the age bias observed for H1N1/09 attack rates, and suggests that this bias may shift in coming months. These results have significant implications for the allocation of public health resources for H1N1/09 and future influenza pandemics. C1 [Bansal, Shweta] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bansal, Shweta; Grenfell, Bryan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pourbohloul, Babak] British Columbia Ctr Dis Control, Div Math Modeling, Vancouver, BC, Canada. [Pourbohloul, Babak] Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Hupert, Nathaniel] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Hupert, Nathaniel] US Ctr Dis Control & Prevent, Preparedness Modeling Unit, Atlanta, GA USA. [Grenfell, Bryan] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Meyers, Lauren Ancel] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Meyers, Lauren Ancel] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Bansal, S (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM shweta@sbansal.com OI Bansal, Shweta/0000-0002-1740-5421 FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center; National Institutes of Health (NIH); James F. McDonnell Foundation; National Science Foundation [DEB-0749097]; NIH Models of Infectious Disease Agent Study (MIDAS) [U01-GM087719-01]; Canadian Institutes of Health Research [PTL97125, PAP93425]; Michael Smith Foundation for Health Research FX This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (NIH); grants from the James F. McDonnell Foundation, National Science Foundation (DEB-0749097), and NIH Models of Infectious Disease Agent Study (MIDAS) (U01-GM087719-01) to L. A. M.; and support from the Canadian Institutes of Health Research (PTL97125 and PAP93425) and the Michael Smith Foundation for Health Research to B. P. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 37 Z9 38 U1 0 U2 7 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 FEB 26 PY 2010 VL 5 IS 2 AR e9360 DI 10.1371/journal.pone.0009360 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RS UT WOS:000274997000004 PM 20195468 ER PT J AU Francischetti, IMB Kotsyfakis, M Andersen, JF Lukszo, J AF Francischetti, Ivo M. B. Kotsyfakis, Michalis Andersen, John F. Lukszo, Jan TI Cyr61/CCN1 Displays High-Affinity Binding to the Somatomedin B (1-44) Domain of Vitronectin SO PLOS ONE LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; UROKINASE RECEPTOR; EXTRACELLULAR-MATRIX; CELL-ADHESION; CCN FAMILY; INTEGRIN ALPHA-V-BETA-3; IXODES-SCAPULARIS; SALIVARY-GLAND; MELANOMA-CELLS; EXPRESSION AB Background: Cyr61 is a member of the CCN (Cyr61, connective tissue growth, NOV) family of extracellular-associated (matricellular) proteins that present four distinct functional modules, namely insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C (vWF), thrombospondin type 1 (TSP), and C-terminal growth factor cysteine knot (CT) domain. While heparin sulphate proteoglycans reportedly mediate the interaction of Cyr61 with the matrix and cell surface, the role of other extracellular associated proteins has not been revealed. Methods and Findings: In this report, surface plasmon resonance (SPR) experiments and solid-phase binding assays demonstrate that recombinant Cyr61 interacts with immobilized monomeric or multimeric vitronectin (VTNC) with K-D in the nanomolar range. Notably, the binding site for Cyr61 was identified as the somatomedin B domain (SMTB (1-44)) of VTNC, which mediates its interaction with PAI-1, uPAR, and integrin alpha v beta 3. Accordingly, PAI-1 outcompetes Cyr61 for binding to immobilized SMTB (1-44), and Cyr61 attenuates uPAR-mediated U937 adhesion to VTNC. In contrast, isothermal titration calorimetry shows that Cyr61 does not display high-affinity binding for SMTB (1-44) in solution. Nevertheless, competitive ELISA revealed that multimeric VTNC, heat-modified monomeric VTNC, or SMTB (1-44) at high concentrations attenuate Cyr61 binding to immobilized VTNC, while monomeric VTNC was ineffective. Therefore, immobilization of VTNC exposes cryptic epitopes that recognize Cyr61 with high affinity, as reported for a number of antibodies, beta-endorphin, and other molecules. Conclusions: The finding that Cyr61 interacts with the SMTB (1-44) domain suggests that VTNC represent a point of anchorage for CCN family members to the matrix. Results are discussed in the context of the role of CCN and VTNC in matrix biology and angiogenesis. C1 [Francischetti, Ivo M. B.; Andersen, John F.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Res Technol Branch,NIH, Bethesda, MD 20892 USA. [Lukszo, Jan] NIAID, Peptide Synth & Anal Lab, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Kotsyfakis, Michalis] Natl Acad Sci Czech Republ, Inst Parasitol, Ctr Biol, Ceske Budejovice, Czech Republic. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Res Technol Branch,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ifrancischetti@niaid.nih.gov RI Kotsyfakis, Michail/G-9525-2014 OI Kotsyfakis, Michail/0000-0002-7526-1876 FU NIH/NIAID FX Funding provided by Intramural Research Program - NIH/NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 9 Z9 10 U1 0 U2 9 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 FEB 26 PY 2010 VL 5 IS 2 AR e9356 DI 10.1371/journal.pone.0009356 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RS UT WOS:000274997000003 PM 20195466 ER PT J AU Levens, D Gupta, A AF Levens, David Gupta, Ashutosh TI Reliable Noise SO SCIENCE LA English DT Editorial Material ID C-MYC EXPRESSION; GENE-EXPRESSION; DNA; CELL C1 [Levens, David; Gupta, Ashutosh] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Gupta, Ashutosh] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. RP Levens, D (reprint author), NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM levensd@mail.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X NR 14 TC 5 Z9 5 U1 0 U2 6 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 FEB 26 PY 2010 VL 327 IS 5969 BP 1088 EP 1089 DI 10.1126/science.1187268 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560KJ UT WOS:000274901100021 PM 20185714 ER PT J AU O'Shea, JJ Paul, WE AF O'Shea, John J. Paul, William E. TI Mechanisms Underlying Lineage Commitment and Plasticity of Helper CD4(+) T Cells SO SCIENCE LA English DT Review ID ROR-GAMMA-T; TH17 CELLS; FATE DETERMINATION; INTERLEUKIN 22; TGF-BETA; DIFFERENTIATION; INFLAMMATION; LYMPHOCYTES; GENERATION; POPULATION AB CD4(+) T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce restricted patterns of cytokines, which are tailored to combat various microbial pathogens. Although classically viewed as distinct lineages, recent work calls into question whether helper CD4(+) T cell subsets are more appropriately viewed as terminally differentiated cells or works in progress. Herein, we review recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell commitment and plasticity. The therapeutic implications of these new findings are also considered. C1 [O'Shea, John J.; Paul, William E.] NIAID, Mol Immunol & Inflammat Branch, NIAMSD, Immunol Lab,NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAID, Mol Immunol & Inflammat Branch, NIAMSD, Immunol Lab,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Allergy and Infectious Disease FX J.O'S. and W. E. P. are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Disease intramural research programs, respectively. NR 48 TC 537 Z9 557 U1 8 U2 55 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 FEB 26 PY 2010 VL 327 IS 5969 BP 1098 EP 1102 DI 10.1126/science.1178334 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560KJ UT WOS:000274901100027 PM 20185720 ER PT J AU Vinh, DC Patel, SY Uzel, G Anderson, VL Freeman, AF Olivier, KN Spalding, C Hughes, S Pittaluga, S Raffeld, M Sorbara, LR Elloumi, HZ Kuhns, DB Turner, ML Cowen, EW Fink, D Long-Priel, D Hsu, AP Ding, L Paulson, ML Whitney, AR Sampaio, EP Frucht, DM Deleo, FR Holland, SM AF Vinh, Donald C. Patel, Smita Y. Uzel, Gulbu Anderson, Victoria L. Freeman, Alexandra F. Olivier, Kenneth N. Spalding, Christine Hughes, Stephen Pittaluga, Stefania Raffeld, Mark Sorbara, Lynn R. Elloumi, Houda Z. Kuhns, Douglas B. Turner, Maria L. Cowen, Edward W. Fink, Danielle Long-Priel, Debra Hsu, Amy P. Ding, Li Paulson, Michelle L. Whitney, Adeline R. Sampaio, Elizabeth P. Frucht, David M. Deleo, Frank R. Holland, Steven M. TI Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia SO BLOOD LA English DT Article ID PULMONARY ALVEOLAR PROTEINOSIS; HAIRY-CELL LEUKEMIA; ACUTE MYELOID-LEUKEMIA; BONE-MARROW ORIGIN; INTERFERON-GAMMA; BLOOD MONOCYTES; AVIUM INFECTION; KAPOSI-SARCOMA; KUPFFER CELLS; IFN-GAMMA AB We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/mu L; median, 14.5 cells/mu L), B lymphocytopenia (mean, 9.4 cells/mu L; median, 4 cells/mu L), and NK lymphocytopenia (mean, 16 cells/mu L; median, 5.5 cells/mu L). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus(+) leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern. (Blood. 2010;115:1519-1529) C1 [Vinh, Donald C.; Patel, Smita Y.; Uzel, Gulbu; Anderson, Victoria L.; Freeman, Alexandra F.; Olivier, Kenneth N.; Spalding, Christine; Elloumi, Houda Z.; Hsu, Amy P.; Ding, Li; Paulson, Michelle L.; Sampaio, Elizabeth P.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] SAIC, Intramural Clin Management & Operat Branch, Frederick, MD USA. [Hughes, Stephen] Newcastle Gen Hosp, Paediat Immunol Unit, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. [Pittaluga, Stefania; Raffeld, Mark] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Sorbara, Lynn R.] NCI, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. [Turner, Maria L.; Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Whitney, Adeline R.; Deleo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Frucht, David M.] US FDA, Cell Biol Lab, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Holland, SM (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bldg 10 CRC,Rm B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI VINH, DONALD/0000-0003-1347-7767; DeLeo, Frank/0000-0003-3150-2516 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Cancer Institute; National Institutes of Health [N01-CO-12400, HHSN261200800001E]; Canadian Institutes of Health Research fellowship FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part with federal funds from the National Cancer Institute, National Institutes of Health (contracts N01-CO-12400 and HHSN261200800001E). D.C.V. is supported by a Canadian Institutes of Health Research fellowship and by a National Institutes of Health Supplemental Visiting fellowship. NR 59 TC 107 Z9 109 U1 0 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 FEB 25 PY 2010 VL 115 IS 8 BP 1519 EP 1529 DI 10.1182/blood-2009-03-208629 PG 11 WC Hematology SC Hematology GA 561KB UT WOS:000274974200009 PM 20040766 ER PT J AU Li, BJ Arime, Y Hall, FS Uhl, GR Sora, I AF Li, BingJin Arime, Yosefu Hall, F. Scott Uhl, George R. Sora, Ichiro TI Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knockout mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Brain-derived neurotrophic factor (BDNF); Y-maze; Frontal cortex; (Dopamine transporter knockout (DAT KO) mouse) ID REPEATED ELECTROCONVULSIVE STIMULI; PREFRONTAL CORTEX; NEUROTROPHIC FACTOR; SPONTANEOUS-ALTERNATION; PLACE PREFERENCE; GENE-EXPRESSION; COCAINE REWARD; IN-VIVO; BRAIN; RATS AB Brain-derived neurotrophic factor (BDNF), one of the key brain neurotrophins, has been implicated in neuronal plasticity and memory. Recent studies document the importance of BDNF for normal long-term memory functions. However, there are few studies of the roles of BDNF in short-term memory. Dopamine is likely to play important roles in BDNF gene expression in specific brain regions, including frontal cortical regions that are implicated in short-term working memory processes that include spontaneous alternation. We have thus tested spatial working memory in dopamine transporter knockout (DAT KO) and wild-type mice. Spontaneous alternation in the Y-maze, an index of short-term spatial working memory in mice, was significantly decreased in DAT KO mice compared to wild-type mice. BDNF protein was significantly decreased in frontal cortex, though not in striatum or hippocampus, of the DAT KO mice. The data support the hypothesis that impaired spatial working memory in DAT KO mice may be related to decreased frontal cortical BDNF in these animals, and document apparent roles for BDNF in a short-term memory process. (C) 2009 Elsevier B.V. All rights reserved. C1 [Li, BingJin; Arime, Yosefu; Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Li, BingJin] Shanxi Univ, Morden Res Ctr Tradit Chinese Med, Taiyuan, Peoples R China. RP Sora, I (reprint author), Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. EM isora@mail.tains.tohoku.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan [17390315, 17022007, 18023007]; Mitsubishi Pharma Research Foundation; National Institute of Health Intramural Research Program (NIDA), DHHS (USA) FX This study was supported in part by Grant-in-Aid for Health and Labor Science Research (Research on Pharmaceutical and Medical Safety) from the Ministry of Health, Labor and Welfare of Japan; by Grants-in-Aid for Scientific Research (B), Scientific Research on Priority Areas - System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders, Core Research for Evolutional Science and Technology (CREST), from the Ministry of Education, Culture, Sports, Science and Technology of Japan (nos. 17390315, 17022007, 18023007); and by the Mitsubishi Pharma Research Foundation. This study was also supported in part by an intramural funding from the National Institute of Health Intramural Research Program (NIDA), DHHS (USA). NR 50 TC 43 Z9 44 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 25 PY 2010 VL 628 IS 1-3 BP 104 EP 107 DI 10.1016/j.ejphar.2009.11.036 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 558YJ UT WOS:000274784500015 PM 19932884 ER PT J AU Regino, CAS Ogawa, M Alford, R Wong, KJ Kosaka, N Williams, M Feild, BJ Takahashi, M Choyke, PL Kobayashi, H AF Regino, Celeste Aida S. Ogawa, Mikako Alford, Raphael Wong, Karen J. Kosaka, Noboyuki Williams, Mark Feild, Brian J. Takahashi, Masatoshi Choyke, Peter L. Kobayashi, Hisataka TI Two-Step Synthesis of Galactosylated Human Serum Albumin as a Targeted Optical Imaging Agent for Peritoneal Carcinomatosis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HEPATIC FUNCTIONAL RESERVE; FLUORESCENT PROTEINS; LIVER-FUNCTION; CANCER-CELLS; IN-VIVO; IMMUNOGENICITY; AVIDIN; METASTASES; CONJUGATE; MODEL AB An optical probe, RG-(gal)(28)GSA, was synthesized to improve the detection of peritoneal implants by targeting the beta-D-galactose receptors highly expressed oil the cell surface of a wide variety of cancers arising from the ovary, pancreas, colon, and stomach. Evaluation of RG-(gal)(28)GSA, RG-(gal)(20)GSA, glucose-analogue RG-(glu)(28)GSA, and control RG-HSA demonstrates specificity for the galactose, binding to several human adenocarcinoma cell lines, and cellular internalization. Studies using peritoneally disseminated SHIN3 xenografts in mice also confirmed a preference for galactose with the ability to detect submillimeter size lesions. Preliminary toxicity study for RG-(gal)(28)GSA using Balb/c mice reveal 110 toxic effects up to 100x of the standard imaging dose of 1 mg/kg administered either intraperitoneally or intravenously. These data Indicate that RG-(gal)(28)GSA can selectively target a variety of human adenocarcinomas, can Improve intraoperative or endoscopic tumor detection and resection, and may have little or no toxic in vivo effects hence, it may be clinically translatable. C1 [Regino, Celeste Aida S.; Ogawa, Mikako; Alford, Raphael; Wong, Karen J.; Kosaka, Noboyuki; Williams, Mark; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Alford, Raphael] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Williams, Mark] NCI, Lab Anim Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Feild, Brian J.; Takahashi, Masatoshi] Shimazdu Sci Instruments, Columbia, MD 21046 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 1B40,MSC 1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 13 Z9 13 U1 1 U2 7 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 FEB 25 PY 2010 VL 53 IS 4 BP 1579 EP 1586 DI 10.1021/jm901228u PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 556HN UT WOS:000274581200014 PM 20102220 ER PT J AU Kang, C 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 Mutations in the Lysosomal Enzyme-Targeting Pathway and Persistent Stuttering SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PSEUDO-HURLER POLYDYSTROPHY; I-CELL DISEASE; MUCOLIPIDOSIS-III; GENE; LINKAGE; N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE; PHENOTYPE; ETIOLOGY; SAMPLE AB BACKGROUND Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12. METHODS We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America. RESULTS We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms. CONCLUSIONS Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism. C1 [Kang, Changsoo; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Friedman, Penelope] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Riazuddin, Sheikh] Univ Punjab, Ctr Excellence Mol Biol, Lahore, Pakistan. [Mundorff, Jennifer] Hollins Commun Res Inst, Roanoke, VA USA. RP Drayna, D (reprint author), 5 Res Ct,Rm 2B-46, Rockville, MD 20850 USA. EM drayna@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders [Z01-000046-09]; National Human Genome Research Institute FX Supported by grants from the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (Z01-000046-09, to Dr. Drayna) and the National Human Genome Research Institute (to Dr. Mullikin). NR 31 TC 73 Z9 84 U1 0 U2 15 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 FEB 25 PY 2010 VL 362 IS 8 BP 677 EP 685 DI 10.1056/NEJMoa0902630 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 559SA UT WOS:000274845600006 PM 20147709 ER PT J AU Bolukbas, S Eberlein, M Schirren, J AF Boeluekbas, Servet Eberlein, Michael Schirren, Joachim TI Management of Lung Nodules Detected by Volume CT Scanning SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Boeluekbas, Servet; Schirren, Joachim] Dr Horst Schmidt Klin, Wiesbaden, Germany. [Eberlein, Michael] NIH, Bethesda, MD 20892 USA. RP Bolukbas, S (reprint author), Dr Horst Schmidt Klin, Wiesbaden, Germany. EM servet_boeluekbas@web.de NR 2 TC 2 Z9 2 U1 0 U2 1 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 FEB 25 PY 2010 VL 362 IS 8 BP 757 EP 758 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 559SA UT WOS:000274845600019 PM 20191664 ER PT J AU Koshimizu, H Kim, T Cawley, NX Loh, YP AF Koshimizu, Hisatsugu Kim, Taeyoon Cawley, Niamh X. Loh, Y. Peng TI Chromogranin A: A new proposal for trafficking, processing and induction of granule biogenesis SO REGULATORY PEPTIDES LA English DT Article DE Chromogranin A; Granule biogenesis; AtT-20 cells; Protease Nexin-1; Secretogranin III ID REGULATED SECRETORY PATHWAY; TRANS-GOLGI NETWORK; CHROMAFFIN GRANULES; SECRETOGRANIN-III; TARGETED ABLATION; SORTING RECEPTOR; BREFELDIN-A; CATHEPSIN-L; CELLS; PROTEINS AB Chromogranin A (CgA), a member of the granin family serves several important cell biological roles in (neuro) endocrine cells which are summarized in this review. CgA is a "prohormone" that is synthesized at the rough endoplasmic reticulum and transported into the cisternae of this organelle via its signal peptide. It is then trafficked to the Golgi complex and then to the trans-Golgi network (TGN) where CgA aggregates at low pH in the presence of calcium. The CgA aggregates provide the physical driving force to induce budding of the TGN membrane resulting in dense core granule (DCG) formation. Within the granule, a small amount of the CgA is processed to bioactive peptides, including a predicted C-terminal peptide, serpinin. Upon stimulation, DCGs undergo exocytosis and CgA and its derived peptides are released. Serpinin, acting extracellularly is able to signal the increase in transcription of a serine protease inhibitor, protease nexin-1 (PN-1) that protects DCG proteins against degradation in the Golgi complex, which then enhances DCG biogenesis to replenish those that were released. Thus CgA and its derived peptide, serpinin, plays a significant role in granule formation and regulation of granule biogenesis, respectively, in (neuro) endocrine cells. Published by Elsevier B.V. C1 [Koshimizu, Hisatsugu; Kim, Taeyoon; Cawley, Niamh X.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, 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 5A-22,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov RI Koshimizu, Hisatsugu/G-5536-2010 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health intramural research programs. NR 42 TC 23 Z9 23 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD FEB 25 PY 2010 VL 160 IS 1-3 BP 153 EP 159 DI 10.1016/j.regpep.2009.12.007 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 560GL UT WOS:000274890000022 PM 20006653 ER PT J AU Gray, MM Sutter, NB Ostrander, EA Wayne, RK AF Gray, Melissa M. Sutter, Nathan B. Ostrander, Elaine A. Wayne, Robert K. TI The IGF1 small dog haplotype is derived from Middle Eastern grey wolves SO BMC BIOLOGY LA English DT Article ID CANINE GENOMIC DIVERSITY; DOMESTIC DOG; MITOCHONDRIAL-DNA; UNCONSCIOUS SELECTION; MORPHOLOGICAL CHANGE; ALU ELEMENTS; WILD CANIDS; ORIGINS; SIZE; RECONSTRUCTION AB Background: A selective sweep containing the insulin-like growth factor 1 (IGF1) gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP) found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog. Results: We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves. Conclusions: The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East. See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10 C1 [Gray, Melissa M.; Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Sutter, Nathan B.] Cornell Univ, Coll Vet Med, Dept Clin Sci, Ithaca, NY 14853 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gray, MM (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM mgray9@ucla.edu RI Gray, Melissa/B-5025-2008; OI Gray, Melissa/0000-0002-1756-5468; Ostrander, Elaine/0000-0001-6075-9738 FU National Institutes of Health [5 T32 HG002536]; US National Science Foundation [0733033]; US National Institutes of Health Intramural Program of the National Human Genome Research Institute (NBS) FX We would like to thank the three anonymous reviewers and Olaf Thalmann, Klaus Koepfli and John Pollinger for their helpful comments and discussions. We would also like to thank countless dog owners and breeders for their sample contribution. This study was supported by US National Institutes of Health training grant 5 T32 HG002536 (MMG), US National Science Foundation award 0733033 (RKW) and by the US National Institutes of Health Intramural Program of the National Human Genome Research Institute (NBS). NR 52 TC 35 Z9 36 U1 2 U2 44 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD FEB 24 PY 2010 VL 8 AR 16 DI 10.1186/1741-7007-8-16 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 569AV UT WOS:000275569200001 PM 20181231 ER PT J AU Yao, RQ Yasuoka, A Kamei, A Kitagawa, Y Tateishi, N Tsuruoka, N Kiso, Y Sueyoshi, T Negishi, M Misaka, T Abe, K AF Yao, Ruiquing Yasuoka, Akihito Kamei, Asuka Kitagawa, Yoshinori Tateishi, Norifumi Tsuruoka, Nobuo Kiso, Yoshionobu Sueyoshi, Tatsuya Negishi, Masahiko Misaka, Takumi Abe, Keiko TI Dietary Flavonoids Activate the Constitutive Androstane Receptor (CAR) SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE Flavonoid; catechin; chrysin; constitutive androstane receptor; pregnane X receptor; cyp2b10; detoxification; energy metabolism ID ENHANCER MODULE; CYP2B6 GENE; X RECEPTOR; NUCLEAR; METABOLISM; INDUCTION; GAMMA; EVOLUTION; CELLS; PXR AB The constitutive androstane receptor (CAR) is known as a xeno-sensor that regulates genes involved in xenobiotic excretion and energy metabolism. This study tested a variety of polyphenols for their ability to modulate CAR activity. HepG2 cells were transfected with a CAR expression plasmid and a reporter plasmid containing the human CYP2B6 regulatory region and then treated with flavonoids, catechins, and other bioactive polyphenols. Luciferase assays revealed that baicalein (5,6,7-OH flavone) was a potent activator of both human and mouse CAR. Catechin gallates also activated human and mouse CAR. Wild-type and CAR knockout mice were treated with baicalein and chrysin (5,7-OH flavone), and their liver mRNA was analyzed by real-time polymerase chain reaction (PCR). A significant increase in cyp2b10 mRNA content was observed only in wildtype mice fed chrysin. These results suggest that dietary flavonoids regulate CAR activity and thereby accelerate both detoxification and energy metabolism. C1 [Yao, Ruiquing; Misaka, Takumi; Abe, Keiko] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Appl Biol Chem, Bunkyo Ku, Tokyo 1138657, Japan. [Yasuoka, Akihito] Maebashi Inst Technol, Dept Biol Engn, Maebashi, Gumma 3710816, Japan. [Kamei, Asuka] Kanagawa Acad Sci & Technol, Takatsu Ku, Kawasaki, Kanagawa 2130012, Japan. [Kitagawa, Yoshinori; Tateishi, Norifumi; Tsuruoka, Nobuo; Kiso, Yoshionobu] Suntory Ltd, Inst Hlth Care Sci, Shimamoto, Osaka 6188503, Japan. [Sueyoshi, Tatsuya; Negishi, Masahiko] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Abe, K (reprint author), Univ Tokyo, Grad Sch Agr & Life Sci, Dept Appl Biol Chem, Bunkyo Ku, 1-1-1 Yayoi, Tokyo 1138657, Japan. EM aka7308@mail.ecc.u-tokyo.ac.jp RI Kiso, Yoshinobu/D-5424-2012 FU Intramural NIH HHS [Z01 ES080040-23] NR 21 TC 13 Z9 16 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD FEB 24 PY 2010 VL 58 IS 4 BP 2168 EP 2173 DI 10.1021/jf903711q PG 6 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 555QZ UT WOS:000274530100017 PM 20099825 ER PT J AU Flandin, P Kimura, S Rubenstein, JLR AF Flandin, Pierre Kimura, Shioko Rubenstein, John L. R. TI The Progenitor Zone of the Ventral Medial Ganglionic Eminence Requires Nkx2-1 to Generate Most of the Globus Pallidus But Few Neocortical Interneurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FOREBRAIN CHOLINERGIC NEURONS; LIM-HOMEOBOX GENE; GABAERGIC INTERNEURONS; MOUSE TELENCEPHALON; EXPRESSION; SUBTYPES; SPECIFICATION; MIGRATION; FATE; LHX6 AB We show that most globus pallidus neurons, but very few neocortical interneurons, are generated from the ventral medial ganglionic eminence and dorsal preoptic area based on fate mapping using an Shh-Cre allele. The Shh-expressing subpallial lineage produces parvalbumin(+) GABAergic neurons, ChAT(+) cholinergic neurons, and oligodendrocytes. Loss of Nkx2-1 function from the Shh-expressing domain eliminated most globus pallidus neurons, whereas most cortical and striatal interneurons continued to be generated, except for striatal cholinergic neurons. Finally, our analysis provided evidence for a novel cellular component (Nkx2-1(+); Npas1(+)) of the globus pallidus. C1 [Flandin, Pierre; Rubenstein, John L. R.] Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94158 USA. [Kimura, Shioko] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rubenstein, JLR (reprint author), Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94158 USA. EM john.rubenstein@ucsf.edu FU Nina Ireland; Weston Havens Foundation; National Institute of Mental Health [MH049428, R01 MH081880]; Swiss National Science Foundation [PBGE33-112882, PA0033-117463] FX This work was supported by research grants to J. L. R. R. from Nina Ireland and the Weston Havens Foundation and National Institute of Mental Health R37 Grants MH049428 and R01 MH081880, and by funding to P. F. from Swiss National Science Foundation Fellowships PBGE33-112882 and PA0033-117463. NR 35 TC 78 Z9 79 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 24 PY 2010 VL 30 IS 8 BP 2812 EP 2823 DI 10.1523/JNEUROSCI.4228-09.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 560VB UT WOS:000274930500003 PM 20181579 ER PT J AU Lee, DJ Leikin, S Wynveen, A AF Lee, D. J. Leikin, S. Wynveen, A. TI Fluctuations and interactions of semi-flexible polyelectrolytes in columnar assemblies SO JOURNAL OF PHYSICS-CONDENSED MATTER LA English DT Article ID DNA DOUBLE HELICES; ENHANCED ELECTROSTATIC FORCES; F-ACTIN; HYDRATION FORCES; FREE-ENERGY; INTERMOLECULAR FORCES; ARTICULAR-CARTILAGE; BUNDLE FORMATION; LIQUID-CRYSTALS; NEMATIC PHASES AB We have developed a statistical theory for columnar aggregates of semi-flexible polyelectrolytes. The applicability of previous, simplified theories was limited to polyelectrolytes with unrealistically high effective charge and, hence, with strongly suppressed thermal undulations. To avoid this problem, we utilized more consistent approximations for short-range image-charge forces and steric confinement, resulting in new predictions for polyelectrolytes with more practically important, lower effective linear charge densities. In the present paper, we focus on aggregates of wormlike chains with uniform surface charge density, although the same basic ideas may also be applied to structured polyelectrolytes. We find that undulations effectively extend the range of electrostatic interactions between polyelectrolytes upon decreasing aggregate density, in qualitative agreement with previous theories. However, in contrast to previous theories, we demonstrate that steric confinement provides the dominant rather than a negligible contribution at higher aggregate densities and significant quantitative corrections at lower densities, resulting in osmotic pressure isotherms that drastically differ from previous predictions. C1 [Lee, D. J.] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. [Leikin, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, DHHS, Bethesda, MD 20892 USA. [Wynveen, A.] Univ Dusseldorf, Inst Theoret Phys Soft Matter 2, D-40225 Dusseldorf, Germany. RP Lee, DJ (reprint author), Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. EM domolee@hotmail.com; leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Max-Planck Society; Intramural Research Program of NICHD; NIH; Alexander von Humboldt Foundation FX This work was supported in part by the Max-Planck Society (DJL), the Intramural Research Program of NICHD, NIH (SL) and the Alexander von Humboldt Foundation (AW). NR 57 TC 7 Z9 7 U1 2 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0953-8984 J9 J PHYS-CONDENS MAT JI J. Phys.-Condes. Matter PD FEB 24 PY 2010 VL 22 IS 7 AR 072202 DI 10.1088/0953-8984/22/7/072202 PG 9 WC Physics, Condensed Matter SC Physics GA 551WP UT WOS:000274244100003 PM 20352061 ER PT J AU Pletnev, S Subach, FV Dauter, Z Wlodawer, A Verkhusha, VV AF Pletnev, Sergei Subach, Fedor V. Dauter, Zbigniew Wlodawer, Alexander Verkhusha, Vladislav V. TI Understanding Blue-to-Red Conversion in Monomeric Fluorescent Timers and Hydrolytic Degradation of Their Chromophores SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CRYSTAL-STRUCTURE; PROTEIN; COLOR; ZOANTHUS; CORAL; CLEAVAGE; REVEALS; BOND AB Fast-FT is a fluorescent timer (FT) engineered from DsRed-like fluorescent protein mCherry Crystal structures of Fast-FT (chromophore Met66-Tyr67-Gly68) and its precursor with blocked blue-to-red conversion Blue102 (chromophore Leu66-Tyr67-Gly68) have been determined at the resolution of 1 15 angstrom and 1 81 angstrom, respectively Structural data suggest that blue-to-red conversion, taking place in Fast-FT and in related FTs, is associated with the oxidation of C alpha 2-C beta 2 bond of Tyr67 Site directed mutagenesis revealed a crucial role of Arg70 and Tyr83 in the delayed oxidation of C alpha 2-C beta 2 bond, introducing the timing factor in maturation of the timer Substitutions Ser217Ala and Ser217Cys in Fast-FT substantially slow down formation of an intermediate blue chromophore but do not affect much blue-to-red conversion, whereas mutations Arg70Lys or Trp83Leu, having little effect on the blue chromophore formation rate, markedly accelerates formation of the red chromophore The chromophore of FTs adopts a cis-conformation stabilized by a hydrogen bond between its phenolate oxygen and the side chain hydroxyl of Ser146. In Blue102, a bulky side chain of IIe146 precludes the chromophore from adopting a "cis-like" conformation, blocking its blue-to-red conversion Both Fast-FT and Blue102 structures revealed hydrolytic degradation of the chromophores In Fast-FT, chromophore-forming Met66 residue is eliminated from the polypeptide chain, whereas Leu66 in Blue102 is cleaved out from the chromophore, decarboxylated and remains attached to the preceding Phe65. Hydrolysis of the chromophore competes with chromophore maturation and is driven by the same residues that participate in chromophore maturation. C1 [Pletnev, Sergei; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. [Pletnev, Sergei] SAIC Frederick, Basic Res Program, Argonne, IL 60439 USA. [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA. [Wlodawer, Alexander] NCI, Prot Struct Sect, Frederick, MD 21702 USA. RP Pletnev, S (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. RI Subach, Fedor/K-7080-2014 FU U S Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E, GM073913] FX Diffraction data were collected at the SERCAT ID22 beamline at the Advanced Photon Source, Argonne National Laboratory Use of the Advanced Photon Source was supported by the U S Department of Energy, Office of Science, Office of Basic Energy Sciences, Under Contract No W-31-109-Eng-38 This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH) Contract No HHSN261200800001E, the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the NIH Grant GM073913 to V.V V 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 U S Government NR 37 TC 30 Z9 32 U1 2 U2 12 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 FEB 24 PY 2010 VL 132 IS 7 BP 2243 EP 2253 DI 10.1021/ja908418r PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 562WD UT WOS:000275085100039 PM 20121102 ER PT J AU Shoemaker, RH AF Shoemaker, Robert H. TI Identification of Bona Fide Esophageal Adenocarcinoma Cell Lines SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Ft Detrick, MD 21702 USA. RP Shoemaker, RH (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Bldg 440, Ft Detrick, MD 21702 USA. EM shoemakr@mail.nih.gov NR 9 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 24 PY 2010 VL 102 IS 4 BP 212 EP 213 DI 10.1093/jnci/djp526 PG 2 WC Oncology SC Oncology GA 561NM UT WOS:000274984500002 PM 20075369 ER PT J AU Boonstra, JJ van Marion, R Beer, DG Lin, L Chaves, P Ribeiro, C Pereira, AD Roque, L Darnton, SJ Altorki, NK Schrump, DS Klimstra, DS Tang, LH Eshleman, JR Alvarez, H Shimada, Y van Dekken, H Tilanus, HW Dinjens, WNM AF Boonstra, Jurjen J. van Marion, Ronald Beer, David G. Lin, Lin Chaves, Paula Ribeiro, Catarina Pereira, A. Dias Roque, Lucia Darnton, S. Jane Altorki, Nasser K. Schrump, David S. Klimstra, David S. Tang, Laura H. Eshleman, James R. Alvarez, Hector Shimada, Yutaka van Dekken, Herman Tilanus, Hugo W. Dinjens, Winand N. M. TI Verification and Unmasking of Widely Used Human Esophageal Adenocarcinoma Cell Lines SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IN-VITRO; BARRETTS-ESOPHAGUS; ACID EXPOSURE; PROLIFERATION; MAPK; ESTABLISHMENT; APOPTOSIS; PATHWAYS; VIVO AB For decades, hundreds of different human tumor type-specific cell lines have been used in experimental cancer research as models for their respective tumors. The veracity of experimental results for a specific tumor type relies on the correct derivation of the cell line. In a worldwide effort, we verified the authenticity of all available esophageal adenocarcinoma (EAC) cell lines. We proved that the frequently used cell lines SEG-1 and BIC-1 and the SK-GT-5 cell line are in fact cell lines from other tumor types. Experimental results based on these contaminated cell lines have led to ongoing clinical trials recruiting EAC patients, to more than 100 scientific publications, and to at least three National Institutes of Health cancer research grants and 11 US patents, which emphasizes the importance of our findings. Widespread use of contaminated cell lines threatens the development of treatment strategies for EAC. C1 [Boonstra, Jurjen J.; van Marion, Ronald; van Dekken, Herman; Dinjens, Winand N. M.] Univ Med Ctr, Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [Boonstra, Jurjen J.; van Marion, Ronald; van Dekken, Herman; Dinjens, Winand N. M.] Univ Med Ctr, Erasmus MC, Josephine Nefkens Inst, Dept Surg, Rotterdam, Netherlands. [Beer, David G.; Lin, Lin] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Chaves, Paula; Ribeiro, Catarina; Pereira, A. Dias; Roque, Lucia] IPOLFG, Grp Estudos Esofago Barrett, Lisbon, Portugal. [Darnton, S. Jane] Birmingham Heartlands Hosp, Dept Thorac Surg, Esophageal Res Lab, Birmingham B9 5ST, W Midlands, England. [Altorki, Nasser K.] Cornell Univ, Coll Med, Dept Surg, New York, NY 10021 USA. [Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Klimstra, David S.; Tang, Laura H.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Eshleman, James R.; Alvarez, Hector] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Shimada, Yutaka] Toyama Univ, Dept Surg, Toyama 930, Japan. RP Dinjens, WNM (reprint author), Erasmus Univ, Med Ctr, Dept Pathol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM w.dinjens@erasmusmc.nl OI Chaves, Paula/0000-0002-0732-2059; Roque, Lucia/0000-0002-4762-7025 FU Erasmus MC Rotterdam [FC0991]; SK foundation FX Revolving Fund (FC0991) of the Erasmus MC Rotterdam and SK foundation. NR 23 TC 62 Z9 64 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 24 PY 2010 VL 102 IS 4 BP 271 EP 274 DI 10.1093/jnci/djp499 PG 4 WC Oncology SC Oncology GA 561NM UT WOS:000274984500012 PM 20075370 ER PT J AU Rosenberg, PS Menashe, I Jatoi, I Anderson, WF AF Rosenberg, Philip S. Menashe, Idan Jatoi, Ismail Anderson, William F. TI Re: Racial Disparities in Cancer Survival Among Randomized Clinical Trials of the Southwest Oncology Group SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID BREAST-CANCER C1 [Rosenberg, Philip S.; Menashe, Idan; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Jatoi, Ismail] Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD USA. RP Rosenberg, PS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Rm 8022, Rockville, MD 20852 USA. EM rosenbep@mail.nih.gov FU Intramural NIH HHS NR 6 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 24 PY 2010 VL 102 IS 4 BP 277 EP 277 DI 10.1093/jnci/djp507 PG 1 WC Oncology SC Oncology GA 561NM UT WOS:000274984500016 PM 20075363 ER PT J AU Prokunina-Olsson, L Chanock, SJ AF Prokunina-Olsson, Ludmila Chanock, Stephen J. TI Cancer Sequencing Gets a Little More Personal SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; RECURRENT GENE FUSIONS; PROSTATE-CANCER; REARRANGEMENT; CHROMOSOME; INSIGHTS; SARCOMA; TUMORS AB In this Perspective, we discuss a paper in this issue of Science Translational Medicine, in which Leary and colleagues present a new method based on massive, parallel, and near complete sequencing of individual tumor genomes. Their findings support the notion that cancer genomes house a spectrum of genetic alterations, many of which are unique to the individual tumor. More validation and a reduction in cost are required for this approach to become common in clinics. C1 [Prokunina-Olsson, Ludmila; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091 NR 28 TC 0 Z9 0 U1 0 U2 0 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 FEB 24 PY 2010 VL 2 IS 20 AR 20ps8 DI 10.1126/scitranslmed.3000929 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591MB UT WOS:000277303700004 PM 20371489 ER PT J AU Lee, S Xie, J Chen, XY AF Lee, Seulki Xie, Jin Chen, Xiaoyuan TI Peptide-Based Probes for Targeted Molecular Imaging SO BIOCHEMISTRY LA English DT Review ID IRON-OXIDE NANOPARTICLES; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO EVALUATION; SEMICONDUCTOR QUANTUM DOTS; RECEPTOR-EXPRESSING TUMORS; GLYCINE-ASPARTIC RGD; CELL LUNG-CANCER; PROSTATE-CANCER; CARBON NANOTUBES; PRECLINICAL EVALUATION AB Targeted molecular imaging techniques have become indispensable tools in modern diagnostics because they provide accurate and specific diagnosis of disease information. Conventional nonspecific contrast agents suffer from low targeting efficiency; thus, the use of molecularly targeted imaging probes is needed depending on different imaging modalities. Although recent technologies have yielded various strategies for designing smart probes, utilization of peptide-based probes has been most successful. Phage display technology and combinatorial peptide chemistry have profoundly impacted the pool of available targeting peptides for the efficient and specific delivery of imaging labels. To date, selected peptides that target a variety of disease-related receptors and biomarkers are in place. These targeting peptides can be coupled with the appropriate imaging moieties or nanoplatforms on demand with the help of sophisticated bioconjugation or radiolabeling techniques. This review article examines the current trends in peptide-based imaging probes developed for in vivo applications. We discuss the advantage of and challenges in developing peptide-based probes and summarize current systems with respect to their unique design strategies and applications. C1 [Lee, Seulki; Xie, Jin; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov RI Xie, Jin/E-8193-2010 FU Intramural NIH HHS [Z99 EB999999, ZII EB000066-01] NR 145 TC 114 Z9 118 U1 10 U2 75 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 23 PY 2010 VL 49 IS 7 BP 1364 EP 1376 DI 10.1021/bi901135x PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 555RF UT WOS:000274530800004 PM 20102226 ER PT J AU Barlow, JH Rothstein, R AF Barlow, Jacqueline H. Rothstein, Rodney TI Timing is everything: cell cycle control of Rad52 SO CELL DIVISION LA English DT Article ID DOUBLE-STRAND BREAK; REPLICATION PROTEIN-A; DNA-DAMAGE CHECKPOINT; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; FORK PROGRESSION; END RESECTION; IN-VIVO; DIFFERENTIAL REGULATION; SUMO MODIFICATION AB Regulation of the repair of DNA double-strand breaks by homologous recombination is extremely important for both cell viability and the maintenance of genomic integrity. Modulation of double-strand break repair in the yeast Saccharomyces cerevisiae involves controlling the recruitment of one of the central recombination proteins, Rad52, to sites of DNA lesions. The Rad52 protein, which plays a role in strand exchange and the annealing of single strand DNA, is positively regulated upon entry into S phase, repressed during the intra-S phase checkpoint, and undergoes posttranslational modification events such as phosphorylation and sumoylation. These processes all contribute to the timing of Rad52 recruitment, its stability and function. Here, we summarize the regulatory events affecting the Rad52 protein and discuss how this regulation impacts DNA repair and cell survival. C1 [Rothstein, Rodney] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10032 USA. [Barlow, Jacqueline H.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Rothstein, R (reprint author), Columbia Univ, Med Ctr, Dept Genet & Dev, 701 W 168th St,HHSC 1608, New York, NY 10032 USA. EM rothstein@cancercenter.columbia.edu FU NIH [GM50237, GM67055, GM70088, GM73568] FX We would like to thank Adriana Antunez de Mayolo for the contribution of unpublished data, Lorraine Symington, Michael Lisby, Sergio Gonzalez-Barrera, Michael Chang, and Kara Bernstein for their helpful comments on the manuscript. This work was supported by grant GM50237 (RR), GM67055 (RR), GM70088 (JHB) and GM73568 (JHB) from the NIH. NR 80 TC 8 Z9 8 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1747-1028 J9 CELL DIV JI Cell Div. PD FEB 23 PY 2010 VL 5 AR 7 DI 10.1186/1747-1028-5-7 PG 8 WC Cell Biology SC Cell Biology GA 675AJ UT WOS:000283795300001 PM 20178629 ER PT J AU Lauer, MS Skarlatos, S AF Lauer, Michael S. Skarlatos, Sonia TI Translational Research for Cardiovascular Diseases at the National Heart, Lung, and Blood Institute Moving From Bench to Bedside and From Bedside to Community SO CIRCULATION LA English DT Article DE cardiovascular diseases; translational research; funding; career counseling ID CARE; TRIAL C1 [Lauer, Michael S.; Skarlatos, Sonia] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [R01 HL072771, R01 HL066004, P50 HL077107] NR 23 TC 17 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 23 PY 2010 VL 121 IS 7 BP 929 EP 933 DI 10.1161/CIRCULATIONAHA.109.917948 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559CI UT WOS:000274797500013 PM 20177007 ER PT J AU Archin, NM Cheema, M Parker, D Wiegand, A Bosch, RJ Coffin, JM Eron, J Cohen, M Margolis, DM AF Archin, Nancie M. Cheema, Manzoor Parker, Daniel Wiegand, Ann Bosch, Ronald J. Coffin, John M. Eron, Joseph Cohen, Myron Margolis, David M. TI Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+Cell Infection SO PLOS ONE LA English DT Article ID THERAPEUTIC STRATEGIES; T-CELLS; EXPRESSION; TYPE-1; RESERVOIR; DEACETYLASES; INHIBITORS; REDUCE; SIZE AB Background: Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART. Methods: Patients with plasma HIV RNA <50 c/mL added sustained-release VPA (Depakote ER (R)) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA). Results: In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA. Conclusions: The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued. C1 [Archin, Nancie M.; Cheema, Manzoor; Parker, Daniel; Eron, Joseph; Cohen, Myron; Margolis, David M.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Wiegand, Ann; Coffin, John M.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Archin, NM (reprint author), Univ N Carolina, Chapel Hill, NC 27515 USA. EM dmargo@med.unc.edu OI Margolis, David/0000-0001-5714-0002 FU National Institutes of Health [AI45297, AI064074, R00046, U54RR024383, AI50410]; Trimeris/Roche Laboratories; F.M. Kirby Foundation FX Funding for the study was provided by National Institutes of Health grants AI45297 and AI064074 to DMM, R00046 and U54RR024383 to the UNC GCRC and CTSA, AI50410 to the UNC CFAR, and Trimeris/Roche Laboratories. J.M.C. was a Research Professor of the American Cancer Society with support from the F.M. Kirby Foundation. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck and Company, Incorporated, Trimeris Incorporated, Roche Pharmaceuticals, or Abbott Laboratories. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 80 Z9 82 U1 0 U2 3 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 FEB 23 PY 2010 VL 5 IS 2 AR e9390 DI 10.1371/journal.pone.0009390 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SV UT WOS:000274924000026 PM 20186346 ER PT J AU Tavel, JA AF Tavel, Jorge A. CA INSIGHT STALWART Study Grp TI Effects of Intermittent IL-2 Alone or with Peri-Cycle Antiretroviral Therapy in Early HIV Infection: The STALWART Study SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; CD4(+) CELL COUNTS; PHASE-II TRIAL; SUBCUTANEOUS INTERLEUKIN-2; INTRAVENOUS INTERLEUKIN-2; T-LYMPHOCYTES; COMBINATION; MORTALITY; IMPACT AB Background: The Study of Aldesleukin with and without antiretroviral therapy ( STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy. Methodology: Participants not on continuous ART with >= 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly. Principal Findings: A total of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (p < 0.001), and 133 cells greater in the IL-2 plus ART group (p < 0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009). Conclusions: IL-2 alone or with peri-cycle HAART increases CD4(+) counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2- induced CD4(+) cells. C1 [Tavel, Jorge A.; INSIGHT STALWART Study Grp] NIAID, NIH, Bethesda, MD 20892 USA. RP Tavel, JA (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jtavel@niaid.nih.gov RI Beral, Valerie/B-2979-2013; OI Antunes, Francisco/0000-0001-7932-1154; Lundgren, Jens/0000-0001-8901-7850; Goetz, Matthew/0000-0003-4542-992X FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068641] FX STALWART was supported by grants U01 AI068641 from the National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 11 Z9 11 U1 0 U2 3 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 FEB 23 PY 2010 VL 5 IS 2 AR e9334 DI 10.1371/journal.pone.0009334 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SV UT WOS:000274924000003 PM 20186278 ER PT J AU Yang, HH Hu, N Wang, CY Ding, T Dunn, BK Goldstein, AM Taylor, PR Lee, MP AF Yang, Howard H. Hu, Nan Wang, Chaoyu Ding, Ti Dunn, Barbara K. Goldstein, Alisa M. Taylor, Philip R. Lee, Maxwell P. TI Influence of Genetic Background and Tissue Types on Global DNA Methylation Patterns SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; DROSOPHILA-TRITHORAX; ESOPHAGEAL CANCER; ACUTE LEUKEMIAS; FAMILY-HISTORY; HYPERMETHYLATION; CHINA; TRANSLOCATIONS; RETINOBLASTOMA; TUMORS AB Recent studies have shown a genetic influence on gene expression variation, chromatin, and DNA methylation. However, the effects of genetic background and tissue types on DNA methylation at the genome-wide level have not been characterized extensively. To study the effect of genetic background and tissue types on global DNA methylation, we performed DNA methylation analysis using the Affymetrix 500K SNP array on tumor, adjacent normal tissue, and blood DNA from 30 patients with esophageal squamous cell carcinoma (ESCC). The use of multiple tissues from 30 individuals allowed us to evaluate variation of DNA methylation states across tissues and individuals. Our results demonstrate that blood and esophageal tissues shared similar DNA methylation patterns within the same individual, suggesting an influence of genetic background on DNA methylation. Furthermore, we showed that tissue types are important contributors of DNA methylation states. C1 [Yang, Howard H.; Lee, Maxwell P.] NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Hu, Nan; Wang, Chaoyu; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ding, Ti] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Dunn, Barbara K.] NCI, Basic Prevent Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Yang, HH (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov; leemax@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 15 Z9 16 U1 0 U2 3 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 FEB 23 PY 2010 VL 5 IS 2 AR e9355 DI 10.1371/journal.pone.0009355 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SV UT WOS:000274924000006 PM 20186319 ER PT J AU Koonin, EV Moss, B AF Koonin, Eugene V. Moss, Bernard TI Viruses know more than one way to don a cap SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MESSENGER-RNA; VACCINIA VIRUS; METHYLTRANSFERASE DOMAIN; GUANYLYLTRANSFERASE; PROTEIN; ENZYME C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov; bmoss@niaid.nih.gov NR 14 TC 11 Z9 12 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 23 PY 2010 VL 107 IS 8 BP 3283 EP 3284 DI 10.1073/pnas.0915061107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900003 PM 20167804 ER PT J AU Cruz, C Maegawa, S Weinberg, ES Wilson, SW Dawid, IB Kudoh, T AF Cruz, Carlos Maegawa, Shingo Weinberg, Eric S. Wilson, Stephen W. Dawid, Igor B. Kudoh, Tetsuhiro TI Induction and patterning of trunk and tail neural ectoderm by the homeobox gene eve1 in zebrafish embryos SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bone morphogenic protein; neural induction; organizer; posterior development; retinoic acid ID CENTRAL-NERVOUS-SYSTEM; ANTERIOR-POSTERIOR AXIS; RETINOIC ACID; TRANSCRIPTIONAL REPRESSION; ORGANIZER FORMATION; STEM-CELLS; XENOPUS; FGF; EXPRESSION; PROTEIN AB In vertebrates, Evx homeodomain transcription factor-encoding genes are expressed in the posterior region during embryonic development, and overexpression experiments have revealed roles in tail development in fish and frogs. We analyzed the molecular mechanisms of posterior neural development and axis formation regulated by eve1. We show that eve1 is involved in establishing trunk and tail neural ectoderm by two independent mechanisms: First, eve1 posteriorizes neural ectoderm via induction of aldh1a2, which encodes an enzyme that synthesizes retinoic acid; second, eve1 is involved in neural induction in the posterior ectoderm by attenuating BMP expression. Further, eve1 can restore trunk neural tube formation in the organizer-deficient ichabod(-/-) mutant. We conclude that eve1 is crucial for the organization of the anteroposterior and dorso-ventral axis in the gastrula ectoderm and also has trunk-and tail-promoting activity. C1 [Dawid, Igor B.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Cruz, Carlos; Kudoh, Tetsuhiro] Univ Exeter, Sch Biosci, Exeter EX4 4SP, Devon, England. [Maegawa, Shingo; Weinberg, Eric S.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Wilson, Stephen W.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov; t.kudoh@exeter.ac.uk RI Wilson, Stephen/B-9404-2008; Zebrafish, UCL/A-3125-2009 OI Wilson, Stephen/0000-0002-8557-5940; FU National Institute of Child Health and Human Development, National Institutes of Health; Welcome Trust; Biotechnology and Biological Sciences Research Council FX We thank Dr. Aya Takesono for help and advice provided throughout the research period and writing of the manuscript. We thank the fish facility personnel at the University of Exeter and University College London. This work was supported in part by the Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health (I. B. D.) and by the Welcome Trust (S. W. W.). C. C. is a PhD student at the University of Exeter and his PhD studentship is provided by the Biotechnology and Biological Sciences Research Council in the United Kingdom. NR 53 TC 10 Z9 11 U1 0 U2 2 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 FEB 23 PY 2010 VL 107 IS 8 BP 3564 EP 3569 DI 10.1073/pnas.1000389107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900053 PM 20142486 ER PT J AU Hou, CH Dale, R Dean, A AF Hou, Chunhui Dale, Ryan Dean, Ann TI Cell type specificity of chromatin organization mediated by CTCF and cohesin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin loops; insulator; CTCF; globin; transcription ID BETA-GLOBIN LOCUS; CONTROL REGION; NUCLEAR-ORGANIZATION; HISTONE MODIFICATION; TARGETED DELETION; HUMAN GENOME; C-MYC; MOUSE; ELEMENTS; BINDING AB CTCF sites are abundant in the genomes of diverse species but their function is enigmatic. We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the beta-globin locus and flanking olfactory receptor genes. Although CTCF occupies these sites in both erythroid K562 cells and fibroblast 293T cells, the long-range interaction frequencies among the sites are highly cell type specific, revealing a more densely clustered organization in the absence of globin gene activity. Both CTCF and cohesins are required for the cell-type-specific chromatin conformation. Furthermore, loss of the organizational loops in K562 cells through reduction of CTCF with shRNA results in acquisition of repressive histone marks in the globin locus and reduces globin gene expression whereas silent flanking olfactory receptor genes are unaffected. These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function. C1 [Hou, Chunhui; Dale, Ryan; Dean, Ann] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov OI Dale, Ryan/0000-0003-2664-3744 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Elissa Lei for helpful comments and Qihui Gong for assistance with ChIP experiments. This research was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 38 TC 153 Z9 159 U1 2 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 FEB 23 PY 2010 VL 107 IS 8 BP 3651 EP 3656 DI 10.1073/pnas.0912087107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900068 PM 20133600 ER PT J AU Branca, RT Cleveland, ZI Fubara, B Kumar, CSSR Maronpot, RR Leuschner, C Warren, WS Driehuys, B AF Branca, Rosa T. Cleveland, Zackary I. Fubara, Boma Kumar, Challa S. S. R. Maronpot, Robert R. Leuschner, Carola Warren, Warren S. Driehuys, Bastiaan TI Molecular MRI for sensitive and specific detection of lung metastases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hyperpolarized gas MRI; superparamagnetic iron oxide nanoparticles; luteinizing hormone-releasing hormone ID IRON-OXIDE NANOPARTICLES; POSITRON-EMISSION-TOMOGRAPHY; BREAST-CANCER; IN-VIVO; CONTRAST AGENTS; LABELED CELLS; HE-3 MRI; RECEPTOR; GAS; GROWTH AB Early and specific detection of metastatic cancer cells in the lung (the most common organ targeted by metastases) could significantly improve cancer treatment outcomes. However, the most widespread lung imaging methods use ionizing radiation and have low sensitivity and/or low specificity for cancer cells. Here we address this problem with an imaging method to detect submillimeter-sized metastases with molecular specificity. Cancer cells are targeted by iron oxide nanoparticles functionalized with cancer-binding ligands, then imaged by high-resolution hyperpolarized (3)He MRI. We demonstrate in vivo detection of pulmonary micrometastates in mice injected with breast adenocarcinoma cells. The method not only holds promise for cancer imaging but more generally suggests a fundamentally unique approach to molecular imaging in the lungs. C1 [Branca, Rosa T.; Warren, Warren S.] Duke Univ, Dept Chem, Ctr Mol & Biomol Imaging, Durham, NC 27708 USA. [Cleveland, Zackary I.; Fubara, Boma; Driehuys, Bastiaan] Duke Univ, Med Ctr, Dept Radiol, Ctr Vivo Microscopy, Durham, NC 27710 USA. [Kumar, Challa S. S. R.] Louisiana State Univ, Ctr Adv Microstruct & Devices, Baton Rouge, LA 70806 USA. [Maronpot, Robert R.] NIEHS, Expt Pathol Labs, Res Triangle Pk, NC 27709 USA. [Leuschner, Carola] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Branca, RT (reprint author), Duke Univ, Dept Chem, Ctr Mol & Biomol Imaging, Durham, NC 27708 USA. EM tamara.branca@duke.edu FU National Institutes of Health [R01 EB02122, P41 RR005959]; National Cancer Institute [U24 CA092656]; Duke Comprehensive Cancer Center FX We thank Prof. Laurence Hedlund for help with our animal protocols; Abraham Thomas for involvement in the first set of imaging experiments; Dr. Zuowei Su for the immunohistochemistry analysis; Sally Zimney for assistance in preparation of the manuscript; NCI Cancer Research Imaging Camp for providing adenocarcinoma mouse models; and Dr. Michael Foster for comments on the manuscript. This work was supported by National Institutes of Health Grants R01 EB02122 and P41 RR005959, National Cancer Institute Grant U24 CA092656, and the Duke Comprehensive Cancer Center. NR 50 TC 58 Z9 58 U1 2 U2 15 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 FEB 23 PY 2010 VL 107 IS 8 BP 3693 EP 3697 DI 10.1073/pnas.1000386107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900075 PM 20142483 ER PT J AU Mi, SL Li, ZJ Chen, P He, CJ Cao, DL Elkahloun, A Lu, J Pelloso, LA Wunderlich, M Huang, H Luo, RT Sun, M He, M Neilly, MB Zeleznik-Le, NJ Thirman, MJ Mulloy, JC Liu, PP Rowley, JD Chen, JJ AF Mi, Shuangli Li, Zejuan Chen, Ping He, Chunjiang Cao, Donglin Elkahloun, Abdel Lu, Jun Pelloso, Luis A. Wunderlich, Mark Huang, Hao Luo, Roger T. Sun, Miao He, Miao Neilly, Mary Beth Zeleznik-Le, Nancy J. Thirman, Michael J. Mulloy, James C. Liu, Paul P. Rowley, Janet D. Chen, Jianjun TI Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell apoptosis and viability; colony-forming/replating assay; MLL binding; gene regulation; miRNA target ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; 11Q23 CHROMOSOMAL TRANSLOCATIONS; MICRORNA EXPRESSION; CELL-PROLIFERATION; FUSION PROTEINS; GENE; CANCER; SIGNATURES; TARGETS AB MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; > 2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes. C1 [Mi, Shuangli; Li, Zejuan; Chen, Ping; He, Chunjiang; Cao, Donglin; Pelloso, Luis A.; Huang, Hao; Luo, Roger T.; He, Miao; Neilly, Mary Beth; Thirman, Michael J.; Rowley, Janet D.; Chen, Jianjun] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Sun, Miao] Univ Chicago, Committee Genet Genom & Syst Biol, Chicago, IL 60637 USA. [Elkahloun, Abdel; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Lu, Jun] Yale Univ, Dept Mol Cell Biol, New Haven, CT 06520 USA. [Lu, Jun] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Lu, Jun] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Wunderlich, Mark; Mulloy, James C.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Div Expt Hematol & Canc Biol,Med Ctr, Cincinnati, OH 45229 USA. [Zeleznik-Le, Nancy J.] Loyola Univ, Med Ctr, Inst Oncol, Maywood, IL 60153 USA. [Cao, Donglin] So Med Univ, Inst Genet Engn, Guangzhou 510515, Guangdong, Peoples R China. [Pelloso, Luis A.] Univ Fed Sao Paulo, Disciplina Hematol & Hemoterapia, BR-04023 Sao Paulo, Brazil. [He, Miao] China Med Univ, Dept Pharmacol, Shenyang 110001, Liaoning, Peoples R China. RP Rowley, JD (reprint author), Univ Chicago, Dept Med, Chicago, IL 60637 USA. EM jrowley@medicine.bsd.uchicago.edu; jchen@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; He, Chunjiang/0000-0002-4868-331X FU Yanamashi University, Japan [KOPN1, KOCL33, KOCL44, KOCL45, KOCL48, KOCL50, KOCL51, KOCL69]; National Institutes of Health (NIH) [CA127277]; University of Chicago Cancer Center Pilot; G. Harold and Leila Y. Mathers Charitable Foundation; Leukemia and Lymphoma Society Translational Research; Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health; Leukemia and Lymphoma Society Specialized Center of Research [NIH PO1CA105049]; [CA118319] FX The authors thank Drs. Y. Sato and K. Sugita at Yanamashi University, Japan, for kindly providing KOPN1, KOCL33, KOCL44, KOCL45, KOCL48, KOCL50, KOCL51, and KOCL69 cell lines. This work was supported in part by the National Institutes of Health (NIH) CA127277 (to J. C.), University of Chicago Cancer Center Pilot Grant (to J. C.), and CA118319 Sub-Award (to J. C. M. and J. C.), the G. Harold and Leila Y. Mathers Charitable Foundation (J. C.), Leukemia and Lymphoma Society Translational Research Grant (to J. D. R.), the Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International (J. D. R.), the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (to P. P. L.), and Leukemia and Lymphoma Society Specialized Center of Research (to M. J. T.), NIH PO1CA105049 (M. J. T.). NR 56 TC 67 Z9 75 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 23 PY 2010 VL 107 IS 8 BP 3710 EP 3715 DI 10.1073/pnas.0914900107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900078 PM 20133587 ER PT J AU Fukunaga, M Li, TQ van Gelderen, P de Zwart, JA Shmueli, K Yao, B Lee, J Maric, D Aronova, MA Zhang, GF Leapman, RD Schenck, JF Merkle, H Duyn, JH AF Fukunaga, Masaki Li, Tie-Qiang van Gelderen, Peter de Zwart, Jacco A. Shmueli, Karin Yao, Bing Lee, Jongho Maric, Dragan Aronova, Maria A. Zhang, Guofeng Leapman, Richard D. Schenck, John F. Merkle, Hellmut Duyn, Jeff H. TI Layer-specific variation of iron content in cerebral cortex as a source of MRI contrast SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE myelin; ferritin; laminar variation; brain structure; magnetic susceptibility ID HUMAN VISUAL-CORTEX; HIGH-RESOLUTION MRI; HIGH-FIELD MRI; HUMAN BRAIN; MAGNETIC-SUSCEPTIBILITY; CELLULAR-DISTRIBUTION; CORTICAL AREAS; WHITE-MATTER; 7.0 T; FERRITIN AB Recent advances in high-field MRI have dramatically improved the visualization of human brain anatomy in vivo. Most notably, in cortical gray matter, strong contrast variations have been observed that appear to reflect the local laminar architecture. This contrast has been attributed to subtle variations in the magnetic properties of brain tissue, possibly reflecting varying iron and myelin content. To establish the origin of this contrast, MRI data from postmortem brain samples were compared with electron microscopy and histological staining for iron and myelin. The results show that iron is distributed over laminae in a pattern that is suggestive of each region's myeloarchitecture and forms the dominant source of the observed MRI contrast. C1 [Fukunaga, Masaki; Li, Tie-Qiang; van Gelderen, Peter; de Zwart, Jacco A.; Shmueli, Karin; Yao, Bing; Lee, Jongho; Merkle, Hellmut; Duyn, Jeff H.] NINDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. [Aronova, Maria A.; Zhang, Guofeng; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Schenck, John F.] Gen Elect Global Res Ctr, Niskayuna, NY 12309 USA. RP Fukunaga, M (reprint author), NINDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM fukunagm@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013; Shmueli, Karin/B-9432-2017; OI Fukunaga, Masaki/0000-0003-1010-2644; Li, Tieqiang/0000-0002-6636-8938; Li, Tie-Qiang/0000-0002-4866-5904 FU NINDS/NIH FX Ken M. Fish (General Electric Global Research Center), Kant M. Matsuda [National Cancer Institute/National Institutes of Health (NIH)], and Eiji Matsuura [National Institute of Neurological Disorders and Stroke (NINDS)/NIH] are acknowledged for help with the iron extraction, providing tissue samples, and histochemical staining respectively. This research was supported by the Intramural Research Program of the NINDS/NIH. NR 46 TC 146 Z9 149 U1 1 U2 13 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 FEB 23 PY 2010 VL 107 IS 8 BP 3834 EP 3839 DI 10.1073/pnas.0911177107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900100 PM 20133720 ER PT J AU Rinschen, MM Yu, MJ Wang, GH Boja, ES Hoffert, JD Pisitkun, T Knepper, MA AF Rinschen, Markus M. Yu, Ming-Jiun Wang, Guanghui Boja, Emily S. Hoffert, Jason D. Pisitkun, Trairak Knepper, Mark A. TI Quantitative phosphoproteomic analysis reveals vasopressin V2-receptor-dependent signaling pathways in renal collecting duct cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aquaporin-2; MAP kinase; mass spectrometry; protein kinase A; SILAC ID PHOSPHORYLATION ANALYSIS; MASS-SPECTROMETRY; KINASE-II; AQUAPORIN-2; KIDNEY; EXPRESSION; IDENTIFICATION; PEPTIDES; TARGET; TOOL AB Vasopressin's action in renal cells to regulate water transport depends on protein phosphorylation. Here we used mass spectrometry-based quantitative phosphoproteomics to identify signaling pathways involved in the short-term V2-receptor-mediated response in cultured collecting duct cells (mpkCCD) from mouse. Using Stable Isotope Labeling by Amino acids in Cell culture (SILAC) with two treatment groups (0.1 nM dDAVP or vehicle for 30 min), we carried out quantification of 2884 phosphopeptides. The majority (82%) of quantified phosphopeptides did not change in abundance in response to dDAVP. Analysis of the 273 phosphopeptides increased by dDAVP showed a predominance of so-called "basophilic" motifs consistent with activation of kinases of the AGC family. Increases in phosphorylation of several known protein kinase A targets were found. In addition, increased phosphorylation of targets of the calmodulin-dependent kinase family was seen, including autophosphorylation of calmodulin-dependent kinase 2 at T286. Analysis of the 254 phosphopeptides decreased in abundance by dDAVP showed a predominance of so-called "proline-directed" motifs, consistent with down-regulation of mitogen-activated or cyclin-dependent kinases. dDAVP decreased phosphorylation of both JNK1/2 (T183/Y185) and ERK1/2 (T183/Y185; T203/Y205), consistent with a decrease in activation of these proline-directed kinases in response to dDAVP. Both ERK and JNK were able to phosphorylate residue S261 of aquaporin-2 in vitro, a site showing a decrease in phosphorylation in response to dDAVP in vivo. The data support roles for multiple vasopressin V2-receptor-dependent signaling pathways in the vasopressin signaling network of collecting duct cells, involving several kinases not generally accepted to regulate collecting duct function. C1 [Rinschen, Markus M.; Yu, Ming-Jiun; Hoffert, Jason D.; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Rinschen, Markus M.] Univ Munster, Dept Internal Med D, Munster, Germany. [Wang, Guanghui; Boja, Emily S.] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI) [ZO1-HL001285]; Braun Foundation (Melsungen, Germany); Biomedical Sciences Exchange Program (Hannover, Germany) FX This work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI; project ZO1-HL001285, M. A. K.). We thank Samuel H. Payne for advice regarding InsPecT. M. M. R. was supported by the Braun Foundation (Melsungen, Germany) and the Biomedical Sciences Exchange Program (Hannover, Germany). Mass spectrometry was performed in the NHLBI Proteomics Core Facility (director, Marjan Gucek). NR 35 TC 79 Z9 81 U1 0 U2 2 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 FEB 23 PY 2010 VL 107 IS 8 BP 3882 EP 3887 DI 10.1073/pnas.0910646107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900108 PM 20139300 ER PT J AU Rajagopalan, S Moyle, MW Joosten, I Long, EO AF Rajagopalan, Sumati Moyle, Mark W. Joosten, Irma Long, Eric O. TI DNA-PKcs Controls an Endosomal Signaling Pathway for a Proinflammatory Response by Natural Killer Cells SO SCIENCE SIGNALING LA English DT Article ID DEPENDENT PROTEIN-KINASE; NF-KAPPA-B; HUMAN NK CELLS; SOLUBLE HLA-G; HYDROPHOBIC MOTIF; IMMUNE-RESPONSE; CUTTING EDGE; RECEPTOR; AKT; ENDOCYTOSIS AB Endosomes are emerging as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses is still unclear. CD158d, which is also known as the killer cell immunoglobulin-like receptor( KIR) 2DL4( KIR2DL4), is an endosome-resident receptor in natural killer( NK) cells that stimulates the release of a unique set of proinflammatory and proangiogenic mediators in response to soluble human leukocyte antigen G( HLA-G). Here, we identified the CD158d signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by CD158d was dependent on the activation of nuclear factor kappa B( NF-kappa B) and the serine-threonine kinase Akt. CD158d associated with the catalytic subunit of DNA-dependent protein kinase( DNA-PKcs), promoted the recruitment of Akt to endosomes, and stimulated the DNA-PKcs-dependent phosphorylation of Akt. The sequential requirement for DNA-PKcs, Akt, and NF-kappa B in signaling by CD158d delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in NK cells. C1 [Rajagopalan, Sumati; Moyle, Mark W.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Joosten, Irma] Radboud Univ Nijmegen, Dept Lab Med, Med Ctr, NL-6500 HB Nijmegen, Netherlands. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sumi@nih.gov; eLong@nih.gov RI Joosten, Irma/D-2374-2010; Long, Eric/G-5475-2011; Joosten, Irma/N-4418-2013 OI Long, Eric/0000-0002-7793-3728; Joosten, Irma/0000-0003-2950-4977 FU NIH; National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 51 TC 30 Z9 32 U1 0 U2 0 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 FEB 23 PY 2010 VL 3 IS 110 AR ra14 DI 10.1126/scisignal.2000467 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570CB UT WOS:000275648100004 PM 20179272 ER PT J AU Klinman, DM Klaschik, S Tomaru, K Shirota, H Tross, D Ikeuchi, H AF Klinman, Dennis M. Klaschik, Sven Tomaru, Koji Shirota, Hidekazu Tross, Debra Ikeuchi, Hidekazu TI Immunostimulatory CpG oligonucleotides: Effect on gene expression and utility as vaccine adjuvants SO VACCINE LA English DT Article DE Innate immunity; Adaptive immunity; Vaccine adjuvant; CpG oligonucleotide; Microarray; Regulation ID LICENSED ANTHRAX VACCINE; BACTERIAL-DNA; INTERFERON-GAMMA; DENDRITIC CELLS; CUTTING EDGE; ACTIVATION; OLIGODEOXYNUCLEOTIDES; IMPROVE; MURINE; MOTIFS AB Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs mimic the immunostimulatory activity of bacterial DNA. CpG ODN directly stimulate B cells and plasmacytoid dendritic cells (pDC), promote the production of Th1 and pro-inflammatory cytokines, and trigger the maturation/activation of professional antigen presenting cells. CpG ODN are finding use as vaccine adjuvants, where they increase the speed, magnitude and duration of vaccine-specific immune responses. For example, CpG ODN significantly prolong the protection induced by AVA (Anthrax Vaccine Adsorbed). Unexpectedly, a majority of animals immunized with CpG-adjuvanted AVA maintain resistance to anthrax infection even after their Ab titers decline to sub-protective levels. This survival is mediated by the de novo production of protective Abs by high affinity long-lived memory B cells. The immunostimulatory activity of CpG ODN was probed at the molecular level by microarray. Results show that a small group of 'inducers' rapidly up-regulated a large network genes following CpG treatment of mice. This stimulatory activity is quenched by 'suppressors' that down-regulate the expression of targeted genes, including most of the 'inducers'. These findings shed light on the mechanism underlying CpG-mediated immune activation and therapeutic activity. Published by Elsevier Ltd. C1 [Klinman, Dennis M.; Klaschik, Sven; Tomaru, Koji; Shirota, Hidekazu; Tross, Debra; Ikeuchi, Hidekazu] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567,Rm 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural NIH HHS [Z01 BC010852-02, ZIA BC010852-03] NR 27 TC 16 Z9 20 U1 0 U2 4 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 FEB 23 PY 2010 VL 28 IS 8 SI SI BP 1919 EP 1923 DI 10.1016/j.vaccine.2009.10.094 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 573MV UT WOS:000275918900005 PM 20188247 ER PT J AU Valentin, A von Gegerfelt, A Rosati, M Miteloudis, G Alicea, C Bergamaschi, C Jalah, R Patel, V Khan, AS Draghia-Akli, R Pavlakis, GN Felber, BK AF Valentin, Antonio von Gegerfelt, Agneta Rosati, Margherita Miteloudis, Georgios Alicea, Candido Bergamaschi, Cristina Jalah, Rashmi Patel, Vainav Khan, Amir S. Draghia-Akli, Ruxandra Pavlakis, George N. Felber, Barbara K. TI Repeated DNA therapeutic vaccination of chronically SIV-infected macaques provides additional virological benefit SO VACCINE LA English DT Article DE Central memory; Effector memory; Therapeutic vaccination; DNA vaccines; Viral load; HIV ID SIMIAN IMMUNODEFICIENCY VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; ELECTROPORATION IN-VIVO; HUMORAL IMMUNE-RESPONSE; DENDRITIC-CELL VACCINE; RHESUS MACAQUES; HIV-1 DNA; GENE-TRANSFER; PLASMID DNA; HIV-1-INFECTED PATIENTS AB We have previously reported that therapeutic immunization by intramuscular injection of optimized plasmid DNAs encoding SIV antigens effectively induces immune responses able to reduce viremia in antiretroviral therapy (ART)-treated SIVmac251-infected Indian rhesus macaques. We subjected such therapeutically immunized macaques to a second round of therapeutic vaccination using a combination of plasmids expressing SIV genes and the IL-15/11-15 receptor alpha as molecular adjuvant, which were delivered by the more efficacious in vivo constant-current electroporation. A very strong induction of antigen-specific responses to Gag, Env, Nef, and Pol, during ART (1.2-1.6% of SIV-specific T cells in the circulating T lymphocytes) was obtained with the improved vaccination method. Immunological responses were characterized by the production of IFN-gamma, IL-2, and TNF-alpha either alone, or in combination as double or triple cytokine positive multifunctional T cells. A significant induction of CD4(+) T cell responses, mainly targeting Gag, Nef, and Pol, as well as of CD8(+) T cells, mainly targeting Env, was found in both T cells with central memory and effector memory markers. After release from ART, the animals showed a virological benefit with a further similar to 1 log reduction in viremia. Vaccination with plasmid DNAs has several advantages over other vaccine modalities, including the possibility for repeated administration, and was shown to induce potent, efficacious, and long-lasting recall immune responses. Therefore, these data support the concept of adding DNA vaccination to the HAART regimen to boost the HIV-specific immune responses. Published by Elsevier Ltd. C1 [Valentin, Antonio; von Gegerfelt, Agneta; Rosati, Margherita; Miteloudis, Georgios; Bergamaschi, Cristina; Patel, Vainav; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Alicea, Candido; Jalah, Rashmi; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Khan, Amir S.; Draghia-Akli, Ruxandra] VGX Pharmaceut, LLC, The Woodlands, TX 77381 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, POB B,Bldg 535,Room 206, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov; felberb@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX We thank D. Weiss, J. Treece, R. Pal, P. Markham and the staff at Advanced BioScience Laboratories, Kensington, MD for their expert help; N. Bischofsberger (Gilead Sciences, Inc.) for PMPA and FTC. We thank T. Jones for editorial assistance. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 89 TC 19 Z9 19 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 23 PY 2010 VL 28 IS 8 SI SI BP 1962 EP 1974 DI 10.1016/j.vaccine.2009.10.099 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 573MV UT WOS:000275918900010 PM 20188252 ER PT J AU Rane, NS Chakrabarti, O Feigenbaum, L Hegde, RS AF Rane, Neena S. Chakrabarti, Oishee Feigenbaum, Lionel Hegde, Ramanujan S. TI Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein SO JOURNAL OF CELL BIOLOGY LA English DT Article ID STRAUSSLER-SCHEINKER SYNDROME; ENDOPLASMIC-RETICULUM; TRANSLOCATION CHANNEL; DISEASE; PRP; FORM; PROTEASOME; PATHWAY; COMPARTMENTALIZATION; DEGRADATION AB Protein translocation into the endoplasmic reticulum is mediated by signal sequences that vary widely in primary structure. In vitro studies suggest that such signal sequence variations may correspond to subtly different functional properties. Whether comparable functional differences exist in vivo and are of sufficient magnitude to impact organism physiology is unknown. Here, we investigate this issue by analyzing in transgenic mice the impact of signal sequence efficiency for mammalian prion protein (PrP). We find that replacement of the average efficiency signal sequence of PrP with more efficient signals rescues mice from neurodegeneration caused by otherwise pathogenic PrP mutants in a downstream hydrophobic domain (HD). This effect is explained by the demonstration that efficient signal sequence function precludes generation of a cytosolically exposed, disease-causing transmembrane form of PrP mediated by the HD mutants. Thus, signal sequences are functionally nonequivalent in vivo, with intrinsic inefficiency of the native PrP signal being required for pathogenesis of a subset of disease-causing PrP mutations. C1 [Rane, Neena S.; Chakrabarti, Oishee; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci, Frederick, MD 21702 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU National Institute of Child Health and Human Development; National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Child Health and Human Development and the National Cancer Institute at the National Institutes of Health. The authors declare no competing financial interests. NR 52 TC 28 Z9 28 U1 0 U2 4 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 FEB 22 PY 2010 VL 188 IS 4 BP 515 EP 526 DI 10.1083/jcb.200911115 PG 12 WC Cell Biology SC Cell Biology GA 558EO UT WOS:000274723800010 PM 20156965 ER PT J AU Bertolino, A Taurisano, P Pisciotta, NM Blasi, G Fazio, L Romano, R Gelao, B Lo Bianco, L Lozupone, M Di Giorgio, A Caforio, G Sambataro, F Niccoli-Asabella, A Papp, A Ursini, G Sinibaldi, L Popolizio, T Sadee, W Rubini, G AF Bertolino, Alessandro Taurisano, Paolo Pisciotta, Nicola Marco Blasi, Giuseppe Fazio, Leonardo Romano, Raffaella Gelao, Barbara Lo Bianco, Luciana Lozupone, Madia Di Giorgio, Annabella Caforio, Grazia Sambataro, Fabio Niccoli-Asabella, Artor Papp, Audrey Ursini, Gianluca Sinibaldi, Lorenzo Popolizio, Teresa Sadee, Wolfgang Rubini, Giuseppe TI Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance SO PLOS ONE LA English DT Article ID DOPAMINE TRANSPORTER FUNCTION; VAL(108/158) MET GENOTYPE; PARKINSONS-DISEASE; RECEPTOR GENE; D-2 RECEPTOR; FUNCTIONAL MRI; PHARMACOLOGICAL CHARACTERIZATION; SCHIZOPHRENIC SUBJECTS; HEALTHY-VOLUNTEERS; N-ACETYLASPARTATE AB Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [(123)I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [(123)I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [(123)I]IBZM and of [(123)I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. C1 [Bertolino, Alessandro; Taurisano, Paolo; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Ursini, Gianluca] Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Bari, Italy. [Bertolino, Alessandro; Fazio, Leonardo; Popolizio, Teresa] IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. [Pisciotta, Nicola Marco; Niccoli-Asabella, Artor; Rubini, Giuseppe] Univ Bari, Dept Internal Med & Publ Med, Nucl Med Unit, Bari, Italy. [Sambataro, Fabio] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Papp, Audrey; Sadee, Wolfgang] Ohio State Univ, Coll Med, Dept Pharmacol, Program Pharmacogenom, Columbus, OH 43210 USA. [Papp, Audrey; Sadee, Wolfgang] Ohio State Univ, Div Biostat, Coll Publ Hlth, Columbus, OH 43210 USA. [Ursini, Gianluca; Sinibaldi, Lorenzo] IRCCS CSS Mendel Inst, Rome, Italy. [Sinibaldi, Lorenzo] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. RP Bertolino, A (reprint author), Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Bari, Italy. EM a.bertolino@psichiat.uniba.it RI Picchioni, Marco/E-3300-2010; Sambataro, Fabio/E-3426-2010; Fazio, Leonardo/J-4570-2012; Niccoli Asabella, Artor/M-1745-2015; Di Giorgio, Annabella /D-7353-2017; OI Picchioni, Marco/0000-0001-6681-147X; Sambataro, Fabio/0000-0003-2102-416X; Fazio, Leonardo/0000-0003-4000-974X; Niccoli Asabella, Artor/0000-0002-1227-029X; Di Giorgio, Annabella /0000-0001-7876-3495; Rubini, Giuseppe/0000-0003-1972-3308 FU National Institutes of Health (NIH) [DA022199] FX Part of this work was supported by a National Institutes of Health (NIH) grant DA022199 (W.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 103 TC 47 Z9 48 U1 1 U2 9 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 FEB 22 PY 2010 VL 5 IS 2 AR e9348 DI 10.1371/journal.pone.0009348 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SU UT WOS:000274923900014 PM 20179754 ER PT J AU Dharajiya, N Vaidya, SV Murai, H Cardenas, V Kurosky, A Boldogh, I Sur, SA AF Dharajiya, Nilesh Vaidya, Swapnil V. Murai, Hiroki Cardenas, Victor Kurosky, Alexander Boldogh, Istvan Sur, Sanjiv A. TI Fc gamma RIIb Inhibits Allergic Lung Inflammation in a Murine Model of Allergic Asthma SO PLOS ONE LA English DT Article ID INDUCED AIRWAY HYPERRESPONSIVENESS; BIFUNCTIONAL FUSION PROTEIN; CLASS-SWITCH RECOMBINATION; MAST-CELL ACTIVATION; DENDRITIC CELLS; IFN-GAMMA; RECEPTOR IIB; IN-VIVO; NEGATIVE REGULATION; IMMUNOGLOBULIN-E AB Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (Fc gamma RIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of Fc gamma RIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. Fc gamma RIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, Fc gamma RIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated Fc gamma RIIb in the lungs. Disruption of IFN-gamma gene abrogated this upregulation. Treatment of naive mice with the Th1-inducing agent CpG DNA increased Fc gamma RIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of Fc gamma RIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated Fc gamma RIIb in the lungs by IFN-gamma- and Th1-dependent mechanisms. RWE challenge upregulated Fc gamma RIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. Fc gamma RIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that Fc gamma RIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of Fc gamma RIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-gamma dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating Fc gamma RIIb may be a therapeutic strategy in allergic airway disorders. C1 [Dharajiya, Nilesh] Univ Texas Galveston, Med Branch, NHLBI, Prote Ctr,Dept Biochem & Mol Biol, Galveston, TX 77550 USA. [Vaidya, Swapnil V.; Murai, Hiroki; Cardenas, Victor; Sur, Sanjiv A.] Univ Texas Galveston, Med Branch, Dept Internal Med, Galveston, TX 77550 USA. [Kurosky, Alexander] Univ Texas Galveston, Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77550 USA. [Boldogh, Istvan] Univ Texas Galveston, Med Branch, Dept Microbiol, Galveston, TX 77550 USA. RP Dharajiya, N (reprint author), Univ Texas Galveston, Med Branch, NHLBI, Prote Ctr,Dept Biochem & Mol Biol, Galveston, TX 77550 USA. EM sasur@utmb.edu FU National Institutes of Health (NIH) [RO1HL071163]; National Institute of Allergy and Infectious Disease (NIAID) [PO1AI062885-01]; National Heart, Lung, and Blood Institute (NHLBI) Proteomics Initiative [NO1HV-28184]; National Institute of Environmental Health Sciences (NIEHS) [EOS 006677] FX This work was supported by grants from National Institutes of Health (NIH) RO1HL071163 (S.S.), National Institute of Allergy and Infectious Disease (NIAID), PO1AI062885-01 (I.B., S.S.), National Heart, Lung, and Blood Institute (NHLBI) Proteomics Initiative, NO1HV-28184 (S.S.) and National Institute of Environmental Health Sciences (NIEHS) Center Grant, EOS 006677 (I.B., S.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of manuscript. NR 71 TC 17 Z9 20 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 FEB 22 PY 2010 VL 5 IS 2 AR e9337 DI 10.1371/journal.pone.0009337 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SU UT WOS:000274923900007 PM 20179765 ER PT J AU Turpin, EA Antao-Menezes, A Cesta, MF Mangum, JB Wallace, DG Bermudez, E Bonner, JC AF Turpin, Elizabeth A. Antao-Menezes, Aurita Cesta, Mark F. Mangum, James B. Wallace, Duncan G. Bermudez, Edilberto Bonner, James C. TI Respiratory syncytial virus infection reduces lung inflammation and fibrosis in mice exposed to vanadium pentoxide SO RESPIRATORY RESEARCH LA English DT Article ID ULTRAFINE CARBON-BLACK; FUEL-OIL ASH; PULMONARY FIBROGENESIS; MURINE MODEL; SUSCEPTIBILITY; EXPRESSION; FIBROBLASTS; MYOFIBROBLASTS; EXACERBATION; INDUCTION AB Background: Vanadium pentoxide (V(2)O(5)) exposure is a cause of occupational bronchitis and airway fibrosis. Respiratory syncytial virus (RSV) is a ubiquitous pathogen that causes airway inflammation. It is unknown whether individuals with pre-existing respiratory viral infection are susceptible to V(2)O(5)-induced bronchitis. We hypothesized that respiratory viral infection will exacerbate vanadium-induced lung fibrosis. Methods: In this study we investigated the effect of RSV pre- or post-exposure to V(2)O(5) in male AKR mice. Mice were pre- exposed by intranasal aspiration to RSV or media vehicle prior to intranasal aspiration of V(2)O(5) or saline vehicle at day 1 or day 7. A parallel group of mice were treated first with V(2)O(5) or saline vehicle at day 1 and day 7 then post-exposed to RSV or media vehicle at day 8. Results: V(2)O(5)-induced airway inflammation and fibrosis were decreased by RSV pre- or post-exposure. Real time quantitative RT-PCR showed that V(2)O(5) significantly increased lung mRNAs encoding pro-fibrogenic growth factors (TGF-beta 1, CTGF, PDGF-C) and collagen (Col1A2), but also increased mRNAs encoding anti-fibrogenic type I interferons (IFN-alpha, -beta) and IFN-inducible chemokines (CXCL9 and CXCL10). RSV pre- or post-exposure caused a significantly reduced mRNAs of pro-fibrogenic growth factors and collagen, yet reduced RNA levels of anti-fibrogenic interferons and CXC chemokines. Conclusions: Collectively these data suggest that RSV infection reduces the severity of V(2)O(5)-induced fibrosis by suppressing growth factors and collagen genes. However, RSV suppression of V(2)O(5)-induced IFNs and IFN-inducible chemokines suggests that viral infection also suppresses the innate immune response that normally serves to resolve V(2)O(5)-induced fibrosis. C1 [Turpin, Elizabeth A.; Antao-Menezes, Aurita; Cesta, Mark F.; Mangum, James B.; Wallace, Duncan G.; Bermudez, Edilberto; Bonner, James C.] Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. [Cesta, Mark F.] NIEHS, Lab Cellular & Mol Pathol, Res Triangle Pk, NC 27709 USA. [Cesta, Mark F.; Bonner, James C.] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Bonner, JC (reprint author), Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. EM james_bonner@ncsu.edu FU National Institutes of Health [R21-ES015801-01]; The Long-Range Research Initiative (LRRI) of the American Chemistry Council (ACC); The Hamner Institutes for Health Sciences; National Institutes of Health, National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Vickie Wong, David Weil, and Deloris Williams at The Hamner Institutes for Health Sciences for outstanding technical expertise. We thank Dr. Mel Andersen at The Hamner Institutes for helpful comments during the preparation of this manuscript. This work was funded by National Institutes of Health (NIH R21-ES015801-01), The Long-Range Research Initiative (LRRI) of the American Chemistry Council (ACC) provided to The Hamner Institutes for Health Sciences, and The Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 41 TC 1 Z9 1 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD FEB 22 PY 2010 VL 11 AR 20 DI 10.1186/1465-9921-11-20 PG 11 WC Respiratory System SC Respiratory System GA 571RD UT WOS:000275771400001 PM 20175905 ER PT J AU Wagner, TH Murray, C Goldberg, J Adler, JM Abrams, J AF Wagner, Todd H. Murray, Christine Goldberg, Jacquelyn Adler, Jeanne M. Abrams, Jeffrey TI Central Institutional Review Board-Facilitated Review Metrics Omit Critical Components Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Wagner, Todd H.] Stanford Univ, Sch Med, Vet Affairs Palo Alto Hlth Care Syst, Menlo Pk, CA USA. [Wagner, Todd H.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Menlo Pk, CA USA. [Goldberg, Jacquelyn] NCI, Cent Inst Review Board Initiat, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Adler, Jeanne M.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Wagner, TH (reprint author), Stanford Univ, Sch Med, Vet Affairs Palo Alto Hlth Care Syst, Menlo Pk, CA USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2010 VL 28 IS 6 BP E106 EP E106 DI 10.1200/JCO.2009.26.8672 PG 1 WC Oncology SC Oncology GA 557EU UT WOS:000274653200037 ER PT J AU Finniss, DG Kaptchuk, TJ Miller, F Benedetti, F AF Finniss, Damien G. Kaptchuk, Ted J. Miller, Franklin Benedetti, Fabrizio TI Biological, clinical, and ethical advances of placebo effects SO LANCET LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; IRRITABLE-BOWEL-SYNDROME; LOW-BACK-PAIN; CHOLECYSTOKININ ANTAGONIST PROGLUMIDE; PARKINSONS-DISEASE; ALTERNATIVE MEDICINE; SUBTHALAMIC NUCLEUS; ENDOGENOUS OPIOIDS; COMPARING PLACEBO; POWERFUL PLACEBO AB For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects. C1 [Finniss, Damien G.] Univ Sydney, Pain Management & Res Inst, Royal N Shore Hosp, St Leonards, NSW 2065, Australia. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA USA. [Miller, Franklin] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Benedetti, Fabrizio] Univ Turin, Sch Med, Dept Neurosci, Turin, Italy. [Benedetti, Fabrizio] Natl Inst Neurosci, Turin, Italy. RP Finniss, DG (reprint author), Univ Sydney, Pain Management & Res Inst, Royal N Shore Hosp, Pacific Hwy, St Leonards, NSW 2065, Australia. EM dfinniss@med.usyd.edu.au FU National Center for Complementary Medicine [K24 AT004095]; National Institutes of Health; Bernard Osher Foundation, San Francisco, CA, USA; Istituto San Paolo; Regione Piemonte (Turin, Italy); Volkswagen Foundation (Hannover, Germany) FX TJK is supported by a grant from National Center for Complementary Medicine (number K24 AT004095), National Institutes of Health and receives support from Bernard Osher Foundation, San Francisco, CA, USA. FB is supported by grants from Istituto San Paolo and Regione Piemonte (Turin, Italy) and Volkswagen Foundation (Hannover, Germany). NR 107 TC 383 Z9 390 U1 19 U2 113 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 20 PY 2010 VL 375 IS 9715 BP 686 EP 695 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 564JT UT WOS:000275210900037 PM 20171404 ER PT J AU Schaap-Nutt, A D'Angelo, C Scull, MA Amaro-Carambot, E Nishio, M Pickles, RJ Collins, PL Murphy, BR Schmidt, AC AF Schaap-Nutt, Anne D'Angelo, Christopher Scull, Margaret A. Amaro-Carambot, Emerito Nishio, Machiko Pickles, Raymond J. Collins, Peter L. Murphy, Brian R. Schmidt, Alexander C. TI Human parainfluenza virus type 2 V protein inhibits interferon production and signaling and is required for replication in non-human primates SO VIROLOGY LA English DT Article DE Parainfluenza virus; V protein; Interferon; Human airway epithelial cultures; Non-human primates ID RESPIRATORY SYNCYTIAL VIRUS; CYSTEINE-RICH DOMAIN; HEMAGGLUTININ-NEURAMINIDASE PROTEIN; UBIQUITIN LIGASE COMPLEXES; ANTIVIRAL INNATE IMMUNITY; HUMAN AIRWAY EPITHELIUM; INDUCIBLE RNA HELICASE; PARAMYXOVIRUS SV5 V; INFLUENZA-A-VIRUS; RIG-I AB In wild-type human parainfluenza virus type 2 (WT HPIV2), one gene (the P/V gene) encodes both the polymerase-associated phosphoprotein (P) and the accessory V protein. We generated a HPIV2 virus (rHPIV2-V(ko)) in which the P/V gene encodes only the P protein to examine the role of V in replication in vivo and as a potential live attenuated virus vaccine. Preventing expression of V protein severely impaired virus recovery from cDNA and growth in vitro, particularly in IFN-competent cells. rHPIV2-V(ko) unlike WT HPIV2, strongly induced IFN-beta and permitted IFN signaling, leading to establishment of a robust antiviral state. rHPIV2-V(ko) infection induced extensive syncytia and cytopathicity that was due to both apoptosis and necrosis. Replication of rHPIV2-V(ko) was highly restricted in the respiratory tract of African green monkeys and in differentiated primary human airway epithelial (HAE) cultures, suggesting that V protein is essential for efficient replication of HPIV2 in organized epithelial cells and that rHPIV2-V(ko) is over-attenuated for use as a live attenuated vaccine. Published by Elsevier Inc. C1 [Schaap-Nutt, Anne; D'Angelo, Christopher; Amaro-Carambot, Emerito; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Scull, Margaret A.; Pickles, Raymond J.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Scull, Margaret A.; Pickles, Raymond J.] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA. [Nishio, Machiko] Mie Univ, Grad Sch Med, Dept Microbiol, Tsu, Mie 5148507, Japan. RP Schaap-Nutt, A (reprint author), NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,Dept Hlth & Human Serv, 50 South Drive,Bldg 50,Room 6515,MSC 8007, Bethesda, MD 20892 USA. EM schaapa@niaid.nih.gov FU Intramural Research Program of the NIH [R01 HL77844]; National Institute of Allergy and Infectious Disease,; NIH Molecular Biology of Viral Diseases [5-T32-AI007419]; NIAID; MedImmune, Inc [CRADA Al-5114] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease, NIH grant R01 HL77844 (RJP), and the NIH Molecular Biology of Viral Diseases Training Grant 5-T32-AI007419. This project was partly performed under a cooperative research and development agreement (CRADA) between NIAID and MedImmune, Inc. (CRADA #Al-5114) for the development of live attenuated virus vaccines for respiratory syncytial viruses, parainfluenza viruses, and human metapneumovirus. NR 91 TC 9 Z9 9 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2010 VL 397 IS 2 BP 285 EP 298 DI 10.1016/j.virol.2009.11.018 PG 14 WC Virology SC Virology GA 558RV UT WOS:000274764100007 PM 19969320 ER PT J AU Brzeska, H Guag, J Remmert, K Chacko, S Korn, ED AF Brzeska, Hanna Guag, Jake Remmert, Kirsten Chacko, Susan Korn, Edward D. TI An Experimentally Based Computer Search Identifies Unstructured Membrane-binding Sites in Proteins APPLICATION TO CLASS I MYOSINS, PAKS, AND CARMIL SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAVY-CHAIN KINASE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; PLASMA-MEMBRANE; ACANTHAMOEBA-CASTELLANII; CAPPING PROTEIN; EFFECTOR DOMAIN; LIPID-BINDING; LOCALIZATION; ACTIN; SEQUENCE AB Programs exist for searching protein sequences for potential membrane-penetrating segments (hydrophobic regions) and for lipid-binding sites with highly defined tertiary structures, such as PH, FERM, C2, ENTH, and other domains. However, a rapidly growing number of membrane-associated proteins (including cytoskeletal proteins, kinases, GTP-binding proteins, and their effectors) bind lipids through less structured regions. Here, we describe the development and testing of a simple computer search program that identifies unstructured potential membrane-binding sites. Initially, we found that both basic and hydrophobic amino acids, irrespective of sequence, contribute to the binding to acidic phospholipid vesicles of synthetic peptides that correspond to the putative membrane-binding domains of Acanthamoeba class I myosins. Based on these results, we modified a hydrophobicity scale giving Arg- and Lys-positive, rather than negative, values. Using this basic and hydrophobic scale with a standard search algorithm, we successfully identified previously determined unstructured membrane-binding sites in all 16 proteins tested. Importantly, basic and hydrophobic searches identified previously unknown potential membrane-binding sites in class I myosins, PAKs and CARMIL (capping protein, Arp2/3, myosin I linker; a membrane-associated cytoskeletal scaffold protein), and synthetic peptides and protein domains containing these newly identified sites bound to acidic phospholipids in vitro. C1 [Brzeska, Hanna; Guag, Jake; Remmert, Kirsten; Korn, Edward D.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Chacko, Susan] NIH, Sci Comp Branch, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Brzeska, H (reprint author), NHLBI, Cell Biol Lab, NIH, 9000 Rockville Pike,Bldg 50,Rm 2515, Bethesda, MD 20892 USA. EM brzeskah@mail.nih.gov RI Korn, Edward/F-9929-2012 NR 56 TC 23 Z9 23 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 FEB 19 PY 2010 VL 285 IS 8 BP 5738 EP 5747 DI 10.1074/jbc.M109.066910 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 565WQ UT WOS:000275327200066 PM 20018884 ER PT J AU Yang, Y Gu, DY Liu, YQ Aisa, HA Ito, Y AF Yang, Yi Gu, Dongyu Liu, Yongqiang Aisa, Haji Akber Ito, Yoichiro TI Compact type-I coil planet centrifuge for counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Compact type-I coil planet centrifuge; Counter-current chromatography; DNP-amino acids; Revolution radius; Retention of the stationary phase; Resolution; Retention time AB A compact type-I coil planet centrifuge has been developed for performing counter-current chromatography It has a revolution radius of 10 cm and a column holder height of 5 cm compared with 37 and 50 cm in the of original prototype. respectively The reduction in the revolution radius and column length permits application of higher revolution speed and more stable balancing of the rotor which leads Lis to learn more about its performance and the future potential of type-I coil planet centrifuge The chromatographic performance of this appal ants was evaluated in terms of retention of the stationary phase (S(r)). peak resolution (R,), theoretical plate(N)and peak retention time (t(R)) The results of the expel invent indicated that increasing the revolution speed slightly improved both the retention of the stationary phase and the peak resolution while the separation time is remarkably shortened to yield an excellent peak resolution at a revolution speed of 800 rpm With a 12 nil capacity coiled column. DNP-DL.glu. DNP-beta-ala and DNP-L-ala were resolved at R, of 2 75 and 2 16 within 90 min at a flow rate of 0 4 ml/min We believe that the compact type-I coil planet centrifuge has a high analytical potential Published by Elsevier 13 V C1 [Yang, Yi; Gu, Dongyu; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Yang, Yi; Gu, Dongyu; Liu, Yongqiang; Aisa, Haji Akber] Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Xinjiang Key Lab Plant Resources & Nat Prod Chem, Urumqi 830011, Peoples R China. [Yang, Yi; Gu, Dongyu; Liu, Yongqiang] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. OI Liu, Yongqiang/0000-0002-2144-4474 FU Intramural NIH HHS [ZIA HL006022-01] NR 9 TC 7 Z9 7 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 19 PY 2010 VL 1217 IS 8 BP 1313 EP 1319 DI 10.1016/j.chroma.2009.12.055 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 561CP UT WOS:000274953400017 PM 20060979 ER PT J AU Luco, RF Pan, Q Tominaga, K Blencowe, BJ Pereira-Smith, OM Misteli, T AF Luco, Reini F. Pan, Qun Tominaga, Kaoru Blencowe, Benjamin J. Pereira-Smith, Olivia M. Misteli, Tom TI Regulation of Alternative Splicing by Histone Modifications SO SCIENCE LA English DT Article ID BINDING; EXON; TRANSCRIPTION; RECOGNITION; ELONGATION; CODE; IIIB; PTB; H3 AB Alternative splicing of pre-mRNA is a prominent mechanism to generate protein diversity, yet its regulation is poorly understood. We demonstrated a direct role for histone modifications in alternative splicing. We found distinctive histone modification signatures that correlate with the splicing outcome in a set of human genes, and modulation of histone modifications causes splice site switching. Histone marks affect splicing outcome by influencing the recruitment of splicing regulators via a chromatin-binding protein. These results outline an adaptor system for the reading of histone marks by the pre-mRNA splicing machinery. C1 [Luco, Reini F.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Pan, Qun; Blencowe, Benjamin J.] Univ Toronto, Banting & Best Dept Med Res, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Tominaga, Kaoru; Pereira-Smith, Olivia M.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Dept Cellular & Struct Biol, San Antonio, TX 78245 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Cancer Institute of Canada; Canadian Institutes of Health Research [MOP-67011]; Genome Canada; NIA/NIH [RO1 AGO32134]; American Heart Association [0765084Y] FX We thank J. Patton, D. Skalnik, B. Strahl, J. Steitz, D. Black, M. Garcia-Blanco, and H. Kimura for reagents; P. Scaffidi for discussions; J. Calarco for validations; C. Misquitta for technical assistance; H. Kosucu and Q. Morris for advice on statistical analysis; and E. Tominaga for cell culture. This research was supported by the Intramural Research Program of NIH, the National Cancer Institute, the Center for Cancer Research (T. M.), grants from the National Cancer Institute of Canada, Canadian Institutes of Health Research (grant MOP-67011) and Genome Canada (administered through the Ontario Genomics Institute) to B. B., NIA/NIH grant RO1 AGO32134 (OMPS) to O.P.S., and American Heart Association grant 0765084Y to K. T. Complete RNA deep-sequencing data are available at the Gene Expression Omnibus (accession no. GSE19373). NR 28 TC 441 Z9 456 U1 9 U2 84 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 FEB 19 PY 2010 VL 327 IS 5968 BP 996 EP 1000 DI 10.1126/science.1184208 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556XE UT WOS:000274625800040 PM 20133523 ER PT J AU Calado, RT AF Calado, Rodrigo T. TI Targeting telomerase: T-cell friendly fire SO BLOOD LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Calado, RT (reprint author), NIH, Bethesda, MD 20892 USA. RI Calado, Rodrigo/G-2619-2011 NR 2 TC 0 Z9 0 U1 0 U2 0 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 FEB 18 PY 2010 VL 115 IS 7 BP 1316 EP 1316 PG 1 WC Hematology SC Hematology GA 557KY UT WOS:000274669200002 PM 20167708 ER PT J AU Kang, HN Chen, IM Wilson, CS Bedrick, EJ Harvey, RC Atlas, SR Devidas, M Mullighan, CG Wang, XF Murphy, M Ar, K Wharton, W Borowitz, MJ Bowman, WP Bhojwani, D Carroll, WL Camitta, BM Reaman, GH Smith, MA Downing, JR Hunger, SP Willman, CL AF Kang, Huining Chen, I. -Ming Wilson, Carla S. Bedrick, Edward J. Harvey, Richard C. Atlas, Susan R. Devidas, Meenakshi Mullighan, Charles G. Wang, Xuefei Murphy, Maurice Ar, Kerem Wharton, Walker Borowitz, Michael J. Bowman, W. Paul Bhojwani, Deepa Carroll, William L. Camitta, Bruce M. Reaman, Gregory H. Smith, Malcolm A. Downing, James R. Hunger, Stephen P. Willman, Cheryl L. TI Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia SO BLOOD LA English DT Article ID MOLECULAR PROGNOSTIC MARKERS; ACUTE MYELOID-LEUKEMIA; TISSUE GROWTH-FACTOR; BREAST-CANCER CELLS; REGULATORY T-CELLS; ONCOLOGY-GROUP; HUMAN HOMOLOG; STEM-CELLS; PROLIFERATION; THERAPY AB To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate( 62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retained independent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603. (Blood. 2010; 115: 1394-1405) C1 [Kang, Huining; Chen, I. -Ming; Wilson, Carla S.; Bedrick, Edward J.; Harvey, Richard C.; Atlas, Susan R.; Wang, Xuefei; Murphy, Maurice; Ar, Kerem; Wharton, Walker; Willman, Cheryl L.] Univ New Mexico, Univ New Mexico Canc Ctr, Albuquerque, NM 87131 USA. [Kang, Huining; Chen, I. -Ming; Wilson, Carla S.; Bedrick, Edward J.; Harvey, Richard C.; Atlas, Susan R.; Murphy, Maurice; Ar, Kerem; Wharton, Walker; Willman, Cheryl L.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Kang, Huining; Chen, I. -Ming; Wilson, Carla S.; Bedrick, Edward J.; Harvey, Richard C.; Atlas, Susan R.; Murphy, Maurice; Ar, Kerem; Wharton, Walker; Willman, Cheryl L.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Kang, Huining; Chen, I. -Ming; Wilson, Carla S.; Bedrick, Edward J.; Harvey, Richard C.; Atlas, Susan R.; Murphy, Maurice; Ar, Kerem; Wharton, Walker; Willman, Cheryl L.] Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. [Kang, Huining; Chen, I. -Ming; Wilson, Carla S.; Bedrick, Edward J.; Harvey, Richard C.; Atlas, Susan R.; Murphy, Maurice; Ar, Kerem; Wharton, Walker; Willman, Cheryl L.] Univ New Mexico, Dept Phys & Astron, Albuquerque, NM 87131 USA. [Chen, I. -Ming; Devidas, Meenakshi; Borowitz, Michael J.; Bowman, W. Paul; Carroll, William L.; Camitta, Bruce M.; Reaman, Gregory H.; Hunger, Stephen P.; Willman, Cheryl L.] Childrens Oncol Grp, Arcadia, CA USA. [Devidas, Meenakshi] Univ Florida, Childrens Oncol Grp, Stat & Data Ctr, Gainesville, FL USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Dept Epidemiol & Hlth Policy Res, Gainesville, FL USA. [Mullighan, Charles G.; Downing, James R.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Borowitz, Michael J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Bowman, W. Paul] Cook Childrens Med Ctr, Ft Worth, TX USA. [Bhojwani, Deepa; Carroll, William L.] NYU, Dept Pediat, Med Ctr, New York, NY 10003 USA. [Bhojwani, Deepa; Carroll, William L.] NYU, Dept Hematol, Med Ctr, New York, NY 10003 USA. [Bhojwani, Deepa; Carroll, William L.] NYU, Dept Oncol, Med Ctr, New York, NY 10003 USA. [Bhojwani, Deepa; Carroll, William L.] NYU, Ctr Canc, Med Ctr, New York, NY 10003 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Hematol, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Oncol, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Transplantat, Milwaukee, WI 53226 USA. [Reaman, Gregory H.] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [Smith, Malcolm A.] NCI, Clin Invest Branch, Bethesda, MD 20892 USA. [Hunger, Stephen P.] Univ Colorado, Denver Sch Med, Childrens Hosp, Dept Pediat, Aurora, CO USA. [Hunger, Stephen P.] Univ Colorado, Denver Sch Med, Univ Colorado Canc Ctr, Aurora, CO USA. RP Willman, CL (reprint author), Univ New Mexico, Canc Res Facil, 2325 Camino Salud NE,Room G03,MSC08 4630 1 Univ N, Albuquerque, NM 87131 USA. EM cwillman@salud.unm.edu OI Harvey, Richard/0000-0002-4904-9767; Bhojwani, Deepa/0000-0002-7559-7927; Mullighan, Charles/0000-0002-1871-1850 FU National Institutes of Health [NCI U01 CA114762, NCI U10 CA98543]; Leukemia & Lymphoma Society Specialized Center of Research Program [7388-06]; NCI [P30 CA118100] FX This work was supported by National Institutes of Health NCI U01 CA114762 Strategic Partnerships to Evaluate Cancer Gene Signatures Program (C. L. W.), NCI U10 CA98543 supporting the Children's Oncology Group and Statistics and Data Center (G. H. R.), and a subcontract to NCI U10 CA98543 in support of the National Cancer Institute TARGET Initiative. Additional funding was provided by a Leukemia & Lymphoma Society Specialized Center of Research Program Grant 7388-06 (C. L. W.). University of New Mexico Cancer Center Shared Resources: Keck-UNM Genomics Resource, Biostatistics, and Bioinformatics and Computational Biology, partially supported by NCI P30 CA118100 (C. L. W.), were also critical for this work. NR 47 TC 84 Z9 85 U1 0 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 FEB 18 PY 2010 VL 115 IS 7 BP 1394 EP 1405 DI 10.1182/blood-2009-05-218560 PG 12 WC Hematology SC Hematology GA 557KY UT WOS:000274669200012 PM 19880498 ER PT J AU Hyde, RK Kamikubo, Y Anderson, S Kirby, M Alemu, L Zhao, L Liu, PP AF Hyde, R. Katherine Kamikubo, Yasuhiko Anderson, Stacie Kirby, Martha Alemu, Lemlem Zhao, Ling Liu, P. Paul TI Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11 SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CORE-BINDING-FACTOR; HEMATOPOIETIC STEM-CELLS; MYOSIN HEAVY-CHAIN; ACUTE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; FETAL LIVER HEMATOPOIESIS; COLONY-STIMULATING FACTOR; CBF-BETA-SUBUNIT; GENE-EXPRESSION AB It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression-independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11(+) leukemia samples. Interestingly, Cbfb-MYH11(+) preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb(+). Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression-independent activities contribute to leukemogenesis by Cbfb-MYH11. (Blood. 2010; 115: 1433-1443) C1 [Hyde, R. Katherine; Kamikubo, Yasuhiko; Anderson, Stacie; Kirby, Martha; Alemu, Lemlem; Zhao, Ling; Liu, P. Paul] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), 49 Convent Dr,49-3A26, Bethesda, MD 20892 USA. EM pliu@nhgri.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of National Human Genome Research Institute, National Institutes of Health. NR 48 TC 9 Z9 9 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 FEB 18 PY 2010 VL 115 IS 7 BP 1433 EP 1443 DI 10.1182/blood-2009-06-227413 PG 11 WC Hematology SC Hematology GA 557KY UT WOS:000274669200016 PM 20007544 ER PT J AU Pierson, TC AF Pierson, Theodore C. TI Modeling Antibody-Enhanced Dengue Virus Infection and Disease in Mice: Protection or Pathogenesis? SO CELL HOST & MICROBE LA English DT Editorial Material AB While antibodies play an important protective role during dengue virus infection, they have also been linked to more severe clinical outcomes. In this issue of Cell Host & Microbe, Zellweger and colleagues (Zellweger et al., 2010) describe the development of a murine model of antibody-enhanced dengue virus infection that provides a formal link between immune enhancement and severe disease. C1 NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov NR 9 TC 7 Z9 8 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD FEB 18 PY 2010 VL 7 IS 2 BP 85 EP 86 DI 10.1016/j.chom.2010.02.004 PG 2 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 582JM UT WOS:000276593200002 PM 20159612 ER PT J AU Escudero, JM Haller, JL Clay, CM Escudero, KW AF Escudero, Jean M. Haller, Jodi L. Clay, Colin M. Escudero, Kenneth W. TI Microarray analysis of Foxl2 mediated gene regulation in the mouse ovary derived KK1 granulosa cell line: Over-expression of Foxl2 leads to activation of the gonadotropin releasing hormone receptor gene promoter SO JOURNAL OF OVARIAN RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR FOXL2; FOLLICULAR DEVELOPMENT; GNRH RECEPTOR; CORPUS-LUTEUM; MESSENGER-RNA; GROWTH-FACTOR; NITRIC-OXIDE; RAT OVARY; PROTEIN; DOMAIN AB Background: The Foxl2 transcription factor is required for ovarian function during follicular development. The mechanism of Foxl2 regulation of this process has not been elucidated. Our approach to begin to understand Foxl2 function is through the identification of Foxl2 regulated genes in the ovary. Methods: Transiently transfected KK1 mouse granulosa cells were used to identify genes that are potentially regulated by Foxl2. KK1 cells were transfected in three groups (mock, activated, and repressed) and twenty-four hours later RNA was isolated and submitted for Affymetrix microarray analysis. Genesifter software was used to carry out analysis of microarray data. One identified target, the gonadotropin releasing hormone receptor (GnRHR) gene, was chosen for further study and validation of Foxl2 responsiveness. Transient transfection analyses were carried out to study the effect of Foxl2 over-expression on GnRHR gene promoter-luciferase fusion activity. Data generated was analyzed with GraphPad Prism software. Results: Microarray analysis identified 996 genes of known function that are potentially regulated by Foxl2 in mouse KK1 granulosa cells. The steroidogenic acute regulatory protein (StAR) gene that has been identified as Foxl2 responsive by others was identified in this study also, thereby supporting the effectiveness of our strategy. The GnRHR gene was chosen for further study because it is known to be expressed in the ovary and the results of previous work has indicated that Foxl2 may regulate GnRHR gene expression. Cellular levels of Foxl2 were increased via transient co-transfection of KK1 cells using a Foxl2 expression vector and a GnRHR promoter-luciferase fusion reporter vector. The results of these analyses indicate that over-expression of Foxl2 resulted in a significant increase in GnRHR promoter activity. Therefore, these transfection data validate the microarray data which suggest that Foxl2 regulates GnRHR and demonstrate that Foxl2 acts as an activator of the GnRHR gene. Conclusions: Potential Foxl2 regulated ovarian genes have been identified through microarray analysis and comparison of these data to other microarray studies. The Foxl2 responsiveness of the GnRHR gene has been validated and provided evidence of Foxl2 transcriptional activation of the GnRHR gene promoter in the mouse ovary derived KK1 granulosa cell line. C1 [Escudero, Jean M.; Escudero, Kenneth W.] Texas A&M Univ, Dept Biol & Hlth Sci, Kingsville, TX USA. [Haller, Jodi L.] NIH, Bethesda, MD 20892 USA. [Clay, Colin M.] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA. RP Escudero, KW (reprint author), Texas A&M Univ, Dept Biol & Hlth Sci, Kingsville, TX USA. EM kfkwe00@tamuk.edu FU College of Veterinary Medicine Research Council at Colorado State University (CSU); CSU Affymetrix Core Facility; NIH; KWE and JME at TAMUK [5 P20MD000216]; NICHD, NIH FX We would like to thank the following for contributing to this study: the College of Veterinary Medicine Research Council at Colorado State University (CSU) for support of the microarray study; the CSU Affymetrix Core Facility; the NIH for awarding a Minority Investigator Supplement to KWE while training in Dr. Colin Clay's Laboratory at CSU and for awarding RIMI Grant 5 P20MD000216 that supported KWE and JME at TAMUK; the Ovarian Kaleidoscope Database which was supported by the Specialized Cooperative Centers Program in Reproduction and Infertility Research, NICHD, NIH. NR 59 TC 12 Z9 12 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-2215 J9 J OVARIAN RES JI J. Ovarian Res. PD FEB 18 PY 2010 VL 3 AR 4 DI 10.1186/1757-2215-3-4 PG 12 WC Reproductive Biology SC Reproductive Biology GA 826MZ UT WOS:000295359600001 PM 20167115 ER PT J AU Sasaki, K Kohanbash, G Hoji, A Ueda, R McDonald, HA Reinhart, TA Martinson, J Lotze, MT Marincola, FM Wang, E Fujita, M Okada, H AF Sasaki, Kotaro Kohanbash, Gary Hoji, Aki Ueda, Ryo McDonald, Heather A. Reinhart, Todd A. Martinson, Jeremy Lotze, Michael T. Marincola, Francesco M. Wang, Ena Fujita, Mitsugu Okada, Hideho TI miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; MICRORNA CLUSTER; GENE-EXPRESSION; ANTITUMOR IMMUNITY; TARGETED DELETION; ADOPTIVE TRANSFER; VLA-4 EXPRESSION; LATE ANTIGEN-4; LUNG CANCERS; TGF-BETA AB Background: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated. Methods: We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells. Results: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT) 6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4(+) T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-gamma production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). Conclusion: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy. C1 [Sasaki, Kotaro; Okada, Hideho] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15213 USA. [Sasaki, Kotaro] Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15213 USA. [Hoji, Aki; Ueda, Ryo; Fujita, Mitsugu; Okada, Hideho] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Lotze, Michael T.; Okada, Hideho] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Kohanbash, Gary; Hoji, Aki; Ueda, Ryo; McDonald, Heather A.; Fujita, Mitsugu; Okada, Hideho] Univ Pittsburgh, Inst Canc, Brain Tumor Program, Pittsburgh, PA 15213 USA. [Kohanbash, Gary; Reinhart, Todd A.; Martinson, Jeremy] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Marincola, Francesco M.; Wang, Ena] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Okada, H (reprint author), Univ Pittsburgh, Sch Med, Dept Immunol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM okadah@upmc.edu RI Fujita, Mitsugu/A-6690-2009; OI Fujita, Mitsugu/0000-0002-0000-9879; Martinson, Jeremy/0000-0003-4673-7238; Kohanbash, Gary/0000-0002-3953-8022 FU National Institutes of Health [1R01NS055140, 2P01 NS40923, 1P01CA132714, P01 CA 101944-01A2]; Musella Foundation FX This study was carried out with Grant Support from: the National Institutes of Health [1R01NS055140 to H.O., 2P01 NS40923 to H.O., 1P01CA132714 to HO and P01 CA 101944-01A2 to MTL] and Musella Foundation to HO. We thank Lisa Baily, Sebnem Unlu, Kayla McKaveney, Sandra Le Quellec, Stephanie Chen, and Munia Islam for their technical assistance. NR 66 TC 30 Z9 40 U1 0 U2 6 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 FEB 18 PY 2010 VL 8 AR 17 DI 10.1186/1479-5876-8-17 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 567MS UT WOS:000275451600001 PM 20167088 ER PT J AU Beroukhim, R Mermel, CH Porter, D Wei, G Raychaudhuri, S Donovan, J Barretina, J Boehm, JS Dobson, J Urashima, M Mc Henry, KT Pinchback, RM Ligon, AH Cho, YJ Haery, L Greulich, H Reich, M Winckler, W Lawrence, MS Weir, BA Tanaka, KE Chiang, DY Bass, AJ Loo, A Hoffman, C Prensner, J Liefeld, T Gao, Q Yecies, D Signoretti, S Maher, E Kaye, FJ Sasaki, H Tepper, JE Fletcher, JA Tabernero, J Baselga, J Tsao, MS Demichelis, F Rubin, MA Janne, PA Daly, MJ Nucera, C Levine, RL Ebert, BL Gabriel, S Rustgi, AK Antonescu, CR Ladanyi, M Letai, A Garraway, LA Loda, M Beer, DG True, LD Okamoto, A Pomeroy, SL Singer, S Golub, TR Lander, ES Getz, G Sellers, WR Meyerson, M AF Beroukhim, Rameen Mermel, Craig H. Porter, Dale Wei, Guo Raychaudhuri, Soumya Donovan, Jerry Barretina, Jordi Boehm, Jesse S. Dobson, Jennifer Urashima, Mitsuyoshi Mc Henry, Kevin T. Pinchback, Reid M. Ligon, Azra H. Cho, Yoon-Jae Haery, Leila Greulich, Heidi Reich, Michael Winckler, Wendy Lawrence, Michael S. Weir, Barbara A. Tanaka, Kumiko E. Chiang, Derek Y. Bass, Adam J. Loo, Alice Hoffman, Carter Prensner, John Liefeld, Ted Gao, Qing Yecies, Derek Signoretti, Sabina Maher, Elizabeth Kaye, Frederic J. Sasaki, Hidefumi Tepper, Joel E. Fletcher, Jonathan A. Tabernero, Josep Baselga, Jose Tsao, Ming-Sound Demichelis, Francesca Rubin, Mark A. Janne, Pasi A. Daly, Mark J. Nucera, Carmelo Levine, Ross L. Ebert, Benjamin L. Gabriel, Stacey Rustgi, Anil K. Antonescu, Cristina R. Ladanyi, Marc Letai, Anthony Garraway, Levi A. Loda, Massimo Beer, David G. True, Lawrence D. Okamoto, Aikou Pomeroy, Scott L. Singer, Samuel Golub, Todd R. Lander, Eric S. Getz, Gad Sellers, William R. Meyerson, Matthew TI The landscape of somatic copy-number alteration across human cancers SO NATURE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; EMBRYONIC STEM-CELLS; LUNG-CANCER; CHROMOSOMAL BREAKPOINT; MALIGNANT-MELANOMA; ADAPTER PROTEINS; ARRAY CGH; GENES; GENOME; AMPLIFICATION AB A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappa B pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. C1 [Beroukhim, Rameen; Mermel, Craig H.; Wei, Guo; Raychaudhuri, Soumya; Barretina, Jordi; Boehm, Jesse S.; Dobson, Jennifer; Pinchback, Reid M.; Haery, Leila; Greulich, Heidi; Reich, Michael; Winckler, Wendy; Lawrence, Michael S.; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Liefeld, Ted; Gao, Qing; Daly, Mark J.; Ebert, Benjamin L.; Gabriel, Stacey; Garraway, Levi A.; Golub, Todd R.; Lander, Eric S.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Canc Program, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Mermel, Craig H.; Wei, Guo; Raychaudhuri, Soumya; Barretina, Jordi; Boehm, Jesse S.; Dobson, Jennifer; Pinchback, Reid M.; Haery, Leila; Greulich, Heidi; Reich, Michael; Winckler, Wendy; Lawrence, Michael S.; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Liefeld, Ted; Gao, Qing; Daly, Mark J.; Ebert, Benjamin L.; Gabriel, Stacey; Garraway, Levi A.; Golub, Todd R.; Lander, Eric S.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Med & Populat Genet Grp, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Lander, Eric S.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Beroukhim, Rameen; Raychaudhuri, Soumya; Ligon, Azra H.; Greulich, Heidi; Bass, Adam J.; Signoretti, Sabina; Fletcher, Jonathan A.; Janne, Pasi A.; Ebert, Benjamin L.; Loda, Massimo] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Raychaudhuri, Soumya; Ligon, Azra H.; Greulich, Heidi; Bass, Adam J.; Signoretti, Sabina; Fletcher, Jonathan A.; Janne, Pasi A.; Ebert, Benjamin L.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Cho, Yoon-Jae; Pomeroy, Scott L.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Nucera, Carmelo] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Porter, Dale; Donovan, Jerry; Mc Henry, Kevin T.; Loo, Alice; Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Urashima, Mitsuyoshi] Jikei Univ, Sch Med, Div Mol Epidemiol, Minato Ku, Tokyo 1058461, Japan. [Maher, Elizabeth] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Kaye, Frederic J.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. [Kaye, Frederic J.] Natl Naval Med Ctr, Bethesda, MD 20889 USA. [Sasaki, Hidefumi] Nagoya City Univ, Sch Med, Dept Surg 2, Nagoya, Aichi 4678601, Japan. [Chiang, Derek Y.; Tepper, Joel E.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Genet & Radiat Oncol, Chapel Hill, NC 27599 USA. [Tabernero, Josep; Baselga, Jose] Vall Hebron Univ Hosp, Res Inst, Vall Hebron Inst Oncol, Med Oncol Program, Barcelona 08035, Spain. [Tabernero, Josep; Baselga, Jose] Autonomous Univ Barcelona, E-08035 Barcelona, Spain. [Tsao, Ming-Sound] Princess Margaret Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound] Princess Margaret Hosp, Univ Hlth Network, Div Appl Mol Oncol, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound] Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. [Demichelis, Francesca; Rubin, Mark A.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Richard B Simches Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA. [Levine, Ross L.; Antonescu, Cristina R.; Ladanyi, Marc; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Levine, Ross L.; Antonescu, Cristina R.; Ladanyi, Marc; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Rustgi, Anil K.] Univ Penn, Dept Med, GI Div, Philadelphia, PA 19104 USA. [Rustgi, Anil K.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Rustgi, Anil K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Beer, David G.] Univ Michigan, Dept Surg, Thorac Surg Sect, Ann Arbor, MI 48109 USA. [True, Lawrence D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Okamoto, Aikou] Jikei Univ, Sch Med, Dept Obstet & Gynecol, Minato Ku, Tokyo 1058461, Japan. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM lander@broadinstitute.org; gadgetz@broadinstitute.org; william.sellers@novartis.com; matthew_meyerson@dfci.harvard.edu RI kaye, frederic/E-2437-2011; Meyerson, Matthew/E-7123-2012; Chiang, Daisy/C-9481-2011; Levine, Rodney/D-9885-2011; OI Chiang, Daisy/0000-0002-8205-4285; Chiang, Derek/0000-0002-1131-6065; Boehm, Jesse/0000-0002-6795-6336; Yecies, Derek/0000-0001-8534-4651; Rubin, Mark/0000-0002-8321-9950; Demichelis, Francesca/0000-0002-8266-8631 FU National Institutes of Health (NIH) [P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101, K08CA122833]; Doris Duke Charitable Foundation; Sarah Thomas Monopoli Lung Cancer Research Fund; Seaman Corporation Fund for Lung Cancer Research; Lucas Foundation FX This work was supported by grants from the National Institutes of Health (NIH) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101 and K08CA122833), the Doris Duke Charitable Foundation, the Sarah Thomas Monopoli Lung Cancer Research Fund, the Seaman Corporation Fund for Lung Cancer Research, and the Lucas Foundation. Medulloblastoma samples were obtained in collaboration with the Children's Oncology Group. N. Vena provided technical assistance with FISH, and I. Mellinghoff, P. S. Mischel, L. Liau and T. F. Cloughesy provided DNA samples. We thank T. Ried, R. Weinberg and B. Vogelstein for critical review of the manuscript and for comments about its context in the field of cancer genetics. NR 49 TC 1241 Z9 1256 U1 12 U2 153 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 18 PY 2010 VL 463 IS 7283 BP 899 EP 905 DI 10.1038/nature08822 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556HZ UT WOS:000274582700036 PM 20164920 ER PT J AU Schuster, SC Miller, W Ratan, A Tomsho, LP Giardine, B Kasson, LR Harris, RS Petersen, DC Zhao, FQ Qi, J Alkan, C Kidd, JM Sun, YZ Drautz, DI Bouffard, P Muzny, DM Reid, JG Nazareth, LV Wang, QY Burhans, R Riemer, C Wittekindt, NE Moorjani, P Tindall, EA Danko, CG Teo, WS Buboltz, AM Zhang, ZH Ma, QY Oosthuysen, A Steenkamp, AW Oostuisen, H Venter, P Gajewski, J Zhang, Y Pugh, BF Makova, KD Nekrutenko, A Mardis, ER Patterson, N Pringle, TH Chiaromonte, F Mullikin, JC Eichler, EE Hardison, RC Gibbs, RA Harkins, TT Hayes, VM AF Schuster, Stephan C. Miller, Webb Ratan, Aakrosh Tomsho, Lynn P. Giardine, Belinda Kasson, Lindsay R. Harris, Robert S. Petersen, Desiree C. Zhao, Fangqing Qi, Ji Alkan, Can Kidd, Jeffrey M. Sun, Yazhou Drautz, Daniela I. Bouffard, Pascal Muzny, Donna M. Reid, Jeffrey G. Nazareth, Lynne V. Wang, Qingyu Burhans, Richard Riemer, Cathy Wittekindt, Nicola E. Moorjani, Priya Tindall, Elizabeth A. Danko, Charles G. Teo, Wee Siang Buboltz, Anne M. Zhang, Zhenhai Ma, Qianyi Oosthuysen, Arno Steenkamp, Abraham W. Oostuisen, Hermann Venter, Philippus Gajewski, John Zhang, Yu Pugh, B. Franklin Makova, Kateryna D. Nekrutenko, Anton Mardis, Elaine R. Patterson, Nick Pringle, Tom H. Chiaromonte, Francesca Mullikin, James C. Eichler, Evan E. Hardison, Ross C. Gibbs, Richard A. Harkins, Timothy T. Hayes, Vanessa M. TI Complete Khoisan and Bantu genomes from southern Africa SO NATURE LA English DT Article ID COPY NUMBER VARIATION; SEQUENCE; INVERSION; POLYMORPHISMS; LINEAGES; MTDNA; GENE; DNA AB The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial(1) and small sets of nuclear markers(2) have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans(1,3). However, until now, fully sequenced human genomes have been limited to recently diverged populations(4-8). Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data. C1 [Schuster, Stephan C.; Miller, Webb; Ratan, Aakrosh; Tomsho, Lynn P.; Giardine, Belinda; Kasson, Lindsay R.; Harris, Robert S.; Zhao, Fangqing; Qi, Ji; Sun, Yazhou; Drautz, Daniela I.; Wang, Qingyu; Burhans, Richard; Riemer, Cathy; Wittekindt, Nicola E.; Buboltz, Anne M.; Zhang, Zhenhai; Ma, Qianyi; Gajewski, John; Zhang, Yu; Pugh, B. Franklin; Makova, Kateryna D.; Nekrutenko, Anton; Chiaromonte, Francesca; Hardison, Ross C.] Penn State Univ, Ctr Comparat Genom & Bioinformat, Wartik Lab 310, University Pk, PA 16802 USA. [Petersen, Desiree C.; Tindall, Elizabeth A.; Teo, Wee Siang; Hayes, Vanessa M.] Univ New S Wales, Lowy Canc Res Ctr C25, Childrens Canc Inst Australia Med Res, Canc Genet Grp, Randwick, NSW 2031, Australia. [Alkan, Can; Kidd, Jeffrey M.; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Alkan, Can; Kidd, Jeffrey M.; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Bouffard, Pascal; Harkins, Timothy T.] Roche Diagnostics Corp, Indianapolis, IN 46250 USA. [Muzny, Donna M.; Reid, Jeffrey G.; Nazareth, Lynne V.; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Moorjani, Priya] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Danko, Charles G.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [Venter, Philippus] Univ Limpopo, ZA-0727 Sovenga, South Africa. [Mardis, Elaine R.] Washington Univ, Sch Med, Genome Ctr, St Louis, MO 63108 USA. [Patterson, Nick] MIT, Broad Inst, Cambridge, MA 02142 USA. [Patterson, Nick] Harvard Univ, Cambridge Ctr, Cambridge, MA 02142 USA. [Pringle, Tom H.] Sperling Fdn, Eugene, OR 97405 USA. [Mullikin, James C.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Schuster, SC (reprint author), Penn State Univ, Ctr Comparat Genom & Bioinformat, Wartik Lab 310, University Pk, PA 16802 USA. EM scs@bx.psu.edu; vhayes@ccia.unsw.edu.au RI Alkan, Can/D-2982-2009; Hardison, Ross/G-1142-2010; Giardine, Belinda/A-1599-2010; Danko, Charles/A-2869-2011; Sincan, Murat /A-3794-2010; Wittekindt, Nicola/G-3469-2013; QI, JI/E-2797-2016; OI Alkan, Can/0000-0002-5443-0706; Hardison, Ross/0000-0003-4084-7516; Wittekindt, Nicola/0000-0002-3310-0919; Kidd, Jeffrey/0000-0002-9631-1465; Nekrutenko, Anton/0000-0002-5987-8032 FU Pennsylvania State University; National Human Genome Research Institute, National Institutes of Health; NSF [DEB-0733029]; NIH [R01GM087472]; Gordon and Betty Moore Foundation FX We particularly want to thank Archbishop Desmond Tutu, !Gubi, G/aq'o, D#kgao and !Ai, as well as their respective families and communities for their willingness to participate in this study. This work is supported by the Pennsylvania State University. The genome sequencing of the four Namibian individuals was supported by Roche Applied Sciences and the exome sequencing capture by Nimblegen (to S. C. S.). Sequencing of Archbishop Tutu's genome was supported by Applied Biosystems (whole genome) (to R. A. G.) and Roche Applied Sciences (exome) (to S. C. S.). Whole-genome genotyping and NRY haplotyping was supported by the Cancer Institute of New South Wales (to V. M. H.). Travel was supported by Penn State University (to S. C. S.) and Hyperion Asset Management Australia (to V. M. H.). We thank K. Walters for assistance in researching geographic facts and help with Fig. 1, B. Schultz for his help with Supplementary Table 5 and R.-A. Hardie for her help with Supplementary Fig. 8b. T. Loughran assisted with medical sample collection. We thank the 1000 Genome Project for early access and use of their data. This work was also supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (J.C.M.). A. R. was supported by an NSF grant DEB-0733029 and K. D. M. was supported by a grant R01GM087472 from NIH. S. C. S. is supported by the Gordon and Betty Moore Foundation. V. M. H. is a Cancer Institute of New South Wales Fellow. NR 30 TC 204 Z9 212 U1 3 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 18 PY 2010 VL 463 IS 7283 BP 943 EP 947 DI 10.1038/nature08795 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556HZ UT WOS:000274582700045 PM 20164927 ER PT J AU Carlo, WA Goudar, SS Jehan, I Chomba, E Tshefu, A Garces, A Parida, S Althabe, F McClure, EM Derman, RJ Goldenberg, RL Bose, C Krebs, NF Panigrahi, P Buekens, P Chakraborty, H Hartwell, TD Wright, LL AF Carlo, Waldemar A. Goudar, Shivaprasad S. Jehan, Imtiaz Chomba, Elwyn Tshefu, Antoinette Garces, Ana Parida, Sailajanandan Althabe, Fernando McClure, Elizabeth M. Derman, Richard J. Goldenberg, Robert L. Bose, Carl Krebs, Nancy F. Panigrahi, Pinaki Buekens, Pierre Chakraborty, Hrishikesh Hartwell, Tyler D. Wright, Linda L. CA First Breath Study Grp TI Newborn-Care Training and Perinatal Mortality in Developing Countries SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEONATAL DEATHS; SRI-LANKA; RESUSCITATION; IMPACT; INTERVENTIONS; STILLBIRTHS; HEALTH; BIRTH; HOSPITALS AB BACKGROUND Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year, 98% occur in developing countries. An evaluation of community-based interventions designed to reduce the number of these deaths is needed. METHODS With the use of a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (which focuses on routine neonatal care, resuscitation, thermoregulation, breast-feeding, "kangaroo" [skin-to-skin] care, care of the small baby, and common illnesses) and ( except in Argentina) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (which teaches basic resuscitation in depth). The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before-and-after design. The Neonatal Resuscitation Program intervention was assessed as a cluster-randomized, controlled trial involving 62,366 infants. The primary outcome was neonatal death in the first 7 days after birth. RESULTS The 7-day follow-up rate was 99.2%. After birth attendants were trained in the Essential Newborn Care course, there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth ( relative risk with training, 0.99; 95% confidence interval [CI], 0.81 to 1.22) or in the rate of perinatal death; there was a significant reduction in the rate of stillbirth ( relative risk with training, 0.69; 95% CI, 0.54 to 0.88; P = 0.003). In clusters of births in which attendants had been randomly assigned to receive training in the Neonatal Resuscitation Program, as compared with control clusters, there was no reduction in the rates of neonatal death in the 7 days after birth, stillbirth, or perinatal death. CONCLUSIONS The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. C1 [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL 35233 USA. [Carlo, Waldemar A.; Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Goudar, Shivaprasad S.] Jawaharlal Nehru Med Coll, Belgaum, India. [Parida, Sailajanandan] Sriramchandra Bhanja Med Coll, Cuttack, Orissa, India. [Jehan, Imtiaz] Aga Khan Univ, Karachi, Pakistan. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Garces, Ana] San Carlos Univ, Guatemala City, Guatemala. [Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [McClure, Elizabeth M.; Chakraborty, Hrishikesh; Hartwell, Tyler D.] RTI Int, Durham, NC USA. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Derman, Richard J.] Univ Missouri Kansas City, Sch Med, Kansas City, MO USA. [Goldenberg, Robert L.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Krebs, Nancy F.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Panigrahi, Pinaki] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Carlo, WA (reprint author), Univ Alabama, 525 New Hillman Bldg,619 S 20th St, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan, Jose/0000-0002-8412-3010 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research [U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636, U01 HD040574]; Bill and Melinda Gates Foundation FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (U01 HD040477, U01 HD043475, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD040636, and U01 HD040574) and by the Bill and Melinda Gates Foundation. NR 35 TC 139 Z9 144 U1 3 U2 16 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 FEB 18 PY 2010 VL 362 IS 7 BP 614 EP 623 DI 10.1056/NEJMsa0806033 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 556ED UT WOS:000274571200009 PM 20164485 ER PT J AU Dumortier, A Durham, AD Di Piazza, M Vauclair, S Koch, U Ferrand, G Ferrero, I Demehri, S Song, LL Farr, AG Leonard, WJ Kopan, R Miele, L Hohl, D Finke, D Radtke, F AF Dumortier, Alexis Durham, Andre-Dante Di Piazza, Matteo Vauclair, Sophie Koch, Ute Ferrand, Gisele Ferrero, Isabel Demehri, Shadmehr Song, Lynda Li Farr, Andrew G. Leonard, Warren J. Kopan, Raphael Miele, Lucio Hohl, Daniel Finke, Daniela Radtke, Freddy TI Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin SO PLOS ONE LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; B-CELL DEVELOPMENT; HUMAN EPITHELIAL-CELLS; T-CELL; STEM-CELLS; IN-VITRO; MOUSE KERATINOCYTES; GROWTH-FACTOR; MICE; EXPRESSION AB Background: The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth. Methodology and Principal Findings: To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia. Significance: Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system. C1 [Dumortier, Alexis; Durham, Andre-Dante; Di Piazza, Matteo; Vauclair, Sophie; Koch, Ute; Ferrand, Gisele; Radtke, Freddy] Ecole Polytech Fed Lausanne, SV, ISREC, CH-1015 Lausanne, Switzerland. [Ferrero, Isabel] Univ Lausanne, Ludwig Inst Canc Res, Lausanne Branch, CH-1066 Epalinges, Switzerland. [Demehri, Shadmehr; Kopan, Raphael] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA. [Demehri, Shadmehr; Kopan, Raphael] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Song, Lynda Li; Miele, Lucio] Loyola Univ, Breast Canc Program, Cardinal Bernardin Canc Ctr, Chicago, IL 60611 USA. [Farr, Andrew G.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Farr, Andrew G.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Hohl, Daniel] CHU Vaudois, Dept Dermatol, Lausanne, Switzerland. [Finke, Daniela] Univ Basel, Ctr Biomed, Dept Clin & Biol Sci DKBW, Basel, Switzerland. RP Dumortier, A (reprint author), Ecole Polytech Fed Lausanne, SV, ISREC, CH-1015 Lausanne, Switzerland. EM Freddy.Radtke@epfl.ch FU Swiss Cancer League [OCS-01560-08-2004]; Swiss National Science Foundation [FNS: 3236B0-111292 (ADD), PPOOA-68855 (DF)]; Eurosystems, Optistem; Division of Intramural Research, National Heart, Lung and Blood Institute, NIH (WJL) FX This work was in part supported by the Swiss Cancer League (OCS-01560-08-2004) and the Swiss National Science Foundation (FNS: 3236B0-111292 (ADD), and PPOOA-68855 (DF)), Eurosystems, Optistem, and the Division of Intramural Research, National Heart, Lung and Blood Institute, NIH (WJL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 90 Z9 90 U1 0 U2 8 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 FEB 18 PY 2010 VL 5 IS 2 AR e9258 DI 10.1371/journal.pone.0009258 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 557FJ UT WOS:000274654700010 PM 20174635 ER PT J AU Schrack, JA Simonsick, EM Ferrucci, L AF Schrack, Jennifer A. Simonsick, Eleanor M. Ferrucci, Luigi TI Comparison of the Cosmed K4b(2) Portable Metabolic System in Measuring Steady-State Walking Energy Expenditure SO PLOS ONE LA English DT Article ID HEALTHY OLDER-ADULTS; GAS-ANALYSIS SYSTEM; INDIRECT CALORIMETRY; OVERGROUND WALKING; ACCURACY; AGREEMENT; TREADMILL; EXERCISE AB Background and Aims: Recent introduction of the Cosmed K4b(2) portable metabolic analyzer allows measurement of oxygen consumption outside of a laboratory setting in more typical clinical or household environments and thus may be used to obtain information on the metabolic costs of specific daily life activities. The purpose of this study was to assess the accuracy of the Cosmed K4b(2) portable metabolic analyzer against a traditional, stationary gas exchange system (the Medgraphics D-Series) during steady-state, submaximal walking exercise. Methods: Nineteen men and women (9 women, 10 men) with an average age of 39.8 years (+/- 13.8) completed two 400 meter walk tests using the two systems at a constant, self-selected pace on a treadmill. Average oxygen consumption (VO2) and carbon dioxide production (VCO2) from each walk were compared. Results: Intraclass Correlation Coefficient (ICC) and Pearson correlation coefficients between the two systems for weight indexed VO2 (ml/kg/min), total VO2 (ml/min), and VCO2 (ml/min) ranged from 0.93 to 0.97. Comparison of the average values obtained using the Cosmed K4b(2) and Medgraphics systems using paired t-tests indicate no significant difference for VO2 (ml/kg/min) overall (p = 0.25), or when stratified by sex (p = 0.21 women, p = 0.69 men). The mean difference between analyzers was - 0.296 ml/kg/min (+/- 0.26). Results were not significantly different for VO2 (ml/min) or VCO2 (ml/min) within the study population (p = 0.16 and p = 0.08, respectively), or when stratified by sex (VO2: p = 0.51 women, p = 0.16 men; VCO2: p =.11 women, p = 0.53 men). Conclusion: The Cosmed K4b(2) portable metabolic analyzer provides measures of VO2 and VCO2 during steady-state, submaximal exercise similar to a traditional, stationary gas exchange system. C1 [Schrack, Jennifer A.; Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Aging & Hlth, Baltimore, MD USA. RP Schrack, JA (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. EM schrackja@mail.nih.gov FU National Institutes of Health (NIH); National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging. The funder(s) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 23 Z9 24 U1 0 U2 5 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 FEB 18 PY 2010 VL 5 IS 2 AR e9292 DI 10.1371/journal.pone.0009292 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 557FJ UT WOS:000274654700020 PM 20174583 ER PT J AU Chung, HS Louis, JM Eaton, WA AF Chung, Hoi Sung Louis, John M. Eaton, William A. TI Distinguishing between Protein Dynamics and Dye Photophysics in Single-Molecule FRET Experiments SO BIOPHYSICAL JOURNAL LA English DT Article ID RESONANCE ENERGY-TRANSFER; CORRELATION SPECTROSCOPY; CONFORMATIONAL DYNAMICS; ELECTRON-TRANSFER; DIFFUSION; DISTRIBUTIONS AB Forster resonance energy transfer (FRET) efficiency distributions in single-molecule experiments contain both structural and dynamical information Extraction of this information from these distributions requires a careful analysis of contributions from dye photophysics. To investigate how mechanisms other than FRET affect the distributions obtained by counting donor and acceptor photons, we have measured single-molecule fluorescence trajectories of a small alpha/beta protein, i.e, protein GB1, undergoing two-state, folding/unfolding transitions. Alexa 488 donor and Alexa 594 acceptor dyes were attached to cysteines at positions 10 and 57 to yield two isomers-donor(10)/acceptor(57) and donor(57)/acceptor(10)-which could not be separated in the purification The protein was immobilized via binding of a histidine tag added to a linker sequence at the N-terminus to cupric ions embedded in a polyethylene-glycol-coated glass surface. The distribution of FRET efficiencies assembled from the trajectories is complex with widths for the individual peaks in large excess of that caused by shot noise Most of this complexity can be explained by two interfering photophysical effects-a photoinduced red shift of the donor dye and differences in the quantum yield of the acceptor dye for the two isomers resulting from differences in quenching rate by the cupric ion. Measurements of steady-state polarization, calculation of the donor-acceptor cross-correlation function from photon trajectories, and comparison of the single molecule and ensemble kinetics all indicate that conformational distributions and dynamics do not contribute to the complexity. C1 [Chung, Hoi Sung; Louis, John M.; Eaton, William A.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Chung, HS (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Chung, Hoi Sung/C-2624-2009 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Attila Szabo, Irina Gopich, and Kevin McHale for helpful discussions and Annie Aniana for technical assitance; This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health NR 30 TC 35 Z9 35 U1 2 U2 22 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 FEB 17 PY 2010 VL 98 IS 4 BP 696 EP 706 DI 10.1016/j.bpj.2009.12.4322 PG 11 WC Biophysics SC Biophysics GA 566CR UT WOS:000275348200022 PM 20159166 ER PT J AU Speare, JO Offerdahl, DK Hasenkrug, A Carmody, AB Baron, GS AF Speare, Jonathan O. Offerdahl, Danielle K. Hasenkrug, Aaron Carmody, Aaron B. Baron, Gerald S. TI GPI anchoring facilitates propagation and spread of misfolded Sup35 aggregates in mammalian cells SO EMBO JOURNAL LA English DT Article DE amyloid; glycosylphosphatidylinositol anchor; nanotube; protein transfer; Sup35 ID ANCHORLESS PRION PROTEIN; IN-VITRO; SCRAPIE INFECTION; TUNNELING NANOTUBES; PSI+ PRION; PRP-RES; YEAST; HSP104; TRANSMISSION; DISEASE AB Prion diseases differ from other amyloid-associated protein misfolding diseases (e.g. Alzheimer's) because they are naturally transmitted between individuals and involve spread of protein aggregation between tissues. Factors underlying these features of prion diseases are poorly understood. Of all protein misfolding disorders, only prion diseases involve the misfolding of a glycosylphosphatidylinositol (GPI)-anchored protein. To test whether GPI anchoring can modulate the propagation and spread of protein aggregates, a GPI-anchored version of the amyloidogenic yeast protein Sup35NM (Sup35(GPI)) was expressed in neuronal cells. Treatment of cells with Sup35NM fibrils induced the GPI anchor-dependent formation of self-propagating, detergent-insoluble, protease-resistant, prion-like aggregates of Sup35(GPI). Live-cell imaging showed intercellular spread of Sup35(GPI) aggregation to involve contact between aggregate-positive and aggregate-negative cells and transfer of Sup35(GPI) from aggregate-positive cells. These data demonstrate GPI anchoring facilitates the propagation and spread of protein aggregation and thus may enhance the transmissibility and pathogenesis of prion diseases relative to other protein misfolding diseases. The EMBO Journal (2010) 29, 782-794. doi: 10.1038/emboj.2009.392; Published online 7 January 2010 C1 [Speare, Jonathan O.; Offerdahl, Danielle K.; Hasenkrug, Aaron; Carmody, Aaron B.; Baron, Gerald S.] NIAID, NIH, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Baron, GS (reprint author), NIAID, NIH, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM gbaron@niaid.nih.gov FU NIH (National Institute of Allergy and Infectious Diseases) FX We thank D Dorward for TEM analysis, R Messer for FACS analysis, K Hasenkrug for flow cytometry interpretation, A Athman for video editing assistance, S Lindquist for anti-Sup35M antibody and pJC45Sup35Stop plasmid, J Weissman for pAEDNMCh plasmid, R Wickner for p530 plasmid and anti-Ure2p antibody, B Nichols and J Lippincott-Schwartz for GFPGPI plasmid, V Boyko for pHIV-gag-mCherry, and R Tsien for permission to use mCherry. We thank M Davis and K Kisiel for helpful input on imaging and image processing. We also thank B Caughey, B Chesebro, and K McNally for critical review of the paper. This research was supported by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases). NR 68 TC 19 Z9 20 U1 0 U2 3 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 FEB 17 PY 2010 VL 29 IS 4 BP 782 EP 794 DI 10.1038/emboj.2009.392 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 556PX UT WOS:000274604600009 PM 20057357 ER PT J AU Gao, GJ Walser, JC Beaucher, ML Morciano, P Wesolowska, N Chen, J Rong, YS AF Gao, Guanjun Walser, Jean-Claude Beaucher, Michelle L. Morciano, Patrizia Wesolowska, Natalia Chen, Jie Rong, Yikang S. TI HipHop interacts with HOAP and HP1 to protect Drosophila telomeres in a sequence-independent manner SO EMBO JOURNAL LA English DT Article DE capping complex; drosophila telomere; epigenetic mechanism; telomere maintenance ID TO-END FUSIONS; CHROMOSOME ENDS; FISSION YEAST; ARABIDOPSIS-THALIANA; BINDING-PROTEIN; DNA BREAKS; MELANOGASTER; HETEROCHROMATIN; MAINTENANCE; CHROMATIN AB Telomeres prevent chromosome ends from being repaired as double-strand breaks (DSBs). Telomere identity in Drosophila is determined epigenetically with no sequence either necessary or sufficient. To better understand this sequence-independent capping mechanism, we isolated proteins that interact with the HP1/ORC-associated protein (HOAP) capping protein, and identified HipHop as a subunit of the complex. Loss of one protein destabilizes the other and renders telomeres susceptible to fusion. Both HipHop and HOAP are enriched at telomeres, where they also interact with the conserved HP1 protein. We developed a model telomere lacking repetitive sequences to study the distribution of HipHop, HOAP and HP1 using chromatin immunoprecipitation (ChIP). We discovered that they occupy a broad region > 10 kb from the chromosome end and their binding is independent of the underlying DNA sequence. HipHop and HOAP are both rapidly evolving proteins yet their telomeric deposition is under the control of the conserved ATM and Mre11-Rad50-Nbs (MRN) proteins that modulate DNA structures at telomeres and at DSBs. Our characterization of HipHop and HOAP reveals functional analogies between the Drosophila proteins and subunits of the yeast and mammalian capping complexes, implicating conservation in epigenetic capping mechanisms. The EMBO Journal (2010) 29, 819-829. doi: 10.1038/emboj.2009.394; Published online 7 January 2010 C1 [Gao, Guanjun; Beaucher, Michelle L.; Morciano, Patrizia; Wesolowska, Natalia; Chen, Jie; Rong, Yikang S.] NCI, LBMB, NIH, Bethesda, MD 20892 USA. [Walser, Jean-Claude] NIDDK, LMCB, NIH, Bethesda, MD USA. [Morciano, Patrizia] Univ Aquila, Bethesda, MD USA. RP Rong, YS (reprint author), NCI, LBMB, NIH, 37 Convent Dr,Room 6056, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI rong, yikang/G-6179-2011; Morciano, Patrizia/K-8871-2016 OI Morciano, Patrizia/0000-0002-8101-0096 FU National Cancer Institute FX We thank Germana Colazzo for constructing the myc-cav targeting construct, Xiao-feng Zheng for characterizing myc-cav reduction events and the initial characterization of terminal deficiencies, Giovanni Cenci at University of L'Aquila for comments and supporting PM; Gaku Mizuguchi for extensive advice on biochemical purification, Qin Wei and Bruce Paterson for assistance on S2 cell culture experiments, Jim Mason at NIEHS for the Gaiano stock, Michael Lichten and Carl Wu at NCI for comments on the paper. The intramural research program of the National Cancer Institute supported this research. NR 61 TC 43 Z9 44 U1 0 U2 3 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 FEB 17 PY 2010 VL 29 IS 4 BP 819 EP 829 DI 10.1038/emboj.2009.394 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 556PX UT WOS:000274604600012 PM 20057353 ER PT J AU Jiang, Z Belforte, JE Lu, Y Yabe, Y Pickel, J Smith, CB Je, HS Lu, B Nakazawa, K AF Jiang, Zhihong Belforte, Juan E. Lu, Yuan Yabe, Yoko Pickel, James Smith, Carolyn Beebe Je, Hyun-Soo Lu, Bai Nakazawa, Kazu TI eIF2 alpha Phosphorylation-Dependent Translation in CA1 Pyramidal Cells Impairs Hippocampal Memory Consolidation without Affecting General Translation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GENETICALLY TARGETED NEURONS; INITIATION-FACTOR EIF2-ALPHA; PROTEIN-SYNTHESIS INHIBITION; LONG-TERM FACILITATION; SYNAPTIC PLASTICITY; TRANSCRIPTION FACTOR; REGULATORY MECHANISMS; MAMMALIAN-CELLS; DIVERSE ARRAY; CREB AB Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2 alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2 alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation. C1 [Jiang, Zhihong; Belforte, Juan E.; Yabe, Yoko; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Lu, Yuan; Lu, Bai] NIMH, Gene Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, Bethesda, MD 20892 USA. [Smith, Carolyn Beebe] NIMH, Unit Neuroadaptat & Prot Metab, Cerebral Metab Lab, Bethesda, MD 20892 USA. [Je, Hyun-Soo; Lu, Bai] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Nakazawa, K (reprint author), NIMH, Unit Genet Cognit & Behav, Mood & Anxiety Disorders Program, Bldg 35,Room 1C-915, Bethesda, MD 20892 USA. EM nakazawk@mail.nih.gov RI Lu, Bai/A-4018-2012; Nakazawa, Kazutoshi/J-6195-2015; OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Je, hyunsoo/0000-0002-2924-5621 FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. We are grateful to ARIAD Pharmaceuticals, Inc. (www.ariad.com/regulationkits), and Dr. Thomas Dever at National Institute of Child Health and Human Development for providing us with AP20187 and pC939 plasmid. We thank Drs. Beatriz Castilho, Jinsheng Dong, Alan Hinnebusch, Pamela Maher, Hiroaki Matsunami, and Kim Christian and Ioline Henter for their technical advice and critical reading of the manuscript. NR 54 TC 49 Z9 49 U1 0 U2 8 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 FEB 17 PY 2010 VL 30 IS 7 BP 2582 EP 2594 DI 10.1523/JNEUROSCI.3971-09.2010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 556OD UT WOS:000274599600021 PM 20164343 ER PT J AU Stroth, N Eiden, LE AF Stroth, N. Eiden, L. E. TI STRESS HORMONE SYNTHESIS IN MOUSE HYPOTHALAMUS AND ADRENAL GLAND TRIGGERED BY RESTRAINT IS DEPENDENT ON PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE SIGNALING SO NEUROSCIENCE LA English DT Article DE restraint; CRH; HPA axis; pituitary adenylate cyclase-activating polypeptide; neuropeptide; stimulus-secretion-synthesis coupling ID IMMEDIATE-EARLY GENES; PARAVENTRICULAR NUCLEUS; CHROMAFFIN CELLS; NEUROSECRETORY NEURONS; BRAIN-STEM; CRH GENE; IN-VIVO; EXPRESSION; PACAP; RAT AB Stress responses are elicited by a variety of stimuli and are aimed at counteracting direct or perceived threats to the well-being of an organism. In the mammalian central and peripheral nervous systems, specific cell groups constitute signaling circuits that indicate the presence of a stressor and elaborate an adequate response. Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in central and peripheral parts of these circuits and has recently been identified as a candidate for regulation of the stress axis. In the present experiments, we tested the involvement of PACAP in the response to a psychological stressor in vivo. We used a restraint paradigm and compared PACAP-deficient mice (PACAP-/-) to wild-type controls (PACAP+/+). Acute secretion of corticosterone elicited by 1 h of restraint was found to be identical between genotypes, whereas sustained secretion provoked by 6 h of unrelieved restraint was 48% lower in PACAP-/-mice. Within the latter time frame, expression of messenger RNA (mRNA) encoding corticotropin-releasing hormone (CRH) was increased in the hypothalamus of wild type, but not PACAP-deficient mice. Expression of the activity-regulated transcription factors Egr1 (early growth response 1) and Fos (FBJ osteosarcoma oncogene) in the hypothalamus was rapidly and transiently induced by restraint in a PACAP-dependent fashion, a pattern that was also found in the adrenal glands. Here, abundance of transcripts encoding enzymes required for adrenomedullary catecholamine biosynthesis, namely TH (tyrosine hydroxylase) and PNMT (phenylethanolamine N-methyltransferase), was higher in PACAP+/+ mice after 6 h of unrelieved restraint. Our results suggest that sustained corticosterone secretion, synthesis of the hypophysiotropic hormone CRH in the hypothalamus, and synthesis of the enzymes producing the hormone adrenaline in the adrenal medulla, are controlled by PACAP signaling in the mouse. These findings identify PACAP as a major contributor to the stimulus-secretion-synthesis coupling that supports stress responses in vivo. Published by Elsevier Ltd on behalf of IBRO. C1 [Stroth, N.; Eiden, L. E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU NIMH [Z01 MH002386-23] FX This work was supported by NIMH Intramural Research Program Project Z01 MH002386-23. NR 33 TC 47 Z9 47 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD FEB 17 PY 2010 VL 165 IS 4 BP 1025 EP 1030 DI 10.1016/j.neuroscience.2009.11.023 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 549VD UT WOS:000274081500003 PM 19931358 ER PT J AU Samuel, AS Paldurai, A Kumar, S Collins, PL Samal, SK AF Samuel, Arthur S. Paldurai, Anandan Kumar, Sachin Collins, Peter L. Samal, Siba K. TI Complete Genome Sequence of Avian Paramyxovirus (APMV) Serotype 5 Completes the Analysis of Nine APMV Serotypes and Reveals the Longest APMV Genome SO PLOS ONE LA English DT Article ID NEWCASTLE-DISEASE VIRUS; HEMAGGLUTININ-NEURAMINIDASE GLYCOPROTEIN; BUDGERIGAR MELOPSITTACUS-UNDULATUS; COMPLETE NUCLEOTIDE-SEQUENCE; FUSION PROTEIN; UNTRANSLATED REGIONS; RNA-SYNTHESIS; REPLICATION; DOMAIN; RULE AB Background: Avian paramyxoviruses (APMV) consist of nine known serotypes. The genomes of representatives of all APMV serotypes except APMV type 5 have recently been fully sequenced. Here, we report the complete genome sequence of the APMV-5 prototype strain budgerigar/Kunitachi/74. Methodology/Principal Findings: APMV-5 Kunitachi virus is unusual in that it lacks a virion hemagglutinin and does not grow in the allantoic cavity of embryonated chicken eggs. However, the virus grew in the amniotic cavity of embryonated chicken eggs and in twelve different established cell lines and two primary cell cultures. The genome is 17,262 nucleotides (nt) long, which is the longest among members of genus Avulavirus, and encodes six non-overlapping genes in the order of 3'N-P/V/W-M-F-HN-L-5' with intergenic regions of 4-57 nt. The genome length follows the 'rule of six' and contains a 55-nt leader sequence at the 3' end and a 552 nt trailer sequence at the 59 end. The phosphoprotein (P) gene contains a conserved RNA editing site and is predicted to encode P, V, and W proteins. The cleavage site of the F protein (G-K-R-K-K-R down arrow F) conforms to the cleavage site motif of the ubiquitous cellular protease furin. Consistent with this, exogenous protease was not required for virus replication in vitro. However, the intracerebral pathogenicity index of APMV-5 strain Kunitachi in one-day-old chicks was found to be zero, indicating that the virus is avirulent for chickens despite the presence of a polybasic F cleavage site. Conclusions/Significance: Phylogenetic analysis of the sequences of the APVM-5 genome and proteins versus those of the other APMV serotypes showed that APMV-5 is more closely related to APMV-6 than to the other APMVs. Furthermore, these comparisons provided evidence of extensive genome-wide divergence that supports the classification of the APMVs into nine separate serotypes. The structure of the F cleavage site does not appear to be a reliable indicator of virulence among APMV serotypes 2-9. The availability of sequence information for all known APMV serotypes will facilitate studies in epidemiology and vaccinology. C1 [Samuel, Arthur S.; Paldurai, Anandan; Kumar, Sachin; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samuel, AS (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [N01A060009]; NIAID; National Institutes of Health (NIH) FX This research was supported by National Institute of Allergy and Infectious Diseases (NIAID) contract no. N01A060009 (85% support) and NIAID, National Institutes of Health (NIH) Intramural Research Program (15% support). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 29 Z9 29 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 FEB 17 PY 2010 VL 5 IS 2 AR e9269 DI 10.1371/journal.pone.0009269 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556KU UT WOS:000274590600022 PM 20174645 ER PT J AU Bluestone, JA Krensky, AM Turka, LA Rotrosen, D Matthews, JB AF Bluestone, Jeffrey A. Krensky, Alan M. Turka, Laurence A. Rotrosen, Daniel Matthews, Jeffrey B. TI Ten Years of the Immune Tolerance Network: An Integrated Clinical Research Organization SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article AB The U. S. National Institutes of Health Roadmap and the U. S. Food and Drug Administration's Critical Path Initiative have endorsed the establishment of large academic clinical research networks as part of the solution to the growing divide between increased R&D spending and the lagging number of new drugs making it to market. Clearly, the role of these networks as translational science incubators that complement industry-sponsored programs is laudable and much-needed. However, the path to success for such organizations is less clear. Here, drawing on the experiences of the Immune Tolerance Network, a multidisciplinary clinical research network founded in 1999, we discuss some of the barriers inherent in developing such consortia and off er firsthand insight into the planning, resources, and organizational infrastructure required for a successful research program. C1 [Bluestone, Jeffrey A.; Krensky, Alan M.; Turka, Laurence A.; Matthews, Jeffrey B.] Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94107 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Krensky, Alan M.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Turka, Laurence A.] Harvard Univ, Beth Israel Deaconess Med Ctr Boston, Sch Med, Transplant Inst, Boston, MA 02115 USA. [Rotrosen, Daniel] NIAID, Div Allergy & Transplantat, Bethesda, MD 20817 USA. RP Bluestone, JA (reprint author), Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94107 USA. EM jbluest@diabetes.ucsf.edu NR 2 TC 0 Z9 0 U1 0 U2 0 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 FEB 17 PY 2010 VL 2 IS 19 AR 19cm7 DI 10.1126/scitranslmed.3000672 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591MA UT WOS:000277303600002 PM 20371484 ER PT J AU Toh, S Hernandez-Diaz, S Logan, R Rossouw, JE Hernan, MA AF Toh, Sengwee Hernandez-Diaz, Sonia Logan, Roger Rossouw, Jacques E. Hernan, Miguel A. TI Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MARGINAL STRUCTURAL MODELS; INITIATIVE CLINICAL-TRIAL; HORMONE-THERAPY; CARDIOVASCULAR-DISEASE; MENOPAUSE; WOMEN; BENEFITS; HEALTHY; HRT AB Background: Estrogen plus progestin therapy increases the risk for coronary heart disease (CHD) in postmenopausal women. However, this increased risk might be limited to the first years of use and to women who start therapy late in menopause. Objective: To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause. Design: Women's Health Initiative randomized, double-blinded, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00000611) Setting: 40 U. S. clinical centers. Patients: 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998. Intervention: Conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo. Measurements: Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting. Results: Compared with no use of hormone therapy, the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 (95% CI, 1.55 to 3.62) for the first 2 years and 1.69 (CI, 0.98 to 2.89) for the first 8 years. For women within 10 years after menopause, the hazard ratios were 1.29 (CI, 0.52 to 3.18) for the first 2 years and 0.64 (CI, 0.21 to 1.99) for the first 8 years, and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years (CI, 2 years to 10 years). Limitation: The analysis may not have fully adjusted for joint determinants of adherence and CHD risk. Sample sizes for some subgroup analyses were small. Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use. C1 Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. NHLBI, Bethesda, MD 20892 USA. RP Toh, S (reprint author), Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM darrentoh@post.harvard.edu RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU National Heart, Lung, and Blood Institute; National Institutes of Health [R01 HL080644-01] FX National Heart, Lung, and Blood Institute.; By the National Institutes of Health (grant R01 HL080644-01). NR 27 TC 50 Z9 54 U1 0 U2 6 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 FEB 16 PY 2010 VL 152 IS 4 BP 211 EP U30 DI 10.7326/0003-4819-152-4-201002160-00005 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 560AF UT WOS:000274873300002 PM 20157135 ER PT J AU Levine, SJ Wenzel, SE AF Levine, Stewart J. Wenzel, Sally E. TI Narrative Review: The Role of Th2 Immune Pathway Modulation in the Treatment of Severe Asthma and Its Phenotypes SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID SEVERE PERSISTENT ASTHMA; ANTI-IGE ANTIBODY; AIRWAY HYPERRESPONSIVENESS; UNCONTROLLED DISEASE; ALLERGIC-ASTHMA; OMALIZUMAB; EXACERBATIONS; INFLAMMATION; EOSINOPHILS; MEPOLIZUMAB AB New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy comprising high doses of inhaled corticosteroids plus long-acting beta(2)-agonists. Current treatment guidelines for patients with severe asthma from the National Asthma Education and Prevention Program recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE. Genetic and translational studies, as well as clinical trials, suggest that in a subgroup of patients, the pathobiology of severe asthma is mediated by immune pathways driven by T-helper 2 (Th2)-type CD4(+) T cells, which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13. Therefore, biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists, are a rational strategy for developing new treatment approaches but will need to be targeted to selected patients in whom the appropriate Th2 immune pathway is "active." The benefits of immune-modifier therapies targeting Th2-type cytokines, however, need to be weighed against the toxicities associated with inhibition of key biological pathways, as well as the expense of future medications. Therefore, future clinical trials need to clearly establish the efficacy and safety of biological modifiers of Th2 immune pathways before these approaches can enter routine clinical practice for the treatment of severe asthma. C1 [Levine, Stewart J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Montefiore Med Ctr, Pittsburgh, PA USA. RP Levine, SJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, National Institute of Health; National Immunologic, Allergic and Infectious Disease Institute [AI 40600]; University of Pittsburgh FX By the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institute of Health; the National Immunologic, Allergic and Infectious Disease Institute (AI 40600); and the University of Pittsburgh. NR 44 TC 46 Z9 51 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 FEB 16 PY 2010 VL 152 IS 4 BP 232 EP U56 DI 10.7326/0003-4819-152-4-201002160-00008 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 560AF UT WOS:000274873300005 PM 20157138 ER PT J AU You, Z Cao, XH Taylor, AB Hart, PJ Levine, RL AF You, Zheng Cao, Xiaohang Taylor, Alexander B. Hart, P. John Levine, Rodney L. TI Characterization of a Covalent Polysulfane Bridge in Copper-Zinc Superoxide Dismutase SO BIOCHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU,ZN-SUPEROXIDE DISMUTASE; DISULFIDE REDUCTION; HYDROGEN-PEROXIDE; WILD-TYPE; BIOPHYSICAL PROPERTIES; DIMER STABILITY; LABILE SULFUR; DNA CLEAVAGE; FAMILIAL ALS AB In the course of studies on human copper-zinc Superoxide dismutase (SOD1), We observed a modified form of the protein whose mass wits increased by 158 mass units. The covalent modification Was characterized, and we established that it is a novel heptasulfane bridge connecting the two Cys111 residues in the SOD1 homodimer. The heptasulfane bridge was visualized directly in the crystal structure of it recombinant human mutant SODI, H46R/H48Q, produced in yeast. The modification is reversible, with the bridge being cleaved by thiols, by cyanide, and by unfolding of the protein to expose the polysulfane. The polysulfane bridge can be introduced in vitro by incubation of purified SOD1 with elemental sulfur, even under anaerobic conditions and in the presence of a metal chelator. Because polysulfanes and polysulfides can catalyze the generation of reactive oxygen and sulfur species, the modification may endow SOD1 with a toxic gain of function. C1 [You, Zheng; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. [Cao, Xiaohang; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Cao, Xiaohang; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [ZIA HL000225-32]; NINDS NIH HHS [NS39112, R01 NS039112, R01 NS039112-08] NR 67 TC 21 Z9 21 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 16 PY 2010 VL 49 IS 6 BP 1191 EP 1198 DI 10.1021/bi901844d PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553CI UT WOS:000274342000016 PM 20052996 ER PT J AU Shalev, U Erb, S Shaham, Y AF Shalev, Uri Erb, Suzanne Shaham, Yavin TI Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking SO BRAIN RESEARCH LA English DT Article DE Conditioned place preference; Extinction; Neuropeptide; Reinstatement; Relapse; Self-administration; Stress ID CORTICOTROPIN-RELEASING-FACTOR; MELANIN-CONCENTRATING HORMONE; CONDITIONED PLACE PREFERENCE; VENTRAL TEGMENTAL AREA; KAPPA-OPIOID RECEPTOR; COCAINE-INDUCED REINSTATEMENT; MIDBRAIN DOPAMINE NEURONS; PROTEIN-COUPLED RECEPTOR; DEPRIVATION-INDUCED REINSTATEMENT; HYPOTHALAMIC OREXIN NEURONS AB A central problem in the treatment of drug addiction is high rates of relapse to drug use after periods of forced or self-imposed abstinence. This relapse is often provoked by exposure to stress. Stress-induced relapse to drug seeking can be modeled in laboratory animals using a reinstatement procedure. In this procedure, drug-taking behaviors are extinguished and then reinstated by acute exposure to stressors like intermittent unpredictable footshock, restraint, food deprivation, and systemic injections of yohimbine, an alpha-2 adrenoceptor antagonist that induces stress-hke responses in humans and nonhumans. For this special issue entitled "The role of neuropeptides in stress and addiction", we review results from studies on the role of corticotropin-releasing factor (CRF) and several other peptides in stress-induced reinstatement of drug seeking in laboratory animals. The results of the studies reviewed indicate that extrahypothalamic CRF plays a critical role in stress-induced reinstatement of drug seeking; this role is largely independent of drug class, experimental procedure, and type of stressor. There is also limited evidence for the role of dynorphins, hypocretins (orexins), nociceptin (orphanin FQ), and leptin in stress-induced reinstatement of drug seeking. (C) 2009 Elsevier B.V. All rights reserved. C1 [Shalev, Uri] Concordia Univ, Dept Psychol, Ctr Studies Behav Neurobiol, Grp Rech Neurobiol Comportementale, Montreal, PQ H3G 1M8, Canada. [Erb, Suzanne] Univ Toronto Scarborough, Dept Psychol, Ctr Neurobiol Stress, Toronto, ON, Canada. [Shaham, Yavin] NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD USA. RP Shalev, U (reprint author), Concordia Univ, Dept Psychol, Ctr Studies Behav Neurobiol, Grp Rech Neurobiol Comportementale, Montreal, PQ H3G 1M8, Canada. EM uri.shalev@concordia.ca; Erb@utsc.utoronto.ca RI shaham, yavin/G-1306-2014 FU NIH; NIDA FX This review was supported in part by the Intramural Research Program of the NIH, NIDA. We thank Dr. Sunila Nair for helpful comments. NR 181 TC 78 Z9 78 U1 2 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD FEB 16 PY 2010 VL 1314 SI SI BP 15 EP 28 DI 10.1016/j.brainres.2009.07.028 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 565RQ UT WOS:000275312400003 PM 19631614 ER PT J AU Wise, RA Morales, M AF Wise, Roy A. Morales, Marisela TI A ventral tegmental CRF-glutamate-dopamine interaction in addiction SO BRAIN RESEARCH LA English DT Article DE CRF; Glutarnate; Dopamine; Binding protein; Cocaine ID CORTICOTROPIN-RELEASING-FACTOR; FACTOR-BINDING-PROTEIN; NUCLEUS-ACCUMBENS DOPAMINE; STRESS-INDUCED RELAPSE; COCAINE-SEEKING; RAT-BRAIN; INDUCED REINSTATEMENT; LIGAND INHIBITOR; SUBSTANTIA-NIGRA; AREA AB Stress-induced reinstatement of cocaine-seeking is blocked by antagonists for the stress-related neurohormone corticotropin-releasing factor (CRF). One site of this action is the ventral tegmental area (VTA), where mild footshock stress causes CRF release, glutamate release, and dopaminergic activation in cocaine-experienced but not cocaine-naive animals. Infusion of CRF into VTA has similar effects to footshock in cocaine-experienced animals but fails to cause significant VTA glutamate release or dopaminergic activation in cocaine-naive animals. The reinstatement, glutamate release, and dopamine release are prevented by VTA infusions of CRF-receptor 2 (CRF-R2) but not CRF-R1 antagonists. Reinstatement is triggered by some but not all CRF-R2 agonists and some but not all CRF-R1 agonists; the common denominator of the effective agonists is that they bind to the CRF-binding protein (CRF-BP), which appears to be essential for the behavioral and VTA effects of stress and CRF in cocaine-experienced animals. In situ hybridization reveals mRNA for CRF-R1 and CRF-BP but not CRF-R2 in a subset of VTA dopamine neurons. Electron microscopy reveals primarily asymmetric synapses between a subset of VTA terminals containing glutamate and CRF and a subset of VTA dopaminergic neurons and primarily symmetric synapses between a subset of CRF terminals that do not contain glutamate and a subset of GABAergic neurons in VTA. Thus, a complex and not yet fully understood interaction of CRF, glutamate, and the mesocorticolimbic dopamine system is established by experience with cocaine, and this alteration appears to contribute importantly to the transition from casual to compulsive cocaine-seeking. Published by Elsevier B.V. C1 [Wise, Roy A.; Morales, Marisela] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rwise@intr.nida.nih.gov RI Wise, Roy/A-6465-2012 FU NIH; National Institute on Drug Abuse FX Preparation of this manuscript was supported by NIH funding through the Intramural Research Program of the National Institute on Drug Abuse. NR 41 TC 48 Z9 50 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 16 PY 2010 VL 1314 SI SI BP 38 EP 43 DI 10.1016/j.brainres.2009.09.101 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 565RQ UT WOS:000275312400005 PM 19800323 ER PT J AU Cunningham, MD Kassis, JA Pfeifer, K AF Cunningham, Melissa D. Kassis, Judith A. Pfeifer, Karl TI Chromatin Modifiers, Cognitive Disorders, and Imprinted Genes SO DEVELOPMENTAL CELL LA English DT Editorial Material C1 [Cunningham, Melissa D.; Kassis, Judith A.; Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. RP Pfeifer, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. EM kpfeifer@helix.nih.gov OI Kassis, Judith/0000-0001-9268-3213; Pfeifer, Karl/0000-0002-0254-682X FU Intramural NIH HHS [Z01 HD001804-12] NR 9 TC 4 Z9 4 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB 16 PY 2010 VL 18 IS 2 BP 169 EP 170 DI 10.1016/j.devcel.2010.01.012 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 563BM UT WOS:000275100400002 PM 20159587 ER PT J AU Hershko, AY Rivera, J AF Hershko, Alon Y. Rivera, Juan TI Mast cell and T cell communication; amplification and control of adaptive immunity SO IMMUNOLOGY LETTERS LA English DT Article DE Communication; Mast cells; Molecular interaction; T cells; T effectors; Tregs ID FC-EPSILON-RI; GENE-EXPRESSION PROFILES; IGE RECEPTOR EXPRESSION; REGULATORY CELLS; OX40 LIGAND; BACTERIAL-INFECTIONS; MULTIPLE-SCLEROSIS; HISTAMINE-RELEASE; MEDIATOR RELEASE; ULTRAVIOLET-B AB Recent advances in understanding the physiological role of mast cells (MCs) point to an important regulatory role for these cells in adaptive immunity. MCs express a diverse array of molecules that can promote their interaction with T cells as well as with other immune cells. New evidence demonstrates that mast cells can directly and indirectly communicate with T cells. They can control both effector and regulatory T cell responses and their activity can in turn be modulated by these interactions. Here we briefly summarize these advances and discuss some of the major challenges in understanding the communication of MCs and T cells. Published by Elsevier B.V. C1 [Hershko, Alon Y.; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Immunogenet Mol Lab, NIH, Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov FU National Institute of Arthritis; Musculoskeletal and Skin Diseases of the National Institutes of Health FX The research of the authors included herein was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 85 TC 32 Z9 35 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB 16 PY 2010 VL 128 IS 2 BP 98 EP 104 DI 10.1016/j.imlet.2009.10.013 PG 7 WC Immunology SC Immunology GA 568MO UT WOS:000275526700002 PM 19900479 ER PT J AU Kaul, H Riazuddin, SA Yasmeen, A Mohsin, S Khan, M Nasir, IA Khan, SN Husnain, T Akram, J Hejtmancik, JF Riazuddin, S AF Kaul, Haiba Riazuddin, S. Amer Yasmeen, Afshan Mohsin, Sadia Khan, Mohsin Nasir, Idrees A. Khan, Shaheen N. Husnain, Tayyab Akram, Javed Hejtmancik, J. Fielding Riazuddin, Sheikh TI A new locus for autosomal recessive congenital cataract identified in a Pakistani family SO MOLECULAR VISION LA English DT Article ID ZONULAR PULVERULENT CATARACT; NONSENSE MUTATION; MISSENSE MUTATION; GENE; BLINDNESS; MAPS AB Purpose: To identify the disease locus for autosomal recessive congenital cataract in a consanguineous Pakistani family. Methods: All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and logarithm of odds (LOD) scores were calculated. Results: The clinical records and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Maximum LOD scores of 5.01, 4.38, and 4.17 at theta=0 were obtained with markers D7630, D7S657, and D7S515, respectively. Fine mapping refined the critical interval and suggested that markers in a 27.78 cM (27.96 Mb) interval are flanked by markers D7S660 and D7S799, which co-segregate with the disease phenotype in family PKCC108. Conclusions: We have identified a new locus for autosomal recessive congenital cataract, localized to chromosome 7q21.11-q31.1 in a consanguineous Pakistani family. C1 [Kaul, Haiba; Riazuddin, S. Amer; Yasmeen, Afshan; Mohsin, Sadia; Khan, Mohsin; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Akram, Javed; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Riazuddin, S (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, 87 W Canal Bank Rd, Lahore 53700, Pakistan. EM riaz@aimrc.org RI Nasim Khan, Shaheen/F-2135-2015; Husnain, Tayyab/G-3805-2015 FU Higher Education Commission, Islamabad, Pakistan; Ministry of Science and Technology, Islamabad, Pakistan FX The authors are thankful to all individuals for their participation in this study. We are also grateful to the staff of Layton Rehmatullah Benevolent Trust (LRBT) hospital, in particular, Dr Waseem for clinical evaluation of affected individuals. This study was supported in part by Higher Education Commission, Islamabad, Pakistan and Ministry of Science and Technology, Islamabad, Pakistan. NR 25 TC 18 Z9 18 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD FEB 16 PY 2010 VL 16 IS 29-30 BP 240 EP 245 PG 6 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 570ZJ UT WOS:000275717100002 PM 20161816 ER PT J AU Kaufmann, H Goldstein, DS AF Kaufmann, Horacio Goldstein, David S. TI Pure autonomic failure A restricted Lewy body synucleinopathy or early Parkinson disease? SO NEUROLOGY LA English DT Editorial Material ID ORTHOSTATIC HYPOTENSION; ALPHA-SYNUCLEIN; DEGENERATION; BODIES C1 [Kaufmann, Horacio] NYU, Sch Med, Dysautonomia Ctr, Dept Neurol, New York, NY 10016 USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Kaufmann, H (reprint author), NYU, Sch Med, Dysautonomia Ctr, Dept Neurol, 530 1st Ave,Suite 9Q, New York, NY 10016 USA. EM Horacio.kaufmann@nyumc.org; goldsteind@ninds.nih.gov OI Kaufmann, Horacio/0000-0002-1851-9981 FU NINDS NIH HHS [U54NS065736] NR 13 TC 19 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 16 PY 2010 VL 74 IS 7 BP 536 EP 537 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 555MX UT WOS:000274517100003 PM 20157156 ER PT J AU Ben-Zvi, I Aranow, C Mackay, M Stanevsky, A Kamen, DL Marinescu, LM Collins, CE Gilkeson, GS Diamond, B Hardin, JA AF Ben-Zvi, Ilan Aranow, Cynthia Mackay, Meggan Stanevsky, Anfisa Kamen, Diane L. Marinescu, L. Manuela Collins, Christopher E. Gilkeson, Gary S. Diamond, Betty Hardin, John A. TI The Impact of Vitamin D on Dendritic Cell Function in Patients with Systemic Lupus Erythematosus SO PLOS ONE LA English DT Article ID INDUCIBLE GENE-EXPRESSION; INTERFERON-ALPHA ACTIVITY; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; D DEFICIENCY; IFN-ALPHA; RHEUMATOID-ARTHRITIS; MICROARRAY ANALYSIS AB Background: Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFN alpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFN alpha-regulated genes in vitro. Methodology/Principal Findings: In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = -.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFN alpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma. Conclusions/Significance: We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFN alpha activity in vivo and, most importantly, improves clinical outcome. C1 [Ben-Zvi, Ilan; Aranow, Cynthia; Mackay, Meggan; Stanevsky, Anfisa; Diamond, Betty] Feinstein Inst Med Res, Div Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. [Marinescu, L. Manuela; Hardin, John A.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kamen, Diane L.; Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol, Charleston, SC 29425 USA. [Collins, Christopher E.; Gilkeson, Gary S.] Ralph H Johnson Vet Adm Med Ctr, Dept Med, Charleston, SC USA. [Hardin, John A.] NIAID, NIH, Washington, DC USA. RP Ben-Zvi, I (reprint author), Feinstein Inst Med Res, Div Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. EM johnhardin@arthritis.org OI Ben-Zvi, Ilan/0000-0002-9160-3098 FU National Institutes of Health [P60 AR049459, RR01070, AR052364]; National Institutes of Health (National Institute of Allergy and Infectious Disease) and the Autoimmunity Centers of Excellence; Autoimmunity Centers of Excellence; American College of Rheumatology Research and Education Foundation; Alliance for Lupus Research; NIAMS FX This work is supported by grants from the National Institutes of Health to GSG (P60 AR049459) and DLK (General Clinical Research Center grant #RR01070); by grants from the National Institutes of Health (National Institute of Allergy and Infectious Disease) and the Autoimmunity Centers of Excellence to BD, MM, CA, and JAH; by an American College of Rheumatology Research and Education Foundation award to DLK; and by a grant from the Alliance for Lupus Research to JAH. Additional support for DLK: K23 Award from NIAMS: NIH K23 AR052364. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 66 Z9 73 U1 1 U2 5 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 FEB 16 PY 2010 VL 5 IS 2 AR e9193 DI 10.1371/journal.pone.0009193 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556KT UT WOS:000274590500003 PM 20169063 ER PT J AU Craigie, R AF Craigie, Robert TI Targeting HIV-1 DNA integration by swapping tethers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HISTONE H3; LEDGF/P75; METHYLATION; CHROMATIN C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Craigie, R (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov FU Intramural NIH HHS NR 17 TC 4 Z9 4 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 2010 VL 107 IS 7 BP 2735 EP 2736 DI 10.1073/pnas.0915097107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500007 PM 20145107 ER PT J AU Lobkovsky, AE Wolf, YI Koonin, EV AF Lobkovsky, Alexander E. Wolf, Yuri I. Koonin, Eugene V. TI Universal distribution of protein evolution rates as a consequence of protein folding physics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE correct folding probability; evolutionary rate distribution; off-lattice models; common structure networks; network average evolution rate ID MODEL PROTEINS; SEQUENCE EVOLUTION; BROWNIAN DYNAMICS; EXPRESSION LEVEL; LATTICE MODEL; STABILITY; PERSPECTIVE; LANDSCAPES; BIOLOGY; ENERGY AB The hypothesis that folding robustness is the primary determinant of the evolution rate of proteins is explored using a coarse-grained off-lattice model. The simplicity of the model allows rapid computation of the folding probability of a sequence to any folded conformation. For each robust folder, the network of sequences that share its native structure is identified. The fitness of a sequence is postulated to be a simple function of the number of misfolded molecules that have to be produced to reach a characteristic protein abundance. After fixation probabilities of mutants are computed under a simple population dynamics model, a Markov chain on the fold network is constructed, and the fold-averaged evolution rate is computed. The distribution of the logarithm of the evolution rates across distinct networks exhibits a peak with a long tail on the low rate side and resembles the universal empirical distribution of the evolutionary rates more closely than either distribution resembles the log-normal distribution. The results suggest that the universal distribution of the evolutionary rates of protein-coding genes is a direct consequence of the basic physics of protein folding. C1 [Lobkovsky, Alexander E.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Department of Health and Human Services (National Institutes of Health, National Library of Medicine) FX The authors' research is supported by the intramural funds of the Department of Health and Human Services (National Institutes of Health, National Library of Medicine). NR 64 TC 35 Z9 36 U1 0 U2 11 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 FEB 16 PY 2010 VL 107 IS 7 BP 2983 EP 2988 DI 10.1073/pnas.0910445107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500051 PM 20133769 ER PT J AU Sotelo, J Esposito, D Duhagon, MA Banfield, K Mehalko, J Liao, HL Stephens, RM Harris, TJR Munroe, DJ Wu, XL AF Sotelo, Jose Esposito, Dominic Duhagon, Maria Ana Banfield, Kelley Mehalko, Jennifer Liao, Hongling Stephens, Robert M. Harris, Timothy J. R. Munroe, David J. Wu, Xiaolin TI Long-range enhancers on 8q24 regulate c-Myc SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; WIDE ASSOCIATION SCAN; PROSTATE-CANCER; COLORECTAL-CANCER; CHROMOSOME CONFORMATION; RISK LOCUS; IN-VIVO; EXPRESSION; PROMOTER; GENE AB Recent genomewide association studies have found multiple genetic variants on chromosome 8q24 that are significantly associated with an increased susceptibility to prostate, colorectal, and breast cancer. These risk loci are located in a "gene desert," a few hundred kilobases telomeric to the Myc gene. To date, the biological mechanism(s) underlying these associations remain unclear. It has been speculated that these 8q24 genetic variant(s) might affect Myc expression by altering its regulation or amplification status. Here, we show that multiple enhancer elements are present within this region and that they can regulate transcription of Myc. We also demonstrate that one such enhancer element physically interacts with the Myc promoter via transcription factor Tcf-4 binding and acts in an allele specific manner to regulate Myc expression. C1 [Sotelo, Jose; Esposito, Dominic; Banfield, Kelley; Mehalko, Jennifer; Liao, Hongling; Stephens, Robert M.; Harris, Timothy J. R.; Munroe, David J.; Wu, Xiaolin] NCI, Adv Technol Program, Frederick, MD 21702 USA. [Sotelo, Jose; Banfield, Kelley; Liao, Hongling; Wu, Xiaolin] NCI, Lab Mol Technol, Frederick, MD 21702 USA. [Esposito, Dominic; Mehalko, Jennifer] NCI, Prot Express Lab, Frederick, MD 21702 USA. [Duhagon, Maria Ana] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Frederick, MD 21702 USA. [Stephens, Robert M.] SAIC Frederick Inc, Adv Biomed Comp Ctr, NCI, Frederick, MD 21702 USA. RP Munroe, DJ (reprint author), NCI, Adv Technol Program, Frederick, MD 21702 USA. EM dmunroe@mail.ncifcrf.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors thank Dr. B. Vogelstein for sharing the Tcf4 beta-catenin plasmids and Drs. Robert Eisenman and David Levens for helpful comments and suggestions. 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. NR 33 TC 106 Z9 111 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 2010 VL 107 IS 7 BP 3001 EP 3005 DI 10.1073/pnas.0906067107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500054 PM 20133699 ER PT J AU Boboila, C Jankovic, M Yan, CT Wang, JH Wesemann, DR Zhang, TT Fazeli, A Feldman, L Nussenzweig, A Nussenzweig, M Alt, FW AF Boboila, Cristian Jankovic, Mila Yan, Catherine T. Wang, Jing H. Wesemann, Duane R. Zhang, Tingting Fazeli, Alex Feldman, Lauren Nussenzweig, Andre Nussenzweig, Michel Alt, Frederick W. TI Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE class switch recombination; DNA double-strand repair; nonhomologous end-joining; switch region internal deletions ID CLASS-SWITCH RECOMBINATION; STRAND BREAK REPAIR; REGION RECOMBINATION; DNA-REPAIR; B-CELLS; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; MAMMALIAN-CELLS; ERROR-PRONE; MU REGION AB Class switch recombination (CSR) in B lymphocytes is initiated by introduction of multiple DNA double-strand breaks (DSBs) into switch (S) regions that flank immunoglobulin heavy chain (IgH) constant region exons. CSR is completed by joining a DSB in the donor S mu to a DSB in a downstream acceptor S region (e. g., S gamma 1) by end-joining. In normal cells, many CSR junctions are mediated by classical nonhomologous end-joining (C-NHEJ), which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation. Alternative end-joining (A-EJ) mediates CSR, at reduced levels, in the absence of C-NHEJ, even in combined absence of Ku70 and ligase 4, demonstrating an A-EJ pathway totally distinct from C-NHEJ. Multiple DSBs are introduced into S mu during CSR, with some being rejoined or joined to each other to generate internal switch deletions (ISDs). In addition, S-region DSBs can be joined to other chromosomes to generate translocations, the level of which is increased by absence of a single C-NHEJ component (e. g., XRCC4). We asked whether ISD and S-region translocations occur in the complete absence of C-NHEJ (e. g., in Ku70/ligase 4 double-deficient B cells). We found, unexpectedly, that B-cell activation for CSR generates substantial ISD in both S mu and S gamma 1 and that ISD in both is greatly increased by the absence of C-NHEJ. IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair. C1 [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Childrens Hosp, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Immune Dis Inst, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Nussenzweig, Michel; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Jankovic, Mila; Nussenzweig, Michel] Rockefeller Univ, Lab Mol Immunol, New York, NY USA. [Yan, Catherine T.; Feldman, Lauren] Beth Israel Deaconess Med Ctr, Dept Pathol, Div Expt Pathol, Boston, MA 02215 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Nussenzweig, Andre] NIH, Bethesda, MD 20892 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Wang, Jing/M-7813-2015 OI Wang, Jing/0000-0003-4343-2527 FU National Institutes of Health (NIH) [AI031541, CA092625, AI037526, T32CA09382-26]; Leukemia and Lymphoma Society of America; Cancer Research Institute FX We thank Klaus Rajewsky, Bjoern Schwer, Monica Gostissa, and Maria-Vivienne Boboila for stimulating discussions, and we thank Michael Lieber, Wesley Dunnick, and Kefei Yu for critical review of the manuscript. This work was supported by National Institutes of Health (NIH) Grants AI031541 and CA092625 ( F. W. A.) and AI037526 (M.N.). J.H.W. was supported by a Leukemia and Lymphoma Society of America Special Fellowship and by NIH Training Grant T32CA09382-26. C. B. is supported by a Cancer Research Institute training grant NR 47 TC 94 Z9 96 U1 0 U2 2 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 FEB 16 PY 2010 VL 107 IS 7 BP 3034 EP 3039 DI 10.1073/pnas.0915067107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500060 PM 20133803 ER PT J AU Ferris, AL Wu, XL Hughes, CM Stewart, C Smith, SJ Milne, TA Wang, GG Shun, MC Allis, CD Engelman, A Hughes, SH AF Ferris, Andrea L. Wu, Xiaolin Hughes, Christina M. Stewart, Claudia Smith, Steven J. Milne, Thomas A. Wang, Gang G. Shun, Ming-Chieh Allis, C. David Engelman, Alan Hughes, Stephen H. TI Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; histone marks; lentiviral vectors ID HUMAN-IMMUNODEFICIENCY-VIRUS; AVIAN-SARCOMA VIRUS; HUMAN GENOME; CHROMATIN-BINDING; TARGET SITES; HISTONE H3; LEDGF/P75; REPLICATION; IDENTIFICATION; RETROTRANSPOSON AB Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1 alpha (HP1 alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1 alpha chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1 alpha chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy. C1 [Ferris, Andrea L.; Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Wu, Xiaolin; Stewart, Claudia] SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. [Hughes, Christina M.; Milne, Thomas A.; Wang, Gang G.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA. [Shun, Ming-Chieh; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov RI Wang, G Greg/L-6666-2014; Milne, Tom/E-1872-2016 OI Wang, G Greg/0000-0002-7210-9940; Milne, Tom/0000-0002-0413-4271 FU National Institutes of Health (NIH) (National Cancer Institute) [AI039394, T32 AI007386, GM53122]; Rockefeller University; Emerald Foundation; [HHSN261200800001E] FX We thank John Coffin and Alex Ruthenburg for helpful discussions; Kathleen Noer and Roberta Matthai of the Center for Cancer Research-Frederick Flow Cytometry Core for cell sorting; Alan Kane and Jiro Wada for helpwith thefigures; and Jeff Skaar and Teresa Burdette for help with themanuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) (National Cancer Institute). A portion of this funding was under Contract no. HHSN261200800001E. Research in the laboratory of A. E. was supported by NIH Grant AI039394, and M.-C. S. was supported in part by NIH Training Grant T32 AI007386. Research in the laboratory of C. D. A. was supported by NIH Method to Extend Research in Time Award GM53122 and The Rockefeller University. C. M. H. was supported by the Emerald Foundation. 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 34 TC 77 Z9 77 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 FEB 16 PY 2010 VL 107 IS 7 BP 3135 EP 3140 DI 10.1073/pnas.0914142107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500077 PM 20133638 ER PT J AU Lagenaur, LA Villarroel, VA Bundoc, V Dey, B Berger, EA AF Lagenaur, Laurel A. Villarroel, Vadim A. Bundoc, Virgilio Dey, Barna Berger, Edward A. TI sCD4-17b bifunctional protein: Extremely broad and potent neutralization of HIV-1 Env pseudotyped viruses from genetically diverse primary isolates SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VAGINAL LACTOBACILLUS STRAIN; GP120 ENVELOPE GLYCOPROTEIN; CORECEPTOR BINDING-SITE; MONOCLONAL-ANTIBODIES; MUCOSAL DELIVERY; RECEPTOR-BINDING; 2-DOMAIN CD4; VIRAL ENTRY; TYPE-1 AB Background: We previously described a potent recombinant HIV-1 neutralizing protein, sCD4-17b, composed of soluble CD4 attached via a flexible polypeptide linker to an SCFv of the 17b human monoclonal antibody directed against the highly conserved CD4-induced bridging sheet of gp120 involved in coreceptor binding. The sCD4 moiety of the bifunctional protein binds to gp120 on free virions, thereby enabling the 17b SCFv moiety to bind and block the gp120/coreceptor interaction required for entry. The previous studies using the MAGI-CCR5 assay system indicated that sCD4-17b (in concentrated cell culture medium, or partially purified) potently neutralized several genetically diverse HIIV-1 primary isolates; however, at the concentrations tested it was ineffective against several other strains despite the conservation of binding sites for both CD4 and 17b. To address this puzzle, we designed variants of sCD4-17b with different linker lengths, and tested the neutralizing activities of the immunoaffinity purified proteins over a broader concentration range against a large number of genetically diverse HIV-1 primary isolates, using the TZM-bl Env pseudotype assay system. We also examined the sCD4-17b sensitivities of isogenic viruses generated from different producer cell types. Results: We observed that immunoaffinity purified sCD4-17b effectively neutralized HIV-1 pseudotypes, including those from HIV-1 isolates previously found to be relatively insensitive in the MAGI-CCR5 assay. The potencies were equivalent for the original construct and a variant with a longer linker, as observed with both pseudotype particles and infectious virions; by contrast, a construct with a linker too short to enable simultaneous binding of the sCD4 and 17b SCFv moieties was much less effective. sCD4-17b displayed potent neutralizing activity against 100% of nearly 4 dozen HIV-1 primary isolates from diverse genetic subtypes (clades A, B, C, D, F, and circulating recombinant forms AE and AG). The neutralization breadth and potency were superior to what have been reported for the broadly neutralizing monoclonal antibodies IgG b12, 2G12, 2F5, and 4E10. The activity of sCD4-17b was found to be similar against isogenic virus particles from infectious molecular clones derived either directly from the transfected producer cell line or after a single passage through PBMCs; this contrasted with the monoclonal antibodies, which were less potent against the PMBC-passaged viruses. Conclusions: The results highlight the extremely potent and broad neutralizing activity of sCD4-17b against genetically diverse HIV-1 primary isolates. The bifunctional protein has potential applications for antiviral approaches to combat HIV infection. C1 [Lagenaur, Laurel A.; Villarroel, Vadim A.; Bundoc, Virgilio; Dey, Barna; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM edward_berger@nih.gov FU NIH, NIAID FX We are grateful to several colleagues for their generous donation of reagents including: J. Mascola for several Env expression plasmids and IMC particles derived from 293T cells and PBMCs; V. Polonis and S. Tovanabutra for some pseudotyped viruses; G. Nabel for the plasmid vector VRC8400. We also thank V. Polonis and S. Tovanabutra for kindly sharing unpublished data. P. Kennedy provided outstanding technical assistance during the early phases of this work. This research was funded in part by the Intramural Program of the NIH, NIAID, including the NIH Intramural AIDS Targeted Antiviral Program. NR 60 TC 19 Z9 19 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 16 PY 2010 VL 7 AR 11 DI 10.1186/1742-4690-7-11 PG 13 WC Virology SC Virology GA 577JE UT WOS:000276218200001 PM 20158904 ER PT J AU Tjernlund, A Zhu, J Laing, K Diem, K McDonald, D Vazquez, J Cao, JH Ohlen, C McElrath, MJ Picker, LJ Corey, L AF Tjernlund, Annelie Zhu, Jia Laing, Kerry Diem, Kurt McDonald, David Vazquez, Julio Cao, Jianhong Ohlen, Claes McElrath, M. Juliana Picker, Louis J. Corey, Lawrence TI In situ detection of Gag-specific CD8(+) cells in the GI tract of SIV infected Rhesus macaques SO RETROVIROLOGY LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; MAJOR HISTOCOMPATIBILITY COMPLEX; CYTOTOXIC T-LYMPHOCYTES; VIRAL-RNA LEVELS; GASTROINTESTINAL-TRACT; LYMPHOID FOLLICLES; HIV-1 REPLICATION; IMMUNE-RESPONSES; LAMINA PROPRIA; MONKEYS AB Background: SIV and HIV predominantly replicate in lymphoid tissue, but the study of virus specific CD8(+) T cells in intact lymphoid tissue is difficult, as traditional in situ tetramer staining requires fresh tissue. Results: In this report, we demonstrate a novel technique using Qdot 655-conjugated peptide-MHC multimers to directly visualize SIV specific cells in cryopreserved tissue biopsies from chronically SIVmac239 infected Rhesus macaques. Qdot 655 multimers showed similar sensitivity and specificity to APC-conjugated tetramers by flow cytometry analysis, but yielded ten-fold higher signal intensity when imaged by fluorescence microscopy. Using this technique, we detected CD8(+) T cells which recognize an immunodominant epitope (Gag CM9) in the spleen, lymph nodes, ileum and colon. In all these tissues, the Gag CM9 positive cells were mainly located in the extra follicular T cell zone. In the ileum and colon, we found Gag CM9 positive cells concentrated in Peyer's patches and solitary lymphoid follicles, a pattern of localization not previously described. Conclusions: The use of Qdot multimers provide an anatomic and quantitative evaluation of SIV specific CD8(+) T cell responses in SIV pathogenesis, and may prove useful to studies of SIV specific CD8(+) T cell responses elicited by vaccines and other immunotherapies in the non-human primate model. C1 [Tjernlund, Annelie; Zhu, Jia; Laing, Kerry; McElrath, M. Juliana; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98104 USA. [Diem, Kurt; McElrath, M. Juliana; Corey, Lawrence] Univ Washington, Dept Med, Seattle, WA USA. [Diem, Kurt; McElrath, M. Juliana; Corey, Lawrence] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Cao, Jianhong] Fred Hutchinson Canc Res Ctr, Immune Monitoring Lab, Seattle, WA 98104 USA. [Ohlen, Claes] NCI, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21701 USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Dept Pathol, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Dept Mol Microbiol, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Dept Immunol, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Vaccine & Gene Therapy Inst, Beaverton, OR USA. RP Corey, L (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, 1124 Columbia St, Seattle, WA 98104 USA. EM lcorey@u.washington.edu RI Laing, Kerry/C-2211-2008; OI Laing, Kerry/0000-0001-9245-5325; Tjernlund, Annelie/0000-0002-1061-5223 FU NCRR NIH HHS [RR00166]; NIAID NIH HHS [R37AI042528] NR 41 TC 9 Z9 9 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 16 PY 2010 VL 7 AR 12 DI 10.1186/1742-4690-7-12 PG 14 WC Virology SC Virology GA 568FI UT WOS:000275507300001 PM 20158906 ER PT J AU Pineda, DA Trujillo-Orrego, N Aguirre-Acevedo, DC Arango, CP Hincapie-Henao, L Montoya-Arenas, DA Lopera, F Pineda-Alvarez, DE Arcos-Burgos, M Muenke, M AF Pineda, David A. Trujillo-Orrego, Natalia Aguirre-Acevedo, Daniel C. Arango, Clara P. Hincapie-Henao, Liliana Montoya-Arenas, David A. Lopera, Francisco Pineda-Alvarez, Daniel E. Arcos-Burgos, Mauricio Muenke, Maxiliam TI Utility of the Wender-Utah Rating Scale and the checklists for the diagnosis of familial attention deficit hyperactivity disorder in adults. Convergent and concurrent validities SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE ADHD; Checklist; Hyperactivity; Inattention; Rating scales; Validity; Wender-Utah ID DEFICIT/HYPERACTIVITY DISORDER; PSYCHIATRIC COMORBIDITY; ENVIRONMENTAL-FACTORS; ADHD; CHILDREN; RELIABILITY; PREVALENCE; INTERVIEW; SYMPTOMS; POPULATION AB Introduction. Standard questionnaires to characterize familial attention deficit hyperactivity disorder (ADHD) of adults have been studied in some studies. Aim. To observe convergent and concurrent validity of four standard rating scales to quantify the familial AND symptoms of adults. Patients and methods. The sample was constituted by the 392 adults; aged 18 through 84 years, belonging to 141 Antioquian families with multiple AND affected members, who fulfilled by self-report the Wender-Utah Rating Scale and the AND checklist; and, beside, answered a questionnaire asking for current and past AND symptoms, in a neurological interview. Correlation analyses were done. Sensitivity and specificity for AND diagnosis were also determined. Results. Significant and over 0.6 correlations were observed between scales that explored past AND symptoms. Distant cut-off points for 90% sensitivity and specificity were observed for all questionnaires. The best LR+ (12.15) was found for the report of 5 or more past hyperactivity-impulsivity symptoms; follow by the report of 7 or more past AND symptoms (6.92). Conclusions. Cut-off points should be taken with caution when these rating scales were used for adult AND screening. Psychometric properties do not allow using these scales as substitution of structured clinical interview for the gold standard AND diagnosis in adults. C1 [Pineda, David A.] Univ Antioquia, SIU, Grp Neurociencias Antioquia, Medellin, Colombia. [Aguirre-Acevedo, Daniel C.; Arango, Clara P.; Montoya-Arenas, David A.; Pineda-Alvarez, Daniel E.] Univ San Buenaventura, Grp Neuropsicol & Conducta, Medellin, Colombia. [Arcos-Burgos, Mauricio] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Pineda-Alvarez, Daniel E.; Arcos-Burgos, Mauricio; Muenke, Maxiliam] NHGRI, Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Pineda, DA (reprint author), Univ Antioquia, SIU, Grp Neurociencias Antioquia, Calle 62,52-59 Lab 412, Medellin, Colombia. EM dpineda12@hotmail.com NR 51 TC 3 Z9 3 U1 2 U2 2 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD FEB 16 PY 2010 VL 50 IS 4 BP 207 EP 216 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 571OL UT WOS:000275763500003 PM 20198592 ER PT J AU Goldner, WS Sandler, DP Yu, F Hoppin, JA Kamel, F LeVan, TD AF Goldner, Whitney S. Sandler, Dale P. Yu, Fang Hoppin, Jane A. Kamel, Freya LeVan, Tricia D. TI Pesticide Use and Thyroid Disease Among Women in the Agricultural Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE agriculture; environmental exposure; hyperthyroidism; hypothyroidism; pesticides; thyroid gland ID POLYCHLORINATED-BIPHENYLS; ENVIRONMENTAL CHEMICALS; HYPOTHYROIDISM; PREVALENCE; MALATHION; HORMONES; WORKERS AB Thyroid disease is common, and evidence of an association between organochlorine exposure and thyroid disease is increasing. The authors examined the cross-sectional association between ever use of organochlorines and risk of hypothyroidism and hyperthyroidism among female spouses (n = 16,529) in Iowa and North Carolina enrolled in the Agricultural Health Study in 1993-1997. They also assessed risk of thyroid disease in relation to ever use of herbicides, insecticides, fungicides, and fumigants. Prevalence of self-reported clinically diagnosed thyroid disease was 12.5%, and prevalence of hypothyroidism and hyperthyroidism was 6.9% and 2.1%, respectively. There was an increased odds of hypothyroidism with ever use of organochlorine insecticides (adjusted odds ratio (OR(adj)) = 1.2 (95% confidence interval (CI): 1.0, 1.6) and fungicides (OR(adj) = 1.4 (95% CI: 1.1, 1.8) but no association with ever use of herbicides, fumigants, organophosphates, pyrethroids, or carbamates. Specifically, ever use of the organochlorine chlordane (OR(adj) = 1.3 (95% CI: 0.99, 1.7), the fungicides benomyl (OR(adj) = 3.1 (95% CI: 1.9, 5.1) and maneb/mancozeb (OR(adj) = 2.2 (95% CI: 1.5, 3.3), and the herbicide paraquat (OR(adj) = 1.8 (95% CI: 1.1, 2.8) was significantly associated with hypothyroidism. Maneb/mancozeb was the only pesticide associated with both hyperthyroidism (OR(adj) = 2.3 (95% CI: 1.2, 4.4) and hypothyroidism. These data support a role of organochlorines, in addition to fungicides, in the etiology of thyroid disease among female spouses enrolled in the Agricultural Health Study. C1 [Goldner, Whitney S.] Univ Nebraska, Med Ctr, Dept Internal Med, Diabet Endocrinol & Metab Sect, Omaha, NE 68198 USA. [LeVan, Tricia D.] Univ Nebraska, Med Ctr, Pulm Crit Care Sleep & Allergy Med Sect, Dept Internal Med, Omaha, NE 68198 USA. [Yu, Fang] Univ Nebraska, Med Ctr, Dept Biostat, Coll Publ Hlth, Omaha, NE 68198 USA. [LeVan, Tricia D.] Univ Nebraska, Med Ctr, Dept Epidemiol, Coll Publ Hlth, Omaha, NE 68198 USA. [Sandler, Dale P.; Hoppin, Jane A.; Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Goldner, WS (reprint author), Univ Nebraska, Med Ctr, Dept Internal Med, Diabet Endocrinol & Metab Sect, 983020 Nebraska Med Ctr, Omaha, NE 68198 USA. EM wgoldner@unmc.edu RI Yu, Fang/B-9874-2013; OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU NIH; National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01-CP010119] FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049030), and National Cancer Institute (Z01-CP010119). NR 32 TC 46 Z9 47 U1 2 U2 11 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 FEB 15 PY 2010 VL 171 IS 4 BP 455 EP 464 DI 10.1093/aje/kwp404 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 553BY UT WOS:000274340900008 PM 20061368 ER PT J AU Reedy, J Wirfalt, E Flood, A Mitrou, PN Krebs-Smith, SM Kipnis, V Midthune, D Leitzmann, M Hollenbeck, A Schatzkin, A Subar, AF AF Reedy, Jill Wirfalt, Elisabet Flood, Andrew Mitrou, Panagiota N. Krebs-Smith, Susan M. Kipnis, Victor Midthune, Douglas Leitzmann, Michael Hollenbeck, Albert Schatzkin, Arthur Subar, Amy F. TI Comparing 3 Dietary Pattern Methods-Cluster Analysis, Factor Analysis, and Index Analysis-With Colorectal Cancer Risk SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE colorectal neoplasms; food habits; risk ID MAJOR CHRONIC DISEASE; FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; GUIDELINES-FOR-AMERICANS; RETIRED-PERSONS DIET; NIH-AARP DIET; NATIONAL-INSTITUTES; PROSPECTIVE COHORT; WOMEN; MORTALITY AB The authors compared dietary pattern methods-cluster analysis, factor analysis, and index analysis-with colorectal cancer risk in the National Institutes of Health (NIH)-AARP Diet and Health Study (n = 492,306). Data from a 124-item food frequency questionnaire (1995-1996) were used to identify 4 clusters for men (3 clusters for women), 3 factors, and 4 indexes. Comparisons were made with adjusted relative risks and 95% confidence intervals, distributions of individuals in clusters by quintile of factor and index scores, and health behavior characteristics. During 5 years of follow-up through 2000, 3,110 colorectal cancer cases were ascertained. In men, the vegetables and fruits cluster, the fruits and vegetables factor, the fat-reduced/diet foods factor, and all indexes were associated with reduced risk; the meat and potatoes factor was associated with increased risk. In women, reduced risk was found with the Healthy Eating Index-2005 and increased risk with the meat and potatoes factor. For men, beneficial health characteristics were seen with all fruit/vegetable patterns, diet foods patterns, and indexes, while poorer health characteristics were found with meat patterns. For women, findings were similar except that poorer health characteristics were seen with diet foods patterns. Similarities were found across methods, suggesting basic qualities of healthy diets. Nonetheless, findings vary because each method answers a different question. C1 [Reedy, Jill] NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. [Leitzmann, Michael] Univ Hosp Regensburg, Regensburg, Germany. [Wirfalt, Elisabet] Lund Univ, Malmo, Sweden. [Flood, Andrew] Univ Minnesota, Minneapolis, MN USA. [Mitrou, Panagiota N.] World Canc Res Fund, London, England. [Mitrou, Panagiota N.] Univ Cambridge, Cambridge, England. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Reedy, J (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,EPN 4005,MSC 7344, Bethesda, MD 20892 USA. EM reedyj@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 31 TC 73 Z9 78 U1 1 U2 11 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 FEB 15 PY 2010 VL 171 IS 4 BP 479 EP 487 DI 10.1093/aje/kwp393 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 553BY UT WOS:000274340900010 PM 20026579 ER PT J AU Muenke, M Solomon, BD Odent, S AF Muenke, Maximilian Solomon, Benjamin D. Odent, Sylvie TI Introduction to the American Journal of Medical Genetics Part C on Holoprosencephaly SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Editorial Material C1 [Muenke, Maximilian] NIH, Bethesda, MD 20892 USA. [Odent, Sylvie] Univ Rennes 1, Holoprosencephaly Grp, Genet Pathol Liees Dev Branch, CNRS,UMR 6061,IGDR, F-35014 Rennes, France. [Odent, Sylvie] Hop Sud Rennes, CHU, Clin Genet Serv, Rennes, France. RP Muenke, M (reprint author), NIH, MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 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 FEB 15 PY 2010 VL 154C IS 1 BP 1 EP 2 DI 10.1002/ajmg.c.30255 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700001 PM 20104593 ER PT J AU Solomon, BD Pineda-Alvarez, DE Mercier, S Raam, MS Odent, S Muenke, M AF Solomon, Benjamin D. Pineda-Alvarez, Daniel E. Mercier, Sandra Raam, Manu S. Odent, Sylvie Muenke, Maximilian TI Holoprosencephaly Flashcards: A Summary for the Clinician SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE holoprosencephaly; flashcards ID MUTATIONS AB This material contains general information regarding the approach to patients with holoprosencephaly. For more detailed discussion, please refer to specific articles in this issue. Published 2010 Wiley-Liss, Inc. C1 [Mercier, Sandra; Odent, Sylvie] Univ Rennes 1, Holoprosencephaly Grp, Genet Pathol Liees Dev Branch, UMR 6061,CNRS,IGDR, F-35014 Rennes, France. [Mercier, Sandra; Odent, Sylvie] CHU Hop Sud Rennes, Clin Genet Serv, Rennes, France. [Raam, Manu S.] HHMI NIH Res Scholars Program, Bethesda, MD USA. RP Muenke, M (reprint author), Bldg 35,1B203,35 Convent Dr,MSC 3717, Bethesda, MD 20892 USA. EM muenke@nih.gov NR 3 TC 9 Z9 9 U1 1 U2 2 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 FEB 15 PY 2010 VL 154C IS 1 BP 3 EP 7 DI 10.1002/ajmg.c.30245 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700002 PM 20104594 ER PT J AU Roessler, E Muenke, M AF Roessler, Erich Muenke, Maximilian TI The Molecular Genetics of Holoprosencephaly SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Review DE HPE; disease genes; holoprosencephaly; multifactorial inheritance ID SONIC HEDGEHOG GENE; 4 BRAZILIAN PATIENTS; HUMAN SIX3 GENE; RETINOIC ACID; NEURAL PLATE; EYE DEVELOPMENT; VERTEBRATE DEVELOPMENT; FUNCTIONAL-ANALYSIS; MOUSE DEVELOPMENT; GENOMIC STRUCTURE AB Holoprosencephaly (HPE) has captivated the imagination of Man for millennia because its most extreme manifestation, the single-eyed cyclopic newborn infant, brings to mind the fantastical creature Cyclops from Greek mythology. Attempting to understand this common malformation of the forebrain in modern medical terms requires a systematic synthesis of genetic, cytogenetic, and environmental information typical for studies of a complex disorder. However, even with the advances in our understanding of HPE in recent years, there are significant obstacles remaining to fully understand its heterogeneity and extensive variability in phenotype. General lessons learned from HPE will likely be applicable to other malformation syndromes. Here we outline the common, and rare, genetic and environmental influences on this conserved developmental program of forebrain development and illustrate the similarities and differences between these malformations in humans and those of animal models. Published 2010 Wiley-Liss, Inc. C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov FU NHGRI, NIH FX The authors thank the clinicians from around the world for their continuing support of research investigations into the genetic basis OF HPE and its clinical manifestations. This work is dedicated to the families who are confronting HPE as a diagnosis and the demands of a special needs child, and for their frequently amazing resilience and strength. This work was supported by the DIR of the NHGRI, NIH. NR 120 TC 83 Z9 83 U1 1 U2 16 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 FEB 15 PY 2010 VL 154C IS 1 BP 52 EP 61 DI 10.1002/ajmg.c.30236 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700008 PM 20104595 ER PT J AU Pineda-Alvarez, DE Dubourg, C David, V Roessler, E Muenke, M AF Pineda-Alvarez, Daniel E. Dubourg, Christele David, Veronique Roessler, Erich Muenke, Maximilian TI Current Recommendations for the Molecular Evaluation of Newly Diagnosed Holoprosencephaly Patients SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE holoprosencephaly; HPE; disease genes; multi-factorial inheritance; molecular diagnostics ID DNA MELTING ANALYSIS; HUMAN SIX3 GENE; FOREBRAIN DEVELOPMENT; MUTATIONS; PHENOTYPE; GENOTYPE; SPECTRUM; FEATURES; DISEASE; ZIC2 AB Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans and is typically characterized by different degrees of hemispheric separation that are often accompanied by similarly variable degrees of craniofacial and midline anomalies. HPE is a classic example of a complex genetic trait with "pseudo"-autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high-resolution karyotyping, clinical assessment to rule-out well recognized syndromes that are associated with HPE (e.g., Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3). In this review, we provide current step-by-step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide. Published 2010 Wley-Liss, Inc. C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [David, Veronique] Univ Rennes 1, Holoprosercephaly Grp, Branch Genet Dev Pathol, UMR 6061,CNRS,IGDR,Fac Med, F-35014 Rennes, France. [David, Veronique] CHU Pontchaillou, Mol Diag Lab, Rennes, France. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Intramural NIH HHS [Z01 HG000209-06] NR 41 TC 30 Z9 30 U1 0 U2 2 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 FEB 15 PY 2010 VL 154C IS 1 BP 93 EP 101 DI 10.1002/ajmg.c.30253 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700012 PM 20104604 ER PT J AU Haas, D Muenke, M AF Haas, Dorothea Muenke, Maximilian TI Abnormal Sterol Metabolism in Holoprosencephaly SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE holoprosencephaly; cholesterol biosynthesis; cholesterol precursors; Smith-Lemli-Opitz syndrome; Shh signaling ID LEMLI-OPITZ-SYNDROME; HEDGEHOG SIGNAL-TRANSDUCTION; CHOLESTEROL MODIFICATION; VERATRUM CALIFORNICUM; REDUCTASE GENE; MUTATIONS; EXPOSURE; CYCLOPAMINE; MEMBRANES; PROTEINS AB Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The HPE phenotype is extremely variable and the etiology is heterogeneous. Among a variety of embryological toxins that can induce HPE, inhibitors, and other pertubations of cholesterol biosynthesis have been shown to be important factors, most likely because cholesterol is required in the Sonic hedgehog signaling cascade. Decreased levels of maternal cholesterol during pregnancy increase the risk for preterm delivery, but they are not associated with congenital malformations. However, if the fetus is affected by an inborn error of endogenous cholesterol synthesis, a reduction of maternal cholesterol concentration and cholesterol transport over the placenta aggravates the phenotypic expression. Exposure to lipophilic statins in early pregnancy may be associated with a substantial risk for structural CNS defects. (c) 2010 Wiley-Liss, Inc. C1 [Haas, Dorothea] Univ Childrens Hosp, Div Inborn Metab Dis, Dept Gen Pediat, D-69120 Heidelberg, Germany. [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. RP Haas, D (reprint author), Univ Childrens Hosp, Div Inborn Metab Dis, Dept Gen Pediat, Neuenheimer Feld 430, D-69120 Heidelberg, Germany. EM dorothea.haas@med.uni-heidelberg.de FU Division of Intramural Research of the National Human Genome Research Institute; National Institutes of Health; Department of Health and Human Services FX Grant sponsor: Division of Intramural Research of the National Human Genome Research Institute; Grant sponsor: National Institutes of Health; Grant sponsor: Department of Health and Human Services. NR 40 TC 9 Z9 9 U1 0 U2 4 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 FEB 15 PY 2010 VL 154C IS 1 BP 102 EP 108 DI 10.1002/ajmg.c.30243 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700013 PM 20104605 ER PT J AU Solomon, BD Mercier, S Velez, JI Pineda-Alvarez, DE Wyllie, A Zhou, N Dubourg, C David, V Odent, S Roessler, E Muenke, M AF Solomon, Benjamin D. Mercier, Sandra Velez, Jorge I. Pineda-Alvarez, Daniel E. Wyllie, Adrian Zhou, Nan Dubourg, Christele David, Veronique Odent, Sylvie Roessler, Erich Muenke, Maximilian TI Analysis of Genotype-Phenotype Correlations in Human Holoprosencephaly SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE holoprosencephaly (HPE) ID HUMAN SIX3 GENE; MUTATIONS; SPECTRUM; BRAIN; DISORDERS; CHILDREN; DEFECTS; MODELS; DOMAIN; GLI2 AB Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non-chromosomal, non-syndromic HPE have been described, with detailed descriptions available in over 300. Comprehensive clinical analysis of these individuals allows examination for the presence of genotype-phenotype correlations. These correlations allow a degree of differentiation between patients with mutations in different HPE-associated genes and for the application of functional studies to determine intragenic correlations. These early correlations are an important advance in the understanding of the clinical aspects of this disease, and in general argue for continued analysis of the genetic and clinical findings of large cohorts of patients with rare diseases in order to better inform both basic biological insight and care and counseling for affected patients and families. Published 2010 Wiley-Liss, Inc. C1 [Wyllie, Adrian; Zhou, Nan; Muenke, Maximilian] NHGRI, NIH, Bethesda, MD 20892 USA. [David, Veronique] Univ Rennes 1, Holoprosencephaly Grp, Genet Pathol Liees Dev Branch, CNRS,IGDR,Fac Med,UMR 6061, F-35014 Rennes, France. [Mercier, Sandra; Odent, Sylvie] CHU Hop Sud Rennes, Clin Genet Serv, Rennes, France. [Velez, Jorge I.] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Wyllie, Adrian] Univ Dist Columbia, Washington, DC USA. [David, Veronique] CHU Pontchaillou, Mol Diag Lab, Rennes, France. RP Muenke, M (reprint author), NHGRI, NIH, MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research; National Human Genome Research Institute; National Institutes of Health and Human Services, United States of America; GIS Maladies Rares, France [GISMR0701/DHOS] FX Grant sponsor: Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America; Grant sponsor: GIS Maladies Rares, France; Grant number: GISMR0701/DHOS. NR 43 TC 70 Z9 72 U1 0 U2 9 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 FEB 15 PY 2010 VL 154C IS 1 BP 133 EP 141 DI 10.1002/ajmg.c.30240 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700016 PM 20104608 ER PT J AU Weaver, DD Solomon, BD Akin-Samson, K Kelley, RI Muenke, M AF Weaver, David D. Solomon, Benjamin D. Akin-Samson, Kelly Kelley, Richard I. Muenke, Maximilian TI Cyclopia (Synophthalmia) in Smith-Lemli-Opitz Syndrome: First Reported Case and Consideration of Mechanism SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE cyclopia; synophthalmia; Smith-Lemli-Opitz syndrome; birth defects; cholesterol; 7-dehydrocholesterol; holoprosencephaly ID ABNORMAL CHOLESTEROL-METABOLISM; GENOTYPE-PHENOTYPE CORRELATION; DELTA-7-STEROL REDUCTASE GENE; SONIC-HEDGEHOG; MUTATIONS; DIAGNOSIS; SPECTRUM; RECEPTOR AB Here we present a 24-week fetus with Smith-Lemli-Opitz syndrome (SLOS), alobar holoprosencephaly (HPE) and cyclopia (synophthalmia). Following birth, we suspected SILOS in this fetus due to the additional findings of ambiguous genitalia and bilateral 2-3 toe syndactyly. The diagnosis of SILOS was confirmed by finding an elevated amniotic fluid 7-dehydrocholesterol level (9,890 ng/ml normal range = 3-9 ng/ml), and molecularly by detecting two different mutations in the DHCR7 gene, the gene causing SLOS. The first mutation was an IVS8-1G > T change and the second was a deletion of exons 3 and 4; this latter mutation has not been reported previously. The mother carries the deletion, while the father carries the splice-site mutation. Also of note, the father has an abnormally low total plasma cholesterol level (104-109 mg/dl). This is the most severe case of HPE described in any patient with SILOS. We postulate that the HPE in this case resulted from severe impairment of Sonic Hedgehog signaling secondary to abnormal cholesterol metabolisms however, the unique combination of mutations in the fetus functionally appears to be no different from other homozygous null mutations reported in DHCR7. Therefore, there must be other yet to be identified factors that contributed to the severity of HPE in SILOS. (c) 2010 Wiley-Liss, Inc. C1 [Weaver, David D.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Akin-Samson, Kelly] Indiana Univ, Maternal & Fetal Med Sect, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Kelley, Richard I.] Johns Hopkins Univ, Baltimore, MD USA. [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Weaver, DD (reprint author), Indiana Univ, Sch Med, Dept Med & Mol Genet, IB 130,975 W Walnut St, Indianapolis, IN 46202 USA. EM dweaver@iupui.edu FU National Human Genome Research Institute, National Institutes of Health FX The cooperation of the parents of the fetus reported here is graciously recognized. Without their support this study could not have been completed. Dr. Steve Dlouhy assisted in the storage and preparation of DNA samples and We recognize his efforts. We also thank Dr. Erich Roessler for his valuable input to the Discussion. This work was supported in part by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. NR 18 TC 22 Z9 22 U1 0 U2 2 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 FEB 15 PY 2010 VL 154C IS 1 BP 142 EP 145 DI 10.1002/ajmg.c.30241 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700017 PM 20104611 ER PT J AU Solomon, BD Rosenbaum, KN Meck, JM Muenke, M AF Solomon, Benjamin D. Rosenbaum, Kenneth N. Meck, Jeanne M. Muenke, Maximilian TI Holoprosencephaly Due To Numeric Chromosome Abnormalities SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE holoprosencephaly; HPE; chromosome anomalies; trisomy; triploidy ID PRENATAL-DIAGNOSIS; METROPOLITAN ATLANTA; TRIPLOIDY; TRISOMY-13; ORIGIN; EPIDEMIOLOGY; ASSOCIATION; MUTATIONS; PHENOTYPE AB Holoprosencephaly (HPE) is the most common malformation of the human forebrain. When a clinician identifies a patient with HPE a routine chromosome analysis is often the first genetic test sent for laboratory analysis in order to assess for a structural or numerical chromosome anomaly. An abnormality of chromosome number is overall the most frequently identified etiology in a patient with HPE. These abnormalities include trisomy 13, trisomy 18, and triploidy though several others have been reported. Such chromosome number abnormalities are almost universally fatal early in gestation or in infancy. Clinical features of specific chromosome number abnormalities may be recognized by phenotypic manifestations in addition to the HPE. Published 2010 Wiley-Liss, Inc. C1 [Muenke, Maximilian] NIH, Bethesda, MD 20892 USA. [Rosenbaum, Kenneth N.] George Washington Univ, Sch Medicine, Washington, DC 20052 USA. [Meck, Jeanne M.] Quest Diagnost Nichols Inst, Chantilly, VA USA. [Meck, Jeanne M.] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. RP Muenke, M (reprint author), NIH, MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America FX Grant sponsor: Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America. NR 26 TC 20 Z9 20 U1 0 U2 1 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 FEB 15 PY 2010 VL 154C IS 1 BP 146 EP 148 DI 10.1002/ajmg.c.30232 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700018 PM 20104610 ER PT J AU Kauvar, EF Solomon, BD Curry, CJR Van Essen, AJ Janssen, N Dutra, A Roessler, E Muenke, M AF Kauvar, Emily F. Solomon, Benjamin D. Curry, Cynthia J. R. Van Essen, Anthonie J. Janssen, Nicole Dutra, Amalia Roessler, Erich Muenke, Maximilian TI Holoprosencephaly and Agnathia Spectrum: Presentation of Two New Patients and Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Review DE holoprosencephaly (HPE); agnathia; dysgnathia; otocephaly; first pharyngeal arch; first branchial arch; situs inversus ID SITUS-INVERSUS; CRANIOFACIAL DEVELOPMENT; GUINEA-PIGS; COMPLEX; ASSOCIATION; CYCLOPIA; MICE; MORPHOGENESIS; MUTATIONS; MOUSE AB Holoprosencephaly (HPE), the most common developmental disorder of the human forebrain, is occasionally associated with the spectrum of agnathia, or virtual absence of the mandible. This condition results in a constellation of structural cerebral and craniofacial abnormalities. Here we present two new patients and review 30 patients from the literature with HPE and variants of agnathia. The majority of these patients are female and have the most severe forms of HPE, with cyclopia present more frequently than is usually observed in cohorts of patients with HPE. Also, many patients have additional clinical findings not typical in patients with classic HPE, particularly situs abnormalities. Recent animal studies suggest that the association of HPE and agnathia may relate to alterations in signaling from forebrain and foregut endoderm organizing centers and subsequent first pharyngeal arch development, although present models are inadequate to explain all of the clinical findings of this enigmatic human syndrome. Further research is required to better elucidate the causal and pathogenic basis of this association. Published 2010 Wley-Liss, Inc. C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Curry, Cynthia J. R.] Univ Calif San Francisco, Fresno, CA USA. [Van Essen, Anthonie J.; Janssen, Nicole] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Dutra, Amalia] NHGRI, Core Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, United States of America FX Grant sponsor: Division of intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, United States of America. NR 65 TC 16 Z9 16 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD FEB 15 PY 2010 VL 154C IS 1 BP 158 EP 169 DI 10.1002/ajmg.c.30235 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700020 PM 20104613 ER PT J AU Keaton, AA Solomon, BD Van Essen, AJ Pfleghaar, KM Slama, MA Martin, JA Muenke, M AF Keaton, Amelia A. Solomon, Benjamin D. Van Essen, Anthonie J. Pfleghaar, Kathleen M. Slama, Michael A. Martin, Judith A. Muenke, Maximilian TI Holoprosencephaly and Ectrodactyly: Report of Three New Patients and Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Review DE holoprosencephaly; HPE; ectrodactyly ID CLEFT-LIP; ASSOCIATION; PALATE AB Holoprosencephaly (HPE) and ectrodactyly represent congenital malformations of the developing forebrain and developing digits, respectively. The combination of these conditions is rare, with only 15 cases known to date (12 previously reported, and 3 new cases described here). While the findings in these patients overlap with previously described genetic conditions, the similarity in phenotypes among these patients has led to the establishment of a at least one distinct syndrome: HPE, ectrodactyly, and bilateral cleft lip-palate syndrome (OMIM 300571). There has been great interest in identifying a genetic cause for the findings in patients with HPE and ectrodactyly; however the cause(s) of this rare association still remain unknown. Published 2010 Wiley-Liss, Inc. C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Keaton, Amelia A.] Univ S Carolina, Columbia, SC 29208 USA. [Van Essen, Anthonie J.] Univ Groningen, Dept Genet, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. [Pfleghaar, Kathleen M.] Abbott NW Hosp, Minneapolis, MN 55407 USA. [Martin, Judith A.] Inland NW Genet Clin, Spokane, WA USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov FU Division of Intramural Research; Grant sponsor: National Human Genome Research Institute; Grant sponsor: National Institutes of Health; Department of Health and Human Services, United States of America FX Grant sponsor: Division of Intramural Research; Grant sponsor: National Human Genome Research Institute; Grant sponsor: National Institutes of Health; Grant sponsor: Department of Health and Human Services, United States of America. NR 13 TC 10 Z9 10 U1 2 U2 4 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 FEB 15 PY 2010 VL 154C IS 1 BP 170 EP 175 DI 10.1002/ajmg.c.30251 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700021 PM 20104609 ER PT J AU Raam, MS Solomon, BD Shalev, SA Muenke, M AF Raam, Manu S. Solomon, Benjamin D. Shalev, Stavit A. Muenke, Maximilian TI Holoprosencephaly and Craniosynostosis: A Report of Two Siblings and Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Review DE holoprosencephaly; craniosynostoses; cranial sutures; receptors; fibroblast growth factor ID GENOA-SYNDROME; FACIAL CLEFTS; SHH; MORPHOGENESIS; ANOMALIES; FEATURES; AMELIA; FGF8 AB Holoprosencephaly (HPE) and craniosynostosis are separate conditions that have occasionally been observed to occur simultaneously in the same patient. Here, we compile patients with both conditions who have been documented in the literature thus far; moreover, we report on two additional siblings who have not been previously described. We also compare the clinical features of these patients and discuss the previously hypothesized possibility of an independent association including both HPE and craniosynostosis. Published 2010 Wiley-Liss, Inc. C1 [Solomon, Benjamin D.] NHGRI, Combined Pediat & Med Genet Residency Program, Bethesda, MD USA. [Shalev, Stavit A.] Emek Med Ctr, Genet Inst, Afula, Israel. [Muenke, Maximilian] NHGRI, Med Genet Branch, Div Intramural Res, Bethesda, MD USA. RP Muenke, M (reprint author), Bldg 35,Room 1B203,35 Convent Dr,MSC 3717, Bethesda, MD 20892 USA. EM muenke@nih.gov FU Howard Hughes Medical Institute; Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America) FX Grant sponsor: Howard Hughes Medical Institute, Grant sponsor: Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America). NR 29 TC 9 Z9 10 U1 1 U2 4 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 FEB 15 PY 2010 VL 154C IS 1 BP 176 EP 182 DI 10.1002/ajmg.c.30234 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 554YE UT WOS:000274471700022 PM 20104614 ER PT J AU Minton, AP AF Minton, Allen P. TI Analysis of membrane binding equilibria of peripheral proteins: Allowance for excluded area of bound protein SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID SURFACE-AREA; ADSORPTION; MODELS AB When peripheral proteins bind to phospholipid membranes lacking discrete binding sites, steric repulsion between bound protein molecules may result in a reduction of the surface area available to additional bound protein by an amount significantly greater than the actual area occupied by bound protein. An approximate treatment of this effect demonstrates that neglect of area exclusion by bound protein may lead to significant errors in the evaluation of equilibrium association constants and the fractional coverage of membrane surface area. Published by Elsevier Inc. C1 NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU Intramural NIH HHS [Z99 DK999999] NR 8 TC 5 Z9 5 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 15 PY 2010 VL 397 IS 2 BP 247 EP 249 DI 10.1016/j.ab.2009.10.023 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 550WN UT WOS:000274163900019 PM 19837044 ER PT J AU Chen, MH Yang, Q AF Chen, Ming-Huei Yang, Qiong TI GWAF: an R package for genome-wide association analyses with family data SO BIOINFORMATICS LA English DT Article AB GWAF, Genome-Wide Association analyses with Family, is an R package designed for GWAF. It implements association tests between a batch of genotyped or imputed single nucleotide polymorphisms (SNPs) and a binary or continuous trait with user specified genetic model, and generates informative results from the analyses. In addition, GWAF provides functions to visualize results. We evaluated GWAF using a simulated continuous trait and a binary trait dichotomized from the simulated continuous trait with real genotype data from the Framingham Heart Study's SNP Health Association Resource project. C1 [Chen, Ming-Huei; Yang, Qiong] Natl Heart Lung Blood Inst Framingham Heart Study, Framingham, MA 01702 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. RP Yang, Q (reprint author), Natl Heart Lung Blood Inst Framingham Heart Study, Framingham, MA 01702 USA. EM qyang@bu.edu RI Yang, Qiong/G-5438-2014; OI Yang, Qiong/0000-0002-3658-1375 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278] FX National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 4 TC 121 Z9 122 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2010 VL 26 IS 4 BP 580 EP 581 DI 10.1093/bioinformatics/btp710 PG 2 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 555CI UT WOS:000274484300023 PM 20040588 ER PT J AU Lee, TL Li, YM Cheung, HH Claus, J Singh, S Sastry, C Rennert, OM Lau, YFC Chan, WY AF Lee, Tin-Lap Li, Yunmin Cheung, Hoi-Hung Claus, Janek Singh, Sumeeta Sastry, Chandan Rennert, Owen M. Lau, Yun-Fai Chris Chan, Wai-Yee TI GonadSAGE: a comprehensive SAGE database for transcript discovery on male embryonic gonad development SO BIOINFORMATICS LA English DT Article ID MALE GERM-CELLS AB ASerial analysis of gene expression ( SAGE) provides an alternative, with additional advantages, to microarray gene expression studies. GonadSAGE is the first publicly available web-based SAGE database on male gonad development that covers six male mouse embryonic gonad stages, including E10.5, E11.5, E12.5, E13.5, E15.5 and E17.5. The sequence coverage of each SAGE library is beyond 150K, 'which is the most extensive sequence-based male gonadal transcriptome to date'. An interactive web interface with customizable parameters is provided for analyzing male gonad transcriptome information. Furthermore, the data can be visualized and analyzed with the other genomic features in the UCSC genome browser. It represents an integrated platform that leads to a better understanding of male gonad development, and allows discovery of related novel targets and regulatory pathways. C1 [Lee, Tin-Lap; Cheung, Hoi-Hung; Rennert, Owen M.; Chan, Wai-Yee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genom, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. [Li, Yunmin; Lau, Yun-Fai Chris] Univ Calif San Francisco, VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Cheung, Hoi-Hung; Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Claus, Janek; Singh, Sumeeta; Sastry, Chandan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Informat Technol, NIH, Bethesda, MD 20892 USA. RP Lee, TL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genom, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. EM leetl@mail.nih.gov RI Cheung, Hoi-Hung/G-7605-2011; Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural Research Program of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [HD33728] FX Intramural Research Program of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (HD33728) in part. NR 11 TC 8 Z9 8 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2010 VL 26 IS 4 BP 585 EP 586 DI 10.1093/bioinformatics/btp695 PG 2 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 555CI UT WOS:000274484300025 PM 20028690 ER PT J AU Goldman, D AF Goldman, David TI Gene X Environment Interactions in Complex Behavior: First, Build a Telescope SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID ALCOHOL; RISK C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, 5625 Fishers Lane, Rockville, MD 20852 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-10] NR 13 TC 5 Z9 5 U1 0 U2 1 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 FEB 15 PY 2010 VL 67 IS 4 BP 295 EP 296 DI 10.1016/j.biopsych.2009.12.005 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 554RC UT WOS:000274451100001 PM 20113740 ER PT J AU Schwandt, ML Lindell, SG Sjoberg, RL Chisholm, KL Higley, JD Suomi, SJ Heilig, M Barr, CS AF Schwandt, Melanie L. Lindell, Stephen G. Sjoeberg, Rickard L. Chisholm, Kelli L. Higley, J. Dee Suomi, Stephen J. Heilig, Markus Barr, Christina S. TI Gene-Environment Interactions and Response to Social Intrusion in Male and Female Rhesus Macaques SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Aggression; serotonin transporter; gene-environment; interaction; Macaca mulatta; sex differences; social intrusion ID SEROTONIN TRANSPORTER GENE; PROMOTER REGION POLYMORPHISM; NONHUMAN PRIMATE MODEL; SEX-DIFFERENCES; EARLY EXPERIENCE; VERVET MONKEYS; CERCOPITHECUS-AETHIOPS; INDIVIDUAL-DIFFERENCES; DISPLACED AGGRESSION; ALCOHOL-CONSUMPTION AB Background: Genetic factors interact with environmental stressors to moderate risk for human psychopathology, but sex may also be an important mediating factor. Different strategies for coping with environmental stressors have evolved in males and females, and these differences may underlie the differential prevalence of certain types of psychopathology in the two sexes. In this study, we investigated the possibility of sex-specific gene-environment interactions in a nonhuman primate model of response to social threat. Methods: Rhesus macaques (77 males and 106 females) were exposed to an unfamiliar conspecific. Using factor analysis, we identified three behavioral factors characterizing the response to social threat. Monkeys were genotyped for the serotonin transporter-linked polymorphism (5-HTTLPR), and the effects of genotype, early life stress, and sex on behavioral responses were evaluated. Results: Factor analysis produced five factors: High-Risk Aggression, Impulsivity/Novelty-Seeking, Gregariousness/Boldness, Harm Avoidance, and Redirected Aggression. Overall, males displayed higher levels of High-Risk Aggression and Gregariousness/Boldness than females. Levels of High-Risk Aggression in males carrying the s allele were significantly higher if they were also exposed to early adversity in the form of peer rearing. Conclusions: Our findings support those from studies in humans suggesting that males are more vulnerable to externalizing or aggression-related disorders. The results highlight the importance of interactions that exist among behavior, genes, and the environment and suggest that sex differences in vulnerability to psychopathology may be grounded in our evolutionary history. C1 [Schwandt, Melanie L.; Lindell, Stephen G.; Heilig, Markus; Barr, Christina S.] NIAAA, Lab Clin & Translat Studies, NIH, Poolesville, MD USA. [Sjoeberg, Rickard L.] Uppsala Univ, Clin Res Ctr, Uppsala, Sweden. [Sjoeberg, Rickard L.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Sjoeberg, Rickard L.] Univ Hosp Umea, Dept Neurosurg, Umea, Sweden. [Chisholm, Kelli L.] NIMH, Div Intramural Res Programs Nonhuman Primate Core, NIH, Poolesville, MD USA. [Higley, J. Dee] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Suomi, Stephen J.] Natl Inst Child Hlth & Dev, Comparat Ethol Lab, NIH, Poolesville, MD USA. RP Schwandt, ML (reprint author), NIAAA, NIH, Lab Clin & Translat Studies, 10 Ctr Dr,10 CRC 15330, Bethesda, MD 20892 USA. EM melanies@mail.nih.gov RI Sjoberg, Rickard/B-9337-2008; Sjoberg, Rickard/M-4690-2014; Schwandt, Melanie/L-9866-2016; OI Heilig, Markus/0000-0003-2706-2482 FU Intramural NIH HHS [Z99 AA999999] NR 66 TC 38 Z9 38 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2010 VL 67 IS 4 BP 323 EP 330 DI 10.1016/j.biopsych.2009.10.016 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 554RC UT WOS:000274451100006 PM 20015482 ER PT J AU Ulrich, NC Kodet, JG Mente, NR Kuder, CH Beutler, JA Hohl, RJ Wiemer, DF AF Ulrich, Natalie C. Kodet, John G. Mente, Nolan R. Kuder, Craig H. Beutler, John A. Hohl, Raymond J. Wiemer, David F. TI Structural analogues of schweinfurthin F: Probing the steric, electronic, and hydrophobic properties of the D-ring substructure SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Schweinfurthin; Stilbene; Synthesis; Anti-proliferative; Bioassay ID MACARANGA-SCHWEINFURTHII; BIOLOGICAL EVALUATION; GLIOBLASTOMA; STILBENES; CANCER; AGENTS AB The natural tetracyclic schweinfurthins are potent and selective inhibitors of cell growth in the National Cancer Institute's 60-cell line screen. An interest in determination of their cellular or molecular target has inspired our efforts to prepare both the natural products and analogues. In this paper, chemical synthesis of analogues modified in different olefinic positions, and preliminary results from studies of their biological activity, are reported. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ulrich, Natalie C.; Kodet, John G.; Mente, Nolan R.; Wiemer, David F.] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Kuder, Craig H.; Hohl, Raymond J.; Wiemer, David F.] Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA. [Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Hohl, Raymond J.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. RP Wiemer, DF (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. EM david-wiemer@uiowa.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU Roy J. Carver Charitable Trust; Roland W. Holden Family Program for Experimental Cancer Therapeutics; NIH [R41CA126020-01]; National Cancer Institute; Center for Cancer Research FX We thank Dr. David G. Covell, NCI-Frederick, for helpful discussions. This project was supported at the UI by the Roy J. Carver Charitable Trust as a Research Program of Excellence, the Roland W. Holden Family Program for Experimental Cancer Therapeutics, and the NIH through R41CA126020-01 to Terpenoid Therapeutics, Inc. This research at the NCI was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; we thank the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, for 60-cell testing. NR 26 TC 14 Z9 14 U1 0 U2 6 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 FEB 15 PY 2010 VL 18 IS 4 BP 1676 EP 1683 DI 10.1016/j.bmc.2009.12.063 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 554HG UT WOS:000274425500033 PM 20116262 ER PT J AU Takada, K Imamura, N Gustafson, KR Henrich, CJ AF Takada, Kentaro Imamura, Nobutaka Gustafson, Kirk R. Henrich, Curtis J. TI Synthesis and structure-activity relationship of botryllamides that block the ABCG2 multidrug transporter SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Natural products; ABCG2 blocker; Structure-activity relationships; Synthesis ID RESISTANCE; INHIBITORS AB In previous work, botryllamides discovered from the marine ascidian Botryllus tyreus were characterized as selective inhibitors of the ABCG2 multidrug transporter. However, the structural basis for this activity could not be established. In this study, botryllamide F, the core botryllamide structure, and botryllamide G, the most potent botryllamide ABCG2 inhibitor, were synthesized along with a series of structural variants for evaluation of structure - activity relationships. The biological activity of synthetic botryllamide analogs implied that the 2-methoxy-p-coumaric acid portion, and the degree of double bond conjugation within this group, were critical for inhibition of ABCG2. However, variations in the substituents on the two aryl groups did not appear to significantly impact the potency or degree of inhibition. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Takada, Kentaro; Imamura, Nobutaka] Ritsumeikan Univ, Lab Microbial Chem, Coll Pharmaceut Sci, Shiga 5258577, Japan. [Gustafson, Kirk R.; Henrich, Curtis J.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, Curtis J.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Takada, K (reprint author), Ritsumeikan Univ, Lab Microbial Chem, Coll Pharmaceut Sci, 1-1-1 Noji Higashi, Shiga 5258577, Japan. EM takada@ph.ritsumei.ac.jp FU Japan Science and Technology Agency; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX We are grateful to Dr. Hiroshi Hirota, RIKEN, JAPAN, for helpful suggestions. This project has been partly supported by Comprehensive Support Programs for Creation of Regional Innovation from Japan Science and Technology Agency. This project has also 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 11 TC 13 Z9 14 U1 1 U2 4 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 FEB 15 PY 2010 VL 20 IS 4 BP 1330 EP 1333 DI 10.1016/j.bmcl.2010.01.016 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 552JJ UT WOS:000274285600002 PM 20097565 ER PT J AU Afzal, A Caballero, S Palii, SS Jurczyk, S Pardue, M Geroski, D Edelhauser, H Hochhaus, G Kim, M Franklin, A Shapiro, G Grant, MB AF Afzal, Aqeela Caballero, Sergio Palii, Stela S. Jurczyk, Simona Pardue, Machelle Geroski, Dale Edelhauser, Henry Hochhaus, Guenther Kim, Moon Franklin, Alan Shapiro, Gideon Grant, Maria B. TI Targeting retinal and choroid neovascularization using the small molecule inhibitor carboxyamidotriazole SO BRAIN RESEARCH BULLETIN LA English DT Article DE Angiogenesis; Therapy; Choroidal Neovascularization; Endothelial cell; Animal model; Carboxyamidotriazole ID MEDIATED SIGNAL-TRANSDUCTION; MACULAR DEGENERATION; GROWTH; CELLS; CALCIUM; EFFICACY; RECEPTOR; CAI; PROLIFERATION; ANGIOGENESIS AB Neovascular ocular diseases as exemplified by proliferative diabetic retinopathy (PDR), exudative age-related macular degeneration (AMD), and retinopathy of prematurity (ROP) are severe diseases affecting all age groups in the US. We asked whether a small molecule, carboxyamidotriazole (CAI) known for its anti-angiogenic and anti-tumor effects and its ability to be administered orally in humans, could have anti-angiogenic effects in ocular in vitro and in vivo angiogenesis models. The anti-proliferative effects of CAI were examined by BrdU incorporation using human retinal and dermal endothelial cells and human pigment epithelial cells. The effect of CAI was determined using the Matrigel tube formation assay. The mouse model of choroidal neovascularization (CNV) initiated by laser rupture of Bruch's membrane was used to quantify in vivo effects of aqueous beta-hydroxypropyl cyclodextrin (bHPCD) formulations of CAI on neovascularization. The pharmacokinetics (PK) of CAI after intravitreal administration of bHPCD-CAI was studied in rabbit. The intravitreal toxicology of bHPCD-CAI was also examined in rat ocular tissue. We observed that CAI treatment of human endothelial cells decreased cell proliferation in a dose-dependent manner. In the in vivo tests bHPCD-CAI treatment reduced choroidal neovascular lesion volume, also in a dose-dependent manner. The intravitreal PK of bHPCD-CAI demonstrated that highly efficacious concentrations of CAI are reached in the vitreous compartment. No ocular toxicology was observed with intravitreous injection of CAI. These studies support the potential of developing intravitreal CAI in an bHPCD ocular formulation for treatment of proliferative retinopathies in humans. (C) 2009 Elsevier Inc. All rights reserved. C1 [Afzal, Aqeela; Caballero, Sergio; Grant, Maria B.] Univ Florida, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA. [Palii, Stela S.] NIEHS, Mol Toxicol Lab, Environm Stress & Canc Grp, NIH, Bethesda, MD USA. [Jurczyk, Simona] Pharmor Inc, Alachua, FL USA. [Pardue, Machelle; Geroski, Dale; Edelhauser, Henry] Emory Univ, Dept Ophthalmol, Atlanta VA Med Ctr, Rehab R&D CoE, Atlanta, GA 30322 USA. [Hochhaus, Guenther] Univ Florida, Dept Pharmaceut, Gainesville, FL 32610 USA. [Franklin, Alan] Retina Specialty Inst, Pensacola, FL USA. [Shapiro, Gideon] Pharmore Inc, Gainesville, FL USA. RP Grant, MB (reprint author), Univ Florida, Dept Pharmacol & Therapeut, POB 100267, Gainesville, FL 32610 USA. EM grantma@ufl.edu FU NIH [EY01 8294, EY01 2601, EY007739] FX This work was supported by research grants NIH Grants EY01 8294 (GS), EY01 2601 (MBG) and EY007739 (MBG). NR 26 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 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB 15 PY 2010 VL 81 IS 2-3 SI SI BP 320 EP 326 DI 10.1016/j.brainresbull.2009.08.001 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 556SA UT WOS:000274610500016 PM 19679174 ER PT J AU Johnson, TV Tomarev, SI AF Johnson, Thomas V. Tomarev, Stanislav I. TI Rodent models of glaucoma SO BRAIN RESEARCH BULLETIN LA English DT Review DE Glaucoma; Animal models; Rodent models; Myocilin; Retina; Retinal ganglion cells; Intraocular pressure ID RETINAL GANGLION-CELLS; ELEVATED INTRAOCULAR-PRESSURE; OPEN-ANGLE GLAUCOMA; OPTIC-NERVE CRUSH; OCULAR HYPERTENSION TREATMENT; ISCHEMIA-REPERFUSION INSULT; METHYL-D-ASPARTATE; ADULT-RAT RETINA; DBA/2J MICE; MOUSE MODEL AB Glaucoma is a progressive, age-related optic neuropathy and a leading cause of irreversible blindness in the world. Animal models of glaucoma are essential to our continued efforts of elucidating the natural course of the disease and to developing therapeutic interventions to halt or reverse the progression of the condition. Over the past 10-15 years, rodents have become a popular model organism to study glaucoma, because of their high degree of availability, relatively low cost, short life-span, and amenability to experimental and genetic manipulation. In this review, we examine the numerous in vivo and in vitro rodent models of glaucoma, discuss the methods used to generate them, summarize some of the major findings obtained in these models, and identify individual strengths and weaknesses for the various systems. Published by Elsevier Inc. C1 [Johnson, Thomas V.; Tomarev, Stanislav I.] NEI, Mol Mech Glaucoma Sect, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Thomas V.] Univ Cambridge, Dept Clin Neurosci, Ctr Brain Repair, Cambridge, England. RP Tomarev, SI (reprint author), NEI, Mol Mech Glaucoma Sect, Mol & Dev Biol Lab, NIH, 5635 Fishers Lane,Room 1124, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov RI Johnson, Thomas/C-9351-2011 OI Johnson, Thomas/0000-0002-5372-5457 FU Intramural Research Program of the National Eye Institute, National Institutes of Health; National Institutes of Health Graduate Partnerships Program Fellowship; Gates-Cambridge Scholarship FX This research was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health; a National Institutes of Health Graduate Partnerships Program Fellowship (TVJ); and a Gates-Cambridge Scholarship (TVJ). NR 110 TC 53 Z9 57 U1 3 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 EI 1873-2747 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB 15 PY 2010 VL 81 IS 2-3 SI SI BP 349 EP 358 DI 10.1016/j.brainresbull.2009.04.004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 556SA UT WOS:000274610500020 PM 19379796 ER PT J AU Moulder, SL Holmes, FA Tolcher, AW Thall, P Broglio, K Valero, V Buzdar, AU Arbuck, SG Seidman, A Hortobagyi, GN AF Moulder, Stacy L. Holmes, Frankie A. Tolcher, Anthony W. Thall, Peter Broglio, Kristine Valero, Vicente Buzdar, Aman U. Arbuck, Susan G. Seidman, Andrew Hortobagyi, Gabriel N. TI A Randomized Phase 2 Trial Comparing 3-Hour Versus 96-Hour Infusion Schedules of Paclitaxel for the Treatment of Metastatic Breast Cancer SO CANCER LA English DT Article DE metastatic breast cancer; paclitaxel; infusion schedule; chemotherapy regimen; toxicity profile ID DOSE PACLITAXEL; II TRIAL; MULTICENTER AB BACKGROUND: This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3-hour versus 96-hour infusion schedules. METHODS: Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m(2) intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m(2) iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance. RESULTS: A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3-hour arm and 29.9% in the 96-hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression-free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96-hour arm. Overall survival was slightly longer in the 3-hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96-hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3-hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3-hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96-hour arm. CONCLUSIONS: Paclitaxel given by 3-hour or 96-hour infusion was active in MBC. The 96-hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3-hour schedule. Cancer 2010;116:814-21. (C) 2070 American Cancer Society. C1 [Moulder, Stacy L.] Univ Texas MD Anderson Canc Ctr, Unit 1354, Dept Breast Med Oncol, Houston, TX 77030 USA. [Tolcher, Anthony W.] British Columbia Canc Ctr, Div Adv Therapeut, Dept Med Oncol, Vancouver, BC, Canada. [Thall, Peter; Broglio, Kristine] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Arbuck, Susan G.] NCI, Dept Invest Drug Res, Div Canc Treatment, Bethesda, MD 20892 USA. [Seidman, Andrew] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, New York, NY 10021 USA. RP Moulder, SL (reprint author), Univ Texas MD Anderson Canc Ctr, Unit 1354, Dept Breast Med Oncol, POB 301438, Houston, TX 77030 USA. EM smoulder@mdanderson.org FU Cancer Center [1-CM-07,310]; National Cancer Institute [CA45809] FX Supported by contract 1-CM-07,310 and Cancer Center Support Grant CA45809 from the National Cancer Institute. NR 20 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2010 VL 116 IS 4 BP 814 EP 821 DI 10.1002/cncr.24870 PG 8 WC Oncology SC Oncology GA 552TF UT WOS:000274315800008 PM 20052721 ER PT J AU Bishop, MR Dean, RM Steinberg, SM Odom, J Pollack, SM Pavletic, SZ Sportes, C Gress, RE Fowler, DH AF Bishop, Michael R. Dean, Robert M. Steinberg, Seth M. Odom, Jeanne Pollack, Seth M. Pavletic, Steven Z. Sportes, Claude Gress, Ronald E. Fowler, Daniel H. TI Correlation of Pretransplant and Early Post-Transplant Response Assessment With Outcomes After Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Non-Hodgkin's Lymphoma SO CANCER LA English DT Article DE chemotherapy sensitivity; hematopoietic stem cell transplantation; non-Hodgkin lymphoma; nonmyeloablative; reduced-intensity ID BONE-MARROW-TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; VERSUS-HOST-DISEASE; LOW-GRADE LYMPHOMA; AUTOLOGOUS TRANSPLANTATION; EUROPEAN GROUP; FOLLICULAR LYMPHOMA; WORKING PARTY; CHEMOTHERAPY; THERAPY AB BACKGROUND: Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity allogeneic hematopoietic stem cell transplantation (allo-HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post-transplant outcomes. METHODS: The impact of pretransplant and early (28 days) post-transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced-intensity allo-HCT. RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) (median potential follow-up after reduced-intensity allo-HCT = 58 months) for all patients was 37% and 47%, respectively. The 3-year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3-year follow-up. The 3-year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3-year EFS based on post-transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post-transplant reached 3-year follow-up. The 3-year OS based on post-transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS. CONCLUSIONS: These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced-intensity allo-HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. Cancer 2010;116:852-62. (C) 2010 American Cancer Society. C1 [Bishop, Michael R.; Dean, Robert M.; Odom, Jeanne; Pollack, Seth M.; Pavletic, Steven Z.; Sportes, Claude; Gress, Ronald E.; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Dean, Robert M.] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Pollack, Seth M.] Univ Washington, Seattle, WA 98195 USA. RP Bishop, MR (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, 10 Ctr Dr,CRC Room 4-3152, Bethesda, MD 20892 USA. EM mbishop@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, Intramural Research Program FX This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program. The authors declare no competing financial interests. NR 51 TC 6 Z9 6 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2010 VL 116 IS 4 BP 852 EP 862 DI 10.1002/cncr.24845 PG 11 WC Oncology SC Oncology GA 552TF UT WOS:000274315800013 PM 20041482 ER PT J AU Han, YY Davis, DL Weissfeld, JL Dinse, GE AF Han, Yueh-Ying Davis, Devra L. Weissfeld, Joel L. Dinse, Gregg E. TI Generational Risks for Cancers Not Related to Tobacco, Screening, or Treatment in the United States SO CANCER LA English DT Article DE generational risk; cancer trends; Surveillance; Epidemiology; and End Results; age-period-cohort model; cancer incidence; cancer mortality; tobacco; screening; occupational cancer; environmental cancer ID FECAL-OCCULT-BLOOD; BODY-MASS INDEX; BREAST-CANCER; OCCUPATIONAL-EXPOSURE; COLORECTAL-CANCER; FEATURING CANCER; MORTALITY; HEALTH; COHORT; DIAGNOSIS AB BACKGROUND: To assess trends in cancer, the authors evaluated the risk of I generation compared with that 25 years earlier (generational risk) for 3 groupings of cancers: those related to tobacco; those that reflect advances in screening or treatment; and a residual category of all other cancers. METHODS: In individuals ages 20 years to 84 years, age-period-cohort models were used to summarize time trends in terms of generational risk and average annual percentage change for US cancer incidence (1975-2004) and mortality (1970-2004) rates associated with these 3 cancer groupings. RESULTS: Adult white men today developed 16% fewer tobacco-related cancers and had 21% fewer deaths because of those cancers than their fathers' generation, whereas adult white women experienced increases of 28% and 19%, respectively, relative to their mothers. The incidence of commonly screened cancers rose 74% in men and 10% in women, whereas mortality fell 25% in men and 31% in women. For cancers that have not been linked chiefly to tobacco or screening, the incidence was 34% and 23% higher in white men and white women, respectively, than in their parents' generation 25 years earlier. Mortality in this residual category decreased 14% in men and 18% in women. Results among blacks were qualitatively similar to those among whites. CONCLUSIONS: Despite declining overall cancer death rates, adults are experiencing increased incidence of cancers that are not associated with tobacco or screening relative to their parents. Future research should examine whether similar patterns are exhibited in other modern nations and should identify population-wide avoidable risks that could account for unexplained increases in these residual cancers. Cancer 2010;116:940-8. (C) 2070 American Cancer Society. C1 [Han, Yueh-Ying; Davis, Devra L.; Weissfeld, Joel L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Han, Yueh-Ying; Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Ctr Environm Oncol, UMPC Canc Pavil, Pittsburgh, PA USA. [Dinse, Gregg E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Davis, DL (reprint author), 328 Maryland Ave NE, Washington, DC 20002 USA. EM devra.davis@gmail.com FU NIH; Center for Environmental Oncology; DSF Charitable Foundation; Pennsylvania Tobacco Settlement Funds; Milton Fine Fund FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Support to the Center for Environmental Oncology came from the Heinz Endowments, the DSF Charitable Foundation, the University of Pittsburgh Cancer Institute, the Pennsylvania Tobacco Settlement Funds, the Milton Fine Fund, and the Collegium Ramazzini. NR 61 TC 5 Z9 5 U1 1 U2 5 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 FEB 15 PY 2010 VL 116 IS 4 BP 940 EP 948 DI 10.1002/cncr.24747 PG 9 WC Oncology SC Oncology GA 552TF UT WOS:000274315800023 PM 20052736 ER PT J AU Wang, SS Carreon, JD Gomez, SL Devesa, SS AF Wang, Sophia S. Carreon, J. Daniel Gomez, Scarlett L. Devesa, Susan S. TI Cervical Cancer Incidence Among 6 Asian Ethnic Groups in the United States, 1996 Through 2004 SO CANCER LA English DT Article DE cervical cancer; race; ethnicity; Asian; incidence; rate ID VIETNAMESE; MORTALITY; WOMEN; CALIFORNIA; SUBGROUPS; PATTERNS; TRENDS; RATES AB BACKGROUND: Cervical cancer incidence was evaluated by histologic type, age at diagnosis, and disease stage for 6 Asian ethnic groups residing in the United States. METHODS: Incidence rates were estimated for cervical squamous cell carcinoma (SCC) and adenocarcinoma by age and stage for 6 Asian ethnic groups-Asian Indian/Pakistani, Chinese, Filipino, Japanese, Korean, and Vietnamese-in 5 US cancer registry areas during 1996 through 2004. For comparison, rates among non-Hispanic whites, non-Hispanic blacks, and Hispanics were also calculated. RESULTS: During 1996 through 2004, Vietnamese women had the highest (18.9 per 100,000) and Asian Indian/Pakistani women had the lowest (4.5) incidence of cervical cancer; this pattern was consistent by histologic type. Vietnamese women also had the highest incidence for localized (7.3) and regional (5.7) SCC and for localized (2.4) adenocarcinoma. Contrary to the plateau of SCC incidence apparent among white women by age 45 years, SCC rates continued to rise with age among Chinese, Filipina, Korean, and Vietnamese women. CONCLUSIONS: There exists large variation in invasive cervical cancer incidence patterns among Asian ethnic groups in the United States and in comparison with rates for blacks, Hispanics, and whites. Early detection and prevention strategies for cervical cancer among Asians require targeted strategies by ethnic group. Cancer 2010;116:949-56. Published 2010 by the American Cancer Society. C1 [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Etiol, Duarte, CA 91010 USA. [Wang, Sophia S.; Carreon, J. Daniel; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Gomez, Scarlett L.] No Calif Canc Ctr, Fremont, CA USA. [Gomez, Scarlett L.] Stanford Univ, Hlth Policy & Res Dept, Stanford, CA 94305 USA. RP Wang, SS (reprint author), City Hope Natl Med Ctr, Dept Populat Sci, Div Etiol, Duarte, CA 91010 USA. EM sowang@coh.org FU National Institutes of Health; National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 21 TC 31 Z9 31 U1 0 U2 1 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 FEB 15 PY 2010 VL 116 IS 4 BP 949 EP 956 DI 10.1002/cncr.24843 PG 8 WC Oncology SC Oncology GA 552TF UT WOS:000274315800024 PM 20029972 ER PT J AU Milenic, DE Brady, ED Garmestani, K Albert, PS Abdulla, A Brechbiel, MW AF Milenic, Diane E. Brady, Erik D. Garmestani, Kayhan Albert, Paul S. Abdulla, Alia Brechbiel, Martin W. TI Improved Efficacy of alpha-Particle-Targeted Radiation Therapy SO CANCER LA English DT Article; Proceedings Paper CT 12th Conference on Cancer Therapy with Antibodies and Immunoconjugates CY OCT 16-18, 2008 CL Parsippany, NJ DE radioimmunotherapy; alpha-particle; Bi-213; humanized CC49 monoclonal antibody; trastuzumab; human epidermal growth factor-2; tumor-associated glycoprotein 72 ID DISSEMINATED PERITONEAL DISEASE; TUMOR-ASSOCIATED GLYCOPROTEIN-72; ANTIBODY F(AB')2 FRAGMENTS; MONOCLONAL-ANTIBODY; PROSTATE-CANCER; RADIOIMMUNOTHERAPEUTIC APPLICATIONS; CARCINOEMBRYONIC ANTIGEN; ADENOCARCINOMA CELLS; OVARIAN-CANCER; HER2 AB BACKGROUND: Human epidermal growth factor receptor-2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with Bi-213 or Pb-212. Bi-213-humanized CC49 monoclonal antibody (HUCC49 Delta CH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously. METHODS: Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HUCC49 Delta CH2 labeled with Bi-213 administered through an intraperitoneal route. The sequence of administration also was examined. RESULTS: Before combining the 2 monoclonal antibodies, the effective doses of Bi-213-CC49 Delta CH2 and Bi-213-trastuzumab for the treatment of peritoneal disease were determined to be 500 mu Ci for each labeled antibody. Treatment with Bi-213-HuCC49 Delta CH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with Bi-213-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when (213)BiHuCC49 Delta CH2 and Bi-213-trastuzumab were coinjected, and a median survival of 147 days was obtained. CONCLUSIONS: Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with cc-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated. Cancer 2010;116(4 suppl):1059-66. Published 2010 by the American Cancer Society. C1 [Milenic, Diane E.; Brady, Erik D.; Garmestani, Kayhan; Abdulla, Alia; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Albert, Paul S.] NCI, Biometrie Res Branch, Bethesda, MD 20892 USA. RP Milenic, DE (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC-1002,Room B3B69, Bethesda, MD 20892 USA. EM milenicd@mail.nih.gov FU Intramural NIH HHS [ZIA SC006353-27] NR 40 TC 25 Z9 25 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2010 VL 116 IS 4 SU S BP 1059 EP 1066 DI 10.1002/cncr.24793 PG 8 WC Oncology SC Oncology GA 552TH UT WOS:000274316000008 PM 20127951 ER PT J AU Banerjee, S Byrd, JN Gianino, SM Harpstrite, SE Rodriguez, FJ Tuskan, RG Reilly, KM Piwnica-Worms, DR Gutmann, DH AF Banerjee, Sutapa Byrd, Jonathan N. Gianino, Scott M. Harpstrite, Scott E. Rodriguez, Fausto J. Tuskan, Robert G. Reilly, Karlyne M. Piwnica-Worms, David R. Gutmann, David H. TI The Neurofibromatosis Type 1 Tumor Suppressor Controls Cell Growth by Regulating Signal Transducer and Activator of Transcription-3 Activity In vitro and In vivo SO CANCER RESEARCH LA English DT Article ID NERVE SHEATH TUMORS; GLIOBLASTOMA-MULTIFORME; MAMMALIAN TARGET; FARNESYLTRANSFERASE INHIBITOR; HEMATOPOIETIC-CELLS; MAXIMAL ACTIVATION; ANTITUMOR-ACTIVITY; RAPAMYCIN PATHWAY; STAT3; NF1 AB Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected individuals develop benign and malignant nerve tumors. The NF1 gene product neurofibromin negatively regulates Ras and mammalian target of rapamycin (mTOR) signaling, prompting clinical trials to evaluate the ability of Ras and mTOR pathway inhibitors to arrest NF1-associated tumor growth. To discover other downstream targets of neurofibromin, we performed an unbiased cell-based high-throughput chemical library screen using NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, cucurbitacin-I (JSI-124), which inhibited NF1-deficient cell growth by inducing apoptosis. We further showed that signal transducer and activator of transcription-3 (STAT3), the target of cucurbitacin-I inhibition, was hyperactivated in NF1-deficient primary astrocytes and neural stem cells, mouse glioma cells, and human MPNST cells through Ser727 phosphorylation, leading to increased cyclin D1 expression. STAT3 was regulated in NF1-deficient cells of murine and human origin in a TORC1- and Rac1-dependent manner. Finally, cucurbitacin-I inhibited the growth of NF1-deficient MPNST cells in vivo. In summary, we used a chemical genetics approach to reveal STAT3 as a novel neurofibromin/mTOR pathway signaling molecule, define its action and regulation, and establish STAT3 as a tractable target for future NF1-associated cancer therapy studies. Cancer Res; 70(4); 1356-66. (C) 2010 AACR. C1 [Banerjee, Sutapa; Byrd, Jonathan N.; Gianino, Scott M.; Gutmann, David H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Gianino, Scott M.; Piwnica-Worms, David R.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Gianino, Scott M.; Piwnica-Worms, David R.] Washington Univ, Sch Med, Mol Imaging Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Rodriguez, Fausto J.] Mayo Clin Fdn, Div Neuropathol, Rochester, MN USA. [Tuskan, Robert G.; Reilly, Karlyne M.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Gutmann, DH (reprint author), Washington Univ, Sch Med, Dept Neurol, Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. EM gutmannd@neuro.wustl.edu FU Department of Defense [W81XWH-06-0222]; NIH [P50 CA94056]; Siteman Cancer Center FX Grant Support; Department of Defense grant W81XWH-06-0222 (D.H. Gutmann) and NIH grant P50 CA94056 (D.R. Piwnica-Worms). The High-Throughput Core is supported by a gift from the Siteman Cancer Center. NR 43 TC 36 Z9 37 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 FEB 15 PY 2010 VL 70 IS 4 BP 1356 EP 1366 DI 10.1158/0008-5472.CAN-09-2178 PG 11 WC Oncology SC Oncology GA 607FY UT WOS:000278485700010 PM 20124472 ER PT J AU Yan, XD Yin, J Yao, HY Mao, N Yang, YL Pan, LY AF Yan, Xuedong Yin, Jie Yao, Huiyu Mao, Ning Yang, Yili Pan, Lingya TI Increased Expression of Annexin A3 Is a Mechanism of Platinum Resistance in Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID CARCINOMA-CELL-LINES; CISPLATIN RESISTANCE; COLORECTAL-CANCER; TUMOR-CELLS; PROTEIN; GENE; CYTOTOXICITY; CHEMOTHERAPY; SENSITIVITY; NEUTROPHILS AB Resistance to platinum drugs has emerged as a major obstacle in the treatment of ovarian cancers. Through proteomic analysis, we have found that the expression of annexin A3, a member of the Ca(2+) and phospholipid-binding annexin family, is significantly increased in platinum-resistant ovarian cell lines. Anti-annexin A3 immunostaining indicated that cancers from platinum-resistant patients also possess higher levels of annexin A3 than those from platinum-sensitive patients. Although expression of annexin A3 made susceptible ovarian cancer cells more resistant to platinum, expression of antisense annexin A3 downregulated its expression and rendered the resistant cells more sensitive to platinum. In athymic mice, the growth of tumors from inoculated SKOV3 cells was inhibited by the administration of platinum, whereas tumors from annexin A3-expressing SKOV3/Ann were resistant to platinum treatment. Interestingly, the intracellular platinum concentration and platinum-DNA binding are significantly lower in annexin A3-overexpressing cells than those in parental cells. The lower cisplatin concentration was also accompanied by reduced induction of p53, which could be restored by downregulation of annexin A3. These results indicate that increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. It seems to act by preventing uptake or accumulation of platinum in cells. Therefore, it is conceivable that annexin A3 could be a target for therapeutic intervention and may also serve as a biomarker for drug resistance in ovarian cancer patients. Cancer Res; 70(4); 1616-24. (C) 2010 AACR. C1 [Yan, Xuedong; Yin, Jie; Pan, Lingya] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Obstet & Gynecol, Beijing 100730, Peoples R China. [Yan, Xuedong; Yin, Jie; Pan, Lingya] Peking Union Med Coll, Beijing 100730, Peoples R China. [Yao, Huiyu; Mao, Ning] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Cell Biol, Beijing 100730, Peoples R China. [Yang, Yili] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. RP Pan, LY (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Obstet & Gynecol, 1 Shuai Fu Yuan,Wang Fu Jing St, Beijing 100730, Peoples R China. EM lingyapan@hotmail.com FU Department of Cell Biology, Institute of Basic Medical Sciences; Key Foundation of Peking Union Medical College Hospital [200203] FX We thank Dr. Joel D. Ernst (University of California, San Francisco, San Francisco, CA) for the anti-annexin A3 antibody; Dr. Alan O. Perantoni (National Cancer Institute, Frederick, MD) and Sheng Zhou (St. Jude Children's Research Hospital, Memphis, TN) for critical reading and comments on the manuscript; and our colleagues in the Department of Cell Biology, Institute of Basic Medical Sciences, for support and technical assistance.; Grant Support; Key Foundation of Peking Union Medical College Hospital grant 200203*. NR 39 TC 42 Z9 46 U1 0 U2 11 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 FEB 15 PY 2010 VL 70 IS 4 BP 1616 EP 1624 DI 10.1158/0008-5472.CAN-09-3215 PG 9 WC Oncology SC Oncology GA 607FY UT WOS:000278485700036 PM 20103635 ER PT J AU Adelman, K Rogatsky, I AF Adelman, Karen Rogatsky, Inez TI RNA polymerase II stalling mediates cytokine gene expression SO CELL CYCLE LA English DT Editorial Material ID INFLAMMATORY RESPONSE; ACTIVATION C1 [Rogatsky, Inez] Cornell Univ, Hosp Special Surg, New York, NY 10021 USA. [Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Rogatsky, Inez] Cornell Univ, Dept Microbiol & Immunol, Weill Med Coll, New York, NY 10021 USA. RP Rogatsky, I (reprint author), Cornell Univ, Hosp Special Surg, New York, NY 10021 USA. EM rogatskyi@hss.edu FU NIAID NIH HHS [R01 AI068820] NR 8 TC 5 Z9 5 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2010 VL 9 IS 4 BP 630 EP 631 DI 10.4161/cc.9.4.10841 PG 2 WC Cell Biology SC Cell Biology GA 572EZ UT WOS:000275811600004 PM 20107307 ER PT J AU Lyakhov, I Zielinski, R Kuban, M Kramer-Marek, G Fisher, R Chertov, O Bindu, L Capala, J AF Lyakhov, Ilya Zielinski, Rafal Kuban, Monika Kramer-Marek, Gabriela Fisher, Robert Chertov, Oleg Bindu, Lakshman Capala, Jacek TI HER2-and EGFR-Specific Affiprobes: Novel Recombinant Optical Probes for Cell Imaging SO CHEMBIOCHEM LA English DT Article DE affiprobes; cancer; EGFR; HER2; imaging agents ID BINDING AFFIBODY MOLECULE; MALIGNANT-TUMORS; HER2-POSITIVE TUMORS; FLUORESCENT PROTEIN; EXPRESSION; TARGET; CANCER; DELIVERY; AFFINITY; THERAPY AB The human epidermal growth factor receptors, EGFR and HER2, are members of the EGFR family of cell-surface receptors/tyrosine kinases. EGFR- and HER2-positive cancers represent a more aggressive disease with greater likelihood of recurrence, poorer prognosis, and decreased survival rate, compared to EGFR- or HER2-negative cancers. The details of HER2 proto-oncogenic functions are not deeply understood, partially because of a restricted availability of tools for EGFR and HER2 detection (A. Sorkin and L. K. Goh, Exp. Cell Res. 2009, 315, 683-696). We have created photostable and relatively simple-to-produce imaging probes for in vitro staining of EGFR and HER2. These new reagents, called affiprobes, consist of a targeting moiety, a HER2- or EGFR-specific Affibody(R) molecule, and a fluorescent moiety, mCherry (red) or EGFP (green). Our flow cytometry and confocal microscopy experiments demonstrated high specificity and signal/background ratio of affiprobes. Affiprobes are able to stain both live cells and frozen tumor xenograph sections. This type of optical probe can easily be extended for targeting other cell-surface antigens/receptors. C1 [Lyakhov, Ilya; Zielinski, Rafal; Kuban, Monika; Kramer-Marek, Gabriela; Capala, Jacek] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lyakhov, Ilya; Fisher, Robert; Chertov, Oleg; Bindu, Lakshman] SAIC Frederick Inc, Prot Chem Lab, NCI Frederick, Frederick, MD 21702 USA. RP Capala, J (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov FU National Cancer Institute, Notional Institutes of Health [HHSN261 200 800 001E]; NIH, Notional Cancer Institute, Center for Cancer Research FX The authors thank Dr. Roger Y. Tsien (USCD, Son Diego, CA) for the clone of mCherry (pRSET-m Cherry). We also appreciate the support obtained from experts from Affibody AB and SAIC-Frederick, Inc., Barbara J. Taylor of CCR FACS Core Facility, and Susan Garfield of CCR Confocal Microscopy Core Facility. This project has been funded in whole or in part with federal funds from the National Cancer Institute, Notional Institutes of Health, under contract HHSN261 200 800 001E. The content of this publication does not necessarily reflect the views or policies of the Deportment 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, Notional Cancer Institute, Center for Cancer Research. I.L, RZ, and J.C. generated the affiprobe concept, designed the experiments, and prepared the manuscript. Protein analysis was done by R.F, O.C., and L.B. affiprobe cloning was done by I.L. Protein purification was done by R.Z. and I.L. Cell-staining experiments in vitro were performed by R.Z, M.K., and G.K-M. NR 35 TC 21 Z9 21 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD FEB 15 PY 2010 VL 11 IS 3 BP 345 EP 350 DI 10.1002/cbic.200900532 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 562GZ UT WOS:000275039500010 PM 20052708 ER PT J AU Lautenbach, E Saint, S Henderson, DK Harris, AD AF Lautenbach, Ebbing Saint, Sanjay Henderson, David K. Harris, Anthony D. TI Initial Response of Health Care Institutions to Emergence of H1N1 Influenza: Experiences, Obstacles, and Perceived Future Needs SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VACCINATION; ATTITUDES; WORKERS; PERSONNEL; WILL AB Background. The emergence of H1N1 influenza is cause for great concern. Although one of the most important components of the response to the H1N1 crisis is the work of health care epidemiology professionals, the beliefs and experiences of this community are unknown, and the optimal approach to managing H1N1 in the future has not been delineated. Methods. To assess attitudes and responses of health care epidemiology professionals to the H1N1 influenza crisis, we conducted a cross-sectional survey of members of the Society for Healthcare Epidemiology of America. We assessed beliefs regarding (1) importance of H1N1, (2) institutional preparedness, (3) time spent on the H1N1 crisis, and (4) the institution's response to H1N1. Results. Of 323 respondents, 195 (60.4%) reported that their hospitals were well prepared for a pandemic. Furthermore, the majority reported that senior administrators provided adequate political support and resources (85.1% and 80.2%, respectively) to respond to H1N1. However, 163 (50.9%) respondents reported that other important infection prevention activities were neglected during the H1N1 crisis. Shortages of antiviral medication were reported by 99 (30.7%) respondents. Furthermore, 126 (39.0%) reported that personal stockpiling of antiviral medications occurred at their institution, and 166 (51.4%) reported that institutional actions were initiated to prevent personal stockpiling. Also, 294 (91.0%) respondents believed that H1N1 influenza would reappear later this year. Vaccine development, health care worker education, and revisions of pandemic influenza plans were identified as the most important future initiatives. Finally, 251 (77.7%) respondents felt that health care workers should be mandated to receive influenza vaccine. Conclusions. Although generally institutions are well prepared for the H1N1 crisis, substantial revisions of pandemic preparedness plans appear to be necessary. Future efforts to optimize the response to H1N1 should include curtailing personal stockpiling of antivirals and vaccine development with consideration of mandatory vaccination of health care workers. C1 [Lautenbach, Ebbing] Univ Penn, Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Lautenbach, Ebbing] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Lautenbach, Ebbing] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lautenbach, Ebbing] Univ Penn, Sch Med, Ctr Educ & Res Therapeut, Philadelphia, PA 19104 USA. [Saint, Sanjay] Univ Michigan, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. [Saint, Sanjay] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Henderson, David K.] NIH, Hosp Epidemiol Serv, Bethesda, MD 20892 USA. [Henderson, David K.] NIH, Off Director, Ctr Clin, Bethesda, MD 20892 USA. [Harris, Anthony D.] Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Harris, Anthony D.] Univ Maryland, VA Maryland Healthcare Syst, Baltimore, MD 21201 USA. RP Lautenbach, E (reprint author), Univ Penn, Sch Med, Dept Med, Div Infect Dis, 825 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM ebbing@mail.med.upenn.edu FU National Institutes of Health [K24AI080942, K24AI079040] FX National Institutes of Health (K24AI080942 to E. L. and K24AI079040 A. D. H.) NR 12 TC 34 Z9 35 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 FEB 15 PY 2010 VL 50 IS 4 BP 523 EP 527 DI 10.1086/650169 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546WX UT WOS:000273846400015 PM 20064038 ER PT J AU Stapleton, CM Joo, JH Kim, YS Liao, G Panettieri, RA Jetten, AM AF Stapleton, Cliona M. Joo, Joung Hyuck Kim, Yong-Sik Liao, Grace Panettieri, Reynold A., Jr. Jetten, Anton M. TI Induction of ANGPTL4 expression in human airway smooth muscle cells by PMA through activation of PKC and MAPK pathways SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE ANGPTL4; PKC; Smooth muscle cells; Tissue remodeling; Lung; PMA; MAPK ID PROTEIN-KINASE-C; ANGIOPOIETIN-LIKE PROTEIN-4; ESTER TUMOR PROMOTERS; PHORBOL ESTERS; INDUCED APOPTOSIS; CIGARETTE-SMOKE; CARCINOMA CELLS; ANGIOGENESIS; METASTASIS; TARGET AB In this study, we demonstrate that protein kinase C (PKC) activators, including phorbol-12-myristate-13-acetate (PMA), 1,2-dioctanoyl-sn-glycerol (DOG), and platelet-derived growth factor alpha are potent inducers of angiopoietin-like protein 4 (ANGPTL4) expression in several normal lung cell types and Carcinoma cell lines. In human airway smooth muscle (HASM) cells induction of ANGPTL4 expression is observed as early as 2 h after the addition of PMA. PMA also increases the level of ANGPTL4 protein released in the medium. PKC inhibitors Ro31-8820 and Go6983 greatly inhibit the induction of ANGPTL4 mRNA by PMA suggesting that this up-regulation involves activation of PKC. Knockdown of several PKCs by corresponding siRNAs suggest a role for PKC alpha. PMA does not activate MAPK p38 and p38 inhibitors have little effect on the induction of ANGPTL4 indicating that p38 is not involved in the regulation of ANGPTL4 by PMA. In contrast, treatment of HASM by PMA induces phosphorylation and activation of Ra, MEK1/2, ERK1/2, JNK, Elk-1, and c-Jun. The Ras inhibitor manumycin A, the MEK1/2 inhibitor U0126, and the JNK inhibitor SP600125, greatly reduce the increase in ANGPTL4 expression by PMA. Knockdown of MEK1/2 and JNK1/2 expression by corresponding siRNAs inhibits the induction of ANGPTL4. Our observations suggest that the induction of ANGPTL4 by PMA in HASM involves the activation of PKC, ERK, and JNK pathways. This induction may play a role in tissue remodeling during lung injury and be implicated in several lung pathologies. Published by Elsevier Inc. C1 [Stapleton, Cliona M.; Joo, Joung Hyuck; Kim, Yong-Sik; Liao, Grace; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Panettieri, Reynold A., Jr.] Univ Penn, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural Research Program of the NIEHS; NIH [Z01-ES-101586] FX This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586). The authors thank Dr. Xiao-Ping Yang for technical assistance. NR 56 TC 15 Z9 17 U1 0 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2010 VL 316 IS 4 BP 507 EP 516 DI 10.1016/j.yexcr.2009.12.004 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 552VG UT WOS:000274321100001 PM 20025870 ER PT J AU Gonzalez-Moreno, O Lecanda, J Green, JE Segura, V Catena, R Serrano, D Calvo, A AF Gonzalez-Moreno, Oscar Lecanda, Jon Green, Jeffrey E. Segura, Victor Catena, Raul Serrano, Diego Calvo, Alfonso TI VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Prostate intraepithelial neoplasia (PIN); VEGF; EMT; Snail; Slug; TGF-beta 1 ID GROWTH-FACTOR-BETA; PANCREATIC-CANCER CELLS; SNAIL EXPRESSION; SMAD7; TRANSCRIPTION; PROGRESSION; TRANSDIFFERENTIATION; ANGIOGENESIS; METASTASIS; MICROARRAY AB Vascular endothelial growth factor (VEGF) is overexpressed during the transition from prostate intraepithelial neoplasia (PIN) to invasive carcinoma. We have mimicked such a process in vitro using the PIN-like C3(1)/Tag-derived Pr-111 cell line, which expresses low levels of VEGF and exhibits very low tumorigenicity in vivo. Elevated expression of VEGF164 in Pr-111 cells led to a significant increase in tumorigenicity, invasiveness, proliferation rates and angiogenesis. Moreover, VEGF164 induced strong changes in cell morphology and cell transcriptome through an autocrine mechanism, with changes in TGF-beta1- and cytoskeleton-related pathways, among others. Further analysis of VEGF-overexpressing Pr-111 cells or following exogenous addition of recombinant VEGF shows acquisition of epithelial-mesenchymal transition (EMT) features, with an increased expression of mesenchymal markers, Such as N-cadherin, Snail1, Snail2 (Slug) and vimentin, and a decrease in E-cadherin. Administration of VEGF led to changes in TGF-beta1 signaling, including reduction of Smad7 (TGF-beta inhibitory Smad), increase in TGF-betaR-II, and translocation of phospho-Smad3 to the nucleus. Our results suggest that increased expression of VEGF in malignant cells during the transition from PIN to invasive carcinoma leads to EMT through an autocrine loop, which would promote tumor cell invasion and motility. Therapeutic blockade of VEGF/TGF-beta1 in PIN lesions might impair not only tumor angiogenesis, but also the early dissemination of malignant cells outside the epithelial layer. (C) 2009 Elsevier Inc. All rights reserved. C1 [Gonzalez-Moreno, Oscar; Catena, Raul; Serrano, Diego; Calvo, Alfonso] Univ Navarra, CIMA, Div Oncol, Lab Novel Therapeut Targets, Pamplona 31008, Spain. [Lecanda, Jon] Univ Navarra, Dept Biochem, Pamplona 31008, Spain. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Segura, Victor] Univ Navarra, CIMA, Unit Prote Genom & Bioinformat, Pamplona 31008, Spain. RP Calvo, A (reprint author), Univ Navarra, CIMA, Div Oncol, Lab Novel Therapeut Targets, Avda Pio XII 55, Pamplona 31008, Spain. EM acalvo@unav.es RI Segura, Victor/E-4531-2010; OI Segura, Victor/0000-0002-7740-6290; Serrano, Diego/0000-0002-3729-9195 FU UTE project CIMA [ISCIII-RETIC RD06/0020] FX This work has been funded by "UTE project CIMA", ISCIII-RETIC RD06/0020 grant. NR 38 TC 44 Z9 48 U1 0 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2010 VL 316 IS 4 BP 554 EP 567 DI 10.1016/j.yexcr.2009.11.020 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 552VG UT WOS:000274321100005 PM 20006606 ER PT J AU Douillard-Guilloux, G Raben, N Takikita, S Ferry, A Vignaud, A Guillet-Deniau, I Favier, M Thurberg, BL Roach, PJ Caillaud, C Richard, E AF Douillard-Guilloux, Gaelle Raben, Nina Takikita, Shoichi Ferry, Arnaud Vignaud, Alban Guillet-Deniau, Isabelle Favier, Maryline Thurberg, Beth L. Roach, Peter J. Caillaud, Catherine Richard, Emmanuel TI Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID ENZYME REPLACEMENT THERAPY; ACID ALPHA-GLUCOSIDASE; MOUSE MODEL; INSULIN-RESISTANCE; SKELETAL-MUSCLE; CLINICAL-TRIAL; MICE; SYNTHASE; RECOMBINANT; INTOLERANCE AB Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease. C1 [Caillaud, Catherine] Univ Paris 05, Dept Genet & Dev, Fac Med Cochin Port Royal, Inst Cochin,CNRS,UMR 8104, F-75014 Paris, France. [Douillard-Guilloux, Gaelle; Guillet-Deniau, Isabelle; Favier, Maryline; Caillaud, Catherine; Richard, Emmanuel] INSERM, U567, F-75013 Paris, France. [Raben, Nina; Takikita, Shoichi] NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. [Ferry, Arnaud; Vignaud, Alban] INSERM, U974, F-75013 Paris, France. [Ferry, Arnaud; Vignaud, Alban] Univ Paris 06, F-75013 Paris, France. [Ferry, Arnaud] Univ Paris 05, F-75006 Paris, France. [Thurberg, Beth L.] Genzyme Corp, Dept Pathol, Framingham, MA 01701 USA. [Roach, Peter J.] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Caillaud, C (reprint author), Univ Paris 05, Dept Genet & Dev, Fac Med Cochin Port Royal, Inst Cochin,CNRS,UMR 8104, 24 Rue Faubourg St Jacques, F-75014 Paris, France. EM gad19@pitt.edu; catherine.caillaud@inserm.fr; Emmanuel.richard@u-bordeaux2.fr FU INSERM; Association Vaincre les Maladies Lysosomales; VML; Association Francaise contre les Myopathies (AFM) FX This work was supported by INSERM and the Association Vaincre les Maladies Lysosomales (VML). E. R. was supported by post-doctoral fellowships from VML and the Association Francaise contre les Myopathies (AFM). G. D. G. was supported by doctoral fellowship from AFM. NR 45 TC 13 Z9 13 U1 0 U2 2 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 FEB 15 PY 2010 VL 19 IS 4 BP 684 EP 696 DI 10.1093/hmg/ddp535 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 545AA UT WOS:000273702200011 PM 19959526 ER PT J AU Karp, DR Marthandan, N Marsh, SGE Ahn, C Arnett, FC DeLuca, DS Diehl, AD Dunivin, R Eilbeck, K Feolo, M Guidry, PA Helmberg, W Lewis, S Mayes, MD Mungall, C Natale, DA Peters, B Petersdorf, E Reveille, JD Smith, B Thomson, G Waller, MJ Scheuermann, RH AF Karp, David R. Marthandan, Nishanth Marsh, Steven G. E. Ahn, Chul Arnett, Frank C. DeLuca, David S. Diehl, Alexander D. Dunivin, Raymond Eilbeck, Karen Feolo, Michael Guidry, Paula A. Helmberg, Wolfgang Lewis, Suzanna Mayes, Maureen D. Mungall, Chris Natale, Darren A. Peters, Bjoern Petersdorf, Effie Reveille, John D. Smith, Barry Thomson, Glenys Waller, Matthew J. Scheuermann, Richard H. TI Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID HLA-DQB1 1ST DOMAIN; DNA TOPOISOMERASE-I; T-CELL-RECEPTOR; AUTOANTIBODY RESPONSE; RHEUMATOID-ARTHRITIS; HAPLOTYPE METHOD; AMINO-ACIDS; SCLERODERMA; ANTIBODIES; PEPTIDE AB We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk. C1 [Karp, David R.] UT SW Med Ctr, Div Rheumat Dis, Dept Internal Med, Dallas, TX 75390 USA. [Marthandan, Nishanth; Guidry, Paula A.; Scheuermann, Richard H.] UT SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. [Marsh, Steven G. E.; Waller, Matthew J.] Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. [Ahn, Chul; Scheuermann, Richard H.] UT SW Med Ctr, Dept Clin Sci, Dallas, TX 75390 USA. [Arnett, Frank C.; Mayes, Maureen D.; Reveille, John D.] UT Houston, Dept Internal Med, Houston, TX 77030 USA. [DeLuca, David S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Diehl, Alexander D.] Jackson Lab, Bar Harbor, ME 04609 USA. [Dunivin, Raymond; Feolo, Michael] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Eilbeck, Karen] Univ Utah, Dept Human Genet, Salt Lake City, UT 84122 USA. [Helmberg, Wolfgang] Med Univ Graz, Dept Blood Grp Serol & Transfus Med, A-8036 Graz, Austria. [Lewis, Suzanna; Mungall, Chris] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. [Natale, Darren A.] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. [Peters, Bjoern] La Jolla Inst Allergy & Immunol, Ctr Infect Dis, La Jolla, CA 92109 USA. [Petersdorf, Effie] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Smith, Barry] SUNY Buffalo, Dept Philosophy, Buffalo, NY 14203 USA. [Smith, Barry] SUNY Buffalo, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY 14203 USA. [Thomson, Glenys] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. RP Karp, DR (reprint author), UT SW Med Ctr, Div Rheumat Dis, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM david.karp@utsouthwestern.edu RI Diehl, Alexander/G-9883-2016; Smith, Barry/A-9525-2011; OI Diehl, Alexander/0000-0001-9990-8331; Smith, Barry/0000-0003-1384-116X; Lewis, Suzanna/0000-0002-8343-612X; Scheuermann, Richard/0000-0003-1355-892X FU National Institutes of Health [N01-AI40076, N01-AR02251, P50-AR054144, UL1-RR024148, UL1-RR024982] FX This work was supported by the National Institutes of Health [contracts N01-AI40076 and N01-AR02251; grants P50-AR054144, UL1-RR024148 and UL1-RR024982]. NR 39 TC 19 Z9 19 U1 1 U2 2 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 FEB 15 PY 2010 VL 19 IS 4 BP 707 EP 719 DI 10.1093/hmg/ddp521 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 545AA UT WOS:000273702200013 PM 19933168 ER PT J AU Mishra, A Bharti, AC Saluja, D Das, BC AF Mishra, Alok Bharti, Alok C. Saluja, Daman Das, Bhudev C. TI Transactivation and expression patterns of Jun and Fos/AP-1 super-family proteins in human oral cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE oral cancer; human biopsies; carcinogenesis; AP-1; constitutive activation; differential expression ID NF-KAPPA-B; SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR-RECEPTOR; TRANSCRIPTION FACTOR AP-1; C-FOS; HUMAN-PAPILLOMAVIRUS; CONSTITUTIVE ACTIVATION; SKIN CARCINOGENESIS; HUMAN HEAD; FRA-1 AB Transcription factor activator protein-1 (AP-1) super-family is known to modulate expression of array of genes during development of many cancers and considered as an important target for modern therapeutics. But the role of AP-1 during development of human oral cancers is still poorly understood. Because oral cancer is one of the most common cancers in India and south-east Asia, we studied the activation and expression pattern of AP-1 family of proteins and mRNA in different stages of oral carcinogenesis. Get-shift assay, western blotting, immunohistochemistry and northern blotting have been used to assess the binding activity and expression pattern of AP-1 family (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2) proteins and mRNA transcripts in a total of 100 fresh oral tissue specimens comprising precancer (n = 40), cancer (n = 50) and healthy control (n = 10). Constitutive activation of AP-1 with concomitant upregulated expression of majority of AP-1 family of proteins and mRNA was observed in cancer cases. Interestingly, almost all precancerous cases showed JunD homodimers, whereas c-Fos/JunD was the most prevalent complex found in cancer tissues. The overexpression of EGFR mRNA, p50:p50/NF-kappa B homodimer formation, together with overexpression of pERK and c-Fos proteins in this study suggests an interesting cross talk between AP-1 and NF-kappa B pathways in oral cancers. Thus, this study demonstrates differential expression and activation of AP-1 super-family proteins in relation to severity of lesion and their crucial role in human oral carcinogenesis. C1 [Saluja, Daman; Das, Bhudev C.] Univ Delhi, ACBR, Dept Med Biotechnol, Delhi 110007, India. [Saluja, Daman; Das, Bhudev C.] Univ Delhi, ACBR, Dept Mol Oncol, Delhi 110007, India. [Mishra, Alok] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Mishra, Alok; Bharti, Alok C.; Das, Bhudev C.] Inst Cytol & Prevent Oncol ICMR, Div Mol Oncol, Noida 201301, India. RP Das, BC (reprint author), Univ Delhi, ACBR, Dept Med Biotechnol, Delhi 110007, India. EM bcdas48@hotmail.com FU Indian Council of Medical Research (ICMR) FX Grant sponsor: Indian Council of Medical Research (ICMR) NR 44 TC 17 Z9 20 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2010 VL 126 IS 4 BP 819 EP 829 DI 10.1002/ijc.24807 PG 11 WC Oncology SC Oncology GA 544TQ UT WOS:000273682600003 PM 19653276 ER PT J AU Park, YY Lee, S Karbowski, M Neutzner, A Youle, RJ Cho, H AF Park, Yong-Yea Lee, Seungmin Karbowski, Mariusz Neutzner, Albert Youle, Richard J. Cho, Hyeseong TI Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1 SO JOURNAL OF CELL SCIENCE LA English DT Article DE MARCH5; Cellular senescence; Mfn1; Drp1 ID DOMINANT OPTIC ATROPHY; SACCHAROMYCES-CEREVISIAE; FUSION MEDIATORS; MAMMALIAN-CELLS; GTPASE ACTIVITY; FISSION; DRP1; MORPHOLOGY; OPA1; PHOSPHORYLATION AB Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1(T109A), a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-beta-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-beta-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria. C1 [Park, Yong-Yea; Lee, Seungmin; Cho, Hyeseong] Ajou Univ, Sch Med, Dept Biochem, Suwon 443721, South Korea. [Park, Yong-Yea; Lee, Seungmin; Cho, Hyeseong] Ajou Univ, Grad Sch Mol Sci & Technol, Suwon 443721, South Korea. [Karbowski, Mariusz] Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Bethesda, MD 20892 USA. [Neutzner, Albert; Youle, Richard J.] NINDS, Biochem Sect, SNB, NIH, Bethesda, MD 20892 USA. RP Cho, H (reprint author), Ajou Univ, Sch Med, Dept Biochem, Suwon 443721, South Korea. EM hscho@ajou.ac.kr OI Neutzner, Albert/0000-0001-9254-5558 FU Korea Research Foundation, Republic of Korea [KRF C00258]; National Institute of Neurological Disorders and Stroke (NINDS) in the Intramural Research Program of the National Institutes of Health (NIH) FX This study was supported by grants from the Korea Research Foundation (KRF C00258), Republic of Korea. R. J. Y. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) in the Intramural Research Program of the National Institutes of Health (NIH). Deposited in PMC for release after 12 months. NR 44 TC 96 Z9 99 U1 1 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 15 PY 2010 VL 123 IS 4 BP 619 EP 626 DI 10.1242/jcs.061481 PG 8 WC Cell Biology SC Cell Biology GA 556MB UT WOS:000274594100014 PM 20103533 ER PT J AU Boboila, C Yan, C Wesemann, DR Jankovic, M Wang, JH Manis, J Nussenzweig, A Nussenzweig, M Alt, FW AF Boboila, Cristian Yan, Catherine Wesemann, Duane R. Jankovic, Mila Wang, Jing H. Manis, John Nussenzweig, Andre Nussenzweig, Michel Alt, Frederick W. TI Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID STRAND BREAK REPAIR; DEPENDENT PROTEIN-KINASE; B-CELL DEVELOPMENT; V(D)J RECOMBINATION; SOMATIC HYPERMUTATION; DEFICIENT LYMPHOCYTES; EMBRYONIC LETHALITY; MAMMALIAN-CELLS; IV; KU80 AB The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; "MH-mediated" joins) or no homologies ("direct" joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via "alternative" end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and Lig4. Ku70- or Ku80-deficient B cells have reduced, but still substantial, CSR. Strikingly, B cells deficient for both Ku plus Lig4 undergo CSR similarly to Ku-deficient B cells, firmly demonstrating that an A-EJ pathway distinct from C-NHEJ can catalyze CSR end-joining. Ku-deficient or Ku-plus Lig4-deficient B cells are also biased toward MH-mediated CSR joins; but, in contrast to XRCC4- or Lig4-deficient B cells, generate substantial numbers of direct CSR joins. Our findings suggest that more than one form of A-EJ can function in CSR. C1 [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Manis, John] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Manis, John; Alt, Frederick W.] Childrens Hosp, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Alt, Frederick W.] Beth Israel Deaconess Med Ctr, Immune Dis Inst, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Nussenzweig, Michel; Alt, Frederick W.] Beth Israel Deaconess Med Ctr, Howard Hughes Med Inst, Boston, MA 02115 USA. [Yan, Catherine] Beth Israel Deaconess Med Ctr, Div Expt Pathol, Dept Pathol, Boston, MA 02115 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Nussenzweig, Andre] NIH, Bethesda, MD 20892 USA. [Jankovic, Mila; Nussenzweig, Michel] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Wang, Jing/M-7813-2015 OI Wang, Jing/0000-0003-4343-2527 FU National Institutes of Health [AI031541, CA092625, AI037526, T32CA09382-26]; Cancer Research Institute FX This work was supported by National Institutes of Health grants AI031541 and CA092625 to FWA, NIH grant AI037526 to MN and T32CA09382-26 to JHW. CB is supported by a Cancer Research Institute training grant. FWA and MN are investigators of the Howard Hughes Medical Institute. NR 50 TC 77 Z9 78 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 15 PY 2010 VL 207 IS 2 BP 417 EP 427 DI 10.1084/jem.20092449 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 555FO UT WOS:000274493900017 PM 20142431 ER PT J AU Do, JS Fink, PJ Li, L Spolski, R Robinson, J Leonard, WJ Letterio, JJ Min, B AF Do, Jeong-su Fink, Pamela J. Li, Lily Spolski, Rosanne Robinson, Janet Leonard, Warren J. Letterio, John J. Min, Booki TI Cutting Edge: Spontaneous Development of IL-17-Producing gamma delta T Cells in the Thymus Occurs via a TGF-beta 1-Dependent Mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; INTERFERON-GAMMA; ADULT THYMUS; TGF-BETA; INFLAMMATION; EXPRESSION; IL-17; DIFFERENTIATION; HETEROGENEITY; NEUTROPHILS AB In naive animals, gamma delta T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. In this study, we show that TGF-beta 1 plays a key role in the generation of IL-17(+) gamma delta T cells and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17(+) gamma delta TCR(+) thymocytes were mainly CD44(high)CD25(low) cells, which seem to derive from double-negative 4 gamma delta TCR(+) cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17-competent gamma delta T cells arise in the thymus by a TGF-beta 1-dependent mechanism. The Journal of Immunology, 2010, 184: 1675-1679. C1 [Do, Jeong-su; Li, Lily; Min, Booki] Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, Cleveland, OH 44195 USA. [Li, Lily] Cleveland Clin Fdn, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. [Fink, Pamela J.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Robinson, Janet; Letterio, John J.] Case Western Reserve Univ, Div Pediat Hematol Oncol, Dept Pediat, Cleveland, OH 44106 USA. RP Min, B (reprint author), Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, NB 30, Cleveland, OH 44195 USA. EM minb@ccf.org RI Do, Jeong su/G-9483-2014 FU National Institutes of Health [R01-AI074932, R01-AI064318]; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by National Institutes of Health Grants R01-AI074932 (to B.M.) and R01-AI064318 (to P.J.F.), and by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health (to R.S. and W.J.L.). NR 25 TC 72 Z9 76 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 FEB 15 PY 2010 VL 184 IS 4 BP 1675 EP 1679 DI 10.4049/jimmunol.0903539 PG 5 WC Immunology SC Immunology GA 556IU UT WOS:000274585100002 PM 20061408 ER PT J AU Bhatia, S Sun, K Almo, SC Nathenson, SG Hodes, RJ AF Bhatia, Sumeena Sun, Kristine Almo, Steven C. Nathenson, Stanley G. Hodes, Richard J. TI Dynamic Equilibrium of B7-1 Dimers and Monomers Differentially Affects Immunological Synapse Formation and T Cell Activation in Response to TCR/CD28 Stimulation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SERIAL TCR ENGAGEMENT; ANTIGEN RECOGNITION; COSTIMULATORY LIGANDS; SURFACE MOLECULES; B-CELLS; CD28; RECEPTOR; CD80; SEGREGATION; ACQUISITION AB Under steady-state conditions, B7-1 is present as a mixed population of noncovalent dimers and monomers on the cell surface. In this study, we examined the physiological significance of this unique dimer-monomer equilibrium state of B7-1. We demonstrate that altering B7-1 to create a uniformly covalent dimeric state results in enhanced CD28-mediated formation of T cell-APC conjugates. The enhanced T cell-APC conjugate formation correlates with persistent concentration of signaling molecules PKC-theta and lck at the immunological synapse. In contrast, T cell acquisition of B7-1 from APCs, an event that occurs as a consequence of CD28 engagement with B7-1/B7-2 and is thought to play a role in the dissociation of T cell-APC conjugates, is highly reduced when B7-1 is present in the covalently dimeric state. The ability of covalently dimeric and wild type B7-1 to costimulate Ag-specific T cell proliferation was also assessed. In contrast to the enhanced ability of dimeric B7-1 to support conjugate formation and early parameters of T cell signaling, sensitivity to competitive inhibition by soluble CTLA-4-Ig indicated that the covalent dimeric. form of B7-1 is less efficient in costimulating T cell proliferation. These findings suggest a novel model in which optimal T cell costimulatory function of B7-1 requires high-avidity CD28 engagement by dimeric B7-1, followed by dissociation of these noncovalent B7-1 dimers, facilitating downregulation of CD28 and internalization of B7-1. These events regulate signaling through TCR/CD28 to maximize T cell activation to proliferation. The Journal of Immunology, 2010, 184: 1821-1828. C1 [Hodes, Richard J.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Almo, Steven C.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [Almo, Steven C.] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. [Nathenson, Stanley G.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Nathenson, Stanley G.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM hodesr@31.nia.nih.gov FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 35 TC 9 Z9 9 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 FEB 15 PY 2010 VL 184 IS 4 BP 1821 EP 1828 DI 10.4049/jimmunol.0902869 PG 8 WC Immunology SC Immunology GA 556IU UT WOS:000274585100018 PM 20065109 ER PT J AU Liu, WL Sohn, HW Tolar, P Meckel, T Pierce, SK AF Liu, Wanli Sohn, Hae Won Tolar, Pavel Meckel, Tobias Pierce, Susan K. TI Antigen-Induced Oligomerization of the B Cell Receptor Is an Early Target of Fc gamma RIIB Inhibition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESONANCE ENERGY-TRANSFER; ELASTIC LIGHT-SCATTERING; ANTIBODY COMPLEXES; SYNAPSE FORMATION; DENDRITIC CELLS; LYMPH-NODE; MEMBRANE MICRODOMAINS; AUTOIMMUNE-DISEASE; SUBCAPSULAR SINUS; IMMUNE SYNAPSE AB The Fc gamma RIIB is a potent inhibitory coreceptor that blocks BCR signaling in response to immune complexes and, as such, plays a decisive role in regulating Ab responses. The recent application of high-resolution live cell imaging to B cell studies is providing new molecular details of the earliest events in the initiation BCR signaling that follow within seconds of Ag binding. In this study, we report that when colligated to the BCR through immune complexes, the Fc gamma RIIB colocalizes with the BCR in microscopic clusters and blocks the earliest events that initiate BCR signaling, including the oligomerization of the BCR within these clusters, the active recruitment of BCRs to these clusters, and the resulting spreading and contraction response. Fluorescence resonance energy transfer analyses indicate that blocking these early events may not require molecular proximity of the cytoplasmic domains of the BCR and Fc gamma RIIB, but relies on the rapid and sustained association of Fc gamma RIIB with raft lipids in the membrane. These results may provide novel early targets for therapies aimed at regulating the Fc gamma RIIB to control Ab responses in autoimmune disease. The Journal of Immunology, 2010, 184: 1977-1989. C1 [Liu, Wanli; Sohn, Hae Won; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Tolar, Pavel] Natl Inst Med Res, London NW7 1AA, England. [Meckel, Tobias] Tech Univ Darmstadt, Dept Biol Membrane Biophys, Darmstadt, Germany. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. EM spierce@nih.gov RI Meckel, Tobias/F-4372-2010; liu, wanli/H-5690-2011 OI Meckel, Tobias/0000-0003-0759-2072; liu, wanli/0000-0003-2624-6802 FU National Institutes of Health, National Institute of Allergy and Infectious Disease FX This work was supported by the Intramural Research program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. NR 47 TC 32 Z9 34 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2010 VL 184 IS 4 BP 1977 EP 1989 DI 10.4049/jimmunol.0902334 PG 13 WC Immunology SC Immunology GA 556IU UT WOS:000274585100033 PM 20083655 ER PT J AU Woszczek, G Chen, LY Alsaaty, S Nagineni, S Shelhamer, JH AF Woszczek, Grzegorz Chen, Li-Yuan Alsaaty, Sara Nagineni, Sahrudaya Shelhamer, James H. TI Concentration-Dependent Noncysteinyl Leukotriene Type 1 Receptor-Mediated Inhibitory Activity of Leukotriene Receptor Antagonists SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN MAST-CELLS; SINGLE-DOSE PHARMACOKINETICS; CYSTEINYL-LEUKOTRIENES; CYSLT(1) RECEPTOR; DENDRITIC CELLS; HUMAN MONOCYTES; CHRONIC ASTHMA; MONTELUKAST; ACTIVATION; EXPRESSION AB The use of cysteinyl leukotriene receptor antagonists (LTRAs) for asthma therapy has been associated with a significant degree of, interpatient variability in response to treatment. Some of that variability may be attributable to noncysteinyl leukotriene type 1 receptor (CysLT(1))-mediated inhibitory mechanisms that have been demonstrated for this group of drugs. We used a model of CysLT(1) signaling in human monocytes to characterize CysLT(1)-dependent and -independent anti-inflammatory activity of two chemically different, clinically relevant LTRAs (montelukast and zafirlukast). Using receptor-desensitization experiments in monocytes and CysLT(1)-transfected HEK293 cells and IL-10-and CysLT(1) small interfering RNA-induced downregulation of CysLT(1) expression, we showed that reported CysLT(1) agonists leukotriene D(4) and UDP signal through calcium mobilization, acting on separate receptors, and that both pathways were inhibited by montelukast and zafirlukast. However, 3-log greater concentrations of LTRAs were required for the inhibition of UDP-induced signaling. In monocytes, UDP, but not leukotriene D(4), induced IL-8 production that was significantly inhibited by both drugs at micromolar concentrations. At low micromolar concentrations, both LTRAs also inhibited calcium ionophore-induced leukotriene (leukotriene B(4) and leukotriene C(4)) production, indicating 5-lipoxygenase inhibitory activities. We report herein that montelukast and zafirlukast, acting in a concentration-dependent manner, can inhibit non-CysLT(1)-mediated proinflammatory reactions, suggesting activities potentially relevant for interpatient variability in response to treatment. Higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a new strategy for finding more efficient therapy for bronchial asthma. The Journal of Immunology, 2010,184: 2219-2225. C1 [Woszczek, Grzegorz; Chen, Li-Yuan; Alsaaty, Sara; Nagineni, Sahrudaya; Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Woszczek, Grzegorz] Kings Coll London, MRC, London WC2R 2LS, England. [Woszczek, Grzegorz] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London WC2R 2LS, England. RP Shelhamer, JH (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jshelhamer@cc.nih.gov RI Woszczek, Grzegorz/H-5792-2012 FU Intramural NIH HHS [ZIA CL008071-06, Z01 CL008071-05] NR 38 TC 17 Z9 19 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2010 VL 184 IS 4 BP 2219 EP 2225 DI 10.4049/jimmunol.0900071 PG 7 WC Immunology SC Immunology GA 556IU UT WOS:000274585100058 PM 20083671 ER PT J AU Deleo, FR Musser, JM AF DeLeo, Frank R. Musser, James M. TI Axis of Coinfection Evil SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID RESISTANT STAPHYLOCOCCUS-AUREUS; PANTON-VALENTINE LEUKOCIDIN; INFLUENZA-A VIRUS; UNITED-STATES; PANDEMIC INFLUENZA; PNEUMONIA; INFECTIONS; RECEPTOR; ERA C1 [DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Musser, James M.] Methodist Hosp, Res Inst, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA. [Musser, James M.] Methodist Hosp, Res Inst, Dept Pathol, Houston, TX 77030 USA. RP Deleo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 25 TC 6 Z9 7 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2010 VL 201 IS 4 BP 488 EP 490 DI 10.1086/650304 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546WF UT WOS:000273843900003 PM 20078214 ER PT J AU Kibuuka, H Kimutai, R Maboko, L Sawe, F Schunk, MS Kroidl, A Shaffer, D Eller, LA Kibaya, R Eller, MA Schindler, KB Schuetz, A Millard, M Kroll, J Dally, L Hoelscher, M Bailer, R Cox, JH Marovich, M Birx, DL Graham, BS Michael, NL de Souza, MS Robb, ML AF Kibuuka, Hannah Kimutai, Robert Maboko, Leonard Sawe, Fred Schunk, Mirjam S. Kroidl, Arne Shaffer, Douglas Eller, Leigh Anne Kibaya, Rukia Eller, Michael A. Schindler, Karin B. Schuetz, Alexandra Millard, Monica Kroll, Jason Dally, Len Hoelscher, Michael Bailer, Robert Cox, Josephine H. Marovich, Mary Birx, Deborah L. Graham, Barney S. Michael, Nelson L. de Souza, Mark S. Robb, Merlin L. TI A Phase 1/2 Study of a Multiclade HIV-1 DNA Plasmid Prime and Recombinant Adenovirus Serotype 5 Boost Vaccine in HIV-Uninfected East Africans (RV 172) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY VIRUS CHALLENGE; MEMORY T-CELLS; CANDIDATE VACCINE; AIDS VACCINE; DOUBLE-BLIND; INFECTION; TRIAL; SURVIVAL; IMMUNITY; MONKEYS AB Background. Human immunodeficiency virus (HIV) vaccine development remains a global priority. We describe the safety and immunogenicity of a multiclade DNA vaccine prime with a replication-defective recombinant adenovirus serotype 5 (rAd5) boost. Methods. The vaccine is a 6-plasmid mixture encoding HIV envelope (env) subtypes A, B, and C and subtype B gag, pol, and nef, and an rAd5 expressing identical genes, with the exception of nef. Three hundred and twenty-four participants were randomized to receive placebo (n = 138), a single dose of rAd5 at 10(10) (n = 24) or 10(11) particle units (n = 24), or DNA at 0, 1, and 2 months, followed by rAd5 at either 10(10) (n = 114) or 10(11) particle units (n = 24) boosting at 6 months. Participants were followed up for 24 weeks after the final vaccination. Results. The vaccine was safe and well tolerated. HIV-specific T cell responses were detected in 63% of vaccinees. Titers of preexisting Ad5 neutralizing antibody did not affect the frequency and magnitude of T cell responses in prime-boost recipients but did affect the response rates in participants that received rAd5 alone (P = .037). Conclusion. The DNA/rAd5 vaccination regimen was safe and induced HIV type 1 multi-clade T cell responses, which were not significantly affected by titers of preexisting rAd5 neutralizing antibody. C1 [Kibuuka, Hannah; Eller, Leigh Anne; Eller, Michael A.; Millard, Monica] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Kimutai, Robert; Sawe, Fred; Shaffer, Douglas; Kibaya, Rukia] US Army Med Res Unit Kenya, Walter Reed Project, Kericho, Kenya. [Maboko, Leonard; Schunk, Mirjam S.; Kroidl, Arne; Schindler, Karin B.; Schuetz, Alexandra; Hoelscher, Michael] Mbeya Med Res Programme, Mbeya, Tanzania. [Schunk, Mirjam S.; Kroidl, Arne; Schindler, Karin B.; Schuetz, Alexandra; Hoelscher, Michael] Klinikum Ludwigs Maximilians Univ, Munich, Germany. [Eller, Leigh Anne; Eller, Michael A.; Marovich, Mary; Michael, Nelson L.; de Souza, Mark S.; Robb, Merlin L.] US Mil, HIV Res Program, Rockville, MD USA. [Kroll, Jason; Dally, Len] Emmes Corp, Rockville, MD USA. [Bailer, Robert; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Cox, Josephine H.] Int AIDS Vaccine Initiat, New York, NY USA. [Birx, Deborah L.] Ctr Dis Control & Prevent, Atlanta, GA USA. [de Souza, Mark S.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. RP Robb, ML (reprint author), 1600 Gude Dr, Rockville, MD 20850 USA. EM mrobb@hivresearch.org RI Hoelscher, Michael/D-3436-2012 FU NIAID NIH HHS [Y01 AI2642-12] NR 24 TC 70 Z9 71 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2010 VL 201 IS 4 BP 600 EP 607 DI 10.1086/650299 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546WF UT WOS:000273843900017 PM 20078213 ER PT J AU Herbeck, JT Gottlieb, GS Winkler, CA Nelson, GW An, P Maust, BS Wong, KG Troyer, JL Goedert, JJ Kessing, BD Detels, R Wolinsky, SM Martinson, J Buchbinder, S Kirk, GD Jacobson, LP Margolick, JB Kaslow, RA O'Brien, SJ Mullins, JI AF Herbeck, Joshua T. Gottlieb, Geoffrey S. Winkler, Cheryl A. Nelson, George W. An, Ping Maust, Brandon S. Wong, Kim G. Troyer, Jennifer L. Goedert, James J. Kessing, Bailey D. Detels, Roger Wolinsky, Steven M. Martinson, Jeremy Buchbinder, Susan Kirk, Gregory D. Jacobson, Lisa P. Margolick, Joseph B. Kaslow, Richard A. O'Brien, Stephen J. Mullins, James I. TI Multistage Genomewide Association Study Identifies a Locus at 1q41 Associated with Rate of HIV-1 Disease Progression to Clinical AIDS SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID WIDE ASSOCIATION; CELL COUNT; INFECTION; VIRUS; PLASMA; GENES; RESTRICTION; GENOTYPE; DELETION; ALLELES AB Background. A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. Methods. The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. Results. Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 x 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 x 10(-6)). Conclusions. This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis. C1 [Herbeck, Joshua T.; Maust, Brandon S.; Wong, Kim G.; Mullins, James I.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [Gottlieb, Geoffrey S.; Mullins, James I.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Winkler, Cheryl A.; Nelson, George W.; An, Ping; Troyer, Jennifer L.; Kessing, Bailey D.] SAIC Frederick, Lab Genom Divers Basic Res Program, Frederick, MD USA. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kirk, Gregory D.; Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Detels, Roger] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, HIV Res Sect, San Francisco, CA USA. [Wolinsky, Steven M.] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Martinson, Jeremy] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Kaslow, Richard A.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. RP Herbeck, JT (reprint author), Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. EM herbeck@u.washington.edu RI Troyer, Jennifer/B-8415-2012; Wolinsky, Steven/B-2893-2012; OI Martinson, Jeremy/0000-0003-4673-7238; Wolinsky, Steven/0000-0002-9625-6697 FU Intramural NIH HHS; NCRR NIH HHS [M01 RR000722, 5M01 RR00722]; NIAID NIH HHS [P30 AI027757, P30 AI027757-119010, P30 AI027757-169012, P30 AI027757-21, P30 AI027757-219021, P30 AI27757, R37 AI047734, R37 AI047734-06A1, R37 AI47734, T32 AI007140, T32 AI07140, U01 AI035039, U01 AI035040, U01 AI035040-18, U01 AI035041, U01 AI035042, U01 AI035042-10, U01 AI035043, U01 AI037613, U01 AI037984, U01 AI037984-04, U01 AI35039, U01 AI35040, U01 AI35041, U01 AI35042, U01 AI35043, U01 AI37613, U01 AI37984]; NIDA NIH HHS [R01 DA004334, R01-DA04334, R56 DA004334]; PHS HHS [R01-1258, U64/CCU900523-08] NR 35 TC 41 Z9 42 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2010 VL 201 IS 4 BP 618 EP 626 DI 10.1086/649842 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546WF UT WOS:000273843900019 PM 20064070 ER PT J AU Vanpouille, C Lisco, A Derudas, M Saba, E Grivel, JC Brichacek, B Scrimieri, F Schinazi, R Schols, D McGuigan, C Balzarini, J Margolis, L AF Vanpouille, Christophe Lisco, Andrea Derudas, Marco Saba, Elisa Grivel, Jean-Charles Brichacek, Beda Scrimieri, Francesca Schinazi, Raymond Schols, Dominique McGuigan, Christopher Balzarini, Jan Margolis, Leonid TI A New Class of Dual-Targeted Antivirals: Monophosphorylated Acyclovir Prodrug Derivatives Suppress Both Human Immunodeficiency Virus Type 1 and Herpes Simplex Virus Type 2 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PHOSPHORAMIDATE PROTIDE TECHNOLOGY; PLACEBO-CONTROLLED TRIAL; HUMAN LYMPHOID-TISSUE; INFECTED EX-VIVO; HIV-1 ACQUISITION; HSV SUPPRESSION; GENITAL HERPES; DOUBLE-BLIND; WOMEN; MEN AB Background. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. Methods. We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. Results. Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 mu mol/L in CD4(+) T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. Conclusions. Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1. C1 [Schols, Dominique; Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. [Vanpouille, Christophe; Lisco, Andrea; Saba, Elisa; Grivel, Jean-Charles; Brichacek, Beda; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Scrimieri, Francesca] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Schinazi, Raymond] Emory Univ, Sch Med, Vet Affairs Med Ctr, Decatur, GA 30033 USA. [Derudas, Marco; McGuigan, Christopher] Cardiff Univ, Welsh Sch Pharm, Cardiff, S Glam, Wales. RP Balzarini, J (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Minderbroedersstr 10, B-3000 Louvain, Belgium. EM jan.balzarini@rega.kuleuven.be RI McGuigan, Chris/P-1580-2014 OI McGuigan, Chris/0000-0001-8409-710X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Katholieke Universiteit Leuven (Geconcerteerde Onderzoeksacties) [05/19] FX Financial support: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Katholieke Universiteit Leuven (Geconcerteerde Onderzoeksacties 05/19). NR 46 TC 19 Z9 19 U1 1 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2010 VL 201 IS 4 BP 635 EP 643 DI 10.1086/650343 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546WF UT WOS:000273843900021 PM 20085496 ER PT J AU Bungay, PM Wang, TL Yang, H Elmquist, WF AF Bungay, Peter M. Wang, Tianli Yang, Hua Elmquist, William F. TI Utilizing transmembrane convection to enhance solute sampling and delivery by microdialysis: Theory and in vitro validation SO JOURNAL OF MEMBRANE SCIENCE LA English DT Article DE Microdialysis; Diffusion; Convection; Ultrafiltration; Mathematical modeling ID PUSH-PULL MICRODIALYSIS; HUMAN SKELETAL-MUSCLE; QUANTITATIVE MICRODIALYSIS; VIVO; DIFFUSION; RECOVERY; PROTEINS; TISSUE; PHARMACODYNAMICS; MACROMOLECULES AB Microdialysis is a well-developed membrane-based tool relying on diffusion to sample diffusible constituents of complex media, such as biological tissue. The objective of this research is to expand the utility of microdialysis by combining transmembrane convection with diffusion to enhance solute exchange between microdialysis probes and the surrounding medium. We have developed a mathematical model to describe probe performance and performed validation experiments utilizing tracer solutes and commercially available probes with 100-kDa molecular weight cutoff membranes. Diffusive and fluid permeabilities of the probe membranes are evaluated for probes immersed in well-stirred bathing media in vitro. Transmembrane convection alters the solute extraction fraction, i.e., the fractional loss of a solute from the probe perfusate during delivery and the fractional gain by the perfusate during sampling. The extraction fraction change depends upon the magnitude and direction (inward or outward) of fluid movement across the membrane. However, for solutes with zero reflection coefficients, equality is maintained between these delivery and sampling extraction fractions. This equality is a prerequisite for probe calibration approaches that rely on analyte delivery from the perfusate. Thus, we have provided the theoretical and experimental basis for exploiting convection in a quantitative manner to enhance solute delivery and sampling in microdialysis applications. Published by Elsevier B.V. C1 [Bungay, Peter M.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Wang, Tianli; Yang, Hua; Elmquist, William F.] Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. RP Bungay, PM (reprint author), NIBIB, Lab Bioengn & Phys Sci, NIH, 13 S Dr,MSC 5766,Bldg 13-3N17, Bethesda, MD 20892 USA. EM bungayp@mail.nih.gov; wangx826@tc.umn.edu; yang@mpi.com; elmqu011@umn.edu FU NIH; National Institute of Biomedical Imaging and Bioengineering FX This research was supported [in part] by the Intramural Research Programs of the NIH, including the National Institute of Biomedical Imaging and Bioengineering. The authors are grateful to Dr. Robert L. Dedrick for his critical assistance in preparation of the manuscript and to Professor Rueben A. Gonzales for establishing that backpressure from effluent flow can produce transmembrane fluid loss in probes constructed from low-fluid-permeability cellulosic membranes. The latter observation was the initial stimulus for the present analysis. NR 28 TC 5 Z9 5 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0376-7388 J9 J MEMBRANE SCI JI J. Membr. Sci. PD FEB 15 PY 2010 VL 348 IS 1-2 BP 131 EP 149 DI 10.1016/j.memsci.2009.10.050 PG 19 WC Engineering, Chemical; Polymer Science SC Engineering; Polymer Science GA 558SE UT WOS:000274765300018 PM 20161534 ER PT J AU Shen, H Wang, Y AF Shen, Hui Wang, Yun TI Correlation of locomotor activity and brain infarction in rats with transient focal ischemia SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Stroke; Middle cerebral artery occlusion; Behavior ID CEREBRAL-ISCHEMIA; STROKE; GERBILS; PROTECTS; BEHAVIOR; MICE AB Occlusion of middle cerebral artery (MCAo) is commonly used to generate stroke in experimental animals. Different behavioral assays have been used to evaluate the severity of lesions or recovery after treatment in this model. In this study, we examined the correlation between the size of infarction and locomotor activity after transient MCAo in adult Sprague-Dawley rats. The right middle cerebral artery was occluded for 30-90-min by ligation with a 10-O suture. At 2 days after MCAo, animals were individually placed in a 3-D infrared activity chamber for 1 h to measure their horizontal, vertical, stereotypic and rotational activity. Body asymmetry was examined using an elevated body swing test. Volume of infarction was measured by triphenyltetrazolium chloride staining. We found that there is a significant correlation between the volume of infarction and vertical movement, such as vertical activity, vertical movement number and vertical movement time. There is also a significant correlation between the infarction volume and body a symmetry. In conclusion, our data suggest that vertical locomotor activity and body a symmetry are useful behavioral indices to estimate the size of lesioning in rodents after MCAo. (C) 2009 Elsevier B.V. All rights reserved. C1 [Shen, Hui] NIDA, Neural Protect & Regenerat Sect, IPR, Baltimore, MD 21224 USA. RP Shen, H (reprint author), NIDA, Neural Protect & Regenerat Sect, IPR, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM hshen@intra.nida.nih.gov FU National Institute on Drug Abuse, IRP FX This study is supported by the National Institute on Drug Abuse, IRP. NR 16 TC 11 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD FEB 15 PY 2010 VL 186 IS 2 BP 150 EP 154 DI 10.1016/j.jneumeth.2009.11.008 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 561NS UT WOS:000274985200002 PM 19917312 ER PT J AU Yakel, J AF Yakel, Jerrel TI Advances and hold-ups in the study of structure, function and regulation of Cys-loop ligand-gated ion channels and receptors SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material C1 NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, J (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov NR 8 TC 6 Z9 6 U1 1 U2 3 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 FEB 15 PY 2010 VL 588 IS 4 BP 555 EP 556 DI 10.1113/jphysiol.2009.185488 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 555CS UT WOS:000274485500003 PM 20173078 ER PT J AU Yakel, JL AF Yakel, Jerrel L. TI Gating of nicotinic ACh receptors: latest insights into ligand binding and function SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article; Proceedings Paper CT Satellite Symposium on Advances and Hold-Ups in the Study of Structure, Function and Regulation of Cys-Loop Ligand-Gated Ion Channels and Receptors CY 2009 CL Chicago, IL SP Soc Neurosci ID ACETYLCHOLINE-RECEPTOR; EXTRACELLULAR DOMAIN; AGONIST-BINDING; ALLOSTERIC MODULATOR; CRYSTAL-STRUCTURE; ION-CHANNEL; PROTEIN; LOOP; DESENSITIZATION; RESOLUTION AB Nicotinic acetylcholine receptors (nAChRs) are in the superfamily of cys-loop receptors, and are widely expressed in the nervous system where they participate in a variety of physiological functions, including regulating excitability and neurotransmitter release, as well as neuromuscular contraction. Members of the cys-loop family of receptors, which also includes the molluscan ACh-binding protein (AChBP), a soluble protein that is analogous to the extracellular ligand-binding domain of the cys-loop receptors, are pentameric assemblies of five subunits, with each subunit arranged around a central pore. The binding of ACh to the extracellular interface between two subunits induces channel opening. With the recent 4 A resolution of the Torpedo nAChR, and the crystal structure of the AChBP, much has been learned about the structure of the ligand-binding domain and the channel pore, as well as major structural rearrangements that may confer channel opening, including a major rearrangement of the C-loop within the ligand binding pocket, and perhaps other regions including the F-loop (the beta 8-beta 9 linker), the beta 1-beta 2 linker and the cys-loop. Here I will review the latest findings from my lab aimed at a further understanding of the function of the neuronal nAChR channels (and in particular the role of desensitization), and our search for novel AChBP species that may lead to a further understanding of the function of the cys-loop receptor family. C1 NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU Intramural NIH HHS NR 33 TC 32 Z9 33 U1 1 U2 7 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 FEB 15 PY 2010 VL 588 IS 4 BP 597 EP 602 DI 10.1113/jphysiol.2009.182691 PG 6 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 555CS UT WOS:000274485500008 PM 19917567 ER PT J AU Bayulkem, K Lopez, G AF Bayulkem, Kemal Lopez, Grisel TI Nonmotor fluctuations in Parkinson's disease: Clinical spectrum and classification SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 9th International Congress on Mental Dysfunction and Other Non-Motor Features in Parkinsons Disease and Related Disorderes CY OCT 16-19, 2008 CL Dresden, GERMANY DE Parkinson's disease; Nonmotor fluctuations; "On-off" periods ID ON-OFF; LEVODOPA; DYSFUNCTION; FATIGUE; MOOD AB The majority of patients with Parkinson's disease (PD) on levodopa (LD) treatment Usually experience motor fluctuations (MFs) within several years of initiation of treatment. Besides the classic MFs, many nonmotor fluctuations (NMFs) may occur in PD NMFs appear both in the "on" state and "off" state However, the clinical spectrum and the frequency of these symptoms are not well recognized NMFs are usually mild and less disabling than MFs but sometimes can lead to unnecessary tests and therapies. NMFs occurring in association with the "on" state are better known and therefore more frequently diagnosed than those occurring in the "off" state. NMFs can be classified into three groups autonomic. cognitive/psychiatric, and sensory They include gastrointestinal and urinary symptoms, drenching sweats, temperature and blood-pressure changes, depression, anxiety, hallucinations, hypomania, moaning/screaming, confusion, cognitive dysfunction, sexual deviations and dopamine dysregulation syndrome (DDS), pain, akathisia, internal tremor, numbness/parasthesia, and dyspnea Conclusion Recognition of NMFs may prevent unnecessary diagnostic tests and may lead to treatment modifications aimed to minimize their occurrence Crown Copyright (C) 2009 Published by Elsevier B V All rights reserved C1 [Bayulkem, Kemal] Univ Istanbul, Dept Neurol, Cerrahpsa Fac Med, Istanbul, Turkey. [Bayulkem, Kemal; Lopez, Grisel] NINDS, NIH, Bethesda, MD 20892 USA. RP Bayulkem, K (reprint author), Univ Istanbul, Dept Neurol, Cerrahpsa Fac Med, Istanbul, Turkey. NR 39 TC 31 Z9 35 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2010 VL 289 IS 1-2 SI SI BP 89 EP 92 DI 10.1016/j.jns.2009.08.022 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 560TL UT WOS:000274925700019 PM 19747695 ER PT J AU Douagi, I Forsell, MNE Sundling, C O'Dell, S Feng, Y Dosenovic, P Li, YX Seder, R Lore, K Mascola, JR Wyatt, RT Hedestam, GBK AF Douagi, Iyadh Forsell, Mattias N. E. Sundling, Christopher O'Dell, Sijy Feng, Yu Dosenovic, Pia Li, Yuxing Seder, Robert Lore, Karin Mascola, John R. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Influence of Novel CD4 Binding-Defective HIV-1 Envelope Glycoprotein Immunogens on Neutralizing Antibody and T-Cell Responses in Nonhuman Primates SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; GP120 GLYCOPROTEIN; RECEPTOR-BINDING; SUBTYPE-B; VACCINE; CORECEPTOR; INFECTION; TRIMERS; EPITOPES AB The high-affinity in vivo interaction between soluble HIV-1 envelope glycoprotein (Env) immunogens and primate CD4 results in conformational changes that alter the immunogenicity of the gp120 subunit. Because the conserved binding site on gp120 that directly interacts with CD4 is a major vaccine target, we sought to better understand the impact of in vivo Env-CD4 interactions during vaccination. Rhesus macaques were immunized with soluble wild-type (WT) Env trimers, and two trimer immunogens rendered CD4 binding defective through distinct mechanisms. In one variant, we introduced a mutation that directly disrupts CD4 binding (368D/R). In the second variant, we introduced three mutations (423I/M, 425N/K, and 431G/E) that disrupt CD4 binding indirectly by altering a gp120 subdomain known as the bridging sheet, which is required for locking Env into a stable interaction with CD4. Following immunization, Env-specific binding antibody titers and frequencies of Env-specific memory B cells were comparable between the groups. However, the quality of neutralizing antibody responses induced by the variants was distinctly different. Antibodies against the coreceptor binding site were elicited by WT trimers but not the CD4 binding-defective trimers, while antibodies against the CD4 binding site were elicited by the WT and the 423I/M, 425N/K, and 431G/E trimers but not the 368D/R trimers. Furthermore, the CD4 binding-defective trimer variants stimulated less potent neutralizing antibody activity against neutralization-sensitive viruses than WT trimers. Overall, our studies do not reveal any potential negative effects imparted by the in vivo interaction between WT Env and primate CD4 on the generation of functional T cells and antibodies in response to soluble Env vaccination. C1 [Douagi, Iyadh; Sundling, Christopher; Dosenovic, Pia; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Douagi, Iyadh; Sundling, Christopher; Dosenovic, Pia; Lore, Karin; Hedestam, Gunilla B. Karlsson] Swedish Inst Infect Dis Control, Solna, Sweden. [Lore, Karin] Karolinska Inst, Ctr Infect Med, S-17177 Stockholm, Sweden. [Forsell, Mattias N. E.; O'Dell, Sijy; Feng, Yu; Li, Yuxing; Seder, Robert; Mascola, John R.; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Box 280, S-17177 Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se RI Feng, Yu/A-3396-2012; OI Sundling, Christopher/0000-0002-6138-690X FU International AIDS Vaccine Initiative; Swedish International Development Agency/Department of Research Cooperation; Vaccine Research Center, NIAID, NIH; Karolinska Institutet FX This study was supported by grants from the International AIDS Vaccine Initiative ( G. K. H. and K. L.), the Swedish International Development Agency/Department of Research Cooperation ( G. K. H. and K. L.), the intramural research program of the Vaccine Research Center, NIAID, NIH ( R. T. W. and J.R.M.), and by the Karolinska Institutet ( G. K. H.). NR 52 TC 34 Z9 34 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 15 PY 2010 VL 84 IS 4 BP 1683 EP 1695 DI 10.1128/JVI.01896-09 PG 13 WC Virology SC Virology GA 546ZB UT WOS:000273853200003 PM 19955308 ER PT J AU Matthijnssens, J Taraporewala, ZF Yang, HY Rao, SJ Yuan, LJ Cao, DJ Hoshino, Y Mertens, PPC Carner, GR McNeal, M Sestak, K Van Ranst, M Patton, JT AF Matthijnssens, Jelle Taraporewala, Zenobia F. Yang, Hongyan Rao, Shujing Yuan, Lijuan Cao, Dianjun Hoshino, Yasutaka Mertens, Peter P. C. Carner, Gerry R. McNeal, Monica Sestak, Karol Van Ranst, Marc Patton, John T. TI Simian Rotaviruses Possess Divergent Gene Constellations That Originated from Interspecies Transmission and Reassortment SO JOURNAL OF VIROLOGY LA English DT Article ID GROUP-A ROTAVIRUS; RNA-RNA HYBRIDIZATION; RHESUS MACAQUES; CELL ENTRY; STRAINS; PROTEIN; VP4; INTUSSUSCEPTION; CLASSIFICATION; HETEROGENEITY AB Although few simian rotaviruses (RVs) have been isolated, such strains have been important for basic research and vaccine development. To explore the origins of simian RVs, the complete genome sequences of strains PTRV (G8P[1]), RRV (G3P[3]), and TUCH (G3P[24]) were determined. These data allowed the genotype constellations of each virus to be determined and the phylogenetic relationships of the simian strains with each other and with nonsimian RVs to be elucidated. The results indicate that PTRV was likely transmitted from a bovine or other ruminant into pig-tailed macaques (its host of origin), since its genes have genotypes and encode outer-capsid proteins similar to those of bovine RVs. In contrast, most of the genes of rhesus-macaque strains, RRV and TUCH, have genotypes more typical of canine-feline RVs. However, the sequences of the canine and/or feline (canine/feline)-like genes of RRV and TUCH are only distantly related to those of modern canine/feline RVs, indicating that any potential transmission of a progenitor of these viruses from a canine/feline host to a simian host was not recent. The remaining genes of RRV and TUCH appear to have originated through reassortment with bovine, human, or other RV strains. Finally, comparison of PTRV, RRV, and TUCH genes with those of the vervet-monkey RV SA11-H96 (G3P[2]) indicates that SA11-H96 shares little genetic similarity to other simian strains and likely has evolved independently. Collectively, our data indicate that simian RVs are of diverse ancestry with genome constellations that originated largely by interspecies transmission and reassortment with nonhuman animal RVs. C1 [Taraporewala, Zenobia F.; Yang, Hongyan; Cao, Dianjun; Hoshino, Yasutaka; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Matthijnssens, Jelle; Van Ranst, Marc] Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Lab Clin & Epidemiol Virol, Leuven, Belgium. [Rao, Shujing; Carner, Gerry R.] Clemson Univ, Dept Entomol, Clemson, SC 29634 USA. [Yuan, Lijuan; Cao, Dianjun] Virginia Polytech Inst & State Univ, Dept Biomed Sci & Pathobiol, Ctr Mol Med & Infect Dis, Blacksburg, VA 24061 USA. [Mertens, Peter P. C.] Inst Anim Hlth, Dept Arbovirol, Woking GU24 0NF, Surrey, England. [McNeal, Monica] Cincinnati Childrens Hosp, Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. [Sestak, Karol] Tulane Univ, Sch Med, New Orleans, LA 70118 USA. [Sestak, Karol] Tulane Natl Primate Res Ctr, New Orleans, LA 70118 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6314, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Yuan, Lijuan/A-2468-2008; Patton, John/P-1390-2014; Matthijnssens, Jelle/A-6770-2015; Matthijnssens, Jelle/B-8634-2016; OI Yuan, Lijuan/0000-0003-0709-5228; Van Ranst, Marc/0000-0002-1674-4157; Mertens, Peter/0000-0002-3438-3738 FU Fund for Scientific Research (FWO) Flanders; National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases.; Virginia Polytechnic Institute and State University; National Center for Research Resources [NIH R21RR024871] FX J. M. was supported by a postdoctoral fellowship from the Fund for Scientific Research (FWO) Flanders. J. T. P., Z. F. T., D. C., and H. Y. were supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases. The sequencing of PTRV was partially supported by startup funds to L. Y. from Virginia Polytechnic Institute and State University. K. S. was supported by NIH R21RR024871 grant awarded to the National Center for Research Resources. NR 51 TC 35 Z9 39 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 15 PY 2010 VL 84 IS 4 BP 2013 EP 2026 DI 10.1128/JVI.02081-09 PG 14 WC Virology SC Virology GA 546ZB UT WOS:000273853200035 PM 19939934 ER PT J AU Raznahan, A Cutter, W Lalonde, F Robertson, D Daly, E Conway, GS Skuse, DH Ross, J Lerch, JP Giedd, JN Murphy, DDGM AF Raznahan, Armin Cutter, William Lalonde, Francois Robertson, Dene Daly, Eileen Conway, Gerard S. Skuse, David H. Ross, Judith Lerch, J. P. Giedd, Jay N. Murphy, Declan D. G. M. TI Cortical anatomy in human X monosomy SO NEUROIMAGE LA English DT Article DE Turner syndrome; MRI; Cortical thickness; Structural covariance ID TURNER-SYNDROME; CEREBRAL-CORTEX; BRAIN-DEVELOPMENT; FEAR RECOGNITION; FEMALE BRAIN; CHROMOSOME; THICKNESS; MRI; GYRIFICATION; PHENOTYPE AB Turner syndrome (TS) is a model for X chromosome influences on neurodevelopment because it is most commonly caused by absence of one X chromosome and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV- cortical thickness (CT) and surface area (SA) - which have differing genetic determinants and may be independently altered. Therefore, in 24 adults with X monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA: (ii) an index of hemispheric gyrification; (iii) CT throughout the cortical sheet; and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV); (ii) reduced hemispheric gyrification bilaterally; (iii) foci of significantly increased CT involving inferior temporal, lateral occipital, intraparietal sulcus (IPS), cingulate and orbitofrontal cortices; and (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral occipital gyri. Our findings suggest that females with TS have complex, sometimes "opposing", abnormalities in SA/gyrification (decreased) and CT (increased), which can result in no overall detectable differences in CV. Thus, haploinsufficiency of X chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype. (C) 2009 Elsevier Inc. All rights reserved. C1 [Raznahan, Armin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Raznahan, Armin] Kings Coll London, Inst Psychiat, Dept Child Psychiat, London, England. [Lalonde, Francois; Giedd, Jay N.] Kings Coll London, Inst Psychiat, Dept Med Psychol, London, England. [Conway, Gerard S.] Middlesex Hosp, Dept Endocrinol, London, England. [Skuse, David H.] Inst Child Hlth, Behav Sci Unit, London, England. [Ross, Judith] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Lerch, J. P.] Hosp Sick Children, Mouse Imaging Ctr, Toronto Ctr Phenogenom, Toronto, ON M5G 1X8, Canada. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,10 Ctr Dr, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/A-3080-2008; daly, eileen/B-6716-2011; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Daly, Eileen/0000-0003-3625-3467 FU UK Medical Research Council [A.R-G0701370]; MRC UK AIMS; Psychiatry Research Trust; South London and Maudsley NHS Foundation Trust (National Division) FX This work was supported by a UK Medical Research Council Clinical Research Training Fellowship (A.R-G0701370) and partially supported by the MRC UK AIMS network, the Psychiatry Research Trust, and the South London and Maudsley NHS Foundation Trust (National Division). The authors also wish to thank the participants who took part in this study. NR 56 TC 32 Z9 32 U1 0 U2 8 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 FEB 15 PY 2010 VL 49 IS 4 BP 2915 EP 2923 DI 10.1016/j.neuroimage.2009.11.057 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500003 PM 19948228 ER PT J AU Kreisl, WC Fujita, M Fujimura, Y Kimura, N Jenko, KJ Kannan, P Hong, J Morse, CL Zoghbi, SS Gladding, RL Jacobson, S Oh, U Pike, VW Innis, RB AF Kreisl, William C. Fujita, Masahiro Fujimura, Yota Kimura, Nobuyo Jenko, Kimberly J. Kannan, Pavitra Hong, Jinsoo Morse, Cheryl L. Zoghbi, Sami S. Gladding, Robert L. Jacobson, Steven Oh, Unsong Pike, Victor W. Innis, Robert B. TI Comparison of [C-11]-(R)-PK 11195 and [C-11]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker SO NEUROIMAGE LA English DT Article DE Translocator protein (18 kDa); [C-11]-(R)-PK 11195; [C-11]PBR28; Positron emission tomography ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; PET RADIOLIGAND; IN-VIVO; BRAIN; NOMENCLATURE; RESISTANCE; INHIBITORS; BINDING; CLONING; GENE AB Ten percent of humans lack specific binding of [C-11]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. "Non-binders" have not been reported using another TSPO radioligand, [C-11]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: (1) What is the cause of nonbinding to PBR28? and (2) Why has this phenomenon not been reported using [C-11]-(R)-PK 11195? Methods: Five binders and five non-binders received whole-body imaging with both [C-11]-(R)-PK 11195 and [C-11]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [C-11]-(R)-PK 11195 at baseline and after blockade of TSPOs. Results: Using [C-11]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [C-11]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [H-3]PBR28 had more than 10-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [C-11]-(R)-PK 11195 in monkey brain was similar to 80-fold lower than that reported for [C-11]PBR28. Conclusions: Based on binding of [H-3]PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [C-11]-(R)-PK 11195 may have obscured its detection of nonbinding in peripheral organs. Published by Elsevier Inc. C1 [Kreisl, William C.; Fujita, Masahiro; Fujimura, Yota; Kimura, Nobuyo; Jenko, Kimberly J.; Kannan, Pavitra; Hong, Jinsoo; Morse, Cheryl L.; Zoghbi, Sami S.; Gladding, Robert L.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Jacobson, Steven; Oh, Unsong] NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Fujimura, Yota] Teikyo Univ, Sch Med, Dept Psychiat, Tokyo 173, Japan. RP Kreisl, WC (reprint author), 31 Ctr Dr,Rm B2-B34, Bethesda, MD 20892 USA. EM kreislw@mail.nih.gov; robert.innis@nih.gov FU NIMH [Z01- MH-002852-04]; National Institutes of Health Biomarkers Consortium; NIH FX This project is funded as a public-private partnership supported by the NIMH (Z01- MH-002852-04) and the Foundation for the National Institutes of Health Biomarkers Consortium (www.biomarkersconsortium.org), through generous contributions from EMD Serono, GlaxoSmithKline, Eli Lilly, Merck, Pfizer, and F. Hoffman LaRoche. We especially thank Linda Brady, PhD (NIMH) for establishing this partnership and her active involvement in its on-going research. Additional support was provided by the Japanese Society for the Promotion of Science Fellowship of the NIH (Y.F.). We thank Yi Zhang, PhD for assistance in the production of radioligands; Michael M. Gottesman, M.D. and Matthew D. Hall, PhD for providing cell lines and technical support for studies involving substrate specificity for ABC transporters; and Maria D. Ferraris-Araneta, C-R.N.P., Barbara Scepura, C-R.N.P,, Gerald Hodges, R.N., Leah Dickstein, B.S., and the NIH PET Department for successfully completing the PET studies. NR 19 TC 83 Z9 83 U1 2 U2 18 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 FEB 15 PY 2010 VL 49 IS 4 BP 2924 EP 2932 DI 10.1016/j.neuroimage.2009.11.056 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500004 PM 19948230 ER PT J AU Savitz, J Nugent, AC Bogers, W Liu, A Sills, R Luckenbaugh, DA Bain, EE Price, JL Zarate, C Manji, HK Cannon, DM Marrett, S Charney, DS Drevets, WC AF Savitz, Jonathan Nugent, Allison C. Bogers, Wendy Liu, Alice Sills, Rebecca Luckenbaugh, David A. Bain, Earle E. Price, Joseph L. Zarate, Carlos Manji, Husseini K. Cannon, Dara M. Marrett, Sean Charney, Dennis S. Drevets, Wayne C. TI Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: The impact of medication SO NEUROIMAGE LA English DT Article ID GRAY-MATTER VOLUME; LITHIUM-TREATED PATIENTS; TEMPORAL-LOBE STRUCTURES; ANXIETY-LIKE BEHAVIOR; DOPAMINERGIC-NEURONS; BRAIN ABNORMALITIES; MOOD STABILIZERS; ALCOHOL-ABUSE; VALPROIC ACID; I DISORDER AB MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size = 0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11 +/- 10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BID patients displayed smaller left and right amygdala volumes than their matched control group (p < 0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p = 0.051). Right and left amygdala volumes were larger (p < 0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications. Published by Elsevier Inc. C1 [Savitz, Jonathan; Nugent, Allison C.; Bogers, Wendy; Liu, Alice; Sills, Rebecca; Luckenbaugh, David A.; Zarate, Carlos; Cannon, Dara M.; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, MAP, Bethesda, MD 20892 USA. [Bain, Earle E.] Abbott Labs Inc, Deerfield, IL USA. [Price, Joseph L.] St Louis Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Manji, Husseini K.] Johnson & Johnson Inc, New Brunswick, NJ USA. [Marrett, Sean] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Charney, Dennis S.] Mt Sinai Sch Med, New York, NY USA. [Savitz, Jonathan; Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. [Savitz, Jonathan; Drevets, Wayne C.] Univ Oklahoma, Coll Med, Laureate Inst Brain Res, Tulsa, OK USA. [Cannon, Dara M.] Natl Univ Ireland, Div Psychiat, Galway, Ireland. RP Savitz, J (reprint author), NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, MAP, 15K N Dr,Room 200, Bethesda, MD 20892 USA. EM savitzj@mail.nih.gov RI Savitz, Jonathan/C-3088-2009; Cannon, Dara/C-1323-2009; OI Savitz, Jonathan/0000-0001-8143-182X; Cannon, Dara/0000-0001-7378-3411; Nugent, Allison/0000-0003-2569-2480; Marrett, Sean/0000-0001-8179-6511 FU Intramural NIH HHS [Z99 MH999999] NR 90 TC 56 Z9 58 U1 2 U2 3 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 FEB 15 PY 2010 VL 49 IS 4 BP 2966 EP 2976 DI 10.1016/j.neuroimage.2009.11.025 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500009 PM 19931399 ER PT J AU Hu, SW Olulade, O Castillo, JG Santos, J Kim, S Tamer, GG Luh, WM Talavage, TM AF Hu, Shuowen Olulade, Olumide Castillo, Javier Gonzalez Santos, Joseph Kim, Sungeun Tamer, Gregory G., Jr. Luh, Wen-Ming Talavage, Thomas M. TI Modeling hemodynamic responses in auditory cortex at 1.5 T using variable duration imaging acoustic noise SO NEUROIMAGE LA English DT Article DE Imaging acoustic noise; Functional MRI; Hemodynamic response; Linear systems ID EVENT-RELATED FMRI; FUNCTIONAL MRI; SCANNER NOISE; BOLD RESPONSE; NONLINEARITY; INSULA; SYSTEM AB A confound for functional magnetic resonance imaging (fMRI), especially for auditory studies, is the presence of imaging acoustic noise generated mainly as a byproduct of rapid gradient switching during volume acquisition and, to a lesser extent, the radiofrequency transmit. This work utilized a novel pulse sequence to present actual imaging acoustic noise for characterization of the induced hemodynamic responses and assessment of linearity in the primary auditory cortex with respect to noise duration. Results show that responses to brief duration (46 ms) imaging acoustic noise is highly nonlinear while responses to longer duration (>1 s) imaging acoustic noise becomes approximately linear, with the right primary auditory cortex exhibiting a higher degree of nonlinearity than the left for the investigated noise durations. This study also assessed the spatial extent ofactivation induced by imaging acoustic noise, showing that the use of modeled responses (specific to imaging acoustic noise) as the reference waveform revealed additional activations in the auditory cortex not observed with a canonical gamma variate reference waveform, suggesting an improvement in detection sensitivity for imaging acoustic noise-induced activity. Longer duration (1.5 s) imaging acoustic noise was observed to induce activity that expanded outwards from Heschl's gyrus to cover the superior temporal gyrus as well as parts of the middle temporal gyrus and insula, potentially affecting higher level acoustic processing. Published by Elsevier Inc. C1 [Hu, Shuowen; Olulade, Olumide; Kim, Sungeun; Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Hu, Shuowen] USA, Res Lab, Adelphi, MD USA. [Castillo, Javier Gonzalez; Santos, Joseph; Tamer, Gregory G., Jr.; Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Luh, Wen-Ming] NIMH, NIH, Bethesda, MD 20892 USA. RP Hu, SW (reprint author), 465 NW Ave, W Lafayette, IN 47906 USA. EM hu@ecn.purdue.edu RI Gonzalez-Castillo, Javier/B-6903-2012; OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIH [R01EB003990]; National Institute of Mental Health FX This research was supported in part by NIH grant R01EB003990 and the Intramural Research Program of the National Institute of Mental Health. NR 41 TC 9 Z9 9 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2010 VL 49 IS 4 BP 3027 EP 3038 DI 10.1016/j.neuroimage.2009.11.051 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500015 PM 19948232 ER PT J AU Reich, DS Ozturk, A Calabresi, PA Mori, S AF Reich, Daniel S. Ozturk, Arzu Calabresi, Peter A. Mori, Susumu TI Automated vs. conventional tractography in multiple sclerosis: Variability and correlation with disability SO NEUROIMAGE LA English DT Article DE Diffusion tensor imaging; Tractography; Magnetization transfer imaging; Multiple sclerosis; Corticospinal tract; Corpus callosum; Visual system ID WHITE-MATTER; CORTICOSPINAL TRACT; OUTCOME MEASURE; FIBER TRACKING; DIFFUSION MR; BRAIN; REPRODUCIBILITY; IMPAIRMENT; REGISTRATION; DISEASE AB Diffusion-tensor-imaging fiber tractography enables interrogation of brain white matter tracts that subserve different functions. However, tract reconstruction can be labor and time intensive and can yield variable results that may reduce the power to link imaging abnormalities with disability. Automated segmentation of these tracts would help make tract-specific imaging clinically useful, but implementation of such segmentation is problematic in the presence of diseases that alter brain structure. In this work, we investigated an automated tract-probability-mapping scheme and applied it to multiple sclerosis, comparing the results to those derived from conventional tractography. We found that the automated method has consistently lower scan-rescan variability (typically 0.7-1.5% vs. up to 3% for conventional tractography) and avoids problems related to tractography failures within and around lesions. In the corpus callosum, optic radiation, and corticospinal tract, tract-specific MRI indices calculated by the two methods were moderately to strongly correlated, though systematic, tract-specific differences were present. In these tracts, the two methods also yielded similar correlation coefficients relating tract-specific MRI indices to clinical disability scores. In the optic tract, the automated method failed. With judicious application, therefore, the automated method may be useful for studies that investigate the relationship between imaging findings and clinical outcomes in disease. Published by Elsevier Inc. C1 [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Reich, Daniel S.; Ozturk, Arzu; Mori, Susumu] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Reich, Daniel S.; Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Reich, Daniel S.; Mori, Susumu] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD 21205 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, 10 Ctr Dr,MSC 1400,Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NIH [K99NS064098, P41RR015241, R01AG020012, K01EB009120]; National Multiple Sclerosis Society [TR3760A3]; NIH, NINDS FX Funding sources: NIH grants K99NS064098, P41RR015241, R01AG020012, and K01EB009120; and National Multiple Sclerosis Society grant TR3760A3. This research was also supported by the intramural research program of the NIH, NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 35 TC 23 Z9 24 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 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2010 VL 49 IS 4 BP 3047 EP 3056 DI 10.1016/j.neuroimage.2009.11.043 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500017 PM 19944769 ER PT J AU Kawai, Y Aoki, I Umeda, M Higuchi, T Kershaw, J Higuchi, M Silva, AC Tanaka, C AF Kawai, Yuko Aoki, Ichio Umeda, Masahiro Higuchi, Toshihiro Kershaw, Jeff Higuchi, Makoto Silva, Afonso C. Tanaka, Chuzo TI In vivo visualization of reactive gliosis using manganese-enhanced magnetic resonance imaging SO NEUROIMAGE LA English DT Article DE Reactive gliosis; Stroke; Brain ischemia; Manganese; MEMRI; MRI ID MIDDLE CEREBRAL-ARTERY; SPINAL-CORD-INJURY; GLUTAMINE-SYNTHETASE; RAT-BRAIN; MICROGLIAL CELLS; ISCHEMIC-INJURY; MRI; ASTROCYTES; ACTIVATION; MICE AB Reactive astrogliosis occurs after diverse central nervous system (CNS) insults. While astrogliosis provides protection against inflammation, it is also obstructive in the progress of neuranagenesis after CNS insults. Thus, a method that enables in vivo visualization and tissue characterization for gliosis would be invaluable for studies of CNS insults and corresponding treatments. Manganese has proven to be a useful MRI contrast agent that enters cells via Ca(2+) channels and has been applied to manganese-enhanced MRI (MEMRI) for neuronal functional mapping. This Study investigated whether MEMRI can detect astrogliosis after focal ischemia in vivo. Rats were divided into groups according to the number of days after either transient middle cerebral artery occlusion or a sham. Ring- or crescent-shaped enhancement of MEMRI corresponded to the GFAP-positive astroglia observed in the peripheral region of the ischemic core 11 days after middle cerebral artery occlusion. This indicates that MEMRI enhancement predominantly reflects reactive astrogliosis after stroke. (C) 2009 Elsevier Inc. All rights reserved. C1 [Aoki, Ichio; Kershaw, Jeff; Higuchi, Makoto] Natl Inst Radiol Sci, Mol Imaging Ctr, Chiba 2638555, Japan. [Kawai, Yuko; Higuchi, Toshihiro; Tanaka, Chuzo] Meiji Univ Integrat Med, Dept Neurosurg, Kyoto 6290392, Japan. [Umeda, Masahiro; Tanaka, Chuzo] Meiji Univ Integrat Med, Dept Med Informat, Kyoto 6290392, Japan. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Aoki, I (reprint author), Natl Inst Radiol Sci, Mol Imaging Ctr, Anagawa 4-9-1, Chiba 2638555, Japan. EM aoki@nirs.go.jp RI Silva, Afonso/A-7129-2009; Aoki, Ichio/G-2529-2011 OI Aoki, Ichio/0000-0002-4429-5053 FU Japan Society for the Promotion of Science (JSPS) FX The authors thank Ms. Noriko Matsumoto (Meiji University of Integrative Medicine) for generating the animal models, Dr. Alan P Koretsky (Chief, Laboratory of Functional and Molecular Imaging, NINDS, NIH), and Dr. Iwao Kanno (Director, Molecular Imaging Center, National Institutes of Radiological Science) for excellent discussion and editing. This work was partly supported by Grants-in-Aid for Scientific Research (Kakenhi) of the Japan Society for the Promotion of Science (JSPS). NR 50 TC 18 Z9 18 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 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2010 VL 49 IS 4 BP 3122 EP 3131 DI 10.1016/j.neuroimage.2009.11.005 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500024 PM 19909819 ER PT J AU Venkatraman, VK Aizenstein, H Guralnik, J Newman, AB Glynn, NW Taylor, C Studenski, S Launer, L Pahor, M Williamson, J Rosano, C AF Venkatraman, Vijay K. Aizenstein, Howard Guralnik, Jack Newman, Anne B. Glynn, Nancy W. Taylor, Christopher Studenski, Stephanie Launer, Lenore Pahor, Marco Williamson, Jeff Rosano, Caterina TI Executive control function, brain activation and white matter hyperintensities in older adults SO NEUROIMAGE LA English DT Article ID AGE-RELATED-CHANGES; PREFRONTAL CORTEX FUNCTION; WORKING-MEMORY; RECRUITMENT; PERFORMANCE; FMRI; SEGMENTATION; RETRIEVAL; COGNITION; DECLINE AB Context: Older adults responding to executive control function (ECF) tasks show greater brain activation on functional MRI (fMRI). It is not clear whether greater fMRI activation indicates a strategy to compensate for underlying brain structural abnormalities while maintaining higher performance. Objective: To identify the patterns of fMRI activation in relationship with ECF performance and with brain structural abnormalities. Design: Cross-sectional analysis. Main variables of interest: fMRI activation, accuracy while performing an ECF task (Digit Symbol Substitution Test), and volume of white matter hyperintensities and of total brain atrophy. Setting: Cohort of community-dwelling older adults. Participants: Data were obtained on 25 older adults (20 women, 81 years mean age). Outcome measure: Accuracy (number of correct response/total number of responses) while performing the Digit Symbol Substitution Test. Results: Greater accuracy was significantly associated with greater peak fMRI activation, from ECF regions, including left middle frontal gyrUs and right posterior parietal cortex. Greater WMH was associated with lower activation within accuracy-related regions. The interaction of accuracy by white matter hyperintensity volume was significant within the left posterior parietal region. Specifically, the correlation of white matter hyperintensity volume with fMRI activation varied as a function of accuracy and it was positive for greater accuracy. Associations with brain atrophy were not significant. Conclusions: Recruitment of additional areas and overall greater brain activation in older adults is associated with higher performance. Posterior parietal activation may be particularly important to maintain higher accuracy in the presence of underlying brain connectivity structural abnormalities. (C) 2009 Elsevier Inc. All rights reserved. C1 [Venkatraman, Vijay K.; Aizenstein, Howard] Univ Pittsburgh, Sch Engn, Dept Bioengn, Pittsburgh, PA 15261 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Guralnik, Jack; Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Newman, Anne B.; Glynn, Nancy W.; Taylor, Christopher; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Studenski, Stephanie] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Pahor, Marco] Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Williamson, Jeff] Wake Forest Univ, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC 27157 USA. RP Aizenstein, H (reprint author), WPIC UPMC, GPN Lab, 3811 OHara St, Pittsburgh, PA 15213 USA. EM aizen@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Glynn, Nancy/0000-0003-2265-0162 FU National Institute of Aging [NIA 263-MA-706016] FX The authors thank P. Vincent, P. Kost, P. Varlashkin and S. Urda, for assistance in obtaining the data necessary for this analysis. This work is supported in part by the Intramural Research Program, National Institute of Aging (NIA 263-MA-706016). NR 41 TC 31 Z9 32 U1 1 U2 8 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 FEB 15 PY 2010 VL 49 IS 4 BP 3436 EP 3442 DI 10.1016/j.neuroimage.2009.11.019 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500054 PM 19922803 ER PT J AU Kadota, M Yang, HH Gomez, B Sato, M Clifford, RJ Meerzaman, D Dunn, BK Wakefield, LM Lee, MP AF Kadota, Mitsutaka Yang, Howard H. Gomez, Bianca Sato, Misako Clifford, Robert J. Meerzaman, Daoud Dunn, Barbara K. Wakefield, Lalage M. Lee, Maxwell P. TI Delineating Genetic Alterations for Tumor Progression in the MCF10A Series of Breast Cancer Cell Lines SO PLOS ONE LA English DT Article ID EPITHELIAL-CELLS; EXPRESSION; MODEL; IMMORTALIZATION; SUPPRESSOR; RECEPTOR; PIK3CA AB To gain insight into the role of genomic alterations in breast cancer progression, we conducted a comprehensive genetic characterization of a series of four cell lines derived from MCF10A. MCF10A is an immortalized mammary epithelial cell line (MEC); MCF10AT is a premalignant cell line generated from MCF10A by transformation with an activated HRAS gene; MCF10CA1h and MCF10CA1a, both derived from MCF10AT xenografts, form well-differentiated and poorly-differentiated malignant tumors in the xenograft models, respectively. We analyzed DNA copy number variation using the Affymetrix 500 K SNP arrays with the goal of identifying gene-specific amplification and deletion events. In addition to a previously noted deletion in the CDKN2A locus, our studies identified MYC amplification in all four cell lines. Additionally, we found intragenic deletions in several genes, including LRP1B in MCF10CA1h and MCF10CA1a, FHIT and CDH13 in MCF10CA1h, and RUNX1 in MCF10CA1a. We confirmed the deletion of RUNX1 in MCF10CA1a by DNA and RNA analyses, as well as the absence of the RUNX1 protein in that cell line. Furthermore, we found that RUNX1 expression was reduced in high-grade primary breast tumors compared to low/mid-grade tumors. Mutational analysis identified an activating PIK3CA mutation, H1047R, in MCF10CA1h and MCF10CA1a, which correlates with an increase of AKT1 phosphorylation at Ser473 and Thr308. Furthermore, we showed increased expression levels for genes located in the genomic regions with copy number gain. Thus, our genetic analyses have uncovered sequential molecular events that delineate breast tumor progression. These events include CDKN2A deletion and MYC amplification in immortalization, HRAS activation in transformation, PIK3CA activation in the formation of malignant tumors, and RUNX1 deletion associated with poorly-differentiated malignant tumors. C1 [Kadota, Mitsutaka; Yang, Howard H.; Gomez, Bianca; Clifford, Robert J.; Meerzaman, Daoud; Lee, Maxwell P.] NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Sato, Misako; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Basic Prevent Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kadota, M (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM leemax@mail.nih.gov FU NIH; National Cancer Institute FX Funding: This research was supported by the Intramural Research Program of the NIH and the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 64 Z9 66 U1 1 U2 8 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 FEB 15 PY 2010 VL 5 IS 2 AR e9201 DI 10.1371/journal.pone.0009201 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554ZD UT WOS:000274474700005 PM 20169162 ER PT J AU Glasier, AF Cameron, ST Fine, PM Logan, SJS Casale, W Van Horn, J Sogor, L Blithe, DL Scherrer, B Mathe, H Jaspart, A Ulmann, A Gainer, E AF Glasier, Anna F. Cameron, Sharon T. Fine, Paul M. Logan, Susan J. S. Casale, William Van Horn, Jennifer Sogor, Laszlo Blithe, Diana L. Scherrer, Bruno Mathe, Henri Jaspart, Amelie Ulmann, Andre Gainer, Erin TI Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis SO LANCET LA English DT Article ID PROGESTERONE-RECEPTOR MODULATOR; YUZPE REGIMEN; INCREASED ACCESS; INTERCOURSE; PREGNANCY; OVULATION; WOMEN; PILLS; MIFEPRISTONE; CONCEPTION AB Background Emergency contraception can prevent unintended pregnancies, but current methods are only effective if used as soon as possible after sexual intercourse and before ovulation. We compared the efficacy and safety of ulipristal acetate with levonorgestrel for emergency contraception. Methods Women with regular menstrual cycles who presented to a participating family planning clinic requesting emergency contraception within 5 days of unprotected sexual intercourse were eligible for enrolment in this randomised, multicentre, non-inferiority trial. 2221 women were randomly assigned to receive a single, supervised dose of 30 mg ulipristal acetate (n=1104) or 1.5 mg levonorgestrel (n=1117) orally. Allocation was by block randomisation stratified by Centre and time from unprotected sexual intercourse to treatment, with allocation concealment by identical opaque boxes labelled with a unique treatment number. participants were masked to treatment assignment whereas investigators were not. Follow-up was done 5-7 days after expected onset of next menses. The primary endpoint was pregnancy rate in women who received emergency contraception within 72 h of unprotected sexual intercourse, with a non-inferiority margin of 1% point difference between groups (limit of 1.6 for odds ratio). Analysis was done on the efficacy-evaluable population, which excluded women lost to follow-up, those aged over 35 years, women with unknown follow-up pregnancy status, and those who had re-enrolled in the study. Additionally, we undertook a meta-analysis of our trial and an earlier study to assess the efficacy of ulipristal acetate compared with levonorgestrel. This trial is registered with ClinicalTrials.gov, number NCT00551616. Findings In the efficacy-evaluable population, 1696 women received emergency contraception within 72 h of sexual intercourse (ulipristal acetate, n=844; levonorgestrel, n=852). There were 15 pregnancies in the ulipristal acetate group (1.8%, 95% CI 1.0-3.0) and 22 in the levonorgestrel group (2.6%, 1.7-3.9; odds ratio [OR] 0.68, 95% CI 0.35-1.31). In 203 women who received emergency contraception between 72 In and 120 h after sexual intercourse, there were three pregnancies, all of which were in the levonorgestrel group. The most frequent adverse event was headache (ulipristal acetate, 213 events [19.3%] in 1104 women; levonorgestrel, 211 events [18.9%] in 1117 women). Two serious adverse events were judged possibly related to use of emergency contraception; a case of dizziness in the ulipristal acetate group and a molar pregnancy in the levonorgestrel group. In the meta-analysis (0-72 h), there were 22 (1.4%) pregnancies in 1617 women in the ulipristal acetate group and 35 (2.2%) in 1625 women in the levonorgestrel group (OR 0.58, 0.33-0.99; p=0.046). Interpretation Ulipristal acetate provides women and health-care providers with an effective alternative for emergency contraception that can be used up to 5 days after unprotected sexual intercourse. Funding HRA Pharma. C1 [Glasier, Anna F.; Cameron, Sharon T.] Natl Hlth Serv Lothian, Edinburgh, Midlothian, Scotland. [Glasier, Anna F.; Cameron, Sharon T.] Univ Edinburgh, Dept Reprod & Dev Sci, Edinburgh, Midlothian, Scotland. [Fine, Paul M.] Planned Parenthood Houston & SE Texas, Houston, TX USA. [Logan, Susan J. S.] Natl Hlth Serv Grampian, Aberdeen, Scotland. [Casale, William] Palm Beach & Treasure Coast, Planned Parenthood Greater Miami, W Palm Beach, FL USA. [Van Horn, Jennifer] Planned Parenthood Assoc Utah, Salt Lake City, UT USA. [Sogor, Laszlo] Planned Parenthood NE Ohio, Akron, OH USA. [Blithe, Diana L.] NICHHD, Bethesda, MD 20892 USA. [Scherrer, Bruno] Bruno Scherrer Conseil, St Arnoult En Yvelines, France. [Mathe, Henri; Jaspart, Amelie; Ulmann, Andre; Gainer, Erin] HRA Pharma, Paris, France. RP Glasier, AF (reprint author), NHS Lothian, Dean Terrace Ctr, Family Planning & Well Woman Serv, 18 Dean Terrace, Edinburgh EH4 1NL, Midlothian, Scotland. EM Anna.Glasier@nhslothian.scot.nhs.uk FU HRA Pharma FX This study was funded by HRA Pharma. NR 34 TC 197 Z9 205 U1 6 U2 27 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 FEB 13 PY 2010 VL 375 IS 9714 BP 555 EP 562 DI 10.1016/S0140-6736(10)60101-8 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 560YO UT WOS:000274941900029 PM 20116841 ER PT J AU Hamza, M Wang, XM Adam, A Brahim, JS Rowan, JS Carmona, GN Dionne, RA AF Hamza, May Wang, Xiao-Min Adam, Albert Brahim, Jaime S. Rowan, Janet S. Carmona, Gilberto N. Dionne, Raymond A. TI Kinin B-1 receptors contributes to acute pain following minor surgery in humans SO MOLECULAR PAIN LA English DT Article ID NF-KAPPA-B; HUMAN LUNG FIBROBLASTS; NECROSIS-FACTOR-ALPHA; ISOLATED RAT SKIN; INDUCED NOCICEPTOR SENSITIZATION; PROSTAGLANDIN E-2 RELEASE; SPINAL-CORD-INJURY; GENE-EXPRESSION; UP-REGULATION; BRADYKININ RECEPTOR AB Background: Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B-1 and B-2 receptors. It is generally accepted that the B-2 receptor is constitutively expressed, whereas the B-1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. Results: Tissue injury resulted in a significant up-regulation in the gene expression of B-1 and B-2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B-1 and B-2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B-1 and B-2 receptors were correlated. Following tissue injury, B-1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B-1 receptor but not B-2 receptor. Conclusions: These results provide evidence at the transcriptional level in a clinical model of tissue injury that upregulation of kinin receptors are involved in the development of the early phase of inflammation and inflammatory pain. The up-regulation of B-1 receptors may contribute to acute inflammatory pain through TRPV1 activation. C1 [Hamza, May; Wang, Xiao-Min; Dionne, Raymond A.] NINR, NIH, Bethesda, MD 20892 USA. [Brahim, Jaime S.; Carmona, Gilberto N.] NIDCR, NIH, Bethesda, MD 20892 USA. [Rowan, Janet S.] NIH, Dept Nursing, Magnuson Clin Res Ctr, Bethesda, MD 20892 USA. [Adam, Albert] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada. [Hamza, May] Ain Shams Univ, Dept Pharmacol, Fac Med, Cairo 11566, Egypt. RP Dionne, RA (reprint author), NINR, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov RI Hamza, May/A-5053-2010 OI Hamza, May/0000-0002-7637-3060 NR 66 TC 12 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD FEB 13 PY 2010 VL 6 AR 12 DI 10.1186/1744-8069-6-12 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 567SZ UT WOS:000275468200001 PM 20152050 ER PT J AU Odeh, H Hunker, KL Belyantseva, IA Azaiez, H Avenarius, MR Zheng, LL Peters, LM Gagnon, LH Hagiwara, N Skynner, MJ Brilliant, MH Allen, ND Riazuddin, S Johnson, KR Raphael, Y Najmabadi, H Friedman, TB Bartles, JR Smith, RJH Kohrman, DC AF Odeh, Hana Hunker, Kristina L. Belyantseva, Inna A. Azaiez, Hela Avenarius, Matthew R. Zheng, Lili Peters, Linda M. Gagnon, Leona H. Hagiwara, Nobuko Skynner, Michael J. Brilliant, Murray H. Allen, Nicholas D. Riazuddin, Saima Johnson, Kenneth R. Raphael, Yehoash Najmabadi, Hossein Friedman, Thomas B. Bartles, James R. Smith, Richard J. H. Kohrman, David C. TI Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACTIN-BUNDLING PROTEINS; HAIR-CELL STEREOCILIA; UNCONVENTIONAL MYOSIN; RECESSIVE DEAFNESS; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; BIRD COCHLEA; HEARING-LOSS; GENE; FILAMENTS AB Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical Surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells. C1 [Odeh, Hana; Hunker, Kristina L.; Avenarius, Matthew R.; Raphael, Yehoash; Kohrman, David C.] Univ Michigan, Sch Med, Kresge Hearing Res Inst, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Odeh, Hana] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Avenarius, Matthew R.; Kohrman, David C.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Belyantseva, Inna A.; Peters, Linda M.; Riazuddin, Saima; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Azaiez, Hela; Smith, Richard J. H.] Univ Iowa, Dept Otolaryngol, Iowa City, IA 52242 USA. [Azaiez, Hela; Smith, Richard J. H.] Univ Iowa, Interdept PhD Genet Program, Iowa City, IA 52242 USA. [Zheng, Lili; Bartles, James R.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Gagnon, Leona H.; Johnson, Kenneth R.] Jackson Lab, Bar Harbor, ME 04609 USA. [Hagiwara, Nobuko; Brilliant, Murray H.] Univ Arizona, Coll Med, Steele Mem Childrens Res Ctr, Dept Pediat, Tucson, AZ 85724 USA. [Skynner, Michael J.; Allen, Nicholas D.] Babraham Inst, Neurobiol Programme, Cambridge CB2 4AT, England. [Najmabadi, Hossein] Univ Social Welf & Rehabil Sci, Genet Res Ctr, Tehran, Iran. RP Kohrman, DC (reprint author), Univ Michigan, Sch Med, Kresge Hearing Res Inst, Dept Otolaryngol, Ann Arbor, MI 48109 USA. EM dkohrman@umich.edu RI allen, nick/A-4336-2010; OI Najmabadi, Hossein/0000-0002-6084-7778 FU Deafness Research Foundation; NIH-NIDCD [R29-DC03049, R01-DC003049, R01-DC004314, R01-DC002842, T32-DC000011, P30-DC05188, DC62108, Z01-DC000048] FX We thank Margaret Lomax and Sally Camper for critical reading of the manuscript, and we thank Ursula Jakob, Jochen Schacht, Suhua Sha, andjohn Moran for helpful discussions. We acknowledge Alyce LaDeau and Kate Donnell for identification of the pi2J and pi3J mutants, Sandra Gray for help with mouse husbandry at The Jackson Laboratory, Tzy-Wen Gong for tissue panel RNA and inner ear dissection expertise, Robert J. Morell for in situ hybridization advice, and Bruce Donohoe and Chris Edwards for assistance with confocal microscopy analysis. We thank Sarah Davis, Joe Schacht, Junghan Kim, and Sue Lee for excellent technical assistance. We also appreciate the genomic sequencing of several BAC clones by the NIH Mouse Genome Sequencing Network, including the group headed by Bruce Birren and Ken Dewar at MIT. This work was Supported by a grant from the Deafness Research Foundation (D.C.K.), by NIH-NIDCD grants R29-DC03049 (D.C.K.), R01-DC003049 (D.C.K.), R01-DC004314 (J.R.B.), R01-DC002842 (R.J.H.S.), T32-DC000011 (H.O.), and P30-DC05188 (D.C.K. and Y.R.), by NIH-NIDCD contract DC62108 (K.R.J.), and by NIH-NIDCD intramural funds Z01-DC000048 (T.B.F.). NR 60 TC 17 Z9 19 U1 0 U2 4 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 FEB 12 PY 2010 VL 86 IS 2 BP 148 EP 160 DI 10.1016/j.ajhg.2010.01.016 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 556ZS UT WOS:000274637200005 PM 20137774 ER PT J AU Kung, AWC Xiao, SM Cherny, S Li, GHY Gao, Y Tso, G Lau, KS Luk, KDK Liu, JM Cui, B Zhang, MJ Zhang, ZL He, JW Yue, H Xia, WB Luo, LM He, SL Kiel, DP Karasik, D Hsu, YH Cupples, LA Demissie, S Styrkarsdottir, U Halldorsson, BV Sigurdsson, G Thorsteinsdottir, U Stefansson, K Richards, JB Zhai, GJ Soranzo, N Valdes, A Spector, TD Sham, PC AF Kung, Annie W. C. Xiao, Su-Mei Cherny, Stacey Li, Gloria H. Y. Gao, Yi Tso, Gloria Lau, Kam S. Luk, Keith D. K. Liu, Jian-min Cui, Bin Zhang, Min-Jia Zhang, Zhen-lin He, Jin-wei Yue, Hua Xia, Wia-bo Luo, Lian-mei He, Shu-li Kiel, Douglas P. Karasik, David Hsu, Yi-Hsiang Cupples, L. Adrienne Demissie, Serkalem Styrkarsdottir, Unnur Halldorsson, Bjarni V. Sigurdsson, Gunnar Thorsteinsdottir, Unnur Stefansson, Kari Richards, J. Brent Zhai, Guangju Soranzo, Nicole Valdes, Ana Spector, Tim D. Sham, Pak C. TI Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CHINESE WOMEN; ALAGILLE-SYNDROME; GENE POLYMORPHISMS; SOUTHERN CHINESE; MASS; DIFFERENTIATION; METAANALYSIS; LINKAGE; RISK; HERITABILITY AB Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent Study Populations of European descent and Asian Populations including 18,098 Subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG]) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% Cl 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (1) = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "N' allele of rs2273061. A mRNA expression Study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG I gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis. C1 [Kung, Annie W. C.; Xiao, Su-Mei; Li, Gloria H. Y.; Gao, Yi; Tso, Gloria; Lau, Kam S.] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Kung, Annie W. C.; Xiao, Su-Mei] Univ Hong Kong, Fac Med, Res Ctr Heart Brain Hormone & Healthy Aging, Hong Kong, Hong Kong, Peoples R China. [Cherny, Stacey; Sham, Pak C.] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Luk, Keith D. K.] Univ Hong Kong, Dept Orthopaed & Traumatol, Hong Kong, Hong Kong, Peoples R China. [Liu, Jian-min; Cui, Bin; Zhang, Min-Jia] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Dept Endocrine & Metab Dis, Shanghai 200025, Peoples R China. [Zhang, Zhen-lin; He, Jin-wei; Yue, Hua] Shanghai Jiao Tong Univ, Peoples Hosp 6, Osteoporosis Res Unit, Ctr Preventing & Treating Osteoporosis, Shanghai 200233, Peoples R China. [Xia, Wia-bo; Luo, Lian-mei; He, Shu-li] Peking Union Med Coll, Peking Union Med Coll Hosp, Minist Hlth, Dept Endocrinol,Key Lab Endocrinol, Beijing 100730, Peoples R China. [Xia, Wia-bo; Luo, Lian-mei; He, Shu-li] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Kiel, Douglas P.; Karasik, David; Hsu, Yi-Hsiang] Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA. [Kiel, Douglas P.; Karasik, David; Hsu, Yi-Hsiang] Harvard Univ, Sch Med, Boston, MA 02131 USA. [Cupples, L. Adrienne; Demissie, Serkalem] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Cupples, L. Adrienne; Demissie, Serkalem] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Styrkarsdottir, Unnur; Halldorsson, Bjarni V.; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, IS-101 Reykjavik, Iceland. [Halldorsson, Bjarni V.] Reykjavik Univ, IS-103 Reykjavik, Iceland. [Sigurdsson, Gunnar] Univ Hosp, Dept Endocrinol & Metab, IS-108 Reykjavik, Iceland. [Sigurdsson, Gunnar; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Richards, J. Brent] McGill Univ, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Zhai, Guangju; Soranzo, Nicole; Valdes, Ana; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. RP Kung, AWC (reprint author), Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. EM awckung@hkucc.hku.hk RI Cherny, Stacey/B-3315-2008; OI Cherny, Stacey/0000-0002-0269-3352; Cupples, L. Adrienne/0000-0003-0273-7965; Soranzo, Nicole/0000-0003-1095-3852; Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530; Halldorsson, Bjarni/0000-0003-0756-0767 FU Hong Kong Research Grant Council; HKU Foundation; Matching Grant; CRCG; The University of Hong Kong; Wellcome Trust; European Community's Sixth and Seventh Framework Programmes [FP7/2007-2013]; ENGAGE [HEALTH-F4-2007-201413]; 1711-5 GenomEUtwin Project [QLG2-CT-2002-01254]; Department of Health via the National Institute for Health Research (NIHR); Biotechnology and Biological Sciences Research Council (BBSRC) [G20234]; National Eye Institute via an NIH/CIDR; US National Institute for Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [R01 AR/AG 41398, R01 AR 050066]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This project is supported by Hong Kong Research Grant Council; The Bone Health Fund of HKU Foundation; and Matching Grant, CRCG Grant, and The Osteoporosis Research Fund of The University of Hong Kong. The Twins UK Study was funded by the Wellcome Trust, European Community's Sixth and Seventh Framework Programmes (FP7/2007-2013), ENGAGE project HEALTH-F4-2007-201413, and the 1711-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives Support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & StThornas' NHS Foundation Trust in partnership with King's College London. T.D.S. is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI, Terri Young). For genotyping of the Twins UK study, we thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Genotypage, France, led by Mark Lathrop; Duke University, North Carolina, USA, led by David Goldstein; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. The Framingham Osteoporosis Study (FOS) study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute oil Aging (R01 AR/AG 41398 to D.P.K. and R01 AR 050066 to D.K.). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted with the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The following are employees of deCODE Company, Iceland, and own stock or stock options of deCODE Company: U.S., B.V.H., U.T., and K.S. NR 47 TC 90 Z9 99 U1 1 U2 10 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 FEB 12 PY 2010 VL 86 IS 2 BP 229 EP 239 DI 10.1016/j.ajhg.2009.12.014 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 556ZS UT WOS:000274637200012 PM 20096396 ER PT J AU Kim, W Shin, YK Kim, BJ Egan, JM AF Kim, Wook Shin, Yu-Kyong Kim, Byung-Joon Egan, Josephine M. TI Notch signaling in pancreatic endocrine cell and diabetes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Review DE Notch signaling; Pancreatic endocrine cell; Diabetes ID EMBRYONIC STEM-CELLS; CANDIDATE GENE; BETA-CELLS; IN-VITRO; DIFFERENTIATION; PROGENITORS; EXPRESSION; LINEAGES; FGF10; DUCT AB Recent studies have improved our understanding of the physiological function of Notch signaling pathway and now there is compelling evidence demonstrating that Notch is a key regulator of embryonic development and tissue homeostasis. Although further extensive studies are necessary to illustrate the molecular mechanisms. new insights into the role of Notch signaling in pancreas development and diabetes have been achieved Importantly, the ability to regulate Notch signaling intensity both positively and negatively may hive therapeutic relevance for diabetes Thus, this paper reviews the current knowledge of the roles of Notch signaling in the pancreatic endocrine cell system Published by Elsevier Inc C1 [Kim, Wook; Shin, Yu-Kyong; Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. [Kim, Byung-Joon] Eulji Univ, Sch Med, Dept Internal Med, Taejon 302120, South Korea. RP Egan, JM (reprint author), NIA, NIH, Bayview Blvd, Baltimore, MD 21224 USA. FU Intramural Research Program of NIA/NIH FX The authors are supported by the Intramural Research Program of NIA/NIH. NR 40 TC 18 Z9 19 U1 0 U2 1 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 FEB 12 PY 2010 VL 392 IS 3 BP 247 EP 251 DI 10.1016/j.bbrc.2009.12.115 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 561ZY UT WOS:000275019800001 PM 20035712 ER PT J AU Arao, Y Carpenter, K Hewitt, S Korach, KS AF Arao, Yukitomo Carpenter, Karen Hewitt, Sylvia Korach, Kenneth S. TI Estrogen Down-regulation of the Scx Gene Is Mediated by the Opposing Strand-overlapping Gene Bop1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HELIX TRANSCRIPTION FACTOR; SENSE-ANTISENSE PAIRS; RIBOSOME BIOGENESIS; X-CHROMOSOME; IN-VIVO; RNA; EXPRESSION; SCLERAXIS; INACTIVATION; TENDON AB Recent genome-wide transcriptome studies suggest the presence of numerous bidirectional overlapping coding gene pairs in mammalian genomes. Various antisense RNAs are reported as non-coding RNAs that regulate the expression of sense RNA. However, it is still unclear whether the expression of bidirectional overlapping coding genes are regulated by the opposite strand gene transcript acting as a non-coding RNA. Bop1 and Scx are a pair of bidirectional overlapping coding genes related to cellular proliferation and differentiation, respectively. Scx gene is localized in the intron 3 region of the Bop1 gene. The expression of these genes is reciprocally regulated by estrogen (E2) in the mouse uterus. In situ hybridization indicated that both genes are expressed in the uterine endometrial epithelial cells and that the antisense RNA of Scx (Bop1 intronic RNA) accumulates as a stable RNA in these cells. The existence of Bop1 intronic RNA was confirmed by reverse transcription-PCR and was increased after E2 treatment, coinciding with a decrease in Scx mRNA. Murine myoblasts expressing doxycycline-inducible endogenous Bop1 gene showed an increase in Bop1 intronic RNA and a simultaneous decrease in Scx mRNA. Murine fibroblasts expressing Scx mRNA from an exogenous Scx mini-gene indicated that the accumulation of Bop1 intronic RNA impairs the Scx gene expression in a trans-acting manner, which resulted in the reduction of the Scx mRNA level. This study demonstrates a novel example of hormone-stimulated intronic noncoding RNA down-regulating the expression of an opposing strand-overlapping coding gene. C1 [Arao, Yukitomo; Carpenter, Karen; Hewitt, Sylvia; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov FU NIEHS [Z01ES70065] FX This work was supported, in whole or in part, by National Institutes of Health Grant Z01ES70065 (to K. S. K.) through the Division of Intramural Research of the NIEHS. NR 41 TC 5 Z9 6 U1 0 U2 5 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 FEB 12 PY 2010 VL 285 IS 7 BP 4806 EP 4814 DI 10.1074/jbc.M109.036681 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 565FN UT WOS:000275274800059 PM 19996321 ER PT J AU Mollapour, M Tsutsumi, S Donnelly, AC Beebe, K Tokita, MJ Lee, MJ Lee, S Morra, G Bourboulia, D Scroggins, BT Colombo, G Blagg, BS Panaretou, B Stetler-Stevenson, WG Trepel, JB Piper, PW Prodromou, C Pearl, LH Neckers, L AF Mollapour, Mehdi Tsutsumi, Shinji Donnelly, Alison C. Beebe, Kristin Tokita, Mari J. Lee, Min-Jung Lee, Sunmin Morra, Giulia Bourboulia, Dimitra Scroggins, Bradley T. Colombo, Giorgio Blagg, Brian S. Panaretou, Barry Stetler-Stevenson, William G. Trepel, Jane B. Piper, Peter W. Prodromou, Chrisostomos Pearl, Laurence H. Neckers, Len TI Swe1(Wee1)-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function SO MOLECULAR CELL LA English DT Article ID SHOCK TRANSCRIPTION FACTOR; MOLECULAR CHAPERONE; STEROID-RECEPTOR; ATP HYDROLYSIS; BUDDING YEAST; IN-VIVO; CRYSTAL-STRUCTURE; PROTEIN-KINASES; CLIENT PROTEINS; CELL-CYCLE AB Saccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90 alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast - increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors. C1 [Mollapour, Mehdi; Tsutsumi, Shinji; Beebe, Kristin; Scroggins, Bradley T.; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, Min-Jung; Lee, Sunmin; Trepel, Jane B.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bourboulia, Dimitra; Stetler-Stevenson, William G.] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Donnelly, Alison C.; Blagg, Brian S.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. [Tokita, Mari J.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD USA. [Morra, Giulia; Colombo, Giorgio] CNR, Inst Chim Riconoscimento Mol, I-20131 Milan, Italy. [Panaretou, Barry] Kings Coll London, Div Life Sci, London SE1 9NN, England. [Piper, Peter W.] Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield S10 2TN, S Yorkshire, England. [Prodromou, Chrisostomos; Pearl, Laurence H.] Chester Beatty Labs, Inst Canc Res, Sect Struct Biol, London SW3 6JB, England. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM neckers@nih.gov RI Stetler-Stevenson, William/H-6956-2012; Colombo, Giorgio/A-2730-2012; Morra, Giulia/O-2311-2015; OI Prodromou, Chrisostomos/0000-0003-4320-1147; Stetler-Stevenson, William/0000-0002-5500-5808; Colombo, Giorgio/0000-0002-1318-668X; Morra, Giulia/0000-0002-9681-7845; Pearl, Laurence/0000-0002-6910-1809 FU National National Cancer Institute FX We are grateful to Dr. Michael Snyder for Swel-GST and Cdc14-GST constructs and to Dr. Daniel C. Masison for anti-Stil antibody. We are also grateful to Dr. Jill Johnson and Dr. Wanping Xu for discussion and helpful suggestions. This work was supported by the Intramural Research Program of the National National Cancer Institute (L.N.). NR 53 TC 87 Z9 89 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 12 PY 2010 VL 37 IS 3 BP 333 EP 343 DI 10.1016/j.molcel.2010.01.005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 558UY UT WOS:000274774600006 PM 20159553 ER PT J AU Caudell, D Harper, DP Novak, RL Pierce, RM Slape, C Wolff, L Aplan, PD AF Caudell, David Harper, David P. Novak, Rachel L. Pierce, Rachel M. Slape, Christopher Wolff, Linda Aplan, Peter D. TI Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SMAD-INTERACTING PROTEIN-1; GENE-EXPRESSION PROFILES; MYELOPROLIFERATIVE DISORDERS; MALIGNANT HEMATOPOIESIS; BETHESDA PROPOSALS; LYMPHOID NEOPLASMS; MOUSE MODEL; CELL-LINES AB The t(10; 11) translocation results in a CALM-AF10 fusion gene in a subset of leukemia patients. Expression of a CALM-AF10 transgene results in leukemia, with prolonged latency and incomplete penetrance, suggesting that additional events are necessary for leukemic transformation. CALM-AF10 mice infected with the MOL4070LTR retrovirus developed acute leukemia, and ligation-mediated polymerase chain reaction was used to identify retroviral insertions at 19 common insertion sites, including Zeb2, Nf1, Mn1, Evi1, Ift57, Mpl, Plag1, Kras, Erg, Vav1, and Gata1. A total of 26% (11 of 42) of the mice had retroviral integrations near Zeb2, a transcriptional corepressor leading to overexpression of the Zeb2-transcript. A total of 91% (10 of 11) of mice with Zeb2 insertions developed B-lineage acute lymphoblastic leukemia, suggesting that Zeb2 activation promotes the transformation of CALM-AF10 hematopoietic precursors toward B-lineage leukemias. More than half of the mice with Zeb2 integrations also had Nf1 integrations, suggesting cooperativity among CALM-AF10, Zeb2, and Ras pathway mutations. We searched for Nras, Kras, and Ptpn11 point mutations in the CALM-AF10 leukemic mice. Three mutations were identified, all of which occurred in mice with Zeb2 integrations, consistent with the hypothesis that Zeb2 and Ras pathway activation promotes B-lineage leukemic transformation in concert with CALM-AF10. (Blood. 2010;115:1194-1203) C1 [Caudell, David; Harper, David P.; Novak, Rachel L.; Pierce, Rachel M.; Aplan, Peter D.] NCI, NIH, CCR, Genet Branch, Bethesda, MD 20889 USA. [Caudell, David] Virginia Tech, Dept Biomed Sci & Pathobiol, Ctr Mol Med & Infect Dis, Virginia Maryland Reg Coll Vet Med, Blacksburg, VA USA. [Harper, David P.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Slape, Christopher] Royal Melbourne Hosp, Bone Marrow Res Lab, Parkville, Vic 3050, Australia. [Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, NIH, CCR, Genet Branch, 8901 Wisconsin Ave,Navy 8,Rm 5101, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; FU National Institutes of Health, National Cancer Institute FX The authors thank Helge Hartung, Sarah Beachy, Sheryl Gough, Yang Jo Chung, R. Mark Simpson, and Siba Samal for insightful discussions and Christine Perella for expert technical assistance with mouse retroviral infection and necropsies.; This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 50 TC 14 Z9 14 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 FEB 11 PY 2010 VL 115 IS 6 BP 1194 EP 1203 DI 10.1182/blood-2009-04-216184 PG 10 WC Hematology SC Hematology GA 554JN UT WOS:000274431400014 PM 20007546 ER PT J AU Ankra-Badu, GA Shriner, D Le Bihan-Duval, E Mignon-Grasteau, S Pitel, F Beaumont, C Duclos, MJ Simon, J Porter, TE Vignal, A Cogburn, LA Allison, DB Yi, NJ Aggrey, SE AF Ankra-Badu, Georgina A. Shriner, Daniel Le Bihan-Duval, Elisabeth Mignon-Grasteau, Sandrine Pitel, Frederique Beaumont, Catherine Duclos, Michel J. Simon, Jean Porter, Tom E. Vignal, Alain Cogburn, Larry A. Allison, David B. Yi, Nengjun Aggrey, Samuel E. TI Mapping main, epistatic and sex-specific QTL for body composition in a chicken population divergently selected for low or high growth rate SO BMC GENOMICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; BAYESIAN MODEL SELECTION; AFFECTING FATNESS; EXPERIMENTAL CROSSES; CARCASS TRAITS; GENETIC ARCHITECTURE; MUSCLE WEIGHT; LAYER CROSS; MICE; OBESITY AB Background: Delineating the genetic basis of body composition is important to agriculture and medicine. In addition, the incorporation of gene-gene interactions in the statistical model provides further insight into the genetic factors that underlie body composition traits. We used Bayesian model selection to comprehensively map main, epistatic and sex-specific QTL in an F-2 reciprocal intercross between two chicken lines divergently selected for high or low growth rate. Results: We identified 17 QTL with main effects across 13 chromosomes and several sex-specific and sex-antagonistic QTL for breast meat yield, thigh + drumstick yield and abdominal fatness. Different sets of QTL were found for both breast muscles [Pectoralis (P) major and P. minor], which suggests that they could be controlled by different regulatory mechanisms. Significant interactions of QTL by sex allowed detection of sex-specific and sex-antagonistic QTL for body composition and abdominal fat. We found several female-specific P. major QTL and sex-antagonistic P. minor and abdominal fatness QTL. Also, several QTL on different chromosomes interact with each other to affect body composition and abdominal fatness. Conclusions: The detection of main effects, epistasis and sex-dimorphic QTL suggest complex genetic regulation of somatic growth. An understanding of such regulatory mechanisms is key to mapping specific genes that underlie QTL controlling somatic growth in an avian model. C1 [Ankra-Badu, Georgina A.; Aggrey, Samuel E.] Univ Georgia, Dept Poultry Sci, Inst Bioinformat, Athens, GA 30602 USA. [Ankra-Badu, Georgina A.; Allison, David B.; Yi, Nengjun] Univ Alabama Birmingham, Sect Stat Genet, Dept Biostat, Birmingham, AL 35294 USA. [Shriner, Daniel] NHGRI, NIH, Bethesda, MD 20892 USA. [Le Bihan-Duval, Elisabeth; Mignon-Grasteau, Sandrine; Beaumont, Catherine; Duclos, Michel J.; Simon, Jean] INRA, Rech Avicoles UR83, F-37380 Nouzilly, France. [Pitel, Frederique; Vignal, Alain] INRA, Lab Genet Cellulaire, F-31326 Castanet Tolosan, France. [Porter, Tom E.] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Cogburn, Larry A.] Univ Delaware, Dept Anim & Food Sci, Newark, DE 19717 USA. [Allison, David B.; Yi, Nengjun] Univ Alabama Birmingham, Clin Nutr Res Ctr, Birmingham, AL 35294 USA. RP Aggrey, SE (reprint author), Univ Georgia, Dept Poultry Sci, Inst Bioinformat, Athens, GA 30602 USA. EM saggrey@uga.edu RI Pitel, Frederique/C-2847-2009; OI Pitel, Frederique/0000-0002-1477-7633; Allison, David/0000-0003-3566-9399 FU USDA-IFAFS Animal Genome Program [00-52100-9614]; Institut National de la Recherche Agronomique (INRA); Analyse du Genome des Animaux d'Elevage (AGENAE) Program; NIH [GM069430, DK056336, DK076050, HL072757] FX This research was supported by grants from the USDA-IFAFS Animal Genome Program to LAC, TEP, SEA and JS (Award Number 00-52100-9614), the , Analyse du Genome des Animaux d'Elevage (AGENAE) Program and NIH grants GM069430, DK056336, DK076050 and HL072757. We thank the technical staff from the breeding facilities and laboratories of Unite de Recherches Avicoles (URA)-INRA (Nouzilly, France) who contributed to breeding of chickens, trait measurements and blood sampling. We also acknowledge Nicole Millet (URA-INRA, Nouzilly, France) for supervising the maintenance of the HG and LG broiler lines and to Katia Feve (INRA, Toulouse, France) for validating the genetic markers at the Centre de Resources, Genotypage, Sequencage platform of the Genopole Toulouse Midi-Pyrenees, Yves Amigues and Sabine Janin (Labogena, INRA Jouy-en-Josas, France) for genotyping the samples and Andre Neau (INRA, Jouy en Josas) for archiving of genotyping data in the INRA database. NR 41 TC 20 Z9 20 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 11 PY 2010 VL 11 AR 107 DI 10.1186/1471-2164-11-107 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 565KZ UT WOS:000275292600001 PM 20149241 ER PT J AU Varkonyi, T Lazar, L Molvarec, A Than, NG Rigo, J Nagy, B AF Varkonyi, Tibor Lazar, Levente Molvarec, Attila Than, Nandor Gabor Rigo, Janos, Jr. Nagy, Balint TI Leptin receptor (LEPR) SNP polymorphisms in HELLP syndrome patients determined by quantitative real-time PCR and melting curve analysis SO BMC MEDICAL GENETICS LA English DT Article ID SEVERE PREECLAMPSIA; GENE POLYMORPHISMS; PREGNANT-WOMEN; ASSOCIATION; EXPRESSION; OBESITY; BINDING; HUMANS; CELLS; SERUM AB Background: Several studies have shown overexpression of leptin in microarray experiments in pre-eclampsia (PE) and in hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. We decided to study four leptin receptor (LEPR) SNP polymorphisms in HELLP syndrome patients by using quantitative real-time PCR and melting curve analysis. Methods: DNA was isolated from blood samples from 83 normotensive pregnant women and 75 HELLP syndrome patients. Four SNPs, LEPR c.326A= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). Conclusion In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy. C1 [Wells, Samuel A., Jr.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas Dallas, SW Med Ctr, Dallas, TX USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Yale Univ, Sch Med, New Haven, CT USA. AstraZeneca, Wilmington, DE USA. Inst Gustave Roussy, Villejuif, France. RP Wells, SA (reprint author), Washington Univ, Sch Med, Dept Surg, Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. EM wellss@wudosis.wustl.edu FU AstraZeneca FX Supported financially by AstraZeneca. NR 21 TC 239 Z9 247 U1 2 U2 25 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 767 EP 772 DI 10.1200/JCO.2009.23.6604 PG 6 WC Oncology SC Oncology GA 553LN UT WOS:000274368300012 PM 20065189 ER PT J AU Landgren, O Goedert, JJ Rabkin, CS Wilson, WH Dunleavy, K Kyle, RA Katzmann, JA Rajkumar, SV Engels, EA AF Landgren, Ola Goedert, James J. Rabkin, Charles S. Wilson, Wyndham H. Dunleavy, Kieron Kyle, Robert A. Katzmann, Jerry A. Rajkumar, S. Vincent Engels, Eric A. TI Circulating Serum Free Light Chains As Predictive Markers of AIDS-Related Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMA; B-CELL ACTIVATION; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; HIV-INFECTION; FOLLOW-UP; MULTIPLE-MYELOMA; HOMOSEXUAL-MEN; RISK-FACTORS AB Purpose HIV-infected persons have an elevated risk of developing non-Hodgkin's lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals. Patients and Methods By using three cohorts of HIV-infected persons (from 1982 to 2005), we identified 66 individuals who developed NHL and 225 matched (by cohort, sex, ethnicity, age, and CD4 count), HIV-infected, lymphoma-free controls who had available stored prediagnostic blood samples. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years before diagnosis/selection were assayed for IgG, IgM, and IgA levels; monoclonal (M) Igs; and kappa and lambda free light chain (FLC) levels. Patients and matched controls were compared by using conditional logistic regression. Results The kappa and lambda FLCs were both significantly higher in patients (eg, in 2- to 5-year window: median kappa, 4.24 v 3.43 mg/dL; median lambda, 4.04 v 3.09 mg/dL) and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection (eg, NHL risk 3.76-fold higher with kappa concentration at least 2.00 times the upper limit of normal, and 8.13-fold higher with lambda concentration at least 2.00 times the upper limit of normal compared with normal levels). In contrast, IgG, IgM, and IgA levels were similar in patients and controls. M proteins were detected in only two patients with NHL (3%) and in nine controls (4%), and they were not significantly associated with NHL risk. Conclusion Elevated FLCs may represent sensitive markers of polyclonal B-cell activation and dysfunction and could be useful for identifying HIV-infected persons at increased NHL risk. C1 [Landgren, Ola] NCI, Natl Inst Hlth, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Mayo Clin, Rochester, MN USA. RP Landgren, O (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, Med Oncol Branch, 9000 Rockville Pike,Bldg 10 Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov OI Rajkumar, S. Vincent/0000-0002-5862-1833 FU National Cancer Institute [CA 62242, CA 107476]; National Institutes of Health FX Supported in part by research Grants No. CA 62242 and CA 107476 from the National Cancer Institute and the Intramural Research Program of the National Institutes of Health. NR 38 TC 52 Z9 52 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 773 EP 779 DI 10.1200/JCO.2009.25.1322 PG 7 WC Oncology SC Oncology GA 553LN UT WOS:000274368300013 PM 20048176 ER PT J AU Lacey, JV Sherman, ME Rush, BB Ronnett, BM Ioffe, OB Duggan, MA Glass, AG Richesson, DA Chatterjee, N Langholz, B AF Lacey, James V., Jr. Sherman, Mark E. Rush, Brenda B. Ronnett, Brigitte M. Ioffe, Olga B. Duggan, Maire A. Glass, Andrew G. Richesson, Douglas A. Chatterjee, Nilanjan Langholz, Bryan TI Absolute Risk of Endometrial Carcinoma During 20-Year Follow-Up Among Women With Endometrial Hyperplasia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NESTED CASE-CONTROL; ADENOCARCINOMA; CLASSIFICATION; MANAGEMENT; DIAGNOSIS AB Purpose The severity of endometrial hyperplasia (EH)-simple (SH), complex (CH), or atypical (AH)-influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking. Materials and Methods We conducted a case-control study nested in a cohort of 7,947 women diagnosed with EH (1970-2002) at one prepaid health plan who remained at risk for at least 1 year. Patient cases (N = 138) were diagnosed with carcinoma, on average, 6 years later (range, 1 to 24 years). Patient controls (N = 241) were matched to patient cases on age at EH, date of EH, and duration of follow-up, and they were counter-matched to patient cases on EH severity. After we independently reviewed original slides and medical records of patient controls and patient cases, we combined progression relative risks (AH v SH, CH, or disordered proliferative endometrium [ie, equivocal EH]) from the case-control analysis with clinical censoring information (ie, hysterectomy, death, or left the health plan) on all cohort members to estimate interval-specific (ie, 1 to 4, 5 to 9, and 10 to 19 years) and cumulative (ie, through 4, 9, and 19 years) progression risks. Results For nonatypical EH, cumulative progression risk increased from 1.2% (95% CI, 0.6% to 1.9%) through 4 years to 1.9% (95% CI, 1.2% to 2.6%) through 9 years to 4.6% (95% CI, 3.3% to 5.8%) through 19 years after EH diagnosis. For AH, cumulative risk increased from 8.2% (95% CI, 1.3% to 14.6%) through 4 years to 12.4% (95% CI, 3.0% to 20.8%) through 9 years to 27.5% (95% CI, 8.6% to 42.5%) through 19 years after AH. Conclusion Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for nonatypical EH but is 28% for AH. C1 NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD USA. Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Univ So Calif, Div Biostat, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA. RP Lacey, JV (reprint author), City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM jlacey@coh.org FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 24 TC 52 Z9 57 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 788 EP 792 DI 10.1200/JCO.2009.24.1315 PG 5 WC Oncology SC Oncology GA 553LN UT WOS:000274368300015 PM 20065186 ER PT J AU Turesson, I Velez, R Kristinsson, SY Landgren, O AF Turesson, Ingemar Velez, Ramon Kristinsson, Sigurdur Y. Landgren, Ola TI Patterns of Improved Survival in Patients With Multiple Myeloma in the Twenty-First Century: A Population-Based Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-DOSE THERAPY; STEM-CELL TRANSPLANTATION; PREDNISONE PLUS THALIDOMIDE; RANDOMIZED CONTROLLED-TRIAL; COMBINATION CHEMOTHERAPY; STANDARD CHEMOTHERAPY; ELDERLY-PATIENTS; MELPHALAN; BORTEZOMIB; YOUNGER AB Purpose Randomized multiple myeloma (MM) studies show improved response rates and better progression-free survival for newer therapies. However, a less pronounced effect has been found for overall survival (OS). Using population-based data including detailed treatment information for individual patients, we assessed survival patterns for all patients diagnosed with MM in Malmo, Sweden from 1950 to 2005. Patients and Methods We identified 773 patients with MM (48% males). On the basis of the age limit used for treatment with high-dose melphalan with autologous stem-cell support (HDM-ASCT; <= 65 years old) in Sweden, we constructed Kaplan-Meier curves and used the Breslow generalized Wilcoxon test to evaluate OS patterns (diagnosed in six calendar periods) for patients 65 years old or younger and patients older than 65 years. Results Including all age groups, patients diagnosed from 1960 to 1969 had a better survival than patients diagnosed from 1950 to 1959. In subsequent 10-year calendar periods, median OS increased from 24.3 to 56.3 months (P = .036) in patients <= 65 years old. In contrast, OS did not improve among patients older than age 65 years (21.2 to 26.7 months, P = .7). Conclusion With the establishment of HDM-ASCT as the standard therapy for younger patients with MM, OS has improved significantly for this age group in the general MM population. With novel therapies being commonly used at disease progression, presumably it becomes increasingly difficult to confirm survival differences between defined induction, consolidation, and maintenance therapies in the future. Consequently, in the era of novel MM therapies, population-based studies will serve as a necessary complement to randomized trials. C1 [Turesson, Ingemar] Malmo Univ Hosp, Dept Med, Sect Hematol, S-2052 Malmo, Sweden. Karolinska Univ Hosp & Inst, Dept Med, Div Hematol, Stockholm, Sweden. Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. NCI, Ctr Canc Res, Med Oncol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Turesson, I (reprint author), Malmo Univ Hosp, Dept Med, Sect Hematol, S-2052 Malmo, Sweden. EM ingemar.turesson@med.lu.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU National Institutes of Health; National Cancer Institute; Foundation for Research on Blood Diseases, Malmo, Sweden FX Supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute and by grants from the Foundation for Research on Blood Diseases, Malmo, Sweden. NR 28 TC 88 Z9 91 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 830 EP 834 DI 10.1200/JCO.2009.25.4177 PG 5 WC Oncology SC Oncology GA 553LN UT WOS:000274368300021 PM 20038719 ER PT J AU Alberts, SR Roh, MS Mahoney, MR O'Connell, MJ Nagorney, DM Wagman, L Smyrk, TC Weiland, TL Lai, LL Schwarz, RE Molina, R Dentchev, T Bolton, JS AF Alberts, Steven R. Roh, Mark S. Mahoney, Michelle R. O'Connell, Michael J. Nagorney, David M. Wagman, Lawrence Smyrk, Thomas C. Weiland, Timothy L. Lai, Lily Lau Schwarz, Roderich E. Molina, Roy Dentchev, Todor Bolton, John S. TI Alternating Systemic and Hepatic Artery Infusion Therapy for Resected Liver Metastases From Colorectal Cancer: A North Central Cancer Treatment Group (NCCTG)/National Surgical Adjuvant Breast and Bowel Project (NSABP) Phase II Intergroup Trial, N9945/CI-66 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IMPROVING RESECTABILITY; CHEMOTHERAPY; CARCINOMA AB Purpose Prior trials have shown that surgery followed by hepatic artery infusion (HAI) of floxuridine (FUDR) alternating with systemic fluorouracil improves survival rates. Oxaliplatin combined with capecitabine has demonstrated activity in advanced colorectal cancer. Based on this observation a trial was conducted to assess the potential benefit of systemic oxaliplatin and capecitabine alternating with HAI of FUDR. The primary end point was 2-year survival. Patients and Methods Patients with liver-only metastases from colorectal cancer amenable to resection or cryoablation were eligible. HAI and systemic therapy was initiated after metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m(2)/d FUDR and dexamethasone, day 1 through 14 weeks 1 and 2. Systemic therapy included oxaliplatin 130 mg/m(2) day 1 with capecitabine at 1,000 mg/m(2) twice daily, days 1 through 14, weeks 4 and 5. Two additional 3-week courses of systemic therapy were given. Capecitabine was reduced to 850 mg/m(2) twice daily after interim review of toxicity. Results Fifty-five of 76 eligible patients were able to initiate protocol-directed therapy and completed median of six cycles (range, one to six). Three postoperative or treatment-related deaths were reported. Overall, 88% of evaluable patients were alive at 2 years. With a median follow-up of 4.8 years, a total of 30 patients have had disease recurrence, 11 involving the liver. Median disease-free survival was 32.7 months. Conclusion Alternating HAI of FUDR and systemic capecitabine and oxaliplatin met the prespecified end point of higher than 85% survival at 2 years and was clinically tolerable. However, the merits of this approach need to be established with a phase III trial. C1 [Alberts, Steven R.] Mayo Clin, Rochester, MN 55905 USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. St Joseph Hosp, Natl Surg Adjuvant Breast & Bowel Project, Orange, CA USA. City Hope Natl Med Ctr, Natl Surg Adjuvant Breast & Bowel Project, Duarte, CA 91010 USA. Altru Hlth Syst, Grand Forks, ND USA. Canc Inst New Jersey, Natl Surg Adjuvant Breast & Bowel Project, New Brunswick, NJ USA. Iowa Oncol Res Assoc, CCOP, Des Moines, IA USA. Ochsner CCOP, New Orleans, LA USA. RP Alberts, SR (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM Alberts.steven@mayo.edu RI Bolton, John/A-5509-2011 FU Public Health Service, National Cancer Institute, Department of Health and Human Services [CA-25224, U10-CA-12027, CA-37404, CA-35101, CA-35272, CA-52352, CA-35448, CA-35103]; Sanofi-Aventis US; Sanofi-Synthelabo; Roche Laboratories, Inc; National Institutes of Health [CA25224-18] FX This study was conducted as a collaborative trial of the North Central Cancer Treatment Group, Mayo Clinic, and National Surgical Adjuvant Breast and Bowel Project and was supported in part by Public Health Service Grants No. CA-25224, U10-CA-12027, CA-37404, CA-35101, CA-35272, CA-52352, CA-35448, CA-35103 from the National Cancer Institute, Department of Health and Human Services; Sanofi-Aventis US; Sanofi-Synthelabo; Roche Laboratories, Inc; and by Grant No. CA25224-18 from the National Institutes of Health. NR 15 TC 23 Z9 26 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 853 EP 858 DI 10.1200/JCO.2009.24.6728 PG 6 WC Oncology SC Oncology GA 553LN UT WOS:000274368300025 PM 20048179 ER PT J AU Raman, B Joseph, J Tang, J Stopfer, M AF Raman, Baranidharan Joseph, Joby Tang, Jeff Stopfer, Mark TI Temporally Diverse Firing Patterns in Olfactory Receptor Neurons Underlie Spatiotemporal Neural Codes for Odors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LOCUST ANTENNAL LOBE; NETWORK DYNAMICS; MUSHROOM BODY; BULB; REPRESENTATIONS; OSCILLATIONS; MODEL; INFORMATION; ASSEMBLIES; SYSTEM AB Odorants are represented as spatiotemporal patterns of spikes in neurons of the antennal lobe (AL; insects) and olfactory bulb (OB; vertebrates). These response patterns have been thought to arise primarily from interactions within the AL/OB, an idea supported, in part, by the assumption that olfactory receptor neurons (ORNs) respond to odorants with simple firing patterns. However, activating the AL directly with simple pulses of current evoked responses in AL neurons that were much less diverse, complex, and enduring than responses elicited by odorants. Similarly, models of the AL driven by simplistic inputs generated relatively simple output. How then are dynamic neural codes for odors generated? Consistent with recent results from several other species, our recordings from locust ORNs showed a great diversity of temporal structure. Furthermore, we found that, viewed as a population, many response features of ORNs were remarkably similar to those observed within the AL. Using a set of computational models constrained by our electrophysiological recordings, we found that the temporal heterogeneity of responses of ORNs critically underlies the generation of spatiotemporal odor codes in the AL. A test then performed in vivo confirmed that, given temporally homogeneous input, the AL cannot create diverse spatiotemporal patterns on its own; however, given temporally heterogeneous input, the AL generated realistic firing patterns. Finally, given the temporally structured input provided by ORNs, we clarified several separate, additional contributions of the AL to olfactory information processing. Thus, our results demonstrate the origin and subsequent reformatting of spatiotemporal neural codes for odors. C1 [Raman, Baranidharan; Joseph, Joby; Tang, Jeff; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. [Raman, Baranidharan] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Stopfer, M (reprint author), NICHHD, NIH, Bldg 35,Room 3A-102, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov FU Joint National Institutes of Health (NIH); National Research Council; NIH-National Institute of Child Health and Human Development FX This work was supported by a Joint National Institutes of Health (NIH), National Institute of Biomedical Imaging and Bioengineering-National Institute of Standards and Technology postdoctoral Fellowship Award from the National Research Council (B. R.) and by an intramural grant from NIH-National Institute of Child Health and Human Development (M. S.). We thank members of the Stopfer laboratory for helpful discussions and Maxim Bazhenov for providing an implementation of a map-based model for neurons. We also thank Kui Sun for excellent animal care. NR 43 TC 51 Z9 52 U1 0 U2 15 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 FEB 10 PY 2010 VL 30 IS 6 BP 1994 EP 2006 DI 10.1523/JNEUROSCI.5639-09.2010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 553WT UT WOS:000274398200002 PM 20147528 ER PT J AU Tricoire, L Pelkey, KA Daw, MI Sousa, VH Miyoshi, G Jeffries, B Cauli, B Fishell, G McBain, CJ AF Tricoire, Ludovic Pelkey, Kenneth A. Daw, Michael I. Sousa, Vitor H. Miyoshi, Goichi Jeffries, Brian Cauli, Bruno Fishell, Gord McBain, Chris J. TI Common Origins of Hippocampal Ivy and Nitric Oxide Synthase Expressing Neurogliaform Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CORTICAL INTERNEURON SUBTYPES; STRATUM LACUNOSUM-MOLECULARE; CAUDAL GANGLIONIC EMINENCE; GREEN FLUORESCENT PROTEIN; CALCIUM-BINDING PROTEINS; GABAERGIC INTERNEURONS; CEREBRAL-CORTEX; NEUROPEPTIDE-Y; CA1 AREA; NONPYRAMIDAL CELLS AB GABAergic interneurons critically regulate cortical computation through exquisite spatiotemporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although interneurons expressing the neuronal isoform of nitric oxide synthase (nNOS) constitute the largest hippocampal interneuron cohort their origin and specification remain unknown. Thus, as neurogliaform cells (NGC) and Ivy cells (IvC) represent the main nNOS(+) interneurons, we investigated their developmental origins. Although considered distinct interneuron subtypes, NGCs and IvCs exhibited similar neurochemical and electrophysiological signatures, including NPY expression and late spiking. Moreover, lineage analyses, including loss-of-function experiments and inducible fate-mapping, indicated that nNOS(+) IvCs and NGCs are both derived from medial ganglionic eminence (MGE) progenitors under control of the transcription factor Nkx2-1. Surprisingly, a subset of NGCs lacking nNOS arises from caudal ganglionic eminence (CGE) progenitors. Thus, while nNOS(+) NGCs and IvCs arise from MGE progenitors, a CGE origin distinguishes a discrete population of nNOS(-) NGCs. C1 [Tricoire, Ludovic; Pelkey, Kenneth A.; Daw, Michael I.; Jeffries, Brian; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Sousa, Vitor H.; Miyoshi, Goichi; Fishell, Gord] NYU, Smilow Neurosci Program, New York, NY 10016 USA. [Sousa, Vitor H.; Miyoshi, Goichi; Fishell, Gord] NYU, Dept Cell Biol, New York, NY 10016 USA. [Cauli, Bruno] Univ Paris 06, Lab Neurobiol Proc Adaptatifs, CNRS, UMR 7102, F-75005 Paris, France. RP McBain, CJ (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, Porter Neurosci Res Ctr, 35 Lincoln Dr,MSC 3715, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov RI Miyoshi, Goichi/H-4759-2012; Sousa, Vitor/E-3679-2016; OI Sousa, Vitor/0000-0001-8768-2742; Daw, Michael/0000-0002-8374-5977 FU National Institutes of Health (NIH) [R01NS039007, R01MH07679]; Simons Foundation; New York State through their New York State Stem Cell Science initiative; Human Frontier Science Program [RGY0070/2007]; Centre National de la Recherche Scientifique (CNRS); Japan Society for the Promotion of Science FX This work was supported by a National Institute of Child Health and Human Development (NICHD) intramural award to C.J.M. Research in Fishell laboratory is supported by National Institutes of Health (NIH) Grants R01NS039007 and R01MH07679 and by generous support from the Simons Foundation and New York State through their New York State Stem Cell Science initiative. B. C. is supported by a Human Frontier Science Program grant (RGY0070/2007) and by a Centre National de la Recherche Scientifique (CNRS) grant ("Nitrex"). L. T. is an NIH Visiting Fellow and a NIH/CNRS ECTA Fellow. G. M. was supported by a grant from the Japan Society for the Promotion of Science. We thank Xiaoqing Yuan, Daniel Abebe, and Helene Geoffroy (Ecole Superieure de Physique et Chimie Industrielles de Paris, France) for expert technical assistance. Microscopy imaging was performed at the Microscopy and Imaging Core (NICHD, NIH) with the assistance of Dr. Vincent Schram. Wethank Dr. Betty A. Eipper for supplying us with the NPY antibody and Dr. Stewart A. Anderson for providing us the Nkx2-1BAC-Cre driver line. NR 74 TC 68 Z9 68 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 FEB 10 PY 2010 VL 30 IS 6 BP 2165 EP 2176 DI 10.1523/JNEUROSCI.5123-09.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 553WT UT WOS:000274398200018 PM 20147544 ER PT J AU Chavez, AE Grimes, WN Diamond, JS AF Chavez, Andres E. Grimes, William N. Diamond, Jeffrey S. TI Mechanisms Underlying Lateral GABAergic Feedback onto Rod Bipolar Cells in Rat Retina SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AII AMACRINE CELLS; MUDPUPPY NECTURUS MACULOSUS; GANGLION-CELLS; TRANSMITTER RELEASE; MAMMALIAN RETINA; GABA(C) RECEPTOR; RABBIT RETINA; MOUSE RETINA; GLUTAMATE RECEPTORS; SURROUND INHIBITION AB GABAergic feedback inhibition from amacrine cells shapes visual signaling in the inner retina. Rod bipolar cells (RBCs), ON-sensitive cells that depolarize in response to light increments, receive reciprocal GABAergic feedback from A17 amacrine cells and additional GABAergic inputs from other amacrine cells located laterally in the inner plexiform layer. The circuitry and synaptic mechanisms underlying lateral GABAergic inhibition of RBCs are poorly understood. A-type and rho-subunit-containing (C-type) GABA receptors (GABA(A)Rs and GABA(C)Rs) mediate both forms of inhibition, but their relative activation during synaptic transmission is unclear, and potential interactions between adjacent reciprocal and lateral synapses have not been explored. Here, we recorded from RBCs in acute slices of rat retina and isolated lateral GABAergic inhibition by pharmacologically ablating A17 amacrine cells. We found that amacrine cells providing lateral GABAergic inhibition to RBCs receive excitatory synaptic input mostly from ON bipolar cells via activation of both Ca(2+)-impermeable and Ca(2+)-permeable AMPA receptors (CP-AMPARs) but not NMDA receptors (NMDARs). Voltage-gated Ca(2+) (Ca(v)) channels mediate the majority of Ca(2+) influx that triggers GABA release, although CP-AMPARs contribute a small component. The intracellular Ca(2+) signal contributing to transmitter release is amplified by Ca(2+)-induced Ca(2+) release from intracellular stores via activation of ryanodine receptors. Furthermore, lateral nonreciprocal feedback is mediated primarily by GABACRs that are activated independently from receptors mediating reciprocal feedback inhibition. These results illustrate numerous physiological differences that distinguish GABA release at reciprocal and lateral synapses, indicating complex, pathway-specific modulation of RBC signaling. C1 [Chavez, Andres E.; Grimes, William N.; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35,Room 3C-1000, Bethesda, MD 20892 USA. EM andres.chavez@einstein.yu.edu; diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU National Institute of Neurological Disorders and Stroke FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. We thank members of the Diamond Laboratory for constructive discussions throughout this project. NR 81 TC 42 Z9 42 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 10 PY 2010 VL 30 IS 6 BP 2330 EP 2339 DI 10.1523/JNEUROSCI.5574-09.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 553WT UT WOS:000274398200033 PM 20147559 ER PT J AU Jeon, J Dencker, D Wortwein, G Woldbye, DPD Cui, YH Davis, AA Levey, AI Schutz, G Sager, TN Mork, A Li, CL Deng, CX Fink-Jensen, A Wess, J AF Jeon, Jongrye Dencker, Ditte Wortwein, Gitta Woldbye, David P. D. Cui, Yinghong Davis, Albert A. Levey, Allan I. Schuetz, Guenther Sager, Thomas N. Mork, Arne Li, Cuiling Deng, Chu-Xia Fink-Jensen, Anders Wess, Juergen TI A Subpopulation of Neuronal M-4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; KNOCKOUT MICE; CEREBRAL-CORTEX; SCHIZOPHRENIA; ADDICTION; SUBTYPES; MOUSE; LOCALIZATION; PROTEINS; PHARMACOLOGY AB Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M-1-M-5 mAChRs). Like other mAChR subtypes, the M-4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M-4 mAChRs are coexpressed with D-1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M-4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M-4 mAChRs only in D-1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D-1 dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M-4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance. C1 [Wess, Juergen] NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Li, Cuiling; Deng, Chu-Xia] NIDDKD, Mammalian Genet Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Dencker, Ditte; Wortwein, Gitta; Woldbye, David P. D.; Fink-Jensen, Anders] Univ Copenhagen, Rigshosp, Ctr Psychiat, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. [Davis, Albert A.; Levey, Allan I.] Emory Univ, Ctr Neurodegenerat Dis, Sch Med, Atlanta, GA 30322 USA. [Davis, Albert A.; Levey, Allan I.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Schuetz, Guenther] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Sager, Thomas N.; Mork, Arne] H Lundbeck & Co AS, Discovery Pharmacol Res, DK-2500 Copenhagen, Denmark. RP Wess, J (reprint author), NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA. EM a.fink-jensen@dadlnet.dk; jwess@helix.nih.gov RI deng, chuxia/N-6713-2016; OI Wortwein, Gitta/0000-0001-6981-7885 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disorders; National Institute of Neurological Disorders and Stroke; National Institute on Aging; PhRMA Foundation; Lundbeck Foundation; Ivan Nielsen Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disorders (J.J., Y.C, C.L., C.D., J.W.), the National Institute of Neurological Disorders and Stroke (A.I.L.), the National Institute on Aging and the PhRMA Foundation (A.A.D.), the Lundbeck Foundation, and the Ivan Nielsen Foundation (A.F.). We thank Drs. Nina Wettschureck and Stephan Offermanns (University of Heidelberg, Heidelberg, Germany) for kindly providing the pFlox vector and Dr. Howard Rees (Emory University, Atlanta, GA) for expert technical assistance. NR 50 TC 56 Z9 58 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 10 PY 2010 VL 30 IS 6 BP 2396 EP 2405 DI 10.1523/JNEUROSCI.3843-09.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 553WT UT WOS:000274398200039 PM 20147565 ER PT J AU Liu, BY Faia, L Hu, MJ Nussenblatt, RB AF Liu, Baoying Faia, Lisa Hu, Mengjun Nussenblatt, Robert B. TI Pro-angiogenic effect of IFN gamma is dependent on the PI3K/mTOR/translational pathway in human retinal pigmented epithelial cells SO MOLECULAR VISION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; INTERFERON-GAMMA; TNF-ALPHA; GENE-EXPRESSION; TRANSGENIC MICE; TRANSCRIPTIONAL SUPPRESSION; PROINFLAMMATORY CYTOKINES; TUMOR ANGIOGENESIS; IN-VITRO AB Purpose: To investigate the molecular signaling pathway of Interferon gamma (IFN gamma) contributing to angiogenesis in retinal pigmented epithelial (RPE) cells and the role of Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) in this process. Methods: Human adult and fetal RPE cells were used in this study. Real-time polymerase chain reaction was used to detect human vascular endothelial growth factor (VEGF) mRNA expression. Thiazolyl blue tetrazolium bromide (MTT) assay was used to detect cell viability. VEGF expression from cell supernatant was measured using enzyme-linked immunosorbent assay (ELISA). Small interfering RNA (SiRNA) of signal transducers and activators of transcription 1 (stat1) and protein kinases B (akt) were transfected into ARPE-19 cells to directly study the roles of these molecules in VEGF expression. Sodium dodecyl sulfate PAGE (SDS-PAGE) and western blot analysis were used to detect the expression of signaling molecules. Results: IFN gamma promoted human VEGF expression in both adult and fetal RPE cells. The PI-3K/Akt/mTOR/p70 S6 kinase pathway is required for IFN gamma-induced VEGF expression in retinal cells. The mTOR inhibitor, rapamycin, along with the SiRNA targeted to akt and the PI3K inhibitor, LY294002, decreased hVEGF secretion from RPE cells. Moreover, IFN gamma-induced hVEGF expression was not affected by SiRNA targeted to Stat1, implying that the classic Jak-Stat1 pathway of IFN gamma may not be involved in this process. Conclusions: We provide evidence that IFN gamma induces VEGF expression in human retinal pigment epithelial cells. Our work emphasizes that the activation of the PI-3K/mTOR/translational pathway is important for IFN gamma-mediated VEGF expression in RPE cells. By elucidating molecular signaling involved in this process, our findings provide further mechanistic insight into the successful clinical application of rapamycin therapy for choroidal neovascularization in age-related macular degeneration (AMD) and uveitis. C1 [Liu, Baoying; Faia, Lisa; Hu, Mengjun; Nussenblatt, Robert B.] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU NIH; National Eye Institute FX We thank Drs. Arvydas Maminishkis and Sheldon Miller for providing fetal RPE cells and Shayma Jawad for her critics of the manuscript. This research was supported by the Intramural Research Program of NIH, National Eye Institute. NR 56 TC 17 Z9 17 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD FEB 10 PY 2010 VL 16 IS 22-26 BP 184 EP 193 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 570ZG UT WOS:000275716800002 PM 20157617 ER PT J AU Huang, TTK Story, MT AF Huang, Terry T. -K. Story, Mary T. TI A Journey Just Started: Renewing Efforts to Address Childhood Obesity SO OBESITY LA English DT Editorial Material ID LARGE SOCIAL NETWORK; SPREAD C1 [Huang, Terry T. -K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Story, Mary T.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Huang, TTK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM huangter@mail.nih.gov NR 9 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD FEB 10 PY 2010 VL 18 SU 1 BP S1 EP S3 DI 10.1038/oby.2009.423 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 551KU UT WOS:000274208100001 PM 20107453 ER PT J AU Olivares-Zavaleta, N Whitmire, W Gardner, D Caldwell, HD AF Olivares-Zavaleta, Norma Whitmire, William Gardner, Donald Caldwell, Harlan D. TI Immunization with the attenuated plasmidless Chlamydia trachomatis L2(25667R) strain provides partial protection in a murine model of female genitourinary tract infection SO VACCINE LA English DT Article DE Live-attenuated Chlamydia vaccine; Immunogenicity; Safety; Protective efficacy; Urogenital infection model ID OUTER-MEMBRANE PROTEIN; CD4(+) T-CELLS; GENITAL-TRACT; VACCINE; IMMUNITY; IMMUNOLOGY; ANTIBODIES; PATHOLOGY; SEROVARS AB Here we report on the safety, immunogenicity, and vaccine efficacy of the naturally occurring plasmid-free attenuated Chlamydia trachomatis L2-25667R (L2R) strain in a murine infection model. Intravaginal immunization induced both chlamydial specific serum antibody and systemic CD4(+) Th1 biased immune responses but failed to induce local IgA antibodies. Immunization induced no pathological changes in the urogenital tract. Protective immunity was evaluated by vaginal challenge with a natural occurring non-attenuated plasmid positive C. trachomatis urogenital strain (serovar D). Vaccinated mice were not protected from colonization/infection but exhibited a reduction in infectious burden at early time periods (1-2 weeks) post-challenge. Partial protective immunity did not protect against inflammatory disease. Thus, intravaginal vaccination with the live-attenuated L2R stain is safe, induces a systemic antibody and CD4(+) Th1 biased immune response, but its protective efficacy is limited to reducing chlamydial burden at early time periods post-infection. Published by Elsevier Ltd. C1 [Olivares-Zavaleta, Norma; Whitmire, William; Caldwell, Harlan D.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Gardner, Donald] NIAID, Vet Pathol Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Caldwell, HD (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov FU NIH; NIAID FX We thank Dr. Kim Hasenkrug, Dr. Laszlo Kari and Dr. Jeff Shannon, for critical reading of the manuscript; Dr. Chiung-Yu Huang from Biostatistics Research Branch/NIAID and Rebecca Rosenke from Veterinary Branch/RML/NIAID for their technical assistance; Gary Hettrick and Kelly Matteson, for editorial assistance. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 25 TC 23 Z9 23 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 FEB 10 PY 2010 VL 28 IS 6 BP 1454 EP 1462 DI 10.1016/j.vaccine.2009.11.073 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565NX UT WOS:000275301900006 PM 20004265 ER PT J AU Van Rompay, KKA Abel, K Earl, P Kozlowski, PA Easlick, J Moore, J Buonocore-Buzzelli, L Schmidt, KA Wilson, RL Simon, I Moss, B Rose, N Rose, J Marthas, ML AF Van Rompay, Koen K. A. Abel, Kristina Earl, Patricia Kozlowski, Pamela A. Easlick, Juliet Moore, Joseph Buonocore-Buzzelli, Linda Schmidt, Kimberli A. Wilson, Robert L. Simon, Ian Moss, Bernard Rose, Nina Rose, John Marthas, Marta L. TI Immunogenicity of viral vector, prime-boost SIV vaccine regimens in infant rhesus macaques: Attenuated vesicular stomatitis virus (VSV) and modified vaccinia Ankara (MVA) recombinant SIV vaccines compared to live-attenuated SIV SO VACCINE LA English DT Article DE Pediatric; SIV; HIV; Oral; Vaccine ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTE; IMMUNE-RESPONSES; ORAL CHALLENGE; TENOFOVIR MONOTHERAPY; MONOCLONAL-ANTIBODIES; COMPLETE PROTECTION; CHILD TRANSMISSION; VAGINAL CHALLENGE; NEWBORN MACAQUES AB In a previously developed infant macaque model mimicking HIV infection by breast-feeding, we demonstrated that intramuscular immunization with recombinant poxvirus vaccines expressing simian immunodeficiency virus (SIV) structural proteins provided partial protection against infection following oral inoculation with virulent SIV. In an attempt to further increase systemic but also local antiviral immune responses at the site of viral entry, we tested the immunogenicity of different orally administered, replicating vaccines. One group of newborn macaques received an oral prime immunization with a recombinant vesicular stomatitis virus expressing SIVmac239 gag, pol and env (VSV-SIVgpe), followed 2 weeks later by an intramuscular boost immunization with MVA-SIV. Another group received two immunizations with live-attenuated SIVmac1A11, administered each time both orally and intravenously. Control animals received mock immunizations or non-SIV VSV and MVA control vectors. Analysis of SIV-specific immune responses in blood and lymphoid tissues at 4 weeks of age demonstrated that both vaccine regimens induced systemic antibody responses and both systemic and local cell-mediated immune responses. The safety and immunogenicity of the VSV-SIVgpe + MVA-SIV immunization regimen described in this report provide the scientific incentive to explore the efficacy of this vaccine regimen against virulent SIV exposure in the infant macaque model. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Van Rompay, Koen K. A.; Abel, Kristina; Easlick, Juliet; Moore, Joseph; Schmidt, Kimberli A.; Marthas, Marta L.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Abel, Kristina] Univ Calif Davis, Sch Med, Div Infect Dis, Dept Internal Med, Davis, CA 95616 USA. [Earl, Patricia; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD USA. [Kozlowski, Pamela A.; Wilson, Robert L.] Louisiana State Univ, Hlth Sci Ctr, Gene Therapy Program, New Orleans, LA 70112 USA. [Kozlowski, Pamela A.; Wilson, Robert L.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. [Buonocore-Buzzelli, Linda; Simon, Ian; Rose, Nina; Rose, John] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Marthas, ML (reprint author), Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. EM mlmarthas@ucdavis.edu FU National Center for Research Resources [R01-AI062518, RR-00169] FX We thank the Colony Services, Pathology, Veterinary, and Clinical Laboratory staff of the California National Primate Research Center for expert technical assistance; Jeffrey Americo for preparation and characterization of recombinant MVAs and for performing vaccine virus ELISAs; the NIH AIDS Research and Reference Reagent Program, Division of AIDS. MAID, NIH for providing the SIV p55 gag protein and the 15mer and 20mer peptides of the p27 gag region, Dr. R. Desrosiers (New England Regional Primate Research Center) for the plasmid containing the SIVmac239 env gene. This work was supported by grants R01-AI062518 (MLM) and grant RR-00169 from the National Center for Research Resources (NCRR; a component of the National Institutes of Health (NIH)) to the California National Primate Research Center. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. NR 62 TC 16 Z9 16 U1 0 U2 2 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 FEB 10 PY 2010 VL 28 IS 6 BP 1481 EP 1492 DI 10.1016/j.vaccine.2009.11.061 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565NX UT WOS:000275301900010 PM 19995539 ER PT J AU Senger, T Schadlich, L Textor, S Klein, C Michael, KM Buck, CB Gissmann, L AF Senger, Tilo Schaedlich, Lysann Textor, Sonja Klein, Corinna Michael, Kristina M. Buck, Christopher B. Gissmann, Lutz TI Virus-like particles and capsomeres are potent vaccines against cutaneous alpha HPVs SO VACCINE LA English DT Article DE Papillomavirus; Cutaneous; Virus-like particle; Capsomeres; Immunogenicity; Prophylactic vaccine ID HUMAN-PAPILLOMAVIRUS TYPE-16; MAJOR CAPSID PROTEIN; RANDOMIZED CONTROLLED-TRIAL; CYTOTOXIC T-LYMPHOCYTES; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; EPIDERMODYSPLASIA-VERRUCIFORMIS; TRANSPLANT RECIPIENTS; SUSTAINED EFFICACY; L1 CAPSOMERES AB The potential as prophylactic vaccines of L1-based particles from cutaneous genus alpha human papillomavirus (HPV) types has not been assessed so far. However, there is a high medical need for such vaccines since HPV-induced skin warts represent a major burden for children and for immunocompromised adults, such as organ transplant recipients. In this study, we have examined the immunogenicity of capsomeres and virus-like particles (VLPs) from HPV types 2, 27, and 57, the most frequent causative agents of skin warts. Immunization of mice induced immune responses resembling those observed upon vaccination with HPV 16 L1-based antigens. The antibody responses were cross-reactive but type-restricted in their neutralizing capacities. Application of adjuvant led to an enhanced potential to neutralize the respective immunogen type but did not improve cross-neutralization. Vaccination with capsomeres and VLPs from all four analyzed HPV types induced robust IFN gamma-associated T-cell activation. Immunization with mixed VLPs from HPV types 2, 27, and 57 triggered an antibody response similar to that after single-type immunization and capable of efficiently neutralizing all three types. Our results imply that vaccination with combinations of VLPs from cutaneous HPV types constitutes a promising strategy to prevent HPV-induced skin lesions. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Senger, Tilo; Schaedlich, Lysann; Textor, Sonja; Klein, Corinna; Michael, Kristina M.; Gissmann, Lutz] German Canc Res Ctr, Dept Genome Modificat & Carcinogenesis, D-69120 Heidelberg, Germany. [Buck, Christopher B.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Senger, T (reprint author), German Canc Res Ctr, Dept Genome Modificat & Carcinogenesis, D-69120 Heidelberg, Germany. EM t.senger@dkfz-heidelberg.de RI Gissmann, Lutz/H-4688-2011; OI Buck, Christopher/0000-0003-3165-8094 FU DKFZ-Canceropole Grand-Est FX We thank Birgit Aengeneyndt, and Birgit Hub for their expert assistance as well as Martin Muller for helpful discussions. We are grateful to Martina Schnolzer and Uwe Warnken for their mass spectrometric analyses. The work was supported by DKFZ-Canceropole Grand-Est (granted to LG). NR 65 TC 14 Z9 14 U1 0 U2 4 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 FEB 10 PY 2010 VL 28 IS 6 BP 1583 EP 1593 DI 10.1016/j.vaccine.2009.11.048 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565NX UT WOS:000275301900023 PM 20003923 ER PT J AU Bodner, CR Maltsev, AS Dobson, CM Bax, A AF Bodner, Christina R. Maltsev, Alexander S. Dobson, Christopher M. Bax, Ad TI Differential Phospholipid Binding of alpha-Synuclein Variants Implicated in Parkinson's Disease Revealed by Solution NMR Spectroscopy SO BIOCHEMISTRY LA English DT Article ID FIBRIL FORMATION; FATTY-ACIDS; VESICLE PERMEABILIZATION; RESIDUAL STRUCTURE; LINKED MUTATIONS; E46K MUTATION; LEWY BODIES; IN-VITRO; AGGREGATION; PROTEIN AB Three familial variants of the presynaptic protein alpha-synuclein (alpha S), A30P, E46K, and A53T, correlate with rare inherited Parkinson's disease (PD), while wild-type alpha S is Implicated in sporadic PD. The classic manifestation of both familiar and sporadic PD is the formation of fibrillar structures of as which accumulate as the main component in intraneuronal Lewy bodies. At presynaptic termini, the partitioning of as between disordered cytosolic and membrane-bound states likely mediates its proposed role in regulation of reserve pools of synaptic vesicles. Previously, we reported on multiple distinct phospholipid binding modes of alpha S with slow binding kinetics. Here, we report the phospholipid binding properties of the disease variants, viewed by solution NMR in a residue-specific manner. Our results agree qualitatively with previous biophysical Studies citing overall decreased lipid affinity for the A30P Mutation, comparable affinity for A53T, and an increased level of binding or E46K, relative to wild-type as. Additionally, Our NMR results describe the distribution of lipid-bound states for as: the population of the SL1 binding mode (residues 3-25 bound as a helix) is augmented by each of the disease variants, relative to wild-type alpha S. We propose that the SL1 binding mode, which anchors the N-terminus of as in the lipoprotein complex while the hydrophobic NAC region remains dynamically disordered, is prone to intermolecular interactions which progress toward disease-associated oligomers and fibrils. The elevation of the SL1 binding mode, unchecked by a proportionate population of binding modes incorporating the full N-terminal domain, may well account for the increased toxicity of the A30P, E46K, and A53T disease variants of alpha S. C1 [Bodner, Christina R.; Maltsev, Alexander S.; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Bodner, Christina R.; Dobson, Christopher M.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Bax, A (reprint author), 5 Mem Dr, Bethesda, MD 20892 USA. EM bax@nih.gov RI Maltsev, Alexander/A-8175-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK029047]; Leverhulme Trust; Wellcome Trust FX This work is funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Grant DK029047 to A.B.), and by the Leverhulme Trust and the Wellcome Trust (to C.M.D.). NR 61 TC 92 Z9 93 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 9 PY 2010 VL 49 IS 5 BP 862 EP 871 DI 10.1021/bi901723p PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 549ZI UT WOS:000274094300007 PM 20041693 ER PT J AU Higgins, RD Shankaran, S Laptook, AR AF Higgins, Rosemary D. Shankaran, Seetha Laptook, Abbot R. TI Hypoxic ischaemic encephalopathy in infants SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID HYPOTHERMIA C1 [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. [Shankaran, Seetha] Wayne State Univ, Detroit, MI 48201 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp Rhode Isl, Providence, RI 02905 USA. RP Higgins, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov FU NICHD NIH HHS [U10 HD021385] NR 6 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD FEB 9 PY 2010 VL 340 AR c397 DI 10.1136/bmj.c397 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 554ZS UT WOS:000274476800003 PM 20144982 ER PT J AU Hilber, AM Francis, SC Chersich, M Scott, P Redmond, S Bender, N Miotti, P Temmerman, M Low, N AF Hilber, Adriane Martin Francis, Suzanna C. Chersich, Matthew Scott, Pippa Redmond, Shelagh Bender, Nicole Miotti, Paolo Temmerman, Marleen Low, Nicola TI Intravaginal Practices, Vaginal Infections and HIV Acquisition: Systematic Review and Meta-Analysis SO PLOS ONE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; SEXUALLY-TRANSMITTED-DISEASES; SOUTH-AFRICAN WOMEN; BACTERIAL VAGINOSIS; HETEROSEXUAL TRANSMISSION; ZIMBABWEAN WOMEN; CONTROLLED-TRIAL; INCREASED RISK; DRY SEX; MICROBICIDES AB Background: Intravaginal practices are commonly used by women to manage their vaginal health and sexual life. These practices could, however, affect intravaginal mucosal integrity. The objectives of this study were to examine evidence for associations between: intravaginal practices and acquisition of HIV infection; intravaginal practices and vaginal infections; and vaginal infections and HIV acquisition. Methodology/Principal Findings: We conducted a systematic review of prospective longitudinal studies, searching 15 electronic databases of journals and abstracts from two international conferences to 31(st) January 2008. Relevant articles were selected and data extracted in duplicate. Results were examined visually in forest plots and combined using random effects meta-analysis where appropriate. Of 2120 unique references we included 22 publications from 15 different studies in sub-Saharan Africa and the USA. Seven publications from five studies examined a range of intravaginal practices and HIV infection. No specific vaginal practices showed a protective effect against HIV or vaginal infections. Insertion of products for sex was associated with HIV in unadjusted analyses; only one study gave an adjusted estimate, which showed no association (hazard ratio 1.09, 95% confidence interval, Cl 0.71, 1.67). HIV incidence was higher in women reporting intravaginal cleansing but confidence intervals were wide and heterogeneity high (adjusted hazard ratio 1.88, 95% Cl 0.53, 6.69, I(2) 83.2%). HIV incidence was higher in women with bacterial vaginosis (adjusted effect 1.57, 95% Cl 1.26, 1.94, I(2) 19.0%) and Trichomonas vaginalis (adjusted effect 1.64, 95% Cl 1.28, 2.09, I(2) 0.0%). Conclusions/Significance: A pathway linking intravaginal cleaning practices with vaginal infections that increase susceptibility to HIV infection is plausible but conclusive evidence is lacking. Intravaginal practices do not appear to protect women from vaginal infections or HIV and some might be harmful. C1 [Hilber, Adriane Martin; Scott, Pippa; Redmond, Shelagh; Bender, Nicole; Low, Nicola] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Francis, Suzanna C.] London Sch Hyg & Trop Med, Infect Dis Epidemiol Unit, London WC1, England. [Chersich, Matthew; Temmerman, Marleen] Univ Ghent, Fac Med & Hlth Sci, Int Ctr Reprod Hlth, B-9000 Ghent, Belgium. [Chersich, Matthew] Univ Witwatersrand, Reprod Hlth & HIV Res Unit, Johannesburg, South Africa. [Miotti, Paolo] US Natl Inst Hlth, Off AIDS Res, Bethesda, MD USA. RP Hilber, AM (reprint author), Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. EM low@ispm.unibe.ch RI Bender, Nicole/C-2237-2009; OI Scott, Pippa/0000-0003-0849-1812; Low, Nicola/0000-0003-4817-8986; Francis, Suzanna Carter/0000-0002-3724-4813 FU Office of AIDS Research, National Institutes of Health, United States of America FX Funding for the study was provided by the Office of AIDS Research, National Institutes of Health, United States of America (http://www.oar.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 45 Z9 46 U1 0 U2 3 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 FEB 9 PY 2010 VL 5 IS 2 AR e9119 DI 10.1371/journal.pone.0009119 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554NV UT WOS:000274442600017 PM 20161749 ER PT J AU Hummer, G AF Hummer, Gerhard TI Catching a protein in the act SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PHOTOACTIVE YELLOW PROTEIN; PHOTOCYCLE INTERMEDIATE; TRANSITION PATHS; CHROMOPHORE C1 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 gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 20 TC 7 Z9 7 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 FEB 9 PY 2010 VL 107 IS 6 BP 2381 EP 2382 DI 10.1073/pnas.0914486107 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100007 PM 20133629 ER PT J AU Peng, H Nogueira, ML Vogel, JL Kristie, TM AF Peng, Hua Nogueira, Mauricio L. Vogel, Jodi L. Kristie, Thomas M. TI Transcriptional coactivator HCF-1 couples the histone chaperone Asf1b to HSV-1 DNA replication components SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE herpes; chromatin ID HERPES-SIMPLEX-VIRUS; HOST-CELL FACTOR; IMMEDIATE-EARLY PROMOTERS; LYTIC INFECTION; GENE-EXPRESSION; REPLISOME INTEGRITY; DAMAGE CHECKPOINT; LATENT INFECTION; SENSORY NEURONS; REPAIR PROTEINS AB The cellular transcriptional coactivator HCF-1 interacts with numerous transcription factors as well as other coactivators and is a component of multiple chromatin modulation complexes. The protein is essential for the expression of the immediate early genes of both herpes simplex virus (HSV) and varicella zoster virus and functions, in part, by coupling chromatin modification components including the Set1 or MLL1 histone methyltransferases and the histone demethylase LSD1 to promote the installation of positive chromatin marks and the activation of viral immediately early gene transcription. Although studies have investigated the role of HCF-1 in both cellular and viral transcription, little is known about other processes that the protein may be involved in. Here we demonstrate that HCF-1 localizes to sites of HSV replication late in infection. HCF-1 interacts directly and simultaneously with both HSV DNA replication proteins and the cellular histone chaperone Asf1b, a protein that regulates the progression of cellular DNA replication forks via chromatin reorganization. Asf1b localizes with HCF-1 in viral replication foci and depletion of Asf1b results in significantly reduced viral DNA accumulation. The results support a model in which the transcriptional coactivator HCF-1 is a component of the HSV DNA replication assembly and promotes viral DNA replication by coupling Asf1b to DNA replication components. This coupling provides a novel function for HCF-1 and insights into the mechanisms of modulating chromatin during DNA replication. C1 [Peng, Hua; Nogueira, Mauricio L.; Vogel, Jodi L.; Kristie, Thomas M.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIAID, Viral Dis Lab, NIH, Bld 4-131,4 Ctr Dr, Bethesda, MD 20892 USA. EM tkristie@niaid.nih.gov RI Nogueira, Mauricio/B-7599-2012 OI Nogueira, Mauricio/0000-0003-1102-2419 FU Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank B. Ruyechan for UL29 antisera, G. Almouzni for Asf1b antisera, R. Roller for the HSV genomic library, M. Kyoo Jang and members of the Molecular Genetics Section Laboratory of Viral Diseases for advice and discussions, J. Kabat and the NIAID RTB Microscopy branch for assistance with confocal microscopy analyses, and T. Pierson and A. McBride for critical reading of this manuscript. These studies were supported by the Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 50 TC 25 Z9 26 U1 1 U2 2 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 FEB 9 PY 2010 VL 107 IS 6 BP 2461 EP 2466 DI 10.1073/pnas.0911128107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100021 PM 20133788 ER PT J AU Oke, OA Burgess, SA Forgacs, E Knight, PJ Sakamoto, T Sellers, JR White, H Trinick, J AF Oke, Olusola A. Burgess, Stan A. Forgacs, Eva Knight, Peter J. Sakamoto, Takeshi Sellers, James R. White, Howard Trinick, John TI Influence of lever structure on myosin 5a walking SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin; powerstroke; electron microscopy; kinetics; molecular motor ID BIOMOLECULAR PROCESSES; NANO-VISUALIZATION; SKELETAL-MUSCLE; NECK LENGTH; STEP-SIZE; F-ACTIN; PROCESSIVITY; KINETICS; MOTOR; FILAMENTS AB Using electron microscopy and image processing, we have observed myosin 5a modified with lever arms of different lengths (four, six, and eight calmodulin-binding IQ domains) and orientations walking along actin filaments. Step lengths were dependent on lever length: 8IQ > 6IQ > 4IQ, which is consistent with myosin 5a having evolved to walk straight along actin. Lead heads were mostly in the prepowerstroke state, tethered there by the trail head. However, improved image processing showed that in 5-10% of molecules the lead motor was in the postpowerstroke state. This is a unique attached state of myosin, where the motor domain has completed its powerstroke at the expense of severe lever distortion, but with little cargo movement. Postpowerstroke lead heads were seen in both wild-type and modified lever molecules, mostly where there was least strain. These data allow the strain dependence of the equilibrium between pre- and postpowerstroke conformations to be measured. Slow rates of ADP dissociation observed from lead heads of these molecules can be explained by the unfavorable equilibrium between the pre- and postpowerstroke conformations preceding ADP loss. C1 [Oke, Olusola A.; Burgess, Stan A.; Knight, Peter J.; Trinick, John] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Oke, Olusola A.; Burgess, Stan A.; Knight, Peter J.; Trinick, John] Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Forgacs, Eva; White, Howard] Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA. [Sakamoto, Takeshi; Sellers, James R.] NIH, Mol Cardiol Lab, Bethesda, MD 20892 USA. RP Trinick, J (reprint author), Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. EM j.trinick@leeds.ac.uk FU National Institutes of Health [EB00209] FX We thank M. Webb for deac-aminoATP, J. Sleep for discussion, M. Walker for help with EM and B. Belknap and S. Cartwright for technical assistance. This work was funded by National Institutes of Health Grant EB00209. NR 41 TC 21 Z9 21 U1 3 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 9 PY 2010 VL 107 IS 6 BP 2509 EP 2514 DI 10.1073/pnas.0906907107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100029 PM 20133809 ER PT J AU Granholm, AC Skirboll, L Schultzberg, M AF Granholm, Ann-Charlotte Skirboll, Lana Schultzberg, Marianne TI Chemical signaling in the nervous system in health and disease: Nils-Ake Hillarp's legacy Introduction SO PROGRESS IN NEUROBIOLOGY LA English DT Editorial Material DE Monoamine neurons; Central nervous system; Hillarp Monoamine conference ID SYMPATHETIC ADRENERGIC NEURONS; CENTRAL MONOAMINE NEURONS; NORADRENALINE; LOCALIZATION; 6-HYDROXYDOPAMINE; DEGENERATION; STEM; RAT C1 [Granholm, Ann-Charlotte] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Granholm, Ann-Charlotte] Med Univ S Carolina, Ctr Aging, HOT, Charleston, SC 29425 USA. [Skirboll, Lana] NIH, Div Program Coordinat, Planning Initiat, Bethesda, MD 20892 USA. [Skirboll, Lana] NIH, Div Program Coordinat, Strateg Initiat, Bethesda, MD 20892 USA. [Schultzberg, Marianne] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Sect Neurodegenerat, SE-14186 Stockholm, Sweden. RP Granholm, AC (reprint author), Med Univ S Carolina, Dept Neurosci, Harborview Towers,19 Hagood Blvd,Ste 806, Charleston, SC 29425 USA. EM Granholm@musc.edu RI Schultzberg, Marianne/E-7076-2014 OI Schultzberg, Marianne/0000-0002-8314-0927 NR 17 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 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD FEB 9 PY 2010 VL 90 IS 2 SI SI BP 71 EP 74 DI 10.1016/j.pneurobio.2009.10.006 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 578KZ UT WOS:000276293700001 PM 19850101 ER PT J AU Westerlund, M Hoffer, B Olson, L AF Westerlund, Marie Hoffer, Barry Olson, Lars TI Parkinson's disease: Exit toxins, enter genetics SO PROGRESS IN NEUROBIOLOGY LA English DT Article; Proceedings Paper CT Conference on Chemical Neuroanatomy held in honor of Nils Ake Hikkarp CY DEC, 2008 CL Stockholm, SWEDEN DE Genetic risk factors; PARK; Mutation; Animal model; Association study; Linkage study ID ALPHA-SYNUCLEIN GENE; EARLY-ONSET PARKINSONISM; LRRK2 G2019S MUTATION; PALLIDO-PYRAMIDAL DEGENERATION; SUPRANUCLEAR UPGAZE PARESIS; CARBOXYL-TERMINAL HYDROLASE; KUFOR-RAKEB-SYNDROME; NORTH-AFRICAN; S18Y POLYMORPHISM; KINASE-ACTIVITY AB Parkinson's disease was long considered a non-hereditary disorder. Despite extensive research trying to find environmental risk factors for the disease, genetic variants now stand out as the major causative factor. Since a number of genes have been implicated in the pathogenesis it seems likely that several molecular pathways and downstream effectors can affect the trophic support and/or the survival of dopamine neurons, subsequently leading to Parkinson's disease. The present review describes how toxin-based animal models have been valuable tools in trying to find the underlying mechanisms of disease, and how identification of disease-linked genes in humans has led to the development of new transgenic rodent models. The review also describes the current status of the most common genetic susceptibility factors for Parkinson's disease identified up to today. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Westerlund, Marie; Olson, Lars] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Hoffer, Barry] Natl Inst Drug Abuse, NIH, Baltimore, MD USA. RP Westerlund, M (reprint author), Karolinska Inst, Dept Neurosci, Stockholm, Sweden. EM marie.westerlund@ki.se FU NINDS NIH HHS [R01 NS070825] NR 143 TC 25 Z9 27 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD FEB 9 PY 2010 VL 90 IS 2 SI SI BP 146 EP 156 DI 10.1016/j.pneurobio.2009.11.001 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 578KZ UT WOS:000276293700006 PM 19925845 ER PT J AU Han, HJ Kannan, RM Wang, SX Mao, GZ Kusanovic, JP Romero, R AF Han, Hye Jung Kannan, Rangaramanujam M. Wang, Sunxi Mao, Guangzhao Kusanovic, Juan Pedro Romero, Roberto TI Multifunctional Dendrimer-Templated Antibody Presentation on Biosensor Surfaces for Improved Biomarker Detection SO ADVANCED FUNCTIONAL MATERIALS LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; ATOMIC-FORCE MICROSCOPY; INFLAMMATORY RESPONSE SYNDROME; PROTEIN-LIGAND INTERACTIONS; LINKED-IMMUNOSORBENT-ASSAY; AFFINITY-SENSING SURFACE; POLY(ETHYLENE GLYCOL); SOLID SUPPORTS; INTRAAMNIOTIC INFECTION; STICKING PROBABILITIES AB Dendrimers, with their well-defined globular shape and high density of functional groups, are ideal nanoscale materials for templating sensor surfaces. This work exploits dendrimers as a versatile platform for capturing biomarkers with improved sensitivity and specificity. The synthesis, characterization, fabrication, and functional validation of the dendrimer-based assay platform are described. Bifunctional hydroxyl/thiol-functionalized G4-polyamidoamine (PAMAM) dendrimer is synthesized and immobilized on the polyethylene-glycol (PEG)-functionalized assay plate by coupling PEG-maleimide and dendrimer thiol groups. Simultaneously, part of the dendrimer thiol groups are converted to hydrazide functionalities. The resulting dendrimer-modified surface is coupled to the capture antibody in the Fc region of the oxidized antibody. This preserves the orientation flexibility of the antigen binding region (Fv) of the antibody. To validate the approach, the fabricated plates are further used as a solid phase for developing a sandwich-type enzyme-linked immunosorbent assay (ELISA) to detect IL-6 and IL-1 beta, important biomarkers for early stages of chorioamnionitis. The dendrimer-modified plate provides assays with significantly enhanced sensitivity, lower nonspecific adsorption, and a detection limit of 0.13 pg mL(-1) for IL-6 luminol detection and 1.15 pg mL(-1) for IL-1 beta TMB detection, which are significantly better than those for the traditional ELISA. The assays were validated in human serum samples from a normal (nonpregnant) woman and pregnant women with pyelonephritis. The specificity and the improved sensitivity of the dendrimer-based capture strategy could have significant implications for the detection of a wide range of cytokines and biomarkers since the capture strategy could be applied to multiplex microbead assays, conductometric immunosensors, and field-effect biosensors. C1 [Han, Hye Jung; Kannan, Rangaramanujam M.; Wang, Sunxi; Mao, Guangzhao] Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [Han, Hye Jung; Kannan, Rangaramanujam M.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NICHD, NIH, DHHS, Detroit, MI 48201 USA. [Kusanovic, Juan Pedro] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Dept Obstet & Gynecol,Hutzel Womens Hosp, Detroit, MI 48201 USA. RP Han, HJ (reprint author), Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. EM rkannan@chem1.eng.wayne.edu RI Zhou, Feng/E-9510-2011; Wang, Sunxi/F-9471-2015 OI Wang, Sunxi/0000-0001-5921-4108 FU National Institute of Child Health and Human Development, NIH, DHHS FX This study was supported by the intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS. Supporting Information is available online from Wiley InterScience or from the author. NR 91 TC 35 Z9 35 U1 4 U2 66 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1616-301X J9 ADV FUNCT MATER JI Adv. Funct. Mater. PD FEB 8 PY 2010 VL 20 IS 3 BP 409 EP 421 DI 10.1002/adfm.200901293 PG 13 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 557BY UT WOS:000274644400006 PM 26290658 ER PT J AU Makhnovskii, YA Berezhkovskii, AM Zitserman, VY AF Makhnovskii, Yu. A. Berezhkovskii, A. M. Zitserman, V. Yu. TI Diffusion in a tube of alternating diameter SO CHEMICAL PHYSICS LA English DT Article DE Diffusion in confined media; Entropic transport; Boundary homogenization ID CROSS-SECTION; BOUNDARY HOMOGENIZATION; VENTRICULAR MYOCARDIUM; RELEASE; PORE; MEDIA; WATER AB The paper deals with diffusion of a particle in a tube that consists of alternating wide and narrow sections. At sufficiently long times the particle motion can be coarse-grained and described as effective free-diffusion along the tube axis. In the coarse-grained description all the details of the tube geometry are packed into the effective diffusion coefficient of the particle. We derive a formula for the effective diffusion coefficient, which shows how it depends on the geometric parameters of the tube. To test the accuracy of this formula we compare its predictions with the values of the effective diffusion coefficient found in Brownian dynamics simulations. The comparison shows that the formula is applicable at arbitrary values of the length and radius of the narrow sections on condition that the radius of the wide sections does not exceed their length. (C) 2009 Elsevier B.V. All rights reserved. C1 [Makhnovskii, Yu. A.] Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. [Berezhkovskii, A. M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Makhnovskii, YA (reprint author), Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Leninskii Pr 29, Moscow 117912, Russia. EM yuam@ips.ac.ru RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU NIH, Center for Information Technology FX A.M.B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 37 TC 15 Z9 15 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD FEB 8 PY 2010 VL 367 IS 2-3 BP 110 EP 114 DI 10.1016/j.chemphys.2009.11.005 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 551BL UT WOS:000274180500007 ER PT J AU Nussenblatt, RB Marincola, FM Schechter, AN AF Nussenblatt, Robert B. Marincola, Francesco M. Schechter, Alan N. TI Translational Medicine - doing it backwards SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID HUMAN IMMUNOLOGY; VACCINE; IMMUNOTHERAPY; RELEVANCE; DISEASE AB In recent years the concept of "translational medicine" has been advanced in an attempt to catalyze the medical applications of basic biomedical research. However, there has been little discussion about the readiness of scientists themselves to respond to what we believe is a required new approach to scientific discovery if this new concept is to bear fruit. The present paradigm of hypothesis-driven research poorly suits the needs of biomedical research unless efforts are spent in identifying clinically relevant hypotheses. The dominant funding system favors hypotheses born from model systems and not humans, bypassing the Baconian principle of relevant observations and experimentation before hypotheses. Here, we argue that that this attitude has born two unfortunate results: lack of sufficient rigor in selecting hypotheses relevant to human disease and limitations of most clinical studies to certain outcome parameters rather than expanding knowledge of human pathophysiology; an illogical approach to translational medicine. If we wish to remain true to our responsibility and duty of performing research relevant to human disease, we must begin to think about fundamental new approaches. NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. NIH is the steward of medical and behavioral research for the Nation. Its mission is science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability [1]. C1 [Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, IDIS, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Trans NIH, CHI, Bethesda, MD 20892 USA. [Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 18 TC 11 Z9 14 U1 0 U2 13 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 FEB 8 PY 2010 VL 8 AR 12 DI 10.1186/1479-5876-8-12 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 567MO UT WOS:000275451200001 PM 20132543 ER PT J AU He, DH Ionides, EL King, AA AF He, Daihai Ionides, Edward L. King, Aaron A. TI Plug-and-play inference for disease dynamics: measles in large and small populations as a case study SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE mechanistic model; iterated filtering; sequential Monte Carlo; measles; state-space model ID LIKELIHOOD-BASED ESTIMATION; TIME-SERIES ANALYSIS; INFECTIOUS PERIODS; EPIDEMIC MODELS; REALISTIC DISTRIBUTIONS; TRANSMISSION RATES; PARTICLE FILTERS; COMMUNITY SIZE; PERSISTENCE; SYSTEMS AB Statistical inference for mechanistic models of partially observed dynamic systems is an active area of research. Most existing inference methods place substantial restrictions upon the form of models that can be fitted and hence upon the nature of the scientific hypotheses that can be entertained and the data that can be used to evaluate them. In contrast, the so-called plug-and-play methods require only simulations from a model and are thus free of such restrictions. We show the utility of the plug-and-play approach in the context of an investigation of measles transmission dynamics. Our novel methodology enables us to ask and answer questions that previous analyses have been unable to address. Specifically, we demonstrate that plug-and-play methods permit the development of a modelling and inference framework applicable to data from both large and small populations. We thereby obtain novel insights into the nature of heterogeneity in mixing and comment on the importance of including extra-demographic stochasticity as a means of dealing with environmental stochasticity and model misspecification. Our approach is readily applicable to many other epidemiological and ecological systems. C1 [He, Daihai; King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Ionides, Edward L.] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Ionides, Edward L.; King, Aaron A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP King, AA (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM kingaa@umich.edu RI He, Daihai/A-9347-2008; King, Aaron/B-8092-2012; OI King, Aaron/0000-0001-6159-3207; He, Daihai/0000-0003-3253-654X FU National Science Foundation [0430120, 0545276, 0805533, DEB-0553768]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Center for Ecological Analysis and Synthesis; University of California, Santa Barbara; State of California FX The authors thank Bryan Grenfell for valuable comments and for making the data available, Pejman Rohani for sharing his insight and Ottar Bjornstad for useful conversations. We acknowledge the financial support of the National Science Foundation (grant EF nos 0430120 and 0545276 and DMS no. 0805533), the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. This work was conducted as a part of the Inference for Mechanistic Models Working Group supported by the National Center for Ecological Analysis and Synthesis, a Center funded by NSF (grant no. DEB-0553768), the University of California, Santa Barbara and the State of California. NR 88 TC 73 Z9 74 U1 1 U2 19 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD FEB 6 PY 2010 VL 7 IS 43 BP 271 EP 283 DI 10.1098/rsif.2009.0151 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535TZ UT WOS:000272995800004 PM 19535416 ER PT J AU Sun, JH Murphy, E AF Sun, Junhui Murphy, Elizabeth TI Protein S-Nitrosylation and Cardioprotection SO CIRCULATION RESEARCH LA English DT Review DE cardioprotection; mitochondria; nitric oxide; nitrosative and oxidative stress; S-nitrosylation ID NITRIC-OXIDE SYNTHASE; ISCHEMIA-REPERFUSION INJURY; MITOCHONDRIAL PERMEABILITY TRANSITION; CARDIAC SARCOPLASMIC-RETICULUM; PERFUSED RAT-HEART; MYOCARDIAL-ISCHEMIA; ISCHEMIA/REPERFUSION INJURY; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; DEFICIENT MICE AB Nitric oxide (NO) plays an important role in the regulation of cardiovascular function. In addition to the classic NO activation of the cGMP-dependent pathway, NO can also regulate cell function through protein S-nitrosylation, a redox dependent, thiol-based, reversible posttranslational protein modification that involves attachment of an NO moiety to a nucleophilic protein sulfhydryl group. There are emerging data suggesting that S-nitrosylation of proteins plays an important role in cardioprotection. Protein S-nitrosylation not only leads to changes in protein structure and function but also prevents these thiol(s) from further irreversible oxidative/nitrosative modification. A better understanding of the mechanism regulating protein S-nitrosylation and its role in cardioprotection will provide us new therapeutic opportunities and targets for interventions in cardiovascular diseases. (Circ Res. 2010; 106: 285-296.) C1 [Sun, Junhui; Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Translat Med Branch, NIH, 10 Ctr Dr,Room 7N112, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov RI Sun, Junhui/C-3499-2011 FU National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health Intramural Program. NR 155 TC 106 Z9 108 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 5 PY 2010 VL 106 IS 2 BP 285 EP 296 DI 10.1161/CIRCRESAHA.109.209452 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 552AW UT WOS:000274258500010 PM 20133913 ER PT J AU Zhu, HL Fernandez, C Fan, JB Shewmaker, F Chen, J Minton, AP Liang, Y AF Zhu, Hai-Li Fernandez, Cristina Fan, Jun-Bao Shewmaker, Frank Chen, Jie Minton, Allen P. Liang, Yi TI Quantitative Characterization of Heparin Binding to Tau Protein IMPLICATION FOR INDUCER-MEDIATED TAU FILAMENT FORMATION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PAIRED HELICAL FILAMENTS; ISOTHERMAL TITRATION CALORIMETRY; STATIC LIGHT-SCATTERING; FULL-LENGTH TAU; ALZHEIMERS-DISEASE; SULFATED GLYCOSAMINOGLYCANS; AGGREGATION; POLYMERIZATION; PATHOGENESIS; FIBRILLIZATION AB Neurofibrillary tangles, principally composed of bundles of filaments formed by the microtubule-associated protein Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer disease. Polyanionic cofactors such as heparin can induce Tau filament formation in vitro. Here we quantitatively characterize the interaction between recombinant human Tau fragment Tau(244-372) and heparin (average molecular mass = 7 kDa) as well as heparin-induced fibril formation by using static light scattering, isothermal titration calorimetry, turbidity assays, and transmission electron microscopy. Our data clearly show that at physiological pH, heparin 7K, and human Tau(244-372) form a tight 1:1 complex with an equilibrium association constant exceeding 10(6) M-1 under reducing conditions, triggering Tau fibrillization. In the absence of dithiothreitol, heparin shows a moderate binding affinity (10(5) M-1) to Tau(244-372), similarly triggering Tau fibrillization. Further fibrillization kinetics analyses show that the lag time appears to be approximately invariant up to a molar ratio of 2:1 and then increases at larger ratios of heparin/Tau. The maximum slope representing the apparent rate constant for fibril growth increases sharply with substoichiometric ratios of heparin/Tau and then decreases to some extent with ratios of >1:1. The retarding effect of heparin in excess is attributed to the large increase in ionic strength of the medium arising from free heparin. Together, these results suggest that the formation of the 1:1 complex of Tau monomer and heparin plays an important role in the inducer-mediated Tau filament formation, providing clues to understanding the pathogenesis of neurodegenerative diseases. C1 [Zhu, Hai-Li; Fan, Jun-Bao; Chen, Jie; Liang, Yi] Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China. [Fernandez, Cristina; Shewmaker, Frank; Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Liang, Y (reprint author), Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China. EM liangyi@whu.edu.cn RI Fan, Jun-bao/E-7155-2012; Fernandez, Cristina/G-2269-2015; OI Fernandez, Cristina/0000-0003-3792-4015; Minton, Allen/0000-0001-8459-1247 FU National Key Basic Research Foundation of China [2006CB910301]; National Natural Science Foundation of China [30770421, 30970599]; Chinese 111 Project [B06018]; NIDDK FX This work was supported by National Key Basic Research Foundation of China Grant 2006CB910301, National Natural Science Foundation of China Grants 30770421 and 30970599, and Chinese 111 Project Grant B06018. This work was also supported in part by National Institutes of Health grants through the Intramural Research Program of the NIDDK. NR 40 TC 32 Z9 32 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 2010 VL 285 IS 6 BP 3592 EP 3599 DI 10.1074/jbc.M109.035691 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000010 PM 19959468 ER PT J AU Chatterjee, A Wang, L Armstrong, DL Rossie, S AF Chatterjee, Anindya Wang, Ling Armstrong, David L. Rossie, Sandra TI Activated Rac1 GTPase Translocates Protein Phosphatase 5 to the Cell Membrane and Stimulates Phosphatase Activity in Vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TETRATRICOPEPTIDE REPEAT DOMAIN; HUMAN BREAST-CANCER; SERINE/THREONINE PHOSPHATASE; EPITHELIAL-CELLS; RHO-GTPASES; TPR DOMAIN; NUCLEAR-LOCALIZATION; CARDIAC-ARRHYTHMIA; TERMINAL REGION; MOLECULAR-BASIS AB Physiological studies of ion channel regulation have implicated the Ser/Thr protein phosphatase 5 (PP5) as an effector of Rac1 GTPase signaling, but direct biochemical evidence for PP5 regulation by Rac1 is lacking. In this study we used immunoprecipitation, in vitro binding, cellular fractionation, and immunofluorescence techniques to show that the tetratricopeptide repeat domain of PP5 interacts specifically and directly with active Rac1. Consequently, activation of Rac1 promoted PP5 translocation to the plasma membrane in intact cells and stimulated PP5 phosphatase activity in vitro. In contrast, neither constitutively active RhoA-V14 nor dominant negative Rac1N17, which preferentially binds GDP and retains an inactive conformation, bound PP5 or stimulated its activity. In addition, Rac1N17 and Rac1(PBRM), a mutant lacking the C-terminal polybasic region required for Rac1 association with the membrane, both failed to cause membrane translocation of PP5. Mutation of predicted contact residues in the PP5 tetratricopeptide repeat domain or within Rac1 also disrupted co-immunoprecipitation of Rac1-PP5 complexes and membrane translocation of PP5. Specific binding of PP5 to activated Rac1 provides a direct mechanism by which PP5 can be stimulated and recruited to participate in Rac1-mediated signaling pathways. C1 [Chatterjee, Anindya; Wang, Ling; Rossie, Sandra] Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA. [Chatterjee, Anindya; Wang, Ling; Rossie, Sandra] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. [Armstrong, David L.] NIEHS, Environm Biol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Rossie, S (reprint author), Purdue Univ, Dept Biochem, 175 S Univ St, W Lafayette, IN 47907 USA. EM rossie@purdue.edu FU National Institutes of Health [NS031221, NCI-2P30CA23168]; National Institutes of Health Intramural Research Program at NIEHS [Z01-ES080043] FX This work was supported, in whole or in part, by National Institutes of Health Grant NS031221 (to S.R.). This work was also supported in part by Purdue Cancer Center NCI Core Grant NCI-2P30CA23168 from the National Institutes of Health and the National Institutes of Health Intramural Research Program at NIEHS through Grant Z01-ES080043 (to D. L. A.). NR 57 TC 6 Z9 9 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 FEB 5 PY 2010 VL 285 IS 6 BP 3872 EP 3882 DI 10.1074/jbc.M109.088427 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000041 PM 19948726 ER PT J AU Jung, YS Cai, ML Clore, GM AF Jung, Young-Sang Cai, Mengli Clore, G. Marius TI Solution Structure of the IIA(Chitobiose)-IIBChitobiose Complex of the N,N '-Diacetylchitobiose Branch of the Escherichia coli Phosphotransferase System SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHORYL TRANSFER COMPLEX; RESIDUAL DIPOLAR COUPLINGS; MANNITOL TRANSPORTER IIMANNITOL; PHOSPHOCARRIER PROTEIN HPR; N-TERMINAL DOMAIN; MACROMOLECULAR STRUCTURE DETERMINATION; POTATO CARBOXYPEPTIDASE INHIBITOR; MOLECULAR-STRUCTURE DETERMINATION; CYTOPLASMIC B-DOMAIN; ENZYME-I AB The solution structure of the IIA-IIB complex of the N,N '-diacetylchitobiose (Chb) transporter of the Escherichia coli phosphotransferase system has been solved by NMR. The active site His-89 of IIA(Chb) was mutated to Glu to mimic the phosphorylated state and the active site Cys-10 of IIBChb was substituted by serine to prevent intermolecular disulfide bond formation. Binding is weak with a K-D of similar to 1.3mM. The two complementary interaction surfaces are largely hydrophobic, with the protruding active site loop (residues 9-16) of IIBChb buried deep within the active site cleft formed at the interface of two adjacent subunits of the IIA(Chb) trimer. The central hydrophobic portion of the interface is surrounded by a ring of polar and charged residues that provide a relatively small number of electrostatic intermolecular interactions that serve to correctly align the two proteins. The conformation of the active site loop in unphosphorylated IIBChb is inconsistent with the formation of a phosphoryl transition state intermediate because of steric hindrance, especially from the methyl group of Ala-12 of IIBChb. Phosphorylation of IIBChb is accompanied by a conformational change within the active site loop such that its path from residues 11-13 follows a mirror-like image relative to that in the unphosphorylated state. This involves a transition of the phi/psi angles of Gly-13 from the right to left alpha-helical region, as well as smaller changes in the backbone torsion angles of Ala-12 and Met-14. The resulting active site conformation is fully compatible with the formation of the His-89-P-Cys-10 phosphoryl transition state without necessitating any change in relative translation or orientation of the two proteins within the complex. C1 [Jung, Young-Sang; Cai, Mengli; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm B1-301, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; Jung, Young-Sang/H-1169-2011 OI Clore, G. Marius/0000-0003-3809-1027; FU NIDDK; National Institutes of Health FX This work was supported, in whole or in part, by the intramural program of NIDDK, National Institutes of Health and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G. M. C.). NR 80 TC 9 Z9 9 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 FEB 5 PY 2010 VL 285 IS 6 BP 4173 EP 4184 DI 10.1074/jbc.M109.080937 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000069 PM 19959833 ER PT J AU Nishimura, T Harashima, S Hu, YF Notkins, AL AF Nishimura, Takuya Harashima, Shin-ichi Hu Yafang Notkins, Abner Louis TI IA-2 modulates dopamine secretion in PC12 cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE IA-2; siRNA; PC12; Dopamine; Hormones; Neurotransmitters ID PROTEIN-TYROSINE-PHOSPHATASE; DEPENDENT DIABETES-MELLITUS; INSULIN-SECRETION; TRANSMEMBRANE PROTEIN; TARGETED DISRUPTION; MOLECULAR-CLONING; DOUBLE KNOCKOUT; AUTOANTIGEN; IA-2-BETA; MICE AB The secretion of the hormone insulin from beta cells is modulated by the expression of the dense core vesicle transmembrane protein IA-2. Since IA-2 is found in neuroendocrine cells throughout the body, the present experiments were initiated to determine whether the expression of IA-2 also modulates the secretion of neurotransmitters. Using the dopamine-secreting pheochromocytoma cell line PC12, we found that the overexpressions of IA-2 increased the cellular content and secretion of dopamine, whereas the knockdown of IA-2 by siRNA decreased the cellular content and secretion of dopamine. Neither the overexpression nor knockdown of IA-2 influenced the uptake of [H(3)]dopamine by PC12 cells, but did influence the amount of [H(3)]dopamine secreted. Overexpression of IA-2 also increased the level of the dense core vesicle-associated proteins Rab3A, IA-2 beta and secretogranin II, whereas the knockdown of IA-2 decreased the level of these proteins. We conclude that the expression of IA-2 profoundly influences the function of dense core vesicles and has a broad modulating effect on the cellular content and secretion of both hormones and neurotransmitters. Published by Elsevier Ireland Ltd. C1 [Nishimura, Takuya; Harashima, Shin-ichi; Hu Yafang; Notkins, Abner Louis] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Harashima, Shin-ichi] Kyoto Univ, Dept Diabet & Clin Nutr, Grad Sch Med, Kyoto, Japan. [Hu Yafang] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bldg 30,Room 106,30 Convent Dr,MSC4322, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov FU National Institute of Dental and Craniofacial Research; National Institutes of Health and in part by a Japan Society for the Promotion of Science Fellowship FX This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health and in part by a Japan Society for the Promotion of Science Fellowship (T.N.). The authors thank Dr. Keiichi Saeki and Dr. Takashi Onodera for providing antibodies. NR 27 TC 7 Z9 8 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 5 PY 2010 VL 315 IS 1-2 BP 81 EP 86 DI 10.1016/j.mce.2009.09.023 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 556RM UT WOS:000274608900010 PM 19799965 ER PT J AU Gandhari, MK Frazier, CR Hartenstein, JS Cloix, JF Bernier, M Wainer, IW AF Gandhari, Mukesh K. Frazier, Chester R. Hartenstein, Julia S. Cloix, Jean-Francois Bernier, Michel Wainer, Irving W. TI Identification and characterization of estrogen receptor-related receptor alpha and gamma in human glioma and astrocytoma cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE DY131; Biochanin A; XCT790; 4-Hydroxytamoxifen; AAB-TATA-Luc; 3xERE-TATA-Luc; T98G; U87MG; A-172 cells; ERR gamma; ERR alpha ID INDEPENDENT TRANSCRIPTIONAL ACTIVATION; BREAST-CANCER-CELLS; ERR-GAMMA; MALIGNANT GLIOMAS; PHASE-2 TRIAL; IN-VITRO; TAMOXIFEN; LIGAND; EXPRESSION; APOPTOSIS AB The purpose of this study was to examine expression and function of estrogen receptor-related receptors (ERRs) in human glioma and astrocytoma cell lines. These estrogen receptor-negative cell lines expressed ERR alpha and ERR gamma proteins to varying degree in a cell context dependent manner, with U87MG glioma cells expressing both orphan nuclear receptors. Cell proliferation assays were performed in the presence of ERR isoform-specific agonists and antagonists, and the calculated EC(50) and IC(50) values were consistent with previous reported values determined in other types of cancer cell lines. Induction of luciferase expression under the control of ERR isoform-specific promoters was also observed in these cells. These results indicate that ERR alpha and ERR gamma are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity. Published by Elsevier Ireland Ltd. C1 [Gandhari, Mukesh K.; Frazier, Chester R.; Hartenstein, Julia S.; Bernier, Michel; Wainer, Irving W.] NIA, Clin Invest Lab, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Cloix, Jean-Francois] Univ Orleans, Neurobiol Lab, F-45067 Orleans 2, France. RP Bernier, M (reprint author), NIA, Clin Invest Lab, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM Bernierm@mail.nih.gov; WainerIr@grc.nia.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU Intramural Research Program of the NIH, National Institute on Aging FX The work was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 37 TC 7 Z9 8 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 5 PY 2010 VL 315 IS 1-2 BP 314 EP 318 DI 10.1016/j.mce.2009.10.001 PG 5 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 556RM UT WOS:000274608900041 PM 19822186 ER PT J AU Ray, B Banerjee, PK Greig, NH Lahiri, DK AF Ray, Balmiki Banerjee, Pradeep K. Greig, Nigel H. Lahiri, Debomoy K. TI Memantine treatment decreases levels of secreted Alzheimer's amyloid precursor protein (APP) and amyloid beta (A beta) peptide in the human neuroblastoma cells SO NEUROSCIENCE LETTERS LA English DT Article DE Amyloid; Alzheimer's drug; beta-Peptide; Dementia; Neuronal cells; Protein processing; sAPP; Secretase; Tissue culture ID MOUSE MODEL; DISEASE; TACRINE; LINES; TRAFFICKING; EXPRESSION; STRATEGIES; TOXICITY; CLEAVAGE; INDUCE AB Memantine, an uncompetitive NMDA receptor antagonist, is a FDA-approved drug used for the treatment of moderate-to-severe Alzheimer's disease (AD). Several studies have documented protective roles of memantine against amyloid beta (A beta) peptide-mediated damage to neurons in both in vitro and in vivo models. Memantine is also effective in reducing amyloid burden in the brain of APP transgenic mice. However, the exact mechanism by which memantine provides protection against A beta-mediated neurodegenerative cascade, including APP metabolism, remains to be elucidated. Herein, we investigated the effect of memantine on levels of the secreted form of A beta precursor protein (APP), secreted A beta and cell viability markers under short/acute conditions. We treated neuronal SK-N-SH cells with 10 mu M memantine and measured levels of secreted total APP (sAPP), APP alpha isoform and A beta((1-40)) in a time dependent manner for up to 24 h. Memantine significantly decreased the levels of the secreted form of sAPP, sAPP alpha and A beta((1-40)) compared to vehicle treated cells. This change started as early as 8 h and continued for up to 24 h of drug treatment. Unlike sAPP, a slight non-significant increase in total intracellular APP level was observed in 24-h treated memantine cells. Taken together, these results suggest a role for memantine in the transport or trafficking of APP molecules away from the site of their proteolytic cleavage by the secretase enzymes. Such a novel property of memantine warrants further study to define its therapeutic utility. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Ray, Balmiki; Lahiri, Debomoy K.] Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. [Banerjee, Pradeep K.] Forest Res Inst, Jersey City, NJ 07311 USA. [Greig, Nigel H.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Lahiri, Debomoy K.] Indiana Univ, Dept Med & Mol Genet, Inst Psychiat Res, Sch Med, Indianapolis, IN 46202 USA. RP Lahiri, DK (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, 791 Union Dr, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu RI Ray, Balmiki/D-6587-2011 FU Alzheimer's Associations; National Institutes of Health [AGI 8379, AG18884]; Intramural Research Program, National Institute on Aging FX We thank B. Maloney, J. Bailey and J. Long, and grants support from the Alzheimer's Associations (Zenith Award) and the National Institutes of Health (AGI 8379 and AG18884) to DKL, as well as by the Intramural Research Program, National Institute on Aging to NHG. NR 31 TC 20 Z9 25 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 5 PY 2010 VL 470 IS 1 BP 1 EP 5 DI 10.1016/j.neulet.2009.11.016 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 561AP UT WOS:000274947500001 PM 19948208 ER PT J AU Furtak, V Mulky, A Rawlings, SA Kozhaya, L Lee, K KewalRamani, VN Unutmaz, D AF Furtak, Vyacheslav Mulky, Alok Rawlings, Stephen A. Kozhaya, Lina Lee, KyeongEun KewalRamani, Vineet N. Unutmaz, Derya TI Perturbation of the P-Body Component Mov10 Inhibits HIV-1 Infectivity SO PLOS ONE LA English DT Article ID VIRUS TYPE-1 RNA; STRESS GRANULES; PROTEIN; BODIES; REPLICATION; FAMILY; OVEREXPRESSION; IDENTIFICATION; ASSOCIATION; COMPLEXES AB Exogenous retroviruses are obligate cellular parasites that co-opt a number of host proteins and functions to enable their replication and spread. Several host factors that restrict HIV and other retroviral infections have also recently been described. Here we demonstrate that Mov10, a protein associated with P-bodies that has a putative RNA-helicase domain, when overexpressed in cells can inhibit the production of infectious retroviruses. Interestingly, reducing the endogenous Mov10 levels in virus-producing cells through siRNA treatment also modestly suppresses HIV infectivity. The actions of Mov10 are not limited to HIV, however, as ectopic expression of Mov10 restricts the production of other lentiviruses as well as the gammaretrovirus, murine leukemia virus. We found that HIV produced in the presence of high levels of Mov10 is restricted at the pre-reverse transcription stage in target cells. Finally, we show that either helicase mutation or truncation of the C-terminal half of Mov10, where a putative RNA-helicase domain is located, maintained most of its HIV inhibition; whereas removing the N-terminal half of Mov10 completely abolished its activity on HIV. Together these results suggest that Mov10 could be required during the lentiviral lifecycle and that its perturbation disrupts generation of infectious viral particles. Because Mov10 is implicated as part of the P-body complex, these findings point to the potential role of cytoplasmic RNA processing machinery in infectious retroviral production. C1 [Furtak, Vyacheslav; Rawlings, Stephen A.; Kozhaya, Lina; Unutmaz, Derya] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Unutmaz, Derya] NYU, Sch Med, Dept Pathol, New York, NY USA. [Mulky, Alok; Lee, KyeongEun; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Furtak, V (reprint author), NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. EM vineet@mac.com; derya@mac.com FU National Institutes of Health [R21 AI078839]; National Cancer Institute's intramural Center for Cancer Research FX This work was supported by National Institutes of Health Grant R21 AI078839 to D. U. and in part by the National Cancer Institute's intramural Center for Cancer Research, which supports the HIV Drug Resistance Program of V.N.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 61 Z9 62 U1 1 U2 3 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 FEB 5 PY 2010 VL 5 IS 2 AR e9081 DI 10.1371/journal.pone.0009081 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554NT UT WOS:000274442400017 PM 20140200 ER PT J AU Gupta, PK Liu, SH Leppla, SH AF Gupta, Pradeep K. Liu, Shihui Leppla, Stephen H. TI Characterization of a Chinese Hamster Ovary Cell Mutant Having a Mutation in Elongation Factor-2 SO PLOS ONE LA English DT Article ID PSEUDOMONAS EXOTOXIN-A; RECEPTOR-RELATED PROTEIN; ADP-RIBOSYLATING TOXINS; ANTHRAX LETHAL FACTOR; DIPHTHERIA-TOXIN; FACTOR-II; MAMMALIAN-CELLS; TRANSLATION ELONGATION-FACTOR-2; AMINO-ACID; DIPHTHAMIDE AB Retroviral insertional mutagenesis provides an effective forward genetic method for identifying genes involved in essential cellular pathways. A Chinese hamster ovary cell line mutant resistant to several bacterial ADP-ribosylating was obtained by this approach. The toxins used catalyze ADP-ribosylation of eukaryotic elongation factor 2 (eEF-2), block protein synthesis, and cause cell death. Strikingly, in the CHO PR328 mutant cells, the eEF-2 substrate of these ADP-ribosylating toxins was found to be modified, but the cells remained viable. A systematic study of these cells revealed the presence of a structural mutation in one allele of the eEF-2 gene. This mutation, Gly717Arg, is close to His715, the residue that is modified to become diphthamide. This Arg substitution prevents diphthamide biosynthesis at His715, rendering the mutated eEF-2 non-responsive to ADP-ribosylating toxins, while having no apparent effect on protein synthesis. Thus, CHO PR328 cells are heterozygous, having wild type and mutant eEF-2 alleles, with the latter allowing the cells to survive even in the presence of ADP-ribosylating toxins. Here, we report the comprehensive characterization of these cells. C1 [Gupta, Pradeep K.; Liu, Shihui; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Gupta, PK (reprint author), NIAID, Lab Bacterial Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 3 Z9 3 U1 0 U2 0 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 FEB 5 PY 2010 VL 5 IS 2 AR e9078 DI 10.1371/journal.pone.0009078 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554NT UT WOS:000274442400015 PM 20140093 ER PT J AU Okpechi, IG Rayner, BL van der Merwe, L Mayosi, BM Adeyemo, A Tiffin, N Ramesar, R AF Okpechi, Ikechi G. Rayner, Brian L. van der Merwe, Lize Mayosi, Bongani M. Adeyemo, Adebowale Tiffin, Nicki Ramesar, Rajkumar TI Genetic Variation at Selected SNPs in the Leptin Gene and Association of Alleles with Markers of Kidney Disease in a Xhosa Population of South Africa SO PLOS ONE LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; STAGE RENAL-DISEASE; UNITED-STATES; EXPLANATORY FACTORS; BLOOD-PRESSURE; EXCESS RISK; OBESE GENE; POLYMORPHISM; GLOMERULOSCLEROSIS AB Background: Chronic kidney disease (CKD) is a significant public health problem that leads to end-stage renal disease (ESRD) with as many as 2 million people predicted to need therapy worldwide by 2010. Obesity is a risk factor for CKD and leptin, the obesity hormone, correlates with body fat mass and markers of renal function. A number of clinical and experimental studies have suggested a link between serum leptin and kidney disease. We hypothesised that variants in the leptin gene (LEP) may be associated with markers of CKD in indigenous black Africans. Methodology/Principal Findings: Black South Africans of Xhosa (distinct cultural Bantu-speaking population) descent were recruited for the study and four common polymorphisms of the LEP (rs7799039, rs791620, rs2167270 and STS-U43653 [ENSSNP5824596]) were analysed for genotype and haplotype association with urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), Serum creatinine (Scr) and serum leptin level. In one of the four single nucleotide polymorphisms (SNPs) we examined, an association with the renal phenotypes was observed. Hypertensive subjects with the T allele (CT genotype) of the ENSSNP5824596 SNP had a significantly higher eGFR (p = 0.0141), and significantly lower Scr (p = 0.0137). This was confirmed by haplotype analysis. Also, the haplotype GAAC had a modest effect on urine albumin-to-creatinine ratio in normotensive subjects (p = 0.0482). Conclusions/Significance: These results suggest that genetic variations of the LEP may be associated with phenotypes that are markers of CKD in black Africans. C1 [Okpechi, Ikechi G.; Rayner, Brian L.; Mayosi, Bongani M.] Groote Schuur Hosp, Dept Med, ZA-7925 Cape Town, South Africa. [van der Merwe, Lize] Univ Cape Town, Dept Stat, ZA-7925 Cape Town, South Africa. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Tiffin, Nicki; Ramesar, Rajkumar] Univ Cape Town, Div Human Genet, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. RP Okpechi, IG (reprint author), Groote Schuur Hosp, Dept Med, ZA-7925 Cape Town, South Africa. EM ikokpechi@yahoo.com RI Tiffin, Nicki/A-5914-2013; Ramesar, Raj/I-6941-2015; OI Ramesar, Raj/0000-0001-5688-1634; Rayner, Brian/0000-0002-0167-9591; Adeyemo, Adebowale/0000-0002-3105-3231; Mayosi, Bongani/0000-0001-6641-8950; van der Merwe, Lize/0000-0001-9705-8126 FU Wyeth Nephrology Funds FX This study was supported by the Wyeth Nephrology Funds administered by the University of Cape Town. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 4 Z9 4 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 FEB 5 PY 2010 VL 5 IS 2 AR e9086 DI 10.1371/journal.pone.0009086 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554NT UT WOS:000274442400022 PM 20140086 ER PT J AU Zeddam, JL Gordon, KHJ Lauber, C Alves, CAF Luke, BT Hanzlik, TN Ward, VK Gorbalenya, AE AF Zeddam, Jean-Louis Gordon, Karl H. J. Lauber, Chris Alves, Cristiano A. Felipe Luke, Brian T. Hanzlik, Terry N. Ward, Vernon K. Gorbalenya, Alexander E. TI Euprosterna elaeasa virus genome sequence and evolution of the Tetraviridae family: Emergence of bipartite genomes and conservation of the VPg signal with the dsRNA Birnaviridae family SO VIROLOGY LA English DT Article DE Tetraviridae; Birnaviridae; Insect virus; Genome sequence; Permuted RNA-dependent RNA polymerase; VPg; Jelly-roll-based capsid; Phylogeny; Recombination; Taxonomy ID CAPENSIS OMEGA-VIRUS; PANCREATIC NECROSIS VIRUS; DEPENDENT RNA-POLYMERASE; ARMIGERA STUNT VIRUS; HELICOVERPA-ARMIGERA; CAPSID PROTEIN; BETA-VIRUS; BACULOVIRUS EXPRESSION; 2A-LIKE SEQUENCES; INSECT VIRUS AB The Tetraviridae is a family of non-enveloped positive-stranded RNA insect viruses that is defined by the T=4 symmetry of virions. We report the complete Euprostema elaeasa virus (EeV) genome sequence of 5698 nt with no poly(A) tail and two overlapping open reading frames, encoding the replicase and capsid precursor, with similar to 67% amino acid identity to Thosea asigna virus (TaV). The N-terminally positioned 17 kDa protein is released from the capsid precursor by a NPGP motif EeV has 40 nm non-enveloped isometric particles composed of 58 and 7 kDa proteins. The 3'-end of TaV/EeV is predicted to form a conserved pseudoknot. Replicases of TaV and EeV include a newly delineated VPg signal mediating the protein priming of RNA synthesis in dsRNA Birnaviridae. Results of rooted phylogenetic analysis of replicase and capsid proteins are presented to implicate recombination between monopartite tetraviruses, involving autonomization of a sgRNA, in the emergence of bipartite tetraviruses. They are also used to revise the Tetraviridae taxonomy. (C) 2009 Elsevier Inc. All rights reserved. C1 [Lauber, Chris; Gorbalenya, Alexander E.] Leiden Univ, Med Ctr, Ctr Infect Dis, Mol Virol Lab,Dept Med Microbiol, NL-2300 RC Leiden, Netherlands. [Zeddam, Jean-Louis] CNRS, IRD, Lab Evolut Genomes & Speciat, UR 072,UPR 9034, F-91198 Gif Sur Yvette, France. [Zeddam, Jean-Louis] Univ Paris 11, F-91405 Orsay, France. [Gordon, Karl H. J.; Hanzlik, Terry N.] CSIRO Entomol, Canberra, ACT 2601, Australia. [Alves, Cristiano A. Felipe; Ward, Vernon K.] Univ Otago, Sch Med Sci, Dept Microbiol & Immunol, Dunedin 9054, New Zealand. [Luke, Brian T.] NCI, Adv Biomed Comp Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Gorbalenya, AE (reprint author), Leiden Univ, Med Ctr, Ctr Infect Dis, Mol Virol Lab,Dept Med Microbiol, Postzone E4-P,POB 9600, NL-2300 RC Leiden, Netherlands. EM A.E.Gorbalenya@lumc.nl RI Gorbalenya, Alexander/J-4818-2012; Gordon, Karl/A-1976-2008 OI Gorbalenya, Alexander/0000-0002-4967-7341; Gordon, Karl/0000-0002-4371-0454 FU New Zealand Marsden Fund [U00212]; Netherlands Bioinformatics Center BioRange [SP 3.2.2] FX We thank Michelle Williams and Susan Dorrian for technical assistance, Fiona Pringle for her contribution to this research and her comments on the manuscript, Andrew Ball and Fiona Pringle for sharing their unpublished data on PrV, and Alexander Kravchenko, Dmitry Samborsky and Igor Sidorov for administrating Viralis software. This work was partially supported by the New Zealand Marsden Fund, Contract U00212 (WV) and the Netherlands Bioinformatics Center BioRange SP 3.2.2 grant (AEG). NR 80 TC 17 Z9 19 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2010 VL 397 IS 1 BP 145 EP 154 DI 10.1016/j.virol.2009.10.042 PG 10 WC Virology SC Virology GA 550MS UT WOS:000274132700018 PM 19954807 ER PT J AU Asagoshi, K Liu, Y Masaoka, A Lan, L Prasad, R Horton, JK Brown, AR Wang, XH Bdour, HM Sobol, RW Taylor, JS Yasui, A Wilson, SH AF Asagoshi, Kenjiro Liu, Yuan Masaoka, Aya Lan, Li Prasad, Rajendra Horton, Julie K. Brown, Ashley R. Wang, Xiao-hong Bdour, Hussam M. Sobol, Robert W. Taylor, John-Stephen Yasui, Akira Wilson, Samuel H. TI DNA polymerase beta-dependent long patch base excision repair in living cells SO DNA REPAIR LA English DT Article DE UV damage endonuclease; Long patch base excision repair; DNA polymerase beta; Flap endonuclease 1; Thymine dimer ID SINGLE-STRAND BREAKS; MAMMALIAN-CELLS; SCHIZOSACCHAROMYCES-POMBE; UV DAMAGE; CELLULAR-RESPONSES; NUCLEAR ANTIGEN; IN-VITRO; ENDONUCLEASE; PATHWAY; STEP AB We examined a role for DNA polymerase beta (Pol beta) in mammalian long patch base excision repair (LP BER). Although a role for Pol beta is well known in single-nucleotide BER, information on this enzyme in the context of LP BER has been limited. To examine the question of Pol beta involvement in LP BER, we made use of nucleotide excision repair-deficient human XPA cells expressing UVDE (XPA-UVDE), which introduces a nick directly 5' to the cyclobutane pyrimidine dimer or 6-4 photoproduct, leaving ends with 3'-OH and 5'-phosphorylated UV lesion. We observed recruitment of GFP-fused Pol beta to focal sites of nuclear UV irradiation, consistent with a role of Pol beta in repair of UV-induced photoproducts adjacent to a strand break. This was the first evidence of Pol recruitment in LP BER in vivo. In cell extract, a 5'-blocked oligodeoxynucleotide substrate containing a nicked 5'-cyclobutane pyrimidine dimer was repaired by Pol beta-dependent LP BER. We also demonstrated Pol beta involvement in LP BER by making use of mouse cells that are double null for XPA and Pol beta. These results were extended by experiments with oligodeoxynucleotide substrates and purified human Pol beta. Published by Elsevier B.V. C1 [Asagoshi, Kenjiro; Liu, Yuan; Masaoka, Aya; Prasad, Rajendra; Horton, Julie K.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lan, Li; Yasui, Akira] Tohoku Univ, Inst Dev Aging & Canc, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. [Lan, Li; Brown, Ashley R.; Wang, Xiao-hong; Sobol, Robert W.] Univ Pittsburgh, Hillman Canc Ctr, Inst Canc, Pittsburgh, PA 15213 USA. [Lan, Li; Brown, Ashley R.; Wang, Xiao-hong; Sobol, Robert W.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15213 USA. [Sobol, Robert W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Bdour, Hussam M.; Taylor, John-Stephen] Washington Univ, Dept Chem, St Louis, MO 63103 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 FU NIH [1 R01 AG24364-01, 1 P20 CA132385-01, CA40463]; National Institute of Environmental Health Sciences [ZO1-ES050158, Z01-ES050159]; American Cancer Society [RSG-05-246-01-GMC]; Ministry of Education, Science, Sports and Culture of Japan FX We thank William A. Beard for critical reading of the manuscript and Bonnie E. Mesmer and Jennifer P. Myers for editorial assistance. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences(ZO1-ES050158 & Z01-ES050159). This work also was supported in part by a Research Scholar grant (RSG-05-246-01-GMC) from the American Cancer Society and grants from NIH (1 R01 AG24364-01; 1 P20 CA132385-01) to R.W.S., by grants from NIH (CA40463) to J.-S.T., and by a genome network project grant from the Ministry of Education, Science, Sports and Culture of Japan to A.Y. NR 34 TC 26 Z9 26 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 4 PY 2010 VL 9 IS 2 BP 109 EP 119 DI 10.1016/j.dnarep.2009.11.002 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 563PB UT WOS:000275143900003 PM 20006562 ER PT J AU Betham, B Shalhout, S Marquez, VE Bhagwat, AS AF Betham, Brittany Shalhout, Sophia Marquez, Victor E. Bhagwat, Ashok S. TI Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli SO DNA REPAIR LA English DT Article DE Anti-cancer chemotherapy; Anti-metabolite chemotherapy; Zebularine; Decitabine ID MULTISUBSTRATE DEOXYRIBONUCLEOSIDE KINASE; SALMONELLA-TYPHIMURIUM; DNA METHYLTRANSFERASES; 5-AZACYTIDINE; ZEBULARINE; MELANOGASTER; CANCER; INHIBITION; MISMATCH; REPAIR AB Most bacteria, including Escherichia coli, lack an enzyme that can phosphorylate deoxycytidine and its analogs. Consequently, most studies of toxicity and mutagenicity of cytosine analogs use ribonu-cleosides such as 5-azacytidine (AzaC) and zebularine (Zeb) instead of their deoxynucleoside forms, 5-aza-2'-deoxycytidine (AzadC) and 2'-deoxy-zebularine (dZeb). The former analogs are incorporated into both RNA and DNA creating complex physiological responses in cells. To circumvent this problem, we introduced into E. coli the Drosophila deoxynucleoside kinase (Dm-dNK), which has a relaxed substrate specificity, and tested these cells for sensitivity to AzadC and dZeb. We find that Dm-dNK expression increases substantially sensitivity of cells to these analogs and dZeb is very mutagenic in cells expressing the kinase. Furthermore, toxicity of dZeb in these cells requires DNA mismatch correction system suggesting a mechanism for its toxicity and mutagenicity. The fluorescence properties of dZeb were used to quantify the amount of this analog incorporated into cellular DNA of mismatch repair-deficient cells expressing Dm-dNK and the results showed that in a mismatch correction-defective strain a high percentage of DNA bases may be replaced with the analog without long term toxic effects. This study demonstrates that the mechanism by which Zeb and dZeb cause cell death is fundamentally different than the mechanism of toxicity of AzaC and AzadC. It also opens up a new way to study the mechanism of action of deoxycytidine analogs that are used in anticancer chemotherapy. (C) 2009 Elsevier B.V. All rights reserved. C1 [Betham, Brittany; Shalhout, Sophia; Bhagwat, Ashok S.] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Bhagwat, AS (reprint author), Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. EM axb@chem.wayne.edu FU National Institutes of Health [GM 57200, CA 97899]; National Cancer Institute; Center for Cancer Research FX We are grateful to Dr. Anna Karlsson (Karolinska Institute, Stockholm, Sweden) for providing a clone of Dm-dNK gene. We would like to thank Dr. Ramon Eritja (Institute for Research in Biomedicine, Barcelona, Spain) for providing a DNA oligomer containing dZeb. We also thank Dr. Kenneth Kreuzer (Duke University School of Medicine, Durham, NC) for providing a protocol for plasmid extraction and valuable comments on the manuscript. This work was supported by grants from National Institutes of Health to ASB (GM 57200 and CA 97899) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 44 TC 6 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 4 PY 2010 VL 9 IS 2 BP 153 EP 160 DI 10.1016/j.dnarep.2009.11.006 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 563PB UT WOS:000275143900007 PM 20005183 ER PT J AU Xu, X Ehdaie, B Ohara, N Yoshino, T Deng, CX AF Xu, X. Ehdaie, B. Ohara, N. Yoshino, T. Deng, C-X TI Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice SO ONCOGENE LA English DT Article DE AKT; mTOR; Notch1; pancreas cancer; transdifferentiation ID SQUAMOUS-CELL CARCINOMA; CONDITIONAL KNOCKOUT MICE; JUVENILE POLYPOSIS; SIGNALING PATHWAY; CANCER CELLS; TUMOR; GENE; MOUSE; EXPRESSION; INDUCTION AB Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis. Oncogene (2010) 29, 674-686; doi: 10.1038/onc.2009.375; published online 9 November 2009 C1 [Xu, X.; Ehdaie, B.; Deng, C-X] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Ohara, N.; Yoshino, T.] Okayama Univ, Grad Sch Med & Dent, Dept Pathol, Okayama 7008530, Japan. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10 Rm 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 FX We thank Dr Douglas Melton for providing Pdx-Cre mice; Dr Hong Wu for Pten conditional mutant mice; and members of the Deng lab for critically reading the paper. This research was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA. NR 60 TC 21 Z9 23 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 4 PY 2010 VL 29 IS 5 BP 674 EP 686 DI 10.1038/onc.2009.375 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 551QI UT WOS:000274223700005 PM 19901970 ER PT J AU Fuentealba, P Klausberger, T Karayannis, T Suen, WY Huck, J Tomioka, R Rockland, K Capogna, M Studer, M Morales, M Somogyi, P AF Fuentealba, Pablo Klausberger, Thomas Karayannis, Theofanis Suen, Wai Yee Huck, Jojanneke Tomioka, Ryohei Rockland, Kathleen Capogna, Marco Studer, Michele Morales, Marisela Somogyi, Peter TI Expression of COUP-TFII Nuclear Receptor in Restricted GABAergic Neuronal Populations in the Adult Rat Hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CAJAL-RETZIUS CELLS; CAUDAL GANGLIONIC EMINENCE; CORTICAL INTERNEURON SUBTYPES; PYRAMIDAL CELLS; MIGRATORY STREAM; FRONTAL-CORTEX; CA1 AREA; REELIN; MOUSE; FOREBRAIN AB The COUP-TFII nuclear receptor, also known as NR2F2, is expressed in the developing ventral telencephalon and modulates the tangential migration of a set of subpallial neuronal progenitors during forebrain development. Little information is available about its expression patterns in the adult brain. We have identified the cell populations expressing COUP-TFII and the contribution of some of them to network activity in vivo. Expression of COUP-TFII by hippocampal pyramidal and dentate granule cells, as well as neurons in the neocortex, formed a gradient increasing from undetectable in the dorsal to very strong in the ventral sectors. In the dorsal hippocampal CA1 area, COUP-TFII was restricted to GABAergic interneurons and expressed in several, largely nonoverlapping neuronal populations. Immunoreactivity was present in calretinin-, neuronal nitric oxide synthase-, and reelin-expressing cells, as well as in subsets of cholecystokinin-or calbindin-expressing or radiatum-retrohippocampally projecting GABAergic cells, but not in parvalbumin-and/or somatostatin-expressing interneurons. In vivo recording and juxtacellular labeling of COUP-TFII-expressing cells revealed neurogliaform cells, basket cells in stratum radiatum and tachykinin-expressing radiatum dentate innervating interneurons, identified by their axodendritic distributions. They showed cell type-selective phase-locked firing to the theta rhythm but no activation during sharp wave/ripple oscillations. These basket cells in stratum radiatum and neurogliaform cells fired at the peak of theta oscillations detected extracellularly in stratum pyramidale, unlike previously reported ivy cells, which fired at the trough. The characterization of COUP-TFII-expressing neurons suggests that this developmentally important transcription factor plays cell type-specific role(s) in the adult hippocampus. C1 [Fuentealba, Pablo; Klausberger, Thomas; Karayannis, Theofanis; Suen, Wai Yee; Huck, Jojanneke; Tomioka, Ryohei; Capogna, Marco; Somogyi, Peter] Univ Oxford, MRC, Anat Neuropharmacol Unit, Oxford OX1 3TH, England. [Fuentealba, Pablo] Pontificia Univ Catolica Chile, Ctr Neurociencias, Escuela Med, Dept Neurol, Santiago, Chile. [Fuentealba, Pablo] Pontificia Univ Catolica Chile, Dept Psiquiatria, Santiago, Chile. [Klausberger, Thomas] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria. [Tomioka, Ryohei; Rockland, Kathleen] RIKEN, Brain Sci Inst, Lab Cort Org & Systemat, Wako, Saitama 3510198, Japan. [Studer, Michele] Telethon Inst Genet & Med, I-80131 Naples, Italy. [Morales, Marisela] NIDA, NIH, Baltimore, MD 21224 USA. RP Fuentealba, P (reprint author), Fundacio St Joan Deu, C Santa Rosa 39-57,4A Planta,Edifici Docent, Barcelona 08950, Spain. EM pjfd@hotmail.com; peter.somogyi@pharm.ox.ac.uk RI Huck, Jojanneke/B-1534-2013; Karayannis, Theofanis/O-5194-2014; Studer, Michele/P-4580-2016 OI Huck, Jojanneke/0000-0002-3853-8581; Studer, Michele/0000-0001-7105-2957 FU European Union [LSHM-CT-2004-005139]; Fondazione Telethon FX This work was supported by INTERDEVO (LSHM-CT-2004-005139) in the Framework 6 program of the European Union. We thank Kristina Detzner, Ben Micklem, and David Roberts for excellent technical assistance, and Dr. Laszlo Marton for computing. We thank the following scientists for their generous gift of antibodies (to molecules indicated in parentheses): A. Beggs (alpha-actinin-2), G. Ohning (CCK), K. G. Baimbridge (parvalbumin), A. Buchan (somatostatin), T. Gorcs (VIP), T. Kaneko (PPTB, Pro-ENK), E. Mugnaini (GAD), W. Sieghart (GABAAR-alpha 1), A. Varro (pro-CCK), R. Shigemoto (NK1R), S. El Mestikawy (vGluT3), and M. Watanabe (CB1 receptor, vGluT3). Antibody 9303 was raised against CCK and provided by Citizens United in Research for in Epilepsy/Digestive Diseases Research Center, Antibody/RIA Core, National Institutes of Health Grant DK41301. NR 74 TC 47 Z9 48 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 3 PY 2010 VL 30 IS 5 BP 1595 EP 1609 DI 10.1523/JNEUROSCI.4199-09.2010 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 551XM UT WOS:000274246700004 PM 20130170 ER PT J AU Freidlin, B McShane, LM Korn, EL AF Freidlin, Boris McShane, Lisa M. Korn, Edward L. TI Randomized Clinical Trials With Biomarkers: Design Issues SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CELL LUNG-CANCER; PHASE-III TRIAL; VALIDATION; PROGNOSIS AB Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility. C1 [Freidlin, Boris; McShane, Lisa M.; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN-8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 26 TC 155 Z9 157 U1 0 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 3 PY 2010 VL 102 IS 3 BP 152 EP 160 DI 10.1093/jnci/djp477 PG 9 WC Oncology SC Oncology GA 553DM UT WOS:000274345800005 PM 20075367 ER PT J AU Drgonova, J Zimonjic, DB Hall, FS Uhl, GR AF Drgonova, J. Zimonjic, D. B. Hall, F. S. Uhl, G. R. TI EFFECT OF KEPI (Ppp1r14c) DELETION ON MORPHINE ANALGESIA AND TOLERANCE IN MICE OF DIFFERENT GENETIC BACKGROUNDS: WHEN A KNOCKOUT IS NEAR A RELEVANT QUANTITATIVE TRAIT LOCUS SO NEUROSCIENCE LA English DT Article DE quantitative trait locus; morphine analgesia; morphine reward; morphine tolerance; protein phosphatase 1; conditioned place preference ID PROTEIN-KINASE-C; OPIOID RECEPTOR FUNCTION; INBRED MOUSE STRAINS; PHYSICAL-DEPENDENCE; OUT MICE; BACKCROSS PROGRAMS; SIGNALING PATHWAY; CONGENIC STRAINS; R7 SUBFAMILY; MUTANT MICE AB We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6xC57BL/6 genetic backgrounds. KEPI maps onto mouse chromosome 10 close to the locus that contains the mu-opioid receptor (Oprm1) and provides a major quantitative trait locus for morphine effects. Analysis of single nucleotide polymorphisms in and near the Oprm1 locus identified a doubly-recombinant mouse with C57BL/6 markers within 1 Mb on either side of the KEPI deletion. This strategy minimized the amount of 129S6 DNA surrounding the transgene and documented the C57BL/6 origin of the Oprm1 gene in this founder and its offspring. Recombinant KEPIKO mice displayed (a) normal analgesic responses and normal locomotion after initial morphine treatments, (b) accelerated development of tolerance to analgesic effects of morphine, (c) elevated activity of protein phosphatase 1 in thalamus, (d) attenuated morphine reward as assessed by conditioned place preference. These data support roles for KEPI action in adaptive responses to repeated administration of morphine that include analgesic tolerance and drug reward. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Drgonova, J.; Hall, F. S.; Uhl, G. R.] NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Zimonjic, D. B.] NCI, Expt Carcinogenesis Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI Hall, Frank/C-3036-2013; OI Hall, Frank/0000-0002-0822-4063; Drgonova, Jana/0000-0002-4623-8466 FU NIH/DHHS FX We thank Dr. Qing-Rong Liu for help with the phosphatase assay and several consultations during this work. We acknowledge valuable support of the breeding assistant Kriss Knestaut from Charles River Laboratories, help with ES cells from Teri Perona, and financial support from the National Institute on Drug Abuse Intramural Research Program (NIH/DHHS). NR 88 TC 11 Z9 11 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD FEB 3 PY 2010 VL 165 IS 3 BP 882 EP 895 DI 10.1016/j.neuroscience.2009.10.007 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 548XH UT WOS:000274002600023 PM 19819304 ER PT J AU Soule, BP Simone, NL DeGraff, WG Choudhuri, R Cook, JA Mitchell, JB AF Soule, Benjamin P. Simone, Nicole L. DeGraff, William G. Choudhuri, Rajani Cook, John A. Mitchell, James B. TI Loratadine dysregulates cell cycle progression and enhances the effect of radiation in human tumor cell lines SO RADIATION ONCOLOGY LA English DT Article ID GRADIENT GEL-ELECTROPHORESIS; DOUBLE-STRAND BREAKS; MAMMALIAN-CELLS; CANCER CELLS; CHECKPOINT; SENSITIVITY; INHIBITION; APOPTOSIS; VITRO AB Background: The histamine receptor-1 (H1)-antagonist, loratadine has been shown to inhibit growth of human colon cancer xenografts in part due to cell cycle arrest in G2/M. Since this is a radiation sensitive phase of the cell cycle, we sought to determine if loratadine modifies radiosensitivity in several human tumor cell lines with emphasis on human colon carcinoma (HT29). Methods: Cells were treated with several doses of loratadine at several time points before and after exposure to radiation. Radiation dose modifying factors (DMF) were determined using full radiation dose response survival curves. Cell cycle phase was determined by flow cytometry and the expression of the cell cycle-associated proteins Chk1, pChk1(ser345), and Cyclin B was analyzed by western blot. Results: Loratadine pre-treatment of exponentially growing cells (75 mu M, 24 hours) increased radiation-induced cytotoxicity yielding a radiation DMF of 1.95. However, treatment of plateau phase cells also yielded a DMF of 1.3 suggesting that mechanisms other than cell cycle arrest also contribute to loratadine-mediated radiation modification. Like irradiation, loratadine initially induced G2/M arrest and activation of the cell-cycle associated protein Chk1 to pChk1(ser345), however a subsequent decrease in expression of total Chk1 and Cyclin B correlated with abrogation of the G2/M checkpoint. Analysis of DNA repair enzyme expression and DNA fragmentation revealed a distinct pattern of DNA damage in loratadine-treated cells in addition to enhanced radiation-induced damage. Taken together, these data suggest that the observed effects of loratadine are multifactorial in that loratadine 1) directly damages DNA, 2) activates Chk1 thereby promoting G2/M arrest making cells more susceptible to radiation-induced DNA damage and, 3) downregulates total Chk1 and Cyclin B abrogating the radiation-induced G2/M checkpoint and allowing cells to re-enter the cell cycle despite the persistence of damaged DNA. Conclusions: Given this unique possible mechanism of action, loratadine has potential as a chemotherapeutic agent and as a modifier of radiation responsiveness in the treatment of cancer and, as such, may warrant further clinical evaluation. C1 [Soule, Benjamin P.; Simone, Nicole L.; DeGraff, William G.; Choudhuri, Rajani; Cook, John A.; Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Soule, BP (reprint author), NCI, Radiat Biol Branch, NIH, 10 Ctr Dr,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM souleb@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 17 TC 13 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND J9 RADIAT ONCOL JI Radiat. Oncol. PD FEB 3 PY 2010 VL 5 AR 8 DI 10.1186/1748-717X-5-8 PG 12 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 562HV UT WOS:000275041700001 PM 20128919 ER PT J AU Siegle, JS Hansbro, N Herbert, C Rosenberg, HF Domachowske, JB Asquith, KL Foster, PS Kumar, RK AF Siegle, Jessica S. Hansbro, Nicole Herbert, Cristan Rosenberg, Helene F. Domachowske, Joseph B. Asquith, Kelly L. Foster, Paul S. Kumar, Rakesh K. TI Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice SO RESPIRATORY RESEARCH LA English DT Article ID RESPIRATORY-SYNCYTIAL-VIRUS; RECEPTOR-DEFICIENT MICE; PNEUMONIA VIRUS; AIRWAY HYPERRESPONSIVENESS; EOSINOPHILIC INFLAMMATION; CHILDHOOD ASTHMA; MODEL; DISEASE; CHILDREN; AGE AB Background: Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma. Methods: We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses. Results: Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor a chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor. Conclusion: In this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response. C1 [Siegle, Jessica S.; Herbert, Cristan; Kumar, Rakesh K.] Univ New S Wales, Dept Pathol, Sydney, NSW 2052, Australia. [Hansbro, Nicole; Asquith, Kelly L.; Foster, Paul S.] Univ Newcastle, Sch Biomed Sci, Ctr Asthma & Resp Dis, Newcastle, NSW 2300, Australia. [Hansbro, Nicole; Asquith, Kelly L.; Foster, Paul S.] Hunter Med Res Inst, Newcastle, NSW 2300, Australia. [Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Div Infect Dis, Syracuse, NY 13210 USA. RP Kumar, RK (reprint author), Univ New S Wales, Dept Pathol, Sydney, NSW 2052, Australia. EM r.kumar@unsw.edu.au RI Kumar, Rakesh/J-6124-2012; Foster, Paul/G-5057-2013 OI Kumar, Rakesh/0000-0002-9531-8411; FU National Health and Medical Research Council of Australia (NHMRC) [455223] FX This work was supported by grant 455223 from the National Health and Medical Research Council of Australia (NHMRC). NR 52 TC 46 Z9 47 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD FEB 3 PY 2010 VL 11 AR 14 DI 10.1186/1465-9921-11-14 PG 15 WC Respiratory System SC Respiratory System GA 571RB UT WOS:000275771200001 PM 20122285 ER PT J AU Barr, IG McCauley, J Cox, N Daniels, R Engelhardt, OG Fukuda, K Grohmann, G Hay, A Kelso, A Klimov, A Odagiri, T Smith, D Russell, C Tashiro, M Webby, R Wood, J Ye, ZP Zhang, WQ AF Barr, Ian G. McCauley, John Cox, Nancy Daniels, Rod Engelhardt, Othmar G. Fukuda, Keiji Grohmann, Gary Hay, Alan Kelso, Anne Klimov, Alexander Odagiri, Takato Smith, Derek Russell, Colin Tashiro, Masato Webby, Richard Wood, John Ye, Zhiping Zhang, Wenqing CA World Hlth Org Consultation No Hem TI Epidemiological, antigenic and genetic characteristics of seasonal influenza A(H1N1), A(H3N2) and B influenza viruses: Basis for the WHO recommendation on the composition of influenza vaccines for use in the 2009-2010 Northern Hemisphere season SO VACCINE LA English DT Article DE Influenza; Vaccine; Human; Seasonal ID SOUTH EAST-ASIA; ADAMANTANE RESISTANCE; ISOLATED WORLDWIDE; AUSTRALIA; COUNTRIES; EMERGENCE AB Influenza vaccines form an important component of the global response against infections and subsequent illness caused in man by influenza viruses. Twice a year, in February and September, the World Health Organisation through its Global Influenza Surveillance Network (GISN), recommends appropriate influenza viruses to be included in the seasonal influenza vaccine for the upcoming Northern and Southern Hemisphere winters. This recommendation is based on the latest data generated from many sources and the availability of viruses that are suitable for vaccine manufacture. This article gives a summary of the data and background to the recommendations for the 2009-2010 Northern Hemisphere influenza vaccine formulation. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Barr, Ian G.; Kelso, Anne] VIDRL, WHO Collaborating Ctr Reference & Res Influenza, Melbourne, Vic, Australia. [Cox, Nancy; Klimov, Alexander] CDC, WHO Collaborating Ctr Surveillance Epidemiol & Co, Atlanta, GA 30333 USA. [McCauley, John; Daniels, Rod; Hay, Alan] NIMR, WHO Collaborating Ctr Reference & Res Influenza, London, England. [Odagiri, Takato; Tashiro, Masato] NIID, WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Fukuda, Keiji; Zhang, Wenqing] WHO GIP, Geneva, Switzerland. [Engelhardt, Othmar G.; Wood, John] NIBSC, London, England. [Ye, Zhiping] CBER, Bethesda, MD USA. [Grohmann, Gary] TGA, Canberra, ACT, Australia. [Smith, Derek; Russell, Colin] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, Derek; Russell, Colin] Univ Cambridge, Cambridge CB2 1TN, England. [Webby, Richard] St Jude Childrens Hosp, WHO Collaborating Ctr Studies Ecol Influenza Anim, Memphis, TN 38105 USA. RP Barr, IG (reprint author), WHO Collaborating Ctr Reference & Res Influenza, VIDRL, 10 Wreckyn St, Melbourne, Vic 3051, Australia. EM Ian.Barr@influenzacentre.org; GISN@who.int OI Russell, Colin/0000-0002-2113-162X FU Medical Research Council [MC_U117585868, MC_U117512723] NR 18 TC 78 Z9 80 U1 2 U2 11 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 FEB 3 PY 2010 VL 28 IS 5 BP 1156 EP 1167 DI 10.1016/j.vaccine.2009.11.043 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 563IN UT WOS:000275122200005 PM 20004635 ER PT J AU Spadaccini, A Virnik, K Ni, YS Prutzman, K Berkower, I AF Spadaccini, Angelo Virnik, Konstantin Ni, Yisheng Prutzman, Kirk Berkower, Ira TI Stable expression of a foreign protein by a replication-competent rubella viral vector SO VACCINE LA English DT Article DE Rubella; Live; Replicating; Viral; Vector ID SIMIAN IMMUNODEFICIENCY VIRUS; EQUINE ENCEPHALITIS-VIRUS; NONSTRUCTURAL PROTEIN; SINDBIS VIRUS; VACCINE; DELETION; SITE; PATHOGENESIS; COMPLEXES; INFECTION AB Live, attenuated rubella vaccine has been used successfully for many years. By expressing additional viral antigens in rubella, we could expand its range and utility as a live, replicating viral vector. Previously, limitations on insert size and stability restricted rubella's ability to express exogenous antigens and immunize against other viruses. in this study, we have overcome this problem by creating a deletion in non-structural protein P150 that makes room for the insert. The resulting rubella hybrid stably expressed a model protein for over 10 passages, while replicating and expressing rubella proteins normally. The foreign protein, GFP, was as large as many important viral antigens, and the virus grew to sufficiently high titers for vaccine use. Further progress in expressing exogenous viral antigens in rubella may produce live viral vectors capable of immunizing against viruses for which attenuation is not currently feasible. Published by Elsevier Ltd. C1 [Spadaccini, Angelo; Virnik, Konstantin; Ni, Yisheng; Prutzman, Kirk; Berkower, Ira] US FDA, Immunoregulat Lab, DVP, Off Vaccine Res & Review,Ctr Biol, Rockville, MD 20857 USA. RP Berkower, I (reprint author), Bldg 29,Room 523,NIH Campus, Bethesda, MD 20892 USA. EM ira.berkower@fda.hhs.gov NR 30 TC 7 Z9 8 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 FEB 3 PY 2010 VL 28 IS 5 BP 1181 EP 1187 DI 10.1016/j.vaccine.2009.11.037 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 563IN UT WOS:000275122200008 PM 19945412 ER EF